UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
FORM
10-K
☒ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For
the fiscal year ended December 31, 2023
☐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 001-41159
IMMIX
BIOPHARMA, INC.
(Exact
name of registrant as specified in charter)
(Address of principal executive offices) (Zip code)
(310)651-8041
(Registrant’s
telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common stock, $0.0001 par value IMMX The Nasdaq Stock Market LLC
Securities
registered pursuant to Section 12(g) of the Act: None.
Indicate
by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate
by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
Indicate
by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange
Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2)
has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate
by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule
405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant
was required to submit such files).Yes ☒ No ☐
Indicate
by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting
company, or an emerging growth company. See definition 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 by Rule 12b-2 of the Exchange Act). Yes ☐ No ☒
The
aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant as of the last business day
of the registrant’s most recently completed second fiscal quarter ended June 30, 2023 was $27,964,126 based upon
the closing price of the registrant’s common stock of $2.69 on The Nasdaq Capital Market as of that date.
Number
of common shares outstanding as of March 29, 2024 was 26,396,420 shares.
Documents
Incorporated by Reference: Portions of the registrant’s definitive proxy statement (the “2024 Proxy Statement”) relating
to its 2043 annual meeting of stockholders (the “2024 Annual Meeting of Stockholders”) are incorporated by reference into
Part III of this Annual Report on Form 10-K where indicated. The 2024 Proxy Statement will be filed with the U.S. Securities and Exchange
Commission within 120 days after the end of the fiscal year to which this report relates.
Table
of Contents
Page
ITEM 1. BUSINESS 6
ITEM 1A. RISK FACTORS. 38
ITEM 1B. UNRESOLVED STAFF COMMENTS 68
ITEM 1C. CYBERSECURITY 68
ITEM 2. PROPERTIES 68
ITEM 3. LEGAL PROCEEDINGS 68
ITEM 4. MINE SAFETY DISCLOSURES 68
ITEM 6. [RESERVED] 69
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 74
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA F-1
ITEM 9A. CONTROLS AND PROCEDURES 75
ITEM 9B. OTHER INFORMATION 76
ITEM 9C. DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS. 76
PART III 77
ITEM 10. DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 77
ITEM 11. EXECUTIVE COMPENSATION 77
ITEM 14. PRINCIPAL ACCOUNTANT FEES AND SERVICES 77
ITEM 15. EXHIBITS AND FINANCIAL STATEMENT SCHEDULES 78
SIGNATURES 80
POWER OF ATTORNEY 80
CAUTIONARY
NOTE ON FORWARD-LOOKING STATEMENTS
This
Annual Report on Form 10-K contains forward-looking statements which are made pursuant to the safe harbor provisions 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”). These statements may be identified by such forward-looking terminology as “may,”
“should,” “expects,” “intends,” “plans,” “anticipates,” “believes,”
“estimates,” “predicts,” “potential,” “continue” or the negative of these terms or other
comparable terminology. Our forward-looking statements are based on a series of expectations, assumptions, estimates and projections
about our company, are not guarantees of future results or performance and involve substantial risks and uncertainty. We may not actually
achieve the plans, intentions or expectations disclosed in these forward-looking statements. Actual results or events could differ materially
from the plans, intentions and expectations disclosed in these forward-looking statements. Our business and our forward-looking statements
involve substantial known and unknown risks and uncertainties, including the risks and uncertainties inherent in our statements regarding:
● our projected financial position and estimated cash burn rate;
● our estimates regarding expenses, future revenues and capital requirements;
● our ability to continue as a going concern;
● our need to raise substantial additional capital to fund our operations;
● the success, cost and timing of our clinical trials;
● our dependence on third parties in the conduct of our clinical trials;
● the results of market research conducted by us or others;
● our reliance on third-party suppliers and manufacturers;
● the success of competing therapies and products that are or become available;
All
of our forward-looking statements are as of the date of this Annual Report on Form 10-K only. In each case, actual results may differ
materially from such forward-looking information. We can give no assurance that such expectations or forward-looking statements will
prove to be correct. An occurrence of, or any material adverse change in, one or more of the risk factors or risks and uncertainties
referred to in this Annual Report on Form 10-K or included in our other public disclosures or our other periodic reports or other documents
or filings filed with or furnished to the U.S. Securities and Exchange Commission (the “SEC”) could materially and adversely
affect our business, prospects, financial condition and results of operations. Except as required by law, we do not undertake or plan
to update or revise any such forward-looking statements to reflect actual results, changes in plans, assumptions, estimates or projections
or other circumstances affecting such forward-looking statements occurring after the date of this Annual Report on Form 10-K, even if
such results, changes or circumstances make it clear that any forward-looking information will not be realized. Any public statements
or disclosures by us following this Annual Report on Form 10-K that modify or impact any of the forward-looking statements contained
in this Annual Report on Form 10-K will be deemed to modify or supersede such statements in this Annual Report on Form 10-K.
This
Annual Report on Form 10-K may include market data and certain industry data and forecasts, which we may obtain from internal company
surveys, market research, consultant surveys, publicly available information, reports of governmental agencies and industry publications,
articles and surveys. Industry surveys, publications, consultant surveys and forecasts generally state that the information contained
therein has been obtained from sources believed to be reliable, but the accuracy and completeness of such information is not guaranteed.
While we believe that such studies and publications are reliable, we have not independently verified market and industry data from third-party
sources.
RISK
FACTOR SUMMARY
Our
business is subject to significant risks and uncertainties that make an investment in us speculative and risky. Below we summarize what
we believe are the principal risk factors but these risks are not the only ones we face, and you should carefully review and consider
the full discussion of our risk factors in the section titled “Risk Factors,” together with the other information in this
Annual Report on Form 10-K. If any of the following risks actually occurs (or if any of those listed elsewhere in this Annual Report
on Form 10-K occur), our business, reputation, financial condition, results of operations, revenue, and future prospects could be seriously
harmed. Additional risks and uncertainties that we are unaware of, or that we currently believe are not material, may also become important
factors that adversely affect our business.
Risks
Relating to Our Financial Position and Capital Needs
Risks
Relating to the Development and Regulatory Approval of Our Product Candidates
Risks
Relating to our Business and Operations
Risks
Relating to our Intellectual Property
Risks
Related to Owning our Common Stock
PART
I
Throughout
this Annual Report on Form 10-K, references to “we,” “our,” “us,” the “Company,” “Immix,”
or “Immix Biopharma” refer to Immix Biopharma, Inc., individually, or as the context requires, collectively with its subsidiaries.
ITEM
1. BUSINESS
Overview
Immix Biopharma, Inc. is a clinical-stage biopharmaceutical company focused
on the application of chimeric antigen receptor cell therapy (“CAR-T”) in light chain (AL) Amyloidosis and autoimmune disease.
Our lead cell therapy candidate is U.S. Food and Drug Administration (“FDA”) investigational new drug (“IND”)
cleared CAR-T NXC-201, currently being evaluated in our ongoing Phase 1b/2a NEXICART-1 (NCT04720313) clinical trial. Based on early clinical
data, we believe NXC-201 has the potential to be the world’s first “Single-Day Cytokine Release Syndrome”, or “Single-Day
CRS” CAR-T (CRS median onset day 1, median duration 1 day), enabling the potential for a faster return home for patients. NXC-201
has been awarded Orphan Drug Designation (“ODD”) by the FDA in both AL Amyloidosis and multiple myeloma, and ODD by the European
Commission (“EMA”) in AL Amyloidosis.
Our
strategy is to:
Our
mission is to harness the immune system through innovative cell therapies and other modalities to deliver widely accessible cures in
autoimmune and other indications, as we believe patients are waiting.
Figure
1: Select ImmixBio Possible Autoimmune Target Indications
Our
N-GENIUS platform has produced our clinical-stage lead candidate NXC-201, a next-generation CAR-T for AL Amyloidosis and autoimmune disease,
complemented by emerging programs.
Figure
2: ImmixBio Pipeline
NXC-201
is in clinical trials to treat relapsed/refractory AL Amyloidosis.
As
of February 2024, we have treated 73 patients in our ongoing Phase 1b/2a NEXICART-1 (NCT04720313), of which 63 were relapsed/refractory
multiple myeloma patients, and 10 were relapsed/refractory AL Amyloidosis patients.
In
September 2023, the FDA granted ODD to NXC-201 for the treatment of AL Amyloidosis. If a product that has ODD subsequently receives the
first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug exclusive approval (or exclusivity),
which means that the FDA may not approve any other applications to market the same drug for the same indication for 7 years (except in
limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity).
In
November 2023, the U.S. FDA cleared an IND application for NXC-201 to enroll U.S. patients into NXC-201 clinical trials.
In
December 2023, NXC-201 clinical data in relapsed/refractory AL Amyloidosis was presented in an oral presentation at the 65th
annual American Society of Hematology (“ASH”) meeting, covering 10 relapsed/refractory AL Amyloidosis patients treated with
NXC-201, indicating an overall response rate of 100% (10/10) and a complete response rate of 70% (7/10).
In
February 2024, the European Commission (“EC”) granted orphan drug designation to NXC-201 for the treatment of AL Amyloidosis. Benefits
of European ODD include: 10 years of market exclusivity once authorized in the EU; Access to the EU centralized authorization procedure;
and reduced fees for EU protocol assistance, marketing authorization applications, inspections before authorization, applications for
changes to marketing authorizations made after approval, and reduced annual fees.
Our
Other Programs
Our
other programs include NXC-201 for autoimmune diseases, a $25 billion combined annual market size according to Grand View Research and
Fortune Business Insights; NXC-201 for relapsed/refractory multiple myeloma, a $14 billion market size growing to $27 billion
according to Wilcock, et al, Nature Reviews; IMX-110 for soft tissue sarcoma, a $3 billion market size according to Medgadget,
and in combination with anti-PD-1 for colorectal cancer, a $27 billion market size according to IndustryARC.
Our
Platform and Technologies
We
believe our N-GENIUS platform has broad potential utility in hematologic and autoimmune diseases.
Our
N-GENIUS platform, which has produced NXC-201, consists of three key elements: (1) Purpose-Built Cell Therapy Evidence Capture
Engine + Relational Database, which relates ImmixBio internal data to external to accelerate therapy design, manufacture, and
preclinical; (2) proprietary EXPAND technology, which is applied to multiple cell therapy indications, already utilized to create
NXC-201; and (3) Atomized, Novel Binding Scaffold Generation Engine, which allows for optimal molecule binding. We believe key
characteristics of NXC-201 may apply to other products candidates produced by the N-GENIUS Platform. Those 3 key characteristics
are: (a) high transduction efficiency (supporting efficient manufacturing), (b) low tonic signaling (lower off-target toxicity may
lead to lower toxicity), and (c) anti-exhaustion capability (increased persistence may lead to activity over an extended period of
time).
Our Lead Program: NXC-201 in relapsed/refractory AL Amyloidosis
Market Opportunity
The
first indication we intend to pursue for NXC-201 is relapsed/refractory AL Amyloidosis.
AL amyloidosis is a life-threatening immunological disorder in which an
abnormal protein called amyloid builds up in tissues and organs. This abnormal protein is produced by long-lived plasma cells (“LLPCs”),
a type of immune B-cell. The signs and symptoms of AL amyloidosis vary among patients because build-up may occur in the heart (most frequent
cause of mortality), liver, kidneys, intestines, muscles, joints, nerves, or spleen, according to the National Institutes of Health (“NIH”).
Diagnosis is frequently delayed, due to varied and non-specific symptoms including: fatigue, weight loss, shortness of breath, dizziness,
and numbness in hands and feet. Upon diagnosis, many patients already have late-stage disease, and are not aware of available treatment
options and clinical trials.
The U.S. observed prevalence of relapsed/refractory AL Amyloidosis is growing 12% per year according to Staron, et
al Blood Cancer Journal, estimated to reach 29,712 patients in 2023. AL amyloidosis has a one-year mortality rate
of 47 percent, 76 percent of which is caused by cardiac amyloidosis, according to Alexion. The current market size for amyloidosis therapies is
$3.6 billion, expected to reach $6 billion in 2027, according to Grand View Research.
As
of February 2024, there are no FDA approved drugs for AL Amyloidosis.
Figure
3: NXC-201 “Blue Ocean Opportunity” in AL Amyloidosis
NXC-201
Composition and Mechanism of Action
NXC-201
is a next-generation CAR-T targeting B-cell maturation antigen (“BCMA”). CAR-T cell therapy is a type of immunotherapy that
uses the patient’s own immune cells, modified with our proprietary technology, to create NXC-201, which is then introduced into
the patient’s body. Then the patient’s modified NXC-201 CAR-T cells are able to recognize and eliminate diseased cells.
Figure
4: NXC-201: What is CAR-T Cell Therapy?
Our N-GENIUS cell engineering platform with EXPAND technology has already
produced clinical-stage CAR-T NXC-201, targeting BCMA, which we believe is the first and only autologous CAR-T being developed to treat
light-chain (AL) Amyloidosis. NXC-201 is currently being evaluated in our ongoing Phase 1b/2a NEXICART-1 (NCT04720313) clinical trial.
Figure
5: NXC-201: First CAR-T Generated by the N-GENIUS Platform
Those
3 key characteristics of NXC-201 are: (a) high transduction efficiency (supporting efficient manufacturing), (b) low tonic signaling
(lower off-target toxicity may lead to lower toxicity), and (c) anti-exhaustion capability (increased persistence may lead to activity
over an extended period of time).
Figure
6: NXC-201: Key Characteristics
NXC-201 has been designed with a proprietary, optimized C3ζγ
for enhanced signal transduction, proprietary, optimized modified-stiffness CD8 hinge, and proprietary, optimized COBRA binder for enhanced
signal binding. We believe the combination of these modifications has the potential to allow for NXC-201 to deliver “digital”
intracellular signaling, potentially eliminating neurotoxicity and reducing CRS duration to 1 day.
Figure
7: N-GENIUS Platform – EXPAND Technology + COBRA Binder
NXC-201 was designed for high activity against disease-causing AL Amyloidosis
LLPCs, which are also the source of autoimmune antibodies in a variety of autoimmune disorders.
NXC-201
Pre-clinical Data
In
AL Amyloidosis, we believe there are two primary challenges with CAR-T patient dosing:
a)
Uneven BCMA expression across disease-causing LLPCs; and
b) frail patient due to pre-existing organ (heart) damage.
Published
in Clinical Cancer Research in 2022, NXC-201 was tested preclinical and clinically in AL Amyloidosis.
Figure
8: In AL Amyloidosis, BCMA expression is at a low-to-medium level
Source:
Clinical Cancer Research, Kfir-Erenfeld,et al, 2022
Our
testing demonstrated low-to-medium expression of BCMA in 18 AL Amyloidosis patient samples.
Figure
9: High Activity Level of NXC-201 in AL Amyloidosis
Source:
Clinical Cancer Research, Kfir-Erenfeld,et al, 2022
NXC-201
demonstrated high activity in the presence of AL Amyloidosis diseased plasma cells.
Figure
10: NXC-201 Targets Diseased AL Amyloidosis LLPCs in Patient Bone Marrow
Source:
Clinical Cancer Research, Kfir-Erenfeld,et al, 2022
Near-complete
elimination of diseased AL Amyloidosis LLPCs was observed in relapsed/refractory AL Amyloidosis patients treated with NXC-201.
NXC-201
Clinical Data – Relapsed/refractory AL Amyloidosis
In
December 2023, NXC-201 clinical data in relapsed/refractory AL Amyloidosis was presented in an oral presentation at the 65th
annual ASH meeting, covering 10 relapsed/refractory AL Amyloidosis patients treated with NXC-201. These data represent the largest cohort
of AL patients treated with CAR T-based therapy reported in the literature thus far.
Clinical
Results
Enrolled
AL amyloidosis patients presented with organ involvement and were heavily pretreated with prior lines of therapy (median 6, range 3-10).
All patients had refractory, progressive disease. No patients received bridging therapy.
NXC-201
was administered at cell doses of either 150 × 106, 450 × 106, and 800 × 106 per patient.
Patient
characteristics:
● 90% (9/10) had high-risk cytogenetics
● 80% (8/10) had cardiac involvement
● 40% (4/10) had Mayo stage 3 (1 stage 3b, 3 stage 3a) AL amyloidosis disease
● Relapsed/refractory to a median 6 lines of prior therapy (range: 3-10)
Clinical
data:
● Overall response rate of 100% (10/10)
● Complete response + very good partial response rate of 90% (9/10)
● Organ response rate of 60% (6/10)
● “Single Day CRS”: Median CRS duration was 1 day (range: 1-4):
○ No grade 4 CRS events
For
the 8 patients with cardiac involvement:
● Overall response rate of 100% (8/8)
● Complete response rate of 63% (5/8) (4 out of 5 were MRD 10-5)
● Organ response rate of 63% (5/8)
For
the 4 patients with t(11;14) disease:
● Overall response rate of 100% (4/4)
● Complete response rate of 75% (3/4) (MRD 10-5)
● Organ response rate of 50% (2/4)
In
Vitro Studies
NXC-201
has demonstrated efficient eradication of plasma cells from patients with AL amyloidosis (Kfir-Erenfeld et al. 2022). Co-cultures of
plasma cells from AL amyloidosis patients and NXC-201 resulted in an almost complete eradication of the plasma cells. A control of AL
amyloidosis plasma cells with non-transduced (“NT”) cells, in contrast, did not result in a similar elimination of the plasma
cells.
Figure
11. Elimination of Plasma Cells After Co-culture with NXC-201 Compared to NT Cells
Abbreviations:
AL: amyloid light chain; NT: non-transduced; HBI0101 = NXC-201. Source: (Kfir-Erenfeld et al. 2022).
This
data suggest that NXC-201 cells were able to recognize the AL amyloidosis plasma cells and exert specific BCMA-directed antitumoral effect,
as further evidenced by the fact that following co-culture with AL amyloidosis plasma cells, NXC-201 cells underwent significant activation,
demonstrated by upregulation of the 4-1BB cell marker and increased secreted levels of inflammatory cytokines (interferon gamma: IFNγ,
tumour necrosis factor alpha: TFNα), which was not seen in NT cells. Furthermore, non-tumour bone marrow derived mononuclear
cells were not affected by co-culture with NXC-201, demonstrating the targeted effect of this therapy.
Figure
12: NXC-201 Activation Following Overnight Co-culture with Amyloid Light Chain Amyloidosis Plasma Cells
Figure
13: 65th ASH NXC-201 presentation: Rapid elimination of disease-causing amyloid chains by NXC-201 within ~30 days was
observed
NXC-201
in Relapsed/refractory multiple myeloma
As
of February 2024, 63 patients with triple-refractory relapsed/refractory multiple myeloma with median 4 lines of prior therapy (range:
3-13) have been treated with NXC-201. A 95% overall response rate to NXC-201 treatment was observed in relapsed/refractory multiple myeloma
patients not previously treated with BCMA-targeted therapy (98% overall response rate observed in relapsed/refractory multiple myeloma
patients without extra-medullary disease). “Single-Day CRS” was demonstrated – median duration of CRS of 1 day, median
onset day 1. Multiple myeloma is a $14 billion market size growing to $27 billion according to Wilcock, et al, Nature Reviews.
NXC-201
Development Strategy
In our lead program, NXC-201 for relapsed/refractory AL Amyloidosis, we
plan to enroll 40 patients in our open label, single-arm clinical trial, and then submit a biologics license application (“BLA”)
for FDA approval.
Figure 14: NXC-201 Clinical Development Plan Through
FDA BLA Submissions
The
primary objectives in relapsed/refractory AL Amyloidosis are to study the safety and efficacy of NXC-201. The efficacy endpoints are
to evaluate response rates according to consensus recommendations for AL amyloidosis treatment response criteria in AL (Palladini et
al. 2012).
The expected primary endpoints
are complete response rate and overall response rate in our NXC-201 relapsed/refractory AL Amyloidosis clinical trial.
Our strategy is to pursue orphan
drug indications in which open-label, single-arm clinical trials may lead to possible BLA submissions, or indications with large populations
with remaining unmet medical need.
IMX-110
– Tissue-Specific TherapeuticTM with tissue micro environment
(“TME”) NormalizationTM Technology
IMX-110
in Colorectal Cancer
The
first potential indication we intend to pursue for IMX-110 (in combination with anti-PD-1 antibody) is relapsed/refractory colorectal
cancer (“CRC”). CRCs are cancers that arise from the colon and rectum. According to American Cancer Society, there were roughly
153,020 new cases of colorectal cancer in the United States in 2023. The five-year survival rate in the United States for all stages
of CRC is 65.1%, but this falls to 15.1% for patients with late-stage metastatic disease according to the National Cancer Institute (“NCI”).
The
CRC market is estimated to reach approximately $31.2 billion by 2025 from the estimated $26.3 billion in 2019 according to IndustryARC.
Drugs used to treat CRC include conventional irinotecan, oxaliplatin, 5-fluorouracil, pembrolizumab (marketed as Keytruda®, by Merck
& Co.), nivolumab (marketed as Opdivo®, by Bristol Meyers Squibb), bevacizumab (marketed as Avastin®, by Roche), ramucirumab
(marketed as Cyramza®, by Eli Lilly), and regorafenib (marketed as Stivarga® by Bayer). $41.11 billion is the total publicly
disclosed combined annual sales of pembrolizumab (Keytruda®, Merck & Co.), nivolumab (Opdivo®), bevacizumab (Avastin®),
and ramucirumab (Cyramza®) according to 2023 available annual reports. In relapsed/refractory proficient mismatch repair (pMMR) (microsatellite-stable
- MSS) relapsed/refractory mCRC, regorafenib (marketed as Stivarga® by Bayer) produced a median progression free survival (“mPFS”)
of 2.0 months according to the FDA approval label.
As
of February 2024, we continue to dose escalate IMX-110 + BeiGene anti-PD-1 Tislelizumab in our IMMINENT-01 (NCT05840835) study. In July
2023, we reported the following clinical data for IMX-110 + Tislelizumab in proficient mismatch repair (“pMMR”, or microsatellite-stable
– “MSS”) relapsed/refractory mCRC in IMMINENT-01: Out of 4 relapsed/refractory metastatic colorectal cancer patients
treated with IMX-110 + tislelizumab: 3 out of 4 (75%) patients experienced tumor shrinkage at 2 months; 1 out of 4 (25%) patients experienced
tumor control at 2 months; 1 out of 4 patients remain on IMX-110 + tislelizumab therapy as of July 7, 2023; Median progression-free survival
and overall survival not yet reached; Patients received a median of 8 earlier anti-cancer treatments that failed to halt cancer growth
(lines of therapy) prior to receiving IMX-110 + tislelizumab.
IMX-110
in Soft Tissue Sarcoma (“STS”)
The
second potential indication we intend to pursue for IMX-110 is relapsed/refractory STS. STSs are cancers that arise from muscle, fat,
nerves, fibrous tissues, blood vessels or deep skin tissues. According to American Cancer Society, there were roughly 13,000 new cases
of soft tissue sarcomas in the United States during 2020 and about 13,400 new cases of soft tissue sarcomas in the United States are
anticipated in 2023. Approximately 160,000 people live with soft tissue cancers in the United States. The five-year survival rate for
all stages of STS is 65.4% in the United States, but this falls to 17.1% for patients with late-stage metastatic disease according the
NCI. The global soft tissue sarcoma market is estimated to reach approximately $6.5 billion by 2030 from the estimated $2.9 billion in
2019 according to Medgadget. Drugs used to treat STS include conventional doxorubicin, eribulin (marketed as Halaven®, by Eisai Co,
Ltd), pazopanib (marketed as Votrient®, by Novartis), and trabectedin (marketed as Yondelis®, by Janssen/Johnson & Johnson).
Objective
response rates are increasingly considered as poor surrogates of clinical activity in STS. Therefore, lack of progression, or progression
free survival (“PFS”), is used as the primary measure of treatment success in STS. Conventional doxorubicin, in three separate
studies as a first-line therapy, produced a mPFS (meaning the time patients live without their cancer progressing) in STS patients of
2.5 months, 4.6 months, and 2.7 months according to Lorigan et al., 2007, Judson et al., 2014 and Chawla et al., 2015. Eribulin (Halaven®),
was trialed in a study producing a mPFS in STS patients of 2.6 months according to Schöffski et al., 2016. Pazopanib (Votrient®),
was trialed in a study producing a mPFS in STS patients of 4.6 months according to van der Graaf et al., 2012. Trabectedin (Yondelis®)
was trialed in a study producing a mPFS in STS patients of 4.2 months according to Demetri et al., 2016.
As
of February 2024, we have treated 21 patients in our ongoing IMX-110 Phase 1b/2a clinical trial in the United States and Australia, of
which clinical analysis has been completed for the initial 14 patients. Of those 14 patients, 8 patients completed a tumor measurement
after the enrollment measurement. Of those 8 patients, a range of late-stage STSs were represented, including: leiomyosarcoma, cholangiocarcinoma,
carcinosarcoma, and poorly differentiated sarcoma. 4 months was the mPFS observed in STS patients treated with IMX-110 in the United
States in our ongoing Phase 1b/2a clinical trial. 6 months of radiological PFS was observed in 50% of our STS patients treated with IMX-110.
100% of these patients received between 3 and 13 lines of therapy prior to IMX-110. Zero drug-related serious adverse events and zero
dose interruptions due to toxicity have been observed in our 1b/2a clinical trial to-date.
IMX-110
Composition and Mechanism of Action
IMX-110, currently in Phase 1b/2a clinical trials, is a Tissue-Specific
TherapeuticTM with TME NormalizationTM, a technology that we are developing initially for mCRC and STS. Tumor growth
is sustained by hypoxia (low oxygen concentration) and acidosis (an excessively acidic condition) which produce recurring waves of activation
of multiple kinases that upregulate NF-κB, STAT3 and other key transcriptional factors which cause recurrent inflammation. This
inflammatory environment activates the TME to provide metabolic and structural support to the tumor and to recruit Treg T-cells (immune
cells suppressing immune response) to suppress anti-tumor immune response. IMX-110’s poly-kinase inhibitor polyphenol curcuminoid
complex (“PCC”) halts this fundamental tumor-sustaining inflammation by blocking multiple kinases and interfering with NF-κB
and STAT3 activation, interrupting the positive feedback loop underlying the inflammatory cycle. With tumor-sustaining inflammation halted,
IMX-110’s apoptosis inducer (Polyethylene glycol – phosphatidylethanolamine (“PEG-PE”)-doxorubicin complex) is
then able to induce tumor cell death where conventional therapies have been hampered by resistance caused by NF-κB and STAT3 activation.
Figure
15: IMX-110 Induces Apoptosis while Blocking Multiple Escape Pathways
IMX-110
Immunomodulation Effects
In
this pre-clinical study of IMX-110 monotherapy in the genetic Kras, p53, and Cre (“KPC”) pancreatic mouse cancer model, our histological analysis showed that
IMX-110 has the potential to transform “cold” tumors into “hot” tumors by eliminating immunosuppressive T-regulatory
immune cells (top), enabling cytotoxic T-lymphocytes to enter the tumor (middle), and eliminating tumor vascularization (bottom).
Figure
16: IMX-110 Tissue-Specific TherapeuticTM with TME NormalizationTM Technology
Monotherapy
Turns “Cold” Tumors “Hot” in Genetic (KPC) Pancreatic Cancer Pre-clinical Model
(See
above paragraph for study description. ImmixBio unpublished results.)
Our
Other Programs
We are also pursuing development of NXC-201 in autoimmune diseases, a $25
billion combined annual market size according to Grand View Research and Fortune Business Insights.
Manufacturing
We
have a strong track record of successful manufacturing. We have already established a track record of producing NXC-201 for patient
dosing and testing in the U.S. and ex-U.S. (73 patients dosed to-date). In addition, we have already developed a scalable, reliable
manufacturing process for our TSTx according to current Good Manufacturing Practice (“cGMP”).
We
will continue to leverage our established technical, manufacturing, analytical, quality, cGMP, project management expertise and existing
relationships to contract with appropriate CMOs to manufacture our cell therapies and TSTx moving forward.
In
January 2024, the Company entered into a long-term operating lease agreement for biopharmaceutical manufacturing space located in
California. To date, we have obtained active pharmaceutical ingredients (“API”) and drug product for our product
candidates from several third party contract manufacturers. We are in the process of developing our supply chain for each of our
product candidates and have entered into agreements pursuant to which third-party contract manufacturers will provide us with
necessary quantities of API and drug product on a project-by-project basis based upon our needs. We rely, and expect to continue to
rely for the foreseeable future, on FDA, EMA, or other jurisdiction-registered third-party contract manufacturing organizations to
produce our product candidates for pre-clinical and clinical testing, as well as for commercial manufacture if our product
candidates receive marketing approval. As part of the manufacture and design process for our product candidates, we rely on
internal, scientific and manufacturing know-how and trade secrets and the know-how and trade secrets of third-party manufacturers.
We also contract with additional third parties for the filling, labeling, packaging, storage and distribution of investigational
drug products. We believe that this strategy allows us to maintain a more efficient infrastructure by eliminating the need for us to
invest in our own manufacturing facilities, equipment and personnel while also enabling us to focus our expertise and resources on
the development of our product candidates. We maintain agreements with our manufacturers that include confidentiality and
intellectual property, and quality provisions to protect our proprietary rights related to our product candidates and satisfy
regulatory requirements.
Competition
The
biotechnology industry is extremely competitive in the race to develop new products. We currently face and will continue to face
competition for our development programs from groups that are developing therapies for oncology and inflammation. The competition is
likely to come from multiple sources, including larger pharmaceutical companies, biotechnology companies, and academic
institutions.
Companies
developing therapies for AL amyloidosis include, but are not limited to, Prothena Corp, Caelum Biosciences (Now Alexion/AstraZeneca),
and Janssen/Johnson & Johnson.
Companies
developing or intend to develop cell therapies for autoimmune indications include, but are not limited to: Kyverna Therapeutics, Inc.;
Cabaletta Bio, Inc.; Fate Therapeutics Inc.; and Arcellx, Inc.
Intellectual
Property
Our
success depends in part on our ability to obtain and maintain proprietary protection for our product candidates, technology and know-how,
to operate without infringing the proprietary rights of others and to prevent others from infringing our proprietary rights. Our strategy
is to seek to protect our proprietary position by, among other methods, pursuing and obtaining patent protection in the United States
and in jurisdictions outside of the United States related to our proprietary technology, inventions, improvements, and product candidates
that are important to the development and implementation of our business. Our patent portfolio is intended to cover our product candidates
and related components, their methods of use and processes for their manufacture, our proprietary reagents and assays, and any other
inventions that are commercially important to our business. We also rely on trademarks as well as trade secret protection of our confidential
information and know-how relating to our proprietary technology platform, and product candidates. We believe that we have substantial
know-how and trade secrets relating to our technology and product candidates.
As
of March 15, 2024, our patent portfolio includes 12 U.S. and foreign granted patents, 11 pending U.S. and foreign patent
applications, 2 pending international (PCT) patent applications related to our technology platform and our product candidates. Of
those, 2 patents has been granted in the U.S. and 10 patents have been granted in the following countries: France, Germany, Ireland,
Switzerland, and the United Kingdom. Two non-provisional patent applications are currently pending in the U.S. and 9 foreign patent
applications are currently pending in Australia, Brazil, Canada, Europe, Hong Kong, Japan and Mexico. Certain platform patents are expected to remain in force until 2036.
The
below patents and patent applications comprise our patent portfolio. All of the patents and patent applications listed below are owned
by us.
*
Provided all maintenance and renewal fees are timely paid.
**
Any resulting patents in this family are expected to expire in 2042 (not including any patent term adjustment and patent term extension
in the United States and equivalents in foreign countries).
Additionally,
as of March 15, 2024, our subsidiary Nexcella, Inc. has global exclusive rights to PCT Application No. PCT/IL2023/050142 filed in 20023 and claiming priority
to U.S. Provisional Patent Application Nos. 63/308,277 and 63/368,002. The application is directed to our N-GENIUS platform, EXPAND technology,
and to our product candidates, including NXC-201. The application relates to a chimeric antigen receptor
(CAR) molecule specific for B cell maturation antigen (BCMA), compositions and methods thereof for the treatment of immune-related disorders.
We plan to enter the national phase of the PCT application in multiple countries. Any resulting patents in this family are expected to
expire in 2043 (not including any patent term adjustment and patent term extension in the United States and equivalents in foreign countries).
We
generally pursue multilayered patent protection covering the composition of matter including the formulations of the product candidates,
and/or the functional characteristics of the product candidates. In addition to composition of matter coverage, we also generally pursue
claims directed to methods of making, and methods of use of the product candidates.
IP
License Agreement with Immix Biopharma Australia Pty Ltd.
On
January 23, 2017, we entered into an IP License Agreement (“License Agreement”) with Immix Biopharma Australia Pty Ltd.,
our wholly-owned subsidiary (“IBAPL”), pursuant to which we granted IBAPL a non-exclusive, non-transferable license to IMX-110
intellectual property that is necessary for the purpose of, among other things, conducting or facilitating the research, development
or clinical trials relating to such intellectual property in the Commonwealth of Australia. Pursuant to the terms of the License Agreement,
during the term of the License Agreement, IBAPL shall pay us a royalty equal to a mid single digit percentage of Net Sales (as defined
in the License Agreement), subject to adjustment as set forth in the License Agreement. The License Agreement may be terminated by either
party (i) upon 20 days prior written notice to the other party, (ii) if the other party breaches any provision of the License Agreement
and fails to remedy such breach within 10 business days after receiving written notice of such breach or (iii) if the other party is
the subject to an insolvency event as set forth in the License Agreement. To date, we have not received any payments pursuant to the
License Agreement.
AxioMx
Master Services Agreement
On
December 22, 2014, we entered into a Master Service Agreement (“MSA”) with AxioMx, Inc. (“AxioMx”) which is in
the business of developing and supplying custom affinity reagents. We entered into the MSA to serve as a master agreement governing multiple
sets of projects as may be agreed upon us and AxioMx from time to time. Pursuant to the MSA, we granted AxioMx a non-exclusive, royalty-free,
worldwide, non-transferable license to certain of our intellectual property to perform services pursuant to the MSA, and AxioMx granted
us an exclusive product assignment option which grants us an exclusive, royalty-bearing right, with the right to sublicense, under the
Deliverable (as defined in the MSA) to further research, develop, use, sell, offer for sale, import and export one or more assigned products
pursuant to the MSA. We exercised the option in 2017. Pursuant to the MSA, AxioMx is entitled to royalties on the sale of any Deliverable
that is used for diagnostic, prognostic or therapeutic purposes, in humans or animals, or for microbiology testing, including food safety
testing or environmental monitoring. Specifically, we shall pay AxioMx a royalty of 3.5% of Net Sales (as defined in the MSA) of assigned
products for each Deliverable used in licensed products for therapeutic purposes. In addition, we shall pay AxioMx a royalty of 1.5%
of Net Sales of assigned products for each Deliverable used in licensed products for diagnostic or prognostic purposes; provided, however,
if three Deliverables are used in an assigned product for diagnostic or prognostic purposes, the royalty shall be 4.5%. As of December
31, 2023, the MSA has expired and the Company does not intend to extend the MSA; however, the royalty obligations described herein shall
survive the termination of the MSA.
Research
and License Agreement with Hadasit and BIRAD
On
December 8, 2022, our subsidiary Nexcella entered into a Research and License Agreement (the “Agreement”) with Hadasit Medical
Research Services & Development, Ltd. and BIRAD – Research and Development Company Ltd. (collectively, the “Licensors”)
pursuant to which the Licensors granted to Nexcella an exclusive, worldwide, royalty-bearing license throughout the world, except Israel,
Cyprus and other countries in the Middle East (the “Territory”), to an invention entitled “Anti-BCMA CAR-T cells to
target plasma cell” to develop, manufacture, have manufactured, use, market, offer for sale, sell, have sold, export and import
the Licensed Product (as defined in the Agreement). Pursuant to the Agreement, Nexcella paid the Licensors an upfront fee of $1,500,000
in December 2022. Additional quarterly payments totaling approximately $13.0 million are due through September 2026 along with an annual
license fee of $50,000. Nexcella has agreed to pay royalties to the Licensors equal to 5% of based on Net Sales (as defined in the Agreement)
during the Royalty Period. “Royalty Period” means for each Licensed Product, on a country-to-country basis, the period commencing
on December 8, 2022 and ending on the later of (a) the expiration of the last to expire Valid Claim (as defined in the Agreement) under
a Licensed Patent (as defined in the Agreement), if any, in such country, (b) the date of expiration of any other Exclusivity Right (as
defined in the Agreement) or data protection period granted by a regulatory or other governmental authority with respect to a Licensed
Product or (c) 15 years from the date of First Commercial Sale (as defined in the Agreement) of a Licensed Product in such country.
In
addition, Nexcella shall pay milestone payments of up to $20 million upon the achievement of certain Net Sales as set forth in the Agreement
and Nexcella has committed to funding NXC-201 clinical trials in Israel over 4 years for an estimated total cost of approximately $13
million, spread on a quarterly basis over that period, which Nexcella believes will generate clinical trial data owned by Nexcella. The
term of the Agreement commenced on December 8, 2022 and, unless earlier terminated pursuant to the terms thereof, shall continue in full
force and effect until the later of the expiration of the last Valid Claim under a Licensed Patent or a Joint Patent (as defined in the
Agreement) or Exclusivity Right covering a Licensed Product or the expiration of a continuous period of 15 years during which there shall
not have been a First Commercial Sale of any Licensed Product in any country in the world. Licensors may terminate the Agreement immediately
if Nexcella or its affiliates or sublicensees commences an action in which it challenges the validity, enforceability or scope of any
of the Licensed Patents or Joint Patents. In addition, either party may terminate the Agreement if the other party materially breaches
the Agreement and fails to cure such breach within 30 days. Additionally, Licensors may terminate the Agreement if Nexcella becomes insolvent
or files for bankruptcy.
Agreements
with Nexcella