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 001-40652
INDAPTUS
THERAPEUTICS, INC.
(Exact
name of Registrant as specified in its Charter)
3 Columbus Circle 15th Floor New York, NY 10019
(Address of principal executive offices) (Zip Code)
Registrant’s
telephone number, including area code: +(646)427-2727
Securities
registered pursuant to Section 12(b) of the Act:
Common stock, par value $0.01 INDP 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, 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☒
At
June 30, 2024, the last business day of the Registrant’s most recently completed second fiscal quarter, the aggregate market value
of the voting and non-voting common equity held by non-affiliates of the Registrant was $15,039,986.
The
number of shares of Registrant’s common stock outstanding as of March 12, 2025 was 14,429,244.
DOCUMENTS
INCORPORATED BY REFERENCE
None.
Table of Contents Page
PART I 6
Item 1. Business 6
Item 1A. Risk Factors 26
Item 1B. Unresolved Staff Comments 61
Item 1C. Cybersecurity 61
Item 2. Properties 62
Item 3. Legal Proceedings 63
Item 4. Mine Safety Disclosures 63
PART II
Item 6. [Reserved] 63
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 70
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 71
Item 9B. Other Information 72
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 72
PART III
Item 10. Directors, Executive Officers and Corporate Governance 72
Item 11. Executive Compensation 80
Item 14. Principal Accountant Fees and Services 94
PART IV
Item 15. Exhibits and Financial Statement Schedules 94
ABOUT
THIS ANNUAL REPORT
All
references to “we,” “us,” “our,” “Indaptus Therapeutics”, “Indaptus”, “the
Company” and “our company”, in this Annual Report on Form 10- K, or our Annual Report, are to Indaptus Therapeutics,
Inc. (formerly Intec Parent, Inc.) and, where appropriate, its consolidated subsidiaries, Intec Pharma Ltd. and Decoy Biosystems, Inc.
All references to “common stock” and “share capital” refer to common stock and share capital of Indaptus. Our
historical results do not necessarily indicate our expected results for any future periods. Any discrepancies in any table between totals
and sums of the amounts listed are due to rounding. Unless otherwise indicated, or the context otherwise requires, references in this
Annual Report to financial and operational data for a particular year refer to the fiscal year of our Company ended December 31 of that
year.
EXPLANATORY
NOTE
Market
data and certain industry data and forecasts used throughout this Annual Report were obtained from market research databases, consultant
surveys commissioned by us, publicly available information, reports of governmental agencies and industry publications and surveys. Industry
surveys, publications, consultant surveys commissioned by us and forecasts generally state that the information contained therein has
been obtained from sources believed to be reliable. We have relied on certain data from third-party sources, including internal surveys,
industry forecasts and market research, which we believe to be reliable based on our management’s knowledge of the industry. Statements
as to our market position are based on the most currently available data. While we are not aware of any misstatements regarding the industry
data presented in this Annual Report, our estimates involve risks and uncertainties and are subject to change based on various factors,
including those discussed under Part I. Item 1A. “Risk Factors” in this Annual Report.
CAUTIONARY
NOTE REGARDING FORWARD-LOOKING STATEMENTS
This
Annual Report contains, and management may make, certain forward-looking statements within the meaning of the Private Securities Litigation
Reform Act of 1995. All statements other than statements of historical facts contained in this Annual Report on Form 10-K are forward-looking
statements. In some cases, forward-looking statements can be identified by the use of terms such as “believe,” “expect,”
“intend,” “plan,” “may,” “should,” “anticipate,” “could,” “might,”
“seek,” “target,” “will,” “project,” “forecast,” “continue” or
their negatives or variations of these words or other comparable words. These statements include, without limitation, our statements
about: our product candidates’ development, including the timing and design of the Phase 1 clinical trial of Decoy20; our expectations
regarding the recommended Phase 2 dose for subsequent multi-dosing and combination studies and related timing; the anticipated effects
of our product candidates; our plans to develop and commercialize our product candidates; the market potential and treatment potential
of our product candidates, including Decoy20; our commercialization, marketing and manufacturing capabilities and strategy; our expectations
about the willingness of healthcare professionals to use our product candidates; our general business strategy and the plans and objectives
of management for future operations; our research and development activities and costs; our future results of operations and condition;
the sufficiency of our cash and cash equivalents to fund our ongoing activities; the impact of current macroeconomic conditions on our
operations, ability to access capital, and liquidity; and any impact of a pandemic, epidemic or other future health crisis on our business.
The
forward-looking statements in this Annual Report are only predictions and are based largely on our current expectations and projections
about future events and financial trends that we believe may affect our business, financial condition and results of operations. These
forward-looking statements speak only as of the date of this Annual Report and are subject to a number of known and unknown risks, uncertainties
and assumptions, including those described under the sections in this Annual Report entitled “Summary Risk Factors,” Part
I. Item 1A. “Risk Factors” and Part II. Item 7. “Management’s Discussion and Analysis of Financial Condition
and Results of Operations” 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 and some
of which are beyond our control, 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. Moreover, we operate in an evolving environment. New risk factors and uncertainties
may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties.
Except
as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as
a result of any new information, future events, changed circumstances or otherwise. We intend the forward-looking statements contained
in this Annual Report to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities
Act of 1933, as amended, or the Securities Act, and Section 21E of the Securities Exchange Act of 1934, as amended, or the Exchange Act.
Summary
Risk Factors
The
principal factors and uncertainties that make investing in our common stock risky, include, among others:
PART
I
Item
1. Business.
Overview
We
are a clinical biotechnology company developing a novel and patented systemically-administered anti-cancer and anti-viral immunotherapy.
We have evolved from more than a century of immunotherapy advances. Our approach is based on the hypothesis that efficient activation
of both innate and adaptive immune cells and associated anti-tumor and anti-viral immune responses will require a multi-targeted package
of immune system activating signals that can be administered safely intravenously. Our patented technology is composed of single strains
of attenuated and killed, non-pathogenic, Gram-negative bacteria, designed to have reduced i.v. toxicity, but largely uncompromised ability
to prime or activate many of the cellular components of innate and adaptive immunity. This approach has led to broad anti-tumor and anti-viral
activity in preclinical models, including durable anti-tumor response synergy observed with each of four different classes of existing
agents, including NSAIDs, checkpoint therapy, targeted antibody therapy and low-dose chemotherapy. Tumor eradication by our technology
was associated with induction of both innate and adaptive immunological memory and, importantly, did not require provision of or targeting
a tumor antigen in preclinical models. We have carried out successful current Good Manufacturing Practice (cGMP) manufacturing of our
lead clinical candidate, Decoy20.
In
May 2022, the U.S. Food and Drug Administration, or the FDA, allowed us to proceed under our IND for a Phase 1 clinical trial in patients
with advanced solid tumors where currently approved therapies have failed. In December 2022, we initiated an open label, multi-center,
dose escalation and expansion, single arm (monotherapy) Phase 1 study conducted in 2 parts. The Phase 1 study began with single dose
administration and has now been followed with continuous weekly dosing of Decoy20 in tumor-specific expansion cohorts. The study is enrolling
patients with any one of six advanced/metastatic solid tumors, who have exhausted approved treatment options. The study’s objectives
are to assess the safety and tolerability of Decoy20, to determine the maximum tolerated dose, the optimal biologically active and recommended
Phase 2 dose, as well as to assess Decoy20 pharmacokinetics (PK), pharmacodynamics and clinical activity. The primary endpoints of the
study are incidence, relatedness and severity of adverse events and treatment-emergent adverse events and determining the number of subjects
per cohort with dose limiting toxicity-based adverse events. Secondary endpoints include the incidence of anti-drug antibodies and neutralizing
antibodies pre- and post-treatment, change in Decoy20 PK parameters over time, objective response rate and duration of response.
In
August 2023, we evaluated the first four patients who received a single dose of 7 x 10^7 Decoy20 in Part 1 of the Phase 1 clinical trial.
All four patients who enrolled were evaluable in the first cohort. These patients experienced generally anticipated transient adverse
events including hemodynamic changes such as changes in pulse or blood pressure that resolved within 30 minutes and laboratory abnormalities
such as grade 1-3 elevations in transaminases (liver function tests) and grade 4 reductions in lymphocytes that generally resolved within
three days. One patient had a dose-limiting toxicity of grade 3 bradycardia (slow heart rate) and grade 2 hypotension (low blood pressure)
which resolved within approximately 90 minutes with i.v. fluids. Patients also experienced transient induction of over 50 different biomarkers
associated with innate and adaptive anti-tumor immune responses. After the end of infusion, Decoy20 was cleared from the blood within
30 to 120 minutes. Peak cytokine and chemokine induction occurred within ~4 to 24 hours and most cytokine/chemokines returned to the
patient’s respective baseline by 24-72 hours. This rapid clearance and associated transient cytokine/chemokine induction are desired
to avoid prolonged toxicity, often associated with longer term cytokine exposure.
In
September 2023, we began the second cohort of the Phase 1 clinical trial after receiving authorization from the Safety Review Committee.
The second cohort dose was a reduction from 7 x 10^7 Decoy20 dose to 3 x 10^7 Decoy20. In March 2024, we completed the second cohort
of patients who received a single dose of 3 x 10^7 Decoy20 in Part 1 of the clinical trial Patients on the second (lower dose) cohort
experienced adverse events similar in frequency and severity to the higher dose cohort with one dose-limiting toxicity of grade 3 ALT
elevation that required one week to resolve. Pharmacodynamic effects included transient induction of multiple biomarkers. Clearance of
Decoy20 was similarly rapid. Following authorization from the Safety Review Committee, we advanced into the weekly dosing part of the
trial.
In
May and June 2024, we enrolled two additional patients in the first cohort who received a single dose of 7 x 10^7 Decoy20, and in August
2024 we received the authorization from the Safety Review Committee to initiate the weekly dosing with 7 x 10^7 Decoy20.
As
of October 2024, we completed one month of the weekly dosing part in the first six patients at the 3 x 10^7 Decoy20 dose and following
the review of the safety data by the Safety Review Committee we received the authorization to initiate unrestricted enrollment of patients
at the 3 x 10^7 Decoy20 dose. As of March 12, 2025, we have enrolled more than 20 patients in the weekly dosing among the two Decoy20 dose levels
and we have observed early signs of potential benefits emerging with some patients with stable disease. We are working to increase the
number of trial sites to accelerate patient enrollment and data collection.
In
October 2024, we entered into a clinical supply agreement, or the Supply Agreement, with BeiGene Switzerland GmbH, or BeiGene, to advance
clinical evaluation of Decoy20 in combination with BeiGene’s anti-PD-1 antibody, tislelizumab, or the BeiGene Product, for the
treatment of patients with advanced solid tumors, or the Combination Study. This Combination Study builds on preclinical results where
Decoy20, combined with a PD-1 inhibitor, demonstrated high tumor eradication rates and established immunological memory. We intend to
seek approval from the FDA to initiate the Combination Study, which is anticipated to begin in 2025.
Under
the terms of the Supply Agreement, we will pay for all costs associated with the Combination Study (other than the cost of the BeiGene
Product), BeiGene will supply the BeiGene Product to us for the purposes of the study, and we will supply Decoy20 for the purposes of
the Combination Study. The Supply Agreement will terminate upon the earlier of (i) the one-year anniversary of the date that we provide
BeiGene with the Combination Study’s final clinical study report or (ii) the date of termination of the Combination Study, subject
to early termination in certain circumstances.
In
February 2025, we announced that we received clinical trial authorization from Health Canada to initiate a clinical trial for Decoy20
which allows us to expand our ongoing U.S. clinical trial to Canadian sites. The trial will enroll patients in Canada under the current
protocol, which involves weekly dosing of Decoy20. We also plan to submit an amendment to Health Canada to initiate the Combination Study
in Canada.
Unlike
many competitor products, our technology does not depend on targeting with or to a specific antigen, providing broad potential across
multiple indications. Our products are designed to have a much shorter half-life and produce less systemic exposure than small molecule,
antibody or human cell-based therapies, potentially reducing the risk of non-specific auto-immune reactions. Our technology has produced
single agent activity and/or combination therapy-based durable responses in lymphoma, hepatocellular, colorectal and pancreatic tumors
and has also showed activity against hepatitis B virus (HBV) and HIV infection in standard preclinical models. Our target indications
include, but are not limited to, colorectal, hepatocellular (± HBV), bladder, cervical and pancreatic carcinoma, which according
to GLOBOCAN 2020, account in the aggregate for 23% of yearly cancer cases and over 28% of yearly cancer deaths world-wide.
Historically,
we have operated virtually with a team of highly experienced consultants and advisors, carrying out research and development at contract
research organizations (CROs). We have developed patented treatment methods (and associated patented compositions) for attenuation and
killing of non-pathogenic, Gram-negative bacteria (34 issued or granted patents). Since our inception, we have funded our operations
primarily through public and private offerings of our equity securities.
Recent
Developments
February
2025 Equity Line
On
February 12, 2025, we entered
into a Standby Equity Purchase Agreement, or the SEPA with YA II PN, LTD., a Cayman Islands exempt limited company, or
Yorkville. Pursuant to the SEPA, we have the right, but not the obligation, to sell to Yorkville from time to time up to $20.0
million of our common stock, during the 36 months following the
execution of the Purchase Agreement, subject to the restrictions and satisfaction of the conditions in the SEPA. At our option, the
shares of common stock would be purchased by Yorkville from time to time at a price equal to 97% of the lowest of the three daily
VWAPs during a three consecutive trading day period commencing on the date that we, subject to certain limitations, deliver a notice
to Yorkville that the Company is committing Yorkville to purchase such shares of common stock. We may also specify a certain minimum
acceptable price per share in each Advance. As consideration for Yorkville’s irrevocable commitment to purchase our shares, we
issued to Yorkville 305,960 shares of common stock. Under the applicable rules of Nasdaq and pursuant to the SEPA, in no event may
we issue or sell to Yorkville more than 2,823,244 shares of common stock, or the Exchange Cap, which is 19.99% of the shares of
common stock outstanding immediately prior to the execution of the SEPA, unless (i) we obtain stockholder approval to issue shares
of common stock in excess of the Exchange Cap or (ii) the average price of all applicable sales of common stock under the SEPA
equals or exceeds $0.81722 per share (which represents the lower of (i) the Nasdaq Official Closing Price (as reflected on
Nasdaq.com) on the trading day immediately preceding the effective date or (ii) the average Nasdaq Official Closing Price of the
common stock (as reflected on Nasdaq.com) for the five trading days immediately preceding the effective date). In addition,
effective February 12, 2025, we terminated the purchase agreement that we entered into with Lincoln Park Capital Fund, LLC in
December 2022.
January
2025 Financing
On
January 12, 2025, we entered into securities purchase agreements, or the January 2025 Purchase Agreements, with certain institutional
and accredited investors, or the January 2025 Purchasers. The January 2025 Purchase Agreements provide for the sale and issuance by us
of an aggregate of: (i) 2,109,383 shares of our common stock and (ii) warrants to purchase 2,109,383 shares of common stock in a private
placement, or the January 2025 Warrants. The shares and January 2025 Warrants were sold on a combined basis for consideration of $1.065
for one share and a January 2025 Warrant. The exercise price of the January 2025 Warrants is $0.94 per share.
The
January 2025 Warrants were immediately exercisable upon issuance and will expire five years following the date of issuance. The January
2025 Warrants contain standard adjustments to the exercise price including for stock splits, stock dividends and reorganizations. In
lieu of making the cash payment otherwise contemplated to be made upon exercise in payment of the aggregate exercise price, the holder
may, in the event the shares underlying the January 2025 Warrants are not registered under the Securities Act, elect instead to receive
upon such exercise (either in whole or in part) the net number of shares of common stock determined according to a formula set forth
in the January 2025 Warrants. Under the terms of the January 2025 Warrants, a holder (together with its affiliates) may not exercise
any portion of its January 2025 Warrant to the extent that the holder would beneficially own more than 4.99% or 9.99%, depending on the
individual investor, of the outstanding common stock immediately after exercise, or the Beneficial Ownership Limitation, except that
upon at least 61 days’ prior notice from the holder to us, the holder may increase the Beneficial Ownership Limitation, provided
that the Beneficial Ownership Limitation in no event exceeds 19.99%.
Paulson
Investment Company, LLC, or Paulson, served as the exclusive placement agent for the issuance and sale of the securities. As compensation
for such placement agent services, we paid Paulson an aggregate cash fee equal to 7.0% of the gross proceeds received by us from the
offering, and a non-accountable expense of $25,000. As additional compensation to Paulson, we issued to the Paulson (or its designees)
a warrant, or the January 2025 Placement Agent Warrants, to purchase an aggregate of 147,656 shares at an exercise price per share equal
to $1.175 per share. The January 2025 Placement Agent Warrants are exercisable six months from the date of issuance and expire on the
fifth anniversary of the issue date.
November
2024 Financing
On
November 22, 2024, we entered into securities purchase agreements, or the November 2024 Purchase Agreements, with certain institutional
and accredited investors, or the November 2024 Purchasers. The November 2024 Purchase Agreements provide for the sale and issuance by
us of an aggregate of: (i) 1,817,017 shares of our common stock in a registered direct offering and (ii) warrants to purchase 1,817,017
shares of common stock in a private placement, or the November 2024 Warrants. The shares and November 2024 Warrants were sold on a combined
basis for consideration of $1.175 for one share and a November 2024 Warrant. The exercise price of the November 2024 Warrants is $1.05
per share. One of the November 2024 Purchasers was our Chief Executive Officer, who purchased 42,553 shares and November 2024 Warrants
to purchase 42,553 shares, or the Affiliate Securities, at the same price and upon the same terms as the other November 2024 Purchasers.
The
November 2024 Warrants were immediately exercisable upon issuance and will expire five years following the date of issuance. The November
2024 Warrants contain standard adjustments to the exercise price including for stock splits, stock dividends and reorganizations. In
lieu of making the cash payment otherwise contemplated to be made upon exercise in payment of the aggregate exercise price, the holder
may, in the event the shares underlying the November 2024 Warrants are not registered under the Securities Act, elect instead to receive
upon such exercise (either in whole or in part) the net number of shares of common stock determined according to a formula set forth
in the November 2024 Warrants. Under the terms of the November 2024 Warrants, a holder (together with its affiliates) may not exercise
any portion of its November 2024 Warrant to the extent that the holder would beneficially own more than the Beneficial Ownership Limitation,
except that upon at least 61 days’ prior notice from the holder to us, the holder may increase the Beneficial Ownership Limitation,
provided that the Beneficial Ownership Limitation in no event exceeds 19.99%.
Paulson
served as the exclusive placement agent for the issuance and sale of the securities. As compensation for such placement agent services,
we paid Paulson an aggregate cash fee equal to 7.0% of the gross proceeds received by us from the offering (excluding the Affiliate Securities),
and a non-accountable expense of $25,000. As additional compensation to Paulson, we issued to the Paulson (or its designees) a warrant,
or the November 2024 Placement Agent Warrants, to purchase an aggregate of 124,212 shares at an exercise price per share equal to $1.3125
per share. The November 2024 Placement Agent Warrants are exercisable six months from the date of issuance and expire on the fifth anniversary
of the issue date.
Supply
Agreement
On
October 17, 2024, we entered into a clinical supply agreement, or the Supply Agreement, with BeiGene Switzerland GmbH, or BeiGene, to
advance clinical evaluation of Decoy20, our novel product candidate designed to induce a broad immune response to fight cancer, in combination
with BeiGene’s anti-PD-1 antibody, tislelizumab, or the BeiGene Product, for the treatment of patients with advanced solid tumors,
or the Combination Study. We intend to seek approval from the FDA to initiate the Combination Study, which is anticipated to begin in
2025. Under the terms of the Supply Agreement, we will pay for all costs associated with the Combination Study (other than the cost of
the BeiGene Product), BeiGene will supply the BeiGene Product to us for the purposes of the study, and we will supply Decoy20 for the
purposes of the Combination Study. The Supply Agreement will terminate upon the earlier of (i) the one-year anniversary of the date that
we provide BeiGene with the Combination Study’s final clinical study report or (ii) the date of termination of the Combination
Study, subject to early termination in certain circumstances
August
2024 Financing
On
August 8, 2024, we completed a registered direct offering, pursuant to which we sold and issued to certain investors, including one of
our officers, 1,643,837 shares of common stock. In addition, in a concurrent private placement, we issued to the investors unregistered
warrants to purchase 1,643,837 shares of common stock, or the August 2024 Private Placement. The warrants were immediately exercisable
at an exercise price of $1.70 per share and expire five years from the date of issuance. The combined purchase price for one share of
common stock and one warrant was $1.825, resulting in gross proceeds of approximately $3.0 million, before deducting placement agent
and other offering expenses in the amount of approximately $0.5 million.
Background
Approved
immunotherapies, such as Interluekin-2, Interferon-alpha and the more recently approved “checkpoint” and CAR-T therapies
produce durable responses in a few percent to about fifty percent of patients across about a dozen out of over one hundred different
types of cancer. Although checkpoint therapies are able to effectively cure many previously incurable patients, only about 15% of patients
receiving this type of therapy respond. The main limitation of existing immunotherapies is that they each activate only one or a small
number of key steps in either the innate or adaptive immune system, but there is general agreement that highly efficient cancer immunotherapy
will require activation of both innate and adaptive immunity. The human body’s innate and adaptive immune systems are each capable
of cell-mediated destruction of tumors if the tumor cells are recognized as foreign or damaged. Activation of innate and adaptive responses
is also dependent on immune cells sensing the presence of “danger.” The most potent immune cell activating danger signals
are released by bacteria and viruses in the setting of infection, and include agonists of immune cell receptors, such as Toll-Like (TLR),
NOD and STING. Bacterial danger signals, including TLR agonists are called pathogen-associated molecular patterns (PAMPs) and can activate
both innate and adaptive immune cells, including antigen-presenting cells, promoting innate (NK, macrophage) and adaptive (T cell-mediated)
destruction of tumors.
The
oldest form of cancer immunotherapy involves the provision of decoy danger signals from bacteria. It was based on the long-standing observation
of tumor regression in the setting of bacterial infection. Treatment of cancer patients with heat-killed bacteria (“Coley’s
toxins”) was established in 1891 and used for 70 years with significant success. For example, ≥5-year survival was reported
for 45% of 432 inoperable sarcoma, lymphoma, melanoma, and carcinoma patients. Despite this success, several limitations led to the abandonment
of this approach by the pharmaceutical industry. Although there was an indication that Coley’s toxins worked best when administered
intravenously (i.v.), it was too toxic when given by this route, limiting the approach to local administration, which produced highly
variable results. Another limitation was lack of knowledge about the mechanism of action, preventing optimization and standardization
of manufacturing, leading to another source of variability in clinical response. Due to this high variability, Coley’s toxins was
not grandfathered-in as an approved drug by the FDA in 1963 and was supplanted by radiation and chemotherapy, despite the fact that these
more modern approaches rarely produce durable responses in advanced cancer patients. Scientists now understand the mechanism of action
of Coley’s toxins. Gram-negative bacteria contain multiple immune-stimulating danger signals, including TLR agonists such as lipopolysaccharide
(LPS). Bacteria and purified or mono-specific TLR agonists, including LPS derivatives, have been validated and approved for prevention
and treatment of early stage cancer. However, a safe and effective TLR agonist-based approach for advanced cancer has been elusive, possibly
due to limitations in the ability of intratumorally administered, mono-specific TLR agonists to induce potent, systemic anti-tumor immune
responses. In addition, the intratumoral approach is not feasible with all tumor types or patients. Our hypothesis is that an effective
TLR agonist-based immunotherapy for advanced cancer will require invention of a packaged, multi-TLR agonist or multi-danger signal product
that is modified or attenuated to allow safe i.v. administration.
Our
Approach
Our
patented approach is based on the hypothesis that efficient activation of both innate and adaptive immune cells and associated anti-tumor
immune responses can be achieved by using intact bacteria, containing multiple PAMPs, which have been attenuated so that they can be
administered safely intravenously. Because LPS appears to be the most important contributor to both toxicity and efficacy, our patented
product candidates are single strains of killed, non-pathogenic Gram-negative bacteria that have been treated in an effort to kill the
bacteria and significantly reduce, but not completely eliminate, the cell surface LPS-endotoxin activity. Our product candidates are
designed to have enhanced sufficient residual LPS to synergize with other PAMPs in the bacteria to efficiently prime innate and adaptive
immune pathways. This approach has led to broad anti-tumor and anti-viral activity in preclinical models, including durable anti-tumor
response synergy observed with each of four different classes of existing agents, including NSAIDs, checkpoint therapy, targeted antibody
therapy and low-dose chemotherapy. Tumor eradication by our technology is designed to produce both innate and adaptive immunological
memory and, importantly, not require provision of an exogenous tumor antigen, potentially due to the ability of LPS and other PAMPS to
activate dendritic cells that have already captured a tumor antigen.
All
immune cells can participate in killing of tumors and viruses. As illustrated below, current therapies activate only one or a small subset
of both pathways and cure only a small percentage of patients.
Our
technology, however, is designed to synergize with existing therapies to activate both innate and adaptive immune cells, inducing efficient
anti- tumor immune responses with a wide safety margin. Induction of adaptive anti-tumor immune responses and immunological memory by
our technology does not require an exogenous tumor antigen.
Innate
and adaptive immune responses require identification of a tumor as foreign or not self. However, most steps required for migration and
activation of immune cells are unrelated to the tumor or are tumor non-specific. All innate and adaptive non-specific steps are induced
or promoted by immune system “danger signal” molecules, such as those found in our bacteria. Bacteria-derived danger signals
are also able to enhance the processing and recognition of tumor antigens, which are frequently present, but not “seen” by
the immune system.
Results
Preclinical
Trials
In
preclinical models, Indaptus treated bacteria induced less systemic toxicity than untreated bacteria but were still able to activate
innate and adaptive immune responses. Despite exhibiting reduced in vivo pyrogenicity and a higher maximally tolerated dose, our bacteria
were able to induce secretion of most cytokines and chemokines from mouse and human immune cells in vitro at levels comparable to those
seen with untreated bacteria. Our bacteria were also able to synergize with human immune cells to kill human tumor cells in vitro.
We
have observed significant single agent anti-tumor activity and/or combination therapy-mediated regression with durable responses in established
non-Hodgkin’s lymphoma, as well as colorectal, hepatocellular and pancreatic carcinoma in preclinical syngeneic and human tumor
xenograft models. Our bacteria synergized with each of four different classes of approved agents in preclinical models, including NSAIDs,
checkpoint therapy, targeted antibody therapy and low-dose chemotherapy to induce tumor regression, providing significant flexibility
for targeting of diverse types of cancer. Our technology is designed to eradicate tumors via activation of both innate (NK cell) and
adaptive (CD4+ and CD8+ T cell) mechanisms, with the goal of producing both innate and adaptive immunological memory. In our preclinical
studies, tumor eradication occurred at non-toxic doses of our bacteria, with a very wide (10 to ≥33-fold) therapeutic index. Notable
mechanism of action information has also been obtained, via gene expression analysis with treated tumors and plasma cytokine analysis,
demonstrating that our combination technology has the potential to turn “cold” tumors into “hot” tumors and induce,
activate or recruit innate and adaptive genes, cells and pathways. Immune cell pre-depletion studies have demonstrated that both innate
(NK) and adaptive (CD4 T and CD8 T) immune cells are involved in tumor eradication. We have also demonstrated significant single agent
activity against chronic Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infection in standard preclinical models.
We
have carried out successful cGMP manufacturing and stability studies with our lead product candidate, Decoy20. In addition, IND-enabling
multi-dose toxicology studies have been completed and did not produce sustained induction of factors that are associated with cytokine
release syndrome.
The
chart above demonstrates that our bacteria synergize with Anti-PD-1 Checkpoint therapy to regress established mouse hepatocellular carcinoma
(HCC) Tumors. All mice (all groups) received a low-dose, non-steroidal anti-inflammatory drug (NSAID/Indomethacin), which increases the
number of regressions in the combination setting. Most regressions were durable, with 5/6 combination regressions stable through termination
at Day 91 and in a repeat experiment through termination at Day 143 (see next Figure below) (CR = complete response or complete regression).
The repeat experiment also produced 5/6 or 6/6 durable regressions per group over a 33-fold Indaptus concentration range and an absence
of safety concerns, demonstrating a very wide therapeutic index. Similar tumor eradication results have been obtained by combining our
bacteria with low-dose chemotherapy in a mouse non-Hodgkin’s lymphoma model. Eradication of established non-Hodgkin’s lymphoma
tumors by our technology has also been observed with human tumor xenografts, via activation of the innate immune system. Development
and preclinical efficacy characterization of a systemically administered multiple Toll-like receptor (TLR) agonist for antitumor immunotherapy
[abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into
Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract
nr B178.
The
chart above illustrates that the synergistic tumor eradication by our technology and Anti-PD-1 produces immunological memory. Established
tumors were regressed in 11 mice by combination treatment as in the Figure above and then the mice were re-challenged with fresh HCC
tumor cells, without further treatment. All of the new tumors were rejected. Similar results have been obtained by combining our bacteria
with low-dose chemotherapy in a non-Hodgkin’s lymphoma model.
Clinical
Trial
In
May 2022, the FDA allowed us to proceed under our IND application for a Phase 1 clinical trial in patients with advanced solid tumors
where currently approved therapies have failed, and in December 2022, we initiated this Phase 1 clinical trial which is an open label,
multi-center, dose escalation and expansion, single arm (monotherapy) study conducted in 2 parts. The Phase 1 study has begun with a
single dose escalation, which is planned to be followed by an expansion part with continuous weekly administration of Decoy20. The study
is enrolling patients with advanced/metastatic solid tumors, who have exhausted approved treatment options. The study’s objectives
are to assess the safety and tolerability of Decoy20, to determine the maximum tolerated dose and recommended Phase 2 dose, as well as
to assess Decoy20 pharmacokinetics PK, pharmacodynamics and clinical activity. The primary endpoint of the study is incidence, relatedness
and severity of adverse events and treatment-emergent adverse events and determining the number of subjects per cohort with dose limiting
toxicity-based adverse events. Secondary endpoints include the incidence of anti-drug antibodies and neutralizing antibodies pre- and
post-treatment, change in Decoy20 PK parameters over time, objective response rate in subjects with measurable disease and duration of
response.
In
August 2023, we completed the first cohort of patients who received a single dose in Part 1 of the Phase 1 clinical trial. Four patients
were enrolled and evaluable in the first cohort. Overall, patients experienced symptoms or adverse events (AEs) that were short-lived
and consistent with the mechanism of action of Decoy20. In September 2023, we advanced into the second cohort of the Phase 1 clinical
trial after receiving authorization from the Safety Review Committee. In early March 2024, we completed the second cohort of patients
who received a single dose in Part 1 of the Phase 1 clinical trial and, following authorization from the Safety Review Committee, advanced
into the multi-dosing cohort of the Phase 1 clinical trial. The second cohort dose was a reduction from the dosing in the first cohort
based on the significant pharmacodynamic effect seen with the first cohort and anticipated optimal Decoy20 safety profile for both multi-dosing
and combination approaches. In May 2024, we successfully dosed the first patient in the multi-dose portion
of the Phase I clinical trial with Decoy20. The primary goal of this stage of the trial was to evaluate the safety of Decoy20 when administered
multiple times to the same patient. We intend to progress Decoy20 into combination studies with a checkpoint inhibitor. In August 2024,
the Safety Review Committee convened to review the safety data at the higher Decoy20 dose with single dose administration and the safety
data at the lower Decoy20 dose with weekly administration. The data led to the decision to continue dosing additional patients at the
lower Decoy20 dose on a weekly schedule and initiate dosing patients at the higher Decoy20 dose on a weekly schedule. In October 2024,
the Safety Review Committee examined weekly administration data at the lower Decoy20 dose and cleared unrestricted enrollment of patients
at this dose. As of March 12, 2025, we have enrolled more than 20 patients in the weekly dosing among the two Decoy20 dose levels
and we have observed early signs of potential benefits emerging with some patients with stable disease. We are working to increase the
number of trial sites to accelerate patient enrollment and data collection.
In
February 2025, we announced that we received clinical trial authorization from Health Canada to initiate a clinical trial for Decoy20
which allows us to expand our ongoing U.S. clinical trial to Canadian sites. The trial will enroll patients in Canada under the current
protocol, which involves weekly dosing of Decoy20. We also plan to submit an amendment to Health Canada to initiate the Combination Study
in Canada.
Business
Strategy
Our
mission is to enhance and expand curative cancer immunotherapy for patients with unresectable or metastatic solid tumors and lymphomas,
which are responsible for approximately 90% of all cancer deaths.
Our
business strategy includes:
● advancing to the expansion portion of the Phase 1 clinical trial for Decoy20;
● maintaining, expanding and protecting our intellectual property portfolio; and
Competitive
Advantages
Our
bacteria contain multiple constituents, capable of priming or activating many of the cellular components of both innate and adaptive
immunity, but have been attenuated by a patented process to reduce the potential for over-stimulation of the immune system and consequential
induction of undesirable autoimmune reactions. Our bacteria are also likely to be cleared very quickly by the liver and spleen, which
may further reduce the risk of non-specific autoimmune side effects, relative to other types of immunotherapy that are designed for continuous
exposure. We believe a short exposure of our products is sufficient to act alone and as a “primer” to enhance other products.
Additionally, our products can be manufactured by a highly cost-efficient process, potentially providing accelerated patient access in
both developed and developing geographical regions.
Governmental
Regulation
Among
others, the FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial and
burdensome requirements upon companies involved in the clinical development, manufacture, marketing and distribution of drugs such as
those we are developing. These agencies and other federal, state and local entities regulate, among other things, the research and development,
testing, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, approval, advertising and promotion,
distribution, post-approval monitoring and reporting, sampling and export and import of our product candidates.
U.S.
Regulation of Drugs and Biologics
In
the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act (FDCA) and its implementing regulations, and
biologics under the FDCA and the Public Health Service Act (PHSA) and its implementing regulations. FDA approval is required before any
new unapproved drug or dosage form, including a new use of a previously approved drug, can be marketed in the United States. Drugs and
biologics are also subject to other federal, state, and local statutes and regulations. The process required by the FDA before product
candidates may be marketed in the United States generally involves the following:
Once
a product candidate is identified for development, it enters the preclinical testing stage. Preclinical tests include laboratory evaluations
of product chemistry, toxicity and formulation, as well as animal studies. An IND sponsor must submit the results of the preclinical
tests, together with manufacturing information and analytical data, to the FDA as part of an IND. An IND is a request for authorization
from the FDA to administer an investigational drug product to humans. An IND will also include a protocol detailing, among other things,
the objectives of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated,
if the trial includes an efficacy evaluation. Some preclinical testing may continue even after the IND is submitted. The IND automatically
becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, places the clinical trial on a clinical
hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. Clinical
holds also may be imposed by the FDA at any time before or during clinical trials due to safety concerns about on-going or proposed clinical
trials or non-compliance with specific FDA requirements, and the trials may not begin or continue until the FDA notifies the sponsor
that the hold has been lifted.
All
clinical trials must be conducted under the supervision of one or more qualified investigators in accordance with GCPs, which include
the requirement that all research subjects provide their informed consent in writing for their participation in any clinical trial. Clinical
trials must be conducted under protocols detailing the objectives of the trial, dosing procedures, subject selection and exclusion criteria
and the safety and effectiveness criteria to be evaluated. Each protocol must be submitted to the FDA as part of the IND, and a separate
submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent
protocol amendments. While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies
performed since the last progress report, among other information, must be submitted at least annually to the FDA, and written IND safety
reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies
suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant
risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the
protocol or investigator brochure.
Furthermore,
an independent IRB at each institution participating in the clinical trial must review and approve each protocol before a clinical trial
commences at that institution and must also approve the information regarding the trial and the consent form that must be provided to
each trial subject or his or her legal representative, monitor the study until completed and otherwise comply with IRB regulations. The
FDA or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients
are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution
if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with
unexpected serious harm to patients. In addition, some clinical trials are overseen by an independent group of qualified experts organized
by the sponsor, known as a data safety monitoring board or committee. Depending on its charter, this group may determine whether a trial
may move forward at designated check points based on access to certain data from the trial. There are also requirements governing the
reporting of ongoing clinical studies and clinical study results to public registries, including clinicaltrials.gov.
The
clinical investigation of a drug is generally divided into three phases. Although the phases are usually conducted sequentially, they
may overlap or be combined.
Post-approval
trials, sometimes referred to as Phase 4 studies, may be conducted after initial marketing approval. These trials are used to gain additional
experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance
of Phase 4 clinical trials as a condition of approval of an NDA.
During
the development of a product candidate, sponsors are given opportunities to meet with the FDA at certain points. These points may be
prior to submission of an IND, at the end of Phase 2, and before an NDA or BLA is submitted. Meetings at other times may be requested.
These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide
advice, and for the sponsor and the FDA to reach agreement on the next phase of development. Concurrent with clinical trials, companies
usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics
of the drug and finalize a process for manufacturing the product in commercial quantities in accordance with cGMPs. The manufacturing
process must be capable of consistently producing quality batches of the product candidate and, among other things, the manufacturer
must develop methods for testing the identity, strength, quality and purity of the final drug. In addition, appropriate packaging must
be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable
deterioration over its shelf life.
NDA
and BLA Review Process
Assuming
successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development,
nonclinical studies and clinical trials are submitted to the FDA as part of an NDA or BLA requesting approval to market the product for
one or more indications. The NDA or BLA must include all relevant data available from pertinent preclinical studies and clinical trials,
including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s
chemistry, manufacturing and controls and proposed labeling, among other things. Data can come from company-sponsored clinical studies
intended to test the safety and effectiveness of the product, or from a number of alternative sources, including studies initiated and
sponsored by investigators. The submission of an NDA or BLA requires payment of a substantial application user fee to the FDA, unless
a waiver or exemption applies.
In
addition, under the Pediatric Research Equity Act, or PREA, an NDA or BLA or supplement to an NDA or BLA must contain data to assess
the safety and effectiveness of the biological product candidate for the claimed indications in all relevant pediatric subpopulations
and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The Food and Drug
Administration Safety and Innovation Act requires that a sponsor who is planning to submit a marketing application for a drug or biological
product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit
an initial pediatric study plan within sixty days after an end-of-Phase 2 meeting or as may be agreed between the sponsor and FDA. Unless
otherwise required by regulation, PREA does not apply to any drug or biological product for an indication for which orphan designation
has been granted.
Within
60 days following submission of the application, the FDA reviews the submitted BLA or NDA to determine if the application is substantially
complete before the agency accepts it for filing. The FDA may refuse to file any NDA or BLA that it deems incomplete or not properly
reviewable at the time of submission and may request additional information. In this event, the NDA or BLA must be resubmitted with the
additional information. Once an NDA or BLA has been accepted for filing, the FDA’s goal is to review standard applications within
ten months after the filing date, or, if the application qualifies for priority review, six months after the FDA accepts the application
for filing. In both standard and priority reviews, the review process may also be extended by FDA requests for additional information
or clarification. The FDA reviews an NDA to determine, among other things, whether a product candidate is safe and effective for its
intended use and whether its manufacturing is sufficient to assure and preserve the product’s identity, strength, quality and purity.
The FDA reviews a BLA to determine, among other things, whether a product candidate is safe, pure and potent and the facility in which