Item 1A. Risk Factors 60
Item 1B. Unresolved Staff Comments 88
Item 2. Properties 88
Item 3. Legal Proceedings 88
Item 4. Mine Safety Disclosures 88
Part II
Item 6. [Reserved] 90
Item 7A. Quantitative and Qualitative Disclosures about Market Risk 96
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 97
Item 9B. Other Information 97
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 97
Part III
Item 10. Directors, Executive Officers and Corporate Governance 98
Item 11. Executive Compensation 98
Item 14. Principal Accountant Fees and Services 98
Part IV
Item 15. Exhibits and Financial Statement Schedules 99
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. has the following two business units:
ImmixBio.
ImmixBio is focused on developing Tissue Specific Therapeutics targeting solid tumors and immune-dysregulated diseases. As of February
2023, 19 patients with advanced solid tumors were treated with IMX-110, ImmixBio’s lead candidate.
Nexcella.
Our majority-owned subsidiary, Nexcella, Inc. (formerly known as Immix Biopharma Cell Therapy, Inc.), is engaged in the discovery and development of novel cell therapies for hematologic
malignancies (blood cancers) and other indications. As of February 2023, 42 patients with relapsed/refractory multiple myeloma (90%
overall response rate at therapeutic dose) and 5 relapsed/refractory light chain (AL) amyloidosis patients (100% organ response,
100% complete response rate) have been treated with next-generation CAR-T NXC-201.
IMMIXBIO
– TISSUE SPECIFIC THERAPEUTICS FOR SOLID TUMORS
Overview
of ImmixBio
We
are a clinical-stage biopharmaceutical company developing a novel class of Tissue-Specific Therapeutics (“TSTx”)TM in
oncology and inflammation. Our lead asset, IMX-110, is currently in Phase 1b/2a clinical trials for solid tumors in the United States
and Australia. IMX-110 is a negatively-charged TSTx that simultaneously disables resistance pathways with a poly-kinase inhibitor (which
inhibits multiple kinases simultaneously) and induces tumor cell death with an apoptosis inducer (which activates apoptosis, a non-inflammatory
programmed cell death pathway), leveraging our TME NormalizationTM Technology, delivered deep into the tumor micro-environment
(“TME”). Our proprietary System Multi-Action RegulaTors SMARxT Tissue-SpecificTM Platform produces
drugs that accumulate at intended therapeutic sites at 3-5 times the rate of conventional medicines. Our TME NormalizationTM Technology
allows our drug candidates to circulate in the bloodstream, exit through tumor blood vessels and simultaneously attack all components
of the TME. To date, we have not generated any revenues. Since inception, we have devoted substantially all of our resources to developing
product and technology rights, conducting research and development, organizing and staffing our Company, business planning and raising
capital.
Pipeline
Our
SMARxT Tissue-SpecificTM Platform has produced 3 drug candidates which we believe derisks the clinical development
of each subsequent candidate due to shared design elements across tolerability, chemistry, manufacturing and controls, regulatory understanding,
and multi-target therapeutic approach, the first of which is IMX-110, currently in Phase 1b/2a oncology clinical trials.
Figure
1: ImmixBio SMARxT Tissue-SpecificTM Platform – Pipeline
Our
Lead Product Candidate
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 soft tissue sarcoma (“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.
As
of February 2023, we have treated the first 2 patients in our ongoing Phase 1b/2a clinical trial of IMX-110 + Novartis/BeiGene anti-PD-1
Tislelizumab.
As
of February 2023, we have treated 17 patients in our ongoing Phase 1b/2a clinical trial in the United States and Australia. 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. In our trial, we observed radiological progression-free-survival
of 6 months in 50% of our STS patients, with a 4-month median progression free survival (“mPFS”) across all STS patients.
mPFS is the time that patients live without their cancer progressing. The trial includes patients with leiomyosarcoma, carcinosarcoma,
poorly differentiated soft tissue sarcoma, cholangiocarcinoma, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer,
breast cancer, and nasopharyngeal cancer.
In
August 2021, we entered into a Clinical Collaboration and Supply Agreement with BeiGene Ltd. (“BeiGene”) for a combination
Phase 1b clinical trial in solid tumors of IMX-110 and anti-PD-1 Tislelizumab (the subject of a collaboration and license agreement among
BeiGene and Novartis). In genetic mouse models of pancreatic cancer, IMX-110 has demonstrated an immunomodulation effect, turning “cold”
tumors “hot,” and, in combination with murine anti-PD-1, IMX-110 produced extended survival versus multi-drug combinations.
The goal of this study is to demonstrate the potential for TSTx to be an integral component of combination therapies for a wide range
of advanced solid tumors. Pursuant to the terms of the agreement, we and BeiGene shall form a committee made up of an equal number
of individuals, but not more than two representatives of each of our Company and BeiGene, which shall, among other things, coordinate
activities with respect to the trial; provided, however, we shall be entitled to receive, review or approve any budgets or other costs
relating to the trial. Pursuant to the terms of the agreement, we shall be responsible for all costs associated with the manufacturing
and supply of IMX-110 for the trial as well as all costs associated with conducting the trial and BeiGene shall be responsible for costs
associated with supplying Tislelizumab for the trial. Notwithstanding the foregoing, if the Tislelizumab supplied by BeiGene is lost,
damaged or destroyed or becomes unable to comply with applicable specifications while under our control, BeiGene shall not be required
to replace such Tislelizumab and in the event BeiGene replaces such Tislelizumab, it may charge us a reasonable replacement cost. The
agreement shall continue until the earlier of (i) the one year anniversary of the date upon which we provide BeiGene with the trial’s
final clinical study report and (ii) the date of termination of the trial. In addition, either party may terminate the agreement (i)
upon 30 days prior written notice to the other party if, in the case of our Company, we cease the development of IMX-110 or, in the case
of BeiGene, it ceases the development, marketing and sale of Tislelizumab, (ii) upon written notice to the other party if there have
been one or more serious adverse events indicating a patient safety issue with continuing the trial, (iii) upon written notice to the
other party if a regulatory authority withdraws approval of IMX-110 or Tislelizumab, as applicable, and/or the trial, (iv) upon 60 days’
notice to the other party with or without reason, (v) immediately upon written notice to the other party if such other party consummates
a Change of Control Transaction (as defined in the agreement) and/or (vi) upon written notice to the other party in the event such other
party is in material breach of the agreement and has not cured such breach within 60 days after receipt of notice from the non-breaching
party. As of the date hereof, we have not paid any amounts to BeiGene.
In
September 2021, the United States Food and Drug Administration (“FDA”) granted Orphan Drug Designation (“ODD”)
to IMX-110 for the treatment of soft tissue sarcoma. 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
January 2022, the FDA granted Rare Pediatric Disease Designation (“RPDD”) to IMX-110 for the treatment of rhabdomyosarcoma,
a life-threatening pediatric cancer in children. RPDD qualifies us to receive fast track review and a priority review voucher (“PRV”)
at the time of marketing approval of IMX-110.
Our
Other Product Candidates
IMX-111
is a Tissue-Specific BiologicTM built on our TME NormalizationTM Technology with proprietary GLUT1 antibody biomarker
targeting coupled with our poly-kinase inhibitor / apoptosis inducer. IMX-111 takes advantage of the fact that GLUT1 is an essential
cancer biomarker that is overexpressed on 92% of colorectal cancer cells and other tumor types. Furthermore, the degree of its overexpression
correlates with more advanced stages of tumor progression. Building on the well-tolerated profile of our lead candidate from our ongoing
clinical trial, we believe IMX-111 is the first cancer therapeutic to be developed that takes advantage of GLUT1 overexpression in cancer.
IMX-120
is a Tissue-Specific BiologicTM built on our Immune Normalization TechnologyTM for inflammatory bowel disease with
proprietary GLUT1 antibody biomarker targeting coupled with polyphenol poly-kinase inhibitors. IMX-120 takes advantage of the fact that
overexpression and activation of GLUT1 on overactive immune cells has been shown to be widely present in patients with inflammatory bowel
diseases (“IBD”). Similar to tumor growth, the inflammatory processes active in IBD are caused by recurring waves of activation
of multiple kinases that upregulate NF-κB, STAT3 and other key transcriptional factors. IMX-120’s polyphenol poly-kinase
inhibitors block upstream kinase signal transduction systems that activate NF-κB and STAT3. GLUT1 presents an ideal targeting moiety
(component of a drug) for these overactive immune cells, allowing for tissue-specific delivery of IMX-120.
Figure
2: ImmixBio SMARxT Tissue-SpecificTM Platform – Summary Rendering
Our
Platform and Technologies
Our
SMARxT Tissue-Specific Platform consists of 3 pillars: first, System-Tissue Biology Model Development, which allows us to
develop robust mechanisms of action in complex pathologies; second, Purpose-Built Physical Biochemistry Engine, which allows us to generate
actionable drug candidates; and third, Predictive Valuation Framework, which allows us to conduct highly predictive IND-enabling activities.
Figure
3: SMARxT Tissue-SpecificTM Platform Overview
Specifically,
the 3 pillars of our platform are:
1)
System-Tissue Biology Model Development: Interplay of cellular elements define and drive disease states. Based on transcriptional
and epigenetic factors operating in key cell types, we have built a proprietary model of network motifs driving human pathologies such
as cancer and auto-immune/inflammatory diseases. We believe this model represents the most complete view of biologic interrelationships
on an organismal and tissue level. We apply this model in the early stages of our drug development to overcome systemic factors that
have prevented traditional “targeted” therapies’ effectiveness in complex pathologies such as cancer and inflammatory
bowel disease.
2)
Purpose-Built Physical Biochemistry Engine: Traditional drug development focuses on “one drug, one target” approach.
In contrast, our proprietary physical biochemistry engine is designed to incorporate wide-ranging elements into our drug design, encompassing
a diverse target profile, allowing our drugs to operate simultaneously in time and space to jointly combat disease at the tissue and
organismal level.
3)
Predictive Validation Framework: Using our unique relationships and our internal expertise, we have developed a proprietary framework
of high-efficiency, rapid development in vitro and in vivo animal models that have high relatability to human disease,
minimizing the traditional poor predictive value of animal models.
The
application of the SMARxT Tissue-Specific Platform in oncology is TME NormalizationTM Technology, and in inflammation
is Immune NormalizationTM Technology.
Figure
4: TME NormalizationTM Technology
The
TME is made up of a tightly packed mass of: 1) cancer associated fibroblasts (“CAFs”), 2) tumor-associated macrophages/immune
cells (“TAMs”), and 3) cancer itself. The TME’s unique biophysical properties include regions of varying degrees of
hypoxia, acidosis and an immunosuppressive milieu. As cancer cells outgrow their blood supply, the resulting hypoxia and acidosis shift
their metabolism towards glycolysis, lactate and lipids. This, in turn, shapes the responses of proximal fibroblasts and resident immune
cells. Fibroblasts begin to secrete lactate that is taken up by nearby cancer cells and consumed as fuel. Lactate in the TME reprograms
the macrophages toward the M2 “tolerant” pro-inflammatory phenotype that drives immunosuppression. At the same time, the
TME hypoxia produces increased levels of reactive oxygen species that enhance tumorigenicity (tendency to form tumors) and immunosuppressive
functions of Treg T-cells, as well as resistance to immune drugs such as PD-1/PD-L1 inhibitors. Our TME NormalizationTM Technology
reverses the hypoxia- and acidosis-activated genetic programs in every cellular component of the TME, “normalizing” the TME,
and reactivating apoptosis cell death pathways. This technology offers an attractive opportunity to reshape the pathological niche that
is the TME and overcome the critical factors that have hampered available treatments to date.
Figure
5: Representation of the TME Composed of CAFs, TAMs, and Cancer Cells
Our
TME NormalizationTM Technology causes tumor apoptosis, a non-inflammatory tumor-cell death (instead of necroptosis, which
results in repeat reignition of the inflammatory cascade leading to tumor progression). Thus, when the inflammatory cascade is inhibited,
tumor resistance can be suppressed, enabling tumor cell apoptosis by ImmixBio therapies.
We
believe that our TME NormalizationTM Technology is a promising direction of research that may enable a new generation of high-therapeutic
index drugs (drugs that have high relative safety as defined by the ratio of toxic to effective dose), unlocking additional therapeutic
benefit without adding toxicity.
IMX-110
- Tissue-Specific TherapeuticTM with TME NormalizationTM Technology
IMX-110
Market Opportunity
The
first potential indication we intend to pursue for IMX-110 is STS. STSs are cancers that arise from muscle, fat, nerves, fibrous tissues,
blood vessels or deep skin tissues. Globally, there are roughly 116,000 new cases of soft tissue sarcomas each year, of which 21,500
are in the European Union and 40,500 are in China. 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.
The
global soft tissue sarcoma market is estimated to reach approximately $6.5 billion by 2030 from the estimated $2.9 billion in 2019. 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).
$844
million is the total publicly disclosed combined annual sales of eribulin (Halaven®), pazopanib (Votrient®), and trabectedin
(Yondelis®) according to the most recent available annual reports.
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 in which 50% of patients received three or more lines of previous chemotherapy prior to eribulin.
Eribulin produced a mPFS in STS patients of 2.6 months according to Schöffski et al., 2016.
Pazopanib
(Votrient®), was trialed in a study in which 21% of patients received three or more lines of treatment prior to pazopanib. Pazopanib
produced a mPFS in STS patients of 4.6 months according to van der Graaf et al., 2012.
Trabectedin
(Yondelis®) was trialed in a study in which 12% of patients received three or more lines of chemotherapy prior to trabectedin. Trabectedin
produced a mPFS in STS patients of 4.2 months according to Demetri et al., 2016.
IMX-110
Clinical Data
As
of March 2023, we have treated 17 patients in our ongoing Phase 1b/2a clinical trial in the United States and Australia, of which 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.
Figure
6: IMX-110 Soft Tissue Sarcoma Median Progression Free Survival and Level of Pre-treatment
In
our ongoing IMX-110 clinical trial:
- 100% of STS patients had controlled disease at 2 months.
Figure
7: IMX-110 Phase 1b/2a Clinical Trial Interim Patient Data:
75%
of Heavily Pretreated Soft Tissue Sarcoma Patients Experienced Tumor Shrinkage
Soft
Tissue Sarcoma % Change in Target Lesion Size from Baseline (Left)
Soft
Tissue Sarcoma Best % Change from Baseline in Size of Target Lesions (Center)
Non-Sarcoma
Cancers % Change in Target Lesion Size from Baseline (Right)
(Source:
Immix Biopharma, Inc. ImmixBio has evaluable data for 8 patients as of March 2022 (out of n=17, the remaining 9 did not complete any
tumor measurements after enrollment scan, of which 2 due to being dosed in December 2022). All 8 evaluable patients have discontinued
treatment. “Heavily Pretreated” refers to 3-13 lines of therapy. Dose expressed in mg/m2. Our employees were involved
in the design of this study and the results are unpublished.)
In
addition to IMX-110 STS data, a colorectal cancer patient originally considered for hospice, was subsequently treated with IMX-110 for
10 months with zero serious drug-related adverse events. This patient experienced 4 month PFS on half of what we expect to be IMX-110’s
recommended Phase 2 therapeutic dose.
IMX-110
Development Strategy
Figure
8: IMX-110: Direct Path To 1st Line Therapy In Soft Tissue Sarcoma – Clinical Trial Plan
We
plan to treat an additional 30 STS patients in our Phase 2a trial with IMX-110 as a first-line therapy.
We
expect our Phase 2a trial to require around 24 months after the first patient is dosed in 2023. The basis for IMX-110 as a first-line
therapy in STS is threefold:
- interest from leading STS PIs.
Subsequently,
we plan to initiate an 80 patient Phase 2b/3 clinical trial.
IMX-110
Composition and Mechanism of Action
Figure
9: IMX-110 Tissue-Specific TherapeuticTM with TME NormalizationTM Technology
for
Soft Tissue Sarcoma
IMX-110
is a negatively-charged Tissue-Specific TherapeuticTM built on our TME NormalizationTM Technology encapsulating
a synergistic 5:1 ratio of poly-kinase inhibitor (PCC) and apoptosis inducer (PEG-PE doxorubicin complex) delivered deep into the TME.
IMX-110
is the first clinical-stage drug built on our TME NormalizationTM Technology.
Figure
10: IMX-110 – the First Oncology Micelle to Achieve “Small Molecule Penetration”
(Intravital
multiphoton imaging of intravenous injection into a mouse bearing an Mu89 melanoma in a dorsal skinfold chamber with a mixture of nanoparticles
with diameters of 12 nm, 60 nm, and 125 nm. Adapted from Popovic, et al., 2010. We did not fund or sponsor this study, and we were not
involved in this study or its publication.)
IMX-110
is 14-16 nanometers in diameter, and is about the size of an Immunoglobulin G (“IgG”) antibody. Tumor blood vessels have
perforations of several hundred nanometers in diameter. Once IMX-110 has exited the bloodstream toward the tumor, it must traverse the
fibrous extracellular matrix, laid down by CAFs, that encases and scaffolds the tumor. IMX-110’s small size enables IMX-110 to
exit perforated tumor blood vessels and penetrate the fibrous extracellular matrix.
Figure
11: Representation of IMX-110 in the Bloodstream, Prior to Exiting Perforated Tumor Blood Vessels
Figure
12: Representation of IMX-110 Traversing the Fibrous Extracellular Matrix Toward the Tumor
Figure
13: IMX-110 – Negative Charge Facilitates Selective Tumor Accumulation
(Concentration
in tumor after IV injection. C-labeled doxorubicin in micellular or free form was injected into the tail veins of C 26-bearing CDF1
female mice (7 weeks old) at a volume of 0.1 ml/10g body weight. After defined time periods (15 min, 1, 4, 24, and 48 h), mice
were anesthetized with diethylether and tumor samples were collected. Adapted from Yokoyama, et al., 1999. We did not fund or sponsor
this study, and we were not involved in this study or its publication.)
We
believe IMX-110’s negative charge enables it to be electrostatically attracted to the tumor, and accumulate at tumor sites at a
rate 4-9 times higher than the rate of existing standard of care chemotherapies such as conventional doxorubicin.
Figure
14: IMX-110 – 12x Tumor Killing vs. Conventional Doxorubicin
(See
below paragraph for study description. Adapted from Sarisozen, et al., 2016)
We
observed that IMX-110 has statistically significantly increased apoptosis in 3D spheroid U87MG glioblastoma model as measured by increase
in caspase 3/7 activity after 24 hours versus groups treated with: control group (empty micelles), 0.1 μM free doxorubicin (free DOX),
0.1 μM micellular doxorubicin (DOX micelles), 20 μM micellular curcumin (CUR micelles). The primary endpoint of the study was level
of apoptosis as measured by increase in caspase 3/7 activity after 24 hours of treatment. 3D Spheroid U87MG glioblastoma cells were treated
with 0.1 μM DOX and 20 μM CUR in micellar formulations for 24 h, followed by the Apo-ONE Homogeneous Caspase-3/7 Assay. Results
were normalized against the control group and presented as mean ± SD. Our employees were involved in the design of this study
and Ilya Rachman, our Chief Executive Officer and Chairman of our board of directors, was a co-author of the results published in 2016.
Results were generated in triplicate using 15 spheroids per treatment.
IMX-110’s
synergistic combination induces caspase 3/7 activity, a proxy for apoptosis/tumor cell killing, at a rate of 12 times higher than that
of conventional doxorubicin, and at a rate 5 times higher than micellular doxorubicin, confirming IMX-110’s potent tumor cell killing
activity.
Figure
15: Representation of IMX-110 Effector Molecules (Orange and Red) Attacking Multiple Protein Targets Simultaneously
Figure
16: IMX-110 Tissue-Specific TherapeuticTM with TME NormalizationTM Technology
Intracellular
Mechanism of Action
Specifically,
IMX-110 induces potent tumor killing by blocking multiple tumor escape pathways targeted by FDA approved targeted agents and targeted
agents in development.
Leveraging
its multi-kinase inhibition capabilities, not only does IMX-110 block activation of NF-κB and STAT3, IMX-110 also simultaneously
blocks activation of other well-known cancer-related proteins such as COX2, BCL2, BCL-xL, Survivin, c-myc, Notch, and Hes1. With these
pathways shut down, IMX-110 is able to activate apoptosis through double-stranded DNA breaks caused by IMX-110’s apoptosis inducer
(PEG-PE doxorubicin complex).
Table
1: Select Drugs Targeting Same Targets That IMX-110 Targets
Company Name Target 2021 status
Venetoclax / Venclexta BCL2 Approved
Navitoclax BCL2, BCL-xL Phase II
ZN-d5 BCL2, BCL-xL Phase I
Celebrex/celecoxib COX2 Off patent
Brontictuzumab Notch1 Phase I
IMX-110
Pre-clinical Data
We
have funded and sponsored pre-clinical experiments to characterize the activity profile of IMX-110 in a range of solid tumor models,
including genetic KPC pancreatic mouse model, xenograft mouse models of various cancers, and in vitro with various cancer cell
lines.
We
observed that IMX-110 has statistically significantly inhibited tumor growth in a pre-clinical study that we funded and was
conducted on an industry sponsored research basis in a HCT-116 colon cancer xenograft mouse model (which is poorly sensitive to
doxorubicin). The primary endpoint of the study was tumor growth inhibition as measured by tumor volume, with the secondary endpoint
being overall survival. Female nude (NU/NU) mice bearing 250mm3 HCT-116 tumors were treated every 2 days starting at day
0 (7 total tail vein injections, arrows correspond to injection days) at a dose of 4 mg/kg CUR and 0.4 mg/kg DOX (six mice per
dosing group). Survival was determined when the tumor reached 1000mm3. Our employees were involved in the design of this
study and Ilya Rachman, our Chief Executive Officer and Chairman of our board of directors, was a co-author of the results published
in 2013. No adverse side effects of IMX-110 were observed as measured by lack of weight loss.
Figure
17: IMX-110 Tissue-Specific TherapeuticTM with TME NormalizationTM Technology Statistically Significantly Inhibited
Tumor Growth in HCT-116 Pre-clinical Xenograft Model
(See
above paragraph for study description. Adapted from Abouzeid et al., 2013)
In
this pre-clinical study of IMX-110 in the HCT-116 colorectal cancer xenograft mouse model, at day 24, 80% of mice treated with 1 cycle
of low-dose IMX-110 were alive while all control animals were dead.
We
observed that IMX-110 monotherapy has statistically significantly inhibited tumor growth in a pre-clinical study that we funded and
was conducted in a genetic pancreatic cancer (KPC) mouse model. The primary endpoint of the study was tumor growth inhibition as
measured by tumor volume and weight. Transgenic mice (Pdx1-Cre) were treated every day starting at day 0 (5 total tail vein
injections, arrows correspond to injection days) at a dose of 6 mg/kg CUR and 1.4 mg/kg DOX (at least six mice per dosing group).
Survival was determined when the tumor reached 1500mm3. Surviving animals were euthanized after the last blood collection
prior to Day 30, tumors were excised, measured, weighted, photographed and sectioned for histological analysis. Our employees were
involved in the design of this study and the results are unpublished. No adverse side effects of IMX-110 were observed as measured
by lack of weight loss.
Figure
18: IMX-110 Tissue-Specific TherapeuticTM with TME NormalizationTM Technology Monotherapy Statistically Significantly
Inhibited Tumor Growth in Genetic (KPC) Pancreatic Cancer Pre-clinical Model
(See
above paragraph for study description. ImmixBio unpublished results.)
In
this pre-clinical study of IMX-110 monotherapy in the genetic KPC pancreatic cancer mouse model, one cycle of low-dose IMX-110 produced
an average 43% reduction in tumor volume and weight at sacrifice vs. tumor volume and weight in untreated controls.
IMX-110
Immunomodulation Effects
In
this pre-clinical study of IMX-110 monotherapy in the genetic 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
19: 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.)
IMX-110
+ Anti-PD-1
In
published literature, the effect of a combination of murine anti-PD-1, gemcitabine, nab-paclitaxel, and murine anti-CD40 was studied
in a genetically engineered mouse model of pancreatic ductal adenocarcinoma (KPC), and produced median survival of 42 days.
The
primary endpoint of the study was tumor growth inhibition as measured by tumor volume and weight. Mice were treated intraperitoneally
(i.p.) with murine anti-PD-1 (RMP1-14; BioXcell; 200 mg/dose) on days 0, 3, 6, 9, 12, 15, 18, and 21 (after enrollment), with chemotherapy
(gemcitabine + nab-paclitaxel) injected i.p. at 120 mg/kg (for each chemotherapeutic) on day 1, and agonistic anti-CD40 (FGK45; BioXcell;
100 mg injected on day 3. For isotype controls, rat IgG2a (2A3; BioXcell; 100 mg) and rat IgG2b (LTF-2; BioXcell; 200 mg/dose) were used
(6-8 mice per group). Duration of survival was studied. We did not fund or sponsor this study, and we were not involved in this study
or its publication.
Figure
20: 4 Drug Combination (Anti-PD-1, Anti-CD40, Gemcitabine, Nab-paclitaxel) Produced
Median
42 day Survival in Genetic (KPC) Pancreatic Cancer Pre-clinical Model
(See
above paragraph for study description. Adapted from Winograd et al., 2015)
A
combination of IMX-110 + murine anti-PD-1 in a pre-clinical study in a genetic pancreatic cancer (KPC) mouse model that we funded produced
extended median survival of 63 days.
The
primary endpoint of the study was tumor growth inhibition as measured by tumor volume and weight. Transgenic mice (Pdx1-Cre) were treated
every day starting at day 0 (5 total tail vein injections) at a dose of 6 mg/kg CUR and 1.5 mg/kg DOX, and treated on days 5, 8, and
11 with murine anti-PD-1 (RMP1-14; BioXcell) 100μg/dose (three mice). This treatment was repeated started on day 21 and day 25. Duration
of survival was studied. Tumors were periodically visualized using an in vivo luciferase assay. Our employees were involved in
the design of this study and the results are unpublished. No adverse side effects of IMX-110 were observed as measured by lack of weight
loss.
Figure
21: IMX-110 + Murine Anti-PD-1 Produced Extended Survival Produced Median 63 Day Survival
in
Genetic (KPC) Pancreatic Cancer Pre-clinical Model
(See
above paragraph for study description. ImmixBio unpublished results.)
In
our genetic pancreatic cancer (KPC) mouse model study, luciferase assay visually demonstrated tumor shrinkage in the IMX-110 + anti-PD-1
combination group throughout the study.
(See
above paragraph for study description. ImmixBio unpublished results.)
We
believe there exists significant potential for TSTx IMX-110 to be an integral component of combination therapies for a wide range of
advanced solid tumors.
IMX-111
Tissue-Specific BiologicTM with TME NormalizationTM Technology
IMX-111
Market Opportunity
The
first potential indication we intend to pursue for IMX-111 is colorectal cancer (“CRC”). CRCs are cancers that arise from
the colon, rectum and anus. According to American Cancer Society, there were roughly 153,020 new cases of colorectal cancer in the United
States in 2023. Globally, there are roughly 1,930,000 new cases of colorectal cancer each year, of which 519,500 are in Europe, 148,500
are in Japan, 20,500 are in Australia and New Zealand, and 555,000 are in China. 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.
The
colorectal cancer market is estimated to reach approximately $31.2 billion by 2025 from the estimated $26.3 billion in 2019. 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), and ramucirumab (marketed
as Cyramza®, by Eli Lilly).
$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 the most recent available annual reports.
However,
these therapies are either approved in combination with chemotherapies, or in a small subset of colorectal cancer patients.
Table
2: Select Drugs Used To Treat Advanced Colorectal Cancer
Drug Comments
We
intend to pursue IMX-111 for treatment of advanced colorectal cancer (“aCRC”), which includes all CRC diagnosed with regional,
distant, and other staging, and includes approximately 63% of all patients newly diagnosed with CRC annually. Treatment of aCRC typically
involves removal of sections of the colon (colectomy) or rerouting of the intestine by colostomy. Radiotherapy and chemotherapy, including
the above drugs, are also used to treat aCRC patients.
IMX-111
Pre-clinical Data
We
have funded and sponsored pre-clinical experiments to characterize the activity profile of IMX-111 in a range of solid tumor models,
xenograft mouse models of various cancers, and in vitro with various cancer cell lines.
We
observed that IMX-111 has statistically significantly inhibited tumor growth in a pre-clinical study that we funded and was
conducted on an industry sponsored research basis in a HCT-116 colon cancer xenograft mouse model (which is poorly sensitive to
doxorubicin). The primary endpoint of the study was tumor growth inhibition as measured by tumor volume, with the secondary endpoint
being overall survival. Female nude (NU/NU) mice bearing 250mm3 HCT-116 tumors were treated every 2 days starting at day
0 (7 total tail vein injections, arrows correspond to injection days) at a dose of 4 mg/kg CUR and 0.4 mg/kg DOX (six mice per
dosing group). Survival was determined when the tumor reached 1000mm3. Our employees were involved in the design of this
study and Ilya Rachman, our Chief Executive Officer and Chairman of our board of directors, was a co-author of the results published
in 2013. No adverse side effects of IMX-111 were observed as measured by lack of weight loss.
Figure
22: IMX-111 Tissue-Specific BiologicTM with TME NormalizationTM Technology Statistically Significantly Inhibited
Tumor Growth in HCT-116 Colorectal Cancer Pre-clinical Xenograft Model
(See
above paragraph for study description. Adapted from Abouzeid et al., 2013)
In
this pre-clinical study of IMX-111 in the HCT-116 colorectal cancer xenograft mouse model, at day 24, 100% of mice treated with 1 cycle
of low-dose IMX-111 were alive while all control animals were dead.
We
observed that IMX-111 has statistically significantly inhibited tumor growth in a pre-clinical study that we funded and was
conducted on an industry sponsored research basis in a MDA-MB-231 triple-negative breast cancer xenograft mouse model (which is
poorly sensitive to doxorubicin). The primary endpoint of the study was tumor growth inhibition as measured by tumor volume, with
the secondary endpoint being overall survival. Female nude (NU/NU) mice bearing 150mm3 MDA-MB-231 tumors were treated
every 2 days starting at day 20 except last injection administered at day 33 (7 total IV injections) at a dose of 6 mg/kg CUR and 1
mg/kg DOX (at least six mice per dosing group). Survival was determined when the tumor reached 1000mm3. Our employees
were involved in the design of this study and Ilya Rachman, our Chief Executive Officer and Chairman of our board of directors, was
a co-author of the results published in 2014. No adverse side effects of IMX-111 were observed as measured by lack of weight
loss.
Figure
23: IMX-111 Tissue-Specific BiologicTM with TME NormalizationTM Technology Statistically Significantly Inhibited
Tumor Growth in MDA-MB-231 Triple-Negative Breast Cancer Xenograft Model
(See
above paragraph for study description. Adapted from Abouzeid et al., 2014)
In
this pre-clinical study of IMX-111 in the MDA-MB-231 triple-negative breast cancer xenograft mouse model, treatment with one cycle of
low-dose IMX-111 resulted in 50% reduction in tumor mass, versus 33% growth in controls. The IMX-111 treatment effect lasted throughout
the 52 day experiment duration.
IMX-111
Composition and Mechanism of Action
Figure
24: IMX-111 Tissue-Specific BiologicTM with TME NormalizationTM Technology
for
CRC
IMX-111
is a Tissue-Specific BiologicTM built on our TME NormalizationTM Technology with proprietary GLUT1 antibody biomarker
targeting facilitating preferential accumulation in glucose-consuming cancer cells such as CRC. IMX-111 takes advantage of the fact that
GLUT1 is an essential cancer biomarker that is overexpressed on 92% of colorectal cancer tumor cells and other tumor types. Furthermore,
the degree of its overexpression correlates with more advanced stage of tumor progression. IMX-111 is the first cancer therapeutic to
take advantage of this fact by coupling anti-GLUT1 antibody to our poly-kinase inhibitor / apoptosis inducer.
IMX-111
is 17-23 nanometers in diameter, which is just larger than the size of an IgG antibody.
Figure
25: IMX-111’s Target GLUT1 is Overexpressed on Colorectal and Other Cancers
(Adapted
from a review paper by Amann, et al., 2009. We did not fund or sponsor this study, and we were not involved in this study or its publication.)
GLUT1
is a glucose transporter which is overexpressed on 92% of CRC, making GLUT1 a prime biomarker for IMX-111 targeting in CRC.
Figure
26: IMX-111’s Target GLUT1 Overexpression is Associated with a Poor Prognosis
(Adapted
from Shen, et al., 2011 and Haber, et al., 1998. Shen, et al.: Expression of GLUT1 in 163 primary patient colorectal cancer tumors was
examined using real-time PCR. Haber, et al.: GLUT1 glucose transporter immunostaining was studied in normal colon and benign colon adenomas
and in 112 colorectal carcinomas from patients with known clinical outcomes. We did not fund or sponsor these studies, and we were not
involved in these studies or their publication.)
GLUT1
overexpression in CRC correlates with advanced, later stage (stage III-IV) disease. Heavy GLUT1 staining is observed in cancerous colorectal