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 ended
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A common stock began trading on the Nasdaq Global Market on November 11, 2021. As of March 24, 2022, the registrant had
$0.0001 par value Class A common stock outstanding and
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
2022 Annual Meeting of Shareholders. We currently anticipate that our definitive proxy statement will be filed with the SEC not later than 120 days
after December 31, 2021, pursuant to Regulation 14A of the Securities Exchange Act of 1934, as amended.
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TABLE OF CONTENTS
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104
105
138
138
139
139
PART III
139
139
139
139
139
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, 2021 (“Report”) contains forward-looking statements. Forward-
looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs,
expectations and assumptions regarding the future of our business, future plans and strategies and other future conditions. In some cases,
you can identify forward-looking statements because they contain words such as “anticipate,” “believe,” “estimate,” “expect,” “intend,”
“may,” “predict,” “project,” “target,” “potential,” “seek,” “will,” “would,” “could,” “should,” “continue,” “contemplate,” “plan,” other
words and terms of similar meaning and the negative of these words or similar terms.
Forward-looking statements are subject to known and unknown risks and uncertainties, many of which may be beyond our control. We
caution you that forward-looking statements are not guarantees of future performance or outcomes and that actual performance and
outcomes may differ materially from those made in or suggested by the forward-looking statements contained in this Report. In addition,
even if our results of operations, financial condition and cash flows, and the development of the markets in which we operate, are
consistent with the forward-looking statements contained in this Report, those results or developments may not be indicative of results
or developments in subsequent periods. New factors emerge from time to time that may cause our business not to develop as we expect,
and it is not possible for us to predict all of them. Factors that could cause actual results and outcomes to differ from those reflected in
forward-looking statements include, among others, the following:
• the prospects of UB-612 and other product candidates, including the timing of data from our clinical trials for UB-612
and other product candidates and our ability to obtain and maintain regulatory approval for our product candidates;
• our ability to develop and commercialize new products and product candidates;
• our ability to leverage our Vaxxine Platform;
• the rate and degree of market acceptance of our products and product candidates;
• our status as a clinical-stage company and estimates of our addressable market, market growth, future revenue,
expenses, capital requirements and our needs for additional financing;
• our ability to comply with multiple legal and regulatory systems relating to privacy, tax, anti-corruption and other
applicable laws;
• our ability to hire and retain key personnel and to manage our future growth effectively;
• competitive companies and technologies and our industry and our ability to compete;
• our and our collaborators’, including United Biomedical’s (“UBI”), ability and willingness to obtain, maintain, defend
and enforce our intellectual property protection for our proprietary and collaborative product candidates, and the scope
of such protection;
• the performance of third party suppliers and manufacturers and our ability to find additional suppliers and
manufacturers;
• our ability and the potential to successfully manufacture our product candidates for pre-clinical use, for clinical trials
and on a larger scale for commercial use, if approved;
• the ability and willingness of our third-party collaborators, including UBI, to continue research and development
activities relating to our product candidates;
• general economic, political, demographic and business conditions in the United States, Taiwan and other jurisdictions;
• the potential effects of government regulation, including regulatory developments in the United States and other
jurisdictions;
• ability to obtain additional financing in future offerings;
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• expectations about market trends; and
• the effects of the Russia-Ukraine conflict and the COVID-19 pandemic on business operations, the initiation,
development and operation of our clinical trials and patient enrollment of our clinical trials.
We discuss many of these factors in greater detail under Item 1A. “Risk Factors.” These risk factors are not exhaustive and other sections
of this report may include additional factors which could adversely impact our business and financial performance. Given these
uncertainties, you should not place undue reliance on these forward-looking statements.
You should read this Report and the documents that we reference in this Report and have filed as exhibits completely and with the
understanding that our actual future results may be materially different from what we expect. We qualify all of the forward- looking
statements in this Report by these cautionary statements. Except as required by law, we undertake no obligation to publicly update any
forward-looking statements, whether as a result of new information, future events or otherwise.
Item 1. Business.
Overview
We are a purpose-driven biotechnology company committed to democratizing healthcare across the globe. Our vision is to disrupt the
existing treatment paradigm for chronic diseases, increasingly dominated by drugs, particularly monoclonal antibodies (“mAbs”), which
suffer from prohibitive costs and cumbersome administration. We believe our synthetic peptide vaccine platform (“Vaxxine
Platform”) has the potential to enable a new class of therapeutics that will improve the quality and convenience of care, reduce costs
and increase access to treatments for a wide range of indications. Our Vaxxine Platform is designed to harness the immune system to
convert the body into its own “drug factory,” stimulating the production of antibodies with a therapeutic or protective effect. While
traditional vaccines have been able to leverage this approach against infectious diseases, they have historically been unable to resolve
key challenges in the fight against chronic diseases. We believe our Vaxxine Platform has the potential to overcome these challenges,
and has the potential to bring the efficiency of vaccines to a whole new class of medical conditions. Specifically, our technology uses
synthetic peptides to mimic and optimally combine biological epitopes in order to selectively activate the immune system, producing
antibodies against only the desired targets, including self- antigens, making possible the safe and effective treatment of chronic diseases
by vaccines. The modular and synthetic nature of our Vaxxine Platform generally provides significant speed and efficiency in candidate
development and has generated multiple product candidates that we are designing to have safety and efficacy equal to or greater than
the standard-of-care treatments for many chronic diseases, with more convenient administration and meaningfully lower costs. Our
current pipeline consists of five chronic disease product candidates from early to late-stage development across multiple therapeutic
areas, including Alzheimer’s Disease (“AD”), Parkinson’s Disease (“PD”), migraine and hypercholesterolemia. Additionally, we believe
our Vaxxine Platform may be used to disrupt the treatment paradigm for a wide range of other chronic diseases, including any that are
or could potentially be successfully treated by mAbs. We also will opportunistically pursue infectious disease treatments. When the
COVID-19 pandemic struck the world in March 2020, we quickly reallocated our resources to develop vaccine candidates for the
condition. We have assembled an industry-leading team with extensive experience developing and commercializing successful drugs
that is committed to realizing our mission of democratizing healthcare. Our website address is www.vaxxinity.com. The information
contained on, or that can be accessed through, our website is not part of, and is not incorporated into, this Report.
Limitations of the Current Healthcare Paradigm
The current healthcare paradigm favors the development of drugs that are primarily intended for the U.S. market, for niche indications
and for treatment of disease rather than prevention. Furthermore, these drugs are expected to be sold at price points that are only
accessible to healthcare systems in developed countries. One class of drugs in particular exemplifies the current environment: biologics,
particularly mAbs. In 2019, biologics represented eight of the ten top selling drugs in the United States, of which seven were mAbs. The
global market for mAbs totaled approximately $163 billion in 2019, representing approximately 70% of the total sales for all
biopharmaceutical products.
While mAbs can provide life-altering care with generally favorable safety characteristics and significant health benefits for the patients
who receive them, regular in-office transfusions and annual treatment costs, which can exceed hundreds of thousands of dollars, present
challenges to both patients and payors. These price and administration hurdles cause mAb treatments to be available to only a fraction
of the population who could benefit from them. Furthermore, mAbs are often restricted to moderate to severe disease and to later lines
of treatment due to their high cost. Based on internal estimates, less than 1% of the worldwide population is on mAbs. Meanwhile, the
alternative to mAbs treatments tends to be small molecules, which are accessible to most 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.
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Our Solution
Monoclonal antibodies are developed, produced and purified outside the body and then transfused into the patient on a regular basis, as
frequently as bi-weekly. Therefore, mAbs are inherently less efficient than vaccines, which instead stimulate antibody production within
the patient’s immune system, requiring both less active material and less frequent treatments. However, while traditional vaccines have
historically been successful addressing infectious diseases, previous attempts to utilize vaccines to address chronic disease have not
achieved both acceptable safety and efficacy. This limitation is driven by a traditional vaccine’s inability to either stimulate the requisite
antibody response against harmful self-antigens, that is, break immune tolerance, or produce acceptable levels of reactogenicity, the
physical manifestation of the immune response to vaccination. Our Vaxxin e Platform technology contains modular components custom-
designed to mimic select biology and activate the immune system, enabling our product candidates to break immune tolerance when
targeting self- antigens, a property observed across multiple clinical and pre-clinical studies. Our Vaxxine Platform depends heavily on
intellectual property licensed from UBI and its affiliates, a related party and a commercial partner for us, who first developed the peptide
vaccine technology utilized by our Vaxxine Platform. The formulation of peptide-based medicines is also complex, requiring significant
expertise from UBI, its affiliates and our other contract manufacturers to produce our product candidates.
We believe our Vaxxine Platform has the potential to generate product candidates with attributes that collectively offer significant
advantages over both mAbs and small molecule therapeutics:
•
Cost
: Monoclonal antibodies require costly and complex biological manufacturing processes. Our
manufacturing process is chemically based and highly scalable and requires lower capital expenditures. In addition, we designed our
product candidates to generate antibody production in the body, thus requiring meaningfully less drug substance relative to mAbs,
leading to commensurately lower costs.
•
Administration
: Our product candidates are designed to be injected in quarterly or longer intervals via
intramuscular injection similar to a flu shot. We believe this offers considerable convenience compared to mAbs, which can require up
to bi-weekly dosing via intravenous infusion or subcutaneous injections, and small molecules, which often require daily dosing.
•
Efficacy
: In our clinical trials conducted to date, our product candidates have yielded high response rates
(95% or above at target dose levels) for UB-311, UB-312 and UB-612, high target-specific antibodies against self-antigens (as seen in
UB-311 and UB-312 clinical trials) and long durations of action for UB-311 (based on titer levels remaining elevated between doses)
and UB-612 (based on half-life). See our descriptions of these clinical trials under “—Our Product Candidates.” We also believe that
the improved convenience of our product candidates as compared to mAbs has the potential to lead to increased adherence by patients.
Furthermore, our Vaxxine Platform enables the combining of target antigens into a single formulation. For indications that could be
treated more effectively with a multivalent approach, we believe our Vaxxine Platform would have an advantage over other modalities.
Finally, because our Vaxxine Platform is designed to elicit endogenous antibodies, we believe our product candidates may lessen or
avoid altogether the phenomenon of anti-drug antibodies which has limited the efficacy of certain mAbs over time.
•
Safety
: Based on our clinical trials to date, our product candidates have been well tolerated, with safety
profiles comparable to placebo. We aim to offer product candidates with safety profiles at least comparable to the competing mAb or
small molecule alternative for the relevant disease.
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Our Pipeline
The following chart reflects our current product candidate pipeline:
As used in the chart above, “IND” signifies a program has begun investigational new drug (“IND”)-enabling studies.
Our pipeline consists of five lead programs focused on chronic disease, particularly neurodegenerative disorders, in addition to other
neurology and cardiovascular indications.
Neurodegenerative Disease Programs:
•
UB-311
: Targets toxic forms of aggregated amyloid-b (“Ab”) in the brain to fight AD. Phase 1, Phase 2a and
Phase 2a Long Term Extension (“LTE”) trials have shown UB-311 to be well tolerated in mild-to-moderate AD subjects over three
years of repeat dosing, with a safety profile comparable to placebo, with no cases of amyloid- related imaging abnormalities-edema
(“ARIA-E”) observed in the Phase 2a trial, and immunogenic, with a high responder rate and antibodies that bind to the desired target.
We expect to initiate a Phase 2b early AD efficacy trial in the second half of 2022.
•
UB-312
: Targets toxic forms of aggregated α-synuclein in the brain to fight PD and other synucleinopathies,
such as Lewy body dementia (“LBD”) and multiple system atrophy (“MSA”). The first part of a Phase 1 trial in healthy volunteers has
shown UB-312 to be well tolerated, with no significant safety findings, and immunogenic, with a high responder rate and antibodies
that cross the blood-brain barrier (“BBB”). No serious adverse events were observed in Part A of the Phase 1 trial. We have initiated
the second part of this Phase 1 trial in PD subjects, and anticipate the completion of an end-of-treatment analysis in the second half of
2022.
•
Anti-tau
: We are developing an anti-tau product candidate that has the potential to address multiple
neurodegenerative conditions, including AD, by targeting abnormal tau proteins alone and in potential combination with other
pathological proteins such as Aβ to combat multiple pathological processes at once. We expect to identify a lead product candidate in
the next two years.
Next Wave Chronic Disease Programs:
•
UB-313
: Targets Calcitonin Gene-Related Peptide (“CGRP”) to fight migraines. We have initiated IND-
enabling studies and expect to begin a first-in-human Phase 1 clinical trial in 2022.
•
Anti-PCSK9
: Targets proprotein convertase subtilisin/kexin type 9 serine protease (“PCSK9”) to lower low-
density lipoprotein (“LDL”) cholesterol and reduce the risk of cardiac events. We expect to initiate IND-enabling studies for this
program in 2022.
Given the global COVID-19 pandemic and our Vaxxine Platform’s applicability to infectious disease, we also have advanced product
candidates that address SARS-CoV-2.
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COVID-19
•
UB-612
: Employs a “multitope” 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. Phase 1 and Phase 2 trials of UB-
612 have shown UB-612 to be well tolerated, with no significant safety findings to date (over 7,500 doses have been administered to
over 3,750 subjects). No serious adverse events were observed in the Phase 1 trial. In the Phase 2 trial, twenty serious adverse events
were observed through interim analysis. Only one led to discontinuation of the study, and none were considered UB-612-related. In
these trials we observed that UB-612 generated antibodies that can bind to the S1-RBD protein and neutralize SARS-CoV-2, in addition
to driving T-lymphocytes (“T-cell”) response. An emergency use authorization (“EUA”) application for UB-612 was denied by the
Taiwan Food and Drug Administration (“TFDA”) in August 2021, but, in collaboration with our partner United Biomedical, Inc., Asia
(“UBIA”), we are appealing that decision. At the same time, we are still pursuing approval of UB-612 elsewhere, including as a
heterologous boost (boosting the immunity of a subject who has already received a different vaccine). In collaboration with University
College London and VisMederi , we analyzed sera from subjects immunized with a booster dose 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,
Gamma, and Omicron, and higher levels of neutralizing antibodies against Omicron than reported with three doses of an approved
mRNA vaccine.
We believe our Vaxxine Platform has application across a multitude of chronic and infectious disease indications beyond our existing
pipeline. We also are developing additional product candidates that we believe may address significant unmet needs both within and
beyond our current pipeline’s therapeutic areas.
Our Team
We have assembled an experienced group of executives with deep scientific, business and leadership expertise in pharmaceutical and
vaccine discovery and development, manufacturing, regulatory and commercialization. Mei Mei Hu, our co-founder and Chief
Executive Officer, has been a member of the executive committee of UBI since 2010. Our board of directors is chaired by our co-founder
Louis Reese, who has been a member of the executive committee of UBI since 2014. Our research efforts are guided by highly
experienced scientists and physicians on our leadership team including Dr. Ulo Palm, our Chief Medical Officer, and Dr. Farshad
Guirakhoo, our Chief Scientific Officer. Our leadership team contributes a diverse range of experiences from leading companies
including Acambis, Allergan, Amgen, Dendreon, Eli Lilly, Merck, Novavax, Novartis, Sanofi, and Schering-Plough, and were
executives in multiple successful mAb and vaccine launches, including Dupixent, Kevzara, Provenge, PreveNile, Ervebo, Imojev and
Dengvaxia. As of December 31, 2021, we have assembled an exceptional team of approximately 86 employees, the majority of whom
hold Ph.D., M.D., J.D. or Master’s degrees, and we are regularly hiring additional personnel. We also have a highly experienced
scientific advisory board consisting of 13 doctors and scientists.
Our Strategy
Our mission is to develop product candidates that improve the quality of care for chronic diseases and are accessible to all patients across
the globe. In order to achieve this mission, we seek to:
•
Advance our chronic disease pipeline through clinical stage development
: We plan to advance UB-311 and
UB-312 through clinical stage development for the treatment of neurodegenerative disorders. In addition, we are conducting IND-
enabling studies on multiple pre-clinical product candidates that are focused on the treatment of chronic migraines, hypercholesterolemia
and additional neurodegenerative disorders. We believe that our differentiated Vaxxine Platform will enable our product candidates, if
successful, to potentially disrupt the treatment paradigm for their respective indications. However, there can be no guarantee that we
will achieve commercialization of any such product candidates.
•
Expand our pipeline of product candidates
: Chronic diseases are prevalent globally and expected to worsen
over the next several decades. In furtherance of our mission, we plan to expand our pipeline by developing new product candidates that
address additional indications. In expanding our pipeline, we rely on our proprietary filtering methodology, which evaluates potential
product candidates across five principal criteria – (i) probability of technical and regulatory success, (ii) addressable market, (iii)
development cost, (iv) competitive dynamics and (v) disruptive potential.
•
Opportunistically develop treatments for infectious diseases
: While our core mission focuses on the treatment
of chronic diseases, we are committed to bringing accessible medicines to people around the world and will address infectious diseases
opportunistically. For example, when the COVID-19 pandemic struck the world, we rapidly deployed resources in pursuit of a product
candidate currently embodied in UB-612.
•
Expand and scale our existing capabilities
: We are investing in our operational processes, facilities and
human capital to accelerate the speed with which we can bring product candidates through the development pipeline, and to expand the
capacity for developing more product candidates simultaneously.
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•
Continue to improve our Vaxxine Platform
: In addition to, and in conjunction with, our product candidate
development efforts, we are continuously working to improve and enhance the richness, breadth and effectiveness of our Vaxxine
Platform. As our Vaxxine Platform further develops, we believe that we can both increase the number of product candidates in concurrent
development and accelerate the process of advancing product candidates through pre-clinical and clinical development.
•
Maximize the value of our product candidates through potential partnerships
: We currently retain worldwide
rights for the majority of our product candidates and will consider entering into development and commercialization partnerships with
third parties that align with our mission on an opportunistic basis.
Background and Limitations of Traditional Vaccines and Monoclonal Antibodies
The immune system, the body’s mechanism for fighting off potential threats, is comprised of cells that form the innate and adaptive
immune responses. The main purpose of the innate immune system is to immediately prevent the spread and movement of foreign
pathogens throughout the body. The adaptive immune response is specific to the pathogen presented to T-cells and B lymphocytes (“B-
cells”) and leads to an enhanced response upon future encounters with those antigens. Antibodies represent an important tool within the
adaptive immune system’s arsenal. Upon detection of a potential threat, B-cells produce antibodies that recognize, bind to and eliminate
the threatening pathogen. Over time, the immune system develops the ability to produce countless types of antibodies, each finely tuned
against a specific threat.
Generally, the immune system is able to function effectively by neutralizing viruses, bacteria and even self-generated cells and proteins
from within our own bodies that could cause harm if unchecked. However, as powerful as the immune system is, there are threats that
it cannot overcome on its own, generating the need for medicine. Conventional forms of medicine include small molecules (e.g.,
antibiotics), which can inhibit or promote action within the body by, for instance, binding to a receptor on the surface of a cell, or directly
inducing toxic effects upon bacteria. These medicines do not necessarily modulate the immune system directly in order to work. Instead,
they work alongside it. While small molecules have provided substantial benefits to human health, they are not designed to interact with
the immune system. They may also have limited efficacy in cases where an immune response to a target can be used against a chronic
condition.
Vaccines
In the first part of the twentieth century, vaccines revolutionized healthcare by directly interacting with, and modulating, the immune
system — training it to recognize a dangerous pathogen by introducing the immune system to a relatively harmless form of the pathogen,
its toxins or one of its surface proteins, thereby promoting the body’s own production of binding antibodies. Once immunized to a
specific pathogen, the immune system can recognize it and generate the antibodies to fight it more quickly and robustly.
Traditional vaccine technologies have generally focused on the prevention of bacterial and viral infections and not on chronic disease.
In chronic disease settings, the disease-causing agents frequently come from within the body. These self-antigens are proteins that
become too abundant, misfolded or aggregated such that they can no longer perform their healthy function and even may induce toxic
effects. The body can sometimes produce antibodies against such proteins, but this often falls short of providing the right types of
antibodies in the right concentrations to ward off disease. Historically, vaccine technologies developed to target these proteins have been
unable to break immune tolerance — that is, the immune system’s general avoidance of reactivity towards self-antigens — with an
acceptable level of reactogenicity. The challenges faced by prior efforts to advance vaccine technologies for chronic diseases included
low response rates, low titer levels, off- target responses and other safety concerns such as T-cell mediated inflammation.
Monoclonal Antibodies
The first mAbs were developed in the later part of the twentieth century. In contrast to vaccines, which prompt the body to produce
antibodies, mAbs are antibodies manufactured outside of the patient’s body and then injected or infused into the body to recognize and
eliminate harmful targets. Monoclonal antibodies have revolutionized the standard-of-care treatment for many chronic diseases.
However, manufacturing mAbs is often an expensive and complex process and administering mAbs is cumbersome, sometimes requiring
infusions as frequently as bi-weekly. These factors have generally limited mAbs’ availability to moderate-to-severe disease, to later
lines of therapy and to wealthier geographies, thus denying access to a substantial portion of the patients who could benefit from them.
Finally, patients on mAbs often experience a loss of effectiveness over time due to a phenomenon known as anti-drug antibodies,
whereby the immune system begins to recognize therapeutic mAbs as foreign, and mounts a response against them, eventually mitigating
their efficacy.
Our Vaxxine Platform
Our Vaxxine Platform is designed to stimulate the patient’s own immune system to generate antibodies and overcome the limitation of
traditional vaccines to effectively and safely target self-antigens 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 six clinical trials,
we have consistently observed that our product candidates have stimulated the development of antibodies against the desired target at
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relevant doses in clinical trial subjects, including the elderly. We have observed favorable tolerability and reactogenicity of our product
candidates across studies of UB-311, UB-312 and UB-612, with no significant safety findings to date. We aim to develop product
candidates that possess clinical advantages against, and safety profiles at least comparable to, relevant mAbs and small molecule
treatments. We believe our product candidates have the potential to eventually capture meaningful market share from mAbs and small
molecules, and to provide therapeutic benefit to large patient populations who currently receive neither form of treatment. This would
represent an unprecedented shift in the treatment paradigm, potentially providing better global access to treatments that have been
previously limited to the wealthiest nations. In particular, we believe our treatments for chronic disease could reflect the following
benefits as compared with the relevant mAbs and small molecule alternatives:
Characteristics of our Product Candidates versus Monoclonal Antibodies and Small Molecules
History and Design
Our Vaxxine Platform utilizes a peptide vaccine technology first developed by UBI and subsequently refined over the last two decades,
with more than three billion doses of animal vaccines sold 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.
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 Vaxxine Platform to develop product candidates that target chronic diseases and COVID-19. Our
Vaxxine Platform comprises a custom, rationally designed antigen capable of evoking an immune response (an “immunogen”)
formulated with a proprietary CpG oligonucleotide. The immunogen contains several advanced synthetic peptides, including B-cell
epitopes, T-helper (“Th”) antigen carrier constructs and epitope linker configurations. This composition enables us to achieve a highly
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specific immune response to the target antigen, with limited inflammation and off-target effects that could cause reactogenicity. This
design process has evolved into a repeatable series of well-defined steps, which has enabled the development of our current pipeline of
product candidates.
Key Elements of our Vaxxine Platform Constructs and Formulations
When developing a product candidate, we use publicly available information and sophisticated bioinformatics tools to investigate the
entire protein structure of a target in a comprehensive manner to identify functional B-cell epitopes that may provide optimal antigens.
We then synthesize custom peptides that mimic these identified antigens to elicit highly specific antibodies against these B-cell epitopes.
To yield favorable tolerability profiles, we design our product candidates such that they lack T-cell epitopes and screen them for lack of
T-cell mediated inflammation and toxicity, as well as reactogenicity. Such screening tests include the measuring of immunogenicity of
each B-cell antigen with and without conjugation to a Th carrier peptide (a response only when conjugated to a Th carrier peptide is
desired), epitope mapping assays and in vivo and ex vivo tests of lymphocyte proliferation, pro-inflammatory cytokine release and T-
cell infiltration. 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. Carrier
molecules used in traditional vaccines often elicit a strong T-cell mediated immune response, resulting in significant off-target activity.
In our pre-clinical trials and clinical trials to date, our product candidates have displayed specific immunogenicity, or the ability to
stimulate an 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 our six human clinical trials to date. Traditional vaccines have faced challenges in
achieving specific responses because they rely on conjugating the antigen to a large toxoid molecule carrier protein, to which most of
the antibody response is directed, causing off-target effects such as inflammation.
10
Our Product Candidate Does not Induce an Antibody Response against its Carrier Molecule
The graph above illustrates that our peptide carriers induce a strong immune response against the target antigen, and a minimal immune
response against themselves, as compared to traditional vaccines formulated with other types of carrier molecules.
Our peptide carriers have short sequence lengths, which contribute to their immunosilence and ability to avoid a direct response by
cytotoxic T-cells. However, the carriers’ sequences mirror those found in naturally ubiquitous pathogens, so they are easily recognized
by T-helper cells. This encourages robust T-helper cell exposure to the carrier peptide 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 exposure to the
carrier peptide, which avoids antibody response to the carrier. We believe that B-cell exposure to the carrier peptide is avoided because
of its relatively small size and its high affinity to T-helper cells, such that T-helper cells are exposed to the carrier peptide rapidly and
robustly, more so than other cell types. UBI first developed a library of such peptide carriers, which contain various Th cell epitopes
and are of critical importance to our vaccine configuration. 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. Other
variables that can be adjusted to modulate the immune response include dosing and formulation optimization. In the case of vaccines
targeting infectious diseases, T-cell mediated activity is desirable, while in the case of chronic diseases, it is not. Our Vaxxine Platform
affords the flexibility to design immunogen constructs that specifically promote cytotoxic T-cell activity when warranted (e.g., for
infectious diseases).
We utilize our linker construct to attach our peptide carriers with our custom antigens. In addition to their binding function, these linkers
also enhance the immune system response further by enabling conformational changes to optimize presentation of the B-cell epitope to
antigen-presenting cells (“APCs”), such as B-cells and dendritic cells (“DC”).
Our Vaxxine Platform also enables the construction of multitope configurations, whereby we can attach multiple immunogens targeting
multiple B-cell epitopes simultaneously, each with different targets, within a single product candidate. Combinations of therapies
targeting different molecular mechanisms are common in treating neurologic, cardiovascular, psychiatric, metabolic, respiratory,
infectious and oncologic disease. Our Vaxxine Platform’s favorable cost of goods and efficient manufacturing process could allow for
viable combinations of targeted 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; combinations of two or more of these might prove
more effective than any single therapy in some patients. Pre-clinical data to date suggests that we can elicit antibody titers against all
three targets in a single formulation. For mAb-based treatments, such combinations might require the individual dosing of multiple
separate mAb therapies, thereby compounding cost and administration burdens.
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Immunogenicity of Single- Versus Combination-Target Formulations in Guinea Pigs
Guinea pigs (three per dose) were tested with either single-target or combination-target formulations, then serum was drawn and
antibody titers compared via enzyme immunoassays (“EIA”). Combination-target formulations elicited similar titer levels against each
target as 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 APCs. In this way, the primary function of CpG
oligonucleotides in our formulations is that of an excipient, even though it has the secondary function of an adjuvant.
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 enhance the
stimulation of an immune response. This is not the same adjuvant used in other companies’ failed neurodegenerative vaccine candidates.
How our Product Candidates 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 neurodegeneration targets, 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.
Vaxxine Platform Immunogenicity upon Re-dosing
As shown in the above graph, a repeatable immune response elicited from our product candidates has been observed with a booster
dose over one year 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 kon, koff and kD values of antibodies elicited by our product
candidates versus mAbs. We also use Western blot or slot blot to evaluate the binding specificity of antibodies elicited by our product
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candidates against the toxic, misfolded or aggregated forms of the target protein, and avoidance of monomers or healthy forms. We use
immunohistochemical analyses to observe the binding of antibodies to pathological inclusions on 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
safety and toxicity issues. We believe that this is unlikely to happen using our vaccine approach since antibodies elicited by our product
candidates come from the body’s own B-cells and are therefore unlikely to induce antibodies against other self-proteins as a foreign
antibody may.
Product Candidate Selection Process
Because our Vaxxine Platform may have applicability across a range of chronic diseases, we employ a proprietary filtering methodology
to best identify new product candidates for development. We evaluate potential product candidates across five principal criteria:
•
Probability of technical and regulatory success
: We examine the probability of success for a product
candidate based on stage of development and therapeutic area, and then make target- specific adjustments for design difficulty, industry
knowledge and clarity of biological mechanism, general safety risk and estimated titer level required for therapeutic effect. This criterion
accounts for the known validity of a given target in the relevant disease context.
•
Market opportunity
: We account for the prevalence, unmet need and drug market size for each likely
indication associated with a given target, as well as the number of potential indications.
•
Development cost
: We estimate the cost of development through BLA submission, the time to submission
and the number of patient-years to proof-of-concept.
•
Competitive advantages
: We evaluate the extent to which the advantages of our Vaxxine Platform compare
to the current and potential future standard of care, including convenience, dosing, safety, efficacy and cost.
•
Disruptive opportunities
: We evaluate the extent to which the potential disruptive properties of our Vaxxine
Platform may play a role in treatment paradigms, including the ability to “leap-frog” mAbs and treat patients in earlier lines of treatment,
to be used as a prophylactic, to combine multiple targets into a single formulation and to be used as an adjuvant therapy.
After assigning values to each criterion for a given product candidate, we weight each criterion according to a confidential algorithm,
and thereby prioritize product candidates for development. We update these values on a regular basis based on new scientific literature,
trial results and our Vaxxine Platform advancements.
As an example, in light of these criteria, AD and other neurodegenerative diseases that involve misfolded proteins are an attractive area
for development. First, as the field has gained knowledge and clinical experience around the biology of targeting aberrant proteins with
antibodies, the relative technical, safety and regulatory risk has decreased. AD and PD have high prevalence worldwide, and large unmet
need with no disease-modifying products readily available to patients. Moreover, the underlying pathologies often begin years or decades
before symptoms may appear and as a result, early intervention in the disease state, as well as prevention or delay of onset strategies,
may be optimal and more practically achievable with a vaccine approach. While mAbs can target the pathology, they face the limitations
of high cost, cumbersome and inefficient administration and limited access, and are not suited for early treatment or prevention, which
we believe provides a disruptive opportunity for our Vaxxine Platform.
We do not currently evaluate oncology and infectious diseases through the above framework. We generally do not pursue oncology
targets given the hyper-segmentation of subjects common in clinical development efforts in oncology that leads to relatively narrow
labels, and due to the strengths of other new modalities such as cell-based therapy in this area. We only consider infectious disease
opportunistically. However, our approach with respect to oncology and infection diseases could change in the future.
We believe that our Vaxxine Platform, and our strategy more generally, will create a significant opportunity for drug development well
beyond our current pipeline of clinical and pre-clinical indications, in therapeutic areas including allergy (e.g., chronic rhinosinusitis,
atopic dermatitis, 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 of aging, osteopenia).
Underlying Drivers of Our Platform Advantages
Our Vaxxine Platform’s properties drive the unique combination of attributes that we believe will be reflected in our product candidates:
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•
Cost
: Our reliance on chemically linked, custom peptide sequences fuels cost efficiencies that we expect to
enable broad accessibility to our product candidates. Foremost among these relates to dosing. Monoclonal antibodies require more
physical material for annual dosing because the patient needs to be delivered the externally manufactured therapeutic antibodies, which
have high molecular weight. In contrast, our product candidates are designed to stimulate the body’s immune system to produce its own
antibodies and have relatively low molecular weight. While an annual supply of mAbs doses may include grams or tens of grams of
drug substance, our current product candidates only require 1 to 2 milligrams each, or even less, leading to a relatively low annual cost
of goods. In our development programs to date, we have achieved a cost of goods amounting to a small fraction of the typical cost of
mAbs (as low as <1%).
•
Administration
: Administration of our product candidates generally requires three priming doses, each in the
range of several hundred micrograms, followed by booster doses of a similar magnitude 2 to 4 times per year. As described in the section
titled “Our Product Candidates” below, in clinical trials we have observed that our product candidates elicited a sustained antibody
response, with elevated antibody levels lasting six months or longer. We believe this presents a meaningful advantage over many mAbs,
which commonly require either bi-weekly or monthly injections, or monthly or quarterly infusions, and many small molecules, which
commonly require a daily pill.
•
Safety
: The antibodies generated by our product candidates are designed to be highly specific to the target
antigen and to avoid an off-target immune response to the peptide carrier, thereby limiting inflammation and other off-target activity.
We believe these characteristics have yielded the high tolerability observed in the clinical studies of our product candidates to date.
Furthermore, the titer response to our product candidates is naturally titrated, which may reduce the likelihood of an antibody Cmax
safety side effect, and is naturally reversible, thus avoiding an uncontrolled or permanent immune response.
•
Efficacy
: In our clinical trials conducted to date, our product candidates have yielded comparatively high
response rates (95% or above at target dose levels) for UB-311, UB-312 and UB-612, high target- specific antibodies against self-
antigens (as seen in UB-311 and UB-312 clinical trials) and long durations of action for UB-311 (based on titer levels remaining elevated
between doses) and UB-612 (based on half-life). Furthermore, our Vaxxine Platform enables the combining of target antigens into a
single formulation. For indications that could be treated more effectively with a multivalent approach, we believe our Vaxxine Platform
would have an advantage over other modalities. Finally, because our Vaxxine Platform is designed to elicit endogenous antibodies, we
believe our product candidates may lessen or avoid altogether the phenomenon of anti-drug antibodies which has limited the efficacy of
certain mAbs over time.
Additionally, our Vaxxine Platform possesses important benefits reflected at the platform level, as opposed to the product candidate
level:
•
Product Candidate Discovery
: Our Vaxxine Platform enables the efficient iteration of product candidates in
the discovery phase through rapid, rational design and formulation. We are able to screen in high throughput rapidly and at low cost.
Upon nominating a target for drug discovery, we can formulate several dozen product candidate compounds for preliminary in vivo
immunogenicity and cross-reactivity screening within 2 to 3 months. This process allows nonviable product candidates to “fail fast” and
allows us to carry top product candidates forward through subsequent pre-clinical development to lead identification. In contrast,
biologics require the maintenance and adjustment of living cultures to design, formulate and iterate, and therefore discovery and early
development is inherently less efficient.
•
Process Development
: Scaling the formulation of a drug product from research grade to clinical grade, then
to commercial grade, typically consumes a great deal of resources. This, together with the development of assays for quality control and
quality assurance, comprise process development. Through our manufacturing partnership with UBI and certain of its affiliates, we
leverage their experience scaling the manufacture of both clinical and commercial compounds that use our Vaxxine Platform technology.
Unlike process development for mAbs, which has inherent challenges such as risk of contamination in cell culture or bioreactors and
time-consuming adjustments to cell lines for any formulation adjustment, our peptide platform relies on chemical synthesis which is
more reproducible and scalable, and relatively quick to manipulate for any modifications.
Our Product Candidates
Neurodegenerative Disease Programs
Neurodegenerative diseases are a collection of conditions defined by progressive nervous system dysfunction, degeneration or death of
neurons, which can cause cognitive decline, functional impairment and eventually death. Neurodegeneration represents one of the most
significant unmet medical needs of our time due to an aging population and lack of effective therapeutic options.
Two of the most common neurodegenerative diseases are AD and PD. In the United States, currently more than six million people suffer
from AD, and approximately one million people suffer from PD according to estimates from the Alzheimer’s Association and the
Parkinson’s Disease Foundation, respectively. As a result, AD and PD bring a heavy burden on our society’s cost of care. The direct
costs of caring for individuals with AD and other dementias in the United States were estimated at $305 billion in 2020 according to a
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study published by the American Journal of Managed Care, and are projected to increase to $1.1 trillion by 2050 according to the
Alzheimer’s Association. The financial burden of PD exceeded $50 billion in the United States in 2019. Many more people around the
world suffer from these two diseases and their related social and economic implications.
UB-311
An Overview of Alzheimer’s Disease
Alzheimer’s disease is a progressive neurodegenerative disorder that slowly destroys memory and cognitive skills and eventually the
ability to carry out simple tasks. Its symptoms include cognitive dysfunction, memory abnormalities, progressive impairment in activities
of daily living and a host of other behavioral and neuropsychiatric symptoms. The exact cause of AD is unknown, but genetic and
environmental factors are established contributors. AD affects more than six million people in the United States and 44 million
worldwide. The 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. These abnormal depositions lead to loss of neurons and neuronal connectivity
and the signs and symptoms of AD.
The Aβ protein involved in AD comes in several different molecular forms that accumulate between neurons. One form, Aβ 42, is
thought to be especially toxic. In the brains of patients with AD, abnormal levels of this naturally occurring protein clump together to
form plaques that collect between neurons and disrupt cell function. 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 inside neurons. 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 abnormal tau, Aβ
proteins 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.
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, helping to preserve
neuronal communication and function temporarily. Glutamatergic modulators are designed to block sustained, low-level activation of
the N-methyl-D-aspartate (“NMDA”) receptor, without inhibiting the normal function of the receptor in memory and cognition.
However, these therapeutic products only address the symptoms of AD and do not modify or alter the progression of the underlying
disease.
Aducanumab, marketed under the trade name Aduhelm, is a mAb developed by Biogen, Inc. (“Biogen”) that targets aggregated forms
of Aß. The FDA approved aducanumab in June 2021, making it the first approved immunotherapy for AD, the first new FDA-approved
treatment since 2003 and, importantly, the first to receive accelerated approval based on a biomarker. By approving aducanumab on the
basis of biomarker evidence, we believe the FDA set a precedent for developers of anti-Aβ immunotherapies. Soon after the FDA’s
decision, 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. Despite the milestone in the treatment of AD that aducanumab’s approval represents, the drug has several
limitations. Approximately one-third of patients experience ARIA-E related adverse events, which can manifest as symptoms ranging
from headaches to confusion to coma. In addition, the drug must be administered monthly via intravenous infusion in locations with
healthcare professionals trained to administer infusion therapies in facilities specifically configured to support an hours-long infusion
process, 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, and thus expected to limit the prescribing of and regular access to
aducanumab. In addition, aducanumab launched at a price of $56,000 annually for the drug product only, not including administration
and ongoing monitoring costs such as positron emission topography (“PET”) and MRI scans. Since that time, Biogen has reduced the
price of Aduhelm. The combination of price, side effects, extra costs and extra administration burden highlight the challenges of, and
have limited access to, this mAb.
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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”)
in 2021 and believe that UB-311 may offer several differentiators versus aducanumab, including the preferential targeting of aggregated
Aβ oligomers over monomers with modest clearance of Aβ plaques, and a tolerability profile comparable to placebo. 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
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, lower
manufacturing costs may support meaningfully lower pricing. 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 (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 ADAS-Cog, CDR-SB, ADCS-ADL and MMSE ratings, 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 high- frequency
(quarterly dosing, or “Q3M”) receiving a total of seven doses, UB-311 low-frequency (every six month dosing, or “Q6M”) receiving a
total of five doses, and placebo. The high-frequency 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 low-frequency cohort, which included 15 subjects, involved the same
initial schedule of three 300μg injections administered over the first 12-week period, followed by the administration of two 300μg
booster doses given at six-month intervals. The placebo group comprised 14 subjects.
In the Phase 2a Main Trial, UB-311 generated an immune response as measured by ELISA in 28 out of 29 subjects. Across this trial
and the Phase 1 trial, 47 of the 48 subjects (98%) that received UB-311 registered an immune response (which we define as a 95%
confidence interval separation from placebo) as measured by ELISA. The intramuscular injection produced appreciable antibody titers
against Aβ. The antibody titers remained elevated through the trial’s duration. Moreover, in vitro studies demonstrate that UB-311
generated serum anti-Aβ antibody titers against oligomers, the components that form Aβ, comparable or greater than those measured
after maximum therapeutic dosing with aducanumab. We believe these results underscore the significant promise of our therapeutic
approach.
Generation of Antibodies Repeatable Across Clinical Studies, and Antibodies Bind Target with High
Specificity as Compared to Monoclonal Antibody
17
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.
Our Phase 1 and Phase 2a trials demonstrated a repeatable anti-Aβ titer response. In an in vitro comparison of titers in serum from
subjects dosed with UB-311 versus pre-immune serum spiked with aducanumab at the published Cmax concentration following 10mg/kg
administration (183μg/mL), antibodies generated by UB-311 bond to Aβ oligomers similarly to or greater than aducanumab as measured
by EIA.
Exploratory analyses of clinical and imaging measures were conducted. Trends of changes in disease assessment scores suggest showing
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.
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.
In addition to the composite above, Pentara Corporation performed a post hoc analysis to estimate the performance of UB-311 on the
integrated Alzheimer’s Disease Rating Scale (“iADRS”) versus placebo in the Phase 2a trial. The results of this analysis suggested that
the UB-311 target dosing regimen (quarterly dosing) on average slowed decline versus placebo by approximately 59% over 78 weeks.
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iADRS Change from Baseline over Time vs. Placebo (Exploratory Analysis)
Compared to placebo, UB-311 (quarterly dosing) declined less on an iADRS-like clinical endpoint over 78 weeks in mild-moderate AD
subjects in the Phase 2a Main Trial. This analysis was performed by Pentara Corporation. The UB-311 Q6M group showed 26% decline
versus placebo which is not shown on the plot.
We have provided a side-by-side summary table of subject baseline characteristics below, with anti-Aβ mAbs using data from the
exploratory endpoints of the Phase 2a Main Trial, in particular CDR-SB, as well as using the post hoc iADRS-like endpoint (no head-
to-head clinical trials of UB-311 against mAbs have been performed). We believe the performance of aducanumab and donanemab on
CDR-SB and iADRS change from baseline over time, the respective primary endpoints from the pivotal trials of those mAbs, represent
meaningful references.
Post hoc
on CDR-SB change from baseline over time, and comparably to donanemab on iADRS change from baseline over time, in an
appropriately powered study, noting that the UB-311 Phase 2a Main Trial was a proof-of-concept study not powered to detect statistically
significant changes, and these are indirect comparisons with aducanumab and donanemab trials. We have provided an overview of the
sample sizes and baseline characteristics of the UB-311 Main Trial and various anti-Aβ mAb trials below.
Baseline Characteristics of Various Anti-Aβ Immunotherapy Clinical Trials
The Phase 2a Main Trial recapitulated the safety and tolerability profile of UB-311 that was observed in an earlier Phase 1 trial. No
subjects discontinued trial participation due to a treatment emergent adverse effect (“TEAE”). No ARIA-E was observed in quarterly
MRI scans. Aβ-related imaging abnormalities related to microhemorrhages or hemosiderosis seemed similar between the UB-311
treatment groups and placebo group. In the Phase 2a Main Trial, six serious adverse events were observed, including three in the Q6M
dosing arm and one in the Q3M dosing arm. None was 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 immediately reach Cmax. We believe this lead to the relatively low rates of ARIA-E observed in our clinical
studies of UB-311 as compared to those observed in clinical studies of mAbs. No meningoencephalitis was observed.
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Summary of Safety Data from UB-311 Phase 1 and Phase 2a Trials
As depicted in the table above, UB-311 was well tolerated across Phase 1 and Phase 2a trials. The most common TEAE was site injection
reactivity, and there were no discontinuations or withdrawals due to TEAEs
An extension of the Phase 2a Main Trial, the Phase 2a LTE trial, involved the continued participation by 34 of the subjects who
participated in the Phase 2a Main Tri al for an additional 78 weeks. The objectives of the Phase 2a LTE trial were 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 much as 12
months between doses and a continued trend toward evidence of disease modification. In the Phase 2a LTE trial, six serious adverse
events were observed. One case of ARIA-E was observed in the Phase 2a LTE trial. None was deemed related or likely related to UB-
311, and all such events were recovered/resolved by the end of the study. Exploratory analyses of the clinical data generated in this
portion of the trial suggested that subjects in the treatment cohorts showed sustained improvement, as measured by the change in CDR-
SB from baseline.
We completed an open-label Phase 1 trial of UB-311 in 19 subjects with mild-to-moderate AD between the ages of 51 to 78 years. The
primary objective of the trial was to assess safety and tolerability. Secondary measures included UB-311 antibody titers along with
changes in the ADAS-Cog, MMSE and the Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change disease
assessment ratings. The 24-week, open label trial was designed as three intramuscular injections of 300μg, the first dose administered
at the start of the trial, a second at week four and a third at week 12. An observation study included additional follow-up visits up to 48
weeks after the first injection to assess the long-term immunogenicity and safety of UB-311. In this trial, UB-311 was well tolerated,
with the most common TEAE being injection site redness and swelling. No TEAE resulted in the discontinuation or withdrawal of any
study participant in the trial. In the Phase 1 trial, one serious adverse event was observed: a case of herpes zoster deemed unlikely related
to UB-311.
Anti-Aβ antibody titers, recorded among all study participants, approached a 100-fold increase during weeks 16 to 48 after
administration of the third 300μg injection at week 12, demonstrating the ability of UB-311 to elicit a strong immune response. Durability
of the response was reflected in elevated anti-Aβ antibody titers measurable well beyond the 24-week duration of the trial.
In a Western blot assay, we observed that UB-311 elicited antibody titers specific to toxic forms of Aβ with minimal binding to normal,
non-plaque-causing, forms of Aβ.
Pre-Clinical Data
Pre-clinical trials of UB-311 included multiple antibody titer studies involving mice, guinea pigs, macaques and baboons. Application
of specific transgenic animal models was intended to emulate both therapeutic and preventive treatment paradigms. These trials
demonstrated that UB-311 generated high antibody titers across multiple species that selectively target aggregated Aβ and both slow the
accumulation of and reduce existing Aβ pathology.
20
We also observed the ability of UB-311 induced antibodies to penetrate the BBB, as well as preferentially bind to toxic Aβ aggregates.
In our study of UB-311 in cynomolgus monkeys, we tested five escalating dose levels of UB-311: 0μg, 30μg, 100μg, 300μg and 900μg.
Each dose level was administered on weeks zero, three and six by intramuscular injection and the cerebrospinal fluid (“CSF”): serum
ratio of UB-311 calculated on week eight (two weeks after the last dose). This analysis concluded that UB-311 antibody titers were
detectable in the CSF in a dose-dependent manner with CSF: serum antibody ratios of 0.1% to 0.2%, ratios similar to published data for
mAbs in development for neurodegenerative diseases.
UB-311 Shows Dependent Response in CSF in Pre-Clinical Study
The above graphs demonstrates that UB-311 achieved CSF: serum ratios in the 0.1% to 0.2% range across five doses in a pre -clinical
study involving cynomolgus monkeys.
Development Plans for UB-311
We have completed a pre-Phase 3 meeting with the FDA and obtained guidance on the further development of UB-311.
Subject to the FDA’s review, we expect to conduct a randomized, double-blinded, placebo-controlled Phase 2b efficacy trial of UB-311
in approximately 670 subjects with early AD. The Phase 2b trial will include subjects diagnosed with early AD with MMSE scores
between 22 and 30. We will also screen to enrich for positive amyloid PET, positive tau PET and positive plasma p-tau181, in quantities
consistent with an early AD population. Subjects in the active arm will receive UB-311 as three 300μg priming doses at weeks 0, 4 and
12, followed by four 300μg booster doses every three months thereafter. The primary objective of this trial will be to assess the effect
of UB-311 on the decline of cognitive and functional performance as measured by the iADRS over the 78-week treatment period.
Secondary endpoints will include the changes from baseline measurements of other validated clinical outcomes scores. The effect of
UB-311 on specific AD biomarkers will also be evaluated, including neurofilament light arm (“NfL”), p-tau, total-tau, brain amyloid as
measured by PET, Aβ-40 and Aβ-42, hippocampal volume and whole brain volume as measured by MRI, and an assessment of certain
CSF biomarkers. We expect to initiate this trial in the second half of 2022.
Assuming positive results in the Phase 2b trial, we expect to initiate a Phase 3 trial in subjects with early AD. The Phase 3 program may
involve one, but more likely two, clinical trials, conducted at multiple international sites. Assuming positive results in the Phase 2b trial,
we may also seek FDA approval under the accelerated approval pathway, which allows for earlier approval of drugs that treat serious
conditions, and that fill an unmet medical need based on a surrogate endpoint. We expect that together, the Phase 2b trial and the Phase
3 program, if successful, will provide sufficient data to enable BLA filing with the FDA, but there can be no guarantee that we will not
need to conduct additional trials or studies prior to a BLA filing with the FDA.
We believe UB-311 could also have a potential therapeutic benefit in a prophylactic setting for the prevention of AD in high-risk patients.
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.
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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 significantly reduced subjects’
motor function decline and delayed clinically meaningful worsening or motor symptoms, compared with placebo. Despite encouraging
preliminary data observed with this mAb, we expect that mAbs, even if approved as therapeutic for PD, 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. Preliminary clinical data from our ongoing Phase 1 trial indicate that UB-312
elicits antibody levels sufficient to cross the BBB (i.e., detectable in CSF). In 2018, the European Medical Agency (“EMA”) granted
UB-312 orphan designation for MSA.
Clinical Development
We have conducted Part A of a randomized, placebo-controlled, double-blind, dose-escalating, single- center Phase 1 clinical trial of
UB-312 in which 50 healthy volunteers between the ages of 40 and 85 years received three intramuscular doses of either UB-312 or
placebo. During this 44-week Part A trial, subjects received three doses (on weeks 1, 5 and 13) with escalating doses ranging from
40μg to 2,000μg. Immunogenicity was evaluated by measuring changes in serum anti-α-synuclein antibody concentrations during the
course of the study. Data from Part A indicated that UB-312 is generally well tolerated, with no significant safety findings. Data from
Part A also suggested that UB-312 is highly immunogenic, with all individuals in the 300μg/dose group showing detectable anti-α-
synuclein antibodies in both serum and CSF samples. CSF: serum ratios appeared similar to those observed in UB-311 non-human
primate studies (approximately 0.2%), and to those observed in clinical trials of mAbs. Based on these results, we are now evaluating
two dosing regimens of UB-312 in Part B of the Phase 1 trial: three doses of 300μg, and one dose of 300μg followed by two doses of
100μg. Part B will evaluate UB-312 and placebo in 20 PD subjects and began enrollment in January 2022. In addition to the endpoints
evaluated in Part A, an exploratory endpoint involving a clinical assessment using the Movement Disorder Society – Unified
Parkinson’s Disease Response Score will be used.
The Michael J. Fox Foundation (“MJFF”) is funding a 2-year collaborative project between Vaxxinity, 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 will evaluate the
potential of protein misfolding cyclic amplification (“PMCA”) to assess target engagement and will also aim to characterize the anti-
α-synuclein antibodies produced after immunization with UB-312. Demonstrating whether pathological forms of α-synuclein are
detectable in the CSF of PD subjects, and whether UB-312-derived antibodies prevent the formation of α-synuclein seeds measured by
PMCA, might provide a meaningful surrogate marker of target engagement.
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UB-312 Demonstrated Dose-Dependent Response in Phase 1 Part A Trial Including Penetration of Titers into CSF
Across four cohorts, UB-312 demonstrated a dose-dependent immunogenic response. Antibodies generated by UB-312 were readily
detectable in CSF, indicating BBB penetration with a CSF: serum ratio of approximately 0.2%.
We paused dosing in high dose cohorts in Part A of the trial after one subject developed an adverse effect (“AE”) of special interest (i.e.,
Grade 3 flu-like symptoms) shortly after receiving the second 1000μg dose of UB-312. Although this AE was transient and not a serious
adverse event (“SAE”), data collected until that point suggested that the 100μg and 300μg dose levels were well tolerated and yielded
relatively high anti-α- synuclein titers. During the evaluation of the AE, the COVID-19 pandemic was becoming increasingly pervasive
throughout Europe, increasing the risk to healthy volunteers participating in the trial. We therefore did not resume dose escalation and
selected 100μg and 300μg doses for Part B in PD subjects.
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 target-mediated clearance by
monomers and bind selectively to the toxic species
(Nimmo et al., Alzheimers Res Ther. 2020;12:159).
Anti-α-synuclein antibodies produced by UB-312 immunization specifically bind pathogenic species of α-synuclein, including
aggregated fibrils, oligomers and ribbons, while demonstrating low affinity for the monomer. This species selectivity contrasted with
Syn-1, a commercial research mAb used as a control, which failed to differentiate the toxic variants.
In an in vivo study of UB-312 using a transgenic mouse model of PD, we demonstrated prevention of motor deficits in treated animals,
which was associated with significant reduction of brain oligomeric forms of α- synuclein. We believe this data supports the potential
of UB-312 to prevent behavioral motor deficits and reduce toxic forms of α-synuclein.
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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
While certain portions of this Phase 1 trial were interrupted by the COVID-19 pandemic, Part A in 50 healthy volunteers was completed
in 2020, and we began dosing PD subjects in Part B in early 2022. In Part B we expect to include exploratory endpoints potentially
relevant to PD, such as total and free α-synuclein in serum and CSF, in addition to T-cell ELISpot analyses and antibody characterization.
Upon the completion of the Phase 1 trial, we expect to advance UB-312 into further clinical development, which may comprise trials
for various synucleinopathies.
Other Neurodegeneration Programs
We are actively engaged in additional initiatives related to neurodegenerative disorders. One of these programs focuses specifically on
tau-protein pathology and its involvement in diseases such as AD and related tauopathies. We believe that targeting different pathological
tau variants simultaneously may enhance treatment efficacy, which will most likely require targeting multiple epitopes concomitantly.
Using our Vaxxine Platform, we have constructed combination product candidates that target these multiple epitopes and have
successfully demonstrated their utility to raise therapeutic antibody titers in in vitro studies as well as early in vivo animal models.
We are also investigating the use of a combination of product candidates targeting Aβ, α-synuclein, tau and C9ORF79 dipeptide repeat
proteins, as multiple proteins could be implicated in neurodegenerative diseases.
Next Wave Chronic Disease Treatments
Pathological endogenous proteins (“self-proteins”) drive a wide range of chronic diseases. While mAbs and small molecules have
provided therapeutic benefits in the treatment of these diseases, inherent limitations of these drug classes have restricted access and
adherence to these treatment modalities globally.
Our next wave chronic disease program is initially focused on migraine and hypercholesterolemia. Monoclonal antibodies have been
approved in both therapeutic areas; however, their high costs have limited access and generally limited use to relatively severe disease.
We aim to develop product candidates in these therapeutic areas that could offer similar efficacy as mAbs at a meaningfully lower cost
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and improved administrative convenience to patients, thereby potentially allowing for access to broader patient populations versus
mAbs, and greater efficacy than small molecules.
UB-313
An Overview of Migraine
Migraine is a chronic and debilitating disorder characterized by recurrent attacks lasting four to 72 hours with multiple symptoms,
including typically one-sided, pulsating headaches of moderate to severe pain intensity that are associated with nausea or vomiting,
sensitivity to sound and sensitivity to light. Over 90% of the patients are unable to function normally during a migraine attack. Many
experience comorbid conditions such as depression, anxiety and insomnia.
The Migraine Research Foundation ranks migraine as the world’s third most prevalent illness. The disease affects 39 million individuals
in the United States and approximately one billion individuals globally. Patients generally suffer from chronic or episodic migraines.
Chronic migraine is defined as 15 headache days or more per month, while episodic migraine is defined as fewer than 15 headache days
per month. Both acute and prophylactic treatments are used to address chronic and episodic migraines.
CGRP’s Role in Migraine
CGRP is a neuropeptide found throughout the body, including in the spinal cord. CGRP activates CGRP receptor in the
trigeminovascular system, which is located within pain-signaling pathways, intracranial arteries and mast cells. Activation of the CGRP
receptor has been demonstrated to induce migraine in migraineurs. Multiple anti-CGRP therapies have been approved for the treatment
of migraine.
Limitations of Current Therapies
Since the early 1990s, there has been minimal improvement in the standard treatment for migraine. Treatments are characterized as elite
acute or prophylactic. Triptans are the current first-line prescription therapy for the acute treatment of migraine, with over 15 million
annual prescriptions written in the United States.
Prophylactic medications approved for migraine include beta blockers, such as propranolol, topiramate, sodium valproate and botulinum
toxin, branded as Botox. However, many of these medications provide limited clinical benefit. In addition, they are often not well
tolerated, with AEs such as cognitive impairment, nausea, fatigue and sleep disturbance.
Therapeutics targeting the CGRP pathway represent an emerging treatment paradigm. Three anti-CGRP mAbs were approved by the
FDA in 2018 for the prophylactic treatment of migraine in adults. These mAbs, erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy)
and galcanezumab-gnlm (Emgality), are all administered subcutaneously. Their side effects are generally mild, including pain and
redness at the site of injection, nasal congestion and constipation. Studies show that these mAbs reduce the number of headache days
by 50% or more in approximately 50% of patients. Sales for marketed and clinical-stage anti-CGRP therapeutics are projected to reach
approximately $7.4 billion by 2026. Despite the commercial success that this class represents, many of these treatments require frequent
administration, creating inconvenience for patients.
Our Product Candidate: UB-313
We are developing UB-313 as a prophylactic treatment initially for chronic migraine. We believe UB-313 has the potential to improve
upon the current treatments for chronic migraine in multiple aspects: we expect UB-313 will require administration quarterly to annually
in contrast to monthly to quarterly for currently marketed mAbs and frequent administration for small molecules. Furthermore, a
potential long durability of response may offer physicians and patients the option to administer UB-313 in an office setting, which can
potentially improve adherence. We expect the cost of UB-313 treatment, if approved, to be lower than that of mAbs for migraine.
Pre-Clinical Studies
We have completed both in vitro and in vivo pre-clinical studies of UB-313. We used an in vivo proof-of-concept capsaicin-induced
dermal blood flow model in mice to demonstrate target engagement of the marketed CGRP-targeting mAbs. In this model, we observed
similar rates in reduction of dermal blood flow as fremanezumab in a head-to-head comparison against fremanezumab.
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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
tested. Characterization of the antibodies produced after immunization with UB-313 indicated that they have limited, if any, off-target
potential, are primarily IgG1 and IgG2, potently bind to CGRP and potently block CGRP activity
in vitro
. We refer to potency as the
amount of drug required to produce a pharmacological effect of given intensity and is not a measure of therapeutic efficacy. In a
comparison of binding affinities with fremanezumab and galcanezumab, UB-313-induced IgG antibodies demonstrated comparable
binding affinities.
UB-313 Demonstrated Induced Antibodies Comparable to Approved CGRP mAbs
We evaluated UB-313 formulations with two different adjuvants in comparison to fremanezumab and galcanezumab; both formulations
demonstrated comparable IgG to these two approved CGRP mAbs.
Additional
in vitro
in vitro
activity to CGRP-targeted mAbs.
26
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.
UB-313 Induced IgGs Demonstrate Comparable Binding Potencies to Marketed CGRP mAbs
Antibodies taken from the serum of guinea pigs 15 weeks following the first injection of UB-313 demonstrated similar binding potencies
to two approved CGRP mAbs as measured by ELISA.
Development Strategy
We have identified a lead candidate and anticipate submitting a clinical trial application (“CTA”) or an IND in 2022. While we are
currently developing UB-313 as a potential treatment of chronic migraine, depending on successful clinical results, we may seek to
address episodic migraine and cluster headaches as well.
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PCSK9
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 central nervous system.
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 statins 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 $1.3 billion in 2020 and is expected to grow to approximately $5.2 billion
by 2026, including the addition of inclisiran to the market. In addition, both must be administered bi-weekly, 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 only twice annually, we believe that it may encounter
similar pricing challenges due to the published cost effectiveness price.
Our Hypercholesterolemia Program
We are developing an anti-PCSK9 product candidate to treat hypercholesterolemia. Our program is dedicated to developing a product
candidate that has long-acting treatment duration, which we believe will offer a more convenient treatment regimen of every six to 12
months compared to the up to bi-weekly dosing required by some mAbs. We believe that lower manufacturing costs commensurate with
the requirement of meaningfully less drug substance relative to mAbs, coupled with our ability to achieve commercial scale production
rapidly may promote expanded use of this drug class as a first-line therapy treating a greater number of hypercholesterolemia patients
than currently treated with mAbs.
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Pre-Clinical Studies
Pre-clinical studies of our anti-PCSK9 vaccine indicate that our product candidate generates therapeutic titer levels of anti-PCSK9
antibodies. These studies also indicate that it produces a high response rate among dosed animals. We achieved proof-of-concept in a
guinea pig model, reducing LDL cholesterol by more than 30% over the 15-week treatment duration, comparable to the reductions
observed with the use of anti-PCSK9 mAbs.
Anti-PCSK9 Product Candidate Reduces LDL by 30 to 50% Over 15 Weeks in Guinea Pigs (n=6)
Development Strategy
We plan to initiate IND-enabling studies of a lead anti-PCSK9 candidate in 2022.
Next Stage Development Candidates
In addition to our initial focus on migraines and hypercholesterolemia, we believe our Vaxxine Platform can generate product candidates
for a range of chronic diseases. We are evaluating opportunities across multiple disease areas, including allergy (e.g., chronic
rhinosinusitis, atopic dermatitis, food allergy), autoimmune (e.g., psoriasis, psoriatic arthritis), pain (e.g., peripheral neuropathy, diabetic
neuropathy) and bone and muscle deterioration (e.g., osteopenia, sarcopenia of aging) indications as they may apply to geriatrics and
space travel health.
COVID-19 Program
An Overview of COVID-19
COVID-19, caused by SARS-CoV-2, has rapidly swept throughout the world. The WHO declared COVID-19 a public health emergency
of international concern. As of February 22, 2022, there have been more than 420 million laboratory-confirmed COVID-19 patients and
more than 5.8 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. According to Our World in Data (ourworldindata.org),
as of March 2, 2022, approximately 87% of people in low-income countries have not received a single dose of a COVID-19 vaccine.
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.
More than twenty vaccines are authorized for use in one or more countries around the world, including three in the United States. 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,
29
including whole inactivated virus, defective adenovirus vectors (three different types) 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
Disparities in COVID-19 vaccine availability and distribution continue to grow despite the myriad of procurement efforts underway.
There exists a shortfall in the supply of COVID-19 vaccines globally for primary immunization, driven by supply constraints along with
substantial challenges around distribution, delivery and poor logistical capacity to administer doses. This primary immunization shortfall
is disproportionately pronounced in low- and middle-income countries (“LMICs”). We estimate that in order for these countries to
approach herd immunity (modeled at 70% vaccinated), there remains a shortfall of hundreds of millions of doses (excluding India and
China).
Furthermore, as knowledge of SARS-CoV-2 and its circulating variants (e.g., Omicron) and vaccination efforts grow, the need for
booster immunizations has become more apparent. We estimate that the size of the COVID-19 vaccine booster dose market globally in
2022 will exceed 1.5 billion doses. We expect the need for heterologous booster vaccines with low reactogenic profiles, broad variant
coverage, durable immunity and mechanisms of action different from presently authorized vaccines to continue through 2022.
UB-612: Our COVID-19 Vaccine Initiative
We are developing UB-612 as a product candidate for the prevention of COVID-19. 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 I and II without significant genetic restriction, so that they may be recognized by the entire
human population. Our mixture of peptides is designed to elicit T-cell activation, memory recall and effector functions similar to those
of natural COVID-19. 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, as compared to a designated adenovirus vectored vaccine, did not meet the TFDA’s specified
evaluation criteria but, in collaboration with UBIA, we are appealing the decision. We are now also pursuing paths to authorization for
UB-612 as a heterologous boost and have agreement with a high income regulator about our development approach.
Components of the UB-612 Multitope Vaccine Product Candidate
UB-612’s construct contains an S1-RBD-sFc fusion protein for the B-cell epitopes, plus five synthetic Th/CTL peptides for class I and
II MHC molecules derived from SARS-CoV-2 S2, M and N proteins, and the UBITh1a peptide. These components are formulated with
CpG1, which binds the positively charged (by design) peptides by dipolar interactions and also serves as an adjuvant, which is then
bound to Adju-Phos adjuvant to constitute the UB-612 product candidate.
Clinical Development
In March 2022, Vaxxinity initiated a Phase 3 pivotal study to compare the immune responses stimulated by mRNA (BNT162b2),
adenovirus (ChAdOx1-S), inactivated virus (Sinopharm BIBP) COVID-19 vaccines, and UB-612, when delivered as third dose boosters.
This is an active-controlled, randomized, multicenter study being conducted in several countries under a platform protocol which enrolls
subjects 16 years and older who completed a two-dose primary immunization with one or more of the vaccines mentioned above. Eligible
subjects will be randomized into one of two treatment arms to receive a single dose of UB-612 or an active comparator. The primary
objective of the study is to determine non-inferiority of UB-612-stimulated neutralizing antibodies against the comparator vaccines.
Additionally, Omicron neutralizing antibodies, non-neutralizing antibodies and T cell responses will be analyzed as part of secondary
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and exploratory objectives. We expect that, if successful, this study may enable conditional approval of UB-612 in multiple high income
countries and LMICs.
3-Dose Data: Phase 1 Extension Trial
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 adults in Taiwan. This trial consisted of three cohorts of 20 subjects each. The first cohort
received two intramuscular injections of 10μg doses of UB-612, the second cohort received two 30μg doses and the third cohort
received two 100μg doses. The first dose in each cohort was administered at the start of the trial, with the second dose administered
on day 28.
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).
After one and two doses in the Phase 1 trial, 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. We selected the highest dose (100μg) to take into the Phase
2 trial.
Similarly, in the Phase 1 extension trial, UB-612 was generally well tolerated after a third dose, with no vaccine-related SAEs
reported.
Local and Systemic Solicited Adverse Events Following 1, 2, and 3 Doses of UB-612 at Varying Dose Levels
Solicited adverse event data from Phase 1 and Phase 1 extension (n=50) suggests UB-612 is well tolerated after each of three doses
across varying dose levels.
Immunogenicity and safety data from the Phase 1 extension suggests that UB-612 elicits a multi-fold increase in neutralizing
antibody titers upon third dose, significantly exceeding those observed in human convalescent sera, and that the third dose is well
tolerated with no vaccine-related SAEs reported. Published studies have shown a correlation between efficacy in randomized
controlled trials and the ratio of neutralizing titers in sera from vaccinated subjects to titers in human
convalescent sera.
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UB-612 Neutralizing Antibodies Against Wuhan Strain of SARS-CoV-2
(GMT, WHO International Units)
UB-612 Phase 1 extension (n=50) demonstrated that a dose of 100μg UB-612 following three doses of various sizes of UB-612 elicits
a multi-fold increase in neutralizing antibody titers.
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.
IgG Binding to RBD by Variant of Concern after 2 and 3 Doses of UB-612
IgG binding titers against SARS-CoV-2 major variants of concern in sera collected 28 days after 2 doses and 14 days after 3 doses of
UB-612 (100µg) from Phase 1 trial participants (n=15). The loss of antibody bindings to RBD of variants compared with the original
RBD (Wuhan) remains stable between 2 doses and 3 doses of UB-612 vaccine, along with a high overall increase in levels of binding
antibodies to RBD.
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Third immunization with UB-612 Produces Neutralizing Antibodies Against Omicron
Phase 1 extension subjects (n=15) received primary series with UB-612 100µg. Serum is taken 28 days after the second dose and 14
days after the third booster immunization administered 7-9 months after the primary series. Live virus neutralization test against
Wuhan and Omicron are performed at VisMederi; results are expressed as virus neutralization antibody GMT ± 95% CI.
2-Dose Data: Phase 2 Trial
A randomized, placebo-controlled, multi-center Phase 2 trial of UB-612 in 3,850 healthy volunteers aged 12 to 85 is ongoing 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, but, in collaboration with UBIA, we are appealing that decision.
In data from over 3,750 subjects, UB-612 appears well tolerated, with no significant safety findings to date. AEs were generally
mild, and no related SAEs were observed. Local injection site AEs occurred in half of the subjects, the most frequent being injection
site pain. Systemic AEs occurred in less than half of the subjects, and the incidence was similar in the active and placebo groups,
except for muscle pain which was more frequent in the active group. Aside from muscle pain, systemic reactions were comparable
across the active and placebo groups, with less than 10% of subjects in either group experiencing fever or chills. Systemic AEs were
similar after the first and second doses. The vast majority of AEs were mild (Grade 1), and all were self-limited. No subject had a
severe (Grade 3) local reaction. The incidence of severe (Grade 3) systemic reactions was <0.1%.
The Phase 2 interim analysis suggests that Phase 1 observations on immunogenicity, neutralizing titers and tolerability are repeatable,
with an overall seroconversion rate of 94.7% one month after the second dose. In a live virus (Wuhan) neutralization test, sera collected
from UB-612 vaccinated younger adults (19-64 years, n=322), 28 days after the second dose (day 57) were estimated to reach geometric
mean titers (“GMT”) of 102 of 50% virus-neutralizing antibodies (VNT
50
).
Sera collected from a subset of subjects (n=48) 28 days after
the second immunization was shown to neutralize several SARS-CoV-2 variants, with the loss of neutralization activity against Delta
estimated at 1.39-fold when compared to the neutralizing antibodies against the parental Wuhan virus.
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Immunogenicity Results from Phase 2 & Phase 1 were Consistent:
Live Virus Neutralization Versus Convalescent Sera
Phase 1 (n=20 in 100μg dose group) and Phase 2 (n=322) sera (taken 28 days after the second dose) titer neutralizing activity, versus
a panel of human convalescent serum titers taken from patients hospitalized with COVID-19, as measured by a live virus neutralization
test, VNT50, shows that two doses of UB-612 may yield neutralizing antibodies comparable to those found in convalescent patients.
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.
UB-612 stimulates T-cell responses with predominately Th1 polarity
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Top panel: ELISPOT analysis of PBMCs collected on day 57 Phase 2 study. Bottom panels (A, B and C): ICS analysis of PBMCs
collected on day 57 Phase 2 study. Placebo (n=14) subjects without IgG ELISA, ACE2 and neutralizing antibody responses. UB-
612 n=86 subjects. Statistical analysis was performed using Mann-Whitney t test. (* p<0.05; ** p<0.01; ***p<0.001; ****
p<0.0001).
2-Dose Data: Phase 1 Trial
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 cohorts of 20 subjects
each. The first cohort received two intramuscular injections of 10μg doses of UB-612, the second cohort received two 30μg doses and
the third cohort received two 100μg doses. The first dose in each cohort was administered at the start of the trial, with the second dose
administered on day 28. The mean titer of antigen-specific antibodies to UB-612 and the seroconversion rate was be evaluated
throughout the six-month duration of the study 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 the 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 VNT50),
we observed neutralizing titers comparable to those in sera from patients hospitalized with COVID-19.
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Since September 2020, a number of genotypic variants of SARS-CoV-2 have emerged and contributed to epidemic spread in multiple
countries. Notable among these are the Alpha or B.1.1.7 (United Kingdom), Beta or B.1.351 (South Africa), Gamma or P.1 (Brazil) and
the Delta or B.1.617.2 variant (India) and Omicron (B.1.1.529). Some SARS-CoV-2 variants containing mutations in the S protein,
especially the N-terminal domain and the RBD, show reduced neutralization by antibody against the Wuhan strain, evidenced both in
persons naturally infected and in vaccinated individuals. The Beta (South Africa) and Omicron variants show the highest level of
resistance, with 13-fold to over 30-fold reduction in neutralization, respectively, and vaccines have shown reduced protection against
these variants.
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. These data align with observations taken from a cynomolgus macaque
study of UB-612 as well.
We measured viral-neutralizing antibody titers up to 154 days after the second dose (day 196) in the Phase 1 trial of UB-612; the level
of VNT50 antibodies remained at 52% of the maximum level observed following the second dose, on average. Based on the interim six-
month cutoff, the UB-612-specific neutralizing antibody half-life was estimated to be 195 days using an exponential model.
Time Course of SARS-CoV-2 Antibody Neutralization Responses after Vaccination
Data from a micro-neutralization assay of sera from subjects who received two 100μg doses of UB-612 yielded an estimated neutralizing
titer half-life of 195 days (CI: 136, 349) using an exponential model.
Pre-Clinical Study Results for UB-612
Initial work to select the S1-RBD-sFc antigen was performed in guinea pig immunogenicity studies, which demonstrated the superiority
of S1-RBD-sFc over other protein designs tested. Product candidate dose and formulation were explored in rat immunogenicity studies,
which allowed the selection of the current formulation of UB-612. Efficacy studies were carried out in mouse and nonhuman primate
models, in which UB-612 showed protective efficacy against live viral challenge. In a nonhuman primate model challenge study, we
observed full protection against SARS-CoV-2.
A GLP toxicology study in rats demonstrated an acceptable safety profile and enabled clinical testing of UB-612. In addition to these
studies, a Developmental and Reproductive Toxicity study yielded no significant findings.
Development Strategy
Based on UB-612 three-dose titer data from the Phase 1 extension, and 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 are pursuing accelerated pathways to
authorization with regulators in multiple jurisdictions,
including high income countries and LMICs based on a heterologous booster trial
of UB-612 beginning in the first half of 2022, with the first dose administered in the U.S. in the first quarter of 2022 under
FDA IND
clearance.
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COVID-19 Diagnostics Program
We have developed an ELISA test that can quickly detect antibodies in human sera or plasma to determine if a patient has had a SARS-
CoV-2 infection post fourteen days of onset. It employs synthetic peptides derived from the M, S and N proteins of SARS-CoV2 for the
detection of IgG antibodies to SARS-CoV2 in human sera or plasma. These synthetic peptides bind antibodies specific to highly
antigenic segments of SARS- CoV2 structural M, N and S proteins and constitute the solid phase antigenic immunosorbant. The FDA
issued an EUA for our ELISA test in January 2021. We are not actively pursuing commercialization of our ELISA tests at this time.
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.
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.
More than twenty COVID-19 vaccines are currently authorized for use in one or more countries around the world, including three in the
United States. All have been shown to be safe and effective in placebo-controlled clinical trials. All these vaccines are based on the S
protein of the SARS-CoV-2 virus, but rely on different mechanisms for presentation or expression of the S antigen, including whole,
inactivated virus, defective adenovirus vectors (three different types) or mRNA.
Neurodegenerative Disorders
We expect that, if approved, our product candidates will compete with the 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, Eli Lilly, Hoffman-LaRoche, Otsuka
Pharmaceuticals, Novartis and Biohaven Pharmaceuticals. 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. Regulatory approval of aducanumab is pending in Europe and Japan.
Pharmaceutical treatments for PD address its symptoms only and do not treat the underlying causes of PD. The majority of prescription
drugs are dopaminergic medications and act by increasing dopamine, a neurotransmitter. We are aware of several companies with
product candidates at various stages of clinical development, including Sanofi, Kyowa Kirin, Cerevel Therapeutics and Hoffman
LaRoche. Hoffman LaRoche is developing prasinezumab, a mAb, as a potential treatment for PD.
CGRP-Directed Migraine Treatments
Six migraine treatments have been approved by the FDA that target CGRP. Four of these therapeutics are mAbs and were approved to
prevent or reduce the number of migraine episodes. These medications are galcanezumab (Emgality), which was developed by Lilly;
erenumabb (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 (Ubvelvy), developed by
Allergan, was approved for the treatment of acute migraine episodes; rimegepant (Nurtec), also approved for the treatment of acute
migraine, is sold by Biohaven.
PCSK-9 Inhibitors
Two companies currently have PCSK-9 inhibitors approved by the FDA to treat hypercholesterolemia. Both are mAbs. Regeneron
Pharmaceuticals developed alirocumab (Praluent), in collaboration with Sanofi, and Amgen developed evolocumab (Repatha). The
Medicines Company, a subsidiary of Novartis, is developing inclisiran, an RNAi construct, to down-regulate synthesis of PCSK-9.
Inclisiran was approved by the EMA in December 2020.
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Collaborations
From time to time, we may enter into licensing and commercialization agreements when they align with our mission, including the
Platform License Agreement described under “—Intellectual Property—Platform License Agreement” and the agreement with our
partner Aurobindo.
Aurobindo License Agreement
In December 2020, we entered into an exclusive license agreement with Aurobindo (as amended, the “Aurobindo Agreement”) to
develop and commercialize UB-612 to India and other territories. Pursuant to the Aurobindo Agreement, we granted Aurobindo an
exclusive license (with certain rights reserved to us) to develop, manufacture and commercialize UB-612 in India and other countries
through UNICEF and a non-exclusive license to develop, manufacture and commercialize UB-612 in other selected emerging and
developing markets.
The Aurobindo Agreement may be terminated (i) by Aurobindo, without cause at any time after three years following the effective date
or prior to such time if UB-612 fails to meet clinical end-points or fails in development, (ii) by us, (a) if Aurobindo disputes the
patentability, enforceability or validity of our patent rights related to the UB-612 technology, (b) in case of a suit alleging Aurobindo’s
use of the licensed intellectual property infringes a third party’s intellectual property rights if we reasonably believe the license is no
longer commercially reasonable in light of such claim or (c) without cause at any time after four years following the effective date, (iii)
by either party in the event of the other party’s material breach of its obligations under the Aurobindo Agreement (subject to a cure
period) or (iv) by either party in the event of the other party’s insolvency.
Manufacturing
The manufacture of our product candidates encompasses both the manufacture of custom components and the formulation, fill and finish
of the final product. We do not currently own or operate manufacturing facilities for these processes. We currently rely upon contract
manufacturing organizations, including those mentioned below, to produce our product candidates for both pre-clinical and clinical use
and will continue to rely upon these relationships for commercial manufacturing if any of our product candidates obtain regulatory
approval. Although we rely upon contract manufacturers, we also have personnel with extensive manufacturing experience that can
oversee the relationships with our manufacturing partners.
Historically, we have depended heavily on UBI and its affiliates for our business operations, including the provision of research,
development and manufacturing services. Currently, UBIA provides testing services for UB-312 and UB-612, UBI Pharma Inc.
(“UBIP”) provides testing relating to formulation-fill-finish services for UB-312, and United BioPharma, Inc. (“UBP”) is the sole
manufacturer of protein for UB-612. Our commercial arrangements with UBI and its affiliates are described in more detail below.
Formulation-fill-finish services for UB-612 are provided by multiple contract manufacturers to ensure adequate capacity and minimize
supply chain risks. For supply of our other custom components, in addition to protein manufacturing conducted by UBP, we have
engaged third party CMOs, including C S Bio Co. (“CSBio”) as our primary peptide supplier for UB-612 peptides and Wuxi STA for
process development and manufacturing services of oligonucleotides.
UBI Group Manufacturing Partnership
We primarily rely on our relationships with third-party contract manufacturing organizations to produce product candidates for our
clinical trials. Historically, we have heavily depended on UBI as a manufacturing partner for these efforts. In support of our COVID-19
program (UB-612), we have entered into a master services agreement with UBP and an additional master services agreement with UBI,
UBIA and UBP. Pursuant to these agreements, UBI and its affiliates have provided research, development, testing and manufacturing
services to us and continue to provide manufacturing services for our protein. Payment terms are mutually agreed in connection with
each work order relating to services rendered. Our agreement with UBP will expire on the later of March 2024 and the completion of
all services under the last work order executed prior to such scheduled expiration and our agreement with UBI, UBIA and UBP will
expire on the later of September 2023 and the completion of all services under the last work order executed prior to such scheduled
expiration. We also have a management services agreement with UBI pursuant to which UBI has provided research and prior back office
administrative services to us and acts as our agent with respect to certain matters relating our COVID-19 program. UBI is compensated
for its services on a cost-plus basis. The agreement terminates upon mutual agreement between the parties.
In support of our chronic disease pipeline, we have entered into master service agreements with each of UBI, UBIA and UBIP. Pursuant
to these agreements, UBI currently provides limited research services to us on a cost-plus basis, UBIA provides testing services related
to UB-312 clinical trial material already manufactured and UBIP has provided manufacturing, quality control, testing, validation, GMP
warehousing and supply services to us for UB-312 on payment terms agreed in connection with work orders relating to the services
rendered. UBI and its affiliates no longer provide clinical or manufacturing services for other programs. These agreements may all be
terminated for convenience upon 180 days’ notice or less.
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We have also entered into a research and development services agreement with UBI. Pursuant to this agreement, UBI and its affiliates
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 will be determined by a joint steering committee and set forth in a research and
development plan. The aggregate services fees payable by us under the research and development services agreement are subject to a
quarterly cap throughout the term of the agreement. The research and development services agreement expires in August 2026.
Intellectual Property
Our ability to obtain and maintain intellectual property protection for our product candidates and core technologies is fundamental to
the long-term success of our business. We rely on a combination of intellectual property protection strategies, including patents,
trademarks, trade secrets, license agreements, confidentiality policies and procedures, nondisclosure agreements, invention assignment
agreements and technical measures designed to protect the intellectual property and commercially valuable confidential information and
data used in our business.
In summary, our patent estate includes issued patents and patent applications which claims cover our Vaxxine Platform and each of our
product candidates. As of December 31, 2021, our patent estate included ten U.S. issued patents, twelve U.S. patent applications, three
U.S. provisional patent applications, four pending Patent Cooperation Treaty (“PCT”) patent applications, 98 issued non-U.S. patents
and 194 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, patent rights are provided by patents and patent applications, the majority of which are being prosecuted in the United States,
Australia, Brazil, Canada, China, the EPO, Hong Kong, Indonesia, India, Israel, Japan, the Republic of Korea, Mexico, Russia,
Singapore, South Africa, Taiwan and the United Arab Emirates directed to peptide vaccines for the prevention and treatment of
neurodegenerative diseases. These issued patents and patent applications, if issued, are expected to expire between 2022 and 2039,
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 may be provided by a patent family being prosecuted in the United States, Australia, Brazil,
Canada, China, India, Indonesia, Japan, Mexico, Russia, the Republic of Korea, Singapore, Taiwan and the United Arab Emirates. These
patent applications, if issued, are expected to expire in 2039, excluding any patent term adjustments or patent term extensions.
For our product candidates targeting cholesterol and cardiovascular disease, including our anti-PCSK9 product candidate targeting
PCSK9 and formulations thereof for prevention and treatment of PCSK9-mediated disorders, we are in the process of acquiring a
pending patent application in Taiwan and a pending PCT patent application. This Taiwanese patent application, if issued, and any U.S.
or non-U.S. patent issuing from this PCT patent application, if such patent is issued, is expected to expire in 2041, excluding any patent
term adjustment or patent term extension.
For our product candidates targeting SARS-CoV-2, including UB-612 for COVID-19, we have pending patent applications in Brazil,
Pakistan and Taiwan, one pending PCT patent application and three provisional patent applications in the United States. These patent
applications, if issued, and any U.S. or non-U.S. patent issuing from this PCT or provisional patent application, are expected to expire
between 2041 and 2042, excluding any patent term adjustments or patent term extensions.
For each product candidate utilizing the Vaxxine platform, additional patent rights directed to artificial T helper cell epitopes and to a
CpG delivery system are provided by patents and patent applications, the majority of which are being prosecuted in the United States,
Australia, Austria, Belgium, Brazil, Canada, Chile, China, Colombia, Denmark, the EPO, France, Germany, Hong Kong, Indonesia,
India, Ireland, Israel, Italy, Japan, Mexico, the Netherlands, New Zealand, Peru, Philippines, the Republic of Korea, Russia, Singapore,
South Africa, Spain, Sweden, Switzerland/Liechtenstein, Taiwan, Thailand, the United Arab Emirates, the United Kingdom and
Vietnam. These issued patents and patent applications, if issued, are expected to expire between 2023 and 2039, excluding any patent
term adjustments or patent term extensions.
The term of individual patents depends on the countries in which they are obtained. The patent term is 20 years from the earliest effective
filing date of a non-provisional patent application in most of the countries in which we file, including the United States. In the United
States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the
USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent. The
term of a patent that covers a drug or biological product may also be eligible for patent term extension when FDA approval is granted
for a portion of the term effectively lost as a result of the FDA regulatory review period, subject to certain limitations and provided
statutory and regulatory requirements are met.
In addition to our reliance on patent protection for our inventions, products and technologies, we also seek to protect our brand through
the procurement of trademark rights. We own registered trademarks and pending trademark applications for our brands, including our
“Vaxxinity”, “United Neuroscience” and “COVAXX” brands and other related names and logos, in the United States and certain foreign
jurisdictions.
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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 inclusde 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.
Coverage and Reimbursement
Sales of our product candidates in the United States will depend, in part, on the extent to which third- party payors, including government
health programs such as Medicare and Medicaid, commercial insurance and managed health care organizations provide coverage and
establish adequate reimbursement levels for such product candidates. The process for determining whether a third-party payor will
provide coverage for a pharmaceutical or biological product is typically separate from the process for setting the price of such a product
or for establishing the reimbursement rate that the payor will pay for the product once coverage is approved, and we may also need to
provide discounts to purchasers, private health plans or government healthcare programs, as increasingly, third-party payors are
requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for
medical products. As a result, a third-party payor’s decision to provide coverage for a pharmaceutical or biological product does not
imply that the reimbursement rate will be adequate for commercial viability, and inadequate reimbursement rates, including significant
patient cost sharing obligations, may deter patients from selecting our product candidates. Obtaining coverage and reimbursement
approval of a product from a third-party payor is a time-consuming and costly process that could require us to provide to each payor
supporting scientific, clinical and cost-effectiveness data for the use of our product on a payor-by-payor basis, with no assurance that
coverage and adequate reimbursement will be obtained. Third-party payors may limit coverage to specific products on an approved list,
also known as a formulary, which might not include all of the approved products for a particular indication.
Further, no uniform policy for coverage and reimbursement exists in the United States, and coverage and reimbursement can differ
significantly from payor to payor. In general, factors a payor considers in determining coverage and reimbursement are based on whether
the product is a covered benefit under its health plan; safe, effective, and medically necessary, including its regulatory approval status;
medically appropriate for the specific patient; cost-effective; and neither experimental nor investigational. Third-party payors often rely
upon Medicare coverage policy and payment limitations in setting their own reimbursement rates, but also have their own methods and
approval process apart from Medicare determinations. As such, one third-party payor’s decision to cover a particular medical product
or service does not ensure that other payors will also provide coverage for the medical product or service, and the level of coverage and
reimbursement can differ significantly from payor to payor. Even if favorable coverage and reimbursement status is attained for one or
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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. 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 GLP or 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 regulations commonly referred to
as GCPs to establish the safety and efficacy of the proposed drug for its intended use;
• 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 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. Clinical trials
must be conducted in accordance with the FDA’s regulations comprising the good clinical practices requirements. Further, each clinical
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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
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 animal studies and must also develop additional information
about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial
quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches
of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final
drug. 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 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
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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 REMS
is necessary to assure the safe use of the drug. 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. 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. The
FDA will issue a complete response letter if the agency decides not to approve the NDA or BLA. 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 in a condition for approval. If a complete
response letter is issued, the applicant may either submit new information, addressing al