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, 2024
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: 001-40877
CERO THERAPEUTICS HOLDINGS, INC.
(Exact name of registrant as specified in its charter)
South San Francisco, CA 94080
(Address of principal executive offices) (Zip Code)
(650)407-2376
(Registrant’s telephone number, including area code)
N/A
(Former name, former address and former fiscal
year, if changed since last report)
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, par value $0.0001 per share CERO Nasdaq Capital Market
Warrants to purchase one share of Common Stock CEROW Nasdaq Capital Market
Securities registered pursuant to Section 12(g)
of the Act: None
Indicate by check mark if the Registrant is a
well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YES ☐NO☒
Indicate by check mark if the Registrant is not
required to file reports pursuant to Section 13 or 15(d) of the Act. YES ☐NO☒
Indicate by check mark whether the registrant
(1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months
(or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements
for the past 90 days. Yes☒ No ☐
Indicate by check mark whether the registrant
has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 232.405
of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes☒ No ☐
Indicate by check mark whether the registrant
is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company.
See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,”
and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☒
If an emerging growth company, indicate by check
mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting
standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant
has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial
reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or
issued its audit report. ☐
If securities are registered pursuant to Section
12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction
of an error to previously issued financial statements. ☐
Indicate by check mark whether any of those error
corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s
executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate by check mark whether the registrant
is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐
No ☒
As of June 30, 2024, the last business day of
the registrant’s most recently completed second fiscal quarter, the aggregate market value of the registrant’s voting securities
held by non-affiliates was approximately $5,765,325 based on the number of shares held by non-affiliates and the last reported sales
price of the registrant’s Class A common stock as of that date.
As of April 11, 2025, the registrant had 5,380,723 shares of common
stock, par value $0.0001 per share, outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
Portions of the Registrant’s Definitive Proxy Statement relating
to the 2025 Annual Meeting of Stockholders, which the Registrant intends to file with the Securities and Exchange Commission pursuant
to Regulation 14A within 120 days after the end of the Registrant's fiscal year ended December 31, 2024, are incorporated by reference
into Part III of this Annual Report on Form 10-K.
Table of Contents
Page
PART I 1
ITEM 1. Business 1
ITEM 1A. Risk Factors 37
ITEM 1B. Unresolved Staff Comments 97
ITEM 1C. Cybersecurity 97
ITEM 2. Properties 98
ITEM 3. Legal Proceedings 98
ITEM 4. Mine Safety Disclosures 98
ITEM 6. [Reserved] 100
ITEM 7A. Quantitative and Qualitative Disclosures About Market Risk 109
ITEM 8. Financial Statements and Supplementary Data 109
ITEM 9A. Controls and Procedures 110
ITEM 9B. Other Information 111
ITEM 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 111
ITEM 10. Directors, Executive Officers and Corporate Governance 112
ITEM 11. Executive Compensation 112
ITEM 14. Principal Accountant Fees and Services 112
ITEM 15. Exhibits and Financial Statement Schedules 113
i
CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form
10-K (this “Annual Report”) contains forward-looking statements within the meaning of
Section 27A of the Securities Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act
of 1934, as amended (the “Exchange Act”). All statements other than statements of historical facts contained in this
Annual Report, including statements regarding our future results of operations and financial position, business strategy, drug candidates,
planned preclinical studies and clinical trials, results of preclinical studies, clinical trials, research and development (“R&D”)
costs, regulatory approvals, timing and likelihood of success, as well as plans and objectives of management for future operations, are
forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that are in some
cases beyond our control and may cause our actual results, performance or achievements to be materially different from any future results,
performance or achievements expressed or implied by the forward-looking statements.
In some cases, you can identify
forward-looking statements by terms such as “may,” “will,” “should,” “would,” “expect,”
“plan,” “anticipate,” “could,” “intend,” “target,” “project,”
“believe,” “estimate,” “predict,” “potential,” or “continue” or the negative
of these terms or other similar expressions. Forward-looking statements contained in this Annual Report include, but are not limited to,
statements about:
● our financial performance;
ii
● our ability to realize the anticipated benefits of any strategic transactions;
● our ability to maintain proper and effective internal controls;
iii
We have based these forward-looking
statements largely on our current expectations and projections about our business, the industry in which we operate and financial trends
that we believe may affect our business, financial condition, results of operations and prospects, and these forward-looking statements
are not guarantees of future performance or development. These forward-looking statements speak only as of the date of this Annual Report
and are subject to a number of risks, uncertainties and assumptions described in “Risk Factors” and elsewhere in this
Annual Report. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted
or quantified, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected
in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the
forward-looking statements. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements
contained herein until after we distribute this Annual Report, whether as a result of any new information, future events or otherwise.
In addition, statements that
“we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon
information available to us as of the date of this Annual Report, and while we believe such information forms a reasonable basis for such
statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an
exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain, and
you are cautioned not to unduly rely upon these statements.
This Annual Report includes
trademarks, tradenames and service marks that are the property of other organizations. Solely for convenience, trademarks and tradenames
referred to in this Annual Report appear without the ® and TM symbols, but those references are not intended to indicate, in
any way, that we will not assert, to the fullest extent under applicable law, our rights, or that the applicable owner will not assert
its rights, to these trademarks and tradenames.
Unless the context otherwise
requires, all references herein to “we,” “us,” “our” or “the Company” refer to the business
and operations of CERo Therapeutics Holdings, Inc. (“CERo”) and its subsidiaries.
iv
SELECTED DEFINITIONS
As used in this Annual Report, unless
otherwise noted or the context otherwise requires, references to the following capitalized terms have the meanings set forth below:
“Arena” refers to Arena Business Solutions
Global SPC II, Ltd. on behalf of and for the account of Segregated Portfolio #13 – SPC #13.
“Arena Commitment Shares”
refer to up to 10,000 shares of Common Stock issued to Arena as consideration for executing and delivering the Arena Purchase Agreement.
“Arena Purchase Agreement”
refers to the Purchase Agreement, dated as of February 23, 2024, by and between CERo and Arena.
“Board” refers
to the board of directors of CERo.
“Business Combination” or “Merger”
refers to the transactions contemplated by the Business Combination Agreement, including the merger between Merger Sub and Legacy CERo.
“Business Combination Agreement” refers
to the Business Combination Agreement, dated as of June 4, 2023, as amended by Amendment No. 1, dated February 5, 2024 and Amendment No.
2, dated February 13, 2024, by and between PBAX, Merger Sub and Legacy CERo.
“Bylaws” refers to the Amended and Restated
Bylaws of CERo.
“Charter” refers to CERo’s Second
Amended and Restated Certificate of Incorporation, as filed with the Secretary of the State of Delaware February 14, 2024.
“Class A Common Stock” refers to the
CERo Class A common stock, par value $0.0001 per share.
“Closing” refers to the closing of the
Business Combination.
“Common Stock” refers to the Class A common stock,
par value $0.0001 per share, of CERo.
“Common Warrants”
refers to the Public Warrants, Private Placement Warrants, the Conversion Warrants, the Series A Warrants, the Series C Warrants, the
December 2024 Common Warrants, the January 2025 Common Warrants, the February 2025 Common Warrants and the Pre-Funded Warrants.
“Conversion Warrants” refer to the warrants
initially issued by CERo Therapeutics, Inc. and converted into warrants to purchase Common Stock in connection with the Business Combination.
“December 2024 Common Warrants”
refer to the warrants to purchase shares of Common Stock, at a current exercise price of $5.61 per share, issued by the Company in a
private placement on December 23, 2024.
“DGCL” refers to the Delaware General
Corporation Law, as may be amended from time to time.
v
“Earnout Shares” refer to the Primary
Earnout Shares, the Secondary Earnout Shares and the Tertiary Earnout Shares, collectively.
“February
2025 Common Warrants” refer to the warrants to purchase shares of Common Stock, at a current exercise price of $1.96 per share,
issued by the Company in a public offering on February 7, 2025.
“First PIPE Financing” refers to the
private placement pursuant to which we issued and sold, and the PIPE Investors purchased, shares of Series A Preferred Stock, the Series
A Warrants and Preferred Warrants, on the terms and conditions set forth in the First Securities Purchase Agreement.
“First PIPE Registration Rights Agreement”
refers to the Registration Rights Agreement, dated as of February 14, 2024, by and between CERo and certain PIPE Investors.
“First Securities Purchase Agreement”
refers to the Amended and Restated Securities Purchase Agreement, dated as of February 14, 2024, by and among PBAX, Legacy CERo and certain
PIPE Investors, pursuant to which CERo agreed to issue and sell 10,039 shares of Series A Preferred Stock, 6,127 Series A Warrants and
2,500 Preferred Warrants.
“Initial Public Offering” refers to the
initial public offering of PBAX, which closed on October 8, 2021.
“January
2025 Common Warrants” refer to the warrants to purchase
shares of Common Stock, at a current exercise price of $5.82 per share, issued by the Company in a private placement on January 6, 2025.
“Keystone” refers to Keystone Capital
Partners, LLC.
“Keystone Commencement Date” refers to
the time when all of the conditions to our right to commence sales of Common Stock to Keystone set forth in the respective Keystone Purchase
Agreements have been satisfied.
“Keystone Commitment Shares” refers to
the 19,833 shares of Common Stock that have been issued to Keystone as consideration for Keystone entering into the Keystone Purchase
Agreements.
“Keystone Purchase Agreements” refers
to the Old Keystone Purchase Agreement and the New Keystone Purchase Agreement.
“Keystone Purchase Shares” refers to
the shares of Common Stock that CERo may elect to issue and sell to Keystone after the Keystone Commencement Date.
vi
“Legacy CERo” refers to CERo Therapeutics,
Inc.
“Legacy CERo common stock” refers to
the common stock, par value $0.0001 per share, of Legacy CERo.
“Legacy CERo preferred stock” refers
to the preferred stock, par value $0.0001 per share, of Legacy CERo.
“Legacy CERo options” refers to the options
to purchase shares of Legacy CERo common stock.
“Legacy CERo Stockholders” refers to
the holders of Legacy CERo common stock and/or Legacy CERo preferred stock prior to the Business Combination.
“Legacy CERo warrants” refers to the
warrants to purchase shares of Legacy CERo preferred stock.
“Merger Sub” refers to PBCE Merger Sub,
Inc., a Delaware corporation.
“New Keystone Purchase Agreement” refers
to the Common Stock Purchase Agreement, dated as of November 8, 2024, by and between CERo and Keystone.
“Old Keystone Purchase Agreement” refers
to the Common Stock Purchase Agreement, dated as of February 14, 2024, by and between PBAX and Keystone.
“PIPE Financings” refers to the First
PIPE Financing, the Second PIPE Financing and the Third PIPE Financing.
“PIPE Investors” refer to the investors
in the PIPE Financings.
“PIPE Registration Rights Agreement”
refers to the First PIPE Registration Rights Agreement, the Second PIPE Registration Rights Agreement and the Third PIPE Registration
Rights Agreement.
“Pre-Funded
Warrants” refer to the warrants to purchase shares of Common Stock, at an exercise price of $0.0001 per Share, issued in a
public offering on February 7, 2025.
“Preferred Stock” refers to the shares of Series
A, Series B, and Series C Preferred Stock, par value $0.0001 per share, of CERo.
“Preferred Shares” refer to the shares
of Series A Preferred Stock, Series B Preferred Stock and Series C Preferred Stock issued in the PIPE Financings, including the Warrant
Preferred Shares.
“Preferred Warrants” refer to warrants
to purchase shares of Series A Preferred Stock.
“Primary Earnout Shares” refer to the
12,000 shares of Common Stock issued to the holders of Legacy CERo common stock and Legacy CERo preferred stock in connection with the
Business Combination, 10,000 of which are subject to vesting upon the achievement of certain stock price-based earnout targets and 2,000
of which are subject to vesting upon a change of control, respectively.
“Private Placement Warrants” refer to
private placement warrants to purchase shares of Common Stock, at an exercise price of $1,150.00 per share, that were originally sold
in a private placement concurrently with the Initial Public Offering.
“Public Warrants” refer to the warrants
to purchase shares of Common Stock, at an exercise price of $1,150.00 per share, that were originally issued in the Initial Public Offering.
“Reverse Stock Split”
refers to the Company’s reverse stock split that became effective at 12:01 a.m. Eastern time on January 8, 2025, pursuant to which
each 100 shares of Common Stock outstanding immediately prior thereto was converted into 1 share of Common Stock outstanding immediately
thereafter.
“Rollover Warrants” refer to warrants
to purchase shares of Common Stock, at an exercise price of $1,000.00 per share, that were converted from Legacy CERo warrants in connection
with the Business Combination.
vii
“SEC” refers to the U.S. Securities and
Exchange Commission.
“Secondary Earnout Shares” refer to the
8,750 shares of Common Stock issued to the holders of Legacy CERo common stock and Legacy CERo preferred stock in connection with the
Business Combination, which became fully vested at Closing.
“Second PIPE Financing” refers to the
private placement pursuant to which we issued and sold, and the PIPE Investors purchased, shares of Series B Preferred Stock, on the terms
and conditions set forth in the Second Securities Purchase Agreement.
“Second PIPE Registration Rights Agreement”
refers to the Registration Rights Agreement, dated as of March 29, 2024, by and between CERo and certain PIPE Investors.
“Second Securities Purchase Agreement”
refers to the Securities Purchase Agreement, dated as of March 29, 2024, by and among CERo and certain PIPE Investors, pursuant to which
CERo agreed to issue and sell 626 shares of Series B Preferred Stock.
“Series A Preferred Stock” refers to
the Series A convertible preferred stock, $0.0001 par value per share, of CERo.
“Series A Warrants” refers to warrants
to purchase Common Stock, at a current exercise price of $139.00 per share, sold to certain PIPE Investors pursuant to the First Securities
Purchase Agreement.
“Series B Preferred Stock” refers to
the Series B convertible preferred stock, $0.0001 par value per share, of CERo.
“Series C Preferred Stock” refers to
the Series C convertible preferred stock, $0.0001 par value per share, of CERo.
“Series C Warrants” refers to warrants to purchase
shares of Common Stock, at a current exercise price of $0.04 per share, sold to certain PIPE Investors pursuant to the Third Securities
Purchase Agreement.
“Sponsor” refers to Phoenix Biotech Sponsor,
LLC, a Delaware limited liability company.
“Tertiary Earnout Shares” refer to the 10,000 shares
of Common Stock issued to the holders of Legacy CERo common stock and Legacy CERo preferred stock in connection with the Business Combination,
which became fully vested upon the achievement of certain regulatory milestone-based earnout targets.
“Third PIPE Financing” refers to the
private placement pursuant to which we issued and sold, and the PIPE Investors purchased, shares of Series C Preferred Stock, on the terms
and conditions set forth in the Third Securities Purchase Agreement.
“Third PIPE Registration Rights Agreement”
refers to the Registration Rights Agreement, dated as of September 26, 2024, by and between CERo and certain PIPE Investors.
“Third Securities Purchase
Agreement” refers to the Securities Purchase Agreement, dated as of September 25, 2024, by and among CERo and certain PIPE Investors,
pursuant to which CERo agreed to issue and sell 2,853 shares of Series C Preferred Stock and the Series C Warrants to purchase 81,753
shares of Common Stock.
“Warrant Preferred Shares” refer to the
shares of Preferred Stock underlying the Preferred Warrants.
“Warrants” refer to the Rollover Warrants,
the Private Placement Warrants, the Common Warrants, the Preferred Warrants, the Public Warrants, the February 2025 Common Warrants and the Pre-Funded Warrants.
viii
RISK FACTORS SUMMARY
Our business is subject to
numerous risks and uncertainties that you should consider before investing in our securities. Some of the principal risk factors are summarized
below:
● There is substantial doubt as to our ability to continue as a going concern.
ix
x
xi
PART I
Item 1. Business.
Overview
We are an innovative immunotherapy
company advancing the development of next-generation engineered T cell therapeutics for the treatment of cancer. Our proprietary approach
to T cell engineering, which enables us to integrate certain desirable characteristics of both innate and adaptive immunity into a single
therapeutic construct, is designed to engage the body’s full immune repertoire to achieve optimized cancer therapy. Our novel cellular
immunotherapy platform is designed to redirect patient-derived T cells to eliminate tumors by building in pathways that employ both cytotoxic
and phagocytic mechanisms to destroy cancer cells, creating what we refer to as CER-T cells. Our lead molecule is CER-1236, an autologous
T-cell product that targets a novel tumor antigen, TIM-4 ligand. Unlike currently approved chimeric antigen receptor (“CAR-T”)
therapies which have largely been active in hematological B cell malignancies, we believe CER-1236 will be active in both hematological
malignancies and solid tumors.
On November 14, 2024, we received notice from the FDA that the Investigational
New Drug Application (“IND”) was cleared after being put on a brief clinical hold due to insufficient nonclinical data to
adequately judge off target toxicity. The clinical hold was lifted after additional in vitro experiments were performed. We submitted
a second IND application for the investigation of CER-T cell therapy in non-small cell lung cancer (“NSCLC”) and ovarian cancer,
which was accepted by the FDA on March 27, 2025.
The ability to enhance the
activity of T cells against human cancers through genetic engineering has been among the most significant advances in cancer therapy in
the last decade. One of the more promising therapeutic uses of T cells to emerge has been CAR-T cell technology. However promising CAR-T
cell therapy has been, its use has been largely limited to the treatment of certain hematological cancers due to lack of specific tumor-associated
antigens and CAR-T cells’ limited ability to proliferate, traffic, and circulate in solid tumors. Curative cell therapies for solid
tumors currently do not exist, and the significance of this limitation is underscored by the prevalence of solid tumor malignancies. The
American Cancer Society estimates that solid tumor cancers accounted for more than 1.7 million of the 1.9 million people newly diagnosed
with cancer in 2022. Even in hematological malignancies with approved CAR-T cell therapies, cure rates do not exceed 60%. Nevertheless,
despite such limitations, sales of CAR-T cell therapies are anticipated to grow rapidly over the next several years and are expected to
exceed $10 billion globally by 2030.
We believe that the preferential
attributes engineered into our CER-T cell therapy enables us to overcome many of the limitations which hinder the wider application of
CAR-T technology. Our CER-T cells employ a novel targeting mechanism that targets a ligand broadly expressed on tumor cells but not healthy
cells. Specifically, CER-1236 targets the TIM-4 Ligand (“TIM-4-L”), otherwise known as phosphatidylserine (“PS”),
a critical component of the cell’s plasma membrane that has a key role in cell removal. Exposure of TIM-4-L on the outer surface
of the plasma membrane acts as an “eat-me” signal and marks abnormal, stressed and dying or dead cells for phagocytosis. The
pro-phagocytic activities of CER-T cells are designed to integrate innate immune effector functions into cytotoxic killer T cells, creating
within a single T cell the ability to directly mediate cytotoxic effects and indirectly prime other immune cells. Moreover, in preclinical
studies, we have observed that CER-1236 cells exhibit superior cross-presentation abilities compared to conventional T cells, potentially
triggering a broad complement of immune effector cells against tumors. Since externally oriented TIM-4-L is broadly expressed by numerous
cancer cell types but has very limited exposure on normal healthy cells, we envision CER-1236 as having differentiated therapeutic utility
with application across a wide array of cancer types.
We have patterned the design
of our CER-T constructs based upon many of the components found in existing conventional CAR-T cell therapies, which we believe could
shorten development timelines and enhance commercial application. The processes and protocols used to genetically modify a patient’s
T cells to produce CAR-T cells are already well recognized, as is the use of lentivirus in the manufacture of these therapies. Accordingly,
we have developed CER-T cell manufacturing processes that closely resemble those used to produce existing engineered CAR-T cells. We also
expect to benefit from the well-defined and recognized regulatory guidelines established by both U.S. and European regulatory authorities
related to CAR-T therapies and their use. In contrast to these attributes, we believe that other emerging CAR-based drug candidates which
involve immune effector cells other than T cells, such as CAR-NK and CAR-M therapies, are unlikely to enjoy similar benefits.
1
In preclinical studies, we have observed CER-1236
to display attractive functional attributes, among which are:
● phagocytosis of tumor cells;
● enhanced antigen acquisition, processing and presentation;
● no evidence of T cell exhaustion despite repeated challenges;
● no observed off-target or off-tumor toxicities;
● well defined and scalable manufacturing protocols.
Based on the
preclinical data regarding the use of CER-1236 T cells to combat hematologic malignancies, we anticipate beginning clinical trials
in the first half of 2025. We anticipate that our initial targets will be relapsed, remitting acute myeloid leukemia
(“AML”) patients as well as AML patients with measurable residual disease (“MRD”) and patients with
mutations in TP53, a gene mutation associated with aggressive AML. AML is a heterogenous and aggressive hematopoietic malignancy
characterized by the rapid buildup of immature myeloid cells in the bone marrow and blood. This process results in the inhibition of
normal hematopoiesis, manifesting as neutropenia, anemia, thrombocytopenia, and the clinical features of bone marrow failure.
According to the American Cancer Society, AML accounts for 90% of all acute leukemias in adults, with an estimated 22,010 new cases
and 11,090 deaths expected in the United States in 2025. The current treatment has remained largely unchanged over several decades
with combination chemotherapy with cytarabine for 7 days and an anthracycline for 3 days (“7+3”). Newer, targeted
approaches that include multi-kinase domain inhibitors and antibody-drug conjugates are now available during induction chemotherapy
for certain patients. For patients that are sufficiently healthy and at unfavorable risk, allogeneic Hematopoietic Stem Cell
Transplants (“HSCTs”) are commonly performed. Despite these interventions, there is significant unmet medical need for
novel therapies, including cell therapeutic approaches. Given the incidence of AML, CER-1236 T cell therapy may qualify for an
Orphan Drug Designation by the FDA, and we have submitted an application to the FDA for an Orphan Drug Designation on March 18,
2025.
Our Phase 1 AML clinical trial is intended to evaluate the safety,
potential therapeutic utility and applicable dose of CER-1236. The approved starting dose for the clinical trial is sufficiently high
that we expect to begin to see clinical activity by the second dose level cohort. Concurrent with a trial in these hematological malignancies,
we intend to expand the clinical development of CER-1236 with an additional IND submission, which has been approved, to investigate solid
tumors such as NSCLC and ovarian cancer. We believe that CER-1236 has the potential to address unmet medical needs in the targeted indications,
and be differentiated from currently available therapeutics by its safety, tolerability and efficacy. Since no clinical trials of CER-1236
have commenced, none of the abovementioned statements regarding any of our products in development are intended to be a prediction or
conclusion of efficacy.
Our Strategy
Our intent is to become a
leading biopharmaceutical company focused on the capital-efficient advancement of innovative anti-cancer product candidates targeting
the unmet medical need associated with aggressive and difficult-to-treat hematological malignancies and solid tumors. To accomplish this
objective, the key elements of our strategy include:
2
The Immune System and its Function
The immune system is a host
defense system comprising multiple structures and processes within an organism that protects against disease. As with other mammalian
species, the human immune system is segregated into two separate yet interconnected components, the innate immune system and the adaptive
immune system. The innate immune system is responsible for an immediate, non-specific response to infected or diseased cells. Triggering
its activation are pathogen-associated and damage-associated molecular patterns recognized by preconfigured pattern recognition receptors
which reside on the surface of various types of leukocytes, or white blood cells, that make up the innate immune system, including macrophages,
dendritic cells, eosinophils and natural killer (“NK”) cells. In addition to its direct participation in eliminating damaged
or diseased cells, certain components of the innate immune system function significantly as antigen-presenting cells (“APCs”)
promoting the activity of the adaptive immune system.
The adaptive immune system
is composed of special types of leukocytes known as T and B lymphocytes, also known as T and B cells, respectively. T cells participate
primarily in the cell-mediated immune response while B cells are involved in the humoral immune response. T cells are an essential component
of the adaptive immune system, targeting specific antigens and either destroying targeted cells directly or participating in their destruction
by activating other immune cells. T cells use T cell specific receptors to recognize antigens presented via major histocompatibility complex
(“MHC”) molecules on APCs. Through this mechanism, T cells have the ability to target tumor-transformed or virus infected
cells, as well as help coordinate the activity of other immune cells.
T cells are differentiated by the expression of protein markers on
their surface. The two most prominent types of T cells are those that express CD8 molecules and are known as CD8 T cells, and those that
express CD4 molecules and are known as CD4 T cells. CD8 T cells, also referred to as cytotoxic lymphocytes (“CTLs”), eliminate
cells which they encounter that are recognized as being infected with viruses or other pathogens or are otherwise damaged or dysfunctional
through a process referred to as cell lysis, which involves the release by these killer T cells of perforins and granzymes to compromise
the integrity of the target cell’s membrane. Endogenous pathogens are broken down by mechanisms present in virtually all cells into
smaller fragments and presented to CD8 T cells in combination with an MHC Class I molecule. CD4 T cells, also referred to as T helper
cells, have limited cytotoxic activity and typically do not kill infected or dysfunctional cells or eliminate pathogens directly. Instead,
they participate in the immune response by providing signals which activate and orchestrate other types of immune cells to perform these
tasks. Professional APCs, such as dendritic cells and macrophages, process exogenous pathogens and then present small fragments of the
degraded pathogen to CD4 T cells in combination with an MHC Class II molecule, through a phenomenon known as cross-presentation, while
antigens of exogenous origin are coupled with an MHC Class I molecule to amplify CD8 T cell activity. Antigen cross presentation is of
particular importance in the immune system’s response to cancer.
3
Genetically Engineered T Cells
The ability to enhance the
activity of T cells against human cancers through genetic engineering has been among the most significant advances in cancer therapy in
the last decade. Advances in understanding T cells and their role in immunology, and an appreciation of their potential use to treat cancer,
has increased interest in the clinical application of T cells in recent years, with the field of adoptive immunotherapy attaining increased
prominence as a means of enhancing immune control over tumors. Modern molecular biological techniques allow scientists to introduce genes
into human T cells that enhance T cell activity, expand their numbers and infuse them back into the patient from whom they were originally
collected. We have developed a novel approach to T cell engineering which has enabled us to integrate certain desirable characteristics
of both the innate immune system and the adaptive immune system into a single therapeutic construct intended to optimize cancer therapy.
This novel cellular immunotherapy platform is designed to redirect T cells to eliminate tumors by building in engulfment pathways that
employ phagocytic programs, creating our CER-T cell therapy.
Phagocytosis is a vital cellular
process by which a phagocytic cell engulfs and internalizes a target for elimination and is a major mechanism for the removal of pathogens
and unwanted cells to maintain tissue homeostasis. The human body removes billions of cells daily through phagocytic processes. Phagocytic
removal employs specific cell clearance programs and machinery to eliminate target cells. The process is a crucial part of the innate
immune system and is distinct from the adaptive immune response which involves the generation of cytotoxic T cells to elicit antigen-specific,
cytolytic target elimination. Compared to traditional CAR-T cell approaches, which largely target the adaptive immune system, we developed
CER-T cell therapy to collaboratively mediate both cytotoxic and phagocytic mechanisms to optimize anti-tumor function. By leveraging
both immune responses, we believe CER-T cell therapy has the potential to eliminate cancer cells more effectively and with fewer side
effects than traditional CAR-T cell therapies.
The recognition of phagocytosis
as a therapeutic modality to directly clear cancer cells and initiate anti-tumor T cell immune responses has fueled interest in effectively
engaging phagocytes for use in cancer therapy. Macrophage cell engineering and macrophage-targeting approaches that enhance cytotoxic,
phagocytic and cytokine-mediated anti-tumor function are in development. Early clinical trial data from therapeutic candidates targeting
myeloid inhibitor function has demonstrated the potential to elicit clinical responses. However, the diverse pro-tumor functions of myelo-monocytic
cells may offset these efforts by supporting cancer cell survival, proliferation and the release of factors that may impede anti-tumor
immune responses. Limited in vivo proliferation and manufacturing challenges have also been hurdles in the development of macrophage-based
cellular therapy.
Experimental evidence demonstrates
the ability of CER-T cells to engulf targeted cells, employ cytolytic and non-cytolytic killing mechanisms, and exhibit pro-inflammatory
and antigen processing capabilities that augment the current capabilities of T cell immunotherapy. To that end, we believe CER-1236 cell
therapy, if approved, may become a component of standard of care treatment regimens, used as a monotherapy or in combination with both
small molecule therapeutics and biologics to direct robust tumor elimination.
The Increasing Prominence of CAR-T Technology
Immunotherapy is a treatment
that harnesses the components and mechanics of the immune system to address diseases and disorders. Cellular immunotherapy is a form of
immunotherapy that focuses on modulating or enhancing the activity of different immune cells. One of the more prominent and promising
therapeutic uses of T-cells to emerge has been CAR-T cell technology.
CAR-T therapy recognizes
specific antigens that are present on the surface of tumor cells and destroys them. The concept of CAR-T builds upon the normal biology
of CTLs, whereby naturally occurring receptors serve to activate these cells when a foreign pathogen or cancerous cell is detected. Conventional
CAR-T cell therapy involves the genetic manipulation of a patient’s T cells to enable these modified cells to express a receptor
designed to bind to a specific surface antigen. To engineer these cells, a fraction of a patient’s T cells are collected from their
blood, and a viral vector containing the genetic instructions for the CAR is used to insert those genes into the genome of the T cell
through a process known as transduction. Contained in a single viral vector are the genes encoding for each component of the CAR. Typical
CAR-T cells include the following components:
4
The assembly of these core
CAR components is depicted in the schematic presented below to which certain non-coding regulatory sequences may be used to augment viral
gene expression.
Delivery of conventional CAR-T cell therapies involves a single
viral vector.
Conventional CAR-T cell therapies
often utilize a lentiviral vector for the delivery of CAR specific genes. Lentiviral particles offer a well-characterized transduction
mechanism and are recognized as efficient and convenient vehicles for gene transfer as they demonstrate broad tropism, or activity, in
a wide array of cell types, and can be used to target quiescent, or non-dividing, cells. In addition, they do not integrate close to the
promoter regions of genes with the frequency of other gene delivery alternatives and lack the immunogenicity of DNA-based vectors, characteristics
which provide for enhanced safety. The use of a lentiviral vector to facilitate ex vivo clinical gene transfer has been demonstrated to
be safe in humans for two decades with minimal genotoxicity observed in hundreds of patients following gene transfer into T cells or hematopoietic
progenitor cells.
Currently, six CAR-T cell
therapies have been approved by the FDA for the treatment of certain types of hematological cancers. The first two, approved in 2017,
are axicabtagene ciloleucel, sold by Gilead Sciences under the brand name Yescarta, and tisagenlecleucel, sold by Novartis under the brand
name Kymriah. A third CAR-T cell therapy, brexucabtagene autoleucel, which is comparable to Yescarta and sold by Gilead under the tradename
Tecartus, was approved in 2020. Lisocabtagene matraleucel, sold by Bristol Myers Squibb under the brand name Breyanzi, received FDA approval
in February 2021 with Bristol Myers Squibb also receiving approval for idecabtagene vicleucel, sold under the tradename Abecma, in March
of that year. Most recently, Janssen Biotech received FDA approval for ciltacabtagene autoleucel, brand name Carvykti, to treat adult
patients with relapsed or refractory multiple myeloma and which targets the BCMA protein expressed on cancer cells rather than CD19, the
target of the other approved CAR-T cell therapies. Each of these therapies is an autologous therapy and is made from T cells first collected
from the patient, which are then genetically modified and administered back to the same patient. Sales of CAR-T cell therapies are anticipated
to grow rapidly over the next several years and are expected to exceed $10 billion by 2030. CAR-constructs incorporating alternate immune
effector cell types, including NK cells and macrophages, are in earlier stages of clinical development and have only recently entered
clinical trials. To date, no CAR-based therapies that employ NK cells or macrophages have received FDA approval. There are at present
no FDA approved CAR T cell products for AML.
5
The Limitations of Current CAR-T Technology
Much of the excitement of
cellular therapy surrounds the curative potential of adoptive transfer of genetically engineered T cells. Adoptively transferred T cells
proliferate upon their engagement with target antigens and represent a form of therapy that can be appropriately characterized as living
and expanding. Efficient targeted killing and tumor elimination may be achieved in a short period of time. However, multiple barriers
limit the efficacy of conventional CAR-T cell therapy. A high rate of side effects often accompany treatment with currently approved products,
especially in those patients with high tumor burdens. In addition, partial responses occur, often associated with immune escape of the
tumor from the CAR or the display by the T cells of an exhaustion phenotype. Moreover, while engineered CAR-T cells have shown remarkable
potential in the treatment of hematological cancers, they have not demonstrated equivalent efficacy in the treatment of solid tumors.
Curative cell therapies for solid tumors currently do not exist and the importance of this limitation is underscored by the prevalence
of solid tumor malignances. The American Cancer Society estimates that solid tumor cancers accounted for more than 1.7 million of the
1.9 million people newly diagnosed with cancer in 2021. Even in hematological malignancies with approved CAR-T cell therapies, less toxic
orthogonal treatment approaches are needed as cure rates for CD19-targeted CAR-T cell therapies do not exceed 60%.
Challenges to the use of
cellular therapy to address solid tumors often relate to difficulty in developing receptors directed towards targets expressed in high
frequency on cancer cells as well as overcoming the immunosuppressive microenvironments that contribute to ineffective immune responses.
The tumor stroma, made up of a dense fibrotic matrix, often surrounds solid tumors and acts as a physical barrier, which restricts CAR-T
cell access to the tumor. CAR-T cell activity may be further hindered by the tumor microenvironment (“TME”). In the TME, multiple
cell types which drive immunosuppression infiltrate solid tumors, including myeloid-derived suppressor cells, tumor-associated macrophages,
and regulatory T cells. The interaction of these cells and the tumor cells increases the expression of signaling molecules that enable
tumor cell proliferation while dampening the generation of co-stimulatory signals necessary for T cell expansion and persistence. In addition,
TME-associated immune dysfunction may result in a down regulation of MHC class I molecules, limiting proper antigen presentation and T
cell proliferation. Collectively, these attributes of solid tumors enable them to avoid normal immune surveillance. Increased engagement
of the endogenous host response is an important, if not critical, component of CAR-T cell therapy clinical success as the recruitment
into the tumor of bystander lymphocytes has been observed in tumor biopsies from patients with curative CAR-T cell therapy. Enhancing
the host’s own response to tumor cells offers an important opportunity to improve current CAR T cell responses.
CAR-T recipients may also
incur serious adverse events (“SAEs”), perhaps the most prominent of which is cytokine release syndrome (“CRS”).
Believed to be related to the rapid proliferation and activation of T cells upon detection of a target antigen, severe or life-threatening
CRS was noted in a significant number of patients who participated in the registrational trials of FDA-approved CAR-T therapies. These
SAEs can result in patients requiring longer hospitalizations and more intensive medical care. The frequency and severity of observed
SAEs is one of the primary reasons that administration of currently approved CAR-T therapy is restricted to a select number of treatment
centers. Moreover, aside from the low-level expression of certain cancer specific neoantigens, most tumor associated antigens are also
found on normal cells which may lead to serious, if not life threatening, “on-target, off-tumor” toxicities.
We believe that the preferential
attributes engineered into our CER-T cell therapies have the potential to represent a next-generation adoptive cellular immunotherapy
approach and enable us to overcome many of the limitations which hinder the wider application of current CAR-T technology. The prophagocytic
and immunomodulatory properties of CER-T cells are designed to overcome some of the immunosuppressive elements in many solid tumors. In
addition, their anticipated superior antigen presentation properties may enhance a patient’s ongoing immune response against tumor
antigens. Lastly, healthy cells have minimal expression of TIM-4-L as compared to tumor cells, reducing the potential for on-target off-tumor
effects. In consequence, we envision CER-1236 as having a differentiated mechanism for tumor clearance that enables the potential for
enhanced activity across a broad array of hematological malignancies and solid tumors.
6
CER-T Cell Therapy Technology
Distinguishing our CER-1236
cell therapy candidate is the integration into a single therapeutic construct of many of the anti-tumor capabilities resident in both
the innate and the adaptive immune systems. We believe the coupling of these functions better emulates normal immune system activity which
may promote enhanced T cell activation, proliferation and durability for more robust elimination of cancerous cells and reduction in tumor
burden.
We have designed our CER-T
constructs to embrace many of the components found in conventional CAR-T cell therapies. The processes and protocols used to genetically
modify a patient’s T cells to produce CAR-T cells are well recognized, as is the use of lentivirus in the manufacture of these therapies.
Accordingly, we have constructed CER-1236 cell manufacturing processes to be similar to those of CAR-T cells. We expect to benefit from
the well-defined regulatory guidelines established by both U.S. and European regulatory authorities related to CAR-T cell therapy and
its use.
The biological foundations for CER-T cell therapy
PS, or TIM-4 ligand, is a
component of a cell’s plasma membrane and has a key role in cell removal. Under normal physiological conditions, TIM-4-L is restricted
to the inner leaflet of the phospholipid bilayer which makes up the plasma membrane of a cell. However, cellular stresses cause the externalization
of TIM-4-L to the cell surface. Exposure of TIM-4-L on the outer surface acts as an “eat-me” signal and marks abnormal, stressed
and dying or dead cells for phagocytic clearance. A variety of tumors have been shown to have constitutively increased surface TIM-4-L
as a result of altered plasma membrane regulation. Among hematologic tumors, loss-of-function mutations in the flippase chaperone transmembrane
protein 30A (“TMEM30A”), have been identified in approximately 11% of patients with diffuse large B cell lymphoma (“DLBCL”),
and this mutation was correlated with improved response to the standard therapeutic regimen suggesting the host’s immune elimination
of TIM-4-L positive tumor cells enhances tumor clearance. We are seeking to exploit the presence of TIM-4-L expressed on the outer cell
surface of both hematological malignancies and solid tumors.
CER-1236: Our Lead Development Candidate
As externally oriented TIM-4-L
is present on many cancerous cells regardless of tumor type, we believe a single CER construct may demonstrate clinical utility in treating
an array of cancers. To that end, we have focused our development activities on optimizing the cancer killing capabilities of a specific
CER-T therapeutic design. These efforts have resulted in our lead clinical candidate, CER-1236. In preclinical studies, we have observed
CER-1236 to display attractive functional capabilities and product characteristics, among which are:
● tumor cell phagocytosis;
● enhanced antigen acquisition, processing and presentation;
● no evidence of T cell exhaustion despite repeated challenges;
● no observed off-target or off-tumor toxicities;
● well defined and scalable manufacturing protocols.
7
We have designed CER-1236
to align with components included in the current generation of conventional CAR-T configurations by fusing the external domain of TIM-4,
a phagocytic receptor, with intracellular signaling domains from T cells and innate immune cells. TIM-4 harbors endogenous phagocytic
capacity through its binding to the pro-phagocytic “eat-me” signal TIM-4-L. CER-1236’s intracellular signaling domains,
including TLR2, CD28 and CD3ξ motifs, are designed to augment both TIM-4 mediated phagocytosis and cytotoxic T cell function. Another
similarity between conventional CAR-T therapeutic formats and our CER-T design is the delivery vehicle used in transduction. As is found
in many approved CAR-T therapies, our CER-T technology also employs a lentiviral vector to facilitate gene delivery to patient-derived
T cells. A schematic of the structural elements of CER-1236 is presented below.
Schematic of CER-1236
Abbreviations: TIM-4 = ectodomain
of the T cell immunoglobulin mucin domain protein 4; TLR2 = toll-like receptor 2.
CER-1236 employs an innovative mechanism of
action
CER-1236 is an autologous
T cell therapy candidate designed to target TIM-4-L through the external domain of the prophagocytic receptor TIM-4 protein. This therapeutic
construct was developed to combine adaptive T cell killing activity with phagocytic clearance and antigen presentation activity to create
T cells with enhanced cancer immunotherapy capabilities. The approach builds on the early success of adoptive T cell transfer, which has