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UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
10-K
(Mark One)
Annual report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
for the
fiscal year
 
ended
December 31, 2023
or
Transition report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934.
for the transition period from
 
to
 
.
Commission File Number
 
001-41058
VAXXINITY, INC.
(Exact name of registrant as specified in its charter)
Delaware
 
86-2083865
(State or other jurisdiction of incorporation or organization)
(IRS Employer Identification No.)
505 Odyssey Way
 
Merritt Island
,
FL
32953
(Address of principal executive offices, including zip code)
Registrant’s telephone number, including area code:
(
254
)
244-5739
Securities registered pursuant to Section 12(b) of the Act:
Title of each class
Trading Symbol
Name of exchange on which registered
Class A Common Stock, par value $0.0001 per
share
VAXX
The
Nasdaq
 
Global Market
Securities registered pursuant to Section 12(g) of the Act: None
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes
No
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes
No
Indicate by
 
check mark
 
whether the
 
registrant (1) has
 
filed all
 
reports required
 
to be
 
filed by
 
Section 13 or
 
15(d) of the
 
Securities Exchange
 
Act of
1934 during the preceding 12 months (or for such shorter
 
period that the registrant was required to file such
 
reports), and (2) has been subject to such
filing requirements for the past 90 days.
Yes
 
No
Indicate by check mark
 
whether the registrant has
 
submitted electronically every Interactive
 
Data File required to
 
be submitted pursuant to
 
Rule 405
of Regulation S-T (§ 232.405 of
 
this chapter) during the preceding
 
12 months (or for such shorter period
 
that the registrant was required
 
to submit such
files).
Yes
 
No
Indicate by check mark whether
 
the registrant is a
 
large accelerated filer,
 
an accelerated filer,
 
a non-accelerated filer,
 
a smaller reporting company or
an emerging growth company. See the definitions of “large accelerated filer,”
 
“accelerated filer,” “smaller reporting company” and "emerging growth
company" in Rule 12b-2 of the Exchange Act.
Large Accelerated Filer
Accelerated Filer
Non-Accelerated Filer
 
Smaller Reporting Company
Emerging Growth Company
If an emerging growth company,
 
indicate by check mark if the registrant has
 
elected not to use the extended transition period
 
for complying with any
new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal
control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that
prepared or issued its audit report.
 
If securities are registered
 
pursuant to Section 12(b)
 
of the Act, indicate
 
by check mark whether
 
the financial statements of
 
the registrant included in
the filing reflect the correction of an error to previously issued financial statements.
Indicate by
 
check mark
 
whether any
 
of those
 
error corrections
 
are restatements
 
that required
 
a recovery
 
analysis of
 
incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b).
Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes
 
No
The aggregate market value of registrant’s voting and non-voting outstanding common stock
 
held by non-affiliates was approximately $
155.6
 
million
based upon the closing stock price of
 
issuer’s common stock on June 30,
2023
, the last business day of the
 
registrant’s most recently completed second
fiscal quarter. Shares of common stock held by each officer and director and by each person who may be deemed to be affiliates of the Company. This
determination of affiliate status is not necessarily a conclusive determination for other purposes.
 
As of March 25,
 
2024, the registrant
 
had
112,873,552
 
shares of $0.0001
 
par value Class
 
A common stock
 
outstanding and
13,874,132
 
shares of $0.0001
par value Class B common stock outstanding.
 
 
DOCUMENTS INCORPORATED BY REFERENCE
Portions of
 
the following document
 
are incorporated
 
by reference in
 
Part III of this
 
Report: the
 
registrant’s definitive
 
proxy statement relating
 
to its
2024 Annual Meeting
 
of Shareholders. We
 
currently anticipate that
 
our definitive proxy
 
statement will be
 
filed with the
 
SEC no later
 
than 120 days
after December 31, 2023, pursuant to Regulation 14A of the Securities Exchange Act of 1934, as amended.
 
2
PART
 
I
Unless otherwise indicated
 
in this report,
 
“Vaxxinity
 
,” “we,” “us,”
 
“our,” and similar terms
 
refer to Vaxxinity,
 
Inc. and our
 
consolidated
subsidiaries.
SPECIAL NOTE REGARDING FORWARD
 
-LOOKING STATEMENTS
This Annual
 
Report on
 
Form 10-K
 
for the
 
year ended December 31,
 
2023 (“Report”) contains
 
forward-looking statements. Forward-
looking
 
statements
 
are
 
neither
 
historical
 
facts
 
nor
 
assurances of
 
future
 
performance.
 
Instead,
 
they
 
are
 
based
 
on
 
our
 
current
 
beliefs,
expectations and assumptions
 
regarding the future
 
of our business,
 
future plans and
 
strategies and other
 
future conditions. In
 
some cases,
you can identify forward-looking
 
statements because they contain
 
words such as “anticipate,”
 
“believe,” “estimate,” “expect,” “intend,”
“may,” “predict,” “project,” “target,” “potential,” “seek,” “will,” “would,” “could,” “should,” “continue,” “contemplate,” “plan,” other
words and terms of similar meaning and the negative of these words or similar terms.
Forward-looking statements are subject to known and unknown risks and uncertainties, many of which may be beyond our control.
 
We
caution you
 
that forward-looking
 
statements are
 
not guarantees
 
of future
 
performance or
 
outcomes and
 
that actual
 
performance and
outcomes may differ
 
materially from those
 
made in or
 
suggested by the
 
forward-looking statements
 
contained in this
 
Report. In addition,
even
 
if
 
our results
 
of
 
operations, financial
 
condition
 
and cash
 
flows,
 
and
 
the development
 
of
 
the
 
markets in
 
which we
 
operate, are
consistent with the forward-looking statements contained in this Report, those results or developments may not be indicative of
 
results
or developments in subsequent periods.
 
New factors emerge from time to
 
time that may cause our
 
business not to develop as
 
we expect,
and it is not possible for us to predict all
 
of them. Factors that could cause actual results and outcomes to differ
 
from those reflected in
forward-looking statements include, among others, the following:
 
the prospects
 
of UB-612
 
and other
 
product candidates,
 
including the
 
timing of
 
data from
 
our clinical
 
trials and
 
our
ability to obtain and maintain regulatory approval for our product candidates;
 
our ability to develop and commercialize new products and product candidates;
 
our substantial doubt about our ability to continue as a going concern;
 
our ability to leverage our AIM Platform (defined below);
 
the rate and degree of market acceptance of our products and product candidates;
 
decreased demand for our COVID-19 product candidate, if and when such product candidate is approved;
 
our
 
status
 
as
 
a
 
clinical-stage
 
company
 
and
 
estimates
 
of
 
our
 
addressable
 
market,
 
market
 
growth,
 
future
 
revenue,
expenses, capital requirements and our needs for additional financing;
 
our ability
 
to comply
 
with multiple
 
legal and
 
regulatory systems
 
relating to
 
privacy,
 
tax, anti-corruption
 
and other
applicable laws;
 
our ability to hire and retain key personnel and to manage our future growth effectively;
 
competitive companies and technologies,
 
including existing third party
 
approved and market accepted
 
products in our
industry and our ability to compete;
 
our and our
 
collaborators’, including United
 
Biomedical’s (“UBI”), ability and
 
willingness to obtain,
 
maintain, defend
and enforce our
 
intellectual property
 
protection for our
 
proprietary and collaborative
 
product candidates,
 
and the scope
of such protection;
 
the
 
performance
 
of
 
third-party
 
suppliers
 
and
 
manufacturers
 
and
 
our
 
ability
 
to
 
find
 
additional
 
suppliers
 
and
manufacturers;
 
our ability and the potential to successfully manufacture our product candidates for pre-clinical use, for clinical trials
and on a larger scale for commercial use, if approved;
 
the ability and willingness of our third-party collaborators to continue research and development activities relating to
our product candidates;
 
general economic,
 
political, demographic
 
and business conditions
 
in the United
 
States, Taiwan and other
 
jurisdictions;
 
3
 
the
 
potential
 
effects
 
of
 
government
 
regulation,
 
including
 
regulatory
 
developments
 
in
 
the
 
United
 
States
 
and
 
other
jurisdictions;
 
our ability to obtain additional financing in future offerings;
 
our ability to maintain our listing on The Nasdaq Global Market;
 
expectations about market trends; and
 
the effects of
 
the ongoing conflicts between Russia
 
and Ukraine or Israel and
 
Hamas and increased tension between
Taiwan and
 
China on business operations, the
 
initiation, development and operation of our
 
clinical trials and patient
enrollment of our clinical trials.
We discuss many of
 
these factors
 
in greater
 
detail under
 
Item 1A. “Risk
 
Factors.” These
 
risk factors are
 
not exhaustive
 
and other sections
of
 
this
 
report
 
may
 
include
 
additional
 
factors
 
which
 
could
 
adversely
 
impact
 
our
 
business
 
and
 
financial
 
performance.
 
Given
 
these
uncertainties, you should not place undue reliance on these forward-looking statements.
You
 
should read
 
this Report
 
and the
 
documents that
 
we reference
 
in this
 
Report and
 
have filed
 
as exhibits
 
completely and
 
with the
understanding that
 
our actual
 
future results
 
may be
 
materially different
 
from what
 
we expect.
 
We
 
qualify all
 
of the
 
forward- looking
statements in this Report by these cautionary statements. Except as required by law, we undertake no obligation to publicly update any
forward-looking statements, whether as a result of new information, future events or otherwise.
 
Item 1. Business.
 
Overview
We
 
are a purpose-driven biotechnology company
 
committed to positively impacting humanity
 
by democratizing healthcare across the
globe. Our metric for success is simple:
 
amount of human suffering alleviated. We doggedly pursue this as our north
 
star, and aim to be
number one in the world at this metric. Our vision is to redefine the paradigm for tackling the global epidemic of chronic diseases, and
provide cheaper, safer, more convenient and effective medicines to all.
 
There are many inventions that have served thousands
 
of lives, and some that have benefited
 
a million lives, but only a select
 
few that
have saved billions
 
lives. These include
 
the innovations of
 
fertilizer of the
 
green revolution to
 
feed an exponentially
 
growing population,
hygienic plumbing to
 
control cholera and
 
typhoid, and vaccines
 
to prevent over
 
20 dangerous or
 
deadly diseases. We
 
believe that we
have a technological innovation in medicine with the potential for a billion-person impact within the chronic disease
 
epidemic.
 
Today’s
 
approach to
 
treating patients
 
suffering from
 
chronic disease
 
is focused
 
on and
 
increasingly dominated by
 
drugs, particularly
monoclonal antibodies (“mAbs”), which can be
 
highly efficacious but remain limited by prohibitive costs,
 
cumbersome administration,
and
 
restricted scale.
 
We
 
believe our
 
synthetic peptide-based
 
Active
 
Immunotherapy Medicines
 
Platform (“AIM
 
Platform” formerly
called the Vaxxine Platform) has the potential to enable a new class of
 
medicines that will improve the quality
 
and convenience of care,
reduce costs and increase access to
 
treatments for a wide range of indications.
 
Moreover, we believe that
 
due to the unique features of
our AIM Platform, these new medicines can
 
enable an expansion from treating sick patients
 
to prevention of illness in healthy people.
Medicine
 
is
 
only
 
as
 
effective
 
as
 
its
 
access,
 
and
 
we
 
believe
 
there
 
is
 
a
 
path
 
to
 
increasing
 
the
 
number
 
of
 
people
 
who
 
have
 
access
 
to
immunotherapies from less than 1% of the world today to nearly anyone that could benefit.
 
Our AIM
 
Platform is
 
designed to
 
harness the
 
immune system
 
to convert
 
the body
 
into its
 
own “mAb
 
drug factory,”
 
stimulating the
production of
 
antibodies with
 
a therapeutic
 
or protective
 
effect. While
 
traditional vaccines
 
have been
 
able to
 
leverage this
 
approach
against infectious diseases,
 
they have historically
 
been unable to resolve
 
key challenges in
 
the fight against
 
chronic diseases. We believe
our AIM Platform
 
has the potential
 
to overcome these challenges
 
and to bring
 
the efficiency of vaccines
 
to a whole new
 
class of medical
conditions. Our technology has
 
been commercialized independently in
 
billions of doses
 
of animal health
 
vaccines, tested in
 
over four
thousand human
 
subjects across
 
multiple candidates
 
and clinical
 
trials, including
 
the company’s
 
first completed
 
Phase 3
 
study.
 
Our
current pipeline
 
consists of
 
five chronic
 
disease product
 
candidates from
 
early to
 
late-stage development
 
across multiple
 
therapeutic
areas, including
 
Alzheimer’s Disease (“AD”),
 
Parkinson’s disease (“PD”),
 
migraine and
 
hypercholesterolemia, diseases
 
that collectively
affect billions
 
of people
 
in the
 
world today
 
and of
 
which hundreds
 
of millions
 
more are
 
at high
 
risk of
 
contracting. Additionally,
 
we
believe our AIM Platform may be used to disrupt the treatment paradigm for a wide range of other chronic diseases, including any that
are
 
or
 
could
 
potentially
 
be
 
successfully
 
treated
 
by
 
mAbs.
 
We
 
have
 
assembled
 
an
 
industry-leading
 
team
 
with
 
extensive
 
experience
developing successful
 
drugs that
 
is committed
 
to realizing
 
our mission
 
of alleviating
 
the greatest
 
amount of
 
suffering we
 
can in
 
the
world. Our website address
 
is www.vaxxinity.com.
 
The information contained on,
 
or that can
 
be accessed through, our
 
website is not
part of, and is not incorporated into, this Report.
 
4
The Chronic Disease Epidemic
More people today are suffering from
 
a chronic disease than ever before. Chronic diseases
 
kill 41 million people each year,
 
or 74% of
all deaths globally.
 
These diseases are
 
ongoing, generally incurable illnesses
 
or conditions that
 
gradually onset and
 
tend to be
 
of long
duration such as heart disease, cancer and AD.
 
Less than a century ago, the chronic
 
disease and disability prevalence was about 7.5% in
 
adults in the U.S. By 2000,
 
the proportion of
Americans with at least
 
one chronic disease had
 
grown to 45%, and
 
today, only two decades later, it has grown
 
to 60% of all
 
adults. The
proportion with multiple
 
chronic diseases
 
has similarly skyrocketed
 
to 40% of
 
adults in the
 
U.S. today. Overall, chronic
 
disease accounts
for 70% of deaths and nearly 90% of overall healthcare expenditure in the U.S.
 
The epidemic
 
is not
 
limited to
 
the U.S.
 
or the
 
developed world.
 
To
 
the contrary,
 
chronic diseases
 
disproportionately affect
 
low- and
middle-income countries (LMICs) where 77% of all
 
chronic disease deaths occur. Each year, 17 million people die of a chronic disease
before age
 
70, and
 
86% of
 
these premature
 
deaths occur
 
in LMICs.
 
According to
 
the World
 
Health Organization
 
(“WHO”), chronic
disease
 
is
 
closely
 
linked
 
with
 
poverty
 
in
 
what
 
can
 
become
 
a
 
vicious
 
cycle.
 
More
 
limited
 
access
 
to
 
health
 
services
 
by
 
socially
disadvantaged people
 
underlies increased
 
incidence of
 
chronic disease.
 
Meanwhile, healthcare
 
costs for
 
treatment of
 
these diseases,
which often become lengthy and expensive,
 
can quickly drain household resources. The WHO
 
estimates millions of people are forced
into poverty annually due to chronic disease.
 
Limitations of the Current Healthcare Paradigm
Since 2000, there have
 
been over 700 new
 
medicines approved by
 
the FDA, mostly to
 
treat chronic illnesses,
 
and yet the chronic
 
disease
epidemic continues to grow.
 
We believe that medicine is only as effective as its access, and many of the newest medicines are limited to less than 1% of the world’s
patient population. The current
 
healthcare paradigm favors the
 
development of drugs that
 
are primarily intended for
 
the U.S. market, for
niche indications and
 
for treatment of
 
disease rather than
 
prevention. Furthermore, these
 
drugs are expected
 
to be sold
 
at price points
that are only accessible to healthcare systems in developed countries, and even within those systems, to a small subset of patients.
 
One class of drugs in particular exemplifies the current environment: biologics, especially mAbs. In
 
2022, biologics represented seven
of
 
the
 
fifteen top
 
selling drugs,
 
of
 
which
 
six were
 
mAbs. The
 
global
 
market for
 
mAbs totaled
 
approximately $202 billion
 
in
 
2022,
representing over 60%
 
of the total
 
sales for all
 
biopharmaceutical products. While
 
mAbs can provide
 
life-altering care with
 
generally
favorable safety
 
characteristics and
 
significant health
 
benefits for
 
the patients
 
who receive
 
them, regular
 
in-office transfusions
 
and annual
treatment costs,
 
which can
 
exceed hundreds
 
of thousands
 
of dollars,
 
present challenges
 
to both
 
patients and
 
payors. These
 
price and
administration
 
hurdles
 
cause
 
mAb
 
treatments
 
to
 
be
 
available
 
to
 
only
 
a
 
fraction
 
of
 
the
 
population
 
who
 
could
 
benefit
 
from
 
them.
Furthermore, mAbs are
 
often restricted to
 
moderate to severe
 
disease and to
 
later lines of
 
treatment due to
 
their high cost,
 
rather than
prevention or early intervention in disease.
Thus, due to their cost and administrative burden, mAbs account for less than 2% of all
 
prescriptions in the U.S., and, based on internal
estimates, less
 
than 1%
 
worldwide. Meanwhile, the
 
alternative to
 
mAb treatments
 
tends to
 
be small
 
molecules, which are
 
sometimes
more accessible to patients, but are often comparatively
 
less effective with more significant side effects. Collectively, this perpetuates a
profound inequity
 
in healthcare
 
access, domestically
 
but even
 
more so
 
globally,
 
that we
 
believe represents
 
a tremendous
 
social and
market opportunity.
 
Our Scalable AIM Platform Solution
Our vision is to disrupt the existing
 
paradigm of chronic disease treatment
 
with a new class of active immunotherapeutic
 
medicines that
can potentially improve the health of more people, more conveniently, for less money.
 
Our AIM Platform
 
is designed to
 
harness the immune
 
system to convert
 
the body into
 
its own “drug
 
factory,” to stimulate
 
the production
of
 
antibodies
 
with
 
a
 
therapeutic
 
or
 
protective
 
effect,
 
and
 
to
 
be
 
scaled
 
to
 
supply
 
millions
 
or
 
even
 
billions
 
of
 
persons.
 
In
 
contrast,
monoclonal antibodies are developed, produced and purified outside the body and then transfused into the patient on a regular basis, as
frequently as bi-weekly. Therefore,
 
mAbs are inherently
 
less efficient than
 
active immunotherapies,
 
or vaccines, which
 
instead stimulate
antibody production
 
within the
 
patient’s
 
immune system,
 
requiring both
 
less active
 
material and
 
less frequent
 
treatments. However,
while traditional
 
vaccines have
 
historically been
 
successful at
 
addressing infectious
 
diseases, previous
 
attempts to
 
utilize vaccines
 
to
address
 
chronic
 
disease
 
have
 
not
 
achieved
 
both
 
acceptable
 
safety
 
and
 
efficacy.
 
Our
 
AIM
 
Platform
 
technology
 
contains
 
modular
components
 
that
 
can
 
be
 
rapidly
 
custom-designed
 
to
 
mimic
 
select
 
biology
 
and
 
activate
 
the
 
immune
 
system,
 
enabling
 
our
 
product
candidates to break
 
immune tolerance when
 
targeting self-antigens, a property
 
observed across multiple
 
clinical and pre-clinical
 
studies.
Our AIM Platform
 
depends heavily on
 
intellectual property licensed
 
from UBI and
 
its affiliates, a
 
related party and
 
a commercial partner
for us,
 
who first
 
developed the
 
synthetic peptide
 
vaccine technology
 
utilized by
 
our AIM
 
Platform. The
 
formulation of
 
our peptide-
based product
 
candidates relies
 
on contract
 
manufacturers at
 
this time,
 
including both
 
related parties
 
as well
 
as third-party
 
manufacturers.
 
 
vaxxq410kp7i0
5
We
 
believe
 
our
 
AIM
 
Platform
 
has
 
the
 
potential
 
to
 
generate
 
product
 
candidates
 
with
 
attributes
 
that
 
collectively
 
offer
 
significant
advantages over both
 
mAbs and small
 
molecule therapeutics, and
 
that some of
 
these advantages may
 
allow for use
 
in a first-line
 
or a
prevention setting for population health level diseases:
Cost and Scalability
: Whereas monoclonal antibodies require
 
costly and complex biological manufacturing
processes,
 
our
 
manufacturing
 
process
 
is
 
chemically
 
based
 
and
 
highly
 
scalable,
 
and
 
requires
 
lower
 
capital
 
expenditures.
 
Our
 
AIM
Platform has
 
been designed
 
and tested
 
to produce
 
on a scale
 
of hundreds
 
of millions
 
of doses
 
of GMP manufactured
 
material. In
 
addition,
we design our product candidates to generate antibody production in the body, thus requiring meaningfully less drug substance relative
to mAbs, leading to commensurately lower costs.
Administration and Convenience
: Our product candidates
 
are designed to be
 
injected in quarterly or
 
longer
intervals via intramuscular
 
injection similar to
 
a flu shot.
 
We
 
believe this offers
 
considerable convenience compared
 
to mAbs, which
can require up to bi-weekly dosing via intravenous infusion or subcutaneous injections, and small molecules, which often require daily
dosing. We
 
are also
 
in the
 
early stages
 
of exploring
 
additional modes
 
of administration,
 
including intradermal
 
delivery that
 
may be
administered in an at-home setting, potentially offering enhanced convenience to patients.
Efficacy
: In
 
our clinical
 
trials conducted
 
to date,
 
our product
 
candidates have
 
yielded high
 
response rates
(90% or above
 
at target
 
dose levels for
 
UB-311, UB-312,
 
UB-313, and UB-612),
 
high target-specific
 
antibodies against self-antigens
(as
 
seen
 
in
 
UB-311,
 
UB-312,
 
and
 
UB-313 clinical
 
trials)
 
and
 
long
 
durations
 
of
 
action (for
 
UB-311
 
based
 
on
 
titer levels
 
remaining
elevated between doses, and UB-612 based on half-life). We have observed target engagement in patient CSF in a Phase 1 clinical trial
of our UB-312
 
program.
 
See our descriptions
 
of these clinical
 
trials under “—Our Product
 
Candidates.” Our AIM
 
Platform also enables
the
 
combining
 
of
 
multiple
 
target
 
antigens
 
into
 
a
 
single
 
formulation.
 
For
 
indications
 
that
 
could
 
be
 
treated
 
more
 
effectively
 
with
 
a
multivalent approach, we
 
believe our AIM
 
Platform would have
 
an advantage over
 
other modalities. Further, because
 
our AIM Platform
is designed to elicit endogenous antibodies, we believe our product candidates may lessen or avoid altogether the phenomenon of anti-
drug antibodies
 
which has
 
limited the
 
efficacy of
 
certain mAbs
 
over time.
 
Finally,
 
we believe
 
that the
 
improved convenience
 
of our
product candidates
 
as compared
 
to mAbs
 
has the
 
potential to
 
lead to
 
increased adherence
 
by patients
 
and therefore
 
improve overall
effectiveness of our candidates.
Safety
: Based on our clinical trials to date, our product candidates have been well tolerated. We aim to offer
product candidates with safety profiles at least comparable to the relevant mAb or small molecule alternative for the relevant disease.
Our Targeted Impact
Our current
 
pipeline addresses
 
leading areas
 
of unmet
 
medical need,
 
from AD
 
to heart
 
disease, impacting
 
nearly 3.5
 
billion persons
worldwide, and resulting
 
in over 8
 
million annual deaths
 
and $4 trillion
 
dollars in economic
 
impact globally. The following table
 
depicts
our R&D pipeline.
As used in the chart above, “IND” signifies a program has begun investigational new drug (“IND”)-enabling studies.
 
Our pipeline
 
consists of
 
five lead
 
programs focused on
 
chronic disease, particularly
 
neurodegenerative disorders, in
 
addition to other
neurology and
 
cardiovascular indications.
 
For each
 
candidate, we
 
believe the
 
targeted biology
 
has been
 
validated or
 
de-risked either
through published genetic evidence or by a successfully licensed mAb against the same target.
 
 
 
 
 
 
 
 
 
 
6
Neurodegenerative Disease Programs:
UB-311
: Targets toxic forms of aggregated amyloid-beta (“Aβ”) in the brain to fight AD, a disease
affecting 44 million people worldwide, resulting in 1.6 million annual deaths and over $3 trillion in estimated economic cost. Phase 1,
Phase 2a and Phase 2a Long Term Extension (“LTE”)
 
trials have shown UB-311 to be well tolerated in mild-to-moderate AD subjects
over three years of repeat dosing, with a safety profile comparable to placebo, with no cases of amyloid-related imaging
abnormalities-edema (“ARIA-E”) observed in the main Phase 2a trial, and only one case of ARIA-E in the LTE trial, which was
clinically not significant according to the study investigator.
 
UB-311 was also shown to be immunogenic, with a high responder rate
and antibodies that bind to the desired target. Although not powered for statistical significance, the Phase 2a trial showed dose-
dependent trends of slowing of cognitive decline by 48% versus placebo, as measured by CDR-SB. We held an End of Phase 2
meeting with the U.S. Food and Drug Administration (“FDA”) and have aligned upon a large scale efficacy trial, which, pending data,
could potentially support initial licensure of UB-311 for the treatment of early AD.
 
The FDA granted UB-311 Fast Track Designation
in the second quarter of 2022.
 
The expected timing of the next clinical trial will be determined based upon the timing of additional
financing or a strategic partnership.
UB-312
: Targets toxic forms of aggregated α-synuclein (“aSyn”) in the brain and peripheral tissues to fight
PD and other synucleinopathies, such as Lewy body dementia (“LBD”) and multiple system atrophy (“MSA”), diseases
 
together
affecting 16 million people worldwide, resulting in 400,000 annual deaths and over $80 billion in estimated economic cost. Part A and
Part B of a Phase 1 trial in healthy volunteers and Parkinson’s patients, respectively, have been completed and have shown UB-312 to
be well tolerated, with no significant safety findings, and immunogenic, with a high responder rate and antibodies that cross the
 
blood-
brain barrier (“BBB”).
 
UB-312-induced antibodies were observed in the serum and CSF of both healthy volunteers and PD patients,
and showed preferential binding to aggregated aSyn and almost no binding to normal monomeric aSyn. Two exploratory biomarkers
were evaluated as measures of target engagement: aggregated aSyn as measured by a semi-quantitative seed amplification assay
(“SAA”), and phosphorylated aSyn (pS129 aSyn).
 
PD patients with UB-312-induced antibodies in the CSF showed a significant
reduction from baseline in pathological aSyn in the CSF compared to the placebo group as measured by both SAA and pS129 aSyn.
A
post hoc
 
analysis showed that patients with detectable UB-312-induced antibodies in the CSF exhibited improvement in activities of
daily living versus placebo, as measured by the MDS-UPDRS II clinical scale. We believe UB-312 is the first immunotherapy
candidate to show data of reduction of pathological aSyn in CSF of PD patients. The next step will be to conduct a Phase 2 trial to
optimize a dose regimen and to confirm target engagement in PD patients.
 
VXX-301
:
 
We
 
are
 
developing
 
an
 
anti-tau
 
product
 
candidate
 
that
 
has
 
the
 
potential
 
to
 
address
 
multiple
neurodegenerative conditions,
 
including AD,
 
traumatic brain
 
injury (“TBI”)
 
and chronic traumatic
 
encephalopathy (“CTE”)
 
by targeting
abnormal tau proteins alone and
 
in potential combination with other pathological
 
proteins such as Aβ to
 
address multiple pathological
processes at once. TBI is estimated to affect 56 million people worldwide and is attributed to approximately 2 million deaths
 
annually.
Our
 
lead
 
candidate targets
 
multiple epitopes
 
of
 
tau
 
and
 
has
 
been
 
shown in
 
preclinical studies
 
to
 
reduce tau
 
spreading
 
and
 
improve
survival in
 
animal models.
 
In an
 
effort to
 
focus internal
 
resources, we
 
have decided
 
to continue
 
the development
 
of VXX-301
 
only
through a
 
preclinical research
 
collaboration with
 
the University
 
of Florida,
 
which has
 
received a
 
grant from the
 
state of
 
Florida in support
of this project.
Next Wave Chronic
 
Disease Programs:
VXX-401
:
 
Targets
 
proprotein
 
convertase
 
subtilisin/kexin type
 
9
 
serine
 
protease
 
(“PCSK9”) to
 
lower
 
low-
density lipoprotein (“LDL”) cholesterol and reduce the risk of cardiac events. Today,
 
cardiovascular disease is the leading killer in the
world, accounting
 
for over
 
18 million
 
annual deaths,
 
affecting both
 
developed and
 
developing countries.
 
Over 2
 
billion people
 
have
high cholesterol globally.
 
As of October 2023, we have expanded
 
the ongoing first-in-human clinical trial of VXX-401
 
in Australia to
include two higher
 
dose cohorts due
 
to its favorable
 
safety and tolerability
 
profile to that
 
point, for
 
a total of
 
six cohorts.
 
In the
 
first
quarter of 2024, we submitted a protocol amendment to add a booster dose to these
 
two higher dose cohorts. We expect to report initial
topline data from this trial in mid-2024, with results from the booster dose later in the second half of 2024.
 
UB-313
: Targets
 
Calcitonin Gene-Related Peptide
 
(“CGRP”) to fight migraines,
 
a disease affecting
 
over 1
billion people worldwide, resulting in an estimated over
 
45 million years lived with disability annually.
 
In 2023, we completed a first-
in-human Phase 1 clinical trial in healthy volunteers in which UB-313 was generally well tolerated and immunogenic: all subjects who
received
 
three
 
doses
 
of
 
UB-313
 
(31
 
out
 
of
 
31)
 
developed
 
anti-CGRP
 
antibodies;
 
however,
 
serum
 
antibody
 
titers
 
were
 
lower
 
than
expected, and due
 
to this lower
 
immunogenicity, UB-313 did not meet
 
the trial’s secondary objective of
 
capsaicin-induced dermal blood
flow inhibition.
 
We believe this
 
was the
 
result of
 
a suboptimal
 
drug product
 
made by
 
a new
 
contract manufacturer, and
 
we have
 
identified
the necessary steps to
 
manufacture a more immunogenic
 
product consistent with prior
 
lots and the known immunogenic
 
potential of our
platform candidates.
 
In an
 
effort to
 
focus internal
 
resources, we
 
have deprioritized
 
this program
 
and are
 
not currently
 
planning on
 
running
another Phase 1 at this time.
Given the
 
global COVID-19
 
pandemic and
 
our AIM
 
Platform’s
 
applicability to
 
infectious disease,
 
we also
 
have advanced
 
a product
candidate that addresses SARS-CoV-2.
7
COVID-19
UB-612
: Employs a “multitope” subunit protein-peptide approach to neutralizing the SARS-CoV-2 virus,
meaning the product candidate is designed to activate both antibody and cellular immunity against multiple viral epitopes.
 
A Phase 3
trial evaluating UB-612 as a heterologous boost against SARS-CoV-2, head-to-head versus homologous boosts of VNT162b2
(mRNA), ChAdOx1-S (adenovirus), and BIBP (inactivated virus), was initiated in the first half of 2022 with funding support from the
Coalition of Epidemic Preparedness Innovations (“CEPI”).
 
In December 2022, we announced positive topline data: UB-612 met
primary and key secondary endpoints, eliciting non-inferior neutralizing antibody titers and seroconversion rates (“SCR(s)”), defined
as a 4-fold or greater increase in neutralizing antibodies from baseline, against both Wuhan and Omicron BA.5 variants as compared
to BNT162b2, and superior neutralizing antibody titers and SCRs against both variants as compared to ChAdOx1-S and BIBP.
 
UB-
612 was well tolerated with balanced reactogenicity and no additional safety risks evoked over the licensed COVID-19 comparators.
 
There were no serious adverse events (“SAEs”) related to UB-612 reported through 12 months of safety follow-up.
 
Phase 1 and Phase
2 trials of UB-612 have also shown UB-612 to be well tolerated, with over 7,500 doses administered to over 3,750 subjects. In March
2023 we completed rolling submissions for conditional/provisional authorization with regulatory authorities in the United Kingdom
and Australia, who are reviewing under their established work share agreement. In November 2023, the MHRA conducted GMP
inspections of our overseas CMO facilities responsible for UB-612 manufacture.
 
We believe a decision on authorization will be made
in 2024.
 
We
 
believe
 
our
 
AIM
 
Platform
 
has
 
application
 
across
 
a
 
multitude of
 
chronic and
 
infectious disease
 
indications beyond
 
our
 
existing
pipeline. We are developing additional product candidates that
 
we believe may address significant
 
unmet needs both within and
 
beyond
our current pipeline’s therapeutic areas.
Our Team
We have assembled an experienced group of executives with deep scientific, business and leadership expertise in pharmaceutical and
vaccine discovery and development, manufacturing, regulatory and commercialization. Mei Mei Hu, our co-founder and Chief
Executive Officer, has been a member of the executive committee of UBI since 2010. Our board of directors is chaired by our co-
founder Louis Reese, who has been a member of the executive committee of UBI since 2014. Our research efforts are guided by
highly experienced scientists and physicians on our leadership team including Dr. Jean-Cosme Dodart, our Senior Vice President of
Research. Our leadership team contributes a diverse range of experiences from leading companies including AstraZeneca, Eli Lilly,
Genentech, Merck, and Pharmacyclics, and were executives in multiple successful mAb and vaccine launches.
 
As of December 31,
2023, we have assembled an exceptional team of 53 employees, the majority of whom hold Ph.D., M.D., J.D. or Master’s degrees. We
also have a highly experienced scientific advisory board consisting of leading doctors and scientists in relevant therapeutic
 
areas.
 
Our Strategy
Our mission is to alleviate the
 
most human suffering possible by developing active
 
immunotherapy product candidates that
 
improve the
quality of care for chronic diseases and are accessible to all patients across the globe. In order to achieve this mission, we seek to:
Advance our chronic disease pipeline through clinical stage development
: We plan to advance UB-311,
UB-312, and VXX-401 through clinical stage development for the treatment or prevention of chronic diseases, either ourselves or with
a strategic partner. We
 
believe that our differentiated AIM Platform will enable our product candidates, if approved and successfully
commercialized, to potentially disrupt the current treatment paradigm for their respective indications. However, there can be no
guarantee that we will obtain regulatory approval or commercialize of any such product candidates.
 
Expand our pipeline of product candidates
: Chronic diseases are prevalent globally and expected to worsen
over the next several decades. In furtherance of our mission, we plan to expand our pipeline
 
by developing new product candidates that
address additional indications. In
 
expanding our pipeline,
 
we rely on
 
our proprietary filtering
 
methodology, which
 
evaluates potential
product
 
candidates
 
across
 
five
 
principal
 
criteria
 
 
(i)
 
probability
 
of
 
technical
 
and
 
regulatory
 
success,
 
(ii)
 
addressable
 
market,
 
(iii)
development cost, (iv) competitive dynamics and (v) disruptive potential.
Continue
 
to
 
improve
 
our
 
AIM
 
Platform
:
 
In
 
addition
 
to,
 
and
 
in
 
conjunction
 
with,
 
our
 
product
 
candidate
development efforts, we are
 
continuously working to
 
improve and enhance
 
the richness, breadth and
 
effectiveness of our AIM
 
Platform.
As our AIM Platform further develops,
 
we believe that we can both
 
increase the speed and efficiency of
 
developing product candidates,
improve the
 
probability of
 
technical success
 
of our
 
product candidates,
 
and increase
 
the number
 
of product
 
candidates in
 
concurrent
development.
Maximize the value
 
of our product candidates
 
through potential partnerships
: We currently retain
 
worldwide
rights for all
 
of our
 
product candidates
 
and will
 
consider entering
 
into development
 
and commercialization
 
partnerships with
 
third parties
that align with our mission on an opportunistic basis.
8
Background and Limitations of Traditional Vaccines
 
and Monoclonal Antibodies
The immune
 
system, the
 
body’s
 
mechanism for
 
fighting off
 
potential threats,
 
is comprised
 
of cells
 
that form
 
the innate
 
and adaptive
immune responses.
 
The main
 
purpose of
 
the innate
 
immune system
 
is to
 
immediately prevent
 
the spread
 
and movement
 
of
 
foreign
pathogens throughout the body. The adaptive immune response is specific
 
to the pathogen presented to T-cells and B lymphocytes (“B-
cells”) and leads to an enhanced
 
response upon future encounters with those
 
antigens. Antibodies represent an important
 
tool within the
adaptive immune system’s arsenal. Upon
 
detection of a potential
 
threat, B-cells produce antibodies
 
that recognize, bind
 
to and eliminate
the threatening pathogen. Over
 
time, the immune system
 
develops the ability to
 
produce countless types of
 
antibodies, each finely tuned
against a specific threat.
Generally, the immune system is able to function effectively by neutralizing
 
viruses, bacteria and even self-generated cells and
 
proteins
from within our own bodies that could
 
cause harm if unchecked. However,
 
as powerful as the immune system is,
 
there are threats that
it
 
cannot
 
overcome
 
on
 
its
 
own,
 
generating
 
the
 
need
 
for
 
medicine.
 
Conventional
 
forms
 
of
 
medicine
 
include
 
small
 
molecules
 
(e.g.,
antibiotics), which
 
can inhibit or
 
promote action within
 
the body by, for
 
instance, binding
 
to a receptor
 
on the surface
 
of a cell,
 
or directly
inducing toxic effects
 
upon bacteria. These
 
medicines do not
 
necessarily modulate the
 
immune system directly
 
in order to
 
work. Instead,
they work
 
alongside it. While
 
small molecules have
 
provided substantial benefits
 
to human health,
 
they are
 
typically not designed
 
to
interact with the
 
immune system. They
 
may also have
 
limited efficacy in
 
cases where an
 
immune response
 
to a target
 
can be used
 
against
a chronic condition.
Vaccines
In the first
 
part of the
 
twentieth century,
 
vaccines revolutionized healthcare
 
by directly interacting
 
with, and modulating,
 
the immune
system — training
 
it to recognize
 
a dangerous pathogen
 
by introducing the
 
immune system
 
to a relatively
 
harmless form
 
of the pathogen,
its toxins
 
or one
 
of its
 
surface proteins,
 
thereby promoting
 
the body’s
 
own production
 
of binding
 
antibodies. Once
 
immunized
 
to a
specific pathogen, the immune system can recognize it and generate the antibodies to fight it more quickly and robustly.
Traditional vaccine technologies have generally
 
focused on the prevention of bacterial and
 
viral infections and not on chronic disease.
In
 
chronic
 
disease
 
settings,
 
the
 
disease-causing
 
agents
 
frequently
 
come
 
from
 
within
 
the
 
body.
 
These
 
self-antigens
 
are
 
proteins
 
that
become too abundant, misfolded or aggregated such
 
that they can no longer perform their
 
healthy function and even may induce
 
toxic
effects.
 
The body
 
can
 
sometimes produce
 
antibodies
 
against
 
such proteins,
 
but
 
this often
 
falls
 
short of
 
providing
 
the right
 
types of
antibodies in the
 
right concentrations to
 
ward off disease.
 
Historically, vaccine technologies developed
 
to target these
 
proteins have been
unable to
 
break immune
 
tolerance —
 
that is,
 
the immune
 
system’s
 
general avoidance
 
of reactivity
 
towards self-antigens
 
— with
 
an
acceptable level of reactogenicity.
 
The challenges faced by prior efforts to
 
advance vaccine technologies for chronic diseases included
low response rates, low titer levels, off-
 
target responses and other safety concerns such as T-cell mediated inflammation.
Monoclonal Antibodies
The first
 
mAbs were
 
developed in
 
the later
 
part of
 
the twentieth
 
century.
 
In contrast
 
to vaccines,
 
which prompt
 
the body
 
to produce
antibodies, mAbs are antibodies manufactured outside of the patient’s body and then injected or infused into the body to recognize and
eliminate
 
harmful
 
targets.
 
Monoclonal
 
antibodies
 
have
 
revolutionized
 
the
 
standard-of-care
 
treatment
 
for
 
many
 
chronic
 
diseases.
However, manufacturing mAbs
 
is often
 
an expensive
 
and complex
 
process and
 
administering mAbs
 
is cumbersome,
 
sometimes requiring
infusions as
 
frequently as
 
bi-weekly.
 
These factors
 
have generally
 
limited mAbs’
 
availability to
 
moderate-to-severe disease,
 
to later
lines of therapy and to wealthier geographies, thus denying access to a substantial portion of the patients who could benefit from them.
Finally,
 
patients
 
on
 
mAbs
 
often
 
experience
 
a
 
loss
 
of
 
effectiveness
 
over
 
time
 
due
 
to
 
a
 
phenomenon
 
known
 
as
 
anti-drug
 
antibodies,
whereby the
 
immune system
 
begins to
 
recognize therapeutic
 
mAbs as
 
foreign, and
 
mounts a
 
response against
 
them, eventually
 
mitigating
their efficacy.
Our AIM Platform
Our AIM
 
Platform is
 
designed to
 
stimulate the
 
patient’s
 
own immune
 
system to
 
generate antibodies
 
and overcome
 
the limitations
 
of
traditional
 
vaccines
 
to
 
target
 
self-antigens
 
safely
 
and
 
effectively
 
in
 
chronic
 
diseases.
 
Our
 
product
 
candidates
 
have
 
broken
 
immune
tolerance against
 
self-antigens consistently.
 
As described
 
in the
 
section titled
 
“Our Product
 
Candidates” below,
 
across seven
 
clinical
trials, we
 
have consistently
 
observed that
 
our product
 
candidates have
 
stimulated the
 
development of
 
antibodies against
 
the desired
target at relevant doses in clinical
 
trial subjects, including the elderly. We have observed favorable tolerability and
 
reactogenicity of our
product candidates
 
across studies
 
of UB-311,
 
UB-312, UB-313,
 
and UB-612,
 
with no
 
significant safety
 
findings to
 
date. We
 
aim to
develop product candidates that are more convenient, more cost-effective
 
and more accessible to large patient populations, with
 
safety
profiles at least comparable
 
to relevant mAbs and
 
small molecule treatments. We
 
believe our product candidates
 
have the potential to
eventually not
 
only capture
 
meaningful market
 
share from
 
mAbs and
 
small molecules,
 
but more
 
importantly,
 
to provide
 
therapeutic
benefit to large patient populations who currently receive neither form of treatment
 
and thereby open up the broadest access to patients.
This would represent
 
an unprecedented shift
 
in the treatment
 
paradigm, potentially providing
 
better global access
 
to treatments that
 
have
been previously limited to the
 
wealthiest nations. In particular, we believe our treatments
 
for chronic disease could reflect
 
the following
benefits as compared with the relevant mAbs and small molecule alternatives:
 
 
vaxxq410kp11i0
9
Characteristics of our Product Candidates versus Monoclonal Antibodies and Small Molecules
History and Design
Our AIM
 
Platform utilizes
 
a peptide
 
vaccine technology
 
first developed
 
by UBI
 
and subsequently
 
refined over
 
the last
 
two decades,
with more
 
than three billion
 
doses of
 
animal vaccines
 
commercialized to
 
date. UBI
 
initiated the
 
development of
 
this technology
 
for
human use; the business focused on human use was then
 
separated from UBI through two separate transactions: a spin-out from
 
UBI in
2014 of operations focused
 
on developing chronic disease
 
product candidates that resulted
 
in United Neuroscience, a
 
Cayman Islands
exempted company
 
(“UNS”), and
 
a second
 
spin-out from
 
UBI in
 
2020 of
 
operations focused
 
on the
 
development of
 
a COVID-19
 
vaccine
that resulted in
 
C19 Corp., a
 
Delaware corporation (“COVAXX”).
 
Our current company,
 
Vaxxinity,
 
Inc., was incorporated
 
under the
laws of the State of Delaware on February 2, 2021 for the purpose of acquiring UNS and COVAXX in March of 2021.
 
On March 2,
 
2021, in
 
accordance with
 
a contribution
 
and exchange
 
agreement among Vaxxinity,
 
UNS, COVAXX
 
and the
 
UNS and
COVAXX stockholders party thereto (the “Contribution and
 
Exchange Agreement”), the
 
existing equity holders
 
of UNS and COVAXX
contributed their equity interests
 
in each of
 
UNS and COVAXX
 
in exchange for equity
 
interests in Vaxxinity
 
(the “Reorganization”).
In
 
connection
 
with
 
the
 
Reorganization,
 
(i) all
 
outstanding
 
shares
 
of
 
UNS
 
and
 
COVAXX
 
preferred
 
stock
 
and
 
common
 
stock
 
were
contributed to
 
Vaxxinity
 
and exchanged for
 
like shares
 
of stock
 
in Vaxxinity,
 
(ii) the outstanding
 
options to
 
purchase shares
 
of UNS
and COVAXX
 
common stock were terminated and substituted with options to purchase shares of Class A common stock in Vaxxinity,
(iii) the outstanding
 
warrant to
 
purchase shares
 
of
 
COVAXX
 
common stock
 
was cancelled
 
and
 
exchanged for
 
a warrant
 
to acquire
Class A common
 
stock in
 
Vaxxinity,
 
and (iv) the
 
outstanding convertible
 
notes
 
and a
 
related party
 
not payable
 
were contributed
 
to
Vaxxinity
 
and the former holders of such notes received Series A
 
preferred stock in Vaxxinity.
 
On December 31, 2022, COVAXX was
merged into Vaxxinity
 
in order to simplify the corporate structure.
 
UBI has used
 
its capabilities in peptide
 
technology for innovations across
 
an array of
 
business endeavors: antibody
 
testing for human
diagnostics, animal health vaccines and the manufacture of
 
medical products. Its innovative products include one of
 
the first approved
peptide-based blood antibody tests in
 
the world (for HIV), one
 
of the first approved peptide
 
vaccines against an infectious disease
 
in the
world in animal health (for a food-and-mouth disease virus) and one of the first approved peptide vaccines against a self-antigen in the
world in
 
animal health
 
(an anti-luteinizing
 
hormone-releasing hormone
 
(“LHRH”) vaccine
 
used for
 
the immunocastration
 
of swine).
Grant funding from the
 
National Institutes of Health
 
supported some of UBI’s
 
work in the fields
 
of vaccines and antibody
 
testing. To
commercialize its
 
animal health vaccine
 
business, UBI and
 
its affiliates scaled
 
up GMP vaccine
 
manufacturing to over
 
500 million doses
per
 
year
 
and
 
partnered
 
with
 
a
 
top-ten
 
animal
 
health
 
company
 
for
 
commercialization
 
of
 
its
 
anti-LHRH
 
vaccine;
 
all
 
together,
 
UBI’s
technology platform is utilized for the vaccination of approximately 25% of the global swine population annually.
We are advancing our peptide-based AIM
 
Platform to develop
 
product candidates that target
 
chronic diseases and COVID-19.
 
Our AIM
Platform
 
comprises
 
a
 
proprietary,
 
custom,
 
rationally
 
designed
 
antigen
 
capable
 
of
 
evoking
 
an
 
immune
 
response
 
(an
 
“immunogen”)
formulated with a proprietary
 
CpG oligonucleotide. The immunogen
 
contains several advanced
 
synthetic peptide domains,
 
including B-
cell epitopes, T-helper
 
(“Th”) peptide carrier
 
constructs and peptide
 
linkers. This composition
 
enables us to
 
achieve a highly
 
specific
immune response
 
to the
 
target antigen,
 
with limited
 
inflammation and
 
off-target
 
effects that
 
could cause
 
reactogenicity.
 
This design
process has evolved into a
 
repeatable series of well-defined
 
steps, which has enabled the
 
development of our current
 
pipeline of product
candidates.
vaxxq410kp12i0
10
Key Elements of our AIM Platform Constructs and Formulations
When developing a
 
product candidate, we
 
use publicly available
 
information and sophisticated
 
bioinformatics tools to
 
investigate the
entire protein structure of a target in a comprehensive manner to identify functional B-cell epitopes that may provide
 
optimal antigens.
We
 
then synthesize peptides
 
that mimic
 
these identified
 
antigens to
 
elicit highly
 
specific antibodies
 
against these
 
B-cell epitopes.
 
To
yield favorable tolerability profiles, we screen our product candidates
 
for lack of toxicity as well as reactogenicity, and design them not
to elicit T-cell
 
mediated inflammation. To
 
enhance effectiveness, we seek to optimize the
 
size and sequence of our custom peptides
 
to
elicit a robust, specific antibody response when linked to a carrier molecule.
We
 
then attach a
 
proprietary carrier molecule,
 
an artificial Th
 
carrier peptide that
 
delivers the synthetic
 
peptide into cells.
 
Traditional
vaccines have
 
faced challenges
 
in achieving
 
specific responses
 
because they
 
rely on
 
conjugating an
 
antigen to
 
a large
 
toxoid carrier
molecule, to which most of the antibody response is directed, causing off-target effects
 
such as inflammation.
 
In our pre-clinical trials
and clinical trials to date, our product candidates have displayed specific immunogenicity, or the ability to stimulate a targeted immune
response, thereby greatly reducing
 
potential off-target effects and increasing
 
the potential for our
 
product candidates to be
 
well tolerated
and
 
efficacious.
 
We
 
have
 
observed
 
that
 
our
 
carrier
 
molecules
 
have
 
produced
 
consistent
 
results
 
across
 
multiple
 
species
 
and
 
against
multiple targets in seven human clinical trials to date.
vaxxq410kp13i0
11
Our Product Candidate Does Not Induce an Antibody Response against its Carrier Molecule
The graph
 
above illustrates
 
that our
 
peptide carriers
 
induce a
 
strong immune response
 
against the
 
target antigen, and
 
a minimal
 
immune
response against themselves, as compared to traditional vaccines formulated with other types of carrier molecules.
Our peptide
 
carriers have
 
short sequence
 
lengths; we
 
design them
 
with the
 
aim that
 
they are
 
not antigenic
 
on their
 
own and
 
do not
stimulate cytotoxic T-cells.
 
The carriers’ sequences model those found in natural
 
pathogens, so they are recognized by T-helper
 
cells.
This encourages robust T-helper
 
cell exposure and
 
promotes activation of other
 
immune cells.
 
In turn, B-cells
 
are exposed to
 
the B-
cell antigen and begin antibody production against the antigen, while avoiding an antibody response to the carrier.
Our library of peptide carriers enables the use of different carrier molecules or different combinations of carrier molecules, which
allows us to potentially regulate the speed of immune response onset as well as the magnitude and duration of that response. For
example, a longer duration of response would allow for less frequent dosing. In the case of vaccines for infectious diseases, where T-
cell mediated activity is desirable, our AIM Platform also affords the flexibility to design immunogen constructs that specifically
promote cytotoxic T-cell activity when warranted.
 
We
 
utilize proprietary
 
linker constructs
 
to fuse
 
our peptide
 
carriers with
 
our custom
 
peptide antigens.
 
These linkers
 
are designed
 
to
promote binding of
 
both B-cell and T-helper epitopes to
 
their respective receptors,
 
contributing to a
 
B-cell response.
 
They may enhance
the immune
 
response by
 
enabling conformational
 
changes to
 
optimize presentation
 
of the
 
B-cell epitope
 
to antigen-presenting
 
cells
(“APCs”), such as dendritic cells (“DCs”).
Our AIM Platform also enables the construction of candidates that target multiple epitopes
 
in a single formulation, whether on multiple
targets or
 
a single
 
target.
 
In certain
 
cases, targeting
 
multiple epitopes
 
of a
 
single target
 
could promote
 
increased target
 
engagement.
 
Combinations of
 
therapies targeting
 
different molecular
 
mechanisms are
 
common in
 
treating neurologic,
 
cardiovascular, psychiatric,
metabolic,
 
respiratory,
 
infectious
 
and
 
oncologic
 
disease.
 
Our
 
AIM
 
Platform’s
 
favorable
 
cost
 
of
 
goods
 
and
 
efficient
 
manufacturing
process could
 
allow for
 
viable multi-target
 
therapies in
 
a single
 
formulation. This
 
concept could
 
be applied
 
in an
 
array of
 
potential
therapeutic areas. Our current
 
pipeline has candidates against
 
amyloid-β, α-synuclein and tau;
 
targeting of two or
 
more of these at
 
the
same time
 
might prove
 
more effective
 
than any
 
single-target therapy
 
in some
 
patients. Pre-clinical
 
data to
 
date suggests
 
that we
 
can
elicit antibody titers against
 
all three targets in
 
a single formulation. In
 
contrast, multi-target therapy with
 
mAbs would compound the
cost and administration burdens as compared to single-target mAb therapy.
vaxxq410kp14i0
12
Immunogenicity of Single- Versus Multi-Target
 
Formulations in Guinea Pigs
Guinea pigs (three
 
per dose) were
 
immunized with
 
either single-target or
 
multi-target formulations, then
 
serum was drawn
 
and antibody
titers compared
 
via enzyme immunoassays (“EIA”).
 
Multi-target formulations
 
elicited similar titer
 
levels against each
 
target as
 
their
corresponding single-target formulations. This suggests we can create product candidates with multiple
 
neurodegenerative targets in a
single formulation and achieve sustainable titer levels.
Product Candidate Formulations
In
 
addition
 
to
 
our
 
immunogen
 
construct,
 
each
 
product
 
candidate
 
formulation
 
includes
 
custom
 
CpG
 
oligonucleotides
 
and
 
adjuvant
selection. CpG
 
oligonucleotides are
 
negatively charged, and
 
we utilize
 
proprietary CpG
 
configurations to
 
stabilize the
 
positively charged
peptides. This
 
stabilization acts
 
to optimize
 
display of
 
the B-cell
 
epitope to
 
the immune
 
system. In
 
this way,
 
the primary
 
function of
CpG oligonucleotides in our formulations is that of an excipient.
A potential secondary
 
function of CpG
 
is that of
 
an adjuvant. Certain
 
CpG configurations are known
 
to act as
 
immunostimulants and
promote direct
 
cytotoxic T-cell activity, while others
 
do not.
 
Accordingly, our selection
 
of the
 
specific CpG
 
modality is
 
highly dependent
on the target indication. For
 
infectious disease indications, the T-cell
 
response generated by the CpG configuration
 
is independent and
in addition to that of the T-cell response generated by the peptide carrier.
The final formulation includes the addition
 
of an adjuvant, such as a well-recognized,
 
alum-derived Adju-Phos or Alhydrogel to further
enhance the immunogenicity of our product candidate. Alum-derived adjuvants are commonly used in vaccines to promote an immune
response. This is not the same adjuvant used in other companies’ failed neurodegenerative vaccine candidates.
How our Product Candidates are Designed to Function
Our immunogens
 
stimulate the
 
body’s
 
adaptive immune
 
system to
 
produce antibodies
 
against a
 
variety of
 
antigen targets,
 
including
secreted
 
peptides
 
or
 
proteins,
 
degenerative
 
or
 
dysfunctional
 
proteins
 
and
 
membrane
 
proteins,
 
as
 
well
 
as
 
infectious
 
pathogens.
 
The
mechanism of action involves the following sequence of steps:
1.
 
The immunogen is taken up
 
by an APC, such as
 
a DC. Antigen uptake leads
 
to DC maturation and
 
migration
to the draining lymph nodes where the DCs interact with CD4+ T-helper cells.
2.
 
DCs engulf and process the
 
antigen internally and present the
 
T-helper
 
epitope on major histocompatibility
complex (“MHC”)
 
Class II
 
molecules. The
 
presentation activates
 
immunogen-specific CD4+
 
T-helper
 
cells causing
 
them to
 
mature,
proliferate and promote B-cell stimulatory activity.
3.
 
B-cells with receptors that recognize the target B-cell
 
epitope bind, internalize and process the immunogen.
The binding of the B-cell receptor to the immunogen provides the first activation signal to the B-cells.
4.
 
When B-cells
 
function as
 
APCs and
 
present the
 
T-helper
 
epitope on
 
MHC Class
 
II molecules,
 
interaction
with immunogen-specific CD4+
 
T-helper
 
cells provides a
 
second activation signal
 
to B-cells, which
 
causes them
 
to differentiate
 
into
plasma cells.
5.
 
B-cell
 
epitope-specific plasma
 
cells produce
 
high
 
affinity
 
antibodies
 
against the
 
target
 
B-cell
 
epitope. Of
particular
 
importance
 
for
 
targets
 
located
 
in
 
the
 
central
 
nervous
 
system
 
(“CNS”),
 
these
 
antibodies
 
are
 
produced
 
in
 
sufficient
concentrations to cross the BBB.
vaxxq410kp15i1 vaxxq410kp15i0
13
Overview of How our Product Candidates Function
Importantly, from both
 
clinical trials and pre-clinical studies, we have
 
observed the rapid expansion of antibodies upon
 
administration
of a booster of our
 
product candidates. Based on
 
the available data to
 
date, we can infer that
 
while antibody titers decline with
 
time after
administration, a small number of memory B-cells
 
and antibody secreting cells are maintained in
 
the lymphoid organs, spleen or bone
marrow. We believe this is important because if a
 
patient misses a dose
 
of our product candidate,
 
they may be able
 
to recall the antibody
response, and therefore the therapeutic effect of the antibodies, with a single booster, even after a long period of time has passed.
AIM Platform Immunogenicity upon Re-dosing
As
 
shown in
 
the above
 
graph, a
 
rapid antibody
 
response
 
is
 
elicited by
 
a
 
booster dose
 
of UB-311
 
given 72
 
weeks after
 
the priming
regimen.
Furthermore, the antibodies elicited
 
by our product candidates
 
have different properties than those
 
of mAbs targeting similar pathology.
In general,
 
we aim
 
to achieve
 
binding affinity,
 
specificity and
 
functionality similar
 
or improved
 
compared to
 
mAbs targeting
 
similar
pathology. We
 
use Bio-Layer Interferometry (ForteBio
®
) to compare the binding kinetics (K
ON
, K
OFF
, and K
D
) of antibodies elicited by
14
our product candidates versus mAbs. We
 
also use Western
 
blot or slot blot to evaluate
 
the binding specificity of antibodies elicited by
our product
 
candidates against
 
the normal,
 
toxic, misfolded
 
or aggregated
 
forms of
 
the target
 
protein. We
 
use immunohistochemical
analyses to observe the binding of antibodies to pathological inclusions on tissue sections,
 
such as brain sections of patients. Moreover,
we use cell-based models and animal models to measure the induced antibodies’ functionality. Additionally, a major challenge in mAb
drug
 
discovery
 
is
 
that
 
mAbs
 
are
 
prone
 
to
 
induce
 
an
 
immune
 
response
 
against
 
themselves,
 
resulting
 
in
 
a
 
potential
inactivation/neutralization of the mAb by
 
the host (i.e., the patient).
 
This is not a concern
 
with our vaccine approach as
 
each patient will
produce its own antibodies against
 
the target. Finally,
 
mAbs have a potential for
 
off-target binding, which
 
could result in non-specific
binding leading to
 
safety and toxicity
 
issues. We
 
believe that this
 
is unlikely to
 
happen using our
 
technology since antibodies elicited
by our product candidates are
 
designed to break immune tolerance
 
against specific targets and
 
should not trigger an
 
immune response
against other self-peptides or proteins.
Product Candidate Selection Process
Because our AIM Platform may
 
have applicability across a range
 
of chronic diseases, we employ
 
a proprietary filtering methodology to
best identify new product candidates for development. We evaluate potential product candidates across five principal criteria:
Probability
 
of
 
technical
 
and
 
regulatory
 
success
:
 
We
 
examine
 
the
 
probability
 
of
 
success
 
for
 
a
 
product
candidate based on stage of development and therapeutic area, and then make target-specific adjustments for design difficulty, industry
knowledge and
 
clarity of biological
 
mechanism, general
 
safety risk and
 
estimated titer
 
level required
 
for therapeutic
 
effect. This criterion
accounts for the known validity of a given target in the relevant disease context.
Market
 
opportunity
:
 
We
 
account
 
for
 
the
 
prevalence,
 
unmet
 
need
 
and
 
drug
 
market
 
size
 
for
 
each
 
likely
indication associated with a given target, as well as the number of potential indications.
Development cost
: We
 
estimate the
 
cost of
 
development through
 
BLA submission,
 
the time
 
to submission
and the number of patient-years to proof-of-concept.
Competitive advantages
: We
 
evaluate the extent
 
to which the
 
advantages of our
 
AIM Platform compare
 
to
the current and potential future standard of care, including convenience, dosing, safety, efficacy and cost.
Disruptive opportunities
:
 
We
 
evaluate
 
the extent
 
to which
 
the potential
 
disruptive properties
 
of
 
our AIM
Platform may play
 
a role in
 
treatment paradigms, including
 
the ability to
 
“leap-frog” mAbs
 
and treat patients
 
in earlier lines
 
of treatment,
to be used as a prophylactic, to include multiple targets in a single formulation and to be used as an adjuvant therapy.
After assigning values to
 
each criterion for a
 
given product candidate, we
 
weight each criterion according
 
to a confidential algorithm,
and thereby prioritize product candidates for development. We update these values on a regular basis based on new scientific
 
literature,
trial results and our AIM Platform advancements.
As an example, in light of these criteria, AD and other neurodegenerative
 
diseases that involve misfolded proteins are an attractive area
for development. First, as the field has gained knowledge and clinical experience
 
around the biology of targeting aberrant proteins with
antibodies, the relative technical, safety and regulatory risk has
 
decreased. For instance, with two FDA-approved products targeting Aβ
for AD, Aβ has been validated as a target.
 
Both AD and PD have high prevalence worldwide, and large unmet need with limited or no
disease-modifying products
 
readily
 
available to
 
patients. Moreover,
 
the underlying
 
pathologies often
 
begin years
 
or
 
decades
 
before
symptoms may appear and as a result,
 
early intervention in the disease state, as
 
well as prevention or delay of onset
 
strategies, may be
optimal and
 
more practically
 
achievable with
 
a vaccine
 
approach. While
 
mAbs can
 
target the
 
pathology,
 
they face
 
the limitations
 
of
high cost, cumbersome and inefficient administration and limited access, and are not suited
 
for early treatment or prevention, which we
believe provides a disruptive opportunity for our AIM Platform.
We
 
believe that
 
our AIM
 
Platform, and
 
our strategy
 
more generally,
 
will create
 
a significant
 
opportunity for
 
drug development
 
well
beyond our current
 
pipeline of clinical
 
and pre-clinical indications,
 
in therapeutic areas
 
including allergy (e.g.,
 
atopic dermatitis,
 
chronic
rhinosinusitis, , food
 
allergy), autoimmune disease
 
(e.g., psoriasis, psoriatic
 
arthritis, Crohn’s disease), pain
 
(e.g., peripheral neuropathy,
diabetic neuropathy) and bone and muscle atrophy (e.g., sarcopenia, osteoporosis, osteopenia).
Underlying Drivers of Our Platform Advantages
Our AIM Platform’s properties drive the unique combination of attributes that we believe will be reflected in our product candidates:
Cost and Scalability
: Whereas monoclonal antibodies require
 
costly and complex biological manufacturing
processes,
 
our
 
manufacturing
 
process
 
is
 
chemically
 
based
 
and
 
highly
 
scalable,
 
and
 
requires
 
lower
 
capital
 
expenditures.
 
Our
 
AIM
Platform has
 
been designed
 
and tested
 
to produce
 
on a scale
 
of hundreds
 
of millions
 
of doses
 
of GMP manufactured
 
material. In
 
addition,
we design our product candidates to generate antibody production in the body, thus requiring meaningfully less drug substance relative
to mAbs, leading to commensurately lower costs.
15
Administration and Convenience
: Our product candidates
 
are designed to be
 
injected in quarterly or
 
longer
intervals via intramuscular
 
injection similar to
 
a flu shot.
 
We
 
believe this offers
 
considerable convenience compared
 
to mAbs, which
can require up to bi-weekly dosing via intravenous infusion or subcutaneous injections, and small molecules, which often require daily
dosing. We
 
are also
 
exploring additional
 
modes of
 
administration, including
 
intradermal delivery
 
that may
 
be administered
 
in an
 
at-
home setting, potentially offering enhanced convenience to patients.
Efficacy
: In
 
our clinical
 
trials conducted
 
to date,
 
our product
 
candidates have
 
yielded high
 
response rates
(90% or above
 
at target
 
dose levels for
 
UB-311, UB-312,
 
UB-313, and UB-612),
 
high target-specific
 
antibodies against self-antigens
(as
 
seen
 
in
 
UB-311,
 
UB-312,
 
and
 
UB-313 clinical
 
trials)
 
and
 
long
 
durations
 
of
 
action (for
 
UB-311
 
based
 
on
 
titer levels
 
remaining
elevated between doses, and UB-612 based on half-life). We have observed target engagement in patient CSF in a Phase 1 clinical trial
of our UB-312
 
program.
 
See our descriptions
 
of these clinical
 
trials under “—Our Product
 
Candidates.” Our AIM
 
Platform also enables
the
 
combining
 
of
 
multiple
 
target
 
antigens
 
into
 
a
 
single
 
formulation.
 
For
 
indications
 
that
 
could
 
be
 
treated
 
more
 
effectively
 
with
 
a
multivalent approach, we
 
believe our AIM
 
Platform would have
 
an advantage over
 
other modalities. Further, because
 
our AIM Platform
is designed to elicit endogenous antibodies, we believe our product candidates may lessen or avoid altogether the phenomenon of anti-
drug antibodies
 
which has
 
limited the
 
efficacy of
 
certain mAbs
 
over time.
 
Finally,
 
we believe
 
that the
 
improved convenience
 
of our
product candidates
 
as compared
 
to mAbs
 
has the
 
potential to
 
lead to
 
increased adherence
 
by patients
 
and therefore
 
improve overall
effectiveness of our candidates.
Safety
: Based on our clinical trials to date, our product candidates have been well tolerated. We aim to offer
product candidates with safety profiles at least comparable to the relevant mAb or small molecule alternative for the relevant disease.
Additionally,
 
we
 
believe
 
our
 
AIM
 
Platform
 
possesses
 
important
 
benefits
 
reflected
 
at
 
the
 
platform
 
level,
 
as
 
opposed
 
to
 
the
 
product
candidate level:
Product Candidate Discovery
: Our AIM Platform enables the efficient iteration of product candidates in the
discovery phase through rapid, rational design and formulation. We are able to screen in high throughput rapidly and at low cost. Upon
nominating
 
a
 
target
 
for
 
drug
 
discovery,
 
we
 
can
 
formulate
 
several
 
dozen
 
product
 
candidate
 
compounds
 
for
 
preliminary
 
in
 
vivo
immunogenicity and cross-reactivity
 
screening within 2 to
 
3 months. This process
 
allows nonviable product
 
candidates to “fail fast”
 
and
allows
 
us
 
to
 
carry
 
top
 
product
 
candidates
 
forward
 
through
 
subsequent
 
pre-clinical
 
development
 
to
 
lead
 
identification.
 
In
 
contrast,
biologics require the maintenance and
 
adjustment of living cultures to design,
 
formulate and iterate, and therefore discovery
 
and early
development is inherently less efficient.
Process Development
: Scaling the formulation of a drug product from research grade
 
to clinical grade, then
to commercial grade, typically
 
consumes a great deal
 
of resources. This, together
 
with the development of
 
assays for quality control
 
and
quality assurance, comprise
 
process development. We
 
leverage our manufacturing
 
expertise, originally developed
 
alongside UBI and
certain of
 
its affiliates,
 
to enable
 
rapid scale-up
 
of the
 
manufacture of
 
both clinical
 
and commercial
 
compounds that
 
use our
 
AIM Platform
technology.
 
Unlike
 
process
 
development
 
for
 
mAbs,
 
which
 
has
 
inherent
 
challenges
 
such
 
as
 
risk
 
of
 
contamination
 
in
 
cell
 
culture
 
or
bioreactors and
 
time-consuming adjustments
 
to cell
 
lines for
 
any formulation
 
adjustment, our
 
peptide platform
 
relies on
 
synthetic peptide
chemistry, which is more reproducible and scalable, and relatively quick to manipulate for any modifications.
Our Product Candidates
Neurodegenerative Disease Programs
Neurodegenerative diseases are a collection of conditions defined by progressive nervous system dysfunction, degeneration or death of
neurons, which can cause cognitive decline,
 
functional impairment and eventually death. Neurodegeneration
 
represents one of the most
significant unmet medical needs of our time due to an aging population and lack of effective therapeutic options.
Two of the most common
 
neurodegenerative diseases are
 
AD and PD.
 
In the United
 
States, currently more
 
than six million people
 
suffer
from
 
AD,
 
and
 
approximately
 
one million
 
people
 
suffer
 
from
 
PD
 
according
 
to
 
estimates
 
from
 
the
 
Alzheimer’s
 
Association
 
and
 
the
Parkinson’s Disease
 
Foundation, respectively.
 
As a result,
 
AD and PD
 
bring a heavy
 
burden on our
 
society’s cost
 
of care. The
 
direct
costs of
 
AD treatment
 
in the
 
United States
 
were
 
estimated at
 
$321 billion in
 
2022 according
 
to a
 
study published
 
by
 
the American
Journal of Managed
 
Care, and are
 
projected to exceed
 
$1 trillion by
 
2050. The financial
 
burden of PD
 
exceeded $50 billion in
 
the United
States in 2019. Many more people around the world suffer from these two diseases and their related social and economic implications.
UB-311
An Overview of Alzheimer’s Disease
Alzheimer’s
 
disease is
 
a progressive
 
neurodegenerative disorder
 
that slowly
 
affects
 
memory and
 
cognitive skills
 
and eventually
 
the
ability to
 
carry out
 
simple tasks.
 
Its symptoms
 
include cognitive
 
dysfunction, memory
 
abnormalities, progressive
 
impairment in
 
activities
16
of daily
 
living and
 
a host
 
of other
 
behavioral and
 
neuropsychiatric symptoms.
 
The exact
 
cause of
 
AD is
 
unknown, but
 
genetic and
environmental
 
factors
 
are
 
established
 
contributors.
 
AD
 
affects
 
more
 
than
 
six million
 
people
 
in
 
the
 
United
 
States
 
and
 
44 million
worldwide. The global economic burden of AD is expected to surpass $2.8 trillion by 2030.
Many molecular and cellular changes take place in the brain of a person with AD. Aβ plaques and neurofibrillary tangles of tau protein
in the
 
brain are
 
the pathological
 
hallmarks of
 
the disease.
 
Several pathological
 
or toxic
 
forms of
 
Aβ and
 
tau seem
 
implicated in
 
the
disease process, leading to loss of neurons and neuronal connectivity underlying the signs and symptoms of AD.
The Aβ protein involved in AD comes in several different pathological
 
forms that accumulate in the brain parenchyma. Soluble species
of
 
 
(e.g.,
 
oligomers)
 
can
 
directly
 
disrupt
 
normal
 
synaptic
 
and
 
neuronal
 
functions.
 
They
 
may
 
also
 
contribute
 
to
 
tau
 
pathology.
 
Research is ongoing to better understand how, and at what stage of the disease, the various forms of Aβ influence AD.
Neurofibrillary tangles are
 
abnormal accumulations of
 
a protein called
 
tau that collect
 
inside neurons. Healthy
 
neurons are
 
supported
internally,
 
in part,
 
by structures called
 
microtubules, which help
 
to guide nutrients
 
and molecules from
 
the cell
 
body to
 
the axon
 
and
dendrites. In healthy neurons, tau normally
 
binds to and stabilizes microtubules. In
 
AD, abnormal chemical changes cause tau
 
to detach
from microtubules
 
and to
 
stick to
 
other tau
 
molecules, forming
 
threads that
 
eventually join
 
to form
 
tangles. These
 
tangles block
 
the
neuron’s transport system, which harms the synaptic communication between neurons.
Converging lines of evidence suggest that
 
AD-related brain changes may result
 
from a complex interplay among
 
Aβ proteins, abnormal
tau, and several other factors. It appears that abnormal tau accumulates in
 
specific brain regions involved in memory. Concurrently, Aβ
clumps into plaques between neurons. As
 
the level of Aβ reaches a
 
tipping point, tau rapidly spreads throughout
 
the brain. In addition
to the spread of Aβ and tau,
 
chronic inflammation and its effect on the
 
cellular functions of microglia and astrocytes,
 
as well as changes
to the vasculature, are thought to be involved in AD’s pathology and progression.
In the last three years, the FDA has approved two different mAbs that target Aβ for the treatment of AD.
Limitations of Current Therapies
Two
 
classes
 
of
 
small
 
molecules
 
approved
 
for
 
the
 
treatment
 
of
 
AD’s
 
symptoms
 
are
 
acetylcholinesterase
 
inhibitors
 
(“AChEIs”)
 
and
glutamatergic modulators.
 
AChEIs are
 
designed to
 
slow the
 
degradation of
 
the neurotransmitter
 
acetylcholine, temporarily
 
compensating
for cholinergic
 
deficits.
 
Glutamatergic modulators
 
are designed
 
to block
 
sustained, low-level
 
activation of
 
the N-methyl-D-aspartate
(“NMDA”)
 
receptor,
 
without
 
inhibiting
 
the
 
normal
 
function
 
of
 
the
 
receptor
 
in
 
memory
 
and
 
cognition.
 
However,
 
these
 
therapeutic
products only address the symptoms of AD and do not modify or alter the progression of the underlying disease.
Aducanumab, marketed under the trade name Aduhelm, is
 
a mAb developed by Biogen, Inc. (“Biogen”) that
 
targets aggregated forms
of Aß. The FDA approved
 
aducanumab in June 2021, making
 
it the first approved immunotherapy
 
for AD, the first new
 
FDA-approved
treatment since 2003 and, importantly, the first to receive accelerated
 
approval based on a biomarker. By approving aducanumab
 
on the
basis of biomarker evidence, we believe the FDA set a precedent for developers of neurodegeneration immunotherapies.
 
Despite
 
the
 
milestone
 
in
 
the
 
treatment
 
of
 
AD
 
that
 
aducanumab’s
 
approval
 
represents,
 
the
 
drug
 
has
 
several
 
limitations,
 
and
 
Biogen
announced
 
its
 
discontinuation
 
in
 
2024.
 
Approximately
 
one-third
 
of
 
patients
 
experience
 
ARIA-E
 
related
 
adverse
 
events,
 
which
 
can
manifest as symptoms
 
ranging from
 
headaches to confusion
 
to coma.
 
In addition, the
 
drug must be
 
administered monthly
 
via intravenous
infusion in healthcare facilities specifically configured
 
to support an hour-long infusion process with
 
healthcare professionals trained to
administer infusion
 
therapies, creating
 
a burden
 
for patients
 
and additional
 
costs resulting
 
from the
 
complex administration
 
process.
Because of the
 
risk of developing
 
ARIA-E, physicians who
 
prescribe aducanumab must
 
titrate dosing and
 
carefully monitor each
 
patient
using magnetic resonance imaging (“MRI”). This process is costly and burdensome The combination of price, side effects, extra costs,
and extra administration burden
 
highlight the challenges of
 
mAbs.
 
The Center for Medicare
 
& Medicaid Services (“CMS”)
 
decided not
to cover aducanumab, leading to its commercial failure.
Soon after the FDA’s approval of aducanumab, Eli Lilly and Company (“Lilly”)
 
announced that it would file
 
for approval of its anti-Aβ
mAb, donanemab, in 2022 on the basis of Phase 2 data.
 
In January 2023, the FDA declined accelerated approval of donanemab due to
an insufficiently sized safety database in its Phase 2 trial; however, Lilly filed for approval later in 2023 on the basis of Phase 3 data.
In January 2023, the
 
FDA granted accelerated
 
approval to lecanemab,
 
another mAb targeting Aβ,
 
jointly developed by
 
Biogen and Eisai
Co., Ltd. (“Eisai”).
 
Over 12.5% of patients on lecanemab experience ARIA-E, and physicians who prescribe lecanemab must monitor
each patient
 
using MRI.
 
Lecanemab must
 
be administered
 
every two
 
weeks as
 
an intravenous
 
infusion in
 
healthcare facilities
 
specifically
configured to
 
support an
 
hour-long infusion
 
process with
 
healthcare professionals
 
trained to
 
administer infusion
 
therapies, creating
 
a
burden for
 
patients and
 
additional costs resulting
 
from the
 
complex administration process.
 
Biogen and
 
Eisai have set
 
the wholesale
acquisition cost (“WAC”)
 
price of lecanemab in
 
the U.S. at $26,500
 
for the drug product
 
only, which
 
does not include administration
and ongoing monitoring costs.
 
CMS has decided to cover lecanemab under
 
Medicare Part B with a 20% coinsurance
 
after a patient has
met their Part B deductible.
 
17
We
 
believe the
 
above examples
 
signify not
 
only the
 
validity of
 
targeting toxic
 
forms of
 
Aβ as
 
a target
 
in AD,
 
but also
 
the practical
limitations of mAbs, which so far despite approval have remained unable to serve a population with high unmet need.
 
Our Product Candidate: UB-311
We are developing a novel product candidate,
 
UB-311, as a potential disease-modifying
 
therapy for the treatment
 
of AD. We completed
a Phase 1 open label trial (V118-AD) and a Phase 2a randomized, double-blinded, placebo-controlled trial (the “Phase 2a
 
Main Trial”).
 
We believe that UB-311
 
may offer several differentiators versus the approved mAbs, including the preferential targeting of aggregated
 
oligomers
 
over
 
monomers,
 
longer
 
durability
 
suggesting
 
greater
 
overall
 
exposure,
 
or
 
area
 
under
 
the
 
curve
 
(“AUC”),
 
improved
convenience in dosing and administration, a safety and tolerability profile comparable to placebo with potentially limited ARIA-E, and
an ability
 
to broaden
 
patient access
 
with greater
 
cost-effectiveness and
 
scalability.
 
No signs
 
of ARIA-E
 
related adverse
 
events were
reported in the Phase 2a Main Trial
 
despite more than two-thirds of the study participants being APOE4
 
carriers.
Post hoc
 
exploratory
analyses of UB-311’s Phase 2a clinical data also
 
suggest that quarterly dosing
 
of UB-311 might slow cognitive decline
 
in some subjects
by up to 50% when compared to
 
placebo, as measured by Clinical Dementia Rating
 
Sum of Boxes (“CDR-SB”), Alzheimer’s Disease
Assessment Scale – Cognitive
 
Subscale (“ADAS-Cog”), Alzheimer’s Disease
 
Cooperative Study – Activities
 
of Daily Living (“ADCS-
ADL”) and Mini-Mental State Examination (“MMSE”) scores, all clinically validated measures of cognition or function in AD. In this
small Phase 2a study, these were secondary measures, as the study
 
was not designed to assess cognitive decline.
 
Although our Phase 2a
trial was a proof-of-concept study,
 
not powered to demonstrate significant changes in any endpoint, we believe the
 
data are suggestive
of potential therapeutic efficacy and may lead to clinical benefit.
UB-311 is
 
formulated for intramuscular administration
 
on a dosing
 
schedule of every
 
three or six
 
months. In addition,
 
manufacturing
costs
 
lower than
 
those of
 
mAbs may
 
support meaningfully
 
lower pricing
 
and access
 
to larger
 
patient populations.
 
We
 
believe such
advantages of UB-311,
 
if ever approved for use,
 
could position it not only
 
to disrupt the emerging
 
mAb-based treatment for early AD
as both
 
a monotherapy
 
and adjuvant
 
therapy to
 
existing mAbs,
 
but
 
also to
 
open up
 
a new
 
paradigm for
 
prevention of
 
AD (i.e.,
 
for
potential prophylactic use to delay or interrupt early disease onset).
Clinical Development
We
 
completed a randomized, double-blind, placebo-controlled Phase 2a
 
trial of two dosing regimens of
 
UB-311 in subjects with
 
mild
AD. The primary objective
 
of this trial was
 
to assess safety and
 
immunogenicity. Secondary measures for exploratory analyses
 
included
assessment of changes
 
in the CDR-SB,
 
ADAS-Cog, ADCS-ADL and
 
MMSE scales, along
 
with amyloid PET
 
imaging evaluations. This
study was intended for proof-of-concept,
 
so no statistical hypothesis testing
 
was planned, and exploratory
 
analyses were performed to
evaluate trends as described below.
A total of 43 patients diagnosed with
 
mild AD were randomized (1:1:1) to one of
 
three treatment groups: UB-311 quarterly
 
dosing, or
“Q3M,” receiving a total of seven doses, UB-311
 
every six-month dosing, or “Q6M,” receiving a total of five doses,
 
and placebo. The
Q3M cohort,
 
which included
 
14 subjects,
 
received an
 
initial regimen
 
of three
 
300μg injections,
 
one injection
 
at the
 
trial start,
 
one at
week 4 and the
 
final at week 12,
 
followed by four single
 
300μg booster doses administered
 
in three-month intervals over
 
the subsequent
12 months. The
 
Q6M cohort, which
 
included 15 subjects,
 
involved the same
 
initial schedule of
 
three 300μg injections
 
administered over
the first 12-week
 
period, followed by
 
the administration of
 
two 300μg booster
 
doses given at
 
six-month intervals. The
 
placebo group
comprised 14 subjects.
In the Phase
 
2a Main Trial,
 
UB-311 generated
 
an immune response
 
as measured by
 
ELISA in 28
 
out of 29
 
subjects. Across this
 
trial
and the
 
Phase 1
 
trial, 47
 
of the
 
48 subjects
 
(98%) that
 
received UB-311
 
registered an
 
immune response
 
(which we
 
define as
 
a 95%
confidence interval separation from placebo) as measured by ELISA. The intramuscular injection produced appreciable antibody titers
against
 
Aβ.
 
The antibody
 
titers remained
 
elevated
 
through the
 
trial’s
 
duration.
 
Moreover,
in
 
vitro
 
studies demonstrate
 
that
 
UB-311
generated serum antibody titers against Aβ oligomers, comparable to or greater than those
 
measured after maximum therapeutic dosing
with an approved mAb. We believe these results underscore the significant promise of our therapeutic approach.
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18
Generation of Antibodies Repeatable Across Clinical Studies, and Antibodies Bind Target with High
Specificity as Compared to Monoclonal Antibody
Across Phase
 
1 and Phase
 
2a trials, UB-311
 
generated an over
 
95% response
 
rates in subjects.
 
In a comparative
 
in vitro
 
study with
aducanumab, we observed that UB-311 elicited titer levels comparable to mAbs.
Phase 1
 
and Phase
 
2a trials
 
of UB-311
 
demonstrated a
 
repeatable anti-Aβ
 
titer response.
 
In an
in vitro
 
comparison of
 
titers in
 
serum
from subjects
 
dosed with
 
UB-311
 
versus pre-immune
 
serum spiked
 
with aducanumab
 
at the
 
published C
max
concentration following
10mg/kg administration
 
(183μg/mL), antibodies
 
generated by
 
UB-311 bond
 
to Aβ
 
oligomers similarly
 
to or
 
greater than
 
the mAb
 
as
measured by EIA.
Exploratory analyses of
 
clinical and imaging
 
measures were conducted.
 
Trends of changes in
 
disease assessment scores
 
suggest slowing
of cognitive decline.
 
Changes in the
 
CDR-SB assessment at
 
week 78 of
 
the Phase 2a
 
Main Trial
 
showed a 48%
 
slowing in cognitive
decline from baseline relative to the placebo group; changes in ADAS-Cog measurements showed a 50% slowing in decline relative to
placebo and showed a 54% slowing in decline in ADCS-ADL relative to placebo.
UB-311 Phase 2a Suggests Slowing of Cognitive Decline in Mild Alzheimer’s Subjects (mITT)
UB-311 Phase 2a secondary endpoint data suggested possible slowing of clinical
 
decline by up to 50% in subjects with
 
mild AD. These
are exploratory analyses, and no statistical inference was performed.
 
In addition,
 
functional MRI
 
suggested marginal
 
increases in
 
connectivity in
 
some brain
 
regions and
 
PET imaging
 
showed a
 
modest
reduction in
 
amyloid plaque
 
burden as
 
measured by
 
standard uptake
 
value ratio.
 
We
 
believe these
 
clinical and
 
biomarker endpoints
suggest a causal
 
effect of UB-311 impacting
 
the underlying
 
molecular pathology
 
of the disease
 
and slowing
 
of clinical
 
decline. Together,
these findings offer some evidence that UB-311 may exhibit disease-modifying effects.
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UB-311 Phase 2a Analysis of Clinical and Biomarker Endpoints Suggests Overall Disease-Modifying Effect
Compared to placebo,
 
UB-311
 
low-frequency dosing and
 
high-frequency dosing demonstrated slowing
 
of overall disease progression
in an independent analysis conducted by Pentara Corporation.
 
The Phase 2a
 
Main Trial
 
recapitulated the safety
 
and tolerability profile
 
of UB-311
 
that was observed
 
in the earlier
 
Phase 1 trial.
 
No
subjects discontinued trial
 
participation due to
 
a treatment emergent
 
adverse effect (“TEAE”).
 
No ARIA-E was
 
observed in quarterly
MRI
 
scans.
 
Aβ-related
 
imaging
 
abnormalities
 
related
 
to
 
microhemorrhages
 
or
 
hemosiderosis
 
seemed
 
similar
 
between
 
the
 
UB-311
treatment groups and placebo group. In the
 
Phase 2a Main Trial,
 
six SAEs were observed, including three in
 
the Q6M dosing arm and
one in the Q3M dosing arm. None were deemed related or likely related to UB-311.
Titers generated by UB-311 ramped up gradually over the
 
course of several months, as
 
opposed to titers following the
 
administration of
anti-Aβ mAbs, which reach C
max
 
very rapidly.
 
We believe this led to the relatively low
 
rates of ARIA-E observed
 
in our clinical studies
of UB-311 as compared to those observed in clinical studies of mAbs. No meningoencephalitis was observed.
Summary of Safety Data from UB-311 Phase 1 and Phase 2a Trials
As depicted
 
in the
 
table above,
 
UB-311 was well
 
tolerated across Phase
 
1 and
 
Phase 2a
 
trials. The
 
most common
 
TEAE was
 
site injection
reactivity, and there
 
were no discontinuations or withdrawals due to TEAEs
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20
An
 
extension
 
of
 
the
 
Phase
 
2a
 
Main
 
Trial,
 
the
 
Phase
 
2a
 
LTE
 
trial,
 
involved
 
the
 
continued
 
participation
 
by
 
34
 
of
 
the
 
subjects
 
who
participated in the
 
Phase 2a Main
 
Trial for
 
an additional 78
 
weeks. The objective
 
of the Phase
 
2a LTE
 
trial was to
 
assess the
 
longer-
term tolerability of extended treatment with UB-311. Following a non-treatment period of up to 26 weeks, participants in the LTE
 
trial
were segmented
 
into two
 
groups: those
 
previously on drug
 
in the
 
Phase 2a
 
Main Trial
 
would receive
 
two placebo
 
doses and
 
a single
300μg priming dose at the start of the LTE
 
treatment period and those previously on placebo would receive three 300μg priming doses
over an
 
initial 12-week
 
period. Due
 
to an
 
error by
 
the CRO
 
responsible for
 
administering blinded
 
placebo and
 
active doses
 
to trial
subjects, which reduced the confidence of subsequently collected data, we decided to discontinue the LTE trial, having determined that
we had collected
 
sufficient data on
 
UB-311’s tolerability and immunogenicity. Analysis of
 
the data collected
 
before trial discontinuation
indicated that
 
UB-311
 
was well
 
tolerated, with
 
return of
 
anti-Aβ antibody
 
titers to
 
peak levels
 
achieved after
 
a gap
 
of as
 
long as
 
12
months
 
between
 
doses
 
and
 
a
 
continued
 
trend
 
toward
 
evidence
 
of
 
disease
 
modification.
 
In
 
the
 
Phase
 
2a
 
LTE
 
trial,
 
six
 
SAEs
 
were
observed. One case of ARIA-E was
 
observed in the Phase 2a LTE
 
trial in a subject 10 weeks
 
after receiving a dose of UB-311,
 
which
was clinically not significant according to the study investigator. No SAE was deemed related or likely related to UB-311, and all such
events were recovered/resolved
 
by the end
 
of the study.
 
Exploratory analyses of
 
the clinical data
 
generated in this
 
portion of the
 
trial
suggested that subjects in the treatment cohorts showed sustained improvement, as measured by the change in CDR-SB from baseline.
We completed an open-label Phase 1 trial of UB-311 in 19 subjects with mild-to-moderate AD between the ages of 51 to 78 years. The
primary objective
 
of the
 
trial was
 
to assess
 
safety and
 
tolerability.
 
Secondary measures
 
included UB-311
 
antibody titers
 
along with
changes in the ADAS-Cog,
 
MMSE and the Alzheimer’s
 
Disease Cooperative Study-Clinician’s
 
Global Impression of Change
 
disease
assessment ratings. The 24-week,
 
open label trial was
 
designed as three intramuscular
 
injections of 300μg, the first
 
dose administered
at the start of the trial, a second at week four and a third at week 12. An observation study included additional follow-up visits up to 48
weeks after the
 
first injection to
 
assess the long-term
 
immunogenicity and safety of
 
UB-311. In
 
this trial, UB-311
 
was well tolerated,
with the most common TEAE being injection site redness and swelling. No TEAE resulted in the discontinuation or withdrawal of any
study participant in the trial. In the Phase 1 trial, one SAE was observed: a case of herpes zoster deemed unlikely related to UB-311.
Anti-Aβ
 
antibody
 
titers,
 
recorded
 
among
 
all
 
study
 
participants,
 
approached
 
a
 
100-fold
 
increase
 
during
 
weeks
 
16
 
to
 
48
 
after
administration of
 
the third
 
300μg injection
 
at week
 
12, demonstrating
 
the ability
 
of UB-311 to
 
elicit a
 
strong immune
 
response. Durability
of the response was reflected in elevated anti-Aβ antibody titers measurable well beyond the 24-week duration of the trial.
In a Western blot assay, we observed that UB-311 elicited antibody titers specific to toxic
 
forms of Aβ with minimal binding
 
to normal,
non-plaque-causing, forms of Aβ.
Pre-Clinical Data
Pre-clinical trials of UB-311
 
included multiple antibody titer studies involving
 
mice, guinea pigs, macaques and baboons. Application
of
 
specific
 
transgenic
 
animal
 
models
 
was
 
intended
 
to
 
emulate
 
both
 
therapeutic
 
and
 
preventive
 
treatment
 
paradigms.
 
These
 
trials
demonstrated that UB-311 generated high
 
antibody titers across
 
multiple species that selectively
 
target aggregated Aβ and
 
both slow the
accumulation of and reduce existing Aβ pathology.
We also observed the ability of UB-311
 
induced antibodies to penetrate the BBB, as well as preferentially bind to toxic Aβ aggregates.
In our study of UB-311 in cynomolgus
 
monkeys, we tested five escalating
 
dose levels of UB-311: 0μg, 30μg, 100μg,
 
300μg and 900μg.
Each dose level was
 
administered on weeks zero,
 
three and six by
 
intramuscular injection and the
 
cerebrospinal fluid (“CSF”): serum
ratio of
 
UB-311
 
calculated on
 
week eight
 
(two weeks
 
after the
 
last dose).
 
This analysis
 
concluded that
 
UB-311
 
antibody titers
 
were
detectable in the CSF in a
 
dose-dependent manner with CSF: serum
 
antibody ratios of 0.1% to
 
0.2%, ratios similar to published
 
data for
mAbs in development for neurodegenerative diseases.
UB-311 Shows Dependent Response in CSF in Pre-Clinical Study
21
The above graphs demonstrates
 
that UB-311
 
induces enough antibodies for
 
BBB penetration, across
 
five dose levels in
 
a pre-clinical
study with cynomolgus monkeys.
Development Plans for UB-311
We have completed an End of Phase 2 meeting with the FDA and obtained guidance on the further development of UB-311.
We believe UB-311 could also have a potential therapeutic benefit in a prophylactic
 
setting for the prevention of AD
 
in at-risk subjects.
We may seek to further develop UB-311
 
for the prevention of AD.
UB-312
An Overview of Parkinson’s
 
Disease
Parkinson’s disease currently affects approximately
 
one million people in
 
the United States
 
and more than
 
10 million people worldwide.
The economic burden of
 
PD is estimated at
 
$52 billion in the United
 
States alone. PD
 
is a chronic and
 
progressive neurodegenerative
disorder that affects
 
predominately dopamine-producing (“dopaminergic”) neurons
 
in the substantia
 
nigra area of
 
the brain. Although
the
 
mechanisms responsible
 
for
 
the
 
dopaminergic
 
cell
 
loss in
 
PD
 
are not
 
fully
 
elucidated, several
 
lines
 
of
 
evidence
 
suggest
 
that α-
synuclein plays a central role in the neurodegenerative process.
Alpha-synuclein
 
is
 
a
 
protein
 
highly
 
expressed
 
in
 
neurons,
 
mostly
 
at
 
presynaptic
 
terminals,
 
suggesting
 
a
 
role
 
in
 
synaptic
 
vesicle
trafficking,
 
synaptic
 
functions
 
and
 
in
 
regulation
 
of
 
neurotransmitter
 
release
 
at
 
the
 
synapse.
 
Duplications,
 
point
 
mutations
 
or
 
single
nucleotide polymorphisms
 
in the
 
gene encoding
 
α-synuclein are
 
known to
 
cause or
 
increase the
 
risk of
 
developing PD
 
or LBD.
 
Mutations
have been shown to primarily alter the
 
secondary structure of α-synuclein, resulting in misfolded and aggregated forms
 
of α-synuclein
(i.e., pathological
 
forms). While
 
mutations in
 
the α-synuclein
 
gene are rare,
 
aggregates of
 
α-synuclein in
 
the form
 
of Lewy bodies
 
(“LB”)
and Lewy neurites are common neuropathological hallmarks of
 
both familial and sporadic PD, suggesting
 
a key role of α-synuclein in
PD
 
neuropathogenesis.
 
Moreover,
 
preformed
 
fibrils
 
of
 
α-synuclein
 
can
 
induce
 
the
 
formation
 
of
 
LB-like
 
inclusions
 
and
 
cellular
dysfunction in
 
cell-based assays
 
as well
 
as in
 
pre-clinical animal
 
models. Together, these data
 
strongly suggest
 
that targeting
 
pathological
forms of α-synuclein has therapeutic potential.
Limitations of Current Therapies
Most approved
 
therapeutic products
 
are aimed
 
at compensating
 
for the
 
dopaminergic deficits
 
and only
 
provide symptomatic
 
relief. While
existing products can indeed
 
provide meaningful symptomatic relief,
 
they often produce significant
 
side effects and lose their
 
beneficial
effects overtime. On the other hand, there are no currently approved disease-modifying therapeutics for PD.
Immunotherapy approaches targeting
 
α-synuclein have been
 
shown to ameliorate
 
α-synuclein pathology as
 
well as functional
 
deficits
in mouse models of PD
 
and are now being investigated in
 
the clinic. These include passive immunization
 
therapy using humanized or
human anti-α-synuclein mAbs or active immunization therapy aimed at inducing a humoral response against pathological α-synuclein.
These approaches have thus far demonstrated good tolerability profiles in Phase 1 clinical trials. A Phase 2 clinical trial in PD subjects
with prasinezumab,
 
a mAb
 
that preferentially
 
recognizes oligomeric
 
and fibrillar
 
forms of
 
α-synuclein, suggested
 
reduced motor
 
function
decline in subjects as
 
compared with placebo; however, this
 
Phase 2 trial did
 
not meet its primary
 
or secondary endpoints.
 
Further trials
of prasinezumab
 
in different
 
patient populations
 
remain ongoing.
 
Even if
 
approved as
 
therapeutic for
 
PD, we
 
expect prasinezumab
would be burdened by the general challenges of cost and administration.
Our Product Candidate: UB-312
We are developing UB-312,
 
an anti-α-synuclein product candidate, as a treatment for PD and other synucleinopathies. We
 
believe that
UB-312 has
 
the potential
 
to be
 
established as
 
a disease-modifying
 
treatment modality
 
for PD,
 
and possibly
 
for LBD
 
and MSA.
 
Pre-
clinical data indicated
 
that UB-312 elicits
 
antibodies that preferentially
 
recognize pathological forms
 
of a-synuclein and
 
improves motor
performance in mouse models of
 
α-synucleinopathies. Clinical data from our
 
Phase 1 trial, which we
 
completed in 2023, indicate that
UB-312 is well tolerated and elicits antibody levels sufficient to
 
cross the BBB (i.e., detectable in CSF) in both healthy volunteers
 
and
PD patients. Antibodies showed preferential
 
binding to aggregated aSyn.
 
Two
 
exploratory biomarkers were evaluated as
 
measures of
disease progression: aggregated α-synuclein
 
as measured by
 
a semi-quantitative SAA, and
 
phosphorylated aSyn (pS129 α-synuclein).
 
A
post hoc
 
analysis showed that
 
PD patients with UB-312-induced
 
antibodies in CSF had
 
significantly less α-synuclein aggregation
 
and
pS129 α-synuclein
 
as compared
 
to placebo.
 
PD patients
 
with UB-312-induced
 
antibodies in
 
CSF also
 
showed improvement
 
in the
clinical Movement Disorder Society – Unified
 
Parkinson’s Disease Response
 
Score (“MDS-UPDRS”) Part II activities of
 
daily living
scale as compared to placebo.
 
In 2018, the European Medical Agency (“EMA”) granted UB-312 orphan designation for MSA.
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Clinical Development
In
 
Part
 
B of
 
a randomized,
 
placebo-controlled, double-blind,
 
dose-escalating, single-center
 
Phase 1
 
clinical trial
 
of
 
UB-312, 20
 
PD
patients between the ages of 40 and
 
85 years received three intramuscular
 
doses of either UB-312 or placebo.
 
During this 44-week Part
B of the trial, subjects received one of
 
two different three-dose priming regimens ("Group A" and "Group
 
B"), with doses on weeks 1,
5, and 13.
 
Immunogenicity was evaluated by
 
measuring changes in
 
serum and CSF
 
anti- α-synuclein antibody
 
concentrations during
the course of the
 
study.
 
In addition, an exploratory
 
endpoint was included involving
 
a clinical assessment
 
using the MDS-UPDRS.
 
The
Michael J. Fox Foundation (“MJFF”) has funded a 2-year collaborative project between Vaxxinity,
 
the Mayo Clinic, and University of
Texas
 
Houston using
 
CSF collected
 
from individuals
 
enrolled in
 
Part B
 
of the
 
Phase 1
 
trial of
 
UB-312.
 
This work
 
is evaluating
 
the
potential of an SAA to assess target engagement, and aims to characterize
 
the anti-α-synuclein antibodies produced after immunization
with UB-312.
UB-312 was
 
generally safe
 
and well-tolerated
 
in PD
 
patients, with
 
19 of
 
20 patients
 
completing dosing.
 
The most
 
common TEAEs
were headache, procedural pain, fatigue, and orthostatic hypotension.
 
The majority of TEAEs was considered either mild or moderate,
and UB-312 was
 
comparable to placebo.
 
Two patients experienced SAEs,
 
of which one
 
was deemed possibly
 
related by the
 
investigator
due to the
 
timing of onset.
 
This SAE was a
 
deep venous thrombosis of
 
the left leg 50
 
days after administration of
 
the second dose of
UB-312.
 
There were no apparent trends in safety signals,
 
including ECG, vital signs, and blood and urine assessments.
 
There was no
difference in
 
either physician
 
or participant
 
reported tolerability
 
within seven
 
days after
 
each administration
 
of UB-312
 
compared to
placebo.
UB-312 generated robust
 
levels of anti-α-synuclein
 
antibody titers detectable
 
in the serum
 
and CSF of
 
PD patients.
 
12 out of
 
13 patients
who completed dosing
 
had anti-α-synuclein antibodies
 
detectable in
 
the serum.
 
In Group A,
 
4 out
 
of 6
 
patients had
 
anti-α-synuclein
antibodies
 
detectable
 
in
 
CSF;
 
in
 
Group
 
B,
 
1
 
out
 
of
 
7
 
patients
 
had
 
anti-α-synuclein antibodies
 
detectable
 
in
 
CSF.
 
Of
 
patients
 
with
detectable
 
anti-α-synuclein
 
titers
 
in
 
CSF,
 
the
 
CSF:serum
 
antibody
 
ratio
 
was
 
approximately
 
0.35%.
 
Antibodies
 
were
 
selective
 
to
aggregated forms of α-synuclein over monomeric α-synuclein as measured by dot blot.
Results
 
from
 
a
 
SAA
 
performed
 
at
 
Mayo
 
Clinic
 
suggest
 
that
 
UB-312-induced
 
antibodies
 
functionally
 
inhibit
 
the
 
aggregation
 
of
 
α-
synuclein when spiked into PD patient CSF.
Spiking UB-312 Antibodies into PD Patient CSF Slows Down Alpha-Synuclein Aggregation
This
 
α-synuclein SAA
 
performed at
 
Mayo Clinic
 
used
 
antibodies purified
 
from
 
subjects in
 
the
 
Phase
 
1
 
trial of
 
UB-312.
 
It
 
suggests
slowing of the aggregation of α-synuclein in
 
PD patient CSF samples seeded
 
with α-synuclein monomers, as measured by
 
fluorescence
intensity.
We also
 
directly measured α-synuclein aggregates in the CSF of the PD
 
patients who participated in the Phase 1 trial of UB-312
 
using
fluorescence max in a SAA.
 
This showed up to a
 
20% reduction of aggregated
 
α-synuclein in PD patient CSF
 
in Group A, as compared
to a 3% increase in the placebo group (p = 0.024), over the 44-week trial period.
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Reduction of Alpha-Synuclein Aggregates in CSF of PD Patients
This α-synuclein SAA performed at Amprion showed a significant reduction
 
in the pathological species of α-synuclein with UB-312 as
compared to placebo.
 
*Placebo vs. Group A, two-way RM ANOVA: F
2,19
 
= 4.047; p = 0.034
An exploratory
post hoc
 
analysis comparing
 
patients with detectable
 
anti-α-synuclein antibodies
 
in CSF to
 
those without
 
was performed.
 
Patients with detectable anti-α-synuclein
 
antibodies in CSF showed
 
significant reduction in aggregated
 
α-synuclein in CSF (28%
 
versus
placebo, p = 0.0183), as well as improvement in MDS-UPDRS Part II), the activities of daily living clinical scale (p = 0.0062).
This exploratory
post hoc
 
analysis also
 
examined differences
 
in levels
 
of phosphorylated
 
α-synuclein (pS129)
 
between patients
 
with
and without detectable
 
anti-α-synuclein antibodies in
 
CSF.
 
Patients with detectable
 
anti-α-synuclein antibodies in
 
CSF showed a
 
27.2%
reduction in pS129 α-synuclein, as compared to a 19.5% increase observed in the placebo group (p = 0.0351).
Reduction of Phosphorylated Alpha-Synuclein in PD Patient CSF
This assay performed at Magqu demonstrates
 
a statistically significant reduction in
 
phosphorylated pS129 α-synuclein in PD patients
with detectable
 
anti-α-synuclein antibody
 
titers in
 
CSF.
 
*Placebo vs.
 
UB-312 with CSF
 
titers at
 
the end
 
of the study, Bonferroni
 
multiple
comparison test p = 0.0351.
Correlations between changes in titers and changes in aggregated α-synuclein were observed.
In Part A of the Phase 1 clinical trial of UB-312, 50 healthy volunteers between the ages of 40 and 85 years received three
intramuscular doses of either UB-312 or placebo. During this 44-week Part A of the trial, subjects received three priming doses on the
same schedule as described for Part B, with escalating doses ranging from 40μg to 2,000μg. Data from Part A indicated that UB-312 is
generally well tolerated, with no significant safety findings. Data from Part A also suggested that UB-312 is highly immunogenic,
with all individuals in the 300μg/dose group showing detectable anti-α-synuclein antibodies in both serum and CSF samples. CSF:
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24
serum ratios appeared similar to those observed in UB-311 non-human primate studies (approximately 0.2%), and to those observed in
clinical trials of mAbs.
UB-312 Demonstrated Dose-Dependent Response in Phase 1 Part A Trial Including Penetration of Titers into CSF
Across
 
four cohorts,
 
UB-312 demonstrated
 
a dose-dependent
 
immunogenic response.
 
Antibodies generated
 
by UB-312
 
were
 
readily
detectable in CSF,
 
indicating BBB penetration with a CSF: serum ratio of approximately 0.2%.
We paused dosing in high dose
 
cohorts in Part A
 
of the trial after
 
one subject developed
 
an adverse effect (“AE”)
 
of special interest
 
(i.e.,
Grade 3 flu-like symptoms) shortly after receiving the second 1000μg dose of UB-312. Although this AE was transient and not a SAE,
data collected
 
until that
 
point suggested
 
that the
 
100μg and
 
300μg dose
 
levels were
 
well tolerated
 
and yielded
 
relatively high
 
anti-α-
synuclein titers. During
 
the evaluation of
 
the AE, the
 
COVID-19 pandemic was
 
becoming increasingly pervasive
 
throughout Europe,
increasing the risk to healthy volunteers
 
participating in the trial. We
 
therefore did not resume dose escalation
 
and selected 100μg and
300μg doses for Part B in PD subjects.
An end-of-treatment analysis of
 
the ongoing Part B
 
of the Phase 1 trial
 
in PD patients was
 
completed in the fourth
 
quarter of 2022.
 
This
analysis has shown UB-312 to be well tolerated and immunogenic, with anti-α-synuclein antibodies observed in the serum and
 
CSF of
PD patients.
 
Three SAEs were observed in Part B, which remains blinded, meaning
 
it remains unknown in which treatment group they
occurred (UB-312 or placebo).
Pre-Clinical Data
We
 
have
 
conducted
 
pre-clinical
 
studies
 
of
 
UB-312
 
across
 
multiple
 
animal
 
species,
 
including
 
mice
 
and
 
guinea
 
pigs.
 
These
 
trials
demonstrated that
 
our product
 
candidates, including
 
UB-312, generated
 
high antibody
 
titers to
 
α-synuclein across
 
animal species.
 
In
addition, in vitro studies provided
 
evidence that anti-α-synuclein antibodies produced
 
after UB-312 immunization are highly
 
selective
to pathological α-synuclein, and do not bind to normal α-synuclein.
UB-312 Demonstrates Selective Binding Towards α-Synuclein Fibrils and Ribbons
This in vitro slot blot analysis of sera from guinea pigs dosed with UB-312 demonstrates that antibodies induced by UB-312 bind to α-
synuclein fibrils
 
and ribbons,
 
the toxic
 
forms of
 
α-synuclein believed
 
to underlie
 
PD, more
 
strongly than
 
they bind
 
to monomers,
 
the
normal form of α-synuclein in the body.
 
We believe
 
this preference will allow UB-312
 
antibodies to avoid altering normal functions of
α-synuclein and selectively neutralize the toxic species
(Nimmo et al., Alzheimers Res Ther. 2020;12:159).
vaxxq410kp27i0
25
Anti-α-synuclein
 
antibodies
 
produced
 
by
 
UB-312
 
immunization
 
specifically
 
bind
 
pathogenic
 
species
 
of
 
α-synuclein,
 
including
aggregated fibrils, oligomers
 
and ribbons, while
 
demonstrating low affinity
 
for the monomer.
 
This species selectivity
 
contrasted with
Syn-1, a commercial research mAb used as a control, which failed to differentiate the toxic variants.
In an in vivo study of UB-312 using a transgenic mouse model of PD, we demonstrated prevention
 
of motor deficits in treated animals,
which was associated with significant
 
reduction of brain oligomeric forms
 
of α- synuclein. We
 
believe this data supports the
 
potential
of UB-312 to prevent behavioral motor deficits and reduce toxic forms of α-synuclein.
UB-312 Demonstrates Improvement in Motor Symptoms in Pre-Clinical Study
UB-312
 
immunization
 
in a
 
transgenic mouse
 
model
 
(α-synuclein
 
overexpression)
 
demonstrates
 
improvement
 
in
 
beam
 
test
 
and
 
wire
hanging test, and reductions in α-synuclein oligomers in various brain regions (Nimmo et al., Acta Neuropathol. 2022;143:55-73).
We
 
have also observed
 
by immunohistochemistry that
 
serum antibodies from
 
guinea pigs dosed
 
with UB-312 can
 
bind to aberrant
 
α-
synuclein in PD, LBD and MSA brain sections.
Finally,
 
antibodies
 
derived
 
from
 
UB-312
 
showed
 
no
 
off-target
 
binding
 
on
 
human
 
tissue
 
sections.
 
UB-312-treated
 
transgenic
 
mice
showed no signs of neuroinflammation,
 
and GLP toxicity studies
 
in rats indicated a
 
good non-clinical safety and
 
tolerability profile. We
believe
 
our
 
preclinical
 
data
 
suggest
 
that
 
UB-312
 
may
 
potentially
 
induce
 
a
 
well-tolerated,
 
strong
 
and
 
specific
 
IgG
 
response
 
against
pathological forms of
a-synuclein
in PD subjects.
Development Strategy
An investigator-initiated
 
Phase 1 trial
 
of UB-312 in
 
PD and
 
MSA patients
 
is ongoing at
 
New York University.
 
Based on
 
the encouraging
results from the 20-patient Phase 1 Part B completed in 2023, we plan to take UB-312 into a Phase 2 trial.
Other Neurodegeneration Programs
We are
 
actively engaged in additional initiatives related to neurodegenerative disorders. One of these programs focuses specifically on
tau-protein pathology
 
and its
 
involvement in
 
diseases such
 
as AD
 
and related
 
tauopathies. We believe
 
that targeting
 
different pathological
tau variants simultaneously may enhance treatment efficacy,
 
which will most likely require targeting
 
multiple epitopes concomitantly.
Using our AIM
 
Platform, we have
 
constructed multi-epitope product candidates
 
that have successfully
 
demonstrated immunogenicity
and in vitro activity in various models.
We
 
are also investigating the use of
 
a multi-target of product candidates
 
targeting Aβ, α-synuclein, and tau,
 
as multiple proteins could
be implicated in neurodegenerative diseases.
Next Wave Chronic Disease Programs
Pathological
 
endogenous
 
proteins
 
(“self-proteins”)
 
drive
 
a
 
wide
 
range
 
of
 
chronic
 
diseases.
 
While
 
mAbs
 
and
 
small
 
molecules
 
have
provided therapeutic
 
benefits in
 
the treatment
 
of these
 
diseases, inherent
 
limitations of
 
these drug
 
classes have
 
restricted access
 
and
adherence to these treatment modalities globally.
26
Our next wave chronic disease programs are initially focused on hypercholesterolemia and migraine. Monoclonal antibodies
 
have been
approved in both therapeutic areas; however, their high costs have limited access and generally limited use to relatively severe disease.
We aim to develop product candidates in these therapeutic areas that could offer similar efficacy as mAbs at a meaningfully lower cost
and
 
improved
 
administrative
 
convenience
 
to
 
patients,
 
thereby
 
potentially
 
allowing
 
for
 
access
 
to
 
broader
 
patient
 
populations
 
versus
mAbs, and greater efficacy than small molecules.
VXX-401
An Overview of Hypercholesterolemia
Hypercholesterolemia is
 
the presence
 
of high
 
levels of
 
cholesterol in
 
the blood
 
and typically
 
results from
 
a combination
 
of environmental
and genetic
 
factors. Cholesterol
 
is transported
 
in the
 
blood plasma
 
within particles
 
called lipoproteins.
 
Lipoproteins are
 
classified by
their density:
 
very low-density
 
lipoprotein, intermediate
 
density lipoprotein,
 
LDL and
 
high-density lipoprotein
 
(“HDL”). All
 
lipoproteins
carry
 
cholesterol,
 
but
 
elevated
 
levels
 
of
 
lipoproteins
 
other
 
than
 
HDL,
 
particularly
 
LDL,
 
are
 
associated
 
with
 
the
 
development
 
of
cardiovascular disease.
 
Approximately 2 billion
 
people worldwide
 
have elevated
 
levels of
 
LDL, potentially
 
putting
 
them at
 
risk for
cardiovascular disease.
Although hypercholesterolemia itself is asymptomatic, elevation of serum cholesterol can over time
 
lead to atherosclerosis. Over many
years, elevated
 
serum cholesterol
 
contributes to
 
formation of
 
atheromatous plaques
 
in the
 
arteries. These
 
plaque deposits
 
can in
 
turn
lead to progressive narrowing of the
 
involved arteries. Smaller plaques may rupture
 
and cause a clot to form and
 
obstruct blood flow. A
sudden blockage of a coronary artery may result in a heart attack. A blockage of an artery supplying the brain can cause a stroke. If the
development
 
of
 
the
 
stenosis
 
or
 
occlusion
 
is
 
gradual,
 
blood
 
supply
 
to
 
the
 
tissues
 
and
 
organs
 
slowly
 
diminishes until
 
organ
 
function
becomes impaired.
PCSK9 is mainly expressed in the liver and, to a lesser extent, in the small
 
intestine, kidney, pancreas and the CNS. The LDL receptors
(“LDLR”) at
 
the cell
 
surface bind
 
and initiate
 
ingestion of
 
LDL particles
 
from extracellular
 
fluid into
 
cells, leading
 
to a
 
reduction in
serum LDL
 
levels. PCSK9
 
protein plays
 
a major
 
regulatory role
 
in cholesterol
 
homeostasis, mainly
 
by reducing
 
LDLR levels
 
on the
plasma membrane,
 
which leads
 
to decreased
 
metabolism of
 
LDL by
 
the cells.
 
Inhibition of
 
PCSK9 prevents
 
this reduction
 
in LDLR
levels on the plasma membrane,
 
and in consequence the
 
cellular process of internalizing
 
LDL particles, resulting in a
 
reduction of LDL.
Limitations of Current Therapies
Statins are the
 
most commonly used
 
drugs to treat
 
hypercholesterolemia and result
 
in a pronounced
 
reduction in LDL.
 
The unambiguous
benefits of
 
statins, together with
 
the prevalence of
 
coronary heart disease,
 
have made statins
 
the most highly
 
prescribed drug
 
class in
developed countries.
 
However,
 
many patients
 
are unable
 
to achieve
 
targeted lipid
 
levels despite
 
intensive statin
 
therapy.
 
In addition,
continued patient adherence to statin therapy,
 
which is necessary to maintain a lower risk for cardiac events, is variable
 
but considered
to be low – as low as 30% to
 
40% after two years in persons following a
 
myocardial infarction. Importantly, at the transcriptional level,
statins
 
up-regulate
 
not
 
only
 
LDLR,
 
but
 
also
 
PCSK9,
 
causing
 
the
 
so-called
 
paradox
 
of
 
statin
 
treatment.
 
Although
 
statins
 
induce
 
a
beneficial increase in LDLR, they also increase
 
PCSK9, thus leading to LDLR degradation, which
 
indirectly increases LDL, mitigating
the overall LDL
 
reduction that statins
 
otherwise cause. Given
 
the limitations in
 
efficacy and adherence,
 
targeting PCSK9 in
 
combination
with statins treatment is an emerging treatment paradigm for hypercholesterolemia.
Two
 
mAbs
 
that
 
inhibit
 
activity
 
have
 
received
 
FDA
 
approval,
 
alirocumab
 
(Praluent)
 
and
 
evolocumab
 
(Repatha).
 
These
 
drugs
 
were
initially approved
 
to treat
 
the genetic
 
condition heterozygous
 
familial hypercholesterolemia,
 
although the
 
approved indications
 
were
expanded after
 
the publication
 
of studies
 
demonstrating that
 
the use
 
of a
 
PCSK9 inhibitor
 
in conjunction
 
with a
 
statin significantly
reduced the risk for major cardiovascular events, including heart attack, stroke, unstable angina requiring hospitalization or death from
coronary heart disease. In addition,
 
inclisiran (Leqvio), an siRNA
 
inhibitor of PCSK9 synthesis,
 
was approved by the EMA
 
in late 2020
for the treatment of heterozygous familial hypercholesterolemia in addition to other dyslipidemia.
While alirocumab
 
and evolucumab
 
have demonstrated clinical
 
benefit, their commercial
 
potential has been
 
limited by their
 
pricing. Both
launched
 
with
 
a
 
wholesale
 
acquisition
 
price
 
exceeding
 
$14,000
 
annually,
 
but
 
prices
 
for
 
both
 
were
 
subsequently
 
reduced
 
in
 
2018.
Nevertheless, this drug
 
class generated sales
 
of approximately $1.5 billion
 
in 2021 and
 
is expected to
 
grow to approximately
 
$2.1 billion
by 2030, including
 
the addition of inclisiran
 
to the market. In
 
addition, both are administered
 
bi-weekly or monthly,
 
which represents
what
 
we
 
believe
 
to
 
be
 
a
 
frequent
 
and
 
inconvenient
 
administration
 
schedule
 
for
 
patients.
 
While
 
inclisiran
 
represents
 
an
 
improved
administration schedule
 
compared to
 
alirocumab and
 
evolucumab, as
 
it must
 
be administered
 
twice annually,
 
we believe
 
that it
 
may
encounter similar pricing challenges due to the published cost effectiveness price.
Our Product Candidate: VXX-401
We are developing VXX-401,
 
an anti-PCSK9
 
product candidate
 
to treat
 
hypercholesterolemia. We are dedicated
 
to developing
 
a product
candidate that has long-acting treatment duration,
 
which we believe will offer a more convenient treatment
 
regimen compared to the up
to
 
bi-weekly
 
dosing
 
required
 
by
 
some
 
mAbs.
 
We
 
believe
 
that
 
lower
 
manufacturing
 
costs
 
commensurate
 
with
 
the
 
requirement
 
of
27
meaningfully
 
less
 
drug
 
substance
 
relative
 
to
 
mAbs,
 
coupled
 
with
 
our
 
ability
 
to
 
achieve
 
commercial
 
scale
 
production
 
rapidly,
 
may
promote expanded use of this drug class as a first-line therapy,
 
allowing for treating a greater number of hypercholesterolemia patients
than currently treated with mAbs.
Pre-Clinical Data
In August 2022 we announced the selection of VXX-401 as our lead anti-PCSK9 vaccine candidate.
 
In pre-clinical studies, VXX-401
generated therapeutic
 
titer levels
 
of anti-PCSK9
 
antibodies, a
 
high response
 
rate among
 
dosed animals,
 
and robust
 
reduction in
 
LDL
across multiple species.
Results from
 
three separate
 
pre-clinical studies
 
of VXX-401
 
in non-human
 
primates, including
 
a GLP
 
toxicity study, have
 
been published
in the
 
Journal of
 
Lipid Research
 
(Vroom
 
et al.
 
2024).
 
This paper
 
reported that
 
VXX-401 triggers
 
a safe
 
humoral immune
 
response
against PCSK9,
 
consistently "resulting
 
in the
 
production of
 
antibodies and
 
a subsequent
 
30-40% reduction
 
in blood
 
LDL-C.”
 
These
effects are sustained over time.
 
Anti-PCSK9 antibodies generated by VXX-401 bind human
 
PCSK9 “with high affinity and block
 
the
inhibitory effects of PCSK9 on LDL-C uptake in a hepatic cell model.”
The GLP toxicology study demonstrated that 5 doses of VXX-401 were safe and well tolerated, with no clinical observations and no
pathological findings.
 
Development Strategy
We
 
have
 
initiated
 
a
 
first-in-human Phase
 
1
 
clinical
 
trial
 
of
 
VXX-401 in
 
Australia
 
in
 
the
 
first quarter
 
of
 
2023.
 
In
 
October 2023
 
we
expanded
 
this
 
trial
 
from
 
48
 
subjects
 
with
 
elevated
 
cholesterol
 
to
 
64
 
subjects,
 
monitoring
 
for
 
safety,
 
immunogenicity,
 
and
 
relevant
biomarkers.
 
We
 
expect a
 
topline readout
 
by mid-2024.
 
In a
 
potential subsequent
 
Phase 2
 
trial we
 
may test
 
VXX-401 alone
 
and in
combination with statins.
UB-313
An Overview of Migraine
Migraine
 
is
 
a
 
chronic
 
and
 
debilitating disorder
 
characterized by
 
recurrent attacks
 
lasting four
 
to
 
72
 
hours
 
with
 
multiple symptoms,
including typically
 
one-sided, pulsating
 
headaches of
 
moderate to
 
severe pain
 
intensity that
 
are associated
 
with nausea
 
or vomiting,
sensitivity to sound
 
and sensitivity to
 
light. Over 90%
 
of the patients
 
are unable to
 
function normally during
 
a migraine attack.
 
Many
experience comorbid conditions such as depression, anxiety and insomnia.
The Migraine Research
 
Foundation ranks migraine
 
as the world’s third
 
most prevalent illness.
 
The disease affects
 
39 million individuals
in the
 
United States and
 
approximately one billion individuals
 
globally.
 
Patients generally suffer
 
from chronic or
 
episodic migraines.
Chronic migraine is defined
 
as 15 headache days or
 
more per month, while
 
episodic migraine is defined
 
as fewer than 15
 
headache days
per month. Both acute and prophylactic treatments are used to address chronic and episodic migraines.
CGRP’s
 
Role in Migraine
CGRP
 
is
 
a
 
neuropeptide
 
found
 
throughout
 
the
 
body,
 
including
 
in
 
the
 
spinal
 
cord.
 
CGRP
 
activates
 
CGRP
 
receptor
 
in
 
the
trigeminovascular system, which is
 
located within pain-signaling pathways,
 
intracranial arteries and mast
 
cells. Activation of the
 
CGRP
receptor has been demonstrated to induce migraine in migraineurs. Multiple anti-CGRP therapies
 
have been approved for the treatment
of migraine.
Limitations of Current Therapies
Since the early 1990s,
 
there has been minimal
 
improvement in the standard
 
treatment for migraine. Treatments are
 
characterized as elite
acute or prophylactic.
 
Triptans are
 
the current first-line
 
prescription therapy for
 
the acute treatment
 
of migraine, with
 
over 15 million
annual prescriptions written in the United States.
Prophylactic medications
 
approved for migraine
 
include beta
 
blockers, such
 
as propranolol, topiramate,
 
sodium valproate
 
and botulinum
toxin,
 
branded
 
as
 
Botox.
 
However,
 
many
 
of
 
these
 
medications
 
provide
 
limited
 
clinical
 
benefit.
 
In
 
addition,
 
they
 
are
 
often
 
not
 
well
tolerated, with AEs such as cognitive impairment, nausea, fatigue and sleep disturbance.
Therapeutics targeting
 
the CGRP pathway
 
represent an emerging
 
treatment paradigm. Three
 
anti-CGRP mAbs were
 
approved by the
FDA in
 
2018 for
 
the prophylactic
 
treatment of
 
migraine in
 
adults. These
 
mAbs, erenumab-aooe
 
(Aimovig), fremanezumab-vfrm
 
(Ajovy)
and
 
galcanezumab-gnlm
 
(Emgality),
 
are
 
all
 
administered
 
subcutaneously.
 
Their
 
side
 
effects
 
are
 
generally
 
mild,
 
including
 
pain
 
and
redness at the
 
site of injection,
 
nasal congestion and
 
constipation. Studies show that
 
these mAbs reduce
 
the number of
 
headache days
by 50%
 
or more
 
in approximately
 
50% of
 
patients. In
 
2020, the
 
FDA approved
 
eptinezumab-jjmr (Vyepti),
 
an intravenously
 
infused
vaxxq410kp30i0
28
anti-CGRP mAb
 
for the
 
preventive treatment
 
of migraine.
 
The FDA
 
has also
 
approved small
 
molecule anti-CGRP
 
drugs, including
atogepant (Qulipta)
 
for the
 
preventive treatment
 
of episodic
 
migraine, ubrogepant
 
(Ubrelvy) for
 
the acute
 
treatment of
 
migraine, and
rimegepant (Nurtec) for both acute
 
and preventive treatment of migraine.
 
Sales for marketed and clinical-stage
 
anti-CGRP therapeutics
are projected
 
to reach
 
approximately $10.1 billion
 
by 2033.
 
Despite the
 
commercial success
 
that this
 
class represents,
 
many of
 
these
treatments require frequent administration, creating inconvenience for patients.
Our Product Candidate: UB-313
We
 
are developing UB-313 as
 
a preventive treatment for
 
migraine. We
 
believe UB-313 has
 
the potential to improve
 
upon the current
preventive treatments for migraine in multiple aspects: we expect UB-313 will require administration quarterly to annually,
 
in contrast
to monthly
 
to quarterly
 
for currently
 
marketed mAbs
 
and frequent
 
administration for
 
small molecules.
 
Furthermore, a
 
potential long
durability of
 
response may
 
offer physicians
 
and patients
 
the option
 
to administer
 
UB-313 in
 
an office
 
setting, which
 
can potentially
improve adherence. We expect the cost of UB-313 treatment, if approved, to be lower than that of mAbs for migraine.
Clinical Development
In 2023, we completed
 
a first-in-human Phase 1
 
clinical trial in 40
 
healthy volunteers in which
 
UB-313 was generally well
 
tolerated and
immunogenic:
 
all
 
subjects
 
who
 
received
 
three
 
doses
 
of
 
UB-313
 
(31
 
out
 
of
 
31)
 
developed
 
anti-CGRP
 
antibodies;
 
however,
 
serum
antibody titers were lower than expected,
 
and due to this lower immunogenicity, UB-313 did not meet
 
the trial’s secondary objective of
capsaicin-induced dermal blood flow
 
inhibition.
 
We
 
believe this was the
 
result of a suboptimal
 
drug product made by
 
a new contract
manufacturer, and we have identified the
 
necessary steps to manufacture
 
a more immunogenic product
 
consistent with prior lots
 
and the
known immunogenic potential of our platform candidates.
Pre-Clinical Data
We
 
have completed both
 
in vitro
 
and in vivo
 
pre-clinical studies of
 
UB-313. We
 
used an
 
in vivo proof-of-concept
 
capsaicin-induced
dermal blood flow model in
 
mice to demonstrate target engagement
 
of the marketed CGRP-targeting mAbs.
 
In this model, we observed
similar rates in reduction of dermal blood flow as fremanezumab in a head-to-head comparison against fremanezumab.
UB-313 Reduces Capsaicin-Induced Dermal Blood Flow in Mice
**Dunnett’s:
 
Ctl vs Vac
 
1p < 0.05; Ctl vs Vac
 
2 p < 0.05
In this preliminary study, dermal blood flow measurements were
 
taken 17 weeks following the first dose of UB-313. There were 3 to 11
animals per treatment group. Reduced dermal blood flow indicates target engagement with CGRP.
 
UB-313 reduced dermal blood flow
versus the control with an approximately similar magnitude to fremanezumab, which was administered 24 hours prior to the capsaicin
test.
We observed similar results in a capsaicin / dermal blood flow model in rats, comparing a rat version of UB-313 head-to-head against
galcanezumab.
Our in
 
vivo studies
 
of UB-313
 
have involved
 
multiple animal
 
species. High
 
immunogenicity was observed
 
in all
 
pre-clinical species
tested. Characterization of the antibodies produced after
 
immunization with UB-313 indicated that they have
 
limited, if any,
 
off-target
potential, are primarily IgG1
 
and IgG2, potently bind
 
to CGRP and potently
 
block CGRP activity
in vitro
. We
 
refer to potency
 
as the
amount
 
of
 
drug
 
required
 
to
 
produce
 
a
 
pharmacological
 
effect
 
of
 
given
 
intensity
 
and
 
is
 
not
 
a
 
measure
 
of
 
therapeutic
 
efficacy.
 
In
 
a
vaxxq410kp31i1 vaxxq410kp31i0
29
comparison
 
of
 
binding
 
affinities
 
with
 
fremanezumab
 
and galcanezumab,
 
UB-313-induced
 
IgG
 
antibodies
 
demonstrated
 
comparable
binding affinities.
UB-313 Demonstrated Induced Antibodies Comparable to Approved CGRP mAbs
We evaluated UB-313 formulations with two different
 
adjuvants in comparison to
 
fremanezumab and galcanezumab; both
 
formulations
demonstrated comparable IgG to these two approved CGRP mAbs.
Additional
in vitro
 
studies using human
 
SK-N-MC cells demonstrated
 
that UB-313-induced IgG
 
antibodies also had
 
comparable
in vitro
activity to CGRP-targeted mAbs.
UB-313 Induced IgGs Have Comparable In Vitro Activities to Marketed CGRP mAbs
In a cyclic AMP
 
(“cAMP”) production assay
 
conducted in human SK-N-MC
 
cells, antibodies taken from
 
the serum of guinea
 
pigs 15
weeks following the first injection of UB-313 demonstrated similar properties to two approved CGRP mAbs.
Moreover, the binding potency of UB-313 was determined to be comparable to these mAbs.
vaxxq410kp32i0
30
UB-313 Induced IgGs Demonstrate Comparable Binding Potencies to Marketed CGRP mAbs
Antibodies taken from the serum
 
of guinea pigs 15
 
weeks following the first
 
injection of UB-313 demonstrated
 
similar binding potencies
to two approved CGRP mAbs as measured by ELISA.
Next Stage Development Candidates
In addition to our
 
initial focus on migraines
 
and hypercholesterolemia, we believe
 
our AIM Platform can
 
generate product candidates
for a range of chronic diseases. We are evaluating opportunities across multiple disease areas, including allergy (e.g., atopic dermatitis,
chronic
 
rhinosinusitis,
 
food
 
allergy),
 
autoimmune
 
(e.g.,
 
psoriasis,
 
psoriatic
 
arthritis),
 
pain
 
(e.g.,
 
peripheral
 
neuropathy,
 
diabetic
neuropathy) and bone and
 
muscle deterioration (e.g., sarcopenia,
 
osteoporosis, osteopenia) indications as
 
they may apply
 
to geriatrics
and space travel health.
COVID-19 Program
An Overview of COVID-19
COVID-19, caused
 
by SARS-CoV-2,
 
has rapidly
 
swept throughout
 
the world.
 
As of
 
February 2024,
 
there have
 
been more
 
than 700
million confirmed COVID-19 cases and more than 6.9 million
 
deaths worldwide. Common symptoms of COVID-19 are fever,
 
cough,
lymphocytopenia and chest radiographic abnormality. A proportion of patients recovering
 
from COVID-19 continue shedding virus for
days, and asymptomatic carriers may also transmit SARS-CoV-2, indicating a risk of a continuous and long-term pandemic.
SARS-CoV-2
 
is an
 
enveloped, single-stranded,
 
positive-sense RNA
 
virus belonging
 
to the
 
family
Coronavidae
 
within the
 
genus β-
coronavirus. The genome of SARS-CoV-2 encodes one large Spike (“S”) protein that plays a pivotal role during
 
viral attachment to the
host receptor, angiotensin converting enzyme 2 (“ACE2”), and
 
entry into host cells. The S protein is the major principal
 
antigen target
for
 
vaccines
 
against
 
human
 
coronavirus,
 
including
 
SARS-Co-V-2.
 
Neutralizing
 
antibodies
 
targeting
 
the
 
receptor
 
binding
 
domain
(“RBD”) subunit
 
of the S
 
protein block the
 
virus from
 
binding to
 
host cells.
 
Over 90% of
 
all neutralizing
 
antibodies produced in
 
response
to infection are directed to the RBD subunit, and mAbs that have shown therapeutic activity target epitopes on the RBD.
Fifty vaccines are authorized for
 
use in one or more
 
countries around the world.
 
Most of these vaccines are
 
based on the S protein
 
of the
SARS-CoV-2,
 
but
 
rely
 
on
 
different
 
mechanisms
 
for
 
presentation or
 
expression of
 
the
 
S
 
antigen,
 
including whole
 
inactivated
 
virus,
defective adenovirus vectors,
 
or mRNA.
 
All have
 
been shown
 
to be
 
safe and
 
effective in
 
placebo- controlled
 
clinical trials. Antiviral
drugs and mAbs have limited availability and effectiveness.
COVID-19 Vaccine Market
As of February 2024, over 5.1
 
billion people have been fully
 
vaccinated against COVID-19.
 
Nearly all of these people received
 
at least
one of three types of
 
vaccine technologies: mRNA, adenovirus vector,
 
or inactivated virus.
 
As SARS-CoV-2
 
continues to evolve and
spread, the market for booster vaccinations has also grown, with over 2.8 billion doses sold to date.
We expect demand for booster vaccinations that are safe and well tolerated, offer long lasting immunity against emerging variants, and
allow
 
for
 
manageable
 
storage
 
and
 
shipping
 
conditions
 
may
 
last
 
for
 
the
 
foreseeable
 
future,
 
particularly
 
in
 
low-
 
and
 
middle-income
countries
 
(“LMICs”), similar
 
to
 
the
 
influenza
 
vaccine
 
market.
 
We
 
also
 
anticipate
 
demand
 
for
 
more
 
types
 
of
 
vaccine
 
technologies,
beyond the readily available mRNA, adenovirus vector, and inactivated virus vaccine options.
31
UB-612: Our COVID-19 Vaccine Initiative
We are developing UB-612 as a product candidate for boosting immunity to COVID-19 in vaccinated individuals. UB-612 is designed
to activate both antibody and cellular immunity against multiple
 
viral targets. The vaccine is composed of
 
a recombinant S1-RBD-sFc
fusion protein
 
combined with
 
rationally designed
 
synthetic Th
 
and CTL
 
epitope peptides
 
selected from
 
the S2
 
domain of
 
the spike,
membrane (“M”),
 
and nucleocapsid
 
(“N”) proteins.
 
These peptides
 
bind to
 
MHC class
 
I and
 
II receptors
 
without significant
 
genetic
restriction, so that they
 
may be recognized broadly by
 
the vast majority of
 
the human population. Our
 
mixture of peptides is
 
designed
to elicit
 
T-cell
 
activation, memory
 
recall and
 
effector functions
 
similar to
 
those of
 
natural SARS-CoV-2
 
infection. The
 
S1-RBD-sFc
fusion protein incorporates essential B-cell epitopes that promote
 
the generation of neutralizing antibodies to the RBD of
 
SARS-CoV-
2. UB-612
 
is formulated
 
with Adju-Phos,
 
an adjuvant
 
widely used
 
in many
 
approved vaccines
 
globally.
 
For added
 
safety,
 
synthetic
peptides in UB-612 are adsorbed by our propriety
 
CpG1 excipient, a Toll
 
-like receptor 9 agonist molecule, known to help
 
to stimulate
balanced T-cell immunity in
 
humans. UB-612
 
can be
 
stored and
 
shipped at
 
2° to
 
8°C (conventional
 
cold chain
 
refrigerated temperatures).
An EUA application
 
for UB-612 was denied
 
by the TFDA in
 
August 2021 because
 
the neutralizing antibody
 
response generated by
 
UB-
612
 
delivered in
 
an accelerated
 
two-dose primary
 
immunization schedule,
 
as
 
compared to
 
that of
 
a designated
 
adenovirus vectored
vaccine, did not meet the TFDA’s specified evaluation criteria. We are now pursuing a path to conditional/provisional authorization for
UB-612 as
 
a heterologous boost
 
with the Medicines
 
and Healthcare products
 
Regulatory Agency (“MHRA”)
 
and Therapeutic Goods
Administration (“TGA”), the regulatory authorities of the United Kingdom and Australia, respectively.
Clinical Development
In March 2022, Vaxxinity
 
initiated a Phase 3 pivotal
 
trial to compare the immune responses
 
stimulated by homologous boosts mRNA
(BNT162b2), adenovirus (ChAdOx1-S), inactivated virus (Sinopharm BIBP) COVID-19 vaccines, to a heterologous boost of UB-612.
This was an
 
active-controlled, randomized trial conducted
 
in the United
 
States, Panama, and
 
Philippines under a
 
platform protocol in
944
 
subjects
 
16
 
years
 
and
 
older
 
who
 
completed
 
a
 
two-dose
 
primary
 
immunization
 
with
 
one
 
or
 
more
 
of
 
the
 
comparator
 
vaccines
mentioned above.
 
Eligible subjects
 
were randomized
 
into one of
 
two treatment
 
arms to
 
receive a
 
single dose
 
of UB-612
 
or an
 
active
comparator. The primary
 
objective of the study was to
 
determine non-inferiority of UB-612-stimulated neutralizing antibodies against
those of the comparator vaccines.
 
CEPI co-funded this trial, which concluded in 2023.
 
Following positive topline
 
results announced in
 
December 2022, we
 
completed submissions for
 
conditional/provisional authorization
with the MHRA in the UK and the TGA
 
in Australia in March 2023.
 
We expect that, if successful, these authorizations may enable the
commercialization of UB-612 in multiple countries including select LMICs.
Heterologous Booster Data: Phase 3 Trial Topline
 
Results
In the global pivotal Phase
 
3 trial, UB-612 elicited strong
 
neutralizing antibodies against SARS-CoV-2 when compared head-to-head to
three globally
 
authorized platform
 
vaccines administered
 
as homologous
 
boosters, successfully
 
meeting primary
 
and key
 
secondary
immunogenicity endpoints.
 
The primary endpoints of the trial were
 
safety and live virus neutralizing antibody
 
titers against the Wuhan
strain of SARS-CoV-2 at day 29.
 
Secondary immunogenicity endpoints included neutralizing antibody titers against Omicron BA.5 at
day 29,
 
SCRs at
 
day 29,
 
and kinetics
 
of neutralizing
 
and RBD
 
binding IgG
 
antibody responses
 
through 12
 
months.
 
The primary
 
objective
of the
 
trial was
 
to determine
 
non-inferiority of
 
UB-612-stimulated neutralizing
 
antibodies against
 
those of
 
the comparator
 
vaccines,
where statistical non-inferiority was defined by the
 
lower bound of the 95% confidence interval
 
(“CI”) of the geometric mean titer ratio
(“GMR”) > 0.67.
 
When delivered as a heterologous booster in populations previously vaccinated with Pfizer-BioNTech’s
 
BNT162b2,
AstraZeneca’s
 
ChAdOx1-S,
 
or
 
Sinopharm’s
 
BIBP,
 
UB-612
 
was
 
shown
 
to
 
generate
 
neutralizing
 
antibody
 
titers
 
28
 
days
 
after
administration that were:
Statistically
 
non-inferior
 
to,
 
and
 
directionally
 
higher
 
than,
 
BNT162b2:
 
1.04
 
GMR
 
against
 
Wuhan
 
(95%
 
CI:
 
0.89,
 
1.21;
p=0.6147), 1.11 GMR against Omicron BA.5 (95% CI: 0.94, 1.31; p=0.2171)
Statistically superior to
 
ChAdOx1-S: 1.92-fold higher
 
geometric mean titers
 
against Wuhan
 
with UB-612 (GMR=1.92;
 
95%
CI: 1.44, 2.56; p<0.0001), 2.85-fold higher against Omicron BA.5 (GMR=2.85; 95% CI: 2.00, 4.05; p<0.0001)
Statistically superior to BIBP:
 
5.77-fold higher geometric mean titers
 
against Wuhan with UB-612 (GMR=5.77; 95%
 
CI: 4.62,
7.20; p<0.0001), 5.93-fold higher against Omicron BA.5 (GMR=5.93; 95% CI: 4.60, 7.65; p<0.0001)
SCR as measured against Wuhan and Omicron BA.5
 
were key secondary endpoints in the
 
Phase 3 trial.
 
Seroconversion was defined as
a ≥4-fold increase of neutralizing antibody titers from baseline.
 
SCR non-inferiority was defined by the lower bound of
 
the 95% CI for
the difference of the UB-612 SCR minus the comparator SCR > -10%.
 
SCR superiority was defined by the lower bound of the 95% CI
for the difference of
 
the UB-612 SCR minus
 
the comparator SCR >
 
0%.
 
UB-612 SCR at day
 
29 was statistically non-inferior to,
 
and
directionally higher than, BNT162b2 against both Wuhan and Omicron BA.5, statistically superior to ChAdOx1-S
 
with 1.9-fold higher
SCR against Wuhan (23.6% absolute
 
difference, p=0.0009) and 2.0-fold
 
higher SCR against
 
Omicron BA.5 (29.2%
 
absolute difference,
32
p<0.0001), and statistically superior to BIBP, with 8.3-fold higher SCR against Wuhan (56.8% absolute difference, p<0.0001) and 5.8-
fold higher SCR against Omicron BA.5 (58.0% absolute difference, p<0.0001).
Safety data from the Phase 3 trial suggested that UB-612 was generally well tolerated; no vaccine-related SAEs were reported.
2-Dose Clinical Data
In early 2021, we completed an open-label dose escalation Phase 1 clinical trial to evaluate the safety, tolerability and immunogenicity
of UB-612 in
 
healthy volunteers between
 
the ages of
 
20 and 55
 
in Taiwan.
 
This six-month trial
 
consisted of three 20-subject
 
cohorts,
each receiving
 
an initial
 
dose at
 
the start
 
of the
 
trial and
 
a second
 
dose on
 
day 28:
 
one cohort
 
received two
 
10µg doses,
 
the second
received two
 
30µg doses,
 
and the
 
third received
 
two 100µg
 
doses.
 
The mean
 
titer of
 
antigen-specific antibodies
 
to UB-612
 
and the
seroconversion rate
 
was evaluated
 
throughout the
 
duration of
 
the trial
 
to determine
 
the humoral
 
immune response
 
and persistence
 
of
immunogenicity. In addition, T-cell responses were evaluated by interferon-γ ELISpot assay and intracellular cytokine
 
staining by flow
cytometry.
 
The Phase 1
 
clinical trial was sponsored
 
by UBIA. UBIA conducted
 
the trial on our
 
behalf in accordance with
 
one of our
related party master services agreements.
After one
 
and two
 
doses, UB-612
 
was considered
 
to be
 
generally safe
 
and well
 
tolerated, with
 
a low
 
frequency of
 
solicited and
 
unsolicited
AEs, which
 
were all
 
Grade 1
 
(mild) in
 
severity.
 
After each
 
vaccination, the
 
most common
 
AE was
 
injection site
 
pain, with
 
no clear
difference in reactogenicity between dose levels. In all dose groups, there was a trend towards
 
increased reactogenicity with increase in
dose.
 
Three
 
cases
 
of
 
mild
 
allergic
 
reactions
 
were
 
reported
 
(e.g.,
 
itching
 
at
 
vaccine
 
site),
 
which
 
were
 
all
 
resolved
 
within
 
1-3
 
days.
Importantly, and
 
in distinction to certain
 
vaccines authorized for emergency
 
use, no other increase
 
in AEs was seen
 
at second dose as
compared to first injection. We selected the highest dose (100μg) to take into a Phase 2 trial.
In an
 
anti-S1-RBD ELISA assay,
 
we observed that
 
all three dose
 
levels of UB-612
 
induced titer levels
 
comparable to or
 
greater than
those in sera from
 
patients hospitalized with COVID-19.
 
Furthermore, in a cytopathic
 
effect viral neutralization assay
 
(CPE VNT
50
), we
observed neutralizing titers comparable to those in sera from patients hospitalized with COVID-19.
Neutralizing activities of sample
 
sera from the Phase 1
 
trial were assessed against
 
live virus variants at the
 
Viral and Rickettsial Disease
Laboratory of the
 
California State Department
 
of Public
 
Health. The
 
results indicate
 
that UB-612
 
induces viral neutralizing
 
antibody
titers against the Alpha, Gamma and Delta variants of SARS-CoV-2, close to the neutralizing titer level against the original (wild-type,
WT) Wuhan
 
strain, while
 
the titer
 
level against
 
the Beta
 
variant is
 
lower in
 
comparison. The
 
latter finding
 
is anticipated
 
by results
published for other COVID-19 vaccines, as pointed out above.
A randomized,
 
placebo-controlled, multi-center
 
Phase 2
 
trial of
 
UB-612 in
 
3,850 healthy
 
volunteers aged
 
12 to
 
85 was
 
conducted in
Taiwan.
 
Subjects in
 
this trial
 
receive two
 
doses of
 
100μg UB-612,
 
or placebo,
 
28 days
 
apart. The
 
objectives of
 
this trial
 
include the
analysis of safety and immunogenicity of
 
UB-612, in particular, antigen-specific antibodies to UB-612, the
 
seroconversion rate and lot-
to-lot consistency
 
of antibody
 
responses. An
 
interim analysis
 
of data
 
from this
 
Phase 2
 
trial in
 
healthy volunteers
 
18 years
 
and older
based on
 
the data
 
cut-off date
 
of June 27,
 
2021 was
 
submitted to
 
the TFDA
 
as part
 
of a
 
filing for
 
an EUA
 
in Taiwan.
 
The EUA
 
was
denied in August 2021 by the TFDA.
 
In data from the Phase 2 trial, UB-612 appears well tolerated. AEs were generally mild, and no UB-612-related SAEs were
observed. Local injection site AEs occurred in half of the subjects, the most frequent being injection site pain. Systemic Aes
occurred in less than half of the subjects, and the incidence was similar in the active and placebo groups, except for muscle pain
which was more frequent in the active group. Aside from muscle pain, systemic reactions were comparable across the active and
placebo groups, with less than 10% of subjects in either group experiencing fever or chills. Systemic Aes were similar after the first
and second doses. The vast majority of AEs were mild (Grade 1), and all were self-limited. No subject had a severe (Grade 3) local
reaction. The incidence of severe (Grade 3) systemic reactions was <0.1%.
Immunization with UB-612 in both
 
Phase 2 and Phase
 
1 studies led to
 
detectable T-cell
 
responses observed in a
 
subset of subjects. In
Phase 2, a total
 
of 88 subjects receiving UB-612
 
and 12 receiving placebo were
 
tested for T cell
 
responses at baseline and on
 
Day 57.
Preliminary results of ELISpot
 
(Interferon-γ and IL-4) and
 
intracellular cytokine staining indicate
 
robust responses to UB-612,
 
with a
strong
 
Th1
 
orientation.
 
Intracellular
 
cytokine
 
staining
 
(ICS)
 
confirmed
 
the
 
Th1
 
orientation
 
of
 
T
 
cell
 
responses.
 
UB-612
 
induced
measurable CD8+ T cell responses and CD107a+/Granzyme secreting cells, which are putative cytotoxic T cells.
3-Dose Clinical Data
In a Phase 1 extension trial, 50 subjects from Phase 1 received a third booster dose of UB-612 approximately 7-9 months after their
second dose (100µg).
 
In this
extension trial, UB-612 was generally well tolerated after a third dose, with no vaccine-related SAEs
reported.
Immunogenicity and safety data from the Phase 1 extension suggests that UB-612 elicits a multi-fold increase in neutralizing
antibody titers upon third dose, significantly exceeding those observed in human convalescent sera, and that the third dose is well
33
tolerated with no vaccine-related SAEs reported.
 
Published studies have shown a correlation between efficacy in randomized
controlled trials and the ratio of neutralizing titers in sera from vaccinated subjects to titers in human
convalescent sera.
In collaboration with University College London and VisMederi, we analyzed sera from subjects immunized with three doses of UB-
612. Data demonstrated that UB-612 elicited a broad IgG antibody response against multiple SARS-CoV-2 variants of concern,
including, Alpha, Beta, Delta, and Gamma, and Omicron, and higher levels of neutralizing antibodies against Omicron than three
doses of an approved mRNA vaccine.
An extension of the Phase 2, observer-blind, multicenter, randomized, placebo-controlled trial was sponsored by UBIA to evaluate the
immunogenicity, safety,
 
tolerability, and lot consistency of a homologous booster dose of UB-612 in adolescents, younger adults, and
elderly adults.
 
Adult subjects who completed the primary 2-dose UB-612 series in the main Phase 2 trial were unblinded and offered
a third dose of UB-612.
 
The third dose of UB-612 stimulated both arms of adaptive immunity in subjects.
 
The frequency of solicited
and unsolicited adverse events following the third dose was consistent with the safety profile observed after the first and
 
second doses.
 
Development Strategy
Based on our
 
belief in UB-612’s
 
potential utility as
 
a heterologous booster
 
dose (boosting the
 
immunity of a
 
subject who has
 
already
received
 
a
 
different
 
vaccine),
 
we
 
have
 
completed
 
rolling
 
submissions
 
for
 
conditional/provisional
 
authorization
 
with
 
regulatory
authorities in the United Kingdom and Australia, who are reviewing under their established work share agreement.
 
Competition
The
 
pharmaceutical
 
industry
 
is
 
characterized
 
by
 
rapidly
 
advancing
 
technologies,
 
intense
 
competition
 
and
 
a
 
strong
 
emphasis
 
on
proprietary
 
products.
 
While
 
we
 
believe
 
that
 
our
 
technology,
 
the
 
expertise
 
of
 
our
 
executive
 
and
 
scientific
 
teams,
 
research,
 
clinical
capabilities, development experience and scientific knowledge
 
provide us with competitive advantages, we face
 
increasing competition
from multiple
 
sources, including
 
pharmaceutical and
 
biotechnology companies,
 
academic institutions,
 
governmental agencies
 
and public
and private research institutions both in the United States and abroad.
Many of our competitors may have significantly greater financial resources and expertise in research and development, manufacturing,
preclinical
 
testing,
 
conducting
 
clinical
 
trials,
 
obtaining
 
regulatory
 
approvals
 
and
 
marketing
 
approved
 
products
 
than
 
we
 
do.
 
These
competitors also
 
compete with
 
us in
 
recruiting and
 
retaining qualified
 
scientific and
 
management personnel
 
and establishing
 
clinical
trial sites
 
and patient
 
enrollment for
 
clinical trials,
 
as well
 
as in acquiring
 
technologies complementary
 
to, or
 
necessary for, our
 
programs.
Smaller or
 
early stage
 
companies may
 
also prove
 
to be
 
significant competitors,
 
particularly through
 
collaborative arrangements
 
with
larger or more established companies.
Vaccines
The global
 
vaccine market
 
is highly
 
concentrated among
 
a small
 
number of
 
multinational pharmaceutical
 
companies: Pfizer,
 
Merck,
GlaxoSmithKline and Sanofi together control most
 
of the global vaccine market.
 
Other pharmaceutical and biotechnology companies,
academic institutions, governmental agencies and public and private research institutions are also working toward new solutions
 
given
the continuing global unmet need.
Neurodegenerative Disorders
We
 
expect
 
that,
 
if
 
approved,
 
our
 
product
 
candidates
 
will
 
compete
 
with
 
currently
 
approved
 
therapies
 
for
 
management
 
of
neurodegenerative diseases, such as AD and PD.
 
In AD, four drugs are currently approved by the FDA for the treatment of symptoms
of AD, based
 
on acetylcholinesterase (“AchE”) inhibition
 
and NMDA receptor
 
antagonism. In addition to
 
the marketed therapies, we
are aware of
 
several companies currently developing
 
therapies for AD,
 
including Eisai, Lilly,
 
Hoffman-LaRoche, Abbvie, Johnson
 
&
Johnson, and Novartis. Biogen’s
 
aducanumab was approved by the
 
FDA in June 2021 under
 
the accelerated approval pathway,
 
which
allows for
 
earlier approval
 
of drugs
 
that treat
 
serious conditions,
 
and that
 
fill an
 
unmet medical
 
need based
 
on a
 
surrogate endpoint.
Aducanumab
 
failed
 
to
 
achieve
 
approval
 
in
 
Europe
 
and
 
Japan.
 
In
 
January
 
2024,
 
Biogen
 
announced
 
its
 
intention
 
to
 
discontinue
aducanumab.
 
Eisai and Biogen’s lecanemab was approved by the FDA in January 2023 under an accelerated approval pathway.
Pharmaceutical treatments for PD address its symptoms
 
only and do not treat the underlying causes
 
of PD. The majority of prescription
drugs
 
are
 
dopaminergic
 
medications
 
and
 
act
 
by
 
increasing
 
dopamine,
 
a
 
neurotransmitter.
 
We
 
are
 
aware
 
of
 
several
 
companies
 
with
product
 
candidates
 
at
 
various
 
stages
 
of
 
clinical
 
development,
 
including
 
Sanofi,
 
Kyowa
 
Kirin,
 
Cerevel
 
Therapeutics
 
and
 
Hoffman-
LaRoche. Hoffman-LaRoche is developing prasinezumab, a mAb, as a potential treatment for PD.
 
 
34
PCSK-9 Inhibitors
Three companies
 
currently have
 
PCSK-9 inhibitors
 
approved by
 
the FDA
 
to treat
 
hypercholesterolemia: Regeneron
 
Pharmaceuticals
developed alirocumab (Praluent),
 
a mAb, in
 
collaboration with Sanofi,
 
and Amgen developed
 
evolocumab (Repatha), another
 
mAb, and
 
Novartis is commercializing inclisiran, an RNAi construct, to down-regulate synthesis of PCSK-9.
CGRP-Directed Migraine Treatments
Seven migraine treatments have been approved by the FDA that target CGRP.
 
Four of these therapeutics are mAbs and were approved
to prevent or reduce the number of
 
migraine episodes. These medications are galcanezumab
 
(Emgality), which was developed by Lilly;
erenumab (Aimovig), which
 
was developed by
 
Amgen in collaboration
 
with Novartis; fremanezumab
 
(Ajovy), which was
 
developed
by
 
Teva;
 
and
 
eptinezumab
 
(Vyepti),
 
which
 
was
 
developed
 
by
 
Alder,
 
acquired
 
by
 
Lundbeck.
 
Ubrogepant
 
(Ubrelvy),
 
developed
 
by
Allergan,
 
was
 
approved
 
for
 
the
 
treatment
 
of
 
acute
 
migraine
 
episodes;
 
rimegepant
 
(Nurtec),
 
approved
 
for
 
both
 
the
 
acute
 
treatment
migraine and the
 
preventive treatment of
 
episodic migraine, is
 
sold by Pfizer
 
following its acquisition
 
of Biohaven. Atogepant
 
(Qulipta),
developed by AbbVie, was approved for the preventive treatment of episodic migraine.
Collaborations
From time to time, we enter into licensing and commercialization agreements when they
 
align with our mission, including the Platform
License Agreement described under
 
“—Intellectual Property—Platform License Agreement.”
 
Current collaboration partners include,
the
 
University of
 
Central Florida,
 
the University
 
of
 
Florida, and
 
the University
 
of
 
Southampton.
 
For more
 
information see
 
Recent
Developments section.
Manufacturing
The manufacture of
 
our product candidates
 
encompasses both
 
the manufacture
 
of custom components
 
and the formulation,
 
fill and finish
of the final product.
 
We
 
do not currently own
 
or operate manufacturing facilities
 
for these processes. We
 
currently rely upon contract
manufacturing organizations, including those mentioned below, to produce our product candidates for both pre-clinical and clinical use
and will
 
continue to
 
rely upon
 
these relationships
 
for commercial
 
manufacturing if
 
any of
 
our product
 
candidates obtain
 
regulatory
approval. Although
 
we rely
 
upon contract
 
manufacturers, we
 
also have
 
personnel with
 
extensive manufacturing
 
experience that
 
can
oversee the relationships with our manufacturing partners.
Historically,
 
we
 
have
 
depended
 
heavily
 
on
 
UBI
 
and
 
its
 
affiliates
 
for
 
our
 
business
 
operations,
 
including
 
the
 
provision
 
of
 
research,
development
 
and
 
manufacturing
 
services.
 
Currently,
 
UBIA
 
provides
 
testing
 
services
 
for
 
UB-312
 
and
 
UB-612,
 
UBI
 
Pharma
 
Inc.
(“UBIP”)
 
provides
 
testing
 
relating
 
to
 
formulation-fill-finish
 
services
 
for
 
UB-312,
 
and
 
United
 
BioPharma,
 
Inc.
 
(“UBP”)
 
is
 
the
 
sole
manufacturer of protein for UB-612. Our commercial arrangements with UBI and its affiliates are described in more detail below.
Formulation-fill-finish services for UB-612 are provided by multiple contract manufacturers to ensure adequate capacity and minimize
supply
 
chain
 
risks.
 
For
 
supply
 
of
 
our
 
other
 
custom
 
components,
 
in
 
addition
 
to
 
protein
 
manufacturing
 
conducted
 
by
 
UBP,
 
we
 
have
engaged third party CMOs,
 
including C S Bio
 
Co. (“CSBio”) as our
 
primary peptide supplier for
 
UB-612 peptides, CPC Scientific
 
as
our primary peptide
 
supplier for VXX-401,
 
Wuxi STA
 
for process development
 
and manufacturing services
 
of oligonucleotides, and
Pharmaceuticals International, Inc (“Pii”) for additional fill-finish services.
 
UBI Group Manufacturing Partnership
We
 
primarily rely
 
on our
 
relationships with
 
third-party contract
 
manufacturing organizations
 
to produce
 
product candidates
 
for our
clinical trials. Historically, we have heavily depended on UBI as a
 
manufacturing partner for these efforts. In support
 
of our COVID-19
program (UB-612), we have entered into a
 
master services agreement with UBP and
 
an additional master services agreement with
 
UBI,
UBIA and UBP.
 
Pursuant to these agreements, UBI
 
and its affiliates have
 
provided research, development, testing
 
and manufacturing
services to us
 
and continue to
 
provide manufacturing services
 
for our protein.
 
Payment terms are
 
mutually agreed in
 
connection with
each work order relating
 
to services rendered. Our
 
agreement with UBP will
 
expire on the later
 
of March 2024 and
 
the completion of
all services
 
under the
 
last work
 
order executed
 
prior to
 
such scheduled
 
expiration and our
 
agreement with UBI,
 
UBIA and
 
UBP will
expire on
 
the later
 
of September
 
2023 and
 
the completion
 
of all
 
services under
 
the last
 
work order
 
executed prior
 
to such
 
scheduled
expiration. We also have
 
a management services
 
agreement with
 
UBI pursuant to
 
which UBI has
 
provided research and
 
prior back office
administrative services to us and acts as our agent with respect
 
to certain matters relating our COVID-19 program. UBI is compensated
for its services on a cost-plus basis. The agreement terminates upon mutual agreement between the parties.
In support of our
 
chronic disease pipeline,
 
we have entered into
 
master service agreements with
 
each of UBI, UBIA
 
and UBIP. Pursuant
to these agreements, UBI currently provides limited research services to us on a cost-plus basis, UBIA provides
 
testing services related
to UB-312 clinical trial material already manufactured
 
and UBIP has provided manufacturing, quality control,
 
testing, validation, GMP
warehousing and
 
supply services
 
to us
 
for UB-312
 
on payment
 
terms agreed
 
in connection
 
with work
 
orders relating
 
to the
 
services
35
rendered. UBI and its
 
affiliates no longer provide
 
clinical or manufacturing services for
 
other programs. These agreements
 
may all be
terminated for convenience upon 180 days’ notice or less.
We have
 
also entered into a research and development services agreement
 
with UBI. Pursuant to this agreement, UBI and
 
its affiliates
may
 
provide
 
research
 
and
 
development
 
services
 
to
 
us.
 
Service
 
fees
 
payable
 
by
 
us
 
to
 
UBI
 
for
 
research
 
and
 
development
 
projects
undertaken in accordance with the research and development plan would be determined by a joint steering committee and set forth in a
research and development plan. Any aggregate services fees payable by us under the research and development services agreement are
subject to a
 
quarterly cap throughout
 
the term of
 
the agreement. The
 
research and development
 
services agreement expires
 
in August
2026.
Intellectual Property
Our ability to
 
obtain and maintain
 
intellectual property protection
 
for our product
 
candidates and core
 
technologies is fundamental
 
to
the
 
long-term
 
success
 
of
 
our
 
business.
 
We
 
rely
 
on
 
a
 
combination
 
of
 
intellectual
 
property
 
protection
 
strategies,
 
including
 
patents,
trademarks, trade secrets, license agreements, confidentiality policies and procedures, nondisclosure agreements, invention assignment
agreements and technical
 
measures designed to
 
protect the intellectual
 
property and commercially
 
valuable confidential information
 
and
data used in our business.
In summary,
 
our patent
 
estate includes
 
issued patents
 
and patent
 
applications which
 
claims cover
 
our AIM
 
Platform and
 
each of
 
our
product candidates.
 
As of
 
December 31, 2023,
 
our patent
 
estate included
 
four U.S.
 
issued patents,
 
ten U.S.
 
patent applications,
 
three
U.S. provisional patent applications, seven pending Patent Cooperation Treaty (“PCT”) patent applications, 34 issued non-U.S. patents
and 153 pending non-U.S. patent applications.
For our
 
product candidates
 
targeting the
 
prevention and
 
treatment of
 
neurodegenerative disease,
 
including claims
 
covering UB-311,
UB-312, and anti-tau,
 
patent rights are
 
provided by patents
 
and patent applications,
 
the majority of
 
which are being
 
prosecuted in the
United States, Australia, Brazil, Canada,
 
China, the EPO, Hong Kong,
 
Indonesia, India, Israel, Japan, the
 
Republic of Korea, Mexico,
Russia,
 
Singapore,
 
South
 
Africa,
 
Taiwan
 
and
 
the
 
United
 
Arab
 
Emirates,
 
and
 
three
 
pending
 
PCT
 
applications
 
and
 
one
 
provisional
application in the
 
U.S., directed to
 
peptide vaccines for
 
the prevention and
 
treatment of neurodegenerative
 
diseases. These issued
 
patents
and patent applications, if issued,
 
and any U.S. or non-U.S.
 
patent issuing from the PCT
 
or provisional patent applications, are
 
expected
to expire between 2033 and 2043, excluding any patent term adjustments or patent term extensions.
For our product candidates directed to peptide immunogens targeting CGRP and formulations thereof for
 
the prevention and treatment
of migraine,
 
including UB-313,
 
patent rights
 
are provided
 
by a
 
patent and
 
patent applications
 
being prosecuted
 
in the
 
United States,
Australia, Brazil, Canada, China, the EPO, India, Indonesia, Japan, Mexico, Russia, the Republic of Korea, Singapore, Taiwan and the
United Arab Emirates. The
 
issued patent and these
 
patent applications, if issued,
 
are expected to expire
 
in 2039, excluding any
 
patent
term adjustments or patent term extensions.
For
 
our
 
product
 
candidates
 
targeting
 
cholesterol
 
and
 
cardiovascular
 
disease,
 
including
 
our
 
anti-PCSK9
 
product
 
candidate
 
targeting
PCSK9 and
 
formulations thereof for
 
prevention and treatment
 
of PCSK9-mediated disorders,
 
we have
 
pending patent applications
 
in
the United States, Australia, Brazil, Canada, the EPO, India, Indonesia, Japan, Mexico, the Philippines, the Republic of Korea, Russia,
Saudi Arabia,
 
Taiwan,
 
the United
 
Arab Emirates,
 
and Vietnam.
 
These patent
 
applications, if
 
issued, are
 
expected to
 
expire in
 
2041,
excluding any patent term adjustment or patent term extension.
For our
 
product candidates
 
targeting SARS-CoV-2,
 
including UB-612
 
for COVID-19,
 
we have
 
an issued
 
patent and
 
pending patent
applications
 
in
 
the
 
United
 
States,
 
Argentina,
 
Australia,
 
Brazil,
 
Canada,
 
the
 
EPO,
 
India,
 
Indonesia,
 
Japan,
 
Mexico,
 
Pakistan,
 
the
Philippines, the Republic of
 
Korea, Russia, Saudi Arabia,
 
Taiwan,
 
United Arab Emirates,
 
and Vietnam,
 
and four pending
 
PCT patent
applications.
 
The
 
issued
 
patent
 
and
 
these
 
patent
 
applications,
 
if
 
issued,
 
and
 
any
 
U.S.
 
or
 
non-U.S.
 
patent
 
issuing
 
from
 
the
 
PCT
applications, are expected to expire between 2041 and 2043, excluding any patent term adjustments or patent term extensions.
For each product candidate utilizing the AIM Platform, additional patent
 
rights directed to artificial T helper cell epitopes and to a CpG
delivery
 
system
 
are
 
provided
 
by
 
patents
 
and
 
patent
 
applications,
 
the
 
majority
 
of
 
which
 
are
 
being
 
prosecuted
 
in
 
the
 
United
 
States,
Australia, Brazil,
 
Canada, Chile,
 
China, Colombia,
 
the EPO,
 
Indonesia, India,
 
Israel, Japan,
 
Mexico, New
 
Zealand, Philippines,
 
the
Republic of Korea, Russia,
 
Singapore, South Africa, Taiwan, Thailand, Ukraine,
 
the United Arab Emirates,
 
and Vietnam. The members
of one family of patents expired
 
in 2023, except for two U.S.
 
patents that will expire in 2025
 
and 2026. With regards to
 
the rest of the
families that cover the
 
AIM Platform, the issued
 
patents and patent applications,
 
if issued, are expected
 
to expire in 2039, excluding
 
any
patent term adjustments or patent term extensions.
The term of
 
individual patents
 
depends on the
 
countries in which
 
they are obtained.
 
The patent
 
term is 20
 
years from the
 
earliest effective
filing date of a
 
non-provisional patent application in most
 
of the countries in
 
which we file, including the
 
United States. In the United
States, a
 
patent’s
 
term may
 
be lengthened
 
by patent
 
term adjustment,
 
which compensates
 
a patentee
 
for administrative
 
delays by
 
the
USPTO in
 
examining and granting
 
a patent, or
 
may be shortened
 
if a patent
 
is terminally disclaimed
 
over an
 
earlier filed patent.
 
The
term of a patent that
 
covers a drug or biological product
 
may also be eligible for patent
 
term extension when FDA approval is
 
granted
36
for a
 
portion of
 
the term
 
effectively lost
 
as a
 
result of
 
the FDA
 
regulatory review
 
period, subject
 
to certain
 
limitations and
 
provided
statutory and regulatory requirements are met.
In addition to our reliance on patent protection for our inventions, products and technologies, we also seek to protect
 
our brand through
the procurement of trademark rights.
 
We
 
own registered trademarks and pending
 
trademark applications for our brands,
 
including our
“Vaxxinity”, “United Neuroscience” and “COVAXX” brands and
 
other related names
 
and logos, in
 
the United States
 
and certain
 
foreign
jurisdictions.
Furthermore, we rely upon trade secrets and know-how and continuing technological innovation to develop and maintain our
competitive position. However, trade secrets and know-how can be difficult to protect. We generally control access to and use of our
trade secrets and know-how, through the use of internal and external controls, including by entering into nondisclosure and
confidentiality agreements with our employees and third parties. We cannot guarantee, however, that we have executed such
agreements with all applicable counterparties, that such agreements will not be breached or that these agreements will afford us
adequate protection of our intellectual property and proprietary rights. Furthermore, although we take steps to protect our proprietary
information and trade secrets, third parties may independently develop substantially equivalent proprietary information and techniques
or otherwise gain access to our trade secrets or disclose our technology. As a result, we may not be able to meaningfully protect our
trade secrets. For further discussion of the risks relating to intellectual property, see “Risk Factors—Risks Related to Our Intellectual
Property Rights.”
 
Platform License Agreement
In August 2021, Vaxxinity
 
entered into a license
 
agreement (the “Platform License
 
Agreement”) with UBI and
 
certain of its affiliates
(collectively, the “Licensors”) that
 
expanded intellectual
 
property rights previously
 
licensed under
 
the Original
 
UBI Licenses (as
 
defined
below). Pursuant
 
to the
 
Platform License
 
Agreement, Vaxxinity
 
obtained a
 
worldwide, sublicensable
 
(subject to
 
certain conditions),
perpetual, fully paid-up, royalty-free (i) exclusive license (even as to the Licensors) under all patents owned or otherwise controlled by
the Licensors or their affiliates
 
existing as of the effective
 
date of the Platform License
 
Agreement, (ii) exclusive license (except
 
as to
the Licensors) under all patents owned or otherwise controlled by the Licensors or their affiliates arising after the effective
 
date during
the term of the Platform License Agreement, and (iii) non-exclusive
 
license under all know-how owned or otherwise controlled by the
Licensors or their affiliates existing as of the
 
effective date or arising during the term of
 
the Platform License Agreement, in each of
 
the
foregoing
 
cases,
 
to
 
research,
 
develop,
 
make,
 
have
 
made,
 
utilize,
 
import,
 
export,
 
market,
 
distribute,
 
offer
 
for
 
sale,
 
sell,
 
have
 
sold,
commercialize or otherwise exploit peptide-based vaccines in the field of all
 
human prophylactic and therapeutic uses, except for such
vaccines related to human
 
immunodeficiency virus (HIV), herpes
 
simplex virus (HSE) and
 
Immunoglobulin E (IgE). The
 
patents and
patent applications licensed under the
 
Platform License Agreement include claims
 
directed to a CpG delivery system,
 
artificial T helper
cell
 
epitopes
 
and
 
certain
 
designer
 
peptides
 
and
 
proteins
 
utilized
 
in
 
UB-612.
 
As
 
partial
 
consideration
 
for
 
the
 
rights
 
and
 
licenses
 
we
received pursuant to the Platform License Agreement, we granted UBI a warrant to purchase 1,928,020 shares of our Class A common
stock (“UBI Warrant”). The UBI
 
Warrant is exercisable at an
 
exercise price of
 
$12.45 per share
 
(subject to adjustment
 
pursuant thereto),
is not subject to vesting, and has a term of five years.
Vaxxinity
 
has the first right to control the filing, prosecution, maintenance and enforcement of the licensed patents
 
at Vaxxinity’s
 
own
expense, subject to the
 
Licensors’ right to comment on
 
and review any patent filings.
 
The Platform License Agreement shall
 
continue
until the parties mutually consent in writing to terminate the agreement. Upon such termination, all licenses granted
 
under the Platform
License Agreement shall
 
terminate and Vaxxinity
 
will assign any
 
regulatory documentation previously assigned
 
to Vaxxinity
 
back to
the Licensors.
Pricing, Coverage and Reimbursement
Sales of our
 
product candidates in
 
the United States
 
will depend, in
 
part, on the
 
extent to which
 
third-party payors, including
 
government
health programs such
 
as Medicare and
 
Medicaid, commercial insurance
 
and managed health
 
care organizations provide
 
coverage and
establish
 
adequate
 
reimbursement levels
 
for
 
such
 
product
 
candidates.
 
The
 
process
 
for
 
determining whether
 
a
 
third-party payor
 
will
provide coverage for a pharmaceutical
 
or biological product is typically separate
 
from the process for setting
 
the price of such a product
or for establishing the reimbursement rate
 
that the payor will pay for
 
the product once coverage is
 
approved, and we may also
 
need to
provide
 
discounts
 
to
 
purchasers,
 
private
 
health
 
plans
 
or
 
government
 
healthcare
 
programs,
 
as
 
increasingly,
 
third-party
 
payors
 
are
requiring that
 
drug companies provide
 
them with
 
predetermined discounts from
 
list prices and
 
are challenging the
 
prices charged
 
for
medical products.
 
As a
 
result, a
 
third-party payor’s
 
decision to
 
provide coverage
 
for a
 
pharmaceutical or
 
biological product
 
does not
imply that the reimbursement rate will be adequate for commercial viability, and inadequate reimbursement rates, including significant
patient
 
cost
 
sharing
 
obligations,
 
may
 
deter
 
patients
 
from
 
selecting
 
our
 
product
 
candidates.
 
Obtaining
 
coverage
 
and
 
reimbursement
approval of a
 
product from a
 
third-party payor is
 
a time-consuming and
 
costly process that
 
could require us
 
to provide to
 
each payor
supporting scientific, clinical
 
and cost-effectiveness data
 
for the use
 
of our product
 
on a payor-by-payor
 
basis, with no
 
assurance that
coverage and adequate reimbursement will
 
be obtained. Third-party payors may limit
 
coverage to specific products on an
 
approved list,
also known as a formulary, which might not include all of the approved products for a particular indication.
37
Further,
 
no uniform
 
policy for
 
coverage and
 
reimbursement exists
 
in the
 
United States,
 
and coverage
 
and reimbursement
 
can differ
significantly from
 
payor to payor. In
 
general, factors
 
a payor
 
considers in
 
determining coverage
 
and reimbursement
 
are based
 
on whether
the product is a covered benefit under its health plan; safe, effective,
 
and medically necessary, including its regulatory approval
 
status;
medically appropriate for the specific
 
patient; cost-effective; and neither experimental
 
nor investigational. Third-party payors
 
often rely
upon Medicare coverage policy and payment limitations in setting their own reimbursement
 
rates, but also have their own methods and
approval process apart from
 
Medicare determinations. As such,
 
one third-party payor’s
 
decision to cover a
 
particular medical product
or service does not ensure that other payors will also
 
provide coverage for the medical product or service, and the level
 
of coverage and
reimbursement can differ significantly from payor to payor. Even if favorable coverage and reimbursement status is attained for one or
more products for which
 
we receive regulatory approval,
 
less favorable coverage
 
policies and reimbursement
 
rates may be implemented
in the future.
Product Approval and Government Regulation
Government authorities in the United States, at the
 
federal, state and local level, and other countries extensively
 
regulate, among other
things,
 
the
 
research,
 
development,
 
testing,
 
manufacture,
 
quality
 
control,
 
approval,
 
labeling,
 
packaging,
 
storage,
 
record-keeping,
promotion, advertising, distribution,
 
post-approval monitoring and
 
reporting, marketing and
 
export and import
 
of products such as
 
those
we are
 
developing. Any
 
product candidate
 
that we
 
develop must
 
be approved
 
by the
 
FDA before
 
it may
 
be legally
 
marketed in
 
the
United States and by the appropriate foreign regulatory agency before it may be legally marketed in foreign countries.
U.S. Drug Development Process
In the United States,
 
the development, manufacturing and marketing
 
of human drugs and vaccines
 
are subject to extensive
 
regulation.
The FDA
 
regulates drugs
 
under the
 
Federal Food,
 
Drug and
 
Cosmetic Act
 
(“FDCA”) and
 
implementing regulations,
 
and biological
products, including vaccines, under provisions of the FDCA and the Public Health Service Act (“PHSA”). Drugs and vaccines are also
subject
 
to
 
other
 
federal,
 
state
 
and
 
local
 
statutes
 
and
 
regulations.
 
The
 
process
 
of
 
obtaining
 
regulatory
 
approvals
 
and
 
the
 
subsequent
compliance with
 
appropriate federal,
 
state, local
 
and foreign
 
statutes and
 
regulations require
 
the expenditure
 
of substantial
 
time and
financial
 
resources.
 
Failure
 
to
 
comply
 
with
 
the
 
applicable
 
U.S.
 
requirements
 
at
 
any
 
time
 
during
 
the
 
product
 
development
 
process,
approval process or after
 
approval, may subject
 
an applicant to administrative
 
or judicial sanctions. FDA
 
sanctions could include refusal
to approve
 
pending applications,
 
withdrawal of
 
an approval,
 
clinical hold,
 
warning letters,
 
product recalls,
 
product seizures,
 
total or
partial
 
suspension
 
of
 
production
 
or
 
distribution,
 
injunctions,
 
fines,
 
refusals
 
of
 
government
 
contracts,
 
debarment,
 
restitution,
disgorgement or civil or criminal penalties. Any agency or
 
judicial enforcement action could have a material adverse effect
 
on us. The
process required by the
 
FDA before a drug
 
or biological product may
 
be marketed in the
 
United States generally involves
 
the following:
 
completion of nonclinical
 
laboratory tests, animal
 
studies and formulation
 
and stability studies
 
according to good
 
laboratory
practices, or GLPs and other applicable regulations;
 
submission to the FDA of an application for an IND, which must become effective before human clinical trials may begin;
 
performance of adequate
 
and well-controlled human
 
clinical trials according
 
to the FDA’s
 
good clinical practice
 
regulations
commonly referred
 
to as
 
GCPs, among
 
other requirements,
 
to establish
 
the safety
 
and efficacy
 
of the
 
proposed drug
 
for its
intended uses;
 
submission to the FDA of an NDA or BLA for a new drug;
 
satisfactory completion of
 
an FDA inspection
 
of the manufacturing
 
facility or facilities
 
where the drug
 
is produced to
 
assess
compliance
 
with
 
the
 
FDA’s
 
cGMP,
 
to
 
assure
 
that
 
the
 
facilities,
 
methods
 
and
 
controls
 
are
 
adequate
 
to
 
preserve
 
the
 
drug’s
identity, strength, quality and purity;
 
potential FDA audit of the nonclinical and clinical trial sites that generated the data in support of the NDA or BLA; and
 
FDA review and approval of the NDA or BLA.
The
 
lengthy process
 
of
 
seeking required
 
approvals and
 
the continuing
 
need for
 
compliance with
 
applicable statutes
 
and
 
regulations
require the expenditure of substantial resources and approvals are inherently uncertain.
Before testing any compounds
 
with potential therapeutic value
 
in humans, the product
 
candidate enters the pre-clinical
 
study stage. Pre-
clinical tests, also
 
referred to as
 
nonclinical studies, include
 
laboratory evaluations of
 
product chemistry,
 
toxicity and formulation,
 
as
well as animal
 
studies to assess
 
the potential safety
 
and activity of
 
the product candidate.
 
The Consolidated Appropriations
 
Act for 2023,
signed into law on December 29, 2022, (P.L. 117
 
-328) amended both the FDCA and PHSA to specify that nonclinical testing for drugs
and biologics, respectively,
 
may, but
 
is not required to,
 
include in vivo animal
 
testing. According to the
 
amended language, a sponsor
may
 
fulfill
 
nonclinical
 
testing
 
requirements
 
by
 
completing
 
various
 
in
 
vitro
 
assays
 
(e.g.,
 
cell-based
 
assays,
 
organ
 
chips,
 
or
38
microphysiological
 
systems),
 
in
 
silico
 
studies
 
(i.e.,
 
computer
 
modeling),
 
other
 
human
 
or
 
non-human
 
biology-based
 
tests
 
(e.g.,
bioprinting), or in vivo animal tests.
The conduct of the
 
pre-clinical tests must comply with
 
federal regulations and requirements including
 
GLP.
 
The sponsor must submit
the results of the pre-clinical tests, together
 
with manufacturing information, analytical data, any available
 
clinical data or literature and
a proposed clinical protocol,
 
to the FDA as
 
part of the IND. The
 
IND automatically becomes effective 30
 
days after receipt by the
 
FDA,
unless the FDA imposes a clinical hold within that 30-day time period. In
 
such a case, the IND sponsor and the FDA must resolve any
outstanding concerns before
 
the clinical trial
 
can begin.
 
The FDA
 
may also
 
impose clinical holds
 
on a
 
product candidate at
 
any time
before or
 
during clinical trials
 
due to
 
safety concerns or
 
non-compliance. Accordingly,
 
we cannot
 
be sure
 
that submission of
 
an IND
will result in the FDA allowing clinical trials to begin, or that, once begun, issues will not arise that suspend or terminate such trial.
Clinical trials
 
involve the
 
administration of
 
the product
 
candidate to
 
healthy volunteers or
 
patients under
 
the supervision
 
of qualified
investigators,
 
generally
 
physicians
 
not
 
employed
 
by
 
or
 
under
 
the
 
trial
 
sponsor’s
 
direct
 
control.
 
Clinical
 
trials
 
are
 
conducted
 
under
protocols detailing, among other
 
things, the objectives of
 
the clinical trial, dosing
 
procedures, subject selection and
 
exclusion criteria,
and the parameters to be used to monitor subject safety. Each protocol must be submitted to the FDA as part of the IND. Congress also
recently amended the FDCA, as part of the Consolidated Appropriations Act
 
for 2023, in order to require sponsors of a Phase 3 clinical
trial, or
 
other “pivotal study”
 
of a new
 
drug to
 
support marketing authorization,
 
to design and
 
submit a diversity
 
action plan for
 
such
clinical
 
trial.
 
The
 
action
 
plan
 
must
 
include
 
the
 
sponsor’s
 
diversity
 
goals
 
for
 
enrollment,
 
as
 
well
 
as
 
a
 
rationale
 
for
 
the
 
goals
 
and
 
a
description of how
 
the sponsor will
 
meet them. Sponsors
 
must submit a
 
diversity action plan
 
to the FDA by
 
the time the
 
sponsor submits
the relevant
 
clinical trial
 
protocol to
 
the agency
 
for review.
 
The FDA
 
may grant
 
a waiver
 
for some
 
or all
 
of the
 
requirements for
 
a
diversity action
 
plan. It
 
is unknown
 
at this
 
time how
 
the diversity
 
action plan
 
may affect
 
Phase 3
 
trial planning
 
and timing
 
or what
specific information
 
FDA will expect
 
in such
 
plans, but
 
if the
 
FDA objects to
 
a sponsor’s
 
diversity action plan
 
or otherwise
 
requires
significant changes to
 
be made, it
 
could delay initiation
 
of the relevant
 
clinical trial. Clinical
 
trials must be conducted
 
in accordance with
the FDA’s
 
regulations comprising the good clinical practices requirements.
 
Further, each clinical trial must
 
be reviewed and approved
by an independent IRB at
 
or servicing each institution at which
 
the clinical trial will be conducted.
 
An IRB is charged with
 
protecting
the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials
are minimized and
 
are reasonable in
 
relation to anticipated
 
benefits. The IRB
 
also approves the
 
form and content
 
of the informed
 
consent
that
 
must
 
be
 
signed
 
by
 
each
 
clinical
 
trial
 
subject
 
or
 
his
 
or
 
her
 
legal
 
representative
 
and
 
provide
 
oversight
 
for
 
the
 
clinical
 
trial
 
until
completed.
Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:
Phase 1
. The drug is initially introduced into healthy human subjects and tested for safety, dosage
tolerance, absorption, metabolism, distribution and excretion. In the case of some products for severe or life-threatening diseases,
especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing
 
may be
conducted in patients;
Phase 2
. The drug is evaluated in a limited patient population to identify possible adverse effects and safety
risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance, optimal
dosage and dosing schedule; and
Phase 3
. Clinical trials are undertaken to further evaluate dosage, clinical efficacy and safety in an
expanded patient population at geographically dispersed clinical trial sites. These clinical trials are intended to establish
 
the overall
risk/benefit ratio of the product and provide an adequate basis for product labeling. Generally, a well-controlled Phase 3 clinical trial is
required by the FDA for approval of an NDA or BLA.
Post-approval clinical trials, sometimes referred
 
to as Phase 4
 
clinical trials, may be
 
conducted after initial marketing approval.
 
These
clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
During all
 
phases of
 
clinical development,
 
regulatory agencies
 
require extensive
 
monitoring and
 
auditing of
 
all clinical
 
activities, clinical
data and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA and
written IND safety reports must
 
be promptly submitted to the
 
FDA and the investigators for
 
serious and unexpected adverse events or
any finding from
 
tests in laboratory
 
animals that suggests
 
a significant risk
 
for human subjects.
 
Phase 1, Phase
 
2 and Phase
 
3 clinical
trials may
 
not be
 
completed successfully
 
within any
 
specified period,
 
if at
 
all. The
 
FDA or
 
the sponsor
 
or its
 
data safety
 
monitoring
board may
 
suspend a clinical
 
trial at
 
any time on
 
various grounds, including
 
a finding that
 
the research subjects
 
or patients
 
are being
exposed to
 
an unacceptable
 
health risk.
 
Similarly,
 
an IRB
 
can suspend
 
or terminate
 
approval of
 
a clinical
 
trial at
 
its institution
 
if the
clinical trial
 
is not being
 
conducted in accordance
 
with the IRB’s requirements
 
or if the
 
drug has been
 
associated with
 
unexpected serious
harm to patients.
Concurrently with
 
clinical trials,
 
companies usually
 
complete additional
 
nonclinical studies
 
and must
 
also develop
 
additional information
about the chemistry and
 
physical characteristics of the drug
 
as well as finalize
 
a process for manufacturing
 
the product in commercial
quantities in
 
accordance with
 
cGMP requirements.
 
The manufacturing
 
process must
 
be capable
 
of consistently
 
producing quality
 
batches
39
of the product candidate and, among other things, must
 
develop methods for testing the identity, strength, quality and purity of the final
drug. For biological
 
products in particular, the
 
PHSA emphasizes the
 
importance of manufacturing
 
control for products
 
whose attributes
cannot be
 
precisely defined
 
in order
 
to help
 
reduce the
 
risk of
 
the introduction
 
of adventitious
 
agents. Additionally, appropriate
 
packaging
must
 
be
 
selected
 
and
 
tested,
 
and
 
stability
 
studies
 
must
 
be
 
conducted
 
to
 
demonstrate
 
that
 
the
 
product
 
candidate
 
does
 
not
 
undergo
unacceptable deterioration over its shelf life.
U.S. Review and Approval Processes
Assuming successful completion of all required
 
testing in accordance with all applicable
 
regulatory requirements, the results of product
development, nonclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests
 
conducted on
the
 
chemistry
 
of
 
the
 
drug,
 
proposed
 
labeling
 
and
 
other
 
relevant
 
information
 
are
 
submitted
 
to
 
the
 
FDA
 
as
 
part
 
of
 
an
 
NDA
 
or
 
BLA
requesting approval to market the product.
 
The submission of an NDA or BLA
 
is subject to the payment of substantial
 
fees; a waiver of
such fees may be obtained under certain limited circumstances.
In addition, under the Pediatric Research Equity Act (“PREA”), an NDA or
 
BLA or supplement to an NDA or BLA must contain data
to assess
 
the safety
 
and effectiveness
 
of the
 
drug for
 
the claimed
 
indications in
 
all relevant
 
pediatric subpopulations
 
and to
 
support
dosing and administration for each
 
pediatric subpopulation for which
 
the product is safe and
 
effective. The FDA may grant
 
deferrals for
submission of data
 
or full or
 
partial waivers. Unless
 
otherwise required by
 
regulation, PREA does
 
not apply to
 
any drug for
 
an indication
for which orphan designation has been granted.
The FDA reviews all NDAs or
 
BLAs submitted to determine if they
 
are substantially complete before it accepts
 
them for filing. If the
FDA determines that an NDA or BLA
 
is incomplete or the application is
 
found to be non-navigable, the filing may
 
be refused and must
be re-submitted for consideration. Once the submission is accepted for filing, the FDA begins an in-depth
 
review of the NDA or BLA.
Under the goals and
 
policies agreed to by the
 
FDA under the Prescription
 
Drug User Fee Act
 
(“PDUFA”), the FDA has 10 months from
acceptance of filing
 
in which to
 
complete its initial
 
review of a standard
 
NDA or BLA
 
and respond to
 
the applicant, and
 
six months from
acceptance of
 
filing for
 
a priority
 
NDA or
 
BLA. The
 
FDA does
 
not always
 
meet its
 
PDUFA
 
goal dates.
 
The review
 
process and
 
the
PDUFA
 
goal date
 
may be
 
extended by
 
three months
 
or longer
 
if the
 
FDA requests
 
or the
 
NDA or
 
BLA sponsor
 
otherwise provides
additional information or clarification regarding information already provided in the submission before the PDUFA goal date.
After the NDA or BLA submission
 
is accepted for filing, the
 
FDA reviews the NDA or BLA
 
to determine, among other things,
 
whether
the proposed product is
 
safe and effective for
 
its intended use, and
 
whether the product is
 
being manufactured in accordance
 
with cGMP
to assure and preserve the product’s identity,
 
strength, quality and purity. The FDA may
 
refer applications for novel drug or biological
products or drug
 
or biological products
 
which present difficult
 
questions of safety
 
or efficacy to
 
an advisory committee,
 
typically a panel
that includes clinicians
 
and other experts,
 
for review, evaluation and
 
a recommendation as
 
to whether the
 
application should be
 
approved
and
 
under
 
what
 
conditions.
 
The
 
FDA
 
is
 
not
 
bound
 
by
 
the
 
recommendations
 
of
 
an
 
advisory
 
committee,
 
but
 
it
 
considers
 
such
recommendations carefully
 
when
 
making decisions.
 
During
 
the drug
 
approval process,
 
the
 
FDA also
 
will determine
 
whether a
 
risk
evaluation and mitigation strategy, or REMS is necessary to ensure that
 
the benefits of the drug outweigh its
 
risks and to assure the safe
use of
 
the drug.
 
The REMS
 
could include
 
medication guides,
 
physician communication
 
plans, assessment
 
plans and/or
 
elements to
assure safe
 
use, such
 
as restricted
 
distribution methods,
 
patient registries
 
or other
 
risk minimization
 
tools. The
 
FDA determines
 
the
requirement for a REMS, as
 
well as the specific
 
REMS provisions, on a case-by-case
 
basis. If the FDA
 
concludes a REMS is needed,
the sponsor
 
of the
 
NDA or
 
BLA must
 
submit a
 
proposed REMS;
 
the FDA
 
will not
 
approve the
 
NDA or
 
BLA without
 
a REMS,
 
if
required.
Before approving an NDA or BLA, the FDA
 
will inspect the facilities at which the product
 
is manufactured. The FDA will not approve
the product unless
 
it determines that
 
the manufacturing processes
 
and facilities are
 
in compliance with
 
cGMP requirements and
 
adequate
to assure consistent
 
production of the
 
product within required
 
specifications. The FDA requires
 
vaccine manufacturers to
 
submit data
supporting
 
the
 
demonstration
 
of
 
consistency
 
between
 
manufacturing
 
batches,
 
or
 
lots.
 
The
 
FDA
 
works
 
together
 
with
 
vaccine
manufacturers to develop
 
a lot release
 
protocol, the tests
 
conducted on each
 
lot of vaccine
 
post-approval. Additionally, before approving
an NDA
 
or BLA, the
 
FDA will
 
typically inspect
 
the sponsor
 
and one
 
or more
 
clinical sites
 
to assure that
 
the clinical
 
trials were conducted
in
 
compliance with
 
IND
 
study
 
requirements
 
and
 
with
 
GCPs.
 
If
 
the
 
FDA
 
determines
 
that
 
the
 
application, manufacturing
 
process
 
or
manufacturing facilities are not acceptable it will
 
outline the deficiencies in the submission and
 
often will request additional testing or
information.
The NDA
 
or BLA
 
review and
 
approval process
 
is lengthy
 
and difficult
 
and the
 
FDA may
 
refuse to
 
approve an
 
NDA or
 
BLA if
 
the
applicable regulatory criteria
 
are not satisfied
 
or may require
 
additional clinical data
 
or other data
 
and information. Even
 
if such data
and information
 
is submitted,
 
the FDA
 
may ultimately
 
decide that
 
the NDA
 
or BLA
 
does not
 
satisfy the
 
criteria for
 
approval. Data
obtained from clinical trials are not
 
always conclusive and the FDA may
 
interpret data differently than we
 
interpret the same data. An
approval
 
letter
 
authorizes
 
commercial
 
marketing
 
of
 
the
 
drug
 
with
 
specific
 
prescribing
 
information
 
for
 
specific
 
indications,
 
while
 
a
complete response
 
letter indicates
 
that the
 
review cycle
 
of the
 
application is
 
complete and
 
the application
 
will not
 
be approved
 
in its
present form. The complete response letter usually describes all of the specific deficiencies in the NDA or BLA identified by the FDA.
The deficiencies identified may be minor,
 
for example, requiring labeling changes, or major,
 
for example, requiring additional clinical
trials. Additionally, the complete response
 
letter may include
 
recommended actions that
 
the applicant might
 
take to place
 
the application
40
in a condition for
 
approval. If a complete
 
response letter is issued,
 
the applicant may either
 
submit new information, addressing
 
all of
the deficiencies identified in the letter, or withdraw the application.
If a product receives regulatory
 
approval, the approval may be
 
significantly limited to specific diseases
 
and dosages or the
 
indications
for use may otherwise be
 
limited, which could restrict the commercial
 
value of the product. Further,
 
the FDA may require that
 
certain
contraindications, warnings or
 
precautions be included
 
in the product
 
labeling. In addition,
 
the FDA may
 
require post-marketing clinical
trials, sometimes referred to as Phase 4 clinical trials, which are
 
designed to further assess a product’s safety and effectiveness and may
require testing and surveillance programs to
 
monitor the safety of approved
 
products that have been commercialized. In
 
addition, new
government requirements, including those
 
resulting from new legislation,
 
may be established, or the
 
FDA’s
 
policies may change, which
could impact the timeline for regulatory approval or otherwise impact ongoing development programs.
Expedited Development and Review Programs
The FDA
 
is authorized
 
to designate
 
certain products
 
for expedited
 
development or
 
review if
 
they are
 
intended to
 
address an
 
unmet
medical
 
need
 
in
 
the
 
treatment
 
of
 
a
 
serious
 
or
 
life-threatening
 
disease
 
or
 
condition.
 
These
 
programs
 
include
 
fast
 
track
 
designation,
breakthrough therapy designation and priority review designation.
The FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs and biologics that meet
certain criteria. Specifically, new drugs and biologics are eligible for fast track designation if they are intended to treat a serious or life-
threatening condition and preclinical
 
or clinical data
 
demonstrate the potential to
 
address unmet medical needs
 
for the condition.
 
Fast
track designation
 
applies to the
 
combination of the
 
product and
 
the specific indication
 
for which
 
it is
 
being studied. The
 
sponsor can
request the FDA to designate the
 
product for fast track status any
 
time before receiving NDA or BLA
 
approval, but ideally no later than
the pre-NDA or pre-BLA meeting.
Additionally,
 
a
 
drug
 
or
 
biologic
 
may
 
be
 
eligible
 
for
 
designation
 
as
 
a
 
breakthrough
 
therapy
 
if
 
the
 
product
 
is
 
intended,
 
alone
 
or
 
in
combination with one or more other drugs or biologics, to treat a serious or life-threatening condition and
 
preliminary clinical evidence
indicates
 
that
 
the
 
product
 
may
 
demonstrate
 
substantial
 
improvement
 
over
 
currently
 
approved
 
therapies
 
on
 
one
 
or
 
more
 
clinically
significant endpoints.
 
The benefits
 
of breakthrough
 
therapy designation
 
include the
 
same benefits
 
as fast
 
track designation,
 
plus intensive
guidance from the FDA to facilitate an efficient drug development program.
Any product
 
submitted to
 
the FDA for
 
marketing, including under
 
a fast track
 
or breakthrough therapy
 
designation program, may
 
be
eligible for
 
other types
 
of FDA
 
programs intended
 
to expedite
 
development and
 
review, such as
 
priority review
 
and accelerated
 
approval.
Any product is eligible
 
for priority review if
 
it treats a serious or
 
life-threatening condition and, if
 
approved, would provide a
 
significant
improvement
 
in
 
safety
 
and
 
effectiveness
 
compared
 
to
 
available
 
therapies.
 
Priority
 
review
 
reduces
 
the
 
review
 
time
 
for
 
an
 
initial
 
or
supplemental marketing application by four months.
Even if a product qualifies
 
for one or more of
 
these programs, the FDA may
 
later decide that the product
 
no longer meets the conditions
for qualification or
 
decide that the time
 
period for FDA
 
review or approval
 
will not be shortened.
 
Fast track designation,
 
priority review,
and breakthrough therapy designation do not change the standards for approval but may expedite the development or approval process.
Accelerated Approval Pathway
A product may be
 
eligible for accelerated
 
approval if it
 
treats a serious
 
or life-threatening condition
 
and generally provides
 
a meaningful
advantage over available therapies based on an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a
clinical endpoint that
 
can be measured
 
earlier than irreversible
 
morbidity or mortality
 
("IMM") that is
 
reasonably likely to
 
predict an
effect on IMM
 
or other clinical
 
benefit. As a
 
condition of accelerated approval,
 
the FDA requires
 
that a sponsor of
 
a drug or
 
biologic
receiving
 
accelerated
 
approval
 
subsequently
 
provide
 
additional
 
data
 
confirming
 
the
 
anticipated
 
clinical
 
benefit,
 
for
 
example
 
by
performing adequate and well-controlled post-marketing clinical
 
trials. If clinical benefit is not confirmed,
 
accelerated approval may be
revoked.
 
In addition, as part of the Consolidated Appropriations Act for 2023, Congress provided FDA additional statutory authority to mitigate
potential risks
 
to patients
 
from continued
 
marketing of
 
ineffective drugs
 
previously granted
 
accelerated approval.
 
Under these
 
recent
amendments to
 
the FDCA,
 
the agency
 
may require
 
a sponsor
 
of a
 
product granted
 
accelerated approval
 
to have
 
a confirmatory
 
trial
underway prior
 
to approval.
 
The sponsor
 
must also
 
submit progress
 
reports on
 
a confirmatory
 
trial every
 
six months
 
until the
 
trial is
complete, and
 
such reports
 
will be
 
published on
 
FDA’s
 
website. Failure
 
to conduct
 
required post-approval
 
studies, or
 
to confirm
 
the
predicted clinical benefit
 
of the product
 
during post-marketing studies,
 
allows the FDA
 
to withdraw approval
 
of the drug
 
or biologic.
Congress also
 
recently amended
 
the law
 
to give
 
FDA the
 
option of
 
using expedited
 
procedures to
 
withdraw product
 
approval if
 
the
sponsor’s confirmatory trial fails to verify the claimed clinical benefits of the product.
41
Granting of an EUA
The Commissioner
 
of the
 
FDA, under
 
delegated authority from
 
the Secretary of
 
the U.S. Department
 
of Health
 
and Human
 
Services
(“DHHS”)
 
may,
 
under
 
certain
 
circumstances,
 
issue
 
an
 
Emergency
 
Use
 
Authorization,
 
or
 
EUA
 
that
 
would
 
permit
 
the
 
use
 
of
 
an
unapproved drug product or unapproved
 
use of an approved drug product.
 
Before an EUA may be issued,
 
the Secretary must declare an
emergency based on one of the following grounds:
 
a
 
determination
 
by
 
the
 
Secretary
 
of
 
the
 
Department
 
of
 
Homeland
 
Security
 
that
 
there
 
is
 
a
 
domestic
 
emergency,
 
or
 
a
significant potential for a domestic
 
emergency, involving a heightened risk of attack with
 
a specified biological, chemical,
radiological or nuclear agent or agents;
 
a determination by the
 
Secretary of the Department
 
of Defense that there
 
is a military emergency, or a significant
 
potential
for a military
 
emergency, involving a heightened
 
risk to U.S.
 
military forces
 
of attack with
 
a specified
 
biological, chemical,
radiological or nuclear agent or agents; or
 
a determination by the Secretary of the DHHS that a
 
public health emergency that affects, or has
 
the significant potential
to affect, national security and that involves a
 
specified biological, chemical, radiological or nuclear agent or agents, or
 
a
specified disease or condition that may be attributable to such agent or agents.
In order to be the subject of an EUA, the FDA Commissioner must conclude that, based on the totality of scientific evidence available,
it is
 
reasonable to
 
believe that
 
the product
 
may be
 
effective in
 
diagnosing, treating
 
or preventing
 
a disease
 
attributable to
 
the agents
described above, that the
 
product’s potential
 
benefits outweigh its potential
 
risks and that
 
there is no adequate
 
approved alternative to
the product.
Although an EUA cannot
 
be issued until after
 
an emergency has been
 
declared by the Secretary
 
of DHHS, the FDA
 
strongly encourages
an entity with a
 
possible candidate product,
 
particularly one at an
 
advanced stage of
 
development, to contact the
 
FDA center responsible
for the candidate
 
product before a determination
 
of actual or potential
 
emergency. Such an entity may submit
 
a request for consideration
that includes data to
 
demonstrate that, based on
 
the totality of scientific
 
evidence available, it is
 
reasonable to believe that
 
the product
may be
 
effective
 
in diagnosing,
 
treating or
 
preventing the
 
serious or
 
life-threatening disease
 
or condition.
 
This is
 
called a
 
pre-EUA
submission and
 
its purpose
 
is to
 
allow FDA
 
review considering
 
that during
 
an emergency,
 
the time
 
available for
 
the submission
 
and
review of an EUA request may be severely limited.
Post-Approval Requirements
Any drug or
 
biological products for
 
which we or
 
our collaborators receive
 
FDA approvals are
 
subject to continuing
 
regulation by the
FDA, including,
 
among other
 
things, record-keeping
 
requirements, reporting
 
of adverse
 
experiences with
 
the product,
 
providing the
FDA with updated safety and efficacy
 
information, product sampling and distribution requirements, complying with
 
certain electronic
records and
 
signature requirements
 
and complying
 
with FDA
 
promotion and
 
advertising requirements, which
 
include, among
 
others,
standards for
 
direct-to-consumer advertising,
 
promoting drugs
 
for uses
 
or in
 
patient populations
 
that are
 
not described
 
in the
 
drug’s
approved
 
labeling
 
(known
 
as
 
“off-label
 
use”),
 
industry-sponsored
 
scientific
 
and
 
educational
 
activities,
 
and
 
promotional
 
activities
involving the internet.
Failure to comply
 
with FDA requirements
 
can have negative
 
consequences, including adverse
 
publicity,
 
enforcement letters from
 
the
FDA,
 
mandated
 
corrective
 
advertising
 
or
 
communications
 
with
 
doctors,
 
and
 
civil
 
or
 
criminal
 
penalties.
 
Although
 
physicians
 
may
prescribe legally available drugs for off-label uses, manufacturers may not market or promote such off-label uses.
Manufacturers of
 
our product
 
candidates are
 
required to
 
comply with
 
applicable FDA
 
manufacturing requirements
 
contained in
 
the
FDA’s
 
cGMP
 
regulations.
 
cGMP
 
regulations
 
require,
 
among
 
other
 
things,
 
quality
 
control
 
and
 
quality
 
assurance
 
as
 
well
 
as
 
the
corresponding maintenance of records and documentation. Following approval, the FDA continues
 
to monitor vaccine quality through
real-time monitoring of lots by requiring manufacturers to submit certain information for each vaccine lot. Vaccine manufacturers may
only distribute a lot following release by the
 
FDA. Drug manufacturers and other entities involved in
 
the manufacture and distribution
of
 
approved drugs
 
are required
 
to register
 
their establishments
 
with the
 
FDA and
 
certain state
 
agencies, and
 
are subject
 
to periodic
unannounced inspections by the
 
FDA and certain state
 
agencies for compliance with
 
cGMP and other laws.
 
Accordingly, manufacturers
must continue to expend time, money and effort
 
in the area of production and quality
 
control to maintain cGMP compliance. Discovery
of problems with a product after approval may result in restrictions on a product, manufacturer or holder
 
of an approved NDA or BLA,
including withdrawal of
 
the product
 
from the
 
market. In
 
addition, changes
 
to the
 
manufacturing process generally
 
require prior
 
FDA
approval before being implemented, and other types of changes to the approved product, such as adding new indications and additional
labeling claims, are also subject to further FDA review and approval.
42
U.S. Patent-term Extension
Depending upon the timing,
 
duration and specifics
 
of FDA approval of
 
our product candidates,
 
some of our U.S.
 
patents may be eligible
for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as
the Hatch-Waxman
 
Amendments to
 
the FDCA.
 
The Hatch-Waxman
 
Amendments permit
 
extension of
 
the patent
 
term of
 
up to
 
five
years as
 
compensation for
 
patent term
 
lost during
 
product development
 
and FDA
 
regulatory review
 
process. Patent-term
 
extension,
however, cannot
 
extend the
 
remaining term
 
of a
 
patent beyond
 
a total
 
of 14
 
years from
 
the product’s
 
approval date.
 
The patent-term
extension period is generally one-half
 
the time between the effective
 
date of an IND and
 
the submission date of an
 
NDA or BLA plus
the time between the submission date of an NDA or BLA and the approval of that application, except that the review period is reduced
by any time during which
 
the applicant failed to exercise
 
due diligence. Only one patent
 
applicable to an approved drug
 
is eligible for
the extension
 
and the
 
application for
 
the extension
 
must be
 
submitted prior
 
to the
 
expiration of
 
the patent.
 
The U.S.
 
Patent and
 
Trademark
Office, or USPTO, in consultation with the FDA,
 
reviews and approves the application for any patent term extension or
 
restoration. In
the future, we may
 
apply for extension of
 
patent term for our
 
currently owned or licensed
 
patents to add patent
 
life beyond its current
expiration date, depending
 
on the expected
 
length of the
 
clinical trials and
 
other factors involved
 
in the filing
 
of the relevant
 
NDA or
BLA.
 
 
U.S. Foreign Corrupt Practices Act
 
In general, the Foreign Corrupt Practices Act of 1977, as amended,
 
or the FCPA, prohibits offering to pay,
 
paying, promising to pay, or
authorizing the
 
payment of
 
money or
 
anything of
 
value to
 
a foreign
 
official in
 
order to
 
influence any
 
act or
 
decision of
 
the foreign
official in his
 
or her official
 
capacity or to secure
 
any other improper advantage
 
in order to obtain
 
or retain business for
 
or with, or
 
in
order to direct business to, any person. The prohibitions apply
 
not only to payments made to “any foreign official,” but also those made
to “any foreign political party
 
or official thereof,” to “any candidate
 
for foreign political office” or to
 
any person, while knowing that
 
all
or a portion of the payment
 
will be offered, given, or
 
promised to anyone in any of
 
the foregoing categories. “Foreign officials” under
the FCPA include officers
 
or employees
 
of a
 
department, agency, or instrumentality
 
of a
 
foreign government.
 
The term
 
“instrumentality”
is broad and can include state-owned or state-controlled entities.
 
Importantly, United States authorities that enforce the FCPA, including the Department of Justice, deem most health care professionals
and other employees of foreign
 
hospitals, clinics, research facilities and
 
medical schools in countries with
 
public health care or
 
public
education systems to be “foreign officials” under the FCPA. When we interact with foreign health care professionals and researchers in
testing and marketing our products abroad, we must have policies and procedures in place sufficient to prevent us and agents acting on
our behalf
 
from providing
 
any bribe,
 
gift or
 
gratuity,
 
including excessive
 
or lavish
 
meals, travel
 
or entertainment
 
in connection
 
with
marketing our future products and services or securing required permits
 
and approvals such as those needed to initiate
 
clinical trials in
foreign jurisdictions.
 
The FCPA
 
also obligates
 
companies whose
 
securities are
 
listed in
 
the United
 
States to
 
comply with
 
accounting
provisions requiring the maintenance
 
of books and records
 
that accurately and fairly
 
reflect all transactions of
 
the corporation, including
international subsidiaries, and the development and
 
maintenance of an adequate system of internal
 
accounting controls for international
operations. The Securities and Exchange Commission is involved with the books and records provisions of the FCPA.
Regulation in Europe and Other Regions
In addition
 
to regulations
 
in the
 
United States,
 
we and
 
our collaborators
 
are subject
 
to a
 
variety of
 
regulations in
 
other jurisdictions
governing, among other things, clinical trials and any commercial sales and distribution of our products.
Whether or
 
not we
 
or our
 
collaborators obtain
 
FDA approval
 
for a
 
product, we
 
must obtain
 
the requisite
 
approvals from
 
regulatory
authorities in
 
foreign countries
 
prior to
 
the commencement
 
of
 
clinical trials
 
or marketing
 
of
 
the product
 
in those
 
countries. Certain
countries outside
 
of the
 
United States
 
have a
 
similar process
 
that requires
 
the submission
 
of a
 
clinical trial
 
application much
 
like the
IND
 
prior
 
to
 
the
 
commencement
 
of
 
human
 
clinical
 
trials.
 
In
 
the
 
European
 
Union,
 
for
 
example,
 
a
 
CTA
 
must
 
be
 
submitted
 
to
 
each
country’s national
 
health authority and
 
an independent ethics committee,
 
much like the
 
FDA and IRB,
 
respectively. Once
 
the CTA
 
is
approved in accordance with a country’s requirements, clinical trial development may proceed.
The requirements and process governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country
to country.
 
In all cases,
 
the clinical trials
 
are conducted in
 
accordance with GCPs
 
and the
 
applicable regulatory requirements
 
and the
ethical principles on human subjects research that have their origin in the Declaration of Helsinki.
To
 
obtain regulatory
 
approval of
 
an investigational
 
drug or
 
biological product
 
under European
 
Union regulatory
 
systems, we
 
or our
strategic partners must submit a marketing authorization application.
 
The application in the European Union is
 
similar to that required
in the United States, with the exception of, among other things, country-specific document requirements.
For other countries
 
outside of the
 
European Union, such
 
as countries in
 
Asia, Europe and
 
Latin America, the
 
requirements governing
the conduct of clinical trials, product licensing,
 
pricing and reimbursement vary from country
 
to country. In all cases, again, the clinical
trials are conducted in
 
accordance with GCPs and
 
the applicable regulatory requirements
 
and the ethical principles
 
that have their origin
in the Declaration of Helsinki.
43
Employees and Human Capital Resources
As of December 31, 2023, we employed 57 full-time
 
employees and 8 part-time employees. Of these 57
 
full-time employees, 54 were
located in the
 
United States, 2
 
were located in
 
Ireland and 1
 
was located in
 
the UK.
 
As of March
 
1, 2024, we
 
employed 50 full-time
employees and 9 part-time employees. Of these 50 full-time employees, 47 were located in the United States, 2 were located in Ireland
and 1 was located in
 
the UK.
 
None of our employees are
 
represented by a labor union
 
or are party to a
 
collective bargaining agreement,
and we have had no labor-related work stoppages.
 
Compensation, Benefits, Recruitment and Retention Strategy
We aim to focus on attracting,
 
motivating and retaining
 
talented employees with
 
relevant experience who
 
can contribute to
 
the sustained
performance of the Company and its day-to-day operations.
We believe our total compensation package helps recruit
 
and retain our employees.
 
We strive to provide compensation and benefits that
are competitive to market
 
and create incentives
 
to attract and retain
 
employees. Our compensation
 
package includes market-competitive
pay,
 
broad-based stock
 
grants, health
 
care and
 
401(k) plan
 
benefits, paid
 
time off
 
and family
 
leave, among
 
others. We
 
also provide
annual incentive bonus opportunities that are
 
tied to both company performance
 
as well as individual performance
 
to foster a pay-for-
performance culture.
Scientific Advisory Board
We have assembled a highly qualified scientific
 
advisory board composed of advisors
 
who have deep expertise
 
in the fields of biologics
and vaccine development, as well as in the relevant therapeutic areas for our product candidates.
Immunology & Vaccinology
Thomas P.
 
Monath, M.D.
Wayne Koff, Ph.D.
Stanley A. Plotkin, M.D.
Neurology
Brad Boeve, M.D.
Richard Mohs, Ph.D.
Jeffrey Cummings, M.D.
Eric Reiman, M.D.
Nick Fox, M.D.
Stephen D. Silberstein, M.D.
Cardiovascular
Kausik K. Ray, M.D.
Stephen Nicholls, Ph.D.
Frederick Raal, Ph.D.
Dirk von Lewinski, M.D.
Parviz Ghahramani, Ph.D.
 
 
44
Item 1A. Risk Factors.
Investing in our Class A common stock involves a high degree of risk.
 
The following information sets forth risk factors that could
cause our actual results to differ materially from those contained in forward-looking statements we have made in this Annual Report
on Form 10-K and those we may make from time to time. You should carefully consider the risks described below, in addition to the
other information contained in this Report and our other public filings, before you decide to purchase shares of our Class A common
stock. Our business, financial condition or results of operations could be harmed by any of these risks. The risks and uncertainties
described below are not the only ones we face. Additional risks not presently known to us or other factors not perceived by us to
present significant risks to our business at this time also may impair our business operations.
 
Summary Risk Factors
Our business is subject to a number of risks, including risks that may prevent us from achieving our business objectives or may
adversely affect our business, financial condition, results of operations and prospects. These risks are discussed more fully under Part
II, Item 1A. “Risk Factors.” The following is a summary of some of the principal risks we face:
 
 
clinical drug development involves a lengthy and expensive process, and if our pre-clinical development or clinical trials
are prolonged or delayed or do not achieve expected results, we may be unable to commercialize our product candidates;
 
 
we depend on intellectual property licensed from UBI and its affiliates, the termination of which could result in the loss
of significant rights;
 
 
even if we obtain regulatory approval of, or commercialize, any of our product candidates in one or more jurisdictions,
we may never obtain approval for, or commercialize,
 
our product candidates in other jurisdictions;
 
 
after receipt of regulatory approval for a product candidate, our products will remain subject to regulatory scrutiny and
post-marketing requirements, which may include burdensome post-approval trial or risk management requirements that
may adversely impact the financial results of any future commercialization efforts or cause us to choose not to
commercialize the product candidate;
 
 
if we are able to commercialize any product candidate, the successful commercialization of such product candidate will
depend on the extent governmental authorities, private health insurers and other third-party payors provide coverage,
adequate reimbursement levels and favorable pricing policies;
 
 
the manufacture of peptide-based medicines is complex and manufacturers often encounter difficulties in production;
 
 
we have no history of commercializing pharmaceutical products, which may make it difficult to evaluate the prospects
for our future viability;
 
 
the regulatory landscape that will govern our product candidates is uncertain, and changes in regulatory requirements
could result in delays or discontinuation of development of our product candidates or unexpected costs;
 
 
developments by competitors may render our products or technologies obsolete or non-competitive or may reduce the
size of our markets;
 
 
our capital resources may not be sufficient to successfully complete the development and commercialization of our
product candidates, which could delay, limit, reduce or terminate our development or commercialization efforts;
 
 
we have incurred significant losses since our inception, we expect to incur losses for the foreseeable future and may
never achieve or maintain profitability and there exists substantial doubt as to our ability to continue as a going
 
concern
over the next twelve months;
 
 
conflicts of interest and disputes exist and may further arise between us and UBI and its affiliates, and these conflicts and
disputes might ultimately be resolved in a manner unfavorable to us;
 
we will need to expand our organization, and we may experience difficulties in managing this growth, which could
disrupt our operations;
 
 
while our Class A common stock is expected to continue listing on The Nasdaq Global Market, there is no guarantee as
to how long such listing will be maintained;
45
 
the dual-class structure of our common stock and the Voting Agreement (as defined below) will have the effect of
concentrating voting power, which will significantly limit your ability to influence significant corporate decisions;
 
 
we rely on contract manufacturers for the manufacture of raw materials for our research programs, pre-clinical studies
and clinical trials and we do not have long-term contracts with many of these parties, which could impact our ability to
develop and commercialize our products;
 
 
undetected errors or defects in our production could harm our reputation or expose us to product liability claims;
 
 
we rely on in-licensed intellectual property and technology, and the loss of such rights, our licensors’ inability or refusal
to enforce or defend such rights, and any requirement to pay amounts under current or future agreements could harm our
business;
 
 
the degree of protection afforded by our intellectual property rights is uncertain because such rights offer only limited
protection and may not adequately protect our rights or permit us to gain or keep a competitive advantage;
 
 
we have previously identified and remediated material weaknesses, in our internal control over financial reporting and if
we are unable to maintain an effective system of internal control over financial reporting, or if we discover material
deficiencies in the future, we may not be able to accurately report our financial results or prevent fraud, and as a result,
shareholders could lose confidence in our financial and other public reporting, which would harm our business and the
trading price of our Class A common stock;
 
 
cyberattacks or other failures in our or our third-party vendors’, contractors’ or consultants’ telecommunications or
information technology systems could result in information theft, compromise, or other unauthorized access, data
corruption and significant disruption of our business operations, and could harm our reputation and subject us to liability,
lawsuits and actions from governmental authorities; and
 
 
we are subject to privacy, tax, anti-corruption and other stringent laws, regulations, policies and contractual obligations
across multiple jurisdictions and changes in, or our failure to comply with, such laws, regulations, policies and
contractual obligations could adversely affect our business, financial condition, results of operations and prospects.
Risks Related to the Discovery and Development of Product Candidates
 
Clinical drug development involves a lengthy and expensive process with uncertain timelines and uncertain outcomes,
 
and results
of earlier studies and trials may not be predictive of future results. If our pre-clinical development or clinical trials are prolonged
or delayed, or if we do not or cannot achieve the results we expect, we may be unable to obtain required regulatory approvals, and
therefore be unable to commercialize our product candidates on a timely basis or at all.
Our business is dependent on the successful development, regulatory approval and commercialization of product candidates based on
our AIM Platform. If we and our collaborators are unable to obtain approval for and effectively commercialize our product candidates,
our business would be significantly harmed. Even if we complete the necessary pre-clinical studies and clinical trials, the regulatory
approval process is expensive, time-consuming and uncertain, and we may not be able to obtain approvals for the commercialization
of any product candidates we may develop. Changes in regulatory approval policies, changes in or the enactment of additional statutes
or regulations, or changes in regulatory review processes, may cause delays in the approval of a particular product candidate or
rejection of an application for a particular product candidate. We have not obtained regulatory approval for any product candidate to
date, and it is possible that none of our existing product candidates or any product candidates we may seek to develop in the
 
future
will ever obtain regulatory approval. Any regulatory approval we ultimately obtain may be limited or subject to restrictions, including
labeling requirements, or post-approval commitments that render the approved product not commercially viable.
 
See “—Even if we
obtain approval of any of our product candidates in one or more jurisdictions, we may never obtain approval for or commercialize any
of our products in other jurisdictions, which would limit our ability to realize the full market potential of our product
 
candidates.”
 
46
To obtain the requisite regulatory approvals to market and sell any of our product candidates, we must demonstrate through extensive
pre-clinical studies and clinical trials that our products are safe and effective in humans. Clinical testing is expensive and can take
many years to complete, and its outcome is inherently uncertain. Failure can occur at any time during the clinical trial process. The
results of pre-clinical studies and early clinical trials of our product candidates may not be predictive of the results of later-stage
clinical trials and results from post-hoc data analysis may not be predictive of final results and may not support product approval.
Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy characteristics despite having
progressed through pre-clinical studies and initial clinical trials. For example, an EUA for UB-612 was denied by the TFDA in August
2021 because the neutralizing antibody response generated by UB-612, as compared to a designated adenovirus vectored vaccine, did
not me