UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
(Mark One)
Annual report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
for the
fiscal year
or
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for the transition period from to .
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The aggregate market value of registrant’s voting and non-voting outstanding common stock held by non-affiliates was approximately $
based upon the closing stock price of issuer’s common stock on June 30,
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determination of affiliate status is not necessarily a conclusive determination for other purposes.
As of March 25, 2024, the registrant had
par value Class B common stock outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
Portions of the following document are incorporated by reference in Part III of this Report: the registrant’s definitive proxy statement relating to its
2024 Annual Meeting of Shareholders. We currently anticipate that our definitive proxy statement will be filed with the SEC no later than 120 days
after December 31, 2023, pursuant to Regulation 14A of the Securities Exchange Act of 1934, as amended.
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TABLE OF CONTENTS
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Item 15.
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PART I
Unless otherwise indicated in this report, “Vaxxinity ,” “we,” “us,” “our,” and similar terms refer to Vaxxinity, Inc. and our consolidated
subsidiaries.
SPECIAL NOTE REGARDING FORWARD -LOOKING STATEMENTS
This Annual Report on Form 10-K for the year ended December 31, 2023 (“Report”) contains forward-looking statements. Forward-
looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs,
expectations and assumptions regarding the future of our business, future plans and strategies and other future conditions. In some cases,
you can identify forward-looking statements because they contain words such as “anticipate,” “believe,” “estimate,” “expect,” “intend,”
“may,” “predict,” “project,” “target,” “potential,” “seek,” “will,” “would,” “could,” “should,” “continue,” “contemplate,” “plan,” other
words and terms of similar meaning and the negative of these words or similar terms.
Forward-looking statements are subject to known and unknown risks and uncertainties, many of which may be beyond our control. We
caution you that forward-looking statements are not guarantees of future performance or outcomes and that actual performance and
outcomes may differ materially from those made in or suggested by the forward-looking statements contained in this Report. In addition,
even if our results of operations, financial condition and cash flows, and the development of the markets in which we operate, are
consistent with the forward-looking statements contained in this Report, those results or developments may not be indicative of results
or developments in subsequent periods. New factors emerge from time to time that may cause our business not to develop as we expect,
and it is not possible for us to predict all of them. Factors that could cause actual results and outcomes to differ from those reflected in
forward-looking statements include, among others, the following:
• the prospects of UB-612 and other product candidates, including the timing of data from our clinical trials and our
ability to obtain and maintain regulatory approval for our product candidates;
• our ability to develop and commercialize new products and product candidates;
• our substantial doubt about our ability to continue as a going concern;
• our ability to leverage our AIM Platform (defined below);
• the rate and degree of market acceptance of our products and product candidates;
• decreased demand for our COVID-19 product candidate, if and when such product candidate is approved;
• our status as a clinical-stage company and estimates of our addressable market, market growth, future revenue,
expenses, capital requirements and our needs for additional financing;
• our ability to comply with multiple legal and regulatory systems relating to privacy, tax, anti-corruption and other
applicable laws;
• our ability to hire and retain key personnel and to manage our future growth effectively;
• competitive companies and technologies, including existing third party approved and market accepted products in our
industry and our ability to compete;
• our and our collaborators’, including United Biomedical’s (“UBI”), ability and willingness to obtain, maintain, defend
and enforce our intellectual property protection for our proprietary and collaborative product candidates, and the scope
of such protection;
• the performance of third-party suppliers and manufacturers and our ability to find additional suppliers and
manufacturers;
• our ability and the potential to successfully manufacture our product candidates for pre-clinical use, for clinical trials
and on a larger scale for commercial use, if approved;
• the ability and willingness of our third-party collaborators to continue research and development activities relating to
our product candidates;
• general economic, political, demographic and business conditions in the United States, Taiwan and other jurisdictions;
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• the potential effects of government regulation, including regulatory developments in the United States and other
jurisdictions;
• our ability to obtain additional financing in future offerings;
• our ability to maintain our listing on The Nasdaq Global Market;
• expectations about market trends; and
• the effects of the ongoing conflicts between Russia and Ukraine or Israel and Hamas and increased tension between
Taiwan and China on business operations, the initiation, development and operation of our clinical trials and patient
enrollment of our clinical trials.
We discuss many of these factors in greater detail under Item 1A. “Risk Factors.” These risk factors are not exhaustive and other sections
of this report may include additional factors which could adversely impact our business and financial performance. Given these
uncertainties, you should not place undue reliance on these forward-looking statements.
You should read this Report and the documents that we reference in this Report and have filed as exhibits completely and with the
understanding that our actual future results may be materially different from what we expect. We qualify all of the forward- looking
statements in this Report by these cautionary statements. Except as required by law, we undertake no obligation to publicly update any
forward-looking statements, whether as a result of new information, future events or otherwise.
Item 1. Business.
Overview
We are a purpose-driven biotechnology company committed to positively impacting humanity by democratizing healthcare across the
globe. Our metric for success is simple: amount of human suffering alleviated. We doggedly pursue this as our north star, and aim to be
number one in the world at this metric. Our vision is to redefine the paradigm for tackling the global epidemic of chronic diseases, and
provide cheaper, safer, more convenient and effective medicines to all.
There are many inventions that have served thousands of lives, and some that have benefited a million lives, but only a select few that
have saved billions lives. These include the innovations of fertilizer of the green revolution to feed an exponentially growing population,
hygienic plumbing to control cholera and typhoid, and vaccines to prevent over 20 dangerous or deadly diseases. We believe that we
have a technological innovation in medicine with the potential for a billion-person impact within the chronic disease epidemic.
Today’s approach to treating patients suffering from chronic disease is focused on and increasingly dominated by drugs, particularly
monoclonal antibodies (“mAbs”), which can be highly efficacious but remain limited by prohibitive costs, cumbersome administration,
and restricted scale. We believe our synthetic peptide-based Active Immunotherapy Medicines Platform (“AIM Platform” formerly
called the Vaxxine Platform) has the potential to enable a new class of medicines that will improve the quality and convenience of care,
reduce costs and increase access to treatments for a wide range of indications. Moreover, we believe that due to the unique features of
our AIM Platform, these new medicines can enable an expansion from treating sick patients to prevention of illness in healthy people.
Medicine is only as effective as its access, and we believe there is a path to increasing the number of people who have access to
immunotherapies from less than 1% of the world today to nearly anyone that could benefit.
Our AIM Platform is designed to harness the immune system to convert the body into its own “mAb drug factory,” stimulating the
production of antibodies with a therapeutic or protective effect. While traditional vaccines have been able to leverage this approach
against infectious diseases, they have historically been unable to resolve key challenges in the fight against chronic diseases. We believe
our AIM Platform has the potential to overcome these challenges and to bring the efficiency of vaccines to a whole new class of medical
conditions. Our technology has been commercialized independently in billions of doses of animal health vaccines, tested in over four
thousand human subjects across multiple candidates and clinical trials, including the company’s first completed Phase 3 study. Our
current pipeline consists of five chronic disease product candidates from early to late-stage development across multiple therapeutic
areas, including Alzheimer’s Disease (“AD”), Parkinson’s disease (“PD”), migraine and hypercholesterolemia, diseases that collectively
affect billions of people in the world today and of which hundreds of millions more are at high risk of contracting. Additionally, we
believe our AIM Platform may be used to disrupt the treatment paradigm for a wide range of other chronic diseases, including any that
are or could potentially be successfully treated by mAbs. We have assembled an industry-leading team with extensive experience
developing successful drugs that is committed to realizing our mission of alleviating the greatest amount of suffering we can in the
world. Our website address is www.vaxxinity.com. The information contained on, or that can be accessed through, our website is not
part of, and is not incorporated into, this Report.
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The Chronic Disease Epidemic
More people today are suffering from a chronic disease than ever before. Chronic diseases kill 41 million people each year, or 74% of
all deaths globally. These diseases are ongoing, generally incurable illnesses or conditions that gradually onset and tend to be of long
duration such as heart disease, cancer and AD.
Less than a century ago, the chronic disease and disability prevalence was about 7.5% in adults in the U.S. By 2000, the proportion of
Americans with at least one chronic disease had grown to 45%, and today, only two decades later, it has grown to 60% of all adults. The
proportion with multiple chronic diseases has similarly skyrocketed to 40% of adults in the U.S. today. Overall, chronic disease accounts
for 70% of deaths and nearly 90% of overall healthcare expenditure in the U.S.
The epidemic is not limited to the U.S. or the developed world. To the contrary, chronic diseases disproportionately affect low- and
middle-income countries (LMICs) where 77% of all chronic disease deaths occur. Each year, 17 million people die of a chronic disease
before age 70, and 86% of these premature deaths occur in LMICs. According to the World Health Organization (“WHO”), chronic
disease is closely linked with poverty in what can become a vicious cycle. More limited access to health services by socially
disadvantaged people underlies increased incidence of chronic disease. Meanwhile, healthcare costs for treatment of these diseases,
which often become lengthy and expensive, can quickly drain household resources. The WHO estimates millions of people are forced
into poverty annually due to chronic disease.
Limitations of the Current Healthcare Paradigm
Since 2000, there have been over 700 new medicines approved by the FDA, mostly to treat chronic illnesses, and yet the chronic disease
epidemic continues to grow.
We believe that medicine is only as effective as its access, and many of the newest medicines are limited to less than 1% of the world’s
patient population. The current healthcare paradigm favors the development of drugs that are primarily intended for the U.S. market, for
niche indications and for treatment of disease rather than prevention. Furthermore, these drugs are expected to be sold at price points
that are only accessible to healthcare systems in developed countries, and even within those systems, to a small subset of patients.
One class of drugs in particular exemplifies the current environment: biologics, especially mAbs. In 2022, biologics represented seven
of the fifteen top selling drugs, of which six were mAbs. The global market for mAbs totaled approximately $202 billion in 2022,
representing over 60% of the total sales for all biopharmaceutical products. While mAbs can provide life-altering care with generally
favorable safety characteristics and significant health benefits for the patients who receive them, regular in-office transfusions and annual
treatment costs, which can exceed hundreds of thousands of dollars, present challenges to both patients and payors. These price and
administration hurdles cause mAb treatments to be available to only a fraction of the population who could benefit from them.
Furthermore, mAbs are often restricted to moderate to severe disease and to later lines of treatment due to their high cost, rather than
prevention or early intervention in disease.
Thus, due to their cost and administrative burden, mAbs account for less than 2% of all prescriptions in the U.S., and, based on internal
estimates, less than 1% worldwide. Meanwhile, the alternative to mAb treatments tends to be small molecules, which are sometimes
more accessible to patients, but are often comparatively less effective with more significant side effects. Collectively, this perpetuates a
profound inequity in healthcare access, domestically but even more so globally, that we believe represents a tremendous social and
market opportunity.
Our Scalable AIM Platform Solution
Our vision is to disrupt the existing paradigm of chronic disease treatment with a new class of active immunotherapeutic medicines that
can potentially improve the health of more people, more conveniently, for less money.
Our AIM Platform is designed to harness the immune system to convert the body into its own “drug factory,” to stimulate the production
of antibodies with a therapeutic or protective effect, and to be scaled to supply millions or even billions of persons. In contrast,
monoclonal antibodies are developed, produced and purified outside the body and then transfused into the patient on a regular basis, as
frequently as bi-weekly. Therefore, mAbs are inherently less efficient than active immunotherapies, or vaccines, which instead stimulate
antibody production within the patient’s immune system, requiring both less active material and less frequent treatments. However,
while traditional vaccines have historically been successful at addressing infectious diseases, previous attempts to utilize vaccines to
address chronic disease have not achieved both acceptable safety and efficacy. Our AIM Platform technology contains modular
components that can be rapidly custom-designed to mimic select biology and activate the immune system, enabling our product
candidates to break immune tolerance when targeting self-antigens, a property observed across multiple clinical and pre-clinical studies.
Our AIM Platform depends heavily on intellectual property licensed from UBI and its affiliates, a related party and a commercial partner
for us, who first developed the synthetic peptide vaccine technology utilized by our AIM Platform. The formulation of our peptide-
based product candidates relies on contract manufacturers at this time, including both related parties as well as third-party manufacturers.
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We believe our AIM Platform has the potential to generate product candidates with attributes that collectively offer significant
advantages over both mAbs and small molecule therapeutics, and that some of these advantages may allow for use in a first-line or a
prevention setting for population health level diseases:
•
Cost and Scalability
: Whereas monoclonal antibodies require costly and complex biological manufacturing
processes, our manufacturing process is chemically based and highly scalable, and requires lower capital expenditures. Our AIM
Platform has been designed and tested to produce on a scale of hundreds of millions of doses of GMP manufactured material. In addition,
we design our product candidates to generate antibody production in the body, thus requiring meaningfully less drug substance relative
to mAbs, leading to commensurately lower costs.
•
Administration and Convenience
: Our product candidates are designed to be injected in quarterly or longer
intervals via intramuscular injection similar to a flu shot. We believe this offers considerable convenience compared to mAbs, which
can require up to bi-weekly dosing via intravenous infusion or subcutaneous injections, and small molecules, which often require daily
dosing. We are also in the early stages of exploring additional modes of administration, including intradermal delivery that may be
administered in an at-home setting, potentially offering enhanced convenience to patients.
•
Efficacy
: In our clinical trials conducted to date, our product candidates have yielded high response rates
(90% or above at target dose levels for UB-311, UB-312, UB-313, and UB-612), high target-specific antibodies against self-antigens
(as seen in UB-311, UB-312, and UB-313 clinical trials) and long durations of action (for UB-311 based on titer levels remaining
elevated between doses, and UB-612 based on half-life). We have observed target engagement in patient CSF in a Phase 1 clinical trial
of our UB-312 program. See our descriptions of these clinical trials under “—Our Product Candidates.” Our AIM Platform also enables
the combining of multiple target antigens into a single formulation. For indications that could be treated more effectively with a
multivalent approach, we believe our AIM Platform would have an advantage over other modalities. Further, because our AIM Platform
is designed to elicit endogenous antibodies, we believe our product candidates may lessen or avoid altogether the phenomenon of anti-
drug antibodies which has limited the efficacy of certain mAbs over time. Finally, we believe that the improved convenience of our
product candidates as compared to mAbs has the potential to lead to increased adherence by patients and therefore improve overall
effectiveness of our candidates.
•
Safety
: Based on our clinical trials to date, our product candidates have been well tolerated. We aim to offer
product candidates with safety profiles at least comparable to the relevant mAb or small molecule alternative for the relevant disease.
Our Targeted Impact
Our current pipeline addresses leading areas of unmet medical need, from AD to heart disease, impacting nearly 3.5 billion persons
worldwide, and resulting in over 8 million annual deaths and $4 trillion dollars in economic impact globally. The following table depicts
our R&D pipeline.
As used in the chart above, “IND” signifies a program has begun investigational new drug (“IND”)-enabling studies.
Our pipeline consists of five lead programs focused on chronic disease, particularly neurodegenerative disorders, in addition to other
neurology and cardiovascular indications. For each candidate, we believe the targeted biology has been validated or de-risked either
through published genetic evidence or by a successfully licensed mAb against the same target.
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Neurodegenerative Disease Programs:
•
UB-311
: Targets toxic forms of aggregated amyloid-beta (“Aβ”) in the brain to fight AD, a disease
affecting 44 million people worldwide, resulting in 1.6 million annual deaths and over $3 trillion in estimated economic cost. Phase 1,
Phase 2a and Phase 2a Long Term Extension (“LTE”) trials have shown UB-311 to be well tolerated in mild-to-moderate AD subjects
over three years of repeat dosing, with a safety profile comparable to placebo, with no cases of amyloid-related imaging
abnormalities-edema (“ARIA-E”) observed in the main Phase 2a trial, and only one case of ARIA-E in the LTE trial, which was
clinically not significant according to the study investigator. UB-311 was also shown to be immunogenic, with a high responder rate
and antibodies that bind to the desired target. Although not powered for statistical significance, the Phase 2a trial showed dose-
dependent trends of slowing of cognitive decline by 48% versus placebo, as measured by CDR-SB. We held an End of Phase 2
meeting with the U.S. Food and Drug Administration (“FDA”) and have aligned upon a large scale efficacy trial, which, pending data,
could potentially support initial licensure of UB-311 for the treatment of early AD. The FDA granted UB-311 Fast Track Designation
in the second quarter of 2022. The expected timing of the next clinical trial will be determined based upon the timing of additional
financing or a strategic partnership.
•
UB-312
: Targets toxic forms of aggregated α-synuclein (“aSyn”) in the brain and peripheral tissues to fight
PD and other synucleinopathies, such as Lewy body dementia (“LBD”) and multiple system atrophy (“MSA”), diseases together
affecting 16 million people worldwide, resulting in 400,000 annual deaths and over $80 billion in estimated economic cost. Part A and
Part B of a Phase 1 trial in healthy volunteers and Parkinson’s patients, respectively, have been completed and have shown UB-312 to
be well tolerated, with no significant safety findings, and immunogenic, with a high responder rate and antibodies that cross the blood-
brain barrier (“BBB”). UB-312-induced antibodies were observed in the serum and CSF of both healthy volunteers and PD patients,
and showed preferential binding to aggregated aSyn and almost no binding to normal monomeric aSyn. Two exploratory biomarkers
were evaluated as measures of target engagement: aggregated aSyn as measured by a semi-quantitative seed amplification assay
(“SAA”), and phosphorylated aSyn (pS129 aSyn). PD patients with UB-312-induced antibodies in the CSF showed a significant
reduction from baseline in pathological aSyn in the CSF compared to the placebo group as measured by both SAA and pS129 aSyn.
A
post hoc
daily living versus placebo, as measured by the MDS-UPDRS II clinical scale. We believe UB-312 is the first immunotherapy
candidate to show data of reduction of pathological aSyn in CSF of PD patients. The next step will be to conduct a Phase 2 trial to
optimize a dose regimen and to confirm target engagement in PD patients.
•
VXX-301
: We are developing an anti-tau product candidate that has the potential to address multiple
neurodegenerative conditions, including AD, traumatic brain injury (“TBI”) and chronic traumatic encephalopathy (“CTE”) by targeting
abnormal tau proteins alone and in potential combination with other pathological proteins such as Aβ to address multiple pathological
processes at once. TBI is estimated to affect 56 million people worldwide and is attributed to approximately 2 million deaths annually.
Our lead candidate targets multiple epitopes of tau and has been shown in preclinical studies to reduce tau spreading and improve
survival in animal models. In an effort to focus internal resources, we have decided to continue the development of VXX-301 only
through a preclinical research collaboration with the University of Florida, which has received a grant from the state of Florida in support
of this project.
Next Wave Chronic Disease Programs:
•
VXX-401
: Targets proprotein convertase subtilisin/kexin type 9 serine protease (“PCSK9”) to lower low-
density lipoprotein (“LDL”) cholesterol and reduce the risk of cardiac events. Today, cardiovascular disease is the leading killer in the
world, accounting for over 18 million annual deaths, affecting both developed and developing countries. Over 2 billion people have
high cholesterol globally. As of October 2023, we have expanded the ongoing first-in-human clinical trial of VXX-401 in Australia to
include two higher dose cohorts due to its favorable safety and tolerability profile to that point, for a total of six cohorts. In the first
quarter of 2024, we submitted a protocol amendment to add a booster dose to these two higher dose cohorts. We expect to report initial
topline data from this trial in mid-2024, with results from the booster dose later in the second half of 2024.
•
UB-313
: Targets Calcitonin Gene-Related Peptide (“CGRP”) to fight migraines, a disease affecting over 1
billion people worldwide, resulting in an estimated over 45 million years lived with disability annually. In 2023, we completed a first-
in-human Phase 1 clinical trial in healthy volunteers in which UB-313 was generally well tolerated and immunogenic: all subjects who
received three doses of UB-313 (31 out of 31) developed anti-CGRP antibodies; however, serum antibody titers were lower than
expected, and due to this lower immunogenicity, UB-313 did not meet the trial’s secondary objective of capsaicin-induced dermal blood
flow inhibition. We believe this was the result of a suboptimal drug product made by a new contract manufacturer, and we have identified
the necessary steps to manufacture a more immunogenic product consistent with prior lots and the known immunogenic potential of our
platform candidates. In an effort to focus internal resources, we have deprioritized this program and are not currently planning on running
another Phase 1 at this time.
Given the global COVID-19 pandemic and our AIM Platform’s applicability to infectious disease, we also have advanced a product
candidate that addresses SARS-CoV-2.
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COVID-19
•
UB-612
: Employs a “multitope” subunit protein-peptide approach to neutralizing the SARS-CoV-2 virus,
meaning the product candidate is designed to activate both antibody and cellular immunity against multiple viral epitopes. A Phase 3
trial evaluating UB-612 as a heterologous boost against SARS-CoV-2, head-to-head versus homologous boosts of VNT162b2
(mRNA), ChAdOx1-S (adenovirus), and BIBP (inactivated virus), was initiated in the first half of 2022 with funding support from the
Coalition of Epidemic Preparedness Innovations (“CEPI”). In December 2022, we announced positive topline data: UB-612 met
primary and key secondary endpoints, eliciting non-inferior neutralizing antibody titers and seroconversion rates (“SCR(s)”), defined
as a 4-fold or greater increase in neutralizing antibodies from baseline, against both Wuhan and Omicron BA.5 variants as compared
to BNT162b2, and superior neutralizing antibody titers and SCRs against both variants as compared to ChAdOx1-S and BIBP. UB-
612 was well tolerated with balanced reactogenicity and no additional safety risks evoked over the licensed COVID-19 comparators.
There were no serious adverse events (“SAEs”) related to UB-612 reported through 12 months of safety follow-up. Phase 1 and Phase
2 trials of UB-612 have also shown UB-612 to be well tolerated, with over 7,500 doses administered to over 3,750 subjects. In March
2023 we completed rolling submissions for conditional/provisional authorization with regulatory authorities in the United Kingdom
and Australia, who are reviewing under their established work share agreement. In November 2023, the MHRA conducted GMP
inspections of our overseas CMO facilities responsible for UB-612 manufacture. We believe a decision on authorization will be made
in 2024.
We believe our AIM Platform has application across a multitude of chronic and infectious disease indications beyond our existing
pipeline. We are developing additional product candidates that we believe may address significant unmet needs both within and beyond
our current pipeline’s therapeutic areas.
Our Team
We have assembled an experienced group of executives with deep scientific, business and leadership expertise in pharmaceutical and
vaccine discovery and development, manufacturing, regulatory and commercialization. Mei Mei Hu, our co-founder and Chief
Executive Officer, has been a member of the executive committee of UBI since 2010. Our board of directors is chaired by our co-
founder Louis Reese, who has been a member of the executive committee of UBI since 2014. Our research efforts are guided by
highly experienced scientists and physicians on our leadership team including Dr. Jean-Cosme Dodart, our Senior Vice President of
Research. Our leadership team contributes a diverse range of experiences from leading companies including AstraZeneca, Eli Lilly,
Genentech, Merck, and Pharmacyclics, and were executives in multiple successful mAb and vaccine launches.
As of December 31,
2023, we have assembled an exceptional team of 53 employees, the majority of whom hold Ph.D., M.D., J.D. or Master’s degrees. We
also have a highly experienced scientific advisory board consisting of leading doctors and scientists in relevant therapeutic areas.
Our Strategy
Our mission is to alleviate the most human suffering possible by developing active immunotherapy product candidates that improve the
quality of care for chronic diseases and are accessible to all patients across the globe. In order to achieve this mission, we seek to:
•
Advance our chronic disease pipeline through clinical stage development
: We plan to advance UB-311,
UB-312, and VXX-401 through clinical stage development for the treatment or prevention of chronic diseases, either ourselves or with
a strategic partner. We believe that our differentiated AIM Platform will enable our product candidates, if approved and successfully
commercialized, to potentially disrupt the current treatment paradigm for their respective indications. However, there can be no
guarantee that we will obtain regulatory approval or commercialize of any such product candidates.
•
Expand our pipeline of product candidates
: Chronic diseases are prevalent globally and expected to worsen
over the next several decades. In furtherance of our mission, we plan to expand our pipeline by developing new product candidates that
address additional indications. In expanding our pipeline, we rely on our proprietary filtering methodology, which evaluates potential
product candidates across five principal criteria – (i) probability of technical and regulatory success, (ii) addressable market, (iii)
development cost, (iv) competitive dynamics and (v) disruptive potential.
•
Continue to improve our AIM Platform
: In addition to, and in conjunction with, our product candidate
development efforts, we are continuously working to improve and enhance the richness, breadth and effectiveness of our AIM Platform.
As our AIM Platform further develops, we believe that we can both increase the speed and efficiency of developing product candidates,
improve the probability of technical success of our product candidates, and increase the number of product candidates in concurrent
development.
•
Maximize the value of our product candidates through potential partnerships
: We currently retain worldwide
rights for all of our product candidates and will consider entering into development and commercialization partnerships with third parties
that align with our mission on an opportunistic basis.
8
Background and Limitations of Traditional Vaccines and Monoclonal Antibodies
The immune system, the body’s mechanism for fighting off potential threats, is comprised of cells that form the innate and adaptive
immune responses. The main purpose of the innate immune system is to immediately prevent the spread and movement of foreign
pathogens throughout the body. The adaptive immune response is specific to the pathogen presented to T-cells and B lymphocytes (“B-
cells”) and leads to an enhanced response upon future encounters with those antigens. Antibodies represent an important tool within the
adaptive immune system’s arsenal. Upon detection of a potential threat, B-cells produce antibodies that recognize, bind to and eliminate
the threatening pathogen. Over time, the immune system develops the ability to produce countless types of antibodies, each finely tuned
against a specific threat.
Generally, the immune system is able to function effectively by neutralizing viruses, bacteria and even self-generated cells and proteins
from within our own bodies that could cause harm if unchecked. However, as powerful as the immune system is, there are threats that
it cannot overcome on its own, generating the need for medicine. Conventional forms of medicine include small molecules (e.g.,
antibiotics), which can inhibit or promote action within the body by, for instance, binding to a receptor on the surface of a cell, or directly
inducing toxic effects upon bacteria. These medicines do not necessarily modulate the immune system directly in order to work. Instead,
they work alongside it. While small molecules have provided substantial benefits to human health, they are typically not designed to
interact with the immune system. They may also have limited efficacy in cases where an immune response to a target can be used against
a chronic condition.
Vaccines
In the first part of the twentieth century, vaccines revolutionized healthcare by directly interacting with, and modulating, the immune
system — training it to recognize a dangerous pathogen by introducing the immune system to a relatively harmless form of the pathogen,
its toxins or one of its surface proteins, thereby promoting the body’s own production of binding antibodies. Once immunized to a
specific pathogen, the immune system can recognize it and generate the antibodies to fight it more quickly and robustly.
Traditional vaccine technologies have generally focused on the prevention of bacterial and viral infections and not on chronic disease.
In chronic disease settings, the disease-causing agents frequently come from within the body. These self-antigens are proteins that
become too abundant, misfolded or aggregated such that they can no longer perform their healthy function and even may induce toxic
effects. The body can sometimes produce antibodies against such proteins, but this often falls short of providing the right types of
antibodies in the right concentrations to ward off disease. Historically, vaccine technologies developed to target these proteins have been
unable to break immune tolerance — that is, the immune system’s general avoidance of reactivity towards self-antigens — with an
acceptable level of reactogenicity. The challenges faced by prior efforts to advance vaccine technologies for chronic diseases included
low response rates, low titer levels, off- target responses and other safety concerns such as T-cell mediated inflammation.
Monoclonal Antibodies
The first mAbs were developed in the later part of the twentieth century. In contrast to vaccines, which prompt the body to produce
antibodies, mAbs are antibodies manufactured outside of the patient’s body and then injected or infused into the body to recognize and
eliminate harmful targets. Monoclonal antibodies have revolutionized the standard-of-care treatment for many chronic diseases.
However, manufacturing mAbs is often an expensive and complex process and administering mAbs is cumbersome, sometimes requiring
infusions as frequently as bi-weekly. These factors have generally limited mAbs’ availability to moderate-to-severe disease, to later
lines of therapy and to wealthier geographies, thus denying access to a substantial portion of the patients who could benefit from them.
Finally, patients on mAbs often experience a loss of effectiveness over time due to a phenomenon known as anti-drug antibodies,
whereby the immune system begins to recognize therapeutic mAbs as foreign, and mounts a response against them, eventually mitigating
their efficacy.
Our AIM Platform
Our AIM Platform is designed to stimulate the patient’s own immune system to generate antibodies and overcome the limitations of
traditional vaccines to target self-antigens safely and effectively in chronic diseases. Our product candidates have broken immune
tolerance against self-antigens consistently. As described in the section titled “Our Product Candidates” below, across seven clinical
trials, we have consistently observed that our product candidates have stimulated the development of antibodies against the desired
target at relevant doses in clinical trial subjects, including the elderly. We have observed favorable tolerability and reactogenicity of our
product candidates across studies of UB-311, UB-312, UB-313, and UB-612, with no significant safety findings to date. We aim to
develop product candidates that are more convenient, more cost-effective and more accessible to large patient populations, with safety
profiles at least comparable to relevant mAbs and small molecule treatments. We believe our product candidates have the potential to
eventually not only capture meaningful market share from mAbs and small molecules, but more importantly, to provide therapeutic
benefit to large patient populations who currently receive neither form of treatment and thereby open up the broadest access to patients.
This would represent an unprecedented shift in the treatment paradigm, potentially providing better global access to treatments that have
been previously limited to the wealthiest nations. In particular, we believe our treatments for chronic disease could reflect the following
benefits as compared with the relevant mAbs and small molecule alternatives:
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Characteristics of our Product Candidates versus Monoclonal Antibodies and Small Molecules
History and Design
Our AIM Platform utilizes a peptide vaccine technology first developed by UBI and subsequently refined over the last two decades,
with more than three billion doses of animal vaccines commercialized to date. UBI initiated the development of this technology for
human use; the business focused on human use was then separated from UBI through two separate transactions: a spin-out from UBI in
2014 of operations focused on developing chronic disease product candidates that resulted in United Neuroscience, a Cayman Islands
exempted company (“UNS”), and a second spin-out from UBI in 2020 of operations focused on the development of a COVID-19 vaccine
that resulted in C19 Corp., a Delaware corporation (“COVAXX”). Our current company, Vaxxinity, Inc., was incorporated under the
laws of the State of Delaware on February 2, 2021 for the purpose of acquiring UNS and COVAXX in March of 2021.
On March 2, 2021, in accordance with a contribution and exchange agreement among Vaxxinity, UNS, COVAXX and the UNS and
COVAXX stockholders party thereto (the “Contribution and Exchange Agreement”), the existing equity holders of UNS and COVAXX
contributed their equity interests in each of UNS and COVAXX in exchange for equity interests in Vaxxinity (the “Reorganization”).
In connection with the Reorganization, (i) all outstanding shares of UNS and COVAXX preferred stock and common stock were
contributed to Vaxxinity and exchanged for like shares of stock in Vaxxinity, (ii) the outstanding options to purchase shares of UNS
and COVAXX common stock were terminated and substituted with options to purchase shares of Class A common stock in Vaxxinity,
(iii) the outstanding warrant to purchase shares of COVAXX common stock was cancelled and exchanged for a warrant to acquire
Class A common stock in Vaxxinity, and (iv) the outstanding convertible notes and a related party not payable were contributed to
Vaxxinity and the former holders of such notes received Series A preferred stock in Vaxxinity. On December 31, 2022, COVAXX was
merged into Vaxxinity in order to simplify the corporate structure.
UBI has used its capabilities in peptide technology for innovations across an array of business endeavors: antibody testing for human
diagnostics, animal health vaccines and the manufacture of medical products. Its innovative products include one of the first approved
peptide-based blood antibody tests in the world (for HIV), one of the first approved peptide vaccines against an infectious disease in the
world in animal health (for a food-and-mouth disease virus) and one of the first approved peptide vaccines against a self-antigen in the
world in animal health (an anti-luteinizing hormone-releasing hormone (“LHRH”) vaccine used for the immunocastration of swine).
Grant funding from the National Institutes of Health supported some of UBI’s work in the fields of vaccines and antibody testing. To
commercialize its animal health vaccine business, UBI and its affiliates scaled up GMP vaccine manufacturing to over 500 million doses
per year and partnered with a top-ten animal health company for commercialization of its anti-LHRH vaccine; all together, UBI’s
technology platform is utilized for the vaccination of approximately 25% of the global swine population annually.
We are advancing our peptide-based AIM Platform to develop product candidates that target chronic diseases and COVID-19. Our AIM
Platform comprises a proprietary, custom, rationally designed antigen capable of evoking an immune response (an “immunogen”)
formulated with a proprietary CpG oligonucleotide. The immunogen contains several advanced synthetic peptide domains, including B-
cell epitopes, T-helper (“Th”) peptide carrier constructs and peptide linkers. This composition enables us to achieve a highly specific
immune response to the target antigen, with limited inflammation and off-target effects that could cause reactogenicity. This design
process has evolved into a repeatable series of well-defined steps, which has enabled the development of our current pipeline of product
candidates.
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Key Elements of our AIM Platform Constructs and Formulations
When developing a product candidate, we use publicly available information and sophisticated bioinformatics tools to investigate the
entire protein structure of a target in a comprehensive manner to identify functional B-cell epitopes that may provide optimal antigens.
We then synthesize peptides that mimic these identified antigens to elicit highly specific antibodies against these B-cell epitopes. To
yield favorable tolerability profiles, we screen our product candidates for lack of toxicity as well as reactogenicity, and design them not
to elicit T-cell mediated inflammation. To enhance effectiveness, we seek to optimize the size and sequence of our custom peptides to
elicit a robust, specific antibody response when linked to a carrier molecule.
We then attach a proprietary carrier molecule, an artificial Th carrier peptide that delivers the synthetic peptide into cells. Traditional
vaccines have faced challenges in achieving specific responses because they rely on conjugating an antigen to a large toxoid carrier
molecule, to which most of the antibody response is directed, causing off-target effects such as inflammation. In our pre-clinical trials
and clinical trials to date, our product candidates have displayed specific immunogenicity, or the ability to stimulate a targeted immune
response, thereby greatly reducing potential off-target effects and increasing the potential for our product candidates to be well tolerated
and efficacious. We have observed that our carrier molecules have produced consistent results across multiple species and against
multiple targets in seven human clinical trials to date.
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Our Product Candidate Does Not Induce an Antibody Response against its Carrier Molecule
The graph above illustrates that our peptide carriers induce a strong immune response against the target antigen, and a minimal immune
response against themselves, as compared to traditional vaccines formulated with other types of carrier molecules.
Our peptide carriers have short sequence lengths; we design them with the aim that they are not antigenic on their own and do not
stimulate cytotoxic T-cells. The carriers’ sequences model those found in natural pathogens, so they are recognized by T-helper cells.
This encourages robust T-helper cell exposure and promotes activation of other immune cells. In turn, B-cells are exposed to the B-
cell antigen and begin antibody production against the antigen, while avoiding an antibody response to the carrier.
Our library of peptide carriers enables the use of different carrier molecules or different combinations of carrier molecules, which
allows us to potentially regulate the speed of immune response onset as well as the magnitude and duration of that response. For
example, a longer duration of response would allow for less frequent dosing. In the case of vaccines for infectious diseases, where T-
cell mediated activity is desirable, our AIM Platform also affords the flexibility to design immunogen constructs that specifically
promote cytotoxic T-cell activity when warranted.
We utilize proprietary linker constructs to fuse our peptide carriers with our custom peptide antigens. These linkers are designed to
promote binding of both B-cell and T-helper epitopes to their respective receptors, contributing to a B-cell response. They may enhance
the immune response by enabling conformational changes to optimize presentation of the B-cell epitope to antigen-presenting cells
(“APCs”), such as dendritic cells (“DCs”).
Our AIM Platform also enables the construction of candidates that target multiple epitopes in a single formulation, whether on multiple
targets or a single target. In certain cases, targeting multiple epitopes of a single target could promote increased target engagement.
Combinations of therapies targeting different molecular mechanisms are common in treating neurologic, cardiovascular, psychiatric,
metabolic, respiratory, infectious and oncologic disease. Our AIM Platform’s favorable cost of goods and efficient manufacturing
process could allow for viable multi-target therapies in a single formulation. This concept could be applied in an array of potential
therapeutic areas. Our current pipeline has candidates against amyloid-β, α-synuclein and tau; targeting of two or more of these at the
same time might prove more effective than any single-target therapy in some patients. Pre-clinical data to date suggests that we can
elicit antibody titers against all three targets in a single formulation. In contrast, multi-target therapy with mAbs would compound the
cost and administration burdens as compared to single-target mAb therapy.
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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.
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Overview of How our Product Candidates Function
Importantly, from both clinical trials and pre-clinical studies, we have observed the rapid expansion of antibodies upon administration
of a booster of our product candidates. Based on the available data to date, we can infer that while antibody titers decline with time after
administration, a small number of memory B-cells and antibody secreting cells are maintained in the lymphoid organs, spleen or bone
marrow. We believe this is important because if a patient misses a dose of our product candidate, they may be able to recall the antibody
response, and therefore the therapeutic effect of the antibodies, with a single booster, even after a long period of time has passed.
AIM Platform Immunogenicity upon Re-dosing
As shown in the above graph, a rapid antibody response is elicited by a booster dose of UB-311 given 72 weeks after the priming
regimen.
Furthermore, the antibodies elicited by our product candidates have different properties than those of mAbs targeting similar pathology.
In general, we aim to achieve binding affinity, specificity and functionality similar or improved compared to mAbs targeting similar
pathology. We use Bio-Layer Interferometry (ForteBio
®
) to compare the binding kinetics (K
ON
, K
OFF
, and K
D
) of antibodies elicited by
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our product candidates versus mAbs. We also use Western blot or slot blot to evaluate the binding specificity of antibodies elicited by
our product candidates against the normal, toxic, misfolded or aggregated forms of the target protein. We use immunohistochemical
analyses to observe the binding of antibodies to pathological inclusions on tissue sections, such as brain sections of patients. Moreover,
we use cell-based models and animal models to measure the induced antibodies’ functionality. Additionally, a major challenge in mAb
drug discovery is that mAbs are prone to induce an immune response against themselves, resulting in a potential
inactivation/neutralization of the mAb by the host (i.e., the patient). This is not a concern with our vaccine approach as each patient will
produce its own antibodies against the target. Finally, mAbs have a potential for off-target binding, which could result in non-specific
binding leading to safety and toxicity issues. We believe that this is unlikely to happen using our technology since antibodies elicited
by our product candidates are designed to break immune tolerance against specific targets and should not trigger an immune response
against other self-peptides or proteins.
Product Candidate Selection Process
Because our AIM Platform may have applicability across a range of chronic diseases, we employ a proprietary filtering methodology to
best identify new product candidates for development. We evaluate potential product candidates across five principal criteria:
•
Probability of technical and regulatory success
: We examine the probability of success for a product
candidate based on stage of development and therapeutic area, and then make target-specific adjustments for design difficulty, industry
knowledge and clarity of biological mechanism, general safety risk and estimated titer level required for therapeutic effect. This criterion
accounts for the known validity of a given target in the relevant disease context.
•
Market opportunity
: We account for the prevalence, unmet need and drug market size for each likely
indication associated with a given target, as well as the number of potential indications.
•
Development cost
: We estimate the cost of development through BLA submission, the time to submission
and the number of patient-years to proof-of-concept.
•
Competitive advantages
: We evaluate the extent to which the advantages of our AIM Platform compare to
the current and potential future standard of care, including convenience, dosing, safety, efficacy and cost.
•
Disruptive opportunities
: We evaluate the extent to which the potential disruptive properties of our AIM
Platform may play a role in treatment paradigms, including the ability to “leap-frog” mAbs and treat patients in earlier lines of treatment,
to be used as a prophylactic, to include multiple targets in a single formulation and to be used as an adjuvant therapy.
After assigning values to each criterion for a given product candidate, we weight each criterion according to a confidential algorithm,
and thereby prioritize product candidates for development. We update these values on a regular basis based on new scientific literature,
trial results and our AIM Platform advancements.
As an example, in light of these criteria, AD and other neurodegenerative diseases that involve misfolded proteins are an attractive area
for development. First, as the field has gained knowledge and clinical experience around the biology of targeting aberrant proteins with
antibodies, the relative technical, safety and regulatory risk has decreased. For instance, with two FDA-approved products targeting Aβ
for AD, Aβ has been validated as a target. Both AD and PD have high prevalence worldwide, and large unmet need with limited or no
disease-modifying products readily available to patients. Moreover, the underlying pathologies often begin years or decades before
symptoms may appear and as a result, early intervention in the disease state, as well as prevention or delay of onset strategies, may be
optimal and more practically achievable with a vaccine approach. While mAbs can target the pathology, they face the limitations of
high cost, cumbersome and inefficient administration and limited access, and are not suited for early treatment or prevention, which we
believe provides a disruptive opportunity for our AIM Platform.
We believe that our AIM Platform, and our strategy more generally, will create a significant opportunity for drug development well
beyond our current pipeline of clinical and pre-clinical indications, in therapeutic areas including allergy (e.g., atopic dermatitis, chronic
rhinosinusitis, , food allergy), autoimmune disease (e.g., psoriasis, psoriatic arthritis, Crohn’s disease), pain (e.g., peripheral neuropathy,
diabetic neuropathy) and bone and muscle atrophy (e.g., sarcopenia, osteoporosis, osteopenia).
Underlying Drivers of Our Platform Advantages
Our AIM Platform’s properties drive the unique combination of attributes that we believe will be reflected in our product candidates:
•
Cost and Scalability
: Whereas monoclonal antibodies require costly and complex biological manufacturing
processes, our manufacturing process is chemically based and highly scalable, and requires lower capital expenditures. Our AIM
Platform has been designed and tested to produce on a scale of hundreds of millions of doses of GMP manufactured material. In addition,
we design our product candidates to generate antibody production in the body, thus requiring meaningfully less drug substance relative
to mAbs, leading to commensurately lower costs.
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•
Administration and Convenience
: Our product candidates are designed to be injected in quarterly or longer
intervals via intramuscular injection similar to a flu shot. We believe this offers considerable convenience compared to mAbs, which
can require up to bi-weekly dosing via intravenous infusion or subcutaneous injections, and small molecules, which often require daily
dosing. We are also exploring additional modes of administration, including intradermal delivery that may be administered in an at-
home setting, potentially offering enhanced convenience to patients.
•
Efficacy
: In our clinical trials conducted to date, our product candidates have yielded high response rates
(90% or above at target dose levels for UB-311, UB-312, UB-313, and UB-612), high target-specific antibodies against self-antigens
(as seen in UB-311, UB-312, and UB-313 clinical trials) and long durations of action (for UB-311 based on titer levels remaining
elevated between doses, and UB-612 based on half-life). We have observed target engagement in patient CSF in a Phase 1 clinical trial
of our UB-312 program. See our descriptions of these clinical trials under “—Our Product Candidates.” Our AIM Platform also enables
the combining of multiple target antigens into a single formulation. For indications that could be treated more effectively with a
multivalent approach, we believe our AIM Platform would have an advantage over other modalities. Further, because our AIM Platform
is designed to elicit endogenous antibodies, we believe our product candidates may lessen or avoid altogether the phenomenon of anti-
drug antibodies which has limited the efficacy of certain mAbs over time. Finally, we believe that the improved convenience of our
product candidates as compared to mAbs has the potential to lead to increased adherence by patients and therefore improve overall
effectiveness of our candidates.
•
Safety
: Based on our clinical trials to date, our product candidates have been well tolerated. We aim to offer
product candidates with safety profiles at least comparable to the relevant mAb or small molecule alternative for the relevant disease.
Additionally, we believe our AIM Platform possesses important benefits reflected at the platform level, as opposed to the product
candidate level:
•
Product Candidate Discovery
: Our AIM Platform enables the efficient iteration of product candidates in the
discovery phase through rapid, rational design and formulation. We are able to screen in high throughput rapidly and at low cost. Upon
nominating a target for drug discovery, we can formulate several dozen product candidate compounds for preliminary in vivo
immunogenicity and cross-reactivity screening within 2 to 3 months. This process allows nonviable product candidates to “fail fast” and
allows us to carry top product candidates forward through subsequent pre-clinical development to lead identification. In contrast,
biologics require the maintenance and adjustment of living cultures to design, formulate and iterate, and therefore discovery and early
development is inherently less efficient.
•
Process Development
: Scaling the formulation of a drug product from research grade to clinical grade, then
to commercial grade, typically consumes a great deal of resources. This, together with the development of assays for quality control and
quality assurance, comprise process development. We leverage our manufacturing expertise, originally developed alongside UBI and
certain of its affiliates, to enable rapid scale-up of the manufacture of both clinical and commercial compounds that use our AIM Platform
technology. Unlike process development for mAbs, which has inherent challenges such as risk of contamination in cell culture or
bioreactors and time-consuming adjustments to cell lines for any formulation adjustment, our peptide platform relies on synthetic peptide
chemistry, which is more reproducible and scalable, and relatively quick to manipulate for any modifications.
Our Product Candidates
Neurodegenerative Disease Programs
Neurodegenerative diseases are a collection of conditions defined by progressive nervous system dysfunction, degeneration or death of
neurons, which can cause cognitive decline, functional impairment and eventually death. Neurodegeneration represents one of the most
significant unmet medical needs of our time due to an aging population and lack of effective therapeutic options.
Two of the most common neurodegenerative diseases are AD and PD. In the United States, currently more than six million people suffer
from AD, and approximately one million people suffer from PD according to estimates from the Alzheimer’s Association and the
Parkinson’s Disease Foundation, respectively. As a result, AD and PD bring a heavy burden on our society’s cost of care. The direct
costs of AD treatment in the United States were estimated at $321 billion in 2022 according to a study published by the American
Journal of Managed Care, and are projected to exceed $1 trillion by 2050. The financial burden of PD exceeded $50 billion in the United
States in 2019. Many more people around the world suffer from these two diseases and their related social and economic implications.
UB-311
An Overview of Alzheimer’s Disease
Alzheimer’s disease is a progressive neurodegenerative disorder that slowly affects memory and cognitive skills and eventually the
ability to carry out simple tasks. Its symptoms include cognitive dysfunction, memory abnormalities, progressive impairment in activities
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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 Aβ (e.g., oligomers) can directly disrupt normal synaptic and neuronal functions. They may also contribute to tau pathology.
Research is ongoing to better understand how, and at what stage of the disease, the various forms of Aβ influence AD.
Neurofibrillary tangles are abnormal accumulations of a protein called tau that collect inside neurons. Healthy neurons are supported
internally, in part, by structures called microtubules, which help to guide nutrients and molecules from the cell body to the axon and
dendrites. In healthy neurons, tau normally binds to and stabilizes microtubules. In AD, abnormal chemical changes cause tau to detach
from microtubules and to stick to other tau molecules, forming threads that eventually join to form tangles. These tangles block the
neuron’s transport system, which harms the synaptic communication between neurons.
Converging lines of evidence suggest that AD-related brain changes may result from a complex interplay among Aβ proteins, abnormal
tau, and several other factors. It appears that abnormal tau accumulates in specific brain regions involved in memory. Concurrently, Aβ
clumps into plaques between neurons. As the level of Aβ reaches a tipping point, tau rapidly spreads throughout the brain. In addition
to the spread of Aβ and tau, chronic inflammation and its effect on the cellular functions of microglia and astrocytes, as well as changes
to the vasculature, are thought to be involved in AD’s pathology and progression.
In the last three years, the FDA has approved two different mAbs that target Aβ for the treatment of AD.
Limitations of Current Therapies
Two classes of small molecules approved for the treatment of AD’s symptoms are acetylcholinesterase inhibitors (“AChEIs”) and
glutamatergic modulators. AChEIs are designed to slow the degradation of the neurotransmitter acetylcholine, temporarily compensating
for cholinergic deficits. Glutamatergic modulators are designed to block sustained, low-level activation of the N-methyl-D-aspartate
(“NMDA”) receptor, without inhibiting the normal function of the receptor in memory and cognition. However, these therapeutic
products only address the symptoms of AD and do not modify or alter the progression of the underlying disease.
Aducanumab, marketed under the trade name Aduhelm, is a mAb developed by Biogen, Inc. (“Biogen”) that targets aggregated forms
of Aß. The FDA approved aducanumab in June 2021, making it the first approved immunotherapy for AD, the first new FDA-approved
treatment since 2003 and, importantly, the first to receive accelerated approval based on a biomarker. By approving aducanumab on the
basis of biomarker evidence, we believe the FDA set a precedent for developers of neurodegeneration immunotherapies.
Despite the milestone in the treatment of AD that aducanumab’s approval represents, the drug has several limitations, and Biogen
announced its discontinuation in 2024. Approximately one-third of patients experience ARIA-E related adverse events, which can
manifest as symptoms ranging from headaches to confusion to coma. In addition, the drug must be administered monthly via intravenous
infusion in healthcare facilities specifically configured to support an hour-long infusion process with healthcare professionals trained to
administer infusion therapies, creating a burden for patients and additional costs resulting from the complex administration process.
Because of the risk of developing ARIA-E, physicians who prescribe aducanumab must titrate dosing and carefully monitor each patient
using magnetic resonance imaging (“MRI”). This process is costly and burdensome The combination of price, side effects, extra costs,
and extra administration burden highlight the challenges of mAbs. The Center for Medicare & Medicaid Services (“CMS”) decided not
to cover aducanumab, leading to its commercial failure.
Soon after the FDA’s approval of aducanumab, Eli Lilly and Company (“Lilly”) announced that it would file for approval of its anti-Aβ
mAb, donanemab, in 2022 on the basis of Phase 2 data. In January 2023, the FDA declined accelerated approval of donanemab due to
an insufficiently sized safety database in its Phase 2 trial; however, Lilly filed for approval later in 2023 on the basis of Phase 3 data.
In January 2023, the FDA granted accelerated approval to lecanemab, another mAb targeting Aβ, jointly developed by Biogen and Eisai
Co., Ltd. (“Eisai”). Over 12.5% of patients on lecanemab experience ARIA-E, and physicians who prescribe lecanemab must monitor
each patient using MRI. Lecanemab must be administered every two weeks as an intravenous infusion in healthcare facilities specifically
configured to support an hour-long infusion process with healthcare professionals trained to administer infusion therapies, creating a
burden for patients and additional costs resulting from the complex administration process. Biogen and Eisai have set the wholesale
acquisition cost (“WAC”) price of lecanemab in the U.S. at $26,500 for the drug product only, which does not include administration
and ongoing monitoring costs. CMS has decided to cover lecanemab under Medicare Part B with a 20% coinsurance after a patient has
met their Part B deductible.
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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
Aβ 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
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
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.
18
Generation of Antibodies Repeatable Across Clinical Studies, and Antibodies Bind Target with High
Specificity as Compared to Monoclonal Antibody
Across Phase 1 and Phase 2a trials, UB-311 generated an over 95% response rates in subjects. In a comparative in vitro study with
aducanumab, we observed that UB-311 elicited titer levels comparable to mAbs.
Phase 1 and Phase 2a trials of UB-311 demonstrated a repeatable anti-Aβ titer response. In an
in vitro
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.
19
UB-311 Phase 2a Analysis of Clinical and Biomarker Endpoints Suggests Overall Disease-Modifying Effect
Compared to placebo, UB-311 low-frequency dosing and high-frequency dosing demonstrated slowing of overall disease progression
in an independent analysis conducted by Pentara Corporation.
The Phase 2a Main Trial recapitulated the safety and tolerability profile of UB-311 that was observed in the earlier Phase 1 trial. No
subjects discontinued trial participation due to a treatment emergent adverse effect (“TEAE”). No ARIA-E was observed in quarterly
MRI scans. Aβ-related imaging abnormalities related to microhemorrhages or hemosiderosis seemed similar between the UB-311
treatment groups and placebo group. In the Phase 2a Main Trial, six SAEs were observed, including three in the Q6M dosing arm and
one in the Q3M dosing arm. None were deemed related or likely related to UB-311.
Titers generated by UB-311 ramped up gradually over the course of several months, as opposed to titers following the administration of
anti-Aβ mAbs, which reach C
max
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
20
An extension of the Phase 2a Main Trial, the Phase 2a LTE trial, involved the continued participation by 34 of the subjects who
participated in the Phase 2a Main Trial for an additional 78 weeks. The objective of the Phase 2a LTE trial was to assess the longer-
term tolerability of extended treatment with UB-311. Following a non-treatment period of up to 26 weeks, participants in the LTE trial
were segmented into two groups: those previously on drug in the Phase 2a Main Trial would receive two placebo doses and a single
300μg priming dose at the start of the LTE treatment period and those previously on placebo would receive three 300μg priming doses
over an initial 12-week period. Due to an error by the CRO responsible for administering blinded placebo and active doses to trial
subjects, which reduced the confidence of subsequently collected data, we decided to discontinue the LTE trial, having determined that
we had collected sufficient data on UB-311’s tolerability and immunogenicity. Analysis of the data collected before trial discontinuation
indicated that UB-311 was well tolerated, with return of anti-Aβ antibody titers to peak levels achieved after a gap of as long as 12
months between doses and a continued trend toward evidence of disease modification. In the Phase 2a LTE trial, six SAEs were
observed. One case of ARIA-E was observed in the Phase 2a LTE trial in a subject 10 weeks after receiving a dose of UB-311, which
was clinically not significant according to the study investigator. No SAE was deemed related or likely related to UB-311, and all such
events were recovered/resolved by the end of the study. Exploratory analyses of the clinical data generated in this portion of the trial
suggested that subjects in the treatment cohorts showed sustained improvement, as measured by the change in CDR-SB from baseline.
We completed an open-label Phase 1 trial of UB-311 in 19 subjects with mild-to-moderate AD between the ages of 51 to 78 years. The
primary objective of the trial was to assess safety and tolerability. Secondary measures included UB-311 antibody titers along with
changes in the ADAS-Cog, MMSE and the Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change disease
assessment ratings. The 24-week, open label trial was designed as three intramuscular injections of 300μg, the first dose administered
at the start of the trial, a second at week four and a third at week 12. An observation study included additional follow-up visits up to 48
weeks after the first injection to assess the long-term immunogenicity and safety of UB-311. In this trial, UB-311 was well tolerated,
with the most common TEAE being injection site redness and swelling. No TEAE resulted in the discontinuation or withdrawal of any
study participant in the trial. In the Phase 1 trial, one SAE was observed: a case of herpes zoster deemed unlikely related to UB-311.
Anti-Aβ antibody titers, recorded among all study participants, approached a 100-fold increase during weeks 16 to 48 after
administration of the third 300μg injection at week 12, demonstrating the ability of UB-311 to elicit a strong immune response. Durability
of the response was reflected in elevated anti-Aβ antibody titers measurable well beyond the 24-week duration of the trial.
In a Western blot assay, we observed that UB-311 elicited antibody titers specific to toxic forms of Aβ with minimal binding to normal,
non-plaque-causing, forms of Aβ.
Pre-Clinical Data
Pre-clinical trials of UB-311 included multiple antibody titer studies involving mice, guinea pigs, macaques and baboons. Application
of specific transgenic animal models was intended to emulate both therapeutic and preventive treatment paradigms. These trials
demonstrated that UB-311 generated high antibody titers across multiple species that selectively target aggregated Aβ and both slow the
accumulation of and reduce existing Aβ pathology.
We also observed the ability of UB-311 induced antibodies to penetrate the BBB, as well as preferentially bind to toxic Aβ aggregates.
In our study of UB-311 in cynomolgus monkeys, we tested five escalating dose levels of UB-311: 0μg, 30μg, 100μg, 300μg and 900μg.
Each dose level was administered on weeks zero, three and six by intramuscular injection and the cerebrospinal fluid (“CSF”): serum
ratio of UB-311 calculated on week eight (two weeks after the last dose). This analysis concluded that UB-311 antibody titers were
detectable in the CSF in a dose-dependent manner with CSF: serum antibody ratios of 0.1% to 0.2%, ratios similar to published data for
mAbs in development for neurodegenerative diseases.
UB-311 Shows Dependent Response in CSF in Pre-Clinical Study
21
The above graphs demonstrates that UB-311 induces enough antibodies for BBB penetration, across five dose levels in a pre-clinical
study with cynomolgus monkeys.
Development Plans for UB-311
We have completed an End of Phase 2 meeting with the FDA and obtained guidance on the further development of UB-311.
We believe UB-311 could also have a potential therapeutic benefit in a prophylactic setting for the prevention of AD in at-risk subjects.
We may seek to further develop UB-311 for the prevention of AD.
UB-312
An Overview of Parkinson’s Disease
Parkinson’s disease currently affects approximately one million people in the United States and more than 10 million people worldwide.
The economic burden of PD is estimated at $52 billion in the United States alone. PD is a chronic and progressive neurodegenerative
disorder that affects predominately dopamine-producing (“dopaminergic”) neurons in the substantia nigra area of the brain. Although
the mechanisms responsible for the dopaminergic cell loss in PD are not fully elucidated, several lines of evidence suggest that α-
synuclein plays a central role in the neurodegenerative process.
Alpha-synuclein is a protein highly expressed in neurons, mostly at presynaptic terminals, suggesting a role in synaptic vesicle
trafficking, synaptic functions and in regulation of neurotransmitter release at the synapse. Duplications, point mutations or single
nucleotide polymorphisms in the gene encoding α-synuclein are known to cause or increase the risk of developing PD or LBD. Mutations
have been shown to primarily alter the secondary structure of α-synuclein, resulting in misfolded and aggregated forms of α-synuclein
(i.e., pathological forms). While mutations in the α-synuclein gene are rare, aggregates of α-synuclein in the form of Lewy bodies (“LB”)
and Lewy neurites are common neuropathological hallmarks of both familial and sporadic PD, suggesting a key role of α-synuclein in
PD neuropathogenesis. Moreover, preformed fibrils of α-synuclein can induce the formation of LB-like inclusions and cellular
dysfunction in cell-based assays as well as in pre-clinical animal models. Together, these data strongly suggest that targeting pathological
forms of α-synuclein has therapeutic potential.
Limitations of Current Therapies
Most approved therapeutic products are aimed at compensating for the dopaminergic deficits and only provide symptomatic relief. While
existing products can indeed provide meaningful symptomatic relief, they often produce significant side effects and lose their beneficial
effects overtime. On the other hand, there are no currently approved disease-modifying therapeutics for PD.
Immunotherapy approaches targeting α-synuclein have been shown to ameliorate α-synuclein pathology as well as functional deficits
in mouse models of PD and are now being investigated in the clinic. These include passive immunization therapy using humanized or
human anti-α-synuclein mAbs or active immunization therapy aimed at inducing a humoral response against pathological α-synuclein.
These approaches have thus far demonstrated good tolerability profiles in Phase 1 clinical trials. A Phase 2 clinical trial in PD subjects
with prasinezumab, a mAb that preferentially recognizes oligomeric and fibrillar forms of α-synuclein, suggested reduced motor function
decline in subjects as compared with placebo; however, this Phase 2 trial did not meet its primary or secondary endpoints. Further trials
of prasinezumab in different patient populations remain ongoing. Even if approved as therapeutic for PD, we expect prasinezumab
would be burdened by the general challenges of cost and administration.
Our Product Candidate: UB-312
We are developing UB-312, an anti-α-synuclein product candidate, as a treatment for PD and other synucleinopathies. We believe that
UB-312 has the potential to be established as a disease-modifying treatment modality for PD, and possibly for LBD and MSA. Pre-
clinical data indicated that UB-312 elicits antibodies that preferentially recognize pathological forms of a-synuclein and improves motor
performance in mouse models of α-synucleinopathies. Clinical data from our Phase 1 trial, which we completed in 2023, indicate that
UB-312 is well tolerated and elicits antibody levels sufficient to cross the BBB (i.e., detectable in CSF) in both healthy volunteers and
PD patients. Antibodies showed preferential binding to aggregated aSyn. Two exploratory biomarkers were evaluated as measures of
disease progression: aggregated α-synuclein as measured by a semi-quantitative SAA, and phosphorylated aSyn (pS129 α-synuclein).
A
post hoc
pS129 α-synuclein as compared to placebo. PD patients with UB-312-induced antibodies in CSF also showed improvement in the
clinical Movement Disorder Society – Unified Parkinson’s Disease Response Score (“MDS-UPDRS”) Part II activities of daily living
scale as compared to placebo. In 2018, the European Medical Agency (“EMA”) granted UB-312 orphan designation for MSA.
22
Clinical Development
In Part B of a randomized, placebo-controlled, double-blind, dose-escalating, single-center Phase 1 clinical trial of UB-312, 20 PD
patients between the ages of 40 and 85 years received three intramuscular doses of either UB-312 or placebo. During this 44-week Part
B of the trial, subjects received one of two different three-dose priming regimens ("Group A" and "Group B"), with doses on weeks 1,
5, and 13. Immunogenicity was evaluated by measuring changes in serum and CSF anti- α-synuclein antibody concentrations during
the course of the study. In addition, an exploratory endpoint was included involving a clinical assessment using the MDS-UPDRS. The
Michael J. Fox Foundation (“MJFF”) has funded a 2-year collaborative project between Vaxxinity, the Mayo Clinic, and University of
Texas Houston using CSF collected from individuals enrolled in Part B of the Phase 1 trial of UB-312. This work is evaluating the
potential of an SAA to assess target engagement, and aims to characterize the anti-α-synuclein antibodies produced after immunization
with UB-312.
UB-312 was generally safe and well-tolerated in PD patients, with 19 of 20 patients completing dosing. The most common TEAEs
were headache, procedural pain, fatigue, and orthostatic hypotension. The majority of TEAEs was considered either mild or moderate,
and UB-312 was comparable to placebo. Two patients experienced SAEs, of which one was deemed possibly related by the investigator
due to the timing of onset. This SAE was a deep venous thrombosis of the left leg 50 days after administration of the second dose of
UB-312. There were no apparent trends in safety signals, including ECG, vital signs, and blood and urine assessments. There was no
difference in either physician or participant reported tolerability within seven days after each administration of UB-312 compared to
placebo.
UB-312 generated robust levels of anti-α-synuclein antibody titers detectable in the serum and CSF of PD patients. 12 out of 13 patients
who completed dosing had anti-α-synuclein antibodies detectable in the serum. In Group A, 4 out of 6 patients had anti-α-synuclein
antibodies detectable in CSF; in Group B, 1 out of 7 patients had anti-α-synuclein antibodies detectable in CSF. Of patients with
detectable anti-α-synuclein titers in CSF, the CSF:serum antibody ratio was approximately 0.35%. Antibodies were selective to
aggregated forms of α-synuclein over monomeric α-synuclein as measured by dot blot.
Results from a SAA performed at Mayo Clinic suggest that UB-312-induced antibodies functionally inhibit the aggregation of α-
synuclein when spiked into PD patient CSF.
Spiking UB-312 Antibodies into PD Patient CSF Slows Down Alpha-Synuclein Aggregation
This α-synuclein SAA performed at Mayo Clinic used antibodies purified from subjects in the Phase 1 trial of UB-312. It suggests
slowing of the aggregation of α-synuclein in PD patient CSF samples seeded with α-synuclein monomers, as measured by fluorescence
intensity.
We also directly measured α-synuclein aggregates in the CSF of the PD patients who participated in the Phase 1 trial of UB-312 using
fluorescence max in a SAA. This showed up to a 20% reduction of aggregated α-synuclein in PD patient CSF in Group A, as compared
to a 3% increase in the placebo group (p = 0.024), over the 44-week trial period.
23
Reduction of Alpha-Synuclein Aggregates in CSF of PD Patients
This α-synuclein SAA performed at Amprion showed a significant reduction in the pathological species of α-synuclein with UB-312 as
compared to placebo. *Placebo vs. Group A, two-way RM ANOVA: F
2,19
An exploratory
post hoc
Patients with detectable anti-α-synuclein antibodies in CSF showed significant reduction in aggregated α-synuclein in CSF (28% versus
placebo, p = 0.0183), as well as improvement in MDS-UPDRS Part II), the activities of daily living clinical scale (p = 0.0062).
This exploratory
post hoc
and without detectable anti-α-synuclein antibodies in CSF. Patients with detectable anti-α-synuclein antibodies in CSF showed a 27.2%
reduction in pS129 α-synuclein, as compared to a 19.5% increase observed in the placebo group (p = 0.0351).
Reduction of Phosphorylated Alpha-Synuclein in PD Patient CSF
This assay performed at Magqu demonstrates a statistically significant reduction in phosphorylated pS129 α-synuclein in PD patients
with detectable anti-α-synuclein antibody titers in CSF. *Placebo vs. UB-312 with CSF titers at the end of the study, Bonferroni multiple
comparison test p = 0.0351.
Correlations between changes in titers and changes in aggregated α-synuclein were observed.
In Part A of the Phase 1 clinical trial of UB-312, 50 healthy volunteers between the ages of 40 and 85 years received three
intramuscular doses of either UB-312 or placebo. During this 44-week Part A of the trial, subjects received three priming doses on the
same schedule as described for Part B, with escalating doses ranging from 40μg to 2,000μg. Data from Part A indicated that UB-312 is
generally well tolerated, with no significant safety findings. Data from Part A also suggested that UB-312 is highly immunogenic,
with all individuals in the 300μg/dose group showing detectable anti-α-synuclein antibodies in both serum and CSF samples. CSF:
24
serum ratios appeared similar to those observed in UB-311 non-human primate studies (approximately 0.2%), and to those observed in
clinical trials of mAbs.
UB-312 Demonstrated Dose-Dependent Response in Phase 1 Part A Trial Including Penetration of Titers into CSF
Across four cohorts, UB-312 demonstrated a dose-dependent immunogenic response. Antibodies generated by UB-312 were readily
detectable in CSF, indicating BBB penetration with a CSF: serum ratio of approximately 0.2%.
We paused dosing in high dose cohorts in Part A of the trial after one subject developed an adverse effect (“AE”) of special interest (i.e.,
Grade 3 flu-like symptoms) shortly after receiving the second 1000μg dose of UB-312. Although this AE was transient and not a SAE,
data collected until that point suggested that the 100μg and 300μg dose levels were well tolerated and yielded relatively high anti-α-
synuclein titers. During the evaluation of the AE, the COVID-19 pandemic was becoming increasingly pervasive throughout Europe,
increasing the risk to healthy volunteers participating in the trial. We therefore did not resume dose escalation and selected 100μg and
300μg doses for Part B in PD subjects.
An end-of-treatment analysis of the ongoing Part B of the Phase 1 trial in PD patients was completed in the fourth quarter of 2022. This
analysis has shown UB-312 to be well tolerated and immunogenic, with anti-α-synuclein antibodies observed in the serum and CSF of
PD patients. Three SAEs were observed in Part B, which remains blinded, meaning it remains unknown in which treatment group they
occurred (UB-312 or placebo).
Pre-Clinical Data
We have conducted pre-clinical studies of UB-312 across multiple animal species, including mice and guinea pigs. These trials
demonstrated that our product candidates, including UB-312, generated high antibody titers to α-synuclein across animal species. In
addition, in vitro studies provided evidence that anti-α-synuclein antibodies produced after UB-312 immunization are highly selective
to pathological α-synuclein, and do not bind to normal α-synuclein.
UB-312 Demonstrates Selective Binding Towards α-Synuclein Fibrils and Ribbons
This in vitro slot blot analysis of sera from guinea pigs dosed with UB-312 demonstrates that antibodies induced by UB-312 bind to α-
synuclein fibrils and ribbons, the toxic forms of α-synuclein believed to underlie PD, more strongly than they bind to monomers, the
normal form of α-synuclein in the body. We believe this preference will allow UB-312 antibodies to avoid altering normal functions of
α-synuclein and selectively neutralize the toxic species
(Nimmo et al., Alzheimers Res Ther. 2020;12:159).
25
Anti-α-synuclein antibodies produced by UB-312 immunization specifically bind pathogenic species of α-synuclein, including
aggregated fibrils, oligomers and ribbons, while demonstrating low affinity for the monomer. This species selectivity contrasted with
Syn-1, a commercial research mAb used as a control, which failed to differentiate the toxic variants.
In an in vivo study of UB-312 using a transgenic mouse model of PD, we demonstrated prevention of motor deficits in treated animals,
which was associated with significant reduction of brain oligomeric forms of α- synuclein. We believe this data supports the potential
of UB-312 to prevent behavioral motor deficits and reduce toxic forms of α-synuclein.
UB-312 Demonstrates Improvement in Motor Symptoms in Pre-Clinical Study
UB-312 immunization in a transgenic mouse model (α-synuclein overexpression) demonstrates improvement in beam test and wire
hanging test, and reductions in α-synuclein oligomers in various brain regions (Nimmo et al., Acta Neuropathol. 2022;143:55-73).
We have also observed by immunohistochemistry that serum antibodies from guinea pigs dosed with UB-312 can bind to aberrant α-
synuclein in PD, LBD and MSA brain sections.
Finally, antibodies derived from UB-312 showed no off-target binding on human tissue sections. UB-312-treated transgenic mice
showed no signs of neuroinflammation, and GLP toxicity studies in rats indicated a good non-clinical safety and tolerability profile. We
believe our preclinical data suggest that UB-312 may potentially induce a well-tolerated, strong and specific IgG response against
pathological forms of
a-synuclein
in PD subjects.
Development Strategy
An investigator-initiated Phase 1 trial of UB-312 in PD and MSA patients is ongoing at New York University. Based on the encouraging
results from the 20-patient Phase 1 Part B completed in 2023, we plan to take UB-312 into a Phase 2 trial.
Other Neurodegeneration Programs
We are actively engaged in additional initiatives related to neurodegenerative disorders. One of these programs focuses specifically on
tau-protein pathology and its involvement in diseases such as AD and related tauopathies. We believe that targeting different pathological
tau variants simultaneously may enhance treatment efficacy, which will most likely require targeting multiple epitopes concomitantly.
Using our AIM Platform, we have constructed multi-epitope product candidates that have successfully demonstrated immunogenicity
and in vitro activity in various models.
We are also investigating the use of a multi-target of product candidates targeting Aβ, α-synuclein, and tau, as multiple proteins could
be implicated in neurodegenerative diseases.
Next Wave Chronic Disease Programs
Pathological endogenous proteins (“self-proteins”) drive a wide range of chronic diseases. While mAbs and small molecules have
provided therapeutic benefits in the treatment of these diseases, inherent limitations of these drug classes have restricted access and
adherence to these treatment modalities globally.
26
Our next wave chronic disease programs are initially focused on hypercholesterolemia and migraine. Monoclonal antibodies have been
approved in both therapeutic areas; however, their high costs have limited access and generally limited use to relatively severe disease.
We aim to develop product candidates in these therapeutic areas that could offer similar efficacy as mAbs at a meaningfully lower cost
and improved administrative convenience to patients, thereby potentially allowing for access to broader patient populations versus
mAbs, and greater efficacy than small molecules.
VXX-401
An Overview of Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood and typically results from a combination of environmental
and genetic factors. Cholesterol is transported in the blood plasma within particles called lipoproteins. Lipoproteins are classified by
their density: very low-density lipoprotein, intermediate density lipoprotein, LDL and high-density lipoprotein (“HDL”). All lipoproteins
carry cholesterol, but elevated levels of lipoproteins other than HDL, particularly LDL, are associated with the development of
cardiovascular disease. Approximately 2 billion people worldwide have elevated levels of LDL, potentially putting them at risk for
cardiovascular disease.
Although hypercholesterolemia itself is asymptomatic, elevation of serum cholesterol can over time lead to atherosclerosis. Over many
years, elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. These plaque deposits can in turn
lead to progressive narrowing of the involved arteries. Smaller plaques may rupture and cause a clot to form and obstruct blood flow. A
sudden blockage of a coronary artery may result in a heart attack. A blockage of an artery supplying the brain can cause a stroke. If the
development of the stenosis or occlusion is gradual, blood supply to the tissues and organs slowly diminishes until organ function
becomes impaired.
PCSK9 is mainly expressed in the liver and, to a lesser extent, in the small intestine, kidney, pancreas and the CNS. The LDL receptors
(“LDLR”) at the cell surface bind and initiate ingestion of LDL particles from extracellular fluid into cells, leading to a reduction in
serum LDL levels. PCSK9 protein plays a major regulatory role in cholesterol homeostasis, mainly by reducing LDLR levels on the
plasma membrane, which leads to decreased metabolism of LDL by the cells. Inhibition of PCSK9 prevents this reduction in LDLR
levels on the plasma membrane, and in consequence the cellular process of internalizing LDL particles, resulting in a reduction of LDL.
Limitations of Current Therapies
Statins are the most commonly used drugs to treat hypercholesterolemia and result in a pronounced reduction in LDL. The unambiguous
benefits of statins, together with the prevalence of coronary heart disease, have made statins the most highly prescribed drug class in
developed countries. However, many patients are unable to achieve targeted lipid levels despite intensive statin therapy. In addition,
continued patient adherence to statin therapy, which is necessary to maintain a lower risk for cardiac events, is variable but considered
to be low – as low as 30% to 40% after two years in persons following a myocardial infarction. Importantly, at the transcriptional level,
statins up-regulate not only LDLR, but also PCSK9, causing the so-called paradox of statin treatment. Although statins induce a
beneficial increase in LDLR, they also increase PCSK9, thus leading to LDLR degradation, which indirectly increases LDL, mitigating
the overall LDL reduction that statins otherwise cause. Given the limitations in efficacy and adherence, targeting PCSK9 in combination
with statins treatment is an emerging treatment paradigm for hypercholesterolemia.
Two mAbs that inhibit activity have received FDA approval, alirocumab (Praluent) and evolocumab (Repatha). These drugs were
initially approved to treat the genetic condition heterozygous familial hypercholesterolemia, although the approved indications were
expanded after the publication of studies demonstrating that the use of a PCSK9 inhibitor in conjunction with a statin significantly
reduced the risk for major cardiovascular events, including heart attack, stroke, unstable angina requiring hospitalization or death from
coronary heart disease. In addition, inclisiran (Leqvio), an siRNA inhibitor of PCSK9 synthesis, was approved by the EMA in late 2020
for the treatment of heterozygous familial hypercholesterolemia in addition to other dyslipidemia.
While alirocumab and evolucumab have demonstrated clinical benefit, their commercial potential has been limited by their pricing. Both
launched with a wholesale acquisition price exceeding $14,000 annually, but prices for both were subsequently reduced in 2018.
Nevertheless, this drug class generated sales of approximately $1.5 billion in 2021 and is expected to grow to approximately $2.1 billion
by 2030, including the addition of inclisiran to the market. In addition, both are administered bi-weekly or monthly, which represents
what we believe to be a frequent and inconvenient administration schedule for patients. While inclisiran represents an improved
administration schedule compared to alirocumab and evolucumab, as it must be administered twice annually, we believe that it may
encounter similar pricing challenges due to the published cost effectiveness price.
Our Product Candidate: VXX-401
We are developing VXX-401, an anti-PCSK9 product candidate to treat hypercholesterolemia. We are dedicated to developing a product
candidate that has long-acting treatment duration, which we believe will offer a more convenient treatment regimen compared to the up
to bi-weekly dosing required by some mAbs. We believe that lower manufacturing costs commensurate with the requirement of
27
meaningfully less drug substance relative to mAbs, coupled with our ability to achieve commercial scale production rapidly, may
promote expanded use of this drug class as a first-line therapy, allowing for treating a greater number of hypercholesterolemia patients
than currently treated with mAbs.
Pre-Clinical Data
In August 2022 we announced the selection of VXX-401 as our lead anti-PCSK9 vaccine candidate. In pre-clinical studies, VXX-401
generated therapeutic titer levels of anti-PCSK9 antibodies, a high response rate among dosed animals, and robust reduction in LDL
across multiple species.
Results from three separate pre-clinical studies of VXX-401 in non-human primates, including a GLP toxicity study, have been published
in the Journal of Lipid Research (Vroom et al. 2024). This paper reported that VXX-401 triggers a safe humoral immune response
against PCSK9, consistently "resulting in the production of antibodies and a subsequent 30-40% reduction in blood LDL-C.” These
effects are sustained over time. Anti-PCSK9 antibodies generated by VXX-401 bind human PCSK9 “with high affinity and block the
inhibitory effects of PCSK9 on LDL-C uptake in a hepatic cell model.”
The GLP toxicology study demonstrated that 5 doses of VXX-401 were safe and well tolerated, with no clinical observations and no
pathological findings.
Development Strategy
We have initiated a first-in-human Phase 1 clinical trial of VXX-401 in Australia in the first quarter of 2023. In October 2023 we
expanded this trial from 48 subjects with elevated cholesterol to 64 subjects, monitoring for safety, immunogenicity, and relevant
biomarkers. We expect a topline readout by mid-2024. In a potential subsequent Phase 2 trial we may test VXX-401 alone and in
combination with statins.
UB-313
An Overview of Migraine
Migraine is a chronic and debilitating disorder characterized by recurrent attacks lasting four to 72 hours with multiple symptoms,
including typically one-sided, pulsating headaches of moderate to severe pain intensity that are associated with nausea or vomiting,
sensitivity to sound and sensitivity to light. Over 90% of the patients are unable to function normally during a migraine attack. Many
experience comorbid conditions such as depression, anxiety and insomnia.
The Migraine Research Foundation ranks migraine as the world’s third most prevalent illness. The disease affects 39 million individuals
in the United States and approximately one billion individuals globally. Patients generally suffer from chronic or episodic migraines.
Chronic migraine is defined as 15 headache days or more per month, while episodic migraine is defined as fewer than 15 headache days
per month. Both acute and prophylactic treatments are used to address chronic and episodic migraines.
CGRP’s Role in Migraine
CGRP is a neuropeptide found throughout the body, including in the spinal cord. CGRP activates CGRP receptor in the
trigeminovascular system, which is located within pain-signaling pathways, intracranial arteries and mast cells. Activation of the CGRP
receptor has been demonstrated to induce migraine in migraineurs. Multiple anti-CGRP therapies have been approved for the treatment
of migraine.
Limitations of Current Therapies
Since the early 1990s, there has been minimal improvement in the standard treatment for migraine. Treatments are characterized as elite
acute or prophylactic. Triptans are the current first-line prescription therapy for the acute treatment of migraine, with over 15 million
annual prescriptions written in the United States.
Prophylactic medications approved for migraine include beta blockers, such as propranolol, topiramate, sodium valproate and botulinum
toxin, branded as Botox. However, many of these medications provide limited clinical benefit. In addition, they are often not well
tolerated, with AEs such as cognitive impairment, nausea, fatigue and sleep disturbance.
Therapeutics targeting the CGRP pathway represent an emerging treatment paradigm. Three anti-CGRP mAbs were approved by the
FDA in 2018 for the prophylactic treatment of migraine in adults. These mAbs, erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy)
and galcanezumab-gnlm (Emgality), are all administered subcutaneously. Their side effects are generally mild, including pain and
redness at the site of injection, nasal congestion and constipation. Studies show that these mAbs reduce the number of headache days
by 50% or more in approximately 50% of patients. In 2020, the FDA approved eptinezumab-jjmr (Vyepti), an intravenously infused
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anti-CGRP mAb for the preventive treatment of migraine. The FDA has also approved small molecule anti-CGRP drugs, including
atogepant (Qulipta) for the preventive treatment of episodic migraine, ubrogepant (Ubrelvy) for the acute treatment of migraine, and
rimegepant (Nurtec) for both acute and preventive treatment of migraine. Sales for marketed and clinical-stage anti-CGRP therapeutics
are projected to reach approximately $10.1 billion by 2033. Despite the commercial success that this class represents, many of these
treatments require frequent administration, creating inconvenience for patients.
Our Product Candidate: UB-313
We are developing UB-313 as a preventive treatment for migraine. We believe UB-313 has the potential to improve upon the current
preventive treatments for migraine in multiple aspects: we expect UB-313 will require administration quarterly to annually, in contrast
to monthly to quarterly for currently marketed mAbs and frequent administration for small molecules. Furthermore, a potential long
durability of response may offer physicians and patients the option to administer UB-313 in an office setting, which can potentially
improve adherence. We expect the cost of UB-313 treatment, if approved, to be lower than that of mAbs for migraine.
Clinical Development
In 2023, we completed a first-in-human Phase 1 clinical trial in 40 healthy volunteers in which UB-313 was generally well tolerated and
immunogenic: all subjects who received three doses of UB-313 (31 out of 31) developed anti-CGRP antibodies; however, serum
antibody titers were lower than expected, and due to this lower immunogenicity, UB-313 did not meet the trial’s secondary objective of
capsaicin-induced dermal blood flow inhibition. We believe this was the result of a suboptimal drug product made by a new contract
manufacturer, and we have identified the necessary steps to manufacture a more immunogenic product consistent with prior lots and the
known immunogenic potential of our platform candidates.
Pre-Clinical Data
We have completed both in vitro and in vivo pre-clinical studies of UB-313. We used an in vivo proof-of-concept capsaicin-induced
dermal blood flow model in mice to demonstrate target engagement of the marketed CGRP-targeting mAbs. In this model, we observed
similar rates in reduction of dermal blood flow as fremanezumab in a head-to-head comparison against fremanezumab.
UB-313 Reduces Capsaicin-Induced Dermal Blood Flow in Mice
**Dunnett’s: Ctl vs Vac 1p < 0.05; Ctl vs Vac 2 p < 0.05
In this preliminary study, dermal blood flow measurements were taken 17 weeks following the first dose of UB-313. There were 3 to 11
animals per treatment group. Reduced dermal blood flow indicates target engagement with CGRP. UB-313 reduced dermal blood flow
versus the control with an approximately similar magnitude to fremanezumab, which was administered 24 hours prior to the capsaicin
test.
We observed similar results in a capsaicin / dermal blood flow model in rats, comparing a rat version of UB-313 head-to-head against
galcanezumab.
Our in vivo studies of UB-313 have involved multiple animal species. High immunogenicity was observed in all pre-clinical species
tested. Characterization of the antibodies produced after immunization with UB-313 indicated that they have limited, if any, off-target
potential, are primarily IgG1 and IgG2, potently bind to CGRP and potently block CGRP activity
in vitro
. We refer to potency as the
amount of drug required to produce a pharmacological effect of given intensity and is not a measure of therapeutic efficacy. In a
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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
in vitro
activity to CGRP-targeted mAbs.
UB-313 Induced IgGs Have Comparable In Vitro Activities to Marketed CGRP mAbs
In a cyclic AMP (“cAMP”) production assay conducted in human SK-N-MC cells, antibodies taken from the serum of guinea pigs 15
weeks following the first injection of UB-313 demonstrated similar properties to two approved CGRP mAbs.
Moreover, the binding potency of UB-313 was determined to be comparable to these mAbs.
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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.
Next Stage Development Candidates
In addition to our initial focus on migraines and hypercholesterolemia, we believe our AIM Platform can generate product candidates
for a range of chronic diseases. We are evaluating opportunities across multiple disease areas, including allergy (e.g., atopic dermatitis,
chronic rhinosinusitis, food allergy), autoimmune (e.g., psoriasis, psoriatic arthritis), pain (e.g., peripheral neuropathy, diabetic
neuropathy) and bone and muscle deterioration (e.g., sarcopenia, osteoporosis, osteopenia) indications as they may apply to geriatrics
and space travel health.
COVID-19 Program
An Overview of COVID-19
COVID-19, caused by SARS-CoV-2, has rapidly swept throughout the world. As of February 2024, there have been more than 700
million confirmed COVID-19 cases and more than 6.9 million deaths worldwide. Common symptoms of COVID-19 are fever, cough,
lymphocytopenia and chest radiographic abnormality. A proportion of patients recovering from COVID-19 continue shedding virus for
days, and asymptomatic carriers may also transmit SARS-CoV-2, indicating a risk of a continuous and long-term pandemic.
SARS-CoV-2 is an enveloped, single-stranded, positive-sense RNA virus belonging to the family
Coronavidae
coronavirus. The genome of SARS-CoV-2 encodes one large Spike (“S”) protein that plays a pivotal role during viral attachment to the
host receptor, angiotensin converting enzyme 2 (“ACE2”), and entry into host cells. The S protein is the major principal antigen target
for vaccines against human coronavirus, including SARS-Co-V-2. Neutralizing antibodies targeting the receptor binding domain
(“RBD”) subunit of the S protein block the virus from binding to host cells. Over 90% of all neutralizing antibodies produced in response
to infection are directed to the RBD subunit, and mAbs that have shown therapeutic activity target epitopes on the RBD.
Fifty vaccines are authorized for use in one or more countries around the world. Most of these vaccines are based on the S protein of the
SARS-CoV-2, but rely on different mechanisms for presentation or expression of the S antigen, including whole inactivated virus,
defective adenovirus vectors, or mRNA. All have been shown to be safe and effective in placebo- controlled clinical trials. Antiviral
drugs and mAbs have limited availability and effectiveness.
COVID-19 Vaccine Market
As of February 2024, over 5.1 billion people have been fully vaccinated against COVID-19. Nearly all of these people received at least
one of three types of vaccine technologies: mRNA, adenovirus vector, or inactivated virus. As SARS-CoV-2 continues to evolve and
spread, the market for booster vaccinations has also grown, with over 2.8 billion doses sold to date.
We expect demand for booster vaccinations that are safe and well tolerated, offer long lasting immunity against emerging variants, and
allow for manageable storage and shipping conditions may last for the foreseeable future, particularly in low- and middle-income
countries (“LMICs”), similar to the influenza vaccine market. We also anticipate demand for more types of vaccine technologies,
beyond the readily available mRNA, adenovirus vector, and inactivated virus vaccine options.
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UB-612: Our COVID-19 Vaccine Initiative
We are developing UB-612 as a product candidate for boosting immunity to COVID-19 in vaccinated individuals. UB-612 is designed
to activate both antibody and cellular immunity against multiple viral targets. The vaccine is composed of a recombinant S1-RBD-sFc
fusion protein combined with rationally designed synthetic Th and CTL epitope peptides selected from the S2 domain of the spike,
membrane (“M”), and nucleocapsid (“N”) proteins. These peptides bind to MHC class I and II receptors without significant genetic
restriction, so that they may be recognized broadly by the vast majority of the human population. Our mixture of peptides is designed
to elicit T-cell activation, memory recall and effector functions similar to those of natural SARS-CoV-2 infection. The S1-RBD-sFc
fusion protein incorporates essential B-cell epitopes that promote the generation of neutralizing antibodies to the RBD of SARS-CoV-
2. UB-612 is formulated with Adju-Phos, an adjuvant widely used in many approved vaccines globally. For added safety, synthetic
peptides in UB-612 are adsorbed by our propriety CpG1 excipient, a Toll -like receptor 9 agonist molecule, known to help to stimulate
balanced T-cell immunity in humans. UB-612 can be stored and shipped at 2° to 8°C (conventional cold chain refrigerated temperatures).
An EUA application for UB-612 was denied by the TFDA in August 2021 because the neutralizing antibody response generated by UB-
612 delivered in an accelerated two-dose primary immunization schedule, as compared to that of a designated adenovirus vectored
vaccine, did not meet the TFDA’s specified evaluation criteria. We are now pursuing a path to conditional/provisional authorization for
UB-612 as a heterologous boost with the Medicines and Healthcare products Regulatory Agency (“MHRA”) and Therapeutic Goods
Administration (“TGA”), the regulatory authorities of the United Kingdom and Australia, respectively.
Clinical Development
In March 2022, Vaxxinity initiated a Phase 3 pivotal trial to compare the immune responses stimulated by homologous boosts mRNA
(BNT162b2), adenovirus (ChAdOx1-S), inactivated virus (Sinopharm BIBP) COVID-19 vaccines, to a heterologous boost of UB-612.
This was an active-controlled, randomized trial conducted in the United States, Panama, and Philippines under a platform protocol in
944 subjects 16 years and older who completed a two-dose primary immunization with one or more of the comparator vaccines
mentioned above. Eligible subjects were randomized into one of two treatment arms to receive a single dose of UB-612 or an active
comparator. The primary objective of the study was to determine non-inferiority of UB-612-stimulated neutralizing antibodies against
those of the comparator vaccines. CEPI co-funded this trial, which concluded in 2023.
Following positive topline results announced in December 2022, we completed submissions for conditional/provisional authorization
with the MHRA in the UK and the TGA in Australia in March 2023. We expect that, if successful, these authorizations may enable the
commercialization of UB-612 in multiple countries including select LMICs.
Heterologous Booster Data: Phase 3 Trial Topline Results
In the global pivotal Phase 3 trial, UB-612 elicited strong neutralizing antibodies against SARS-CoV-2 when compared head-to-head to
three globally authorized platform vaccines administered as homologous boosters, successfully meeting primary and key secondary
immunogenicity endpoints. The primary endpoints of the trial were safety and live virus neutralizing antibody titers against the Wuhan
strain of SARS-CoV-2 at day 29. Secondary immunogenicity endpoints included neutralizing antibody titers against Omicron BA.5 at
day 29, SCRs at day 29, and kinetics of neutralizing and RBD binding IgG antibody responses through 12 months. The primary objective
of the trial was to determine non-inferiority of UB-612-stimulated neutralizing antibodies against those of the comparator vaccines,
where statistical non-inferiority was defined by the lower bound of the 95% confidence interval (“CI”) of the geometric mean titer ratio
(“GMR”) > 0.67. When delivered as a heterologous booster in populations previously vaccinated with Pfizer-BioNTech’s BNT162b2,
AstraZeneca’s ChAdOx1-S, or Sinopharm’s BIBP, UB-612 was shown to generate neutralizing antibody titers 28 days after
administration that were:
●
Statistically non-inferior to, and directionally higher than, BNT162b2: 1.04 GMR against Wuhan (95% CI: 0.89, 1.21;
p=0.6147), 1.11 GMR against Omicron BA.5 (95% CI: 0.94, 1.31; p=0.2171)
●
Statistically superior to ChAdOx1-S: 1.92-fold higher geometric mean titers against Wuhan with UB-612 (GMR=1.92; 95%
CI: 1.44, 2.56; p<0.0001), 2.85-fold higher against Omicron BA.5 (GMR=2.85; 95% CI: 2.00, 4.05; p<0.0001)
●
Statistically superior to BIBP: 5.77-fold higher geometric mean titers against Wuhan with UB-612 (GMR=5.77; 95% CI: 4.62,
7.20; p<0.0001), 5.93-fold higher against Omicron BA.5 (GMR=5.93; 95% CI: 4.60, 7.65; p<0.0001)
SCR as measured against Wuhan and Omicron BA.5 were key secondary endpoints in the Phase 3 trial. Seroconversion was defined as
a ≥4-fold increase of neutralizing antibody titers from baseline. SCR non-inferiority was defined by the lower bound of the 95% CI for
the difference of the UB-612 SCR minus the comparator SCR > -10%. SCR superiority was defined by the lower bound of the 95% CI
for the difference of the UB-612 SCR minus the comparator SCR > 0%. UB-612 SCR at day 29 was statistically non-inferior to, and
directionally higher than, BNT162b2 against both Wuhan and Omicron BA.5, statistically superior to ChAdOx1-S with 1.9-fold higher
SCR against Wuhan (23.6% absolute difference, p=0.0009) and 2.0-fold higher SCR against Omicron BA.5 (29.2% absolute difference,
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p<0.0001), and statistically superior to BIBP, with 8.3-fold higher SCR against Wuhan (56.8% absolute difference, p<0.0001) and 5.8-
fold higher SCR against Omicron BA.5 (58.0% absolute difference, p<0.0001).
Safety data from the Phase 3 trial suggested that UB-612 was generally well tolerated; no vaccine-related SAEs were reported.
2-Dose Clinical Data
In early 2021, we completed an open-label dose escalation Phase 1 clinical trial to evaluate the safety, tolerability and immunogenicity
of UB-612 in healthy volunteers between the ages of 20 and 55 in Taiwan. This six-month trial consisted of three 20-subject cohorts,
each receiving an initial dose at the start of the trial and a second dose on day 28: one cohort received two 10µg doses, the second
received two 30µg doses, and the third received two 100µg doses. The mean titer of antigen-specific antibodies to UB-612 and the
seroconversion rate was evaluated throughout the duration of the trial to determine the humoral immune response and persistence of
immunogenicity. In addition, T-cell responses were evaluated by interferon-γ ELISpot assay and intracellular cytokine staining by flow
cytometry. The Phase 1 clinical trial was sponsored by UBIA. UBIA conducted the trial on our behalf in accordance with one of our
related party master services agreements.
After one and two doses, UB-612 was considered to be generally safe and well tolerated, with a low frequency of solicited and unsolicited
AEs, which were all Grade 1 (mild) in severity. After each vaccination, the most common AE was injection site pain, with no clear
difference in reactogenicity between dose levels. In all dose groups, there was a trend towards increased reactogenicity with increase in
dose. Three cases of mild allergic reactions were reported (e.g., itching at vaccine site), which were all resolved within 1-3 days.
Importantly, and in distinction to certain vaccines authorized for emergency use, no other increase in AEs was seen at second dose as
compared to first injection. We selected the highest dose (100μg) to take into a Phase 2 trial.
In an anti-S1-RBD ELISA assay, we observed that all three dose levels of UB-612 induced titer levels comparable to or greater than
those in sera from patients hospitalized with COVID-19. Furthermore, in a cytopathic effect viral neutralization assay (CPE VNT
50
), we
observed neutralizing titers comparable to those in sera from patients hospitalized with COVID-19.
Neutralizing activities of sample sera from the Phase 1 trial were assessed against live virus variants at the Viral and Rickettsial Disease
Laboratory of the California State Department of Public Health. The results indicate that UB-612 induces viral neutralizing antibody
titers against the Alpha, Gamma and Delta variants of SARS-CoV-2, close to the neutralizing titer level against the original (wild-type,
WT) Wuhan strain, while the titer level against the Beta variant is lower in comparison. The latter finding is anticipated by results
published for other COVID-19 vaccines, as pointed out above.
A randomized, placebo-controlled, multi-center Phase 2 trial of UB-612 in 3,850 healthy volunteers aged 12 to 85 was conducted in
Taiwan. Subjects in this trial receive two doses of 100μg UB-612, or placebo, 28 days apart. The objectives of this trial include the
analysis of safety and immunogenicity of UB-612, in particular, antigen-specific antibodies to UB-612, the seroconversion rate and lot-
to-lot consistency of antibody responses. An interim analysis of data from this Phase 2 trial in healthy volunteers 18 years and older
based on the data cut-off date of June 27, 2021 was submitted to the TFDA as part of a filing for an EUA in Taiwan. The EUA was
denied in August 2021 by the TFDA.
In data from the Phase 2 trial, UB-612 appears well tolerated. AEs were generally mild, and no UB-612-related SAEs were
observed. Local injection site AEs occurred in half of the subjects, the most frequent being injection site pain. Systemic Aes
occurred in less than half of the subjects, and the incidence was similar in the active and placebo groups, except for muscle pain
which was more frequent in the active group. Aside from muscle pain, systemic reactions were comparable across the active and
placebo groups, with less than 10% of subjects in either group experiencing fever or chills. Systemic Aes were similar after the first
and second doses. The vast majority of AEs were mild (Grade 1), and all were self-limited. No subject had a severe (Grade 3) local
reaction. The incidence of severe (Grade 3) systemic reactions was <0.1%.
Immunization with UB-612 in both Phase 2 and Phase 1 studies led to detectable T-cell responses observed in a subset of subjects. In
Phase 2, a total of 88 subjects receiving UB-612 and 12 receiving placebo were tested for T cell responses at baseline and on Day 57.
Preliminary results of ELISpot (Interferon-γ and IL-4) and intracellular cytokine staining indicate robust responses to UB-612, with a
strong Th1 orientation. Intracellular cytokine staining (ICS) confirmed the Th1 orientation of T cell responses. UB-612 induced
measurable CD8+ T cell responses and CD107a+/Granzyme secreting cells, which are putative cytotoxic T cells.
3-Dose Clinical Data
In a Phase 1 extension trial, 50 subjects from Phase 1 received a third booster dose of UB-612 approximately 7-9 months after their
second dose (100µg). In this
extension trial, UB-612 was generally well tolerated after a third dose, with no vaccine-related SAEs
reported.
Immunogenicity and safety data from the Phase 1 extension suggests that UB-612 elicits a multi-fold increase in neutralizing
antibody titers upon third dose, significantly exceeding those observed in human convalescent sera, and that the third dose is well
33
tolerated with no vaccine-related SAEs reported. Published studies have shown a correlation between efficacy in randomized
controlled trials and the ratio of neutralizing titers in sera from vaccinated subjects to titers in human
convalescent sera.
In collaboration with University College London and VisMederi, we analyzed sera from subjects immunized with three doses of UB-
612. Data demonstrated that UB-612 elicited a broad IgG antibody response against multiple SARS-CoV-2 variants of concern,
including, Alpha, Beta, Delta, and Gamma, and Omicron, and higher levels of neutralizing antibodies against Omicron than three
doses of an approved mRNA vaccine.
An extension of the Phase 2, observer-blind, multicenter, randomized, placebo-controlled trial was sponsored by UBIA to evaluate the
immunogenicity, safety, tolerability, and lot consistency of a homologous booster dose of UB-612 in adolescents, younger adults, and
elderly adults. Adult subjects who completed the primary 2-dose UB-612 series in the main Phase 2 trial were unblinded and offered
a third dose of UB-612. The third dose of UB-612 stimulated both arms of adaptive immunity in subjects. The frequency of solicited
and unsolicited adverse events following the third dose was consistent with the safety profile observed after the first and second doses.
Development Strategy
Based on our belief in UB-612’s potential utility as a heterologous booster dose (boosting the immunity of a subject who has already
received a different vaccine), we have completed rolling submissions for conditional/provisional authorization with regulatory
authorities in the United Kingdom and Australia, who are reviewing under their established work share agreement.
Competition
The pharmaceutical industry is characterized by rapidly advancing technologies, intense competition and a strong emphasis on
proprietary products. While we believe that our technology, the expertise of our executive and scientific teams, research, clinical
capabilities, development experience and scientific knowledge provide us with competitive advantages, we face increasing competition
from multiple sources, including pharmaceutical and biotechnology companies, academic institutions, governmental agencies and public
and private research institutions both in the United States and abroad.
Many of our competitors may have significantly greater financial resources and expertise in research and development, manufacturing,
preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. These
competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical
trial sites and patient enrollment for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
Smaller or early stage companies may also prove to be significant competitors, particularly through collaborative arrangements with
larger or more established companies.
Vaccines
The global vaccine market is highly concentrated among a small number of multinational pharmaceutical companies: Pfizer, Merck,
GlaxoSmithKline and Sanofi together control most of the global vaccine market. Other pharmaceutical and biotechnology companies,
academic institutions, governmental agencies and public and private research institutions are also working toward new solutions given
the continuing global unmet need.
Neurodegenerative Disorders
We expect that, if approved, our product candidates will compete with currently approved therapies for management of
neurodegenerative diseases, such as AD and PD. In AD, four drugs are currently approved by the FDA for the treatment of symptoms
of AD, based on acetylcholinesterase (“AchE”) inhibition and NMDA receptor antagonism. In addition to the marketed therapies, we
are aware of several companies currently developing therapies for AD, including Eisai, Lilly, Hoffman-LaRoche, Abbvie, Johnson &
Johnson, and Novartis. Biogen’s aducanumab was approved by the FDA in June 2021 under the accelerated approval pathway, which
allows for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint.
Aducanumab failed to achieve approval in Europe and Japan. In January 2024, Biogen announced its intention to discontinue
aducanumab. Eisai and Biogen’s lecanemab was approved by the FDA in January 2023 under an accelerated approval pathway.
Pharmaceutical treatments for PD address its symptoms only and do not treat the underlying causes of PD. The majority of prescription
drugs are dopaminergic medications and act by increasing dopamine, a neurotransmitter. We are aware of several companies with
product candidates at various stages of clinical development, including Sanofi, Kyowa Kirin, Cerevel Therapeutics and Hoffman-
LaRoche. Hoffman-LaRoche is developing prasinezumab, a mAb, as a potential treatment for PD.
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PCSK-9 Inhibitors
Three companies currently have PCSK-9 inhibitors approved by the FDA to treat hypercholesterolemia: Regeneron Pharmaceuticals
developed alirocumab (Praluent), a mAb, in collaboration with Sanofi, and Amgen developed evolocumab (Repatha), another mAb, and
Novartis is commercializing inclisiran, an RNAi construct, to down-regulate synthesis of PCSK-9.
CGRP-Directed Migraine Treatments
Seven migraine treatments have been approved by the FDA that target CGRP. Four of these therapeutics are mAbs and were approved
to prevent or reduce the number of migraine episodes. These medications are galcanezumab (Emgality), which was developed by Lilly;
erenumab (Aimovig), which was developed by Amgen in collaboration with Novartis; fremanezumab (Ajovy), which was developed
by Teva; and eptinezumab (Vyepti), which was developed by Alder, acquired by Lundbeck. Ubrogepant (Ubrelvy), developed by
Allergan, was approved for the treatment of acute migraine episodes; rimegepant (Nurtec), approved for both the acute treatment
migraine and the preventive treatment of episodic migraine, is sold by Pfizer following its acquisition of Biohaven. Atogepant (Qulipta),
developed by AbbVie, was approved for the preventive treatment of episodic migraine.
Collaborations
From time to time, we enter into licensing and commercialization agreements when they align with our mission, including the Platform
License Agreement described under “—Intellectual Property—Platform License Agreement.” Current collaboration partners include,
the University of Central Florida, the University of Florida, and the University of Southampton. For more information see Recent
Developments section.
Manufacturing
The manufacture of our product candidates encompasses both the manufacture of custom components and the formulation, fill and finish
of the final product. We do not currently own or operate manufacturing facilities for these processes. We currently rely upon contract
manufacturing organizations, including those mentioned below, to produce our product candidates for both pre-clinical and clinical use
and will continue to rely upon these relationships for commercial manufacturing if any of our product candidates obtain regulatory
approval. Although we rely upon contract manufacturers, we also have personnel with extensive manufacturing experience that can
oversee the relationships with our manufacturing partners.
Historically, we have depended heavily on UBI and its affiliates for our business operations, including the provision of research,
development and manufacturing services. Currently, UBIA provides testing services for UB-312 and UB-612, UBI Pharma Inc.
(“UBIP”) provides testing relating to formulation-fill-finish services for UB-312, and United BioPharma, Inc. (“UBP”) is the sole
manufacturer of protein for UB-612. Our commercial arrangements with UBI and its affiliates are described in more detail below.
Formulation-fill-finish services for UB-612 are provided by multiple contract manufacturers to ensure adequate capacity and minimize
supply chain risks. For supply of our other custom components, in addition to protein manufacturing conducted by UBP, we have
engaged third party CMOs, including C S Bio Co. (“CSBio”) as our primary peptide supplier for UB-612 peptides, CPC Scientific as
our primary peptide supplier for VXX-401, Wuxi STA for process development and manufacturing services of oligonucleotides, and
Pharmaceuticals International, Inc (“Pii”) for additional fill-finish services.
UBI Group Manufacturing Partnership
We primarily rely on our relationships with third-party contract manufacturing organizations to produce product candidates for our
clinical trials. Historically, we have heavily depended on UBI as a manufacturing partner for these efforts. In support of our COVID-19
program (UB-612), we have entered into a master services agreement with UBP and an additional master services agreement with UBI,
UBIA and UBP. Pursuant to these agreements, UBI and its affiliates have provided research, development, testing and manufacturing
services to us and continue to provide manufacturing services for our protein. Payment terms are mutually agreed in connection with
each work order relating to services rendered. Our agreement with UBP will expire on the later of March 2024 and the completion of
all services under the last work order executed prior to such scheduled expiration and our agreement with UBI, UBIA and UBP will
expire on the later of September 2023 and the completion of all services under the last work order executed prior to such scheduled
expiration. We also have a management services agreement with UBI pursuant to which UBI has provided research and prior back office
administrative services to us and acts as our agent with respect to certain matters relating our COVID-19 program. UBI is compensated
for its services on a cost-plus basis. The agreement terminates upon mutual agreement between the parties.
In support of our chronic disease pipeline, we have entered into master service agreements with each of UBI, UBIA and UBIP. Pursuant
to these agreements, UBI currently provides limited research services to us on a cost-plus basis, UBIA provides testing services related
to UB-312 clinical trial material already manufactured and UBIP has provided manufacturing, quality control, testing, validation, GMP
warehousing and supply services to us for UB-312 on payment terms agreed in connection with work orders relating to the services
35
rendered. UBI and its affiliates no longer provide clinical or manufacturing services for other programs. These agreements may all be
terminated for convenience upon 180 days’ notice or less.
We have also entered into a research and development services agreement with UBI. Pursuant to this agreement, UBI and its affiliates
may provide research and development services to us. Service fees payable by us to UBI for research and development projects
undertaken in accordance with the research and development plan would be determined by a joint steering committee and set forth in a
research and development plan. Any aggregate services fees payable by us under the research and development services agreement are
subject to a quarterly cap throughout the term of the agreement. The research and development services agreement expires in August
2026.
Intellectual Property
Our ability to obtain and maintain intellectual property protection for our product candidates and core technologies is fundamental to
the long-term success of our business. We rely on a combination of intellectual property protection strategies, including patents,
trademarks, trade secrets, license agreements, confidentiality policies and procedures, nondisclosure agreements, invention assignment
agreements and technical measures designed to protect the intellectual property and commercially valuable confidential information and
data used in our business.
In summary, our patent estate includes issued patents and patent applications which claims cover our AIM Platform and each of our
product candidates. As of December 31, 2023, our patent estate included four U.S. issued patents, ten U.S. patent applications, three
U.S. provisional patent applications, seven pending Patent Cooperation Treaty (“PCT”) patent applications, 34 issued non-U.S. patents
and 153 pending non-U.S. patent applications.
For our product candidates targeting the prevention and treatment of neurodegenerative disease, including claims covering UB-311,
UB-312, and anti-tau, patent rights are provided by patents and patent applications, the majority of which are being prosecuted in the
United States, Australia, Brazil, Canada, China, the EPO, Hong Kong, Indonesia, India, Israel, Japan, the Republic of Korea, Mexico,
Russia, Singapore, South Africa, Taiwan and the United Arab Emirates, and three pending PCT applications and one provisional
application in the U.S., directed to peptide vaccines for the prevention and treatment of neurodegenerative diseases. These issued patents
and patent applications, if issued, and any U.S. or non-U.S. patent issuing from the PCT or provisional patent applications, are expected
to expire between 2033 and 2043, excluding any patent term adjustments or patent term extensions.
For our product candidates directed to peptide immunogens targeting CGRP and formulations thereof for the prevention and treatment
of migraine, including UB-313, patent rights are provided by a patent and patent applications being prosecuted in the United States,
Australia, Brazil, Canada, China, the EPO, India, Indonesia, Japan, Mexico, Russia, the Republic of Korea, Singapore, Taiwan and the
United Arab Emirates. The issued patent and these patent applications, if issued, are expected to expire in 2039, excluding any patent
term adjustments or patent term extensions.
For our product candidates targeting cholesterol and cardiovascular disease, including our anti-PCSK9 product candidate targeting
PCSK9 and formulations thereof for prevention and treatment of PCSK9-mediated disorders, we have pending patent applications in
the United States, Australia, Brazil, Canada, the EPO, India, Indonesia, Japan, Mexico, the Philippines, the Republic of Korea, Russia,
Saudi Arabia, Taiwan, the United Arab Emirates, and Vietnam. These patent applications, if issued, are expected to expire in 2041,
excluding any patent term adjustment or patent term extension.
For our product candidates targeting SARS-CoV-2, including UB-612 for COVID-19, we have an issued patent and pending patent
applications in the United States, Argentina, Australia, Brazil, Canada, the EPO, India, Indonesia, Japan, Mexico, Pakistan, the
Philippines, the Republic of Korea, Russia, Saudi Arabia, Taiwan, United Arab Emirates, and Vietnam, and four pending PCT patent
applications. The issued patent and these patent applications, if issued, and any U.S. or non-U.S. patent issuing from the PCT
applications, are expected to expire between 2041 and 2043, excluding any patent term adjustments or patent term extensions.
For each product candidate utilizing the AIM Platform, additional patent rights directed to artificial T helper cell epitopes and to a CpG
delivery system are provided by patents and patent applications, the majority of which are being prosecuted in the United States,
Australia, Brazil, Canada, Chile, China, Colombia, the EPO, Indonesia, India, Israel, Japan, Mexico, New Zealand, Philippines, the
Republic of Korea, Russia, Singapore, South Africa, Taiwan, Thailand, Ukraine, the United Arab Emirates, and Vietnam. The members
of one family of patents expired in 2023, except for two U.S. patents that will expire in 2025 and 2026. With regards to the rest of the
families that cover the AIM Platform, the issued patents and patent applications, if issued, are expected to expire in 2039, excluding any
patent term adjustments or patent term extensions.
The term of individual patents depends on the countries in which they are obtained. The patent term is 20 years from the earliest effective
filing date of a non-provisional patent application in most of the countries in which we file, including the United States. In the United
States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the
USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent. The
term of a patent that covers a drug or biological product may also be eligible for patent term extension when FDA approval is granted
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for a portion of the term effectively lost as a result of the FDA regulatory review period, subject to certain limitations and provided
statutory and regulatory requirements are met.
In addition to our reliance on patent protection for our inventions, products and technologies, we also seek to protect our brand through
the procurement of trademark rights. We own registered trademarks and pending trademark applications for our brands, including our
“Vaxxinity”, “United Neuroscience” and “COVAXX” brands and other related names and logos, in the United States and certain foreign
jurisdictions.
Furthermore, we rely upon trade secrets and know-how and continuing technological innovation to develop and maintain our
competitive position. However, trade secrets and know-how can be difficult to protect. We generally control access to and use of our
trade secrets and know-how, through the use of internal and external controls, including by entering into nondisclosure and
confidentiality agreements with our employees and third parties. We cannot guarantee, however, that we have executed such
agreements with all applicable counterparties, that such agreements will not be breached or that these agreements will afford us
adequate protection of our intellectual property and proprietary rights. Furthermore, although we take steps to protect our proprietary
information and trade secrets, third parties may independently develop substantially equivalent proprietary information and techniques
or otherwise gain access to our trade secrets or disclose our technology. As a result, we may not be able to meaningfully protect our
trade secrets. For further discussion of the risks relating to intellectual property, see “Risk Factors—Risks Related to Our Intellectual
Property Rights.”
Platform License Agreement
In August 2021, Vaxxinity entered into a license agreement (the “Platform License Agreement”) with UBI and certain of its affiliates
(collectively, the “Licensors”) that expanded intellectual property rights previously licensed under the Original UBI Licenses (as defined
below). Pursuant to the Platform License Agreement, Vaxxinity obtained a worldwide, sublicensable (subject to certain conditions),
perpetual, fully paid-up, royalty-free (i) exclusive license (even as to the Licensors) under all patents owned or otherwise controlled by
the Licensors or their affiliates existing as of the effective date of the Platform License Agreement, (ii) exclusive license (except as to
the Licensors) under all patents owned or otherwise controlled by the Licensors or their affiliates arising after the effective date during
the term of the Platform License Agreement, and (iii) non-exclusive license under all know-how owned or otherwise controlled by the
Licensors or their affiliates existing as of the effective date or arising during the term of the Platform License Agreement, in each of the
foregoing cases, to research, develop, make, have made, utilize, import, export, market, distribute, offer for sale, sell, have sold,
commercialize or otherwise exploit peptide-based vaccines in the field of all human prophylactic and therapeutic uses, except for such
vaccines related to human immunodeficiency virus (HIV), herpes simplex virus (HSE) and Immunoglobulin E (IgE). The patents and
patent applications licensed under the Platform License Agreement include claims directed to a CpG delivery system, artificial T helper
cell epitopes and certain designer peptides and proteins utilized in UB-612. As partial consideration for the rights and licenses we
received pursuant to the Platform License Agreement, we granted UBI a warrant to purchase 1,928,020 shares of our Class A common
stock (“UBI Warrant”). The UBI Warrant is exercisable at an exercise price of $12.45 per share (subject to adjustment pursuant thereto),
is not subject to vesting, and has a term of five years.
Vaxxinity has the first right to control the filing, prosecution, maintenance and enforcement of the licensed patents at Vaxxinity’s own
expense, subject to the Licensors’ right to comment on and review any patent filings. The Platform License Agreement shall continue
until the parties mutually consent in writing to terminate the agreement. Upon such termination, all licenses granted under the Platform
License Agreement shall terminate and Vaxxinity will assign any regulatory documentation previously assigned to Vaxxinity back to
the Licensors.
Pricing, Coverage and Reimbursement
Sales of our product candidates in the United States will depend, in part, on the extent to which third-party payors, including government
health programs such as Medicare and Medicaid, commercial insurance and managed health care organizations provide coverage and
establish adequate reimbursement levels for such product candidates. The process for determining whether a third-party payor will
provide coverage for a pharmaceutical or biological product is typically separate from the process for setting the price of such a product
or for establishing the reimbursement rate that the payor will pay for the product once coverage is approved, and we may also need to
provide discounts to purchasers, private health plans or government healthcare programs, as increasingly, third-party payors are
requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for
medical products. As a result, a third-party payor’s decision to provide coverage for a pharmaceutical or biological product does not
imply that the reimbursement rate will be adequate for commercial viability, and inadequate reimbursement rates, including significant
patient cost sharing obligations, may deter patients from selecting our product candidates. Obtaining coverage and reimbursement
approval of a product from a third-party payor is a time-consuming and costly process that could require us to provide to each payor
supporting scientific, clinical and cost-effectiveness data for the use of our product on a payor-by-payor basis, with no assurance that
coverage and adequate reimbursement will be obtained. Third-party payors may limit coverage to specific products on an approved list,
also known as a formulary, which might not include all of the approved products for a particular indication.
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Further, no uniform policy for coverage and reimbursement exists in the United States, and coverage and reimbursement can differ
significantly from payor to payor. In general, factors a payor considers in determining coverage and reimbursement are based on whether
the product is a covered benefit under its health plan; safe, effective, and medically necessary, including its regulatory approval status;
medically appropriate for the specific patient; cost-effective; and neither experimental nor investigational. Third-party payors often rely
upon Medicare coverage policy and payment limitations in setting their own reimbursement rates, but also have their own methods and
approval process apart from Medicare determinations. As such, one third-party payor’s decision to cover a particular medical product
or service does not ensure that other payors will also provide coverage for the medical product or service, and the level of coverage and
reimbursement can differ significantly from payor to payor. Even if favorable coverage and reimbursement status is attained for one or
more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented
in the future.
Product Approval and Government Regulation
Government authorities in the United States, at the federal, state and local level, and other countries extensively regulate, among other
things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping,
promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of products such as those
we are developing. Any product candidate that we develop must be approved by the FDA before it may be legally marketed in the
United States and by the appropriate foreign regulatory agency before it may be legally marketed in foreign countries.
U.S. Drug Development Process
In the United States, the development, manufacturing and marketing of human drugs and vaccines are subject to extensive regulation.
The FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (“FDCA”) and implementing regulations, and biological
products, including vaccines, under provisions of the FDCA and the Public Health Service Act (“PHSA”). Drugs and vaccines are also
subject to other federal, state and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent
compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and
financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process,
approval process or after approval, may subject an applicant to administrative or judicial sanctions. FDA sanctions could include refusal
to approve pending applications, withdrawal of an approval, clinical hold, warning letters, product recalls, product seizures, total or
partial suspension of production or distribution, injunctions, fines, refusals of government contracts, debarment, restitution,
disgorgement or civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us. The
process required by the FDA before a drug or biological product may be marketed in the United States generally involves the following:
• completion of nonclinical laboratory tests, animal studies and formulation and stability studies according to good laboratory
practices, or GLPs and other applicable regulations;
• submission to the FDA of an application for an IND, which must become effective before human clinical trials may begin;
• performance of adequate and well-controlled human clinical trials according to the FDA’s good clinical practice regulations
commonly referred to as GCPs, among other requirements, to establish the safety and efficacy of the proposed drug for its
intended uses;
• submission to the FDA of an NDA or BLA for a new drug;
• satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the drug is produced to assess
compliance with the FDA’s cGMP, to assure that the facilities, methods and controls are adequate to preserve the drug’s
identity, strength, quality and purity;
• potential FDA audit of the nonclinical and clinical trial sites that generated the data in support of the NDA or BLA; and
• FDA review and approval of the NDA or BLA.
The lengthy process of seeking required approvals and the continuing need for compliance with applicable statutes and regulations
require the expenditure of substantial resources and approvals are inherently uncertain.
Before testing any compounds with potential therapeutic value in humans, the product candidate enters the pre-clinical study stage. Pre-
clinical tests, also referred to as nonclinical studies, include laboratory evaluations of product chemistry, toxicity and formulation, as
well as animal studies to assess the potential safety and activity of the product candidate. The Consolidated Appropriations Act for 2023,
signed into law on December 29, 2022, (P.L. 117 -328) amended both the FDCA and PHSA to specify that nonclinical testing for drugs
and biologics, respectively, may, but is not required to, include in vivo animal testing. According to the amended language, a sponsor
may fulfill nonclinical testing requirements by completing various in vitro assays (e.g., cell-based assays, organ chips, or
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microphysiological systems), in silico studies (i.e., computer modeling), other human or non-human biology-based tests (e.g.,
bioprinting), or in vivo animal tests.
The conduct of the pre-clinical tests must comply with federal regulations and requirements including GLP. The sponsor must submit
the results of the pre-clinical tests, together with manufacturing information, analytical data, any available clinical data or literature and
a proposed clinical protocol, to the FDA as part of the IND. The IND automatically becomes effective 30 days after receipt by the FDA,
unless the FDA imposes a clinical hold within that 30-day time period. In such a case, the IND sponsor and the FDA must resolve any
outstanding concerns before the clinical trial can begin. The FDA may also impose clinical holds on a product candidate at any time
before or during clinical trials due to safety concerns or non-compliance. Accordingly, we cannot be sure that submission of an IND
will result in the FDA allowing clinical trials to begin, or that, once begun, issues will not arise that suspend or terminate such trial.
Clinical trials involve the administration of the product candidate to healthy volunteers or patients under the supervision of qualified
investigators, generally physicians not employed by or under the trial sponsor’s direct control. Clinical trials are conducted under
protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria,
and the parameters to be used to monitor subject safety. Each protocol must be submitted to the FDA as part of the IND. Congress also
recently amended the FDCA, as part of the Consolidated Appropriations Act for 2023, in order to require sponsors of a Phase 3 clinical
trial, or other “pivotal study” of a new drug to support marketing authorization, to design and submit a diversity action plan for such
clinical trial. The action plan must include the sponsor’s diversity goals for enrollment, as well as a rationale for the goals and a
description of how the sponsor will meet them. Sponsors must submit a diversity action plan to the FDA by the time the sponsor submits
the relevant clinical trial protocol to the agency for review. The FDA may grant a waiver for some or all of the requirements for a
diversity action plan. It is unknown at this time how the diversity action plan may affect Phase 3 trial planning and timing or what
specific information FDA will expect in such plans, but if the FDA objects to a sponsor’s diversity action plan or otherwise requires
significant changes to be made, it could delay initiation of the relevant clinical trial. Clinical trials must be conducted in accordance with
the FDA’s regulations comprising the good clinical practices requirements. Further, each clinical trial must be reviewed and approved
by an independent IRB at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with protecting
the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials
are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the form and content of the informed consent
that must be signed by each clinical trial subject or his or her legal representative and provide oversight for the clinical trial until
completed.
Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:
•
Phase 1
. The drug is initially introduced into healthy human subjects and tested for safety, dosage
tolerance, absorption, metabolism, distribution and excretion. In the case of some products for severe or life-threatening diseases,
especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing may be
conducted in patients;
•
Phase 2
. The drug is evaluated in a limited patient population to identify possible adverse effects and safety
risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance, optimal
dosage and dosing schedule; and
•
Phase 3
. Clinical trials are undertaken to further evaluate dosage, clinical efficacy and safety in an
expanded patient population at geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall
risk/benefit ratio of the product and provide an adequate basis for product labeling. Generally, a well-controlled Phase 3 clinical trial is
required by the FDA for approval of an NDA or BLA.
Post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval. These
clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical
data and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA and
written IND safety reports must be promptly submitted to the FDA and the investigators for serious and unexpected adverse events or
any finding from tests in laboratory animals that suggests a significant risk for human subjects. Phase 1, Phase 2 and Phase 3 clinical
trials may not be completed successfully within any specified period, if at all. The FDA or the sponsor or its data safety monitoring
board may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being
exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the
clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious
harm to patients.
Concurrently with clinical trials, companies usually complete additional nonclinical studies and must also develop additional information
about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial
quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches
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of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final
drug. For biological products in particular, the PHSA emphasizes the importance of manufacturing control for products whose attributes
cannot be precisely defined in order to help reduce the risk of the introduction of adventitious agents. Additionally, appropriate packaging
must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo
unacceptable deterioration over its shelf life.
U.S. Review and Approval Processes
Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product
development, nonclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on
the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA or BLA
requesting approval to market the product. The submission of an NDA or BLA is subject to the payment of substantial fees; a waiver of
such fees may be obtained under certain limited circumstances.
In addition, under the Pediatric Research Equity Act (“PREA”), an NDA or BLA or supplement to an NDA or BLA must contain data
to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations and to support
dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may grant deferrals for
submission of data or full or partial waivers. Unless otherwise required by regulation, PREA does not apply to any drug for an indication
for which orphan designation has been granted.
The FDA reviews all NDAs or BLAs submitted to determine if they are substantially complete before it accepts them for filing. If the
FDA determines that an NDA or BLA is incomplete or the application is found to be non-navigable, the filing may be refused and must
be re-submitted for consideration. Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA or BLA.
Under the goals and policies agreed to by the FDA under the Prescription Drug User Fee Act (“PDUFA”), the FDA has 10 months from
acceptance of filing in which to complete its initial review of a standard NDA or BLA and respond to the applicant, and six months from
acceptance of filing for a priority NDA or BLA. The FDA does not always meet its PDUFA goal dates. The review process and the
PDUFA goal date may be extended by three months or longer if the FDA requests or the NDA or BLA sponsor otherwise provides
additional information or clarification regarding information already provided in the submission before the PDUFA goal date.
After the NDA or BLA submission is accepted for filing, the FDA reviews the NDA or BLA to determine, among other things, whether
the proposed product is safe and effective for its intended use, and whether the product is being manufactured in accordance with cGMP
to assure and preserve the product’s identity, strength, quality and purity. The FDA may refer applications for novel drug or biological
products or drug or biological products which present difficult questions of safety or efficacy to an advisory committee, typically a panel
that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved
and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such
recommendations carefully when making decisions. During the drug approval process, the FDA also will determine whether a risk
evaluation and mitigation strategy, or REMS is necessary to ensure that the benefits of the drug outweigh its risks and to assure the safe
use of the drug. The REMS could include medication guides, physician communication plans, assessment plans and/or elements to
assure safe use, such as restricted distribution methods, patient registries or other risk minimization tools. The FDA determines the
requirement for a REMS, as well as the specific REMS provisions, on a case-by-case basis. If the FDA concludes a REMS is needed,
the sponsor of the NDA or BLA must submit a proposed REMS; the FDA will not approve the NDA or BLA without a REMS, if
required.
Before approving an NDA or BLA, the FDA will inspect the facilities at which the product is manufactured. The FDA will not approve
the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate
to assure consistent production of the product within required specifications. The FDA requires vaccine manufacturers to submit data
supporting the demonstration of consistency between manufacturing batches, or lots. The FDA works together with vaccine
manufacturers to develop a lot release protocol, the tests conducted on each lot of vaccine post-approval. Additionally, before approving
an NDA or BLA, the FDA will typically inspect the sponsor and one or more clinical sites to assure that the clinical trials were conducted
in compliance with IND study requirements and with GCPs. If the FDA determines that the application, manufacturing process or
manufacturing facilities are not acceptable it will outline the deficiencies in the submission and often will request additional testing or
information.
The NDA or BLA review and approval process is lengthy and difficult and the FDA may refuse to approve an NDA or BLA if the
applicable regulatory criteria are not satisfied or may require additional clinical data or other data and information. Even if such data
and information is submitted, the FDA may ultimately decide that the NDA or BLA does not satisfy the criteria for approval. Data
obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data. An
approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications, while a
complete response letter indicates that the review cycle of the application is complete and the application will not be approved in its
present form. The complete response letter usually describes all of the specific deficiencies in the NDA or BLA identified by the FDA.
The deficiencies identified may be minor, for example, requiring labeling changes, or major, for example, requiring additional clinical
trials. Additionally, the complete response letter may include recommended actions that the applicant might take to place the application
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in a condition for approval. If a complete response letter is issued, the applicant may either submit new information, addressing all of
the deficiencies identified in the letter, or withdraw the application.
If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications
for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain
contraindications, warnings or precautions be included in the product labeling. In addition, the FDA may require post-marketing clinical
trials, sometimes referred to as Phase 4 clinical trials, which are designed to further assess a product’s safety and effectiveness and may
require testing and surveillance programs to monitor the safety of approved products that have been commercialized. In addition, new
government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which
could impact the timeline for regulatory approval or otherwise impact ongoing development programs.
Expedited Development and Review Programs
The FDA is authorized to designate certain products for expedited development or review if they are intended to address an unmet
medical need in the treatment of a serious or life-threatening disease or condition. These programs include fast track designation,
breakthrough therapy designation and priority review designation.
The FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs and biologics that meet
certain criteria. Specifically, new drugs and biologics are eligible for fast track designation if they are intended to treat a serious or life-
threatening condition and preclinical or clinical data demonstrate the potential to address unmet medical needs for the condition. Fast
track designation applies to the combination of the product and the specific indication for which it is being studied. The sponsor can
request the FDA to designate the product for fast track status any time before receiving NDA or BLA approval, but ideally no later than
the pre-NDA or pre-BLA meeting.
Additionally, a drug or biologic may be eligible for designation as a breakthrough therapy if the product is intended, alone or in
combination with one or more other drugs or biologics, to treat a serious or life-threatening condition and preliminary clinical evidence
indicates that the product may demonstrate substantial improvement over currently approved therapies on one or more clinically
significant endpoints. The benefits of breakthrough therapy designation include the same benefits as fast track designation, plus intensive
guidance from the FDA to facilitate an efficient drug development program.
Any product submitted to the FDA for marketing, including under a fast track or breakthrough therapy designation program, may be
eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.
Any product is eligible for priority review if it treats a serious or life-threatening condition and, if approved, would provide a significant
improvement in safety and effectiveness compared to available therapies. Priority review reduces the review time for an initial or
supplemental marketing application by four months.
Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions
for qualification or decide that the time period for FDA review or approval will not be shortened. Fast track designation, priority review,
and breakthrough therapy designation do not change the standards for approval but may expedite the development or approval process.
Accelerated Approval Pathway
A product may be eligible for accelerated approval if it treats a serious or life-threatening condition and generally provides a meaningful
advantage over available therapies based on an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a
clinical endpoint that can be measured earlier than irreversible morbidity or mortality ("IMM") that is reasonably likely to predict an
effect on IMM or other clinical benefit. As a condition of accelerated approval, the FDA requires that a sponsor of a drug or biologic
receiving accelerated approval subsequently provide additional data confirming the anticipated clinical benefit, for example by
performing adequate and well-controlled post-marketing clinical trials. If clinical benefit is not confirmed, accelerated approval may be
revoked.
In addition, as part of the Consolidated Appropriations Act for 2023, Congress provided FDA additional statutory authority to mitigate
potential risks to patients from continued marketing of ineffective drugs previously granted accelerated approval. Under these recent
amendments to the FDCA, the agency may require a sponsor of a product granted accelerated approval to have a confirmatory trial
underway prior to approval. The sponsor must also submit progress reports on a confirmatory trial every six months until the trial is
complete, and such reports will be published on FDA’s website. Failure to conduct required post-approval studies, or to confirm the
predicted clinical benefit of the product during post-marketing studies, allows the FDA to withdraw approval of the drug or biologic.
Congress also recently amended the law to give FDA the option of using expedited procedures to withdraw product approval if the
sponsor’s confirmatory trial fails to verify the claimed clinical benefits of the product.
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Granting of an EUA
The Commissioner of the FDA, under delegated authority from the Secretary of the U.S. Department of Health and Human Services
(“DHHS”) may, under certain circumstances, issue an Emergency Use Authorization, or EUA that would permit the use of an
unapproved drug product or unapproved use of an approved drug product. Before an EUA may be issued, the Secretary must declare an
emergency based on one of the following grounds:
• a determination by the Secretary of the Department of Homeland Security that there is a domestic emergency, or a
significant potential for a domestic emergency, involving a heightened risk of attack with a specified biological, chemical,
radiological or nuclear agent or agents;
• a determination by the Secretary of the Department of Defense that there is a military emergency, or a significant potential
for a military emergency, involving a heightened risk to U.S. military forces of attack with a specified biological, chemical,
radiological or nuclear agent or agents; or
• a determination by the Secretary of the DHHS that a public health emergency that affects, or has the significant potential
to affect, national security and that involves a specified biological, chemical, radiological or nuclear agent or agents, or a
specified disease or condition that may be attributable to such agent or agents.
In order to be the subject of an EUA, the FDA Commissioner must conclude that, based on the totality of scientific evidence available,
it is reasonable to believe that the product may be effective in diagnosing, treating or preventing a disease attributable to the agents
described above, that the product’s potential benefits outweigh its potential risks and that there is no adequate approved alternative to
the product.
Although an EUA cannot be issued until after an emergency has been declared by the Secretary of DHHS, the FDA strongly encourages
an entity with a possible candidate product, particularly one at an advanced stage of development, to contact the FDA center responsible
for the candidate product before a determination of actual or potential emergency. Such an entity may submit a request for consideration
that includes data to demonstrate that, based on the totality of scientific evidence available, it is reasonable to believe that the product
may be effective in diagnosing, treating or preventing the serious or life-threatening disease or condition. This is called a pre-EUA
submission and its purpose is to allow FDA review considering that during an emergency, the time available for the submission and
review of an EUA request may be severely limited.
Post-Approval Requirements
Any drug or biological products for which we or our collaborators receive FDA approvals are subject to continuing regulation by the
FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product, providing the
FDA with updated safety and efficacy information, product sampling and distribution requirements, complying with certain electronic
records and signature requirements and complying with FDA promotion and advertising requirements, which include, among others,
standards for direct-to-consumer advertising, promoting drugs for uses or in patient populations that are not described in the drug’s
approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities, and promotional activities
involving the internet.
Failure to comply with FDA requirements can have negative consequences, including adverse publicity, enforcement letters from the
FDA, mandated corrective advertising or communications with doctors, and civil or criminal penalties. Although physicians may
prescribe legally available drugs for off-label uses, manufacturers may not market or promote such off-label uses.
Manufacturers of our product candidates are required to comply with applicable FDA manufacturing requirements contained in the
FDA’s cGMP regulations. cGMP regulations require, among other things, quality control and quality assurance as well as the
corresponding maintenance of records and documentation. Following approval, the FDA continues to monitor vaccine quality through
real-time monitoring of lots by requiring manufacturers to submit certain information for each vaccine lot. Vaccine manufacturers may
only distribute a lot following release by the FDA. Drug manufacturers and other entities involved in the manufacture and distribution
of approved drugs are required to register their establishments with the FDA and certain state agencies, and are subject to periodic
unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws. Accordingly, manufacturers
must continue to expend time, money and effort in the area of production and quality control to maintain cGMP compliance. Discovery
of problems with a product after approval may result in restrictions on a product, manufacturer or holder of an approved NDA or BLA,
including withdrawal of the product from the market. In addition, changes to the manufacturing process generally require prior FDA
approval before being implemented, and other types of changes to the approved product, such as adding new indications and additional
labeling claims, are also subject to further FDA review and approval.
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U.S. Patent-term Extension
Depending upon the timing, duration and specifics of FDA approval of our product candidates, some of our U.S. patents may be eligible
for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as
the Hatch-Waxman Amendments to the FDCA. The Hatch-Waxman Amendments permit extension of the patent term of up to five
years as compensation for patent term lost during product development and FDA regulatory review process. Patent-term extension,
however, cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date. The patent-term
extension period is generally one-half the time between the effective date of an IND and the submission date of an NDA or BLA plus
the time between the submission date of an NDA or BLA and the approval of that application, except that the review period is reduced
by any time during which the applicant failed to exercise due diligence. Only one patent applicable to an approved drug is eligible for
the extension and the application for the extension must be submitted prior to the expiration of the patent. The U.S. Patent and Trademark
Office, or USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration. In
the future, we may apply for extension of patent term for our currently owned or licensed patents to add patent life beyond its current
expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA or
BLA.
U.S. Foreign Corrupt Practices Act
In general, the Foreign Corrupt Practices Act of 1977, as amended, or the FCPA, prohibits offering to pay, paying, promising to pay, or
authorizing the payment of money or anything of value to a foreign official in order to influence any act or decision of the foreign
official in his or her official capacity or to secure any other improper advantage in order to obtain or retain business for or with, or in
order to direct business to, any person. The prohibitions apply not only to payments made to “any foreign official,” but also those made
to “any foreign political party or official thereof,” to “any candidate for foreign political office” or to any person, while knowing that all
or a portion of the payment will be offered, given, or promised to anyone in any of the foregoing categories. “Foreign officials” under
the FCPA include officers or employees of a department, agency, or instrumentality of a foreign government. The term “instrumentality”
is broad and can include state-owned or state-controlled entities.
Importantly, United States authorities that enforce the FCPA, including the Department of Justice, deem most health care professionals
and other employees of foreign hospitals, clinics, research facilities and medical schools in countries with public health care or public
education systems to be “foreign officials” under the FCPA. When we interact with foreign health care professionals and researchers in
testing and marketing our products abroad, we must have policies and procedures in place sufficient to prevent us and agents acting on
our behalf from providing any bribe, gift or gratuity, including excessive or lavish meals, travel or entertainment in connection with
marketing our future products and services or securing required permits and approvals such as those needed to initiate clinical trials in
foreign jurisdictions. The FCPA also obligates companies whose securities are listed in the United States to comply with accounting
provisions requiring the maintenance of books and records that accurately and fairly reflect all transactions of the corporation, including
international subsidiaries, and the development and maintenance of an adequate system of internal accounting controls for international
operations. The Securities and Exchange Commission is involved with the books and records provisions of the FCPA.
Regulation in Europe and Other Regions
In addition to regulations in the United States, we and our collaborators are subject to a variety of regulations in other jurisdictions
governing, among other things, clinical trials and any commercial sales and distribution of our products.
Whether or not we or our collaborators obtain FDA approval for a product, we must obtain the requisite approvals from regulatory
authorities in foreign countries prior to the commencement of clinical trials or marketing of the product in those countries. Certain
countries outside of the United States have a similar process that requires the submission of a clinical trial application much like the
IND prior to the commencement of human clinical trials. In the European Union, for example, a CTA must be submitted to each
country’s national health authority and an independent ethics committee, much like the FDA and IRB, respectively. Once the CTA is
approved in accordance with a country’s requirements, clinical trial development may proceed.
The requirements and process governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country
to country. In all cases, the clinical trials are conducted in accordance with GCPs and the applicable regulatory requirements and the
ethical principles on human subjects research that have their origin in the Declaration of Helsinki.
To obtain regulatory approval of an investigational drug or biological product under European Union regulatory systems, we or our
strategic partners must submit a marketing authorization application. The application in the European Union is similar to that required
in the United States, with the exception of, among other things, country-specific document requirements.
For other countries outside of the European Union, such as countries in Asia, Europe and Latin America, the requirements governing
the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country. In all cases, again, the clinical
trials are conducted in accordance with GCPs and the applicable regulatory requirements and the ethical principles that have their origin
in the Declaration of Helsinki.
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Employees and Human Capital Resources
As of December 31, 2023, we employed 57 full-time employees and 8 part-time employees. Of these 57 full-time employees, 54 were
located in the United States, 2 were located in Ireland and 1 was located in the UK. As of March 1, 2024, we employed 50 full-time
employees and 9 part-time employees. Of these 50 full-time employees, 47 were located in the United States, 2 were located in Ireland
and 1 was located in the UK. None of our employees are represented by a labor union or are party to a collective bargaining agreement,
and we have had no labor-related work stoppages.
Compensation, Benefits, Recruitment and Retention Strategy
We aim to focus on attracting, motivating and retaining talented employees with relevant experience who can contribute to the sustained
performance of the Company and its day-to-day operations.
We believe our total compensation package helps recruit and retain our employees. We strive to provide compensation and benefits that
are competitive to market and create incentives to attract and retain employees. Our compensation package includes market-competitive
pay, broad-based stock grants, health care and 401(k) plan benefits, paid time off and family leave, among others. We also provide
annual incentive bonus opportunities that are tied to both company performance as well as individual performance to foster a pay-for-
performance culture.
Scientific Advisory Board
We have assembled a highly qualified scientific advisory board composed of advisors who have deep expertise in the fields of biologics
and vaccine development, as well as in the relevant therapeutic areas for our product candidates.
Immunology & Vaccinology
●
Thomas P. Monath, M.D.
●
Wayne Koff, Ph.D.
●
Stanley A. Plotkin, M.D.
Neurology
●
Brad Boeve, M.D.
●
Richard Mohs, Ph.D.
●
Jeffrey Cummings, M.D.
●
Eric Reiman, M.D.
●
Nick Fox, M.D.
●
Stephen D. Silberstein, M.D.
Cardiovascular
●
Kausik K. Ray, M.D.
●
Stephen Nicholls, Ph.D.
●
Frederick Raal, Ph.D.
●
Dirk von Lewinski, M.D.
●
Parviz Ghahramani, Ph.D.
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Item 1A. Risk Factors.
Investing in our Class A common stock involves a high degree of risk. The following information sets forth risk factors that could
cause our actual results to differ materially from those contained in forward-looking statements we have made in this Annual Report
on Form 10-K and those we may make from time to time. You should carefully consider the risks described below, in addition to the
other information contained in this Report and our other public filings, before you decide to purchase shares of our Class A common
stock. Our business, financial condition or results of operations could be harmed by any of these risks. The risks and uncertainties
described below are not the only ones we face. Additional risks not presently known to us or other factors not perceived by us to
present significant risks to our business at this time also may impair our business operations.
Summary Risk Factors
Our business is subject to a number of risks, including risks that may prevent us from achieving our business objectives or may
adversely affect our business, financial condition, results of operations and prospects. These risks are discussed more fully under Part
II, Item 1A. “Risk Factors.” The following is a summary of some of the principal risks we face:
• clinical drug development involves a lengthy and expensive process, and if our pre-clinical development or clinical trials
are prolonged or delayed or do not achieve expected results, we may be unable to commercialize our product candidates;
• we depend on intellectual property licensed from UBI and its affiliates, the termination of which could result in the loss
of significant rights;
• even if we obtain regulatory approval of, or commercialize, any of our product candidates in one or more jurisdictions,
we may never obtain approval for, or commercialize, our product candidates in other jurisdictions;
• after receipt of regulatory approval for a product candidate, our products will remain subject to regulatory scrutiny and
post-marketing requirements, which may include burdensome post-approval trial or risk management requirements that
may adversely impact the financial results of any future commercialization efforts or cause us to choose not to
commercialize the product candidate;
• if we are able to commercialize any product candidate, the successful commercialization of such product candidate will
depend on the extent governmental authorities, private health insurers and other third-party payors provide coverage,
adequate reimbursement levels and favorable pricing policies;
• the manufacture of peptide-based medicines is complex and manufacturers often encounter difficulties in production;
• we have no history of commercializing pharmaceutical products, which may make it difficult to evaluate the prospects
for our future viability;
• the regulatory landscape that will govern our product candidates is uncertain, and changes in regulatory requirements
could result in delays or discontinuation of development of our product candidates or unexpected costs;
• developments by competitors may render our products or technologies obsolete or non-competitive or may reduce the
size of our markets;
• our capital resources may not be sufficient to successfully complete the development and commercialization of our
product candidates, which could delay, limit, reduce or terminate our development or commercialization efforts;
• we have incurred significant losses since our inception, we expect to incur losses for the foreseeable future and may
never achieve or maintain profitability and there exists substantial doubt as to our ability to continue as a going concern
over the next twelve months;
• conflicts of interest and disputes exist and may further arise between us and UBI and its affiliates, and these conflicts and
disputes might ultimately be resolved in a manner unfavorable to us;
• we will need to expand our organization, and we may experience difficulties in managing this growth, which could
disrupt our operations;
• while our Class A common stock is expected to continue listing on The Nasdaq Global Market, there is no guarantee as
to how long such listing will be maintained;
45
• the dual-class structure of our common stock and the Voting Agreement (as defined below) will have the effect of
concentrating voting power, which will significantly limit your ability to influence significant corporate decisions;
• we rely on contract manufacturers for the manufacture of raw materials for our research programs, pre-clinical studies
and clinical trials and we do not have long-term contracts with many of these parties, which could impact our ability to
develop and commercialize our products;
• undetected errors or defects in our production could harm our reputation or expose us to product liability claims;
• we rely on in-licensed intellectual property and technology, and the loss of such rights, our licensors’ inability or refusal
to enforce or defend such rights, and any requirement to pay amounts under current or future agreements could harm our
business;
• the degree of protection afforded by our intellectual property rights is uncertain because such rights offer only limited
protection and may not adequately protect our rights or permit us to gain or keep a competitive advantage;
• we have previously identified and remediated material weaknesses, in our internal control over financial reporting and if
we are unable to maintain an effective system of internal control over financial reporting, or if we discover material
deficiencies in the future, we may not be able to accurately report our financial results or prevent fraud, and as a result,
shareholders could lose confidence in our financial and other public reporting, which would harm our business and the
trading price of our Class A common stock;
• cyberattacks or other failures in our or our third-party vendors’, contractors’ or consultants’ telecommunications or
information technology systems could result in information theft, compromise, or other unauthorized access, data
corruption and significant disruption of our business operations, and could harm our reputation and subject us to liability,
lawsuits and actions from governmental authorities; and
• we are subject to privacy, tax, anti-corruption and other stringent laws, regulations, policies and contractual obligations
across multiple jurisdictions and changes in, or our failure to comply with, such laws, regulations, policies and
contractual obligations could adversely affect our business, financial condition, results of operations and prospects.
Risks Related to the Discovery and Development of Product Candidates
Clinical drug development involves a lengthy and expensive process with uncertain timelines and uncertain outcomes, and results
of earlier studies and trials may not be predictive of future results. If our pre-clinical development or clinical trials are prolonged
or delayed, or if we do not or cannot achieve the results we expect, we may be unable to obtain required regulatory approvals, and
therefore be unable to commercialize our product candidates on a timely basis or at all.
Our business is dependent on the successful development, regulatory approval and commercialization of product candidates based on
our AIM Platform. If we and our collaborators are unable to obtain approval for and effectively commercialize our product candidates,
our business would be significantly harmed. Even if we complete the necessary pre-clinical studies and clinical trials, the regulatory
approval process is expensive, time-consuming and uncertain, and we may not be able to obtain approvals for the commercialization
of any product candidates we may develop. Changes in regulatory approval policies, changes in or the enactment of additional statutes
or regulations, or changes in regulatory review processes, may cause delays in the approval of a particular product candidate or
rejection of an application for a particular product candidate. We have not obtained regulatory approval for any product candidate to
date, and it is possible that none of our existing product candidates or any product candidates we may seek to develop in the future
will ever obtain regulatory approval. Any regulatory approval we ultimately obtain may be limited or subject to restrictions, including
labeling requirements, or post-approval commitments that render the approved product not commercially viable. See “—Even if we
obtain approval of any of our product candidates in one or more jurisdictions, we may never obtain approval for or commercialize any
of our products in other jurisdictions, which would limit our ability to realize the full market potential of our product candidates.”
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To obtain the requisite regulatory approvals to market and sell any of our product candidates, we must demonstrate through extensive
pre-clinical studies and clinical trials that our products are safe and effective in humans. Clinical testing is expensive and can take
many years to complete, and its outcome is inherently uncertain. Failure can occur at any time during the clinical trial process. The
results of pre-clinical studies and early clinical trials of our product candidates may not be predictive of the results of later-stage
clinical trials and results from post-hoc data analysis may not be predictive of final results and may not support product approval.
Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy characteristics despite having
progressed through pre-clinical studies and initial clinical trials. For example, an EUA for UB-612 was denied by the TFDA in August
2021 because the neutralizing antibody response generated by UB-612, as compared to a designated adenovirus vectored vaccine, did
not meet the TFDA’s specified evaluation criteria. If results from our clinical trials differ from previous reports or market
expectations, such as a potential development of market expectations that COVID-19 boosters or vaccines be developed specifically to
address certain variants which we fail to satisfy, or if we fail to obtain a required regulatory approval, the price of our Class A
common stock could decrease substantially. Several companies in the biopharmaceutical industry have suffered significant setbacks in
advanced clinical trials due to lack of efficacy or adverse safety profiles, notwithstanding promising results in earlier trials. Our
ongoing and future clinical trials may not be successful.
Further, while we have conducted limited head-to-head comparisons in pre-clinical studies of UB-313 and VXX-401, we have not
conducted a head-to-head comparison of any competing products to any of our chronic disease product candidates in any clinical trial
to date. We have compared the published data for certain of our competitors’ products to the clinical trial results of certain of our
product candidates. Accordingly, the value of comparisons of our product candidates to any alternative products in this report may be
limited because they are not derived from a head-to-head clinical trial, rather they are from trials that were conducted under different
protocols, at different sites, with different patient populations, at different times and results were analyzed using non-standardized
assays performed internally or by different clinical research organizations (“CROs”). Without head-to-head data, we will be unable to
make comparative claims for our product candidates, if any such product candidate is approved. Future clinical trials may not confirm
the comparisons or analyses we have made to date.
Clinical trials must be conducted in accordance with applicable regulatory authorities’ legal requirements, regulations or guidelines
and are subject to oversight by these governmental agencies as well as Institutional Review Boards (“IRBs”) at the medical
institutions where the clinical trials are conducted. In addition, clinical trials must be conducted with supplies of our product
candidates produced in accordance with current good manufacturing practices (“cGMP”) and other legal and regulatory requirements.
Defects in manufacturing of a clinical trial batch or a failure of a batch to meet all quality control test specifications could result in
delays to initiation of our clinical trials. We depend on medical institutions and CROs to conduct our clinical trials in compliance with
good clinical practice (“GCP”), and other applicable laws and regulations. Failure to follow and document adherence to such laws and
regulations may lead to significant delays in the availability of product for our clinical trials, result in the termination of or a clinical
hold being placed on one or more of our clinical trials, or delay or prevent submission or approval of marketing applications for our
product candidates.
To the extent our CROs fail to enroll participants for our clinical trials, fail to conduct the trial in accordance with the trial protocol
GCP or are delayed for a significant time in the execution of trials, including achieving full enrollment, we may be affected by
increased costs, program delays or both, which may harm our business and delay our ability to seek approval for our product
candidates. For example, due in part 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 a Phase 2a LTE trial for UB-311. In
that case, however, we determined that we had collected sufficient data on UB-311’s tolerability and immunogenicity.
The completion of clinical trials for our clinical product candidates may be delayed, suspended or terminated because of many factors,
including but not limited to:
• the delay or refusal of regulators or IRBs to authorize us to commence a clinical trial at a prospective trial site;
• changes in regulatory requirements, policies and guidelines;
• delays or failure to reach agreement on acceptable terms with prospective CROs and clinical trial sites, the terms of
which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites;
• delays in patient enrollment and variability in the number and types of patients available for clinical trials;
• negative or inconclusive results, which may require us to conduct additional pre-clinical or clinical trials or to abandon
product candidates that we expect to be promising;
• delays in manufacturing and control of clinical trial materials;
• shortages of materials required for the production of our product candidates;
47
• disruptions from events surrounding the ongoing conflicts between Russia and Ukraine or Israel and Hamas and
increased tension between Taiwan and China;
• safety or tolerability concerns causing us to suspend or terminate a trial if it is determined that the participants are being
exposed to unacceptable health risks;
• lower than anticipated retention rates of patients and volunteers in clinical trials and difficulty in maintaining contact
with patients after treatment, resulting in incomplete data;
• failure of us, our CROs or clinical trial sites to comply with regulatory requirements;
• failure of our CROs or clinical trial sites to meet their contractual obligations to us in a timely manner, or at all, deviating
from the clinical trial protocol or dropping out of a trial;
• delays relating to adding new clinical trial sites;
• delays in establishing necessary pre-clinical or clinical data;
• the occurrence of unexpected severe or serious product-related adverse events in a clinical trial;
• the quality or stability of the product candidate falling below acceptable standards;
• the inability to produce or obtain sufficient quantities of the product candidate to complete clinical trials on time, or
delays in sufficiently developing, characterizing or controlling a manufacturing process suitable for clinical trials;
• supply chain constraints and inflationary pressures;
• the lack of adequate funding to continue the clinical trial;
• developments observed in trials conducted by competitors for related technology that raises general concerns from
regulatory authorities about risk to patients of similar vaccine technology;
• the determination that a product candidate will not be producible in relevant quantities at the manufacturing stage;
• the failure of regulatory authorities such as the FDA, MHRA or TGA to approve our manufacturing processes or
facilities or those of contract manufacturers with which we contract for clinical and commercial supplies; and
• the transfer of manufacturing processes to larger-scale facilities operated by contract manufacturers or by us, and delays
or failure by our contract manufacturers or us to make any necessary changes to such manufacturing process.
In addition, pre-clinical and clinical data are often susceptible to varying interpretations and analyses and results from post-hoc data
analysis may not be predictive of final results and may not support product approval. Many companies that believed their product
candidates performed satisfactorily in pre-clinical studies and clinical trials have nonetheless failed to obtain marketing approval for
their product candidates. Regulatory authorities have substantial discretion in the approval process and in determining when or
whether regulatory approval will be obtained for any of our product candidates. Additionally, the FDA typically does not accept post-
hoc data analyses as support for regulatory approval. Even if we believe the data collected from clinical trials of our product
candidates are promising, such data may not be sufficient to support approval by regulatory authorities. Regulatory authorities may
disagree with the design or implementation of our clinical trials and may disagree with our interpretation of data from pre-clinical
studies or clinical trials.
In some instances, there can be significant variability in safety or efficacy results between different trials of the same product
candidate due to numerous factors, including changes in trial procedures set forth in protocols, differences in the size and type of the
patient populations, adherence to the dosing regimen and other trial procedures and the rate of dropout among clinical trial
participants. Further, none of our trials to date of UB-311 have been large enough to determine whether their assessments of efficacy
were statistically significant. Therefore, we are able to report potential trends on such measures, but we will not be able to make more
definitive statements about the efficacy of our product candidates until we complete clinical trials that are adequately powered to
demonstrate statistical significance of clinically meaningful results.
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Moreover, for AD, given the difficulties in assessing whether a product candidate is disease-modifying in terms of interrupting disease
pathology and delaying cognitive decline, we plan to include in our trial designs for UB-311 biomarker endpoints and, if our trial
results warrant, may apply for regulatory approval based on biomarker data. While the FDA recently approved aducanumab based on
biomarker data, there is no assurance that the FDA will accept biomarker data for other product candidates, including UB-311, in the
future.
Even if we obtain approval of any of our product candidates in one or more jurisdictions, we may never obtain approval for or
commercialize any of our products in other jurisdictions, which would limit our ability to realize the full market potential of our
product candidates.
To market any products, we must establish and comply with numerous and varying regulatory requirements in different countries
regarding safety and efficacy and obtain relevant approvals to market our product candidates. As discussed in another risk factor
above (“
Clinical drug development involves a lengthy and expensive process…
”) an EUA for UB-612 was denied by the TFDA in
August 2021. Approval by a foreign regulatory authority in any other jurisdiction does not ensure approval by comparable regulatory
authorities in other countries or jurisdictions, including approval by the FDA in the United States. The failure to obtain approval in
one jurisdiction may delay or otherwise negatively impact our ability to obtain approval elsewhere. In addition, clinical trials
conducted in one country may not be accepted by regulatory authorities in other countries. Approval procedures vary among countries
and even if we have obtained approval in one country, approval in other countries can involve additional product testing and
validation and additional administrative review periods.
Seeking regulatory approvals in different countries could result in additional and unexpected costs for us, including as a result of
additional required pre-clinical studies or clinical trials which would be costly and time-consuming. Satisfying regulatory
requirements is costly, time-consuming, uncertain and may be subject to unanticipated delays. In addition, our failure to obtain
regulatory approval in any country may delay or have negative effects on the process for regulatory approval in other countries.
Interim, “top-line” and preliminary data from our clinical trials that we announce or publish from time to time may change as
more patient data become available and are also subject to audit and verification procedures that could result in material changes
in the final data.
From time to time, we may publicly disclose preliminary or top-line data from our pre-clinical studies and clinical trials, which are
based on a preliminary analysis of then-available data, and the results and related findings and conclusions are subject to change
following a more comprehensive review of the data related to the particular study or trial. We also may make assumptions,
estimations, calculations and conclusions as part of our analyses of data, and we may not have received or had the opportunity to fully
and carefully evaluate all data. As a result, the top-line or preliminary results that we report may differ from future results of the same
studies, or different conclusions or considerations may qualify such results, once additional data have been received and fully
evaluated. Top-line data also remain subject to audit and verification procedures that may result in the final data being materially
different from the preliminary data we previously published. As a result, top-line data should be viewed with caution until the final
data are available.
From time to time, we may also disclose interim data from our pre-clinical studies and clinical trials. Interim data from clinical trials
that we may complete are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment
continues and more patient data become available or as patients from our clinical trials continue other treatments for their disease.
Adverse differences between preliminary or interim data and final data could significantly harm our business prospects. Further,
disclosure of interim data by us or by our competitors could result in volatility in the price of our Class A common stock.
Further, others, including regulatory authorities, may not accept or agree with our assumptions, estimates, calculations, conclusions or
analyses or may interpret or weigh the importance of data differently, which could impact the value of the particular program, the
approvability or commercialization of the particular product candidate or product and the Company in general. In addition, the
information we choose to publicly disclose regarding a particular study or clinical trial is based on what is typically extensive
information, and you or others may not agree with what we determine is material or otherwise appropriate information to include in
our disclosure.
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If we encounter difficulties enrolling patients in our clinical trials, our clinical development activities could be delayed and result
in increased costs and longer development periods or otherwise be adversely affected.
We will be required to identify and enroll a sufficient number of patients for our planned clinical trials. Trial participant enrollment
could be limited in future trials given that many potential participants may be ineligible because of pre-existing conditions, medical
treatments or other reasons. For example, the next phase of our UB-311 development could be affected by worldwide effects resulting
from the ongoing conflicts between Russia and Ukraine or Israel and Hamas, increased tension between Taiwan and China and other
geopolitical factors.
We
may not be able to initiate or continue clinical trials required by applicable regulatory authorities or any of our
other product candidates that we pursue if we are unable to locate and enroll enough eligible patients or volunteers to participate in
these clinical trials. Patient enrollment is affected by other factors, as well, including the incidence and severity of the disease under
investigation; the design of the clinical trial protocol; the size and nature of the patient population; the eligibility criteria for the trial in
question; the perceived risks and benefits of the product candidate under trial; the perceived safety and tolerability of the product
candidate; the proximity and availability of clinical trial sites for prospective patients; the availability of competing therapies and
clinical trials; effects of the COVID-19 pandemic on our clinical trial sites; our ability to monitor patients adequately during and after
treatment; patient referral practices of physicians; clinicians’ and patients’ perceptions as to the potential advantages of the drug being
studied in relation to other av