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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, 2022
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
 
$
94.5
 
million
based upon the closing stock price of
 
issuer’s common stock on June 30, 2022, 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 15,
 
2023, the registrant
 
had
112,188,911
 
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
2023
 
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,
2022
, 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, 2022
 
(“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 for UB-612
and other product candidates 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 ability to leverage our Vaxxine
 
Platform;
 
the rate and degree of market acceptance of our products and product
 
candidates;
 
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 and 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;
 
the
 
potential
 
effects
 
of
 
government
 
regulation,
 
including
 
regulatory
 
developments
 
in
 
the
 
United
 
States
 
and
 
other
jurisdictions;
 
ability to obtain additional financing in future offerings;
 
3
 
expectations about market trends; and
 
the
 
effects
 
of
 
the
 
Russia-Ukraine
 
conflict
 
and
 
the
 
COVID-19
 
pandemic
 
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 democratizing
 
healthcare across the
 
globe. Our vision
 
is to disrupt the
existing treatment paradigm for
 
chronic diseases, increasingly dominated by
 
drugs, particularly monoclonal antibodies
 
(“mAbs”), which
suffer
 
from
 
prohibitive
 
costs
 
and
 
cumbersome
 
administration.
 
We
 
believe
 
our
 
synthetic
 
peptide
 
vaccine
 
platform
 
(“Vaxxine
Platform”) has the
 
potential to
 
enable a
 
new class
 
of therapeutics
 
that will
 
improve the
 
quality and
 
convenience of
 
care, reduce
 
costs
and increase
 
access to treatments
 
for a wide
 
range of indications.
 
Our Vaxxine
 
Platform is designed
 
to harness the
 
immune system
 
to
convert
 
the body
 
into its
 
own “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
 
Vaxxine
 
Platform has the
 
potential to
 
overcome these
 
challenges
and
 
has the
 
potential to
 
bring the
 
efficiency
 
of vaccines
 
to a
 
whole
 
new class
 
of medical
 
conditions.
 
Specifically,
 
our technology
 
is
designed
 
to
 
use
 
synthetic
 
peptides
 
to
 
mimic
 
and
 
optimally
 
combine
 
biological
 
epitopes
 
in
 
order
 
to
 
selectively
 
activate
 
the
 
immune
system,
 
producing
 
highly
 
specific
 
antibodies
 
against
 
only
 
the
 
desired
 
targets,
 
including
 
self-antigens,
 
making
 
possible
 
the
 
safe
 
and
effective
 
treatment
 
of
 
chronic
 
diseases
 
by
 
vaccines.
 
The
 
modular
 
and
 
synthetic
 
nature
 
of
 
our
 
Vaxxine
 
Platform
 
generally
 
provides
significant speed and efficiency in candidate
 
development and has generated multiple product candidates
 
that we are designing to have
safety
 
and
 
efficacy
 
equal
 
to
 
or
 
greater
 
than
 
the
 
standard-of-care
 
treatments
 
for
 
many
 
chronic
 
diseases,
 
with
 
more
 
convenient
administration and meaningfully lower costs. 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. Additionally,
 
we believe our
 
Vaxxine
 
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
 
also will
 
opportunistically
pursue infectious disease treatments. When the COVID-19 pandemic struck the world in March 2020, we quickly reallocated resources
to develop a
 
vaccine candidate. We have
 
assembled an industry-leading
 
team with
 
extensive experience developing and
 
commercializing
successful drugs
 
that is
 
committed to
 
realizing our
 
mission of
 
democratizing healthcare.
 
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.
Limitations of the Current Healthcare Paradigm
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. One class
 
of drugs in particular exemplifies the current environment: biologics,
particularly mAbs. In 2019, biologics represented eight of
 
the ten top selling drugs in
 
the United States, of which seven
 
were mAbs. The
global
 
market
 
for
 
mAbs
 
totaled
 
approximately
 
$163 billion
 
in
 
2019,
 
representing
 
approximately
 
70%
 
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.
 
Based
 
on
 
internal
 
estimates,
 
less
 
than
 
1%
 
of
 
the
 
worldwide
 
population
 
is
 
treated
 
with
 
mAbs.
Meanwhile, the
 
alternative to mAbs
 
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.
4
Our Solution
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 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 addressing
 
infectious
 
diseases, previous
 
attempts to
 
utilize vaccines
 
to address
 
chronic
 
disease have
 
not
achieved both acceptable safety and efficacy. This limitation is driven by a
 
traditional vaccine’s inability to either stimulate the requisite
antibody
 
response against
 
harmful
 
self-antigens,
 
that is,
 
break immune
 
tolerance,
 
or produce
 
acceptable levels
 
of reactogenicity,
 
the
physical manifestation of the immune
 
response to vaccination. Our
 
Vaxxine Platform technology contains modular components 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
 
Vaxxine
 
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 peptide
vaccine
 
technology
 
utilized
 
by
 
our
 
Vaxxine
 
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.
 
We
 
believe
 
our
 
Vaxxine
 
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:
Cost
:
 
Monoclonal
 
antibodies
 
require
 
costly
 
and
 
complex
 
biological
 
manufacturing
 
processes.
 
Our
manufacturing
 
process
 
is
 
chemically
 
based
 
and
 
highly
 
scalable
 
and
 
requires
 
lower
 
capital
 
expenditures.
 
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
:
 
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.
Efficacy
: In
 
our
 
clinical
 
trials conducted
 
to
 
date, our
 
product
 
candidates
 
have yielded
 
high
 
response
 
rates
(95% or above at target
 
dose levels) for UB-311,
 
UB-312 and UB-612, high
 
target-specific antibodies against
 
self-antigens (as seen in
UB-311 and
 
UB-312 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).
 
See our descriptions
 
of these clinical
 
trials under
 
“—Our Product
 
Candidates.” We
 
also believe that
the improved convenience of our product candidates
 
as compared to mAbs has the potential to lead to increased
 
adherence by patients.
Furthermore,
 
our Vaxxine
 
Platform enables
 
the combining
 
of target
 
antigens into
 
a single
 
formulation.
 
For indications
 
that could
 
be
treated more effectively with a multivalent approach, we believe our Vaxxine
 
Platform would have an advantage over other modalities.
Finally,
 
because our
 
Vaxxine
 
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.
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 competing mAb or small molecule alternative for the relevant disease.
vaxxq410kp7i0
5
Our Pipeline
The following chart reflects our current product candidate 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.
Neurodegenerative Disease Programs:
UB-311
: Targets toxic
 
forms of aggregated amyloid-beta (“Aβ”) in the brain to fight AD. 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. 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 Phase 2b
initiation will be determined based upon the timing of a strategic partnership.
UB-312
: Targets toxic
 
forms of aggregated α-synuclein in the brain and peripheral tissues to fight PD and
other synucleinopathies, such as Lewy body dementia (“LBD”) and
 
multiple system atrophy (“MSA”). Part A of a Phase 1 trial in
healthy volunteers has been completed and has 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”). No serious
 
adverse events were
observed in Part A of the Phase 1 trial. We
 
have completed an end-of-treatment analysis of the ongoing Part
 
B of the Phase 1 trial in
PD patients, which has similarly shown UB-312 to be well tolerated and immunogenic,
 
with anti-α-synuclein antibodies observed in
the serum and CSF of PD patients.
 
We anticipate the
 
completion of Part B of the trial in PD patients in mid-2023.
 
VXX-301
:
 
We
 
are
 
developing
 
an
 
anti-tau
 
product
 
candidate
 
that
 
has
 
the
 
potential
 
to
 
address
 
multiple
neurodegenerative
 
conditions,
 
including
 
AD,
 
by
 
targeting
 
abnormal
 
tau
 
proteins
 
alone
 
and
 
in
 
potential
 
combination
 
with
 
other
pathological proteins such as Aβ to combat multiple pathological processes at once. Our lead candidate targets multiple epitopes of tau.
Next Wave Chronic
 
Disease Programs:
UB-313
:
 
Targets
 
Calcitonin
 
Gene-Related
 
Peptide
 
(“CGRP”) to
 
fight
 
migraines.
 
We
 
have
 
completed
enrollment in a first-in-human Phase 1 clinical trial, which began in
 
September 2022, and anticipate a topline readout in the mid-2023.
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. As of March
 
2023, we have begun
 
dosing of subjects in
a first-in-human clinical trial of VXX-401 in Australia.
6
Given the global COVID-19 pandemic and our Vaxxine
 
Platform’s applicability to infectious disease, we also have advanced a product
candidate that addresses SARS-CoV-2.
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.
 
Preliminary safety data show that UB-612 has been generally well tolerated
 
with no serious adverse events reported through day 57 of
data cut-off.
 
The trial is ongoing, with long-term safety and immunogenicity follow-up
 
planned through 12 months.
 
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 will review under their established work
 
share agreement.
 
We
 
believe our Vaxxine
 
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. Ulo Palm, our Chief Medical
 
Officer, and Dr.
 
Jean-
Cosme Dodart, our Senior Vice
 
President of Research. Our leadership team contributes a diverse range of
 
experiences from leading
companies including Allergan, Amgen, Eli Lilly,
 
LEO, Merck, Novavax, Novartis, and Schering-Plough, and were executives in
multiple successful mAb and vaccine launches.
 
As of December 31, 2022, we have assembled an exceptional team of approximately
92 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 develop 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, UB-313, and VXX-401 through clinical stage development
 
for the treatment of chronic diseases, either ourselves or with a
strategic partner. We
 
believe that our differentiated Vaxxine
 
Platform will enable our product candidates, if approved and successfully
commercialized,
 
to potentially disrupt the 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.
Opportunistically develop treatments for
 
infectious diseases
: While
 
our core mission
 
focuses on the
 
treatment
of chronic diseases, we are committed to bringing accessible medicines to people around
 
the world and will address infectious diseases
opportunistically. For
 
example, when the COVID-19 pandemic struck the world,
 
we rapidly deployed resources in pursuit of a product
candidate currently embodied in UB-612.
Expand
 
and
 
scale
 
our
 
existing
 
capabilities
:
 
We
 
are
 
investing
 
in
 
our
 
operational
 
processes,
 
facilities
 
and
human capital to accelerate the speed with which we can bring
 
product candidates through the development pipeline, and to
 
strengthen
the capacity for developing more product candidates simultaneously.
7
Continue to
 
improve
 
our Vaxxine
 
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
 
Vaxxine
Platform. As our
 
Vaxxine Platform further develops, we
 
believe that
 
we can
 
both increase the
 
number of product
 
candidates in
 
concurrent
development and efficiently advance product candidates
 
through pre-clinical and clinical development.
Maximize the value of
 
our product candidates through potential partnerships
: We currently retain worldwide
rights for the majority
 
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.
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 Vaxxine
 
Platform
Our Vaxxine
 
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
vaxxq410kp10i0
8
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
 
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:
Characteristics of our Product Candidates versus Monoclonal Antibodies and Small
 
Molecules
History and Design
Our Vaxxine
 
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).
vaxxq410kp11i0
9
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 Vaxxine
 
Platform to develop product
 
candidates that target chronic
 
diseases and COVID-19.
 
Our
Vaxxine
 
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.
Key Elements of our Vaxxine
 
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.
vaxxq410kp12i0
10
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 Vaxxine
 
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
 
Vaxxine
 
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
 
Vaxxine
 
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.
vaxxq410kp13i0
11
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.
vaxxq410kp14i1 vaxxq410kp14i0
12
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.
Vaxxine
 
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
13
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 Vaxxine 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 Vaxxine
 
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 Vaxxine
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 Vaxxine
 
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
 
for AD, Aβ
 
has been validated
 
as a target.
 
Both AD and
 
PD have high
 
prevalence worldwide,
 
and large unmet
 
need with 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 Vaxxine
 
Platform.
We
 
do not
 
currently
 
evaluate oncology
 
and infectious
 
diseases through
 
the above
 
framework. We
 
generally
 
do not
 
pursue oncology
targets
 
given the
 
hyper-segmentation
 
of subjects
 
common in
 
clinical development
 
efforts in
 
oncology that
 
leads to
 
relatively narrow
labels, and
 
due
 
to the
 
strengths of
 
other new
 
modalities such
 
as cell-based
 
therapy in
 
this area.
 
We
 
only consider
 
infectious disease
opportunistically. However,
 
our approach with respect to oncology and infection diseases could change
 
in the future.
We believe that our Vaxxine
 
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 Vaxxine Platform’s
 
properties drive the unique combination
 
of attributes that we
 
believe will be reflected in
 
our product candidates:
14
Cost
: Our reliance
 
on chemically linked,
 
custom peptide sequences
 
fuels cost efficiencies
 
that we expect
 
to
enable
 
broad
 
accessibility
 
to
 
our
 
product
 
candidates.
 
Foremost
 
among
 
these
 
relates
 
to
 
dosing.
 
Monoclonal
 
antibodies
 
require
 
more
physical material for annual dosing because the patient needs to be delivered the externally manufactured therapeutic antibodies, which
have high molecular weight. In contrast, our product candidates are designed to
 
stimulate the body’s immune system to produce its own
antibodies and
 
have relatively
 
low molecular
 
weight. While
 
an annual
 
supply of
 
mAbs doses
 
may include
 
grams or
 
tens of
 
grams of
drug substance, our current product candidates only
 
require 1 to 2 milligrams each, or even less, leading
 
to a relatively low annual cost
of goods. In
 
our development programs
 
to date, we
 
have achieved
 
a cost of
 
goods amounting to
 
a small fraction
 
of the typical
 
cost of
mAbs (as low as <1%).
Administration
: Administration of our product candidates generally requires three priming doses, each in the
range of several hundred
 
micrograms, followed by booster
 
doses of a similar
 
magnitude 2 to
 
4 times per
 
year. As described in the section
titled
 
“Our
 
Product
 
Candidates” below,
 
in clinical
 
trials we
 
have
 
observed
 
that our
 
product
 
candidates
 
elicited
 
a
 
sustained
 
antibody
response, with elevated antibody levels lasting six
 
months or longer. We believe this presents a meaningful advantage over many mAbs,
which commonly
 
require either bi-weekly
 
or monthly injections,
 
or monthly or
 
quarterly infusions, and
 
many small molecules,
 
which
commonly require a daily pill regimen.
Safety
: The
 
antibodies generated
 
by our
 
product candidates
 
are designed
 
to be
 
highly specific
 
to the
 
target
antigen and
 
to avoid an
 
off-target immune
 
response to the
 
peptide carrier,
 
thereby limiting
 
inflammation and
 
other off-target
 
activity.
We
 
believe
 
these characteristics
 
have yielded
 
the high
 
tolerability observed
 
in the
 
clinical studies
 
of our
 
product candidates
 
to date.
Furthermore, the
 
titer response
 
to our
 
product candidates
 
is naturally
 
titrated, which
 
may reduce
 
the likelihood
 
of an
 
antibody Cmax
safety side effect, and is naturally reversible, thus avoiding an uncontrolled
 
or permanent immune response.
Efficacy
: In
 
our
 
clinical
 
trials conducted
 
to date,
 
our
 
product candidates
 
have
 
yielded
 
comparatively
 
high
response rates (95%
 
or above at
 
target dose levels)
 
for UB-311, UB-312 and
 
UB-612, high target-specific
 
antibodies against
 
self-antigens
(as
 
seen
 
in
 
UB-311
 
and
 
UB-312
 
clinical
 
trials)
 
and
 
a
 
long
 
duration
 
of
 
action
 
for
 
UB-311
 
(based
 
on
 
titer
 
levels
 
remaining
 
elevated
between doses)
 
and UB-612
 
(based on
 
half-life). Furthermore,
 
our Vaxxine
 
Platform enables
 
the combining
 
of target
 
antigens into
 
a
single formulation. For indications that could be treated more effectively with a multivalent approach, we believe our Vaxxine Platform
would have an advantage over other modalities. Finally,
 
because our Vaxxine
 
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.
Additionally,
 
we believe our
 
Vaxxine
 
Platform possesses important
 
benefits reflected
 
at the platform
 
level, as opposed
 
to the product
candidate level:
Product Candidate Discovery
: Our Vaxxine
 
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
 
Vaxxine
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 caring for
 
individuals with AD and other
 
dementias in the United
 
States were estimated at
 
$305 billion in 2020 according
 
to a
15
study
 
published
 
by
 
the
 
American
 
Journal
 
of
 
Managed
 
Care,
 
and
 
are
 
projected
 
to
 
increase
 
to
 
$1.1
 
trillion
 
by
 
2050
 
according
 
to
 
the
Alzheimer’s Association. 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
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 two 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 anti-Aβ immunotherapies.
 
Despite the milestone
 
in the treatment
 
of AD that
 
aducanumab’s
 
approval represents,
 
the drug has
 
several limitations.
 
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
 
hours-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
16
an insufficiently
 
sized safety database
 
in its Phase
 
2 trial; however,
 
Lilly has announced
 
its intention to
 
file 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 hours-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 announced that their
wholesale
 
acquisition
 
cost
 
(“WAC”)
 
launch
 
price
 
in
 
the
 
U.S.
 
will
 
be
 
$26,500
 
for
 
the
 
drug
 
product
 
only,
 
which
 
does
 
not
 
include
administration and
 
ongoing monitoring
 
costs.
 
It remains to
 
be seen whether
 
and to what
 
extent CMS will
 
reimburse treatment
 
of AD
patients with lecanemab.
 
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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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
 
an 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 serious adverse events 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
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
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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
 
serious adverse
events 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 serious
 
adverse event
 
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 serious adverse
 
event 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
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.
20
Development Plans for UB-311
We have completed
 
a pre-Phase 3 meeting with the FDA and obtained guidance on the further development of
 
UB-311.
Subject to the
 
FDA’s
 
review, we
 
plan to conduct
 
a randomized, double-blinded,
 
placebo-controlled Phase
 
2b efficacy trial
 
of UB-311
in approximately
 
900 subjects
 
with early
 
AD. The
 
Phase 2b
 
trial will
 
include subjects
 
diagnosed
 
with early
 
AD with
 
MMSE scores
between 22 and 30. We will also screen to enrich
 
for positive amyloid PET, positive tau PET and positive
 
plasma p-tau181, in quantities
consistent with an early AD population. Subjects in the active arm will receive UB-311 as three 300μg priming
 
doses at weeks 0, 4 and
12, followed by
 
four 300μg booster
 
doses every three
 
months thereafter.
 
The primary objective
 
of this trial will
 
be to assess
 
the effect
of UB-311
 
on the
 
decline of
 
cognitive
 
and functional
 
performance as
 
measured by
 
the CDR-SB
 
over the
 
78-week
 
treatment period.
Secondary endpoints
 
will include
 
the changes
 
from baseline
 
measurements of
 
other validated
 
clinical outcomes
 
scores. The
 
effect of
UB-311 on specific AD biomarkers will also be evaluated, including neurofilament light arm (“NfL”), p-tau, total-tau, brain amyloid as
measured by PET,
 
Aβ-40 and Aβ-42, hippocampal volume and whole brain volume
 
as measured by MRI, and an assessment of certain
CSF biomarkers.
 
We
 
plan to
 
collaborate the
 
development of
 
UB-311
 
with a
 
strategic partner
 
and plan
 
to initiate
 
the Phase
 
2b trial
 
in
collaboration with such strategic partner.
Assuming positive
 
results in the
 
Phase 2b trial,
 
we intend to
 
initiate (with the
 
same partner) a
 
Phase 3 trial
 
in subjects with
 
early AD.
The Phase 3 program may involve one, but more likely two, clinical trials,
 
conducted at multiple international sites. Assuming
 
positive
results in the Phase 2b trial, we may also seek FDA approval 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. If
 
such Phase 2b trial
 
and the
Phase
 
3
 
program
 
are
 
successful,
 
they
 
may
 
together provide
 
sufficient
 
data
 
to enable
 
BLA filing
 
with
 
the FDA,
 
but
 
there
 
can be
 
no
guarantee that these trials
 
will lead to positive data
 
or that we will not need
 
to conduct additional trials or
 
studies prior to a BLA
 
filing
with the FDA.
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.
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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.
 
Preliminary clinical
 
data from
 
our ongoing
 
Phase 1
 
trial indicate
 
that UB-312
elicits antibody
 
levels sufficient
 
to cross
 
the BBB (i.e.,
 
detectable in
 
CSF). In
 
2018, the
 
European Medical
 
Agency (“EMA”)
 
granted
UB-312 orphan designation for MSA.
Clinical Development
We have completed
 
Part A of a randomized, placebo-controlled, double-blind, dose-escalating,
 
single- center Phase 1 clinical trial of
UB-312 in which 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 trial, subjects received three doses
 
(on weeks 1, 5 and 13) with escalating doses ranging from
40μg to 2,000μg. Immunogenicity was evaluated by measuring changes
 
in serum anti-α-synuclein antibody concentrations during the
course of the study.
 
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: 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. Based on these results, we are now evaluating
two dosing regimens of UB-312 in Part B of the Phase 1 trial: three doses of 300μg,
 
and one dose of 300μg followed by two doses of
100μg. Part B, which began enrollment in January 2022, is evaluating
 
UB-312 and placebo in 20 PD subjects. In addition to the
endpoints evaluated in Part A, an exploratory endpoint involving a clinical
 
assessment using the Movement Disorder Society –
Unified Parkinson’s Disease Response
 
Score will be used.
The Michael J. Fox Foundation (“MJFF”) is funding 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 protein misfolding cyclic amplification (“PMCA”) to
 
assess target engagement and will also aim to
characterize the anti-α-synuclein antibodies produced after immunization
 
with UB-312. Demonstrating whether pathological forms of
α-synuclein are detectable in the CSF of PD subjects, and whether UB-312
 
-derived antibodies alter CSF levels of α-synuclein seeds
measured by PMCA, might provide a meaningful surrogate marker of
 
target engagement.
 
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 serious
adverse event (“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
 
serious adverse
 
events were
 
observed
 
in Part
 
B, which
 
remains
 
blinded,
 
meaning
 
it remains
 
unknown
 
in which
treatment group they occurred (UB-312 or placebo).
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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).
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).
23
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
While certain portions of this Phase 1
 
trial were interrupted by the COVID-19 pandemic, Part
 
A in 50 healthy volunteers was
 
completed
in 2020, and we began dosing
 
PD subjects in Part B in
 
early 2022. In Part B
 
we have included exploratory endpoints potentially relevant
to PD, such
 
as total and
 
free α-synuclein
 
in serum and
 
CSF,
 
in addition to
 
T-cell
 
ELISpot analyses and
 
antibody characterization.
 
We
expect to complete Part B in mid-2023.
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
 
Vaxxine
 
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
 
Treatments
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.
Our next
 
wave chronic
 
disease program
 
is initially
 
focused on
 
migraine and
 
hypercholesterolemia. 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.
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.
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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. Sales for marketed
 
and clinical-stage anti-CGRP therapeutics are projected to reach
approximately $7.4 billion by 2026. 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 prophylactic
 
treatment initially for chronic migraine.
 
We believe
 
UB-313 has the potential to improve
upon the current treatments for
 
chronic 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.
Pre-Clinical Studies
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.
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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
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 proper
 
ties to two approved CGRP mAbs.
Moreover, the binding potency of
 
UB-313 was determined to be comparable to these mAbs.
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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.
Development Strategy
A single-site,
 
randomized, placebo-controlled,
 
first-in-human Phase
 
1 clinical
 
trial is
 
underway in
 
40 healthy
 
volunteers, designed
 
to
measure the
 
safety,
 
tolerability,
 
and immunogenicity
 
of multiple priming
 
dose regimens of
 
UB-313, was
 
initiated in September
 
2022.
 
The study
 
is also
 
measuring dermal
 
blood flow
 
following a
 
capsaicin
 
challenge at
 
multiple timepoints,
 
a well-established
 
model for
CGRP
 
target
 
engagement
 
and efficacy
 
in
 
the preventive
 
treatment
 
of
 
migraine.
 
The
 
trial is
 
fully
 
enrolled,
 
and
 
we
 
expect a
 
topline
readout in the first half of 2023.
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,
vaxxq410kp29i0
27
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 $1.3 billion in 2020
 
and is expected to
 
grow to approximately $5.2 billion
by 2026, including the addition of inclisiran to the
 
market. In addition, both are administered bi-weekly (evolocumab also allows
 
for the
option of taking
 
a higher dose
 
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
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 Studies
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.
In two studies
 
of VXX-401 in
 
cynomolgus monkeys,
 
VXX-401 reduced LDL-c
 
by up to 54%,
 
an effect sustained
 
for a long
 
duration.
 
In the first study, 3 monkeys received six 300µg IM injections of VXX-401,
 
and 6 monkeys started on placebo with the same schedule.
 
At week 19 (final dose),
 
3 of the 6 placebo
 
monkeys were given 3mg/kg
 
evolocumab to determine the
 
comparability of the magnitude
of LDL reduction with
 
VXX-401.
 
LDL in monkeys treated
 
with evolocumab reduced
 
to approximately the level
 
of those treated with
VXX-401, then returned to near-baseline, while LDL levels in
 
the VXX-401-treated group remained low.
VXX-401 Reduces LDL up to 54% vs. Placebo, Comparable to a
 
Single Dose of an Approved MAb
The
 
VXX-401
 
group
 
(n=3)
 
received
 
a
 
non-optimized
 
vaccine
 
formulation
 
containing
 
the
 
same
 
peptide
 
immunogen
 
as
 
the
 
VXX-401
clinical vaccine
 
candidate and
 
experienced up
 
to a 54%
 
reduction in
 
serum LDL-c from
 
baseline.
 
The placebo
 
and VXX-401 groups
received IM injections at weeks 0, 3, 6, 13, 16, and 19.
 
The evolocumab group received
 
placebo IM injections at weeks 0, 3, 6, 13, and
16, and a dose of evolocumab at week 19.
vaxxq410kp30i0
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In the second study we explored a range of doses in 15 cynomolgus monkeys, which received either 0, 10, 30,
 
100, 300, or 900µg/dose
by 0.5mL IM injection at weeks
 
0, 3, and 6, with follow-up
 
through week 24.
 
In this study we found that
 
three doses of VXX-401 could
product a sustained
 
reduction of serum
 
LDL, returning to near-baseline
 
after 24 weeks.
 
Furthermore, animals received
 
a booster dose
of VXX-401 at week 24, which triggered a rapid anti-PCSK9 antibody response
 
and a corresponding reduction in serum LDL.
Reduction in LDL Correlates with Anti-PCSK9 Antibodies Elicited by
 
VXX-401
The left-hand panel shows the generation of serum anti-PCSK9 antibody
 
titers in cynomolgus monkeys treated with 100µg VXX-401
at weeks 0, 3, 6, and 24 as measured by EIA.
 
These levels correlate with serum LDL level over time, as
 
depicted in the right-hand
panel, represented
 
as a difference from controls.
 
An adjuvant control group
 
(n=3, not shown), was also included in the study;
animals in the adjuvant group did not produce
 
an anti-PCSK9 antibody response, similar to the
 
PBS control group.
A GLP toxicology study was completed in monkeys, which demonstrated
 
that 5 doses of VXX-401 were safe and well tolerated, with
no clinical observations and no pathological findings.
 
Importantly, we found that LDL
 
reduction in VXX-401-treated monkeys in this
study was consistent with observations from preclinical efficacy
 
studies, and supportive of moving VXX-401 into clinical trials.
 
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 this
 
trial we
 
aim to
evaluate 48
 
subjects with
 
elevated cholesterol,
 
monitoring for
 
safety,
 
immunogenicity,
 
and relevant
 
biomarkers.
 
We
 
expect a
 
topline
readout by early 2024.
 
In a potential subsequent Phase 2 trial we may test VXX-401 alone and in combination
 
with statins.
Next Stage Development Candidates
In addition to our
 
initial focus on
 
migraines and hypercholesterolemia, we
 
believe our Vaxxine 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.
 
The
 
World
 
Health
 
Organization
 
(“WHO”)
 
declared
COVID-19 a public health
 
emergency of international
 
concern. As of January 2023,
 
there have been more
 
than 694 million confirmed
COVID-19 cases and
 
more than
 
6.7 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.
vaxxq410kp31i0
29
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 January 2023, over five 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 2.6
 
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
 
will
 
last
 
for
 
the
 
foreseeable
 
future,
 
particularly
 
in
 
low-
 
and
 
middle-income
countries
 
(“LMICs”).
 
We
 
also
 
anticipate
 
demand
 
for
 
more
 
types
 
of
 
vaccine
 
technologies,
 
beyond
 
the
 
readily
 
available
 
mRNA,
adenovirus vector, and inactivated virus vaccine
 
options.
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
 
authorization
 
for
 
UB-612
 
as
 
a
heterologous boost and have agreement with two high-income country regulators
 
about our development approach.
Components of the UB-612 Multitope Vaccine
 
Product Candidate
UB-612’s
 
construct contains an S1-RBD-sFc fusion protein for its B-cell epitopes, plus five synthetic Th/CTL peptides for class I and II
MHC molecules
 
derived from
 
SARS-CoV-2
 
S2, M
 
and N
 
proteins,
 
and the
 
UBITh1a peptide.
 
These components
 
are
 
formulated with
CpG1, which binds the positively charged peptides by dipolar interactions and also serves as an adjuvant, which is then bound to Adju-
Phos adjuvant to constitute the UB-612 product
 
candidate.
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 is an active-controlled,
 
randomized trial being 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
 
have been 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
 
is to
 
determine
 
non-inferiority
 
of UB-612-stimulated
 
neutralizing
 
antibodies against
those of the comparator vaccines.
 
CEPI is co-funding this trial, which is expected to conclude in the second half of 2023.
 
vaxxq410kp32i0
30
Following
 
positive
 
topline
 
results
 
announced
 
in
 
December
 
2022,
 
we
 
have
 
completed
 
submissions
 
for
 
conditional/provisional
authorization
 
with
 
the
 
Medicines
 
and
 
Healthcare
 
products
 
Regulatory
 
Agency
 
(“MHRA”)
 
in
 
the
 
UK,
 
and
 
the
 
Therapeutic
 
Goods
Administration
 
(“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 ongoing 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
 
at topline readout.
 
The primary endpoints
 
of the trial
 
are safety and
 
live virus
 
neutralizing antibody
titers against
 
the Wuhan
 
strain of
 
SARS-CoV-2
 
at day
 
29.
 
Secondary immunogenicity
 
endpoints include
 
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
 
study is to determine non-inferiority
 
of UB-612-stimulated neutralizing
 
antibodies against those
of the comparator vaccines, where statistical non-inferiority is 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)
Neutralizing Antibodies Against Wuhan
 
(left panel) and Omicron BA.5 (right panel) at Day 29
The above results from a live virus neutralization assay at day 29
 
suggests that the immune response of UB-612 as a
 
heterologous boost
is non-inferior to that
 
of BNT162b2 as a
 
homologous boost, superior to
 
ChAdOx1-S, and superior to
 
BIBP.
 
The relative performance
of UB-612 versus the comparators against Omicron
 
BA.5 is better than that against Wuh
 
an.
SCR as measured
 
against Wuhan
 
and Omicron BA.5 are
 
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,
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).
vaxxq410kp33i0
31
Preliminary safety data from the
 
Phase 3 trial shows that UB-612
 
continues to be generally well tolerated; no
 
serious adverse reactions
were reported.
 
The trial remains ongoing, and the long term safety profile
 
continues to be evaluated.
 
The trial is expected to conclude
in the second half of 2023.
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.
Viral-neutralizing
 
antibody titers
 
(VNT
50
) up
 
to 154
 
days after
 
the second
 
dose (day
 
196) in
 
the Phase
 
1 trial
 
of UB-612
 
remained at
52% of the maximum level
 
observed following the second dose,
 
on average. Based on
 
the interim six-month cutoff, the
 
UB-612-specific
neutralizing antibody half-life was estimated to be 195 days using
 
an exponential model.
Time Course of SARS-CoV-2 Antibody Neutralization
 
Responses after Vaccination
Data from a micro-neutralization assay
 
of sera from subjects
 
who received two 100μg
 
doses of UB-612
 
yielded an estimated
 
neutralizing
titer half-life of 195 days (CI: 136, 349) using an exponential model.
32
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%.
The Phase 2 interim analysis suggests that
 
Phase 1 observations on immunogenicity, neutralizing titers and tolerability are reproducible,
with an overall seroconversion rate of 94.7% one month after the second dose. In a live virus
 
(Wuhan) neutralization test, sera collected
from UB-612 vaccinated younger adults (19-64
 
years, n=322), 28 days after
 
the second dose (day 57)
 
were estimated to reach geometric
mean titers (“GMT”) of 102 of
 
50% virus-neutralizing antibodies (VNT
50
).
Sera collected from a subset of
 
subjects (n=48) 28 days after
the second
 
immunization was shown
 
to neutralize several
 
SARS-CoV-2
 
variants, with
 
the loss of
 
neutralization activity
 
against Delta
estimated at 1.39-fold when compared to the neutralizing antibodies against the parental Wuhan
 
virus.
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
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.
vaxxq410kp35i0
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Third immunization with UB-612 Produces Neutralizing
 
Antibodies Against Omicron
 
Phase 1 extension subjects (n=15) received primary
 
series with UB-612 100µg. Serum is taken 28 days after the second dose and 14
days after the third booster immunization
 
administered 7-9 months after the primary series. Live virus neutralization
 
test against
Wuhan and Omicron
 
are performed at VisMederi;
 
results are expressed
 
as virus neutralization antibody GMT ± 95% CI.
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 around 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 will review under their
 
established work share agreement.
 
We expect to complete the ongoing Phase 3 trial
 
of UB-612 as a heterologous booster
 
in the second half of
 
2023, with continued support
from CEPI.
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.
34
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.
 
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.
 
CGRP-Directed Migraine Treatments
Six 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),
 
also approved
 
for
 
the treatment
 
of acute
migraine,
 
is sold
 
by Pfizer
 
following
 
its acquisition
 
of Biohaven.
 
Atogepant
 
(Qulipta), developed
 
by AbbVie,
 
was approved
 
for
 
the
preventive treatment of episodic migraine.
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.
Collaborations
From
 
time to
 
time, we
 
may
 
enter
 
into licensing
 
and
 
commercialization
 
agreements
 
when they
 
align with
 
our mission,
 
including
 
the
Platform
 
License
 
Agreement
 
described
 
under
 
“—Intellectual
 
Property—Platform
 
License
 
Agreement”
 
and
 
the
 
agreement
 
with
 
our
partner Aurobindo.
Aurobindo License Agreement
In
 
December
 
2020,
 
we
 
entered
 
into
 
an
 
exclusive
 
license
 
agreement
 
with
 
Aurobindo
 
(as
 
amended,
 
the
 
“Aurobindo
 
Agreement”)
 
to
develop
 
and
 
commercialize
 
UB-612
 
to India
 
and
 
other
 
territories.
 
Pursuant
 
to
 
the Aurobindo
 
Agreement,
 
we
 
granted
 
Aurobindo
 
an
exclusive license
 
(with certain
 
rights reserved
 
to us) to
 
develop, manufacture
 
and commercialize UB-612
 
in India
 
and other countries
through
 
UNICEF
 
and
 
a
 
non-exclusive
 
license
 
to
 
develop,
 
manufacture
 
and
 
commercialize
 
UB-612
 
in
 
other
 
selected
 
emerging
 
and
developing markets.
 
The Aurobindo Agreement may be terminated (i) by Aurobindo, without
 
cause at any time after three years following the effective
date or prior to such time if UB-612 fails to meet clinical endpoints or fails in development,
 
(ii) by us, (a) if Aurobindo disputes the
patentability, enforceability
 
or validity of our patent rights related to the UB-612 technology,
 
(b) in case of a suit alleging Aurobindo’s
use of the licensed intellectual property infringes a third party’s
 
intellectual property rights if we reasonably believe the license is no
longer commercially reasonable in light of such claim or (c) without cause
 
at any time after four years following the effective date,
(iii) by either party in the event of the other party’s
 
material breach of its obligations under the Aurobindo Agreement (subject to
 
a
cure period) or (iv) by either party in the event of the other party’s
 
insolvency.
 
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
35
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 and Wuxi
 
STA
 
for
process development and manufacturing services of oligonucleotides.
 
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
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 Vaxxine
 
Platform and each of our
product candidates. As of December 31, 2022 our patent estate include
 
d
 
three U.S. issued patents, twelve U.S. patent applications, five
U.S. provisional
 
patent applications,
 
four pending
 
Patent Cooperation
 
Treaty (“PCT”)
 
patent applications,
 
60 issued
 
non-U.S. patents
and 158 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 directed to peptide vaccines for the prevention and treatment of
neurodegenerative
 
diseases.
 
These
 
issued
 
patents
 
and
 
patent
 
applications,
 
if
 
issued,
 
are
 
expected
 
to
 
expire
 
between
 
2023
 
and
 
2043,
excluding any patent term adjustments or patent term extensions.
36
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 may be
 
provided by a
 
patent family being prosecuted
 
in the United
 
States, Australia, Brazil,
Canada, China, India, Indonesia,
 
Japan, Mexico, Russia,
 
the Republic of
 
Korea, Singapore, Taiwan and the United
 
Arab Emirates. 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,
 
India, Indonesia, Japan,
 
Mexico, the Philippines,
 
the Republic of
 
Korea, Taiwan,
 
and the
United
 
Arab Emirates.
 
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 pending patent applications
 
in the United
States,
 
Australia,
 
Brazil,
 
Canada,
 
India,
 
Indonesia,
 
Japan,
 
Pakistan,
 
the
 
Philippines,
 
the
 
Republic
 
of
 
Korea,
 
Russia,
 
Saudi
 
Arabia,
 
Taiwan, United Arab Emirates, and Vietnam, four pending
 
PCT patent applications and
 
one provisional patent applications
 
in the United
States. These 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 2041 and 2042, excluding any patent term adjustments
 
or patent term extensions.
For each product
 
candidate utilizing the
 
Vaxxine
 
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, Austria,
 
Belgium, Brazil,
 
Canada, Chile,
 
China, Colombia,
 
Denmark,
 
the EPO,
 
France, Germany,
 
Hong Kong,
 
Indonesia,
India, Ireland, Israel, Italy, Japan, Mexico,
 
the Netherlands, New Zealand, Peru, Philippines, the Republic of Korea, Russia, Singapore,
South
 
Africa,
 
Spain,
 
Sweden,
 
Switzerland/Liechtenstein,
 
Taiwan,
 
Thailand,
 
the
 
United
 
Arab
 
Emirates,
 
the
 
United
 
Kingdom
 
and
Vietnam.
 
These issued patents
 
and patent applications,
 
if issued, are
 
expected to expire
 
between 2023
 
and 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
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
37
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.
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.
38
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
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
39
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
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.
40
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