UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
Form
10-K
(Mark
One)
☒
Annual Report Pursuant to Section 13 OR 15(d) of the Securities Exchange Act of 1934
For
the fiscal year ended December 31, 2023
or
☐
Transition report pursuant to Section 13 OR 15(d) of the Securities Exchange Act of 1934
For
the transition period from ______ to ______
Commission
file number: 001-41002
Tevogen
Bio Holdings Inc.
(Exact
name of registrant as specified in its charter)
15 Independence Boulevard, Suite #410 Warren, New Jersey 07059
(Address of principal executive offices) (Zip Code)
Registrant’s
telephone number, including area code: (877)838-6436
Securities
registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common Stock, $0.0001 par value per share TVGN The Nasdaq Stock Market LLC
Securities
registered pursuant to Section 12(g) of the Act: None
Indicate
by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.
Yes
☐No☒
Indicate
by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act.
Yes
☐No☒
Indicate
by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange
Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2)
has been subject to such filing requirements for the past 90 days. Yes☒ No ☐
Indicate
by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule
405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant
was required to submit such files).
Yes☒ No ☐
Indicate
by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting
company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,”
“smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐ Non-accelerated filer ☒
Smaller reporting company ☒ Emerging growth company ☒
If
an emerging growth company indicate by check mark if the registrant has elected not to use the extended transition period for complying
with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate
by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered
public accounting firm that prepared or issued its audit report. ☐
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to § 240.10D-1(b). ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act).
Yes ☐ No ☒
The
aggregate market value of the registrant’s common stock held by non-affiliates as of June 30, 2023, the last business day of the
registrant’s most recently completed second fiscal quarter, computed by reference to the price at which the common stock was last
sold on The Nasdaq Stock Market LLC on that date, was approximately $25,451,000.
The
total number of shares of common stock outstanding as of April 26, 2024, was 164,614,418.
DOCUMENTS
INCORPORATED BY REFERENCE
None.
TEVOGEN
BIO HOLDINGS INC.
FORM
10-K
INDEX
Page
PART I
Item 1 Business 7
Item 1A Risk Factors 37
Item 1B Unresolved Staff Comments 77
Item 1C Cybersecurity 77
Item 2 Properties 78
Item 3 Legal Proceedings 78
Item 4 Mine Safety Disclosures 78
PART II
Item 6 [Reserved] 80
Item 7A Quantitative and Qualitative Disclosures About Market Risk 85
Item 8 Financial Statements and Supplementary Data 85
Item 9A Controls and Procedures 86
Item 9B Other Information 86
Item 9C Disclosure Regarding Foreign Jurisdictions that Prevent Inspection 86
PART III
Item 10 Directors, Executive Officers, and Corporate Governance 87
Item 11 Executive Compensation 93
Item 14 Principal Accounting Fees and Services 109
PART IV
Item 15 Exhibits and Financial Statement Schedule 110
EXPLANATORY
NOTE
Prior
to February 14, 2024, Semper Paratus Acquisition Corporation (“Semper Paratus”) was a special purpose acquisition company
formed for the purpose of effecting a merger, stock purchase, reorganization, or similar acquisition or business combination with one
or more businesses. On February 14, 2024 (the “Closing Date”), subsequent to the end of the fiscal year ended December 31,
2023, the fiscal year to which this Annual Report on Form 10-K (this “Annual Report”) relates, Semper Paratus completed the
previously announced business combination pursuant to that certain Agreement and Plan of Merger by and among Semper Paratus, Semper Merger
Sub, Inc., a Delaware corporation and a wholly owned subsidiary of Semper Paratus (“Merger Sub”), SSVK
Associates, LLC, Semper Paratus’s sponsor (the “Sponsor”), in its capacity as purchaser representative, Tevogen Bio
Inc, a Delaware corporation (“Tevogen Bio”), and Dr. Ryan Saadi, in his capacity as seller representative (the “Merger
Agreement”).
As
contemplated by the Merger Agreement, on the Closing Date, Merger Sub merged with and into Tevogen Bio, with Tevogen Bio being the surviving
company and a wholly owned subsidiary of Semper Paratus (the “Merger,” and together with the other transactions contemplated
by the Merger Agreement, the “Business Combination”). In connection with the closing of the Business Combination (the “Closing”),
we changed our name from “Semper Paratus Acquisition Corporation” to “Tevogen Bio Holdings Inc.”
As
of the open of trading on February 15, 2024, our common stock and public warrants began trading on The Nasdaq Stock Market LLC (“Nasdaq”)
as “TVGN” and “TVGNW,” respectively.
Substantially
concurrently with the filing of this Annual Report, we will be filing Amendment No. 2 to our Current Report on Form 8-K originally
filed on February 14, 2024, which will include the audited financial statements of Tevogen Bio for the year ended December 31, 2023,
and related Management’s Discussion and Analysis of Financial Condition and Results of Operations and unaudited pro forma
condensed combined financial information of the Company and Tevogen Bio as of December 31, 2023, and for the year then ended.
Interested parties should refer to our Current Reports on Form 8-K for more information.
Except
as otherwise expressly provided herein or as the context otherwise requires, the information in this Annual Report does not reflect the
consummation of the Business Combination, which, as discussed above, occurred subsequent to the period covered hereunder.
As
used in this Annual Report, unless otherwise noted or the context otherwise requires: (i) references to the “Company,” “Tevogen,”
“we,” “us,” “our,” and similar terms refer to Tevogen Bio Holdings Inc. (f/k/a Semper Paratus Acquisition
Corporation) and its subsidiaries; (ii) references to “Semper Paratus” are to Semper Paratus Acquisition Corporation prior
to the close of the Business Combination; (iii) references to “Tevogen Bio” are to Tevogen Bio Inc. (f/k/a Tevogen Bio Inc)
prior to the close of the Business Combination; (iv) references to “Sponsor” are to SSVK Associates, LLC; and (v) references
to “Original Sponsor” are to Semper Paratus Sponsor LLC.
CAUTIONARY
NOTE REGARDING FORWARD-LOOKING STATEMENTS
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; and
● 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.
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 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
● The price of our Common Stock and Warrants may fluctuate significantly.
● We have no current plans to pay regular cash dividends on our Common Stock.
● 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.
● We may redeem warrants at a time that is disadvantageous to warrant holders.
● Our public warrants may never be in the money and they may expire worthless.
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 (“CD8+ CTLs” or “CTLs”), to develop off-the-shelf, precision T cell therapies for the treatment
of infectious diseases, cancers, and neurological 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 across the development lifecycle and healthcare system. We aspire
to be the first biotechnology company offering commercially attractive, economically viable, and cost-effective personalized T cell therapies.
We
believe our allogeneic, precision T cell technology platform, ExacTcellTM, represents a significant scientific breakthrough
that has the potential to produce a new class of off-the-shelf – manufactured and stored for immediate use – drugs with diverse applications
spanning virology, oncology, and neurology. 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. We are focused on using ExacTcell to develop allogeneic
therapeutics, meaning therapeutics that are intended to be infused in patients other than the original donor.
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 cancer cells, which can render existing treatments
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 large patient populations grappling with life-threatening viral
diseases, both viral and non-viral induced cancers, and neurological disorders such as multiple sclerosis.
The
first clinical product of ExacTcell, TVGN 489, is 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 that are 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 showing
a rapid reduction of viral load and that infusion of TVGN 489 did not prevent development of the patients’ own T cell-related (cellular)
or antibody-related (humoral) anti-COVID-19 immunity were also met. None of the 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. We hope to launch a pivotal trial of TVGN 489 in COVID-19
patients with B cell malignancies as soon as late 2024, with studies of other highly vulnerable populations thereafter. TVGN 489 is also
in preclinical development for treatment and prevention of Long COVID.
Business
Combination
Prior
to February 14, 2024, Semper Paratus Acquisition Corporation (“Semper Paratus”) was a special purpose acquisition
company formed for the purpose of effecting a merger, stock purchase, reorganization or similar acquisition or business combination
with one or more businesses. On February 14, 2024 (the “Closing Date”), Semper Paratus completed the previously
announced business combination pursuant to that certain Agreement and Plan of Merger by and among Semper Paratus, Semper Merger Sub,
Inc., a Delaware corporation and a wholly owned subsidiary of Semper Paratus (“Merger Sub”), SSVK Associates, LLC,
Semper Paratus’s sponsor (the “Sponsor”), in its capacity as purchaser representative, Tevogen Bio Inc, a Delaware
corporation (“Tevogen Bio”), and Dr. Ryan Saadi, in his capacity as seller representative (the “Merger
Agreement”).
As
contemplated by the Merger Agreement, on the Closing Date, Merger Sub merged with and into Tevogen Bio, with Tevogen Bio being the surviving
company and a wholly owned subsidiary of Semper Paratus (the “Merger,” and together with the other transactions contemplated
by the Merger Agreement, the “Business Combination”). In connection with the closing of the Business Combination, we changed
our name from “Semper Paratus Acquisition Corporation” to “Tevogen Bio Holdings Inc.” As of the open of trading
on February 15, 2024, our common stock and public warrants began trading on The Nasdaq Stock Market LLC (“Nasdaq”) as “TVGN”
and “TVGNW,” respectively.
Our
Pipeline
We
are leveraging our understanding of immunotherapy and our ExacTcell platform to discover, validate, and build a proprietary pipeline
of T cell therapies with diverse targets in infectious disease, cancer, and neurological 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 neurological disease. Key elements of our strategy to advance toward this goal include
the following:
Our
ExacTcell Platform
Our
ExacTcell platform 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 platform 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 certain neurological disorders.
ExacTcell
focuses on the selection and expansion of naturally occurring, genetically unmodified CD8+ CTLs to target multiple, distinct, preselected
antigens 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.
Most 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 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
defined smaller peptides that are selected to bind to a single HLA-class I molecule, 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.
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. 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 a combination of computer-facilitated prediction of the ability
of specific peptide candidates to bind to specific HLA molecules and published scientific research. Once candidates are selected, 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 them for use. Through our Tevogen.ai artificial intelligence initiative, we are exploring ways to deploy artificial
intelligence-powered target detection to further accelerate our product development pace, either internally or in collaboration with
leading entities in the field of artificial intelligence.
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.
More
recently, in November of 2023, FDA announced that it had “received reports of T-cell malignancies, including chimeric antigen receptor
positive lymphoma, in patients who received treatment with BCMA- or CD19-directed autologous CAR T cell immunotherapies.” These
secondary malignancies resulted in hospitalization and death in a small subset of patients. On January 19, 2024, FDA required a class-wide
black box warning be added to the label of these CAR T products regarding this risk. FDA also underscored that the benefits of CAR-T
therapies continue to outweigh their risks but recommended lifelong monitoring of this potential side effect. 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 platform 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. The genetic modifications necessary to make CAR-T cells, which may be associated with the recent reports
of T-cell malignancies, are not utilized in the manufacture of our products made on the ExacTcell platform. Moreover, secondary malignancies
have not been described in the unmodified T cell products given to hundreds of post-transplant patients. Although our ExacTcell products
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 platform.
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 in the case of treatments against viruses where 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” – manufactured and stored for immediate 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 (“TCR-T”), 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 gap in COVID-19
therapeutic solutions for the immunocompromised and the high-risk elderly, 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 endpoints showing a rapid reduction of COVID-19 viral load and to show 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 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. 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 TVGN 489 has the potential to be less susceptible to viral mutation than monoclonal antibodies, less susceptible to drug resistance
than antivirals, and to rapidly be able to overcome any increased immune evasion of current and emerging SARS-CoV-2 variants. We also
believe ExacTcell can enable us to deliver products faster, at a greater scale, and at lower cost than future competing cell therapies,
if any. Despite selection of T cell targets in 2020, the HLA-A*02:01 TVGN 489 product has maintained a high degree of activity through
the full range of studied delta and subsequent omicron variants. In contrast, most monoclonal antibodies were withdrawn from the market
for lack of efficacy related to the emergence 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 currently
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. For example, recent 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. Of US adults, 17.6% had experienced symptoms of Long COVID, according to the Centers for Disease Control and Prevention’s
(“CDC’s”) household pulse survey taken from January 9 through February 5, 2024. As of October 2023, 5% of all adults
were still experiencing symptoms of Long COVID, according to a USA FACTS review of U.S. Census Bureau data. 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.
As
of May 2023, about 103 million cumulative confirmed COVID-19 cases were reported in the United States alone. While there has been a decrease
in the number of confirmed and reported cases, this is a multifactorial issue due in part to a decrease in testing by younger or healthier
individuals, reliance on home tests, the results of which are often not reported, expiration of federal funding for testing, and the
CDC’s discontinuation of collection of testing data. However, 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,
and treatment could lead to higher pricing for diagnostics and therapeutics.
Only
two anti-viral agents, Nirmatrelvir/Ritonavir (Paxlovid) and Remdesivir, have been FDA-approved for the treatment of COVID-19. While
Paxlovid is indicated for treatment in individuals at high risk for viral progression, neither drug has been specifically authorized
for use in immunocompromised patients, creating a need for the development of novel therapies in this area. Both drugs 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 on 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. 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. 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 ongoing spread 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 believe TVGN 489 has been shown to be 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 led to the withdrawal
of emergency use authorizations (“EUAs”) that had been granted during the now-expired COVID-19 National Public Health Emergency.
For example, the EUA for AbCellera Biologics’ and Eli Lilly’s bamlanivimab administered alone, which was granted in November
2020, was revoked in April 2021 due to a sustained increase in viral variants that were not sensitive to this product.
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 83% of patients in the interventional arm had negative
nasal swab polymerase chain reaction tests within 14 days. The consistency of the resolution was suggestive of a treatment effect and
the observed period is in contrast to a range of up to 90 days in the general population. This observed consistency and rapidity of nasal
swab COVID-19 resolution was in a population where five individuals were on active immunosuppression for cancer and one for lupus at
the time of COVID-19 infection. 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. 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 investigational new drug application (“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.
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 CDC, 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. 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. 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, primarily
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