Item 1A Risk Factors 40
Item 1B Unresolved Staff Comments 80
Item 1C Cybersecurity 80
Item 2 Properties 81
Item 3 Legal Proceedings 81
Item 4 Mine Safety Disclosures 81
PART II
Item 6 [Reserved] 82
Item 7A Quantitative and Qualitative Disclosures About Market Risk 94
Item 8 Financial Statements and Supplementary Data 94
Item 9A Controls and Procedures 94
Item 9B Other Information 95
Item 9C Disclosure Regarding Foreign Jurisdictions that Prevent Inspection 95
PART III
Item 10 Directors, Executive Officers, and Corporate Governance 96
Item 11 Executive Compensation 96
Item 14 Principal Accounting Fees and Services 96
PART IV
Item 15 Exhibits and Financial Statement Schedule 97
SPECIAL
NOTE REGARDING FORWARD-LOOKING STATEMENTS
This
Annual Report on Form 10-K (this “Annual Report”) contains statements that constitute “forward-looking statements”
for purposes of the federal securities laws. Forward-looking statements include, but are not limited to, statements that discuss future
events, hopes, expectations, beliefs, intentions, or strategies regarding the future, projections of results of operations or financial
condition, changes in the markets in which we compete, and trends in our business. In addition, any statements that refer to projections,
forecasts, or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking statements.
The words “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,”
“expect,” “intends,” “may,” “might,” “plan,” “possible,” “potential,”
“predict,” “project,” “should,” “will,” “would,” and similar expressions
or their opposites may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking.
Forward-looking statements in this Annual Report may include, for example, statements about:
● the anticipated benefits of ExacTcell;
● our expectations regarding our future clinical trials;
● our manufacturing plans;
● our ability to generate revenue in the future;
● expectations regarding the healthcare and biopharmaceutical industries;
● the potential liquidity and trading of our securities;
● the future business, operations, and financial performance of our Company.
The
forward-looking statements contained in this Annual Report are based on management’s current expectations, assumptions, and beliefs
concerning future developments and their potential effects on us. There can be no assurance that future developments affecting us will
be those that we have anticipated. These forward-looking statements involve a number of risks, uncertainties (some of which are beyond
our control), or other assumptions that may cause actual results or performance to be materially different from those expressed or implied
by these forward-looking statements. These risks and uncertainties include, but are not limited to, the factors set forth below in “Summary
of Risk Factors.”
Forward-looking
statements should be considered in light of these factors and the factors described elsewhere in this Annual Report, including in the
sections titled “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of
Operations.” You should read these factors and the other cautionary statements made in this Annual Report as being applicable to
all related forward-looking statements wherever they appear in this Annual Report. It is not possible to predict or identity all such
risks. We undertake no obligation to update or revise any forward-looking statements, whether as a result of new information, future
events, or otherwise, except as may be required under applicable law.
Unless
the context otherwise requires or unless stated otherwise, references to “Tevogen”, “we,” “us,” “our,”
“the Company” and “our Company” refer to Tevogen Bio Holdings Inc. and its consolidated subsidiary.
SUMMARY
OF RISK FACTORS
We
are subject to a variety of risks and uncertainties, including risks that could have a material adverse effect on our business, financial
condition, results of operations, and cash flows. The following summary of the principal factors that make an investment in our securities
speculative or risky should not be relied upon as an exhaustive summary of the material risks facing us. You should read the following
summary together with the more detailed description of risks under “Risk Factors” in Part I, Item 1A of this Annual Report
and the other information contained in this Annual Report before investing in our securities. Capitalized terms not otherwise defined
below have been defined elsewhere in this Annual Report.
Risks
Related to Our Financial Position and Need for Additional Capital
Risks
Related to Development, Regulatory Review, and Product Approval
● The FDA regulatory approval process is lengthy and time-consuming.
● Our business is highly dependent on our first product candidate, TVGN 489.
● ExacTcell is unproven and may not result in marketable products.
● We may encounter difficulties enrolling patients in our clinical trials.
Risks
Related to Business Development and Commercialization
● Regulated biologics may be subject to biosimilar competition.
● We may be unable to establish sales and marketing capabilities.
● Computer systems may fail or suffer security breaches.
Risks
Related to Manufacturing and Reliance on Third Parties
Risks
Related to Intellectual Property
● Changes in patent law could diminish the value of patents in general.
● Our trademarks and trade names may be inadequately protected.
● Intellectual property rights do not necessarily address all potential threats.
Risks
Related to Our Business
● We are highly dependent on our key personnel.
● We may face substantial competition.
● We will need to grow the size of our organization.
● We may be limited in our ability to use our net operating loss carryforwards.
Risks
Related to Being a Public Company and Ownership of Securities
● We are an “emerging growth company” and a “smaller reporting company”.
● Our management team has limited experience managing a public company.
● We could become subject to securities litigation or stockholder activism.
● Certain individuals have substantial control over us.
PART
I
Item
1. Business.
Overview
We
are a clinical-stage specialty immunotherapy company harnessing one of nature’s most powerful immunological weapons, CD8+ cytotoxic
T lymphocytes (“CTLs”), to develop off-the-shelf, precision T cell therapies for the treatment of infectious diseases, cancers,
and other disorders, with the aim of addressing the significant unmet needs of large patient populations. We believe that sustainability
and commercial success in the forthcoming era of medicine will rely on ensuring patient accessibility through advanced science, innovative
business models and engagement throughout various stages of the drug development and commercialization lifecycle. We believe the full
potential of T cell therapies remains largely untapped, and aspire to be the first biotechnology company offering commercially attractive,
economically viable, and cost-effective personalized T cell therapies.
We
believe our precision T cell technology, ExacTcellTM, represents a significant scientific breakthrough with the potential
to mainstream cell therapy with a new class of off-the-shelf – pre-manufactured and ready-to-use – allogeneic T cell
therapies with diverse applications across virology, oncology, and other areas. Allogeneic therapeutics are intended to be infused
into individuals other than the original donor. ExacTcell is a set of processes and methodologies to develop, enrich, and expand
single human leukocyte antigen (“HLA”) restricted CTL therapies with proactively selected, precisely defined targets.
HLA molecules are proteins that play an important role in the immune system’s ability to recognize “self” versus
“foreign.” There are numerous HLA types that vary from person to person. CD8+ CTLs, also known as killer T cells, are
white blood cells that are part of the immune system and destroy infected, malignant, or otherwise damaged cells.
ExacTcell
therapies are based on carefully selected, naturally occurring CTLs that are designed to recognize targets of interest from the body’s
native T cell receptor pool, unlike genetically engineered T cell therapies. CD8+ CTLs in ExacTcell-based products target multiple and
distinct antigens, with the aim to circumvent the impact of mutations in viruses and virally driven as well as sporadic cancer cells,
which can render existing treatments focused on a single target ineffective. ExacTcell is designed to maximize the immunologic specificity
of our products in order to eliminate malignant and virally infected cells while allowing healthy cells to remain intact. We believe
this high degree of specificity has the potential to significantly reduce the chances of cross-reactivity or adverse impact on healthy
cells. Our confidence in ExacTcell is reflected in our development pipeline, which has been carefully tailored to address the unmet needs
of patient populations grappling with life-threatening viral diseases, cancers, and other disorders.
The
first clinical product of ExacTcell, TVGN 489, is initially being developed to fill a critical gap in COVID-19 therapeutics for the immunocompromised
and the high-risk elderly, with potential applications in both treatment and prevention of chronic, lingering symptoms of the disease
(“Long COVID”). Viruses, including COVID-19, hijack cellular machinery to transform infected cells into virus production
plants. Elimination of infected cells is necessary to allow them to be replaced by healthy, uninfected counterparts. TVGN 489 consists
of CTLs designed to be active against multiple precise, well defined, and well characterized targets spread across the SARS-CoV-2 genome.
The product progressed from pre-discovery to the clinic in less than 18 months, and in January 2023, we completed the Phase 1 proof-of-concept
clinical trial of TVGN 489 for the treatment of ambulatory, high-risk adult COVID-19 patients. No dose-limiting toxicities or significant
treatment-related adverse events were observed in the treatment arm. Secondary endpoints showed a rapid reduction of viral load and that
infusion of TVGN 489 did not prevent the development of the patients’ own T cell-related (cellular) or antibody-related (humoral)
anti-COVID-19 immunity. None of the treated patients reported progression of infection, reinfection, or the development of Long COVID
during the six-month follow-up period. These clinical observations were mirrored by laboratory evidence of the persistence of TVGN 489
cells for at least six months after treatment. The results of the trial were published in Blood Advances in June 2024 following
peer review. We believe these findings validate our initiative to develop off-the-shelf T cell therapies for outpatient administration,
targeting diseases that affect large patient populations - for the very first time. We are planning a pivotal trial of TVGN 489 in COVID-19
patients with B cell malignancies, with studies of other highly vulnerable populations thereafter. TVGN 489 is also in development for
treatment and prevention of Long COVID based on evidence of a persistent viral reservoir in Long COVID patients.
Our
Pipeline
We
are leveraging our understanding of immunotherapy and our ExacTcell technology to discover, validate, and build a proprietary pipeline
of T cell therapies with diverse targets in infectious disease, cancer, and other disorders. The figure below details our pipeline of
product candidates and their targets:
Our
Strategy
Our
goal is to have a positive impact on patients’ health and treatment equity by developing and commercializing personalized cell
therapies to treat infectious disease, cancer, and other diseases. Our strategy is to target large or underserved patient populations
for each pipeline product. Key elements of our strategy to advance toward this goal include the following:
We
believe that positive data from studies and clinical trials can help pave the way for positive regulatory discussions, strategic partnerships,
and future label expansions, furthering our ability to meet our goal.
Our
ExacTcell Technology
Our
ExacTcell technology and our therapies harness one of nature’s own approaches to eradicating cancer and other diseases: the cytotoxic
or killer T cell. We believe that our patented ExacTcell precision allogeneic T cell development technology has the potential to be a
broadly applicable approach for developing convenient and reasonably priced cellular immunotherapies for the treatment of acute viral
infections, long-term consequences of viral infections such as Long COVID, viral- and non-viral-induced cancers, and other disorders.
Although our initial product development has been in the area of infectious disease, we believe our technology also holds promise for
applications in cancers and autoimmune diseases, which would increase our total addressable market. We also believe that ExacTcell can
enable us to deliver products faster, at a greater scale, and at lower cost than future competing cell therapies, if any.
ExacTcell
focuses on the selection and expansion of naturally occurring, genetically unmodified CD8+ CTLs to target multiple, distinct, preselected
antigenic peptides present only on virus-infected or malignant cells and to kill those cells. We believe that by relying on CD8+ CTLs,
ExacTcell has the potential to produce an entirely new class of drugs that could present numerous benefits over existing platforms. In
contrast to other approaches, ExacTcell enables a single, specific HLA molecule to be targeted in a clinical product and the specific
target peptides to be known with certainty and precision. HLA molecules are proteins present on the cell surface that play an important
role in the immune system’s ability to recognize “self” versus “foreign.” Specifically, HLA molecules present
foreign antigens to T cells for eradication. There are numerous HLA types that vary from person to person.
Killer
T cells are white blood cells that play a vital role in the immune system’s defense against diseases, including viruses and cancer.
CTLs, including those developed with ExacTcell, express T cell receptors (“TCRs”), which are surface proteins that provide
each T cell with its unique immune specificity to recognize and react against specific foreign antigenic peptides of infected or malignant
cells. These foreign antigenic peptides are presented in conjunction with an HLA molecule. The CTLs destroy their infected or malignant
cell targets by inducing them to undergo apoptosis, or programmed cell death, by releasing cytolytic granules that produce pores in the
target cell’s membrane. CTLs also possess a protein that spans the entirety of the cell membrane, known as Cluster Differentiation
8 (which makes them CD8+), that aids in the reaction. CD8+ T cells work in conjunction with HLA-class I molecules, and CD4+ T cells work
in conjunction with HLA-class II molecules.
Currently
available allogeneic cell-based immunotherapy approaches include genetically unmodified T cells applied to the treatment of viruses early
after transplant and genetically modified chimeric antigen receptor (“CAR”) T cells used to treat a selected subset of malignancies.
We believe that to date, cellular therapy has not been harnessed to its full potential for clinical application. We believe that our
proprietary approach will allow T cell products to be generated with a much higher target-specific CD8+ content and better-defined target
specificity than existing commercially available approaches. Contrasted with our approach, the genetically unmodified T cells used after
hematopoietic stem cell transplantation for the treatment of viral infections have used large viral proteins, pools of peptides, or infected
cells to stimulate CTLs. These broader targets may stimulate both CD4+ and CD8+ T cell responses, resulting in more heterogeneous T cell
products with little information regarding the specific peptide targets recognized by the T cells. By stimulating with only carefully
selected smaller peptides that are known to bind to a single HLA-class I molecule and to be recognized by CTLs, our approach elicits
a high degree of target-specific CD8+ responses, which we believe may result in improved outcomes as compared to these other approaches.
Knowing the specific peptide targets also allows rapid identification of the impact of mutations on our CTL products. Having multiple
targets within a product also blunts the impact of any one mutation.
Due
to the targeted nature of the cells ExacTcell can produce, we also believe we may be able to avoid some of the unwanted corollary effects
observed in other T cell immunotherapies. For example, we believe products developed through ExacTcell could potentially avoid the high
incidence of adverse events, some life-threatening, such as cytokine release syndrome and neurotoxicity, that have been observed with
autologous and allogeneic CAR-T platforms. Data from our Phase 1 trial strongly supports this belief. Autologous cell therapies are derived
from a donor’s own cells, as contrasted with allogenic therapies such as ours, where cells are from third party donors.
In
order to select candidate peptides for ExacTcell products, we rely on computer-facilitated prediction of the ability of specific peptide
candidates to bind to specific HLA molecules. Once candidates are selected and used to stimulate T cells in the laboratory, we use tetramer
staining to assess whether T cells recognize the target peptides and assess cytotoxicity against individual peptide-pulsed and non-pulsed
targets. This allows us to rapidly and proactively select multiple, precise, candidate T cell targets and then quickly experimentally
confirm their effectiveness. Through our Tevogen.AI artificial intelligence initiative, we are exploring ways to deploy artificial intelligence-powered
target detection to accelerate our product development pace, either internally or in collaboration with leading entities in the field
of artificial intelligence, such as through our enrollment in the Microsoft for Startups program and use of Microsoft Azure.
As
illustrated in the figure below, we begin the ExacTcell process by collecting cells from a healthy donor. T cells from the donor are
exposed to the preselected targeted peptides and through a repetitive process of selection and expansion. CD8+ CTLs specific for the
targeted, antigenic peptides become the major cellular component of the final product. The expansion of the antigen-specific CTLs is
extensive enough to produce over 100, and up to hundreds, of doses from a single donor. Those doses can then be used to treat hundreds
of patients who share the same HLA type.
ExacTcell
stands in contrast with both autologous and allogeneic CAR-T platforms, which target antigens present on both healthy and diseased cells
and require genetic modification of the T cells. In autologous CAR-T approaches, the quantity and health of desired T cells in patient
blood samples used to manufacture the CAR-T product have been among the largest obstacles for T cell therapies to date. Much of this
is due to the chemotherapy treatments the patients have already received. Some existing CAR-T therapies may take weeks to manufacture,
may require patients to receive pre-infusion lymphodepleting (i.e., immunosuppressing) chemotherapy as part of a lengthy preparation
process, and be hospitalized in many cases during the CAR-T cell infusion or afterwards due to the frequency of side effects from the
therapy such as cytokine release syndrome. These treatments may also require lifelong monitoring for the development and treatment of
infections due to eradication of normal parts of the immune system along with the cancer.
In
November 2023, FDA announced that it had “received reports of T-cell malignancies” in patients who received certain CAR T
cell immunotherapies. In January 2024, FDA required a class-wide black box warning be added to the label of these CAR T products regarding
this risk, and continues to recommend long-term monitoring. Currently approved autologous CAR-T platforms utilize the patient’s
own T cells to manufacture their products. These cells have previously been exposed to cancer therapy and are genetically altered and
subsequently expanded.
In
contrast, CTLs generated using the ExacTcell technology come from a healthy donor with a normal immune system. ExacTcell CTLs are not
genetically altered in the manufacturing process and although they expand during manufacture, this is the expected response of a T-lymphocyte
when encountering its target antigen. Moreover, in contrast to CAR-T cell products, secondary malignancies have not been described in
the unmodified T cell products given to hundreds of post-transplant patients. Although products from our ExacTcell technology are not
designed to be genetically modified, they are still in the early stages of testing, and only limited human and laboratory study data
are available regarding the risk profiles of our products. Allogeneic CAR-T approaches are in early-stage development, but concerns exist
regarding side effects similar to autologous CAR-T, and additionally, the development of graft versus host disease with allogeneic CAR-T
products, both of which we believe will be of lower risk with our technology.
Hundreds
of doses per donor can be obtained using the ExacTcell approach, which is expected to facilitate off-the-shelf use and the ability to
administer doses within hours of diagnosis when rapid therapeutic intervention is crucial. Use of TVGN 489, for example, is expected
to begin with a confirmatory COVID-19 test and rapid HLA typing for which results would be available in six to eight hours, allowing
selection of the proper product based on HLA type. After confirmation of HLA type, thawing takes minutes, and cells are infused within
ten minutes of thawing.
The
convenience of “off-the-shelf” – pre-manufactured and ready-to-use - therapy has the potential to offer timely and
cost-efficient therapeutics by potentially eliminating the need for specialized medical facilities, unlike existing platforms. By producing
products in which the active CD8+ T cell components are present at high concentrations, we believe relatively small volumes will be required,
allowing our therapies to be easily and promptly delivered in the ambulatory setting as a very brief intravenous administration such
as in a physician’s office.
We
are working to further advance ExacTcell with a new, proprietary T cell receptor-engineered process, which we believe may substantially
increase the number of doses that can be produced from a single donor. Available technology can be used to allow us to interrogate over
a thousand individual T cells to determine which one kills peptide-pulsed targets fastest or kills the most in a given timeframe. This
highest performing T cell can then be isolated, and its T cell receptor sequenced, allowing us to make an artificial TCR gene that can
be introduced into CD8+ T cells collected from healthy donors. We believe this could allow at least a several-fold increase in the number
of desired CTLs as compared to our current approach. We expect efforts to produce second generation products based on this process may
begin shortly after and if initial regulatory approval of the first-generation product is obtained.
Our
First Product Candidate
Our
first product candidate, TVGN 489, is an off-the-shelf, allogeneic cytotoxic CD8+ T cell therapy designed to fill a critical remaining
gap in COVID-19 therapeutic solutions for the immunocompromised and the high-risk elderly, who remain at substantial risk for poor outcomes,
with potential applications in both treatment and prevention of Long COVID. Treatment for these groups represents an area of unmet or
incompletely met need which we believe TVGN 489 can significantly address. We rapidly progressed TVGN 489 from pre-discovery to the clinic
in only 18 months. TVGN 489 cells are derived from healthy donors who recovered from a prior COVID-19 infection, and TVGN 489 is active
against multiple, precise targets spread across the SARS-CoV-2 genome.
In
January 2023, we completed a Phase 1 proof-of-concept trial of TVGN 489 for the treatment of ambulatory high-risk adult COVID-19 patients.
No dose-limiting toxicities or significant TVGN 489-related adverse events were observed in this trial at any of the four dosing levels
tested. Secondary endpoint analysis showed a rapid reduction in COVID-19 viral load and that the infusion of TVGN 489 did not prevent
the development of the patient’s own T cell-related (cellular) and antibody-related (humoral) anti-COVID-19 immunity. In addition,
none of the patients in the treatment arm reported progression of infection, reinfection, or the development of Long COVID during the
six-month follow-up period. Two patients on this trial were admitted for autologous and allogeneic hematopoietic stem cell transplantation
within one month of treatment with TVGN 489, and neither patient developed evidence of recurrent COVID-19 despite the significant immunocompromised
state related to transplantation. The TVGN 489 in the Phase 1 trial was formulated to match patients expressing HLA-A*02:01, the most
common HLA type in the population.
We
believe that TVGN 489 targets are less susceptible to viral mutations due to their small size than monoclonal antibody targets and less
susceptible to drug resistance than antivirals. As evidence of this, despite selection of T cell targets in 2020, more than 95% of the
targets for the HLA-A*02:01 TVGN 489 product targets have remained intact through March 2026. In contrast, most monoclonal
antibodies were withdrawn from the market for lack of efficacy related to the lack of recognition of new variants, providing what we
believe to be evidence of decreased susceptibility of TVGN 489 to viral mutation. In addition, knowing the precise peptide targets of
our therapy helps allow rapid assessment regarding their preservation or loss as soon as new variants are sequenced. We check emerging
COVID-19 variants against TVGN 489 targets on an ongoing basis.
COVID-19
Background
COVID-19,
caused by the SARS-CoV-2 virus, has killed millions and infected hundreds of millions since its emergence in late 2019. Groups most at
risk for poor outcomes due to COVID-19 are immunocompromised individuals unable to mount an adequate immune response, such as those with
immune system cancers, immunodeficiency disorders, transplant recipients, patients with immune-mediated disorders requiring immunosuppressive
therapy, or high doses of corticosteroids, the elderly and the unvaccinated. Data shows that the majority of COVID-19 deaths occur in
people over the age of 65. The risk of severe illness from COVID-19 for an individual tends to escalate with an increase in their number
of underlying medical conditions. In addition to the acute impacts of infection, a significant portion of those who have been infected
by COVID-19 in the past develop more chronic and potentially debilitating symptoms afterwards, a condition termed Long COVID. Despite
the availability of vaccines and emergence of initial therapeutics, significant gaps and shortcomings in treatment remain both for vulnerable
patients experiencing an acute infection and for Long Covid sufferers for whom there are no treatment options approved for the indication
or its underlying causes.
Like
other viruses that have RNA as their genetic material, SARS-CoV-2 is constantly evolving through random mutations. New mutations can
potentially increase or decrease infectiousness and virulence. In addition, mutations can increase the virus’ ability to evade
adaptive immune responses from past SARS-CoV-2 infection or vaccination. New variants of the SARS-CoV-2 virus continue to emerge, and
many people continue to be adversely affected by COVID-19, particularly those at the highest risk and sufferers of Long COVID. Moreover,
a growing body of scientific data suggests new immune-evasive variants are more likely to arise in immunocompromised patients because
they are less able to eradicate the virus. The longer duration of infection within the host affords the virus more opportunity to mutate
so as to evade the immune system. The potential rise of immune-evasive variants in immunocompromised patients provides a public health
rationale for the treatment of immunocompromised patients in order to more rapidly and aggressively eliminate the virus and avoid generation
of new variants.
A
large number of Americans remain highly vulnerable to COVID-19 infection, including immunocompromised and elderly patients. For example,
the rate of hospitalization in cancer patients with COVID-19 infection remains high, specifically for those under active chemotherapy
or immunosuppression. There is therefore a high unmet need to have an effective treatment available for these populations. Classic herd
immunity leading to eradication of COVID-19 is unlikely, much as is the case for influenza, respiratory syncytial virus (RSV), and other
endemic respiratory viruses. This contrasts with smallpox, for example, where both natural infection and vaccination eliminated virus
transmission. SARS-CoV-2 infection and vaccination produce a steadily waning natural and vaccine-induced immunity, respectively, but
do not eliminate transmission. Although the number of daily reported cases and deaths has declined, the emergence of more transmissible
variants has led to spikes in cases and mortality, and variants are expected to continue to evolve over time.
The
current COVID-19 landscape is also characterized by continued vaccine hesitancy among a significant portion of the population, unequal
access to vaccines and treatment, lack of response in some immunocompromised and other high-risk groups, and breakthrough cases among
the vaccinated due in part to increased immune evasion by current and emerging variants and the relatively short duration of protection
by booster shots. We expect these circumstances to continue, which could adversely impact long-term community-level protective immunity.
In addition, we believe that the expiration of the U.S. federal Public Health Emergency and U.S. government funding for COVID-19 testing,
surveillance, and treatment could lead to higher pricing for diagnostics and therapeutics.
Only
two antiviral agents, Paxlovid (nirmatrelvir with ritonavir) and Veklury (remdesivir), have been FDA-approved for the treatment of COVID-19, with Lagevrio (molnupiravir) available under emergency use authorization (“EUA”).
While Paxlovid is indicated for treatment in individuals at high risk for viral progression, these drugs have not been specifically authorized
for use in immunocompromised patients, creating a need for the development of novel therapies in this area. These therapies also present
challenges for subsets of patients. Paxlovid is associated with many drug-drug interactions, resulting in the need to temporarily stop
ongoing medications or seek alternative therapy and thereby making it difficult for some patients to take. This is especially true for
patients taking multiple medications, which is often true of high-risk patients requiring anti-COVID-19 treatment. Paxlovid is also known
to be associated with COVID-19 rebound, which has been calculated as high as 21% in ambulatory patients, according to a study published
in the Annals of Internal Medicine in November 2023. Although the rate of rebound in high-risk subgroups is less well-documented, we
anticipate it may be as high or higher in this group. Paxlovid also must be started within five days of symptom development to be effective.
Remdesivir must be given within seven days and is only available in intravenous form, requiring three daily infusions in a treatment
center. Remdesivir has also been associated with liver enzyme abnormalities and gastrointestinal side effects. Lagevrio (molnupiravir)
is an anti-viral agent that has received emergency use authorization for the treatment of COVID-19, but is rarely used due to reports
of limited efficacy. Monoclonal antibodies to the viral spike protein were introduced early in the pandemic for treatment of COVID-19
but typically have been rendered ineffective over time as the virus continues to evolve. One prophylactic monoclonal antibody for COVID-19
prevention, Pemgarda (Pemivibart), has received emergency use authorization for moderate to severely immune compromised patients. Whether
this monoclonal antibody will remain more durable than other monoclonal antibody remains to be seen, although resistance to the drug
has already been observed in some variants. No therapies have been approved to treat the underlying causes of the symptoms of Long COVID,
and significant research is ongoing to determine why some patients fully recover while others develop long-term complications.
Key
Advantages of TVGN 489
Given
the persistence of COVID-19 and its effects and continued gaps in treatment, there is a clear need for alternatives to current therapeutic
options for COVID-19. We have shown that TVGN 489 is less susceptible to viral mutations than monoclonal antibodies and thus able to
overcome the increased immune evasion of current and emerging COVID-19 variants. We also believe TVGN 489 has the potential to be less
susceptible to drug resistance than antivirals. As contrasted with existing therapies, TVGN 489 is designed to recognize multiple specific
target peptides from distinct COVID-19 proteins, versus one or two targets typically derived only from the spike protein. Whereas other
viral therapies buy time for natural immunity to emerge and definitively control the virus, TVGN 489 provides natural immunity directly
and immediately to patients.
TVGN
489’s targets have also persisted in studied COVID-19 variants. We have observed TVGN 489’s targets to be generally retained,
in nearly all cases at greater than a 95% level of retention, in the genome of all of the isolates of SARS-CoV-2 variants that we have
studied to date. This is in significant contrast with the target loss of anti-spike monoclonal antibody therapies, which has led to the
withdrawal of EUAs that had been granted during the now-expired COVID-19 National Public
Health Emergency.
COVID-19
variants have demonstrated how this virus is able to escape our immune system through mutation. However, we believe our proprietary approach
to manufacturing TVGN 489 may allow us to monitor the sequences of emerging variants and, if necessary, to proactively adjust or fine
tune our products to ensure that they continue to recognize and treat current and future variants of this and other viruses. For example,
with our approach, if a product contains T cells that recognize and target seven different peptides and one is lost through mutation,
that peptide can be dropped from future product batches. Similarly, if the mutation generates a new peptide target, that target can be
added to future batches. However, making these types of changes to TVGN 489 may require additional regulatory approvals, and there is
no guarantee that we will receive such approvals.
TVGN
489 is also designed to be fast acting, as the cells are fully mature and crafted to be primed to act as soon as they find their way
to infected cells. All patients in the interventional arm of our Phase 1 clinical trial noted improved symptoms within two to three days,
which is shorter than the average noted by patients in the observational arm, and there was a ≥ 99% viral load reduction in all patients
by PCR within 14 days. The consistency of the resolution was suggestive of a treatment effect and the rapidity of nasal swab COVID-19
resolution was shown in a population where five individuals were on active immunosuppression for cancer (three with hematological malignancy,
two with solid tumors) and one for lupus at the time of COVID-19 infection. Moreover, a more recent study showed that the median time
to SARS-CoV-2 nasal swab PCR negativity was 72 days for patients with a hematologic malignancy highlighting the rapidity of response
in the Tevogen phase I study. Two patients on the trial went on to stem cell transplantation, an immunosuppressive procedure, within
a month of treatment. Neither experienced COVID-19 reactivation, which we believe further attests to the rapid acting nature of this
product. When immunocompromised patients get sick from COVID-19, their current treatment regimens for existing conditions are often stopped.
For oncology patients, this can be especially disruptive or even harmful to the curative potential of their treatment. Given TVGN 489’s
design and these results, we believe TVGN 489 may allow immunocompromised patients to recover and be able to return to their pre-COVID-19
treatment regimen with minimal delays.
Production
of TVGN 489 and Mechanism of Action
TVGN
489 cells are sourced from healthy donors who have recovered from a previous COVID-19 infection. These donor cells are subsequently expanded
by 600-fold or more by restimulating them toward specific peptide targets. This is accomplished by exposing them to antigen-presenting
cells and selectively isolating the T cells that recognize the specific targets. TVGN 489 is formulated to precisely target multiple
peptide targets spread across the SARS-CoV-2 genome, rather than focusing solely on the mutation-susceptible spike protein, which is
the primary target of most vaccines and monoclonal antibodies. Upon completion of the manufacturing process, the cells are frozen and
stored for future intravenous infusion.
Administration
of TVGN 489 infuses the body with killer T cells that have been designed to attack COVID-19 infected cells. These highly purified, multi-target
CD8+ CTLs are intended to bind to and eliminate infected cells expressing the targeted peptides against which the CTLs were manufactured.
Peptides are presented in conjunction with the HLA molecule and the CTLs eradicate diseased cells expressing these viral or malignant
targets. To be clinically effective, a T cell therapy must be compatible with the patient’s specific HLA type. Therefore, a panel
of HLA-specific CTL products is necessary to broadly cover and treat the population. In our next clinical trial of TVGN 489, we expect
to treat patients with the six most common HLA types, which we believe would represent between 60% and 65% of the COVID-19 infected population.
We plan to continue expansion into additional HLA types until we are confident that between 90% and 95% of the population could be treated
based on our research.
We
believe that once bound to infected cells, TVGN 489 cells then destroy the infected cells through formation of an immunological synapse
between the killer cell and target and the release of cytotoxic granules from TVGN 489 into the target. These both produce pores in the
target cell’s membrane and also trigger a process known as apoptosis, or programmed cell death, which is built into all our cells.
Then, once the infected cells die, new, healthy cells are able to grow in their place.
Discovery
and Preclinical Data
Our
approach to identifying CTL targets starts with computer-based prediction and then tests candidate peptides functionally with T cells.
We use a technique known as tetramer staining to assess whether T cells recognized these target peptides, assessed cytotoxicity against
individual peptide-pulsed and non-pulsed targets, and selected final peptides for use in TVGN 489 on that basis.
We
conducted multiple in-vitro studies of TVGN 489 in preparation for filing the IND with FDA and observed strong antiviral activity against
SARS-CoV-2 in these laboratory studies. In preclinical studies, we observed that TVGN 489 cells kill target cells that are exposed to
SARS-CoV-2 peptides, but not cells that are not exposed to those peptides. This is illustrated in the figure below, which shows the percentage
of cells killed over a four-hour period when targets were pulsed with the peptides and when they were not, with the x-axis showing the
lysis rates based on the ratio of CTLs to target cells.
Identification
of appropriate COVID-19 peptide targets for additional HLA molecules remains ongoing, and we plan to continue this testing until we are
confident that between 90% and 95% of the COVID-19 infected population could be treated based on our research. We have completed final
peptide selection for six HLA restrictions (HLA-A*02:01, HLA-A*01:01, HLA-A*03:01, HLA-A*11:01, HLA-A*23:01, and HLA-A*24:02), which
we believe would cover approximately two thirds of the U.S. population. We believe generating these CTLs can provide treatment for SARS-CoV-2
or, with the appropriate targets, for other viral infections. Immunizing an individual to these specific targets could form the basis
of helping to prevent a subsequent infection through a T cell vaccine. Target identification thus has the potential to assist with prevention
as well as treatment. Over the last year, we have moved toward a more enclosed manufacturing process and increased the number of active
CTLs in our candidates. In the proof-of-concept trial, TVGN 489 contained 68.5% SARS-CoV-2-specific CTLs. Modifications to the ExacTcell
platform have increased the content of active CTLs to over 80% on a consistent basis.
Clinical
Development for COVID-19 Patients
FDA
permitted our IND for TVGN 489 to proceed in May 2021, and we began enrolling patients in the Phase 1 proof-of-concept trial of TVGN
489 for the treatment of high-risk ambulatory adult COVID-19 patients in October 2021. Patients in the trial were newly diagnosed with
COVID-19 and were deemed to be at high risk for complications due to the presence of one or more underlying medical conditions defined
as high risk by the Centers for Disease Control and Prevention, including among others cancer, hypertension, obesity, diabetes, cardiovascular
disease, and old age. The trial, which was conducted at Thomas Jefferson University Hospital in Philadelphia, was completed in January
2023.
The
trial included two arms, with 12 patients in the treatment (or interventional) arm and 18 patients in the observational arm. Assignment
to the interventional arm versus the observational arm was based on each patient’s HLA type. Patients expressing HLA-A*02:01, the
most common HLA type in the population, matched the CTLs and were enrolled in the interventional arm. Patients in the treatment arm had
been infected with either the delta variant or one of three omicron variants of COVID-19. Patients on the interventional arm had a higher
median number of comorbid conditions, a higher incidence of immune compromise, and a higher number of patients who were unvaccinated
or failed to respond to vaccination versus patients on the observational arm.
Each
patient in the treatment arm received a single intravenous infusion of TVGN 489 within four days of diagnosis. Analysis of COVID-19 viral
load showed that the patients were early in their COVID-19 disease course at the time of treatment. Patients were treated with TVGN 489
at one of four dose levels: 1 x 105/kg; 3 x 105/kg; 1 x 106/kg; or 3 x 106/kg. Patients treated
on the first dosing level had the high-risk delta variant of COVID-19. These dose levels were chosen based on data regarding antiviral
T cell therapy in hematopoietic transplant patients involving the administration of similar cell numbers. Three patients were enrolled
at each dosing level with the option to enroll three more if a significant side effect was observed. Each dose level concluded with three
patients rather than six and the treatment arm concluded with a total of 12 patients rather than 24, due to the absence of appreciable
toxicities across all dose levels. The comparative arm, which was designed to end enrollment when treatment arm enrollment was completed,
concluded with 18 patients, appreciably less than what would have occurred if the treatment group required additional enrollment. Observational
arm patients received standard of care treatment, including monoclonal antibodies. Interventional arm patients were monitored in the
hospital for four days before being discharged and then were observed daily at home for ten additional days and again at the one, two,
three, and six-month anniversary of the initial infusion. Observational arm patients were monitored at home over the same interval.
The
primary endpoints of the trial, which were safety-related, were met. No dose-limiting toxicities or significant adverse events related
to TVGN 489, including acute infusion reactions, cytokine release syndrome, neurotoxicity, or instances of graft versus host disease,
were observed in any patient at any dose level of our Phase 1 trial of TVGN 489.
Secondary
endpoints showing a rapid reduction of COVID-19 viral load and showing that infusion of TVGN 489 did not prevent development of the patient’s
own T cell-related (cellular) and antibody-related (humoral) anti-COVID-19 immunity were also met. In other words, observations indicate
that TVGN 489 did not prevent the body from responding to the infection and generating its own CTLs and antibodies to COVID-19.
All
treatment arm patients reported returning to their baseline level of health without COVID-19 symptoms within 14 days of treatment. All
such patients also reported symptom improvement within two to three days of treatment, which corresponded with a decrease in the COVID-19
viral load on PCR testing in the majority of patients. None of the patients who participated in the trial reported progression of their
COVID-19 infection and none developed recurrent COVID-19 or Long COVID during the six-month follow-up period. These clinical observations
were mirrored by laboratory evidence of the persistence of infused TVGN 489 cells for at least six months after treatment.
Persistence
of infused therapeutic cells remains a significant issue in the T cell therapy space, leading to challenges in controlling viral infections,
preventing viral recurrence, and managing cancer relapse. The shorter the CTLs persist in the recipient, the less opportunity they have
to perform their intended therapeutic tasks. Genetic differences between donor and recipient in allogeneic cell products and new genes
introduced into autologous products can be recognized by the patient’s immune system, which can encourage elimination of the administered
cells. This is one of the reasons why lymphodepleting therapy is commonly administered prior to CAR-T treatments. Maximizing the percentage
of CTLs in the products is also useful as the CTLs may receive re-stimulation from the virus infecting the patient and have a better
ability to protect themselves against elimination by the patient’s immune system. Most studies of genetically unmodified CTLs have
suggested that they are eliminated within weeks, with three months, in highly immune-suppressed hematopoietic blood and marrow transplant
(“HSCT”) patients, being the longest that they typically are reported to persist. The highly immune-suppressed nature of
the HSCT patient group is thought to allow for longer than typical persistence.
In
our Phase 1 clinical trial for TVGN 489, following infusion, peripheral blood of six patients was collected at various timepoints throughout
the follow-up period. These samples were sent to Adaptive Biotechnologies (“Adaptive”) to evaluate the persistence of infused
TVGN 489 in the patients following treatment, and Adaptive conducted analyses by sequencing protein chains of TCRs in the samples. Four
of these patients had samples analyzed through the six-month end of study follow-up, and as seen in the figure below, Adaptive’s
data showed persistence of T cells present in the TVGN 489 product but absent from the recipients prior to administration of TVGN 489.
This subset of CTLs was found in all samples tested, including at the final study assessment at six months. The TCRs used to recognize
TVGN 489’s peptides were also shown to be largely distinct from person to person, making it highly unlikely that the cells from
later timepoints derive from anything other than the product in these five different patients. Taken together, we believe this data shows
the persistence of TVGN 489 cells six months after administration.
TVGN
489 COVID-19 Reactive CD8+ T Cells Detected Throughout the Six-Month Follow Up Period
Expansion
and persistence of allogeneic T cells has been associated with disease control in many settings. Whether the prolonged persistence of
the CTLs used in this study is of benefit in the treatment of COVID-19, Long COVID, or alternate future viral or oncologic targets for
these CTLs merits further examination. However, the evidence of their prolonged persistence provides us with encouragement for future
applications of the ExacTcell technology, particularly in oncology.
We
believe based on precedential industry examples, including in areas with high unmet needs or strong early phase clinical trial results,
that we may be able to commence pivotal trials of TVGN 489 on the basis of the results of our completed Phase 1 trial. A pivotal trial
is a trial designed to generate data sufficient to support the filing of an application for regulatory approval. Although the clinical
trial process usually includes three phases, a pivotal trial may not necessarily be denoted as a Phase 3 clinical trial and instead may
be a Phase 2 or Phase 2/3 clinical trial. We hope to begin a pivotal trial of TVGN 489 for the treatment of COVID-19 in select vulnerable
populations with humoral immune suppression due to B cell malignancy or the treatment thereof. Patients with hematological malignancies
continue to experience higher rates of hospitalization and death as compared to the general population and those with solid tumors. Increased
mortality, hospitalization, and persistence of COVID-19 infection are higher in patients with B cell malignancies due to inadequate vaccination
response and the immunosuppressive consequences of treatment received for B cell cancers. While the major acute outcomes of patients
with hematological malignancies and COVID-19 have improved with increasing experience, for cancer patients who contract COVID-19, uninterrupted
treatment is critical, as delays can impact long-term outcomes. Whereas treatment arm patients in our Phase 1 proof-of-concept clinical
trial all had a single HLA type, we expect to treat patients in this pivotal trial who have any of the six most common HLA types, which
we believe would represent between 60% and 65% of the population. The primary endpoint of this trial is planned to be reduction in SARS-CoV-2
viral load and reduction in the delays of cancer treatment. Secondary endpoints include the incidence and duration of hospitalization,
intensive care unit admissions, hours on supplemental oxygen, mortality, COVID-19 recurrence, and Long COVID diagnosis. At this stage,
however, we cannot be certain whether we will be permitted to move from a Phase 1 trial directly to a pivotal trial until FDA reviews
and concurs with or rejects our proposed plans, and FDA may require us to conduct further trials to generate additional safety and efficacy
data.
As
development of TVGN 489 continues, we may also seek FDA’s RMAT designation for TVGN 489, which as explained in “Regulatory
Environment - Expedited Development and Review Programs” below, is intended to facilitate efficient development and expedited review
or potentially, the FDA Commissioner’s National Priority Voucher pilot program, which the FDA is exploring as a pathway to reduce
review times, even as compared to other priority review programs, for candidates meeting certain criteria.
Other
Target Patient Populations and Indications for TVGN 489
Although
the majority of younger and healthier adults with COVID-19 avoid poor outcomes after infection without treatment, there remain subsets
of the population (such as humorally suppressed patients with B cell malignancies, as described above) who are vulnerable to significant
complications from COVID-19 because of a weak immune system or suboptimal responses to vaccines. Treatment of these individuals is an
area of unmet need that we believe TVGN 489 therapy has the opportunity to fill. These target populations also include COVID-19 patients
with a non-B-cell cancer indication, elderly and infirm acute COVID-19 patients, and those with immune suppression due to solid organ
or hematopoietic transplantation or autoimmunity or treatment of these conditions. Regardless of age or comorbidity, individuals with Long
COVID represent another critical area of unmet need. As noted above, these patients are among those with the greatest need for effective
treatment. We believe that the safety and the clinical benefit data from our completed Phase 1 clinical trial in ambulatory, high-risk
adult patients should be sufficient to serve as the basis for later-stage and potentially pivotal trials in these patient groups as well
as for the prevention of Long COVID. However, whether such trials may serve as pivotal trials, the phase of these trials, and the dose
level to be selected in each trial remains subject to discussions with and agreement by FDA.
Recent
studies have detected persistent viral spike and nucleocapsid proteins in some Long COVID patients, suggesting a persistent viral reservoir
in those patients. If that is correct, we believe that TVGN 489 may circumvent Long COVID by preventing such a reservoir from being established
or by minimizing its size. No treated patients in our Phase 1 proof-of-concept trial developed Long COVID. We expect considerable additional
information on Long COVID prevention to be obtained from our planned acute COVID-19 treatment trials in which patients treated with TVGN
489 are expected to be compared to patients receiving standard of care treatment. We believe that the comparative data with respect to
patients in these trial arms going on to develop Long COVID should provide sufficient information to obviate a separate Phase 1 Long
COVID prevention trial, and that the significant unmet need for treatment in vulnerable patients as well as the efficacy data in preventing
Long COVID generated in these studies will lend further support for a streamlined development pathway. However, we cannot be certain
whether FDA will require us to conduct a separate prevention trial until FDA reviews and concurs with or rejects our proposed plans.
Studies
have indicated that there is not an HLA class I-based predisposition to Long COVID. Therefore, it was not necessary for us to undertake
a genetic prediction study to determine optimal class I HLA types for CTL donor selection. Instead, a Phase 2 study is in development
that will examine the effect of treatment with TVGN 489 on specific categories of Long COVID sufferers such as those with fatigue or
brain fog based on the existence of a SARS-CoV-2 reservoir which may cause these symptoms. This protocol is in a very early stage of
development.
Other
Discovery Programs, Product Candidates and Indications
In
addition to TVGN 489, we have several product candidates under early-stage development in virology, neurology, and oncology using our
ExacTcell technology. For example, investigative work is also underway to develop product candidates targeted at human papilloma virus
(“HPV”)-related diseases, including TVGN 920 in cervical cancer and TVGN 960 in oropharyngeal cancer, which is a type of
mouth and throat cancer. Cervical cancer and oropharyngeal cancer are both commonly caused by HPV. According to the World Health Organization
(the “WHO”), HPV is responsible for 99% of cervical cancers. Mouth and throat cancers are more diverse, but the WHO estimates
that in the U.S., about 60% to 70% of oropharyngeal cancers are due to HPV. Although a vaccine for HPV exists, the National Cancer Institute
estimates that as of 2023, only 57.3% of adolescents between the ages of 13 and 15 had received the recommended doses, estimated vaccination
among older populations is lower, and the COVID pandemic has shown that significant portions of the population will avoid vaccination.
We believe that as with other viral infections, the availability of both a preventative strategy and a treatment strategy is important
to reduce incidence and impact of disease and we are investigating peptide candidates for HPV to further the development of TVGN 920
and TVGN 960. We are also beginning investigative work to develop TVGN 116, a product candidate targeted at chronic hepatitis B, with
the hope of avoiding the need for liver transplant due to cirrhosis or liver cancer. While treatments for hepatitis B exist, these are
generally not curative and require patient compliance for a lifetime. We believe that a single treatment with hepatitis B-specific CTLs
may produce better treatment acceptance and compliance. We are also developing Epstein-Barr virus (“EBV”) specific CTLs for
potential use in multiple sclerosis (“MS”) and EBV-associated lymphomas. Our TVGN 601 is being developed for MS, and our
TVGN 930 is being developed for EBV-associated lymphomas. EBV is a common virus that infects over 90% of the world’s adult population,
according to the WHO, and is mainly transmitted through saliva, but also through other body fluids such as blood and semen. EBV is the
leading cause of infectious mononucleosis, and infects B-cells, a type of immune cell. Recent studies have suggested a potential link
between infection with EBV and later onset of inflammation that causes MS, and EBV infection can lead to a variety of cancers and cancer-like
disorders, including lymphomas, nasopharyngeal cancers, Post-Transplant Lymphoproliferative Disorder, and others. Given the widespread
nature of EBV and the serious health problems it can cause, investigative work is underway to identify effective peptide targets for
this virus to further the development of TVGN 601 and TVGN 930. Testing of EBV peptides in our laboratory is currently underway.
We
believe that our ExacTcell approach also presents a novel and highly specific technique to combating virally induced cancers with T cell
therapy. Unlike CAR-T or Bispecific T-cell Engager (BiTE) antibody approaches, which recruit a heterogeneous group of T cells to the
tumor, our approach would instead focus a highly purified population of CTLs on the tumor, which we believe may provide more potential
to accomplish the task of eradicating the cancer. Non-viral (sporadic) cancers may not always express an ideal T cell target on their
own. However, it is possible to coat this sort of cancer cell with a well-recognized target peptide using monoclonal antibodies or liposomes.
We believe this would allow our target specific CTLs to then attack the cancer cells. We also believe that our approach has the potential
to eventually bring the benefits of cell therapies to first-line options in oncology, as well as to create products that may overcome
current limitations of checkpoint inhibitors.
T
cells can lose their ability to fight viruses and tumors in prolonged infections and cancer in a state called T cell exhaustion that
is characterized by the presence of certain biomarkers. Expression of these markers, which include PD-1, PDL-1, and LAG-3, has been observed
to be low level to absent in TVGN 489 cells. Moreover, TVGN 489 cells are functionally tested after generation, and have been observed
to remain strongly cytolytic at very low ratios of CTLs to target cells, which shows that they are not displaying the functional limitations
associated with T cell exhaustion.
Manufacturing
We
relied on a Clinical Trial Services and Materials Agreement with Thomas Jefferson University for the manufacture of TVGN 489 for our