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, 2020
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: 001-38022
MATINAS
BIOPHARMA HOLDINGS, INC.
(Exact
name of registrant as specified in its charter)
1545
Route 206 South, Suite 302
Bedminster,
New Jersey07921
(Address
of principal executive offices) (Zip Code)
908-443-1860
(Registrant’s
telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Act:
Title of Each Class Trading Symbol Name of Each Exchange on Which Registered
Common Stock, par value $0.0001 MTNB NYSE American
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 and posted on its corporate Web site, if any, every Interactive
Data File required to be submitted and posted 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 and post 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 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 is a shell company (as defined in Rule 12b-2 of the Act). Yes ☐ No ☒
The
aggregate market value of the registrant’s voting and non-voting common stock held by non-affiliates of the registrant computed
by reference to the price at which the common stock was last sold on June 30, 2020 was approximately $141.9 million.
As
of March 24, 2021, there were 204,276,412shares of the registrant’s common
stock, $0.0001 par value, outstanding.
DOCUMENTS
INCORPORATED BY REFERENCE
None.
MATINAS
BIOPHARMA HOLDINGS, INC.
Annual
Report on Form 10-K
Fiscal
Year Ended December 31, 2020
Table
of Contents
Page
PART I 1
Item 1. Business 2
Item 1A. Risk Factors 41
Item 1B. Unresolved Staff Comments 73
Item 2. Properties 73
Item 3. Legal Proceedings 73
Item 4. Mine Safety Disclosures 73
Item 6. Selected Financial Data 74
Item 7A. Quantitative And Qualitative Disclosures About Market Risk 81
Item 8. Financial Statements And Supplementary Data 81
Item 9A. Controls And Procedures 82
Item 9B. Other Information 82
PART III 83
Item 10. Directors, Executive Officers And Corporate Governance 83
Item 11. Executive Compensation 87
Item 14. Principal Accounting Fees And Services 97
Item 15. Exhibits And Financial Statement Schedules 98
Financial Statements F-1
i
PART
I
CAUTIONARY
NOTE REGARDING FORWARD-LOOKING STATEMENTS
This
report on Form 10-K contains forward-looking statements made pursuant to the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995 under Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange
Act of 1934, as amended. Forward-looking statements include statements with respect to our beliefs, plans, objectives, goals,
expectations, anticipations, assumptions, estimates, intentions and future performance, and involve known and unknown risks, uncertainties
and other factors, which may be beyond our control, and which may cause our actual results, performance or achievements to be
materially different from future results, performance or achievements expressed or implied by such forward-looking statements.
All statements other than statements of historical fact are statements that could be forward-looking statements. You can identify
these forward-looking statements through our use of words such as “may,” “can,” “anticipate,”
“assume,” “should,” “indicate,” “would,” “believe,” “contemplate,”
“expect,” “seek,” “estimate,” “continue,” “plan,” “point to,”
“project,” “predict,” “could,” “intend,” “target,” “potential”
and other similar words and expressions of the future.
There
are a number of important factors that could cause the actual results to differ materially from those expressed in any forward-looking
statement made by us. These factors include, but are not limited to:
● our ability to retain and recruit key personnel;
● our ability to internally develop new inventions and intellectual property;
● interpretations of current laws and the passages of future laws;
● developments and projections relating to our competitors or our industry; and
These
forward-looking statements reflect our management’s beliefs and views with respect to future events and are based on estimates
and assumptions as of the date of this Annual Report on Form 10-K and are subject to risks and uncertainties. We discuss many
of these risks in greater detail under “Risk Factors.” Moreover, we operate in a very competitive and rapidly changing
environment. New risks emerge from time to time. It is not possible for our management to predict all risks, nor can we assess
the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results
to differ materially from those contained in any forward-looking statements we may make. Given these uncertainties, you should
not place undue reliance on these forward-looking statements.
You
should read this Annual Report on Form 10-K and the documents that we reference and have filed as exhibits to the Annual Report
on Form 10-K completely and with the understanding that our actual future results may be materially different from what we expect.
We qualify all of the forward-looking statements in this Annual Report on Form 10-K by these cautionary statements. Except as
required by law, we undertake no obligation to publicly update any forward-looking statements, whether as a result of new information,
future events or otherwise.
Item 1. Business
Company
Overview
We
are a biopharmaceutical company focused on improving the intracellular delivery of critical therapeutics through our paradigm-changing
lipid nanocrystal (LNC) delivery platform. We are also focused on creating value through identifying a partner to continue
the development of LYPDISOTM (formerly MAT9001), a next generation, highly purified, prescription-only omega-3 free fatty
acid formulation specifically designed for the treatment of cardiovascular and metabolic conditions.
Matinas
BioPharma is dedicated to maximizing the value associated with our unique LNC platform delivery technology. This proprietary platform
technology, licensed from Rutgers University on an exclusive worldwide basis, nano-encapsulates target molecules in a way that
facilitates safe, efficient, and targeted intracellular delivery. Comprised of phospholipids, like phosphatidylserine, and calcium,
our LNCs can be differentiated from any other delivery technology today both in terms of how LNCs provide flexibility with route
of administration as well as how LNCs gain access to cells and how they can also provide flexibility with route of administration.
LNCs have been delivered orally, intramuscularly, intravenously and through inhalation. Because of their unique composition, LNCs
can be delivered into a cell through any or all of phagocytosis, membrane fusion, or clathrin-mediated endocytosis.
In
addition to efficient intracellular delivery to treat a variety of cell-based pathogens, diseases and conditions, our technology
allows for the targeted and safe delivery of pharmaceutical agents directly to sites of infection or inflammation. This highly
stable, efficient and broadly applicable drug delivery platform has the potential to deliver a broad range of therapeutic agents,
including small molecules, vaccines, peptides and proteins, as well as nucleic acid polymers (e.g., antisense, oligonucleotides,
siRNA, mRNA) for use in treating a broad range of inflammatory, infectious and other intracellular diseases (e.g., intracellular
pathogen-related, genetic disorders, and cancer).
Our
lead drug candidate based on the LNC platform delivery technology is MAT2203, an oral formulation of amphotericin B, a well-known
and highly effective, antifungal drug (though frequently associated with significant renal toxicity and currently only
available in an intravenous formulation) currently used and approved to treat a variety of invasive, and potentially deadly, fungal
infections. MAT2203 has been developed to date with the assistance and financial support of the National Institutes of Allergy
and Infectious Disease (NIAID) of the National Institutes of Health (NIH). MAT2203 has been designated as a Qualified Infectious
Disease Product (QIDP) with Fast Track Status for the treatment of invasive candidiasis, the treatment of aspergillosis, the prevention
of invasive fungal infections in patients who are on immunosuppressive therapy, and, most recently, the treatment of cryptococcosis.
While we continue to believe that MAT2203 could become an important solution to the significant unmet medical need to prevent
invasive fungal infections in immunosuppressed patients, we also believe there are opportunities for a more rapid approval of
MAT2203 for the treatment of certain invasive fungal infections in areas of high unmet medical need.
In
partnership with the NIH, we have conducted numerous preclinical studies of MAT2203 in cryptococcal meningitis and demonstrated
that MAT2203 was able to (a) cross the blood-brain barrier, (b) effectively treat this infection and (c) eliminate the toxicity
normally associated with delivery of amphotericin B intravenously. The NIH has funded a grant submission from the University of
Minnesota for a clinical study of MAT2203 in patients with cryptococcal meningitis in Uganda, where this disease is highly prevalent
among the human immunodeficiency virus (HIV)-positive community. This study, which has been called the Encochleated Oral Amphotericin
for Cryptococcal Meningitis Trial (EnACT), initiated in 2019 and currently enrolling patients in Cohort 2 of the trial,
is exploring the use of MAT2203 for both induction and maintenance therapy, and we believe that, if positive, it could form the
foundation for registrational approval in this indication. Moreover, since this study potentially validates the use of MAT2203
in what is arguably one of the most difficult-to-treat fungal infections, we believe MAT2203 is well-positioned to become a best-in-class
antifungal drug for the treatment of invasive fungal infections. Furthermore, a demonstration that MAT2203 can effectively cross
the blood-brain barrier in humans could potentially position our LNC platform delivery technology for use with molecules designed
to treat other inflammatory diseases of the central nervous system through an oral route of administration. Developing MAT2203
utilizing primarily non-dilutive, government-sponsored, financing allows us to focus our internal cash resources on LYPDISO while
advancing MAT2203, MAT2501 and our innovative LNC platform delivery technology.
We
are also progressing the development of MAT2501, our oral amikacin development program, which is funded in large part by the Cystic
Fibrosis Foundation (CFF) which we are developing for the treatment of non-tuberculous mycobacterial (NTM) infection, a highly
prevalent lung infection in patients with underlying cystic fibrosis. We received funding of $3.75 million from the CFF in November
2020 which was based upon the positive preclinical proof-of-concept data generated by Colorado State University testing MAT2501
efficacy against both amikacin-sensitive and resistant strains of infecting organisms in a CF mouse model for NTM infections.
We
have been engaged in discussions with various large, well-established and well-financed biotech and global pharmaceutical companies
on potential applications of the LNC platform delivery technology.
We
continue to evaluate additional potential strategic collaborations with other interested biotech and pharmaceutical partners.
These early stage, proof-of-concept evaluations could provide an efficient, less expensive pathway to create numerous strategic
verticals in areas of innovative medicine while capitalizing on the development expertise and financial resources of well-established
pharmaceutical and biotech companies. Data from these evaluations could position us as a licensor of our LNC platform delivery
technology to numerous strategic partners better positioned to absorb the risks and costs of drug development while allowing our
company to become a royalty aggregator with the potential to generate upfront license, milestone and royalty payments as we maximize
the value of the overall LNC platform delivery technology.
We
are also focused on securing value for LYPDISO through a collaboration or partnership in the United States or globally. LYPDISO
is a soft gelatin capsule containing a complex mixture of multiple long-chain omega-3 fatty acids, primarily eicosapentaenoic
acid (EPA) and docosapentaenoic acid (DPA). There are a number of existing FDA-approved prescription omega-3 products, including
Lovaza®, Vascepa® and Epanova®, and this class of drugs has extensive evidence of safety and well-documented clinical
efficacy in lowering triglycerides (TGs) in patients with hypertriglyceridemia (HTG). We believe that given LYPDISO’s enhanced
bioavailability (as a free fatty acid rather than an ethyl ester) and its unique composition (high EPA plus DPA, with very little
DHA), it is differentiated from other existing products in the omega-3 class.
Triglycerides
(TGs) and cholesterol are integral components of lipoproteins, the primary transport vehicle for lipids in the body. High levels
of triglyceride-rich lipoproteins are associated with a substantially increased risk of atherosclerotic cardiovascular disease,
and, in the case of very high triglycerides, acute pancreatitis. Triglyceride elevations can be due to both genetic and environmental
factors and are frequently associated with comorbid conditions such as diabetes, chronic renal failure, and nephrotic syndrome.
Unlike the currently approved pharmaceutical omega-3 products, all of which have been repurposed following clinical failures in
their originally intended indications, LYPDISO has been specifically designed and developed to treat HTG, dyslipidemia and other
cardiovascular and metabolic conditions.
We
had previously been focused on the initial development of LYPDISO for an initial indication for the treatment of severe hypertriglyceridemia
(SHTG), which are those patients with triglyceride levels ≥ 500mg/dL, since TG-lowering is a well-accepted surrogate outcome
marker of clinical efficacy in these patients. Additionally, the prescription omega-3 product Vascepa has been approved for cardiovascular
risk reduction in patients at high cardiovascular risk with TGs ≥ 150 md/dL. The development plan for LYPDISO is via a 505(b)(2)
regulatory pathway, which tends to be shorter and less expensive than under Section 505(b)(1) (for new chemical entities that
have never been approved in the United States). The 505(b)(2) pathway allows us to rely, at least in part, on U.S. Food and Drug
Administration (FDA) findings of safety and/or effectiveness for a previously approved drug. Based on prior written feedback received
from the FDA in 2014, and additional verbal and written feedback from FDA in August of 2020, we believe that a 505(b)(2) pathway
is possible and appropriate for LYPDISO.
In
parallel with the preclinical and clinical studies necessary for FDA approval of LYPDISO, we also recently completed the ENHANCE-IT
study, a head-to-head crossover study of LYPDISO vs. Vascepa, which was intended to differentiate LYPDISO from the current leading
prescription omega-3 therapy. While the primary endpoint of percent change in TGs from baseline to end-of-treatment did not meet
statistical significance in the prespecified pharmacodynamic (PD) population, analysis of the per protocol (PP) population demonstrated
statistically significant improvement and superiority of LYPDISO over Vascepa in TGs, total cholesterol and very-low-density lipoprotein
(VLDL) cholesterol. A key secondary endpoint in ENHANCE-IT was the measurement of eicosapentaenoic acid, or EPA levels, in the
blood, as that has become a key surrogate marker in determining cardiovascular risk reduction. In ENHANCE-IT, plasma EPA concentrations
were significantly higher with LYPDISO vs. Vascepa (46% relative percent increase change from baseline EPA level vs. Vascepa)
and we believe indicate the potential for superior cardioprotection with LYPDISO vs. Vascepa. Overall, the data from ENHANCE-IT
support the pursuit of cardiovascular outcomes indication for LYPDISO. Given the significant time and expense of conducting a
cardiovascular outcomes trial, we have determined that a partner will be required to further develop LYPDISO. We have initiated
a process to identify and secure a partner over the next few quarters.
Strategy
We
are focused on improving the intracellular delivery of critical therapeutics through our paradigm-changing lipid
nanocrystal (LNC) drug delivery platform and its application to overcome current challenges in safely and effectively delivering
small molecules, nucleic acids, gene therapies, proteins/peptides, and vaccines. We are also focused on creating value through
finding a partner to continue the development of LYPDISO, our proprietary, next-generation prescription omega-3 drug, which we
believe is differentiated from all other prescription omega-3 products and positioned to potentially demonstrate superior cardioprotective
effects.
Key
elements of our strategy include:
Our
Lipid Nanocrystal (LNC) Platform Delivery Technology
Efficient
and safe delivery of medicines remains one of the biggest challenges in the pharmaceutical and biotech industry today. The advancement
of science and the emerging importance of cell-mediated immunity and current challenges associated with effective intracellular
drug delivery has created a significant area of need. Current technology options, including liposomes, lipid nanoparticles (LNPs)
and viral vectors, have been widely adopted but each have significant limitations including inefficient delivery, undesirable
and dangerous toxicity and immunogenicity, and unstable formulations forcing challenging storage conditions (Figure 1). The method
in which these technologies gain access to a cell varies and often is responsible for significant adverse effects for patients.
Despite these known challenges, adoption has been widespread due to the lack of viable alternatives. Today, LNPs and viral vectors
are being used to deliver both small molecules and gene therapy.
Figure
1: Current Delivery Technologies
Our
Solution: LNCs
Our
proprietary lipid nanocrystals (LNCs) are primarily composed of two naturally occurring materials: a phospholipid, like phosphatidylserine
(PS), and calcium. They are stable and have a unique multilayered structure consisting of a large, continuous, solid, lipid bilayer
sheet rolled up in a spiral or as stacked sheets, with no internal aqueous space. This unique structure provides protection from
degradation for molecules trapped in or between lipid bilayers. Components within the interior of the LNCs remain intact, even
though the outer layers of the LNCs may be exposed to harsh environmental conditions or enzymes (Figure 2).
Figure
2 LNC Formulation
Our
LNCs protect active pharmaceutical ingredients in lipid bilayers and can intercalate into the phospholipid interior or otherwise
remain trapped within the bilayers (Figure 3). The presence of minimal amounts of calcium keeps the LNCs intact.
Figure
3 LNCs Protect API in Bilayers
LNCs
can be delivered in a variety of ways, including orally, intramuscularly, intravenously and through inhalation. This flexibility
represents a significant advantage over other delivery modalities and presents significant opportunities to efficiently encapsulate
many different molecules, both water soluble and water insoluble, including small molecules, nucleic acids such as antisense oligonucleotides
(ASOs), messenger RNA (mRNA) and small interfering RNA (siRNA), and nucleotides as large as eleven kilobases including DNA plasmids
and potentially CRISPR/Cas9, a gene editing technology.
Intracellular
delivery of molecules is usually accomplished by either phagocytosis, clathrin-mediated endocytosis (CME) or through membrane
fusion. LNPs are limited in that they can typically only access a cell through the CME process, followed by disruption of the
endosomal membrane within the cell to gain access to the cytoplasm. LNPs typically are very inefficient, and patients also experience
injection site adverse events and other toxicities associated with CME delivery, thereby limiting chronic use. LNPs also cannot
be delivered orally. Viral vectors, including adeno-associated virus, attempts to utilize nature’s intracellular delivery
mechanisms to facilitate fusion with the cell membrane and delivery of molecules into a cell. Unfortunately, viral vectors have
historically been associated with severe negative immune responses and, like LNPs, cannot be delivered orally. We believe LNCs
can effectively delivery molecules through all three mechanisms, in addition to having great flexibility with the desired route
of administration.
We
believe that LNC’s unique ability to enter a cell through phagocytosis, membrane fusion or CME, or a combination thereof,
relates directly to the presence of a phospholipid, like phosphatidylserine. Phosphatidylserine (PS) is present in virtually all
cells and is an integral part of the cell membrane. PS is normally localized to the inner part of the membrane bilayer by active
cellular processes. However, with cell “activation”, which occurs when there is infection, inflammation, injury, stimulation,
cell death or some other issue impacting a particular cell, PS moves from the inner layer to the outer layer and facilitates fusion
with our LNCs (Figure 4). Certain cells also contain PS receptors, which actively take up LNCs due to the presence of PS (Figure
5).
Figure
4: Asymmetry of the Phospholipid Membrane
Figure
5: Role of PS and PS Receptors in the Uptake of LNCs into Cells
Through
phagocytosis, macrophage and other cells containing PS receptors readily engulf LNCs and their drug cargo into vesicles, or endosomes,
facilitating intracellular delivery. LNCs can also fuse with cell membranes and deliver drug cargo directly to the cytoplasm.
LNCs have been designed to mimic enveloped viruses and can efficiently deliver drugs and/or molecules to cells without adverse
immune responses.
For
some molecules, the goal is simply to achieve safe and effective intracellular delivery. This is especially relevant when delivering
sensitive genetic material and other molecules desiring cellular impact (i.e., antivirals). For other molecules, or drugs, utilizing
activated cells as a mechanism to deliver drug to infected tissues or other areas of the body becomes critical.
LNCs
in pre-clinical studies have been shown to improve existing drugs by providing 1) cell-targeted delivery; 2) reduced blood
levels thereby reducing toxicity; and 3) oral delivery of drugs now only available intravenously. For example, LNCs delivered
orally work by encapsulating molecules of drugs in a solid, anhydrous, crystalline structure, protecting them as they pass through
the GI tract where they cross the mucous membrane. Once the LNCs have crossed the mucosal barrier of the GI tract into the lymphatic
system, they are picked up by activated cells including cells of the mononuclear phagocytic system, such as macrophages and dendritic
cells. Activated macrophages, with drug-loaded LNCs inside, follow natural signal molecule paths and migrate to the site of infection
or to the target organ and deliver their payload.
Therapeutic
applications of our proprietary delivery technology have been initially focused on the delivery of several potent and highly efficacious
anti-fungal and anti-bacterial agents, which are currently still associated with serious side effects, including irreversible
toxic effects on kidney and hearing function. We believe our technology has the potential for targeted delivery of these agents,
which positions us to be at the forefront of dealing with these very serious problems. We have now also expanded our research
and development efforts for our LNC platform delivery technology to focus on the delivery of a wide range of therapeutic treatments,
in particular those in the oligonucleotide class of agents (antisense oligonucleotides, mRNA, and CRISPR-Cas9).We continue to
push forward our business development efforts to further expand our collaborations across pharma and biotech companies who have
innovative therapies with delivery challenges, which may be addressed with our LNC platform delivery technology.
Multi-organ
Protection: A key innovation of our LNC platform delivery technology is our ability to package medication inside lipid-crystal
particles without leaking. Because of their crystalline nature, these particles are truly solid and hold on tightly to their medication
payload. This is where the LNC platform delivery technology differs markedly from other lipid-based delivery technology, such
as liposomal delivery. Liposomes are liquid delivery systems which typically leak some of their drug content into the circulatory
system, thus still exposing vulnerable organs and tissues to potential toxic effects. Keeping potentially organ-toxic medications
inside the lipid-crystal particles significantly differentiates our LNC platform delivery technology from other drug-delivery
approaches.
Targeted
Delivery: The size of our individual LNCs is typically in the range of 50-500 nm. This is very small and by comparison
close to the size of a large virus or a small bacterium. Our body produces many activated cell-types that are predisposed to interact
with our LNCs. These activated cell types, including bone marrow-derived hematopoietic cells such as macrophages, infected cells,
injured cells, tumor cells and epithelial cells are all prone to engulf or fuse with our phosphatidylserine-based LNCs. Because
of the size of our LNCs and their PS surface structure (the cell membranes of bacteria are also made up from PS), activated cells
tend to take up these LNCs very efficiently and without any adverse immune response.
Oral
Formulation: Many drugs that are currently on the market are only effective in treating diseases when administered intravenously.
For example, many anti-infective drugs must be administered intravenously in order to be effective. IV administration presents
several challenges to care, such as risk of infection, patient discomfort from injections, and higher cost of care than anti-infective
drugs that can be taken orally (IV delivery must be performed by a doctor or nurse, often within a very expensive hospital setting).
Although several technologies have been used to attempt to convert IV drugs to orally delivered medications, success has been
limited due to the difficulty in achieving adequate bioavailability (i.e., the amount of drug that is absorbed into the body)
with an oral formulation. We believe that the unique LNC structure in our platform technology protects the drug from degradation
when it passes through the GI tract and that its lipid surface features facilitate the particle being absorbed into the blood
stream. The potential application of our LNC platform delivery technology for the delivery of injectable medications offers significant
clinical and commercial value with successfully demonstrated safety and efficacy in human clinical trials.
Our
LNC platform technology changes the delivery of medicines in a unique manner and alters the bio-distribution of these medications
by targeting tissues and organs that are affected by infection and inflammation. In addition to IV-only anti-infectives such as
amphotericin B and amikacin, we have orally delivered in animal studies the influenza vaccine, siRNA, NSAIDs, other anti-infectives
such as atovaquone, and many other compounds across multiple therapeutic areas, demonstrating the potential broad application
of our technology. We have observed rapid local accumulation in infected tissues, which appear to be the result of transport of
our drug-loaded LNCs by and to activated cells.
Our
LNC Clinical Stage Assets
We
have leveraged our platform LNC delivery technology to develop two clinical-stage products that we believe have the potential
to become best-in-class drugs in their respective therapeutic classes. Our lead LNC platform delivery technology product candidate,
MAT2203, is an orally-administered LNC formulation of a broad spectrum anti-fungal drug called amphotericin B. We believe there
are opportunities for a potentially rapid approval of MAT2203 for the treatment of certain invasive fungal infections in areas
of high unmet medical need. In partnership with the National Institutes of Health (NIH), we have conducted numerous preclinical
studies of MAT2203 for the treatment of cryptococcal meningitis (CM), a deadly fungal infection that affects the brain, typically
in immunocompromised individuals. In such studies, we observed the potential for MAT2203, utilizing our LNC platform delivery
technology, to (a) cross the blood-brain barrier, (b) treat this infection and (c) eliminate the toxicity normally associated
with intravenous delivery of amphotericin B.
Based
upon the preclinical data generated by the NIH, the NIH has financially supported a grant application from the University of Minnesota
to conduct the EnACT study in Uganda. This study was initiated in October 2019 and is exploring the use of MAT2203 for both induction
and maintenance therapy in the treatment of CM, which is one of the most frequent and opportunistic infections in HIV patients.
Given the high morbidity and mortality associated with CM in HIV patients, the clinical unmet need is globally very high with
the global burden estimated at 1 million cases annually. We plan to leverage a 505(b)(2) regulatory pathway for MAT2203, in part
relying upon FDA’s findings of the efficacy of IV amphotericin B. This strategy was discussed with the FDA in June 2019,
where we outlined our development plans for MAT2203 in CM and received FDA approval to proceed with the EnACT study which is currently
enrolling subjects in Cohort 2 of the trial. We have received four qualified infectious disease (QIDP) designations as well as
an orphan designation for the treatment of cryptococcosis, which, if approved, would result in twelve years of regulatory exclusivity
for MAT2203. We plan to seek accelerated approval for this indication following the availability of the results of the ongoing
EnACT Study. We believe that this study may have the potential to become a potential pivotal study to support approval of MAT2203
for the treatment of CM during both induction and maintenance phases of treatment.
Our
second clinical stage LNC-based product candidate is MAT2501, an orally administered formulation of the broad-spectrum aminoglycoside
antibiotic amikacin, which may be used to treat different types of multidrug-resistant bacteria, including non-tuberculous mycobacterium
infections (NTM), as well as various multidrug-resistant gram negative and intracellular bacterial infections. In May 2017, we
completed and announced topline results from a Phase 1 single escalating dose clinical trial of MAT2501 in healthy volunteers
in which no serious adverse events were reported and where oral administration of MAT2501 at all tested doses yielded blood levels
that were well below the safety levels recommended for injected amikacin, supporting further development of MAT2501 for the treatment
of NTM infections. Following reformulation work, in 2019, we received a grant from the Cystic Fibrosis Foundation (CFF) to complete
preclinical studies with Colorado State University which further demonstrated the potential for MAT2501 in treating cystic fibrosis-associated
NTM lung infections. In November 2020, we received an additional grant from the CFF in the amount of 3.75 million USD to support
the continued development of MAT2501 through a comprehensive preclinical tox program and a single ascending dose (SAD) study in
healthy volunteers with our new and improved formulation of MAT2501. This most recent grant was based upon the positive preclinical
proof of concept data generated by Dr. Diane Ordway at Colorado State University in a rigorous mouse model of NTM infection in
mice with underlying CF disease.
MAT2203
Our
lead anti-fungal product candidate, MAT2203, is an application of our LNC platform delivery technology to a broad spectrum and
potent anti-fungal drug called amphotericin B. Traditionally, amphotericin B is an IV-administered drug used as a last resort
for treatment of systemic fungal infections resistant to triazoles and echinocandins, including resistant candidiasis, cryptococcal
meningoencephalitis, and aspergillosis. To date, there have been little to no reports of clinically observed drug-resistance to
amphotericin B, further bolstering the use of this compound as the most likely last resort treatment for fungal infections in
the foreseeable future. However, the use of amphotericin B is relatively limited because it is currently only available as an
IV-administered product and has documented history of severe toxicity (most notably nephrotoxicity). By utilizing our LNC platform
delivery technology to nano-encapsulate amphotericin B, there is now an opportunity for the drug to be administered orally with
targeted delivery to infected cells, which we believe may have fewer side effects than the currently available IV-formulations
of amphotericin B. Our LNC delivery of amphotericin B changes the bio-distribution, resulting in a higher level of the drug at
the site of infection and a lower level of free circulating amphotericin B. By reducing the amount of circulating drug, our LNC
platform delivery technology may reduce overall toxicity. Importantly, drug concentrations will be high only in target tissues
due to the migratory nature of activated cells to inflammatory regions. Based upon our studies to date, we believe MAT2203 has
the potential to offer improved safety and reduced toxicity and, as a result, we believe MAT2203 will be able to offer a categorically
different and improved formulation that delivers orally administered amphotericin B, directly to the target cell at the site of
infection. In collaboration with the NIH, in multiple studies, we have demonstrated in CM mouse models that our LNC-delivered
amphotericin B, following oral administration, can successfully cross the blood brain barrier to the site of infection in mice.
This demonstration provides important data indicating that our LNC platform delivery technology could become an important delivery
solution for a variety of CNS-based disorders and diseases.
We
believe that MAT2203 has the potential to become a best-in-class induction, consolidation, and maintenance therapy for the treatment
of CM in HIV patients by offering the following key benefits:
The
FDA has granted MAT2203 designations for Qualified Infectious Disease Product, or QIDP, and Fast Track for the treatment of invasive
candidiasis and aspergillosis, for the prevention of invasive fungal infections in patients on immunosuppressive therapy, and
the treatment of cryptococcosis. We recently also received Orphan Drug Designation for MAT2203 for the treatment of cryptococcosis
and associated CM. The FDA may designate a product candidate as an orphan drug if it is intended to treat a rare disease or condition,
which is generally defined as having a patient population of fewer than 200,000 individuals in the United States, or a patient
population greater than 200,000 in the United States where there is no reasonable expectation that the cost of developing the
drug will be recovered from sales in the United States. The orphan drug designation provides eligibility for orphan drug exclusivity
in the United States upon FDA approval if a product that has orphan drug designation subsequently receives the first FDA approval
for a particular active ingredient for the disease for which it has such designation. For a product that obtains orphan drug designation
based on a plausible hypothesis that it is clinically superior to the same drug that is already approved for the same indication,
in order to obtain orphan drug exclusivity upon approval, clinical superiority of such product to this same drug that is already
approved for the same orphan indication must be demonstrated. Orphan drug exclusivity means that the FDA may not approve any other
applications, including an NDA, to market the same drug for the same indication for seven years, except in limited circumstances
such as if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient
quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated. Similarly,
the FDA can subsequently approve a drug with the same active moiety for the same condition during the exclusivity period if the
FDA concludes that the later drug is clinically superior, meaning the later drug is safer, more effective or makes a major contribution
to patient care. Orphan drug designation also entitles a party to financial incentives such as opportunities for grant funding
towards clinical trial costs, a waiver from payment of user fees, an exemption from performing clinical studies in pediatric patients
unless the FDA requires otherwise by regulation, and tax credits for the cost of the clinical research. The QIDP designation,
provided under the Generating Antibiotic Incentives Now Act, or the GAIN Act, offers certain incentives for the development of
new antibacterial or antifungal drugs, including eligibility for Fast Track designation, priority review and, if approved by the
FDA, eligibility for an additional five years of marketing exclusivity. Fast Track designation enables more frequent interactions
with FDA to expedite drug development and review. Fast Track designation does not change the standards for approval, and we can
provide no assurances that we can maintain Fast Track designation for MAT2203 or that such designation will result in faster regulatory
review. The seven-year period of marketing exclusivity provided through orphan designation, if granted, combined with an additional
five years of marketing exclusivity provided by the QIDP designation positions MAT2203 with a potential for a total of 12 years
of marketing exclusivity to be granted at the time of FDA approval.
MAT2203
- Product Profile
MAT2203
is an orally-administered, LNC formulation of amphotericin B (a broad-spectrum fungicidal agent). Little to no clinical resistance
has been reported to date with amphotericin B as compared to the rapidly emerging drug resistance seen with other antifungal therapies.
Currently, IV administered amphotericin B is the only broad spectrum fungicidal; however, it has significant treatment-limiting
side effects, most notably nephrotoxicity. We believe that the ability to provide amphotericin B orally using our proprietary
and novel oral formulation comprising our LNC platform delivery technology, may offer a new and promising alternative for patients
and doctors.
The
data from animal toxicity studies for MAT2203 indicate a side-effect advantage over other amphotericin B formulations, which we
believe is based on two phenomena:
Development
History of MAT2203 and Initial Target Indication
MAT2203
has been studied extensively in animal model studies of various fungal infections including invasive candidiasis, aspergillosis,
and CM.
In
a clinical Phase 1 single-dose, double-blind, dose-escalating, pharmacokinetic study of 48 healthy volunteers, oral MAT2203 was
observed to be well-tolerated with no serious adverse events reported, and without any observed nephrotoxicity. The most commonly
reported adverse events (AEs) were nausea and abdominal pain. None of the AEs were related to abnormal laboratory evaluations.
All treatment emergent adverse events (TEAEs) were mild except 1 instance of “upper respiratory tract infection” which
was moderate in a subject following 800 mg MAT2203. No AEs led to withdrawal. There were no serious AEs. There was one pregnancy
(subsequently determined that the conception date was 1 to 2 days prior to dosing) resulting in elective termination from the
study. More recently, in our Phase 2 trial of MAT2203 conducted by the NIH, four out of four enrolled patients suffering from
chronic refractory mucocutaneous candidiasis met their primary efficacy endpoint. One patient continues on treatment with no evidence
of kidney or other toxicity frequently associated with the use of amphotericin B.
In
October 2020, results from Phase 1 of the EnACT Study were published in the Journal of Antimicrobial Agents and Chemotherapy (C.
Skipper, et.al) which was a Phase 1 ascending-dose trial of MAT2203 administered at 1.0 g, 1.5 g, or 2.0 g per day in 4 to 6 divided
doses among HIV-positive survivors of cryptococcosis (n=9 per cohort). We assessed the tolerability of MAT2203, and the AEs associated
with MAT2203 treatment over three days. The second part of the Phase 1 trial assessed the tolerability of 1.5 grams/day (the 100%
tolerated dose) administered for seven days. In the singe-ascending dose part of the study, all subjects in the 1.5 g treatment
group received their full dose without vomiting (100% tolerability). The cohort receiving 1 g had 4 transient clinical AEs in
2 subjects. The cohort receiving 1.5 g had 7 clinical AEs in 1 subject. The cohort receiving 2 g had 20 clinical AEs in 5 subjects.
From a qualitative survey, 26 of 27 (96%) preferred their experience with MAT2203 over their prior experience with IV amphotericin
(AMB).
The
second, multiple dose cohort received 1.5 g/day for 1 week, which was the 100% tolerated dose, with 98.4% of doses taken. Overall,
5 clinical AEs occurred in this cohort of subjects without any observed kidney toxicity. Oral MAT2203 was well-tolerated when
given in 4 to 6 divided daily doses without the toxicities commonly seen with IV AMB.
Based
on the findings from Phase 1 of the EnACT Trial, 2.0 g was selected as the target dose for the induction phase of treatment and
1.5 g for the maintenance dose for Stage 1 of the study. Phase 2 of the trial is evaluating the safety, tolerability, and efficacy
of MAT2203 in approximately 100 HIV-infected patients with cryptococcal meningitis. Participants enrolled in the experimental
arm of each cohort received oral MAT2203 and flucytosine (5FC) in four separate stages and duration for induction therapy, using
the maximum tolerated dose of MAT2203 that was identified in the preceding Phase 1 Trial. The experimental arm receives MAT2203
through induction and maintenance therapy for a total of approximately 6 weeks. Participants randomized to the control arm in
each cohort receive the 2018 WHO recommended standard of care, which is IV AMB and 5FC, followed by fluconazole.
The
first cohort of EnACT has been completed. A key objective of Cohort 1 was to assess the safety and tolerability of oral MAT2203
while assessing efficacy. Ten participants were randomized to the experimental arm and 4 to the control arm. The study treatments
received are summarized in the following figure:
Patients
in the experimental arm received induction therapy with IV AMB (1 mg/kg/day) for the first five days, oral MAT2203 (2 g/day in
divided doses) from Day 5-14, and oral 5FC (100 mg/kg/day) for the first 14 days of treatment. Induction therapy was followed
by consolidation or maintenance therapy with oral MAT2203 (1.5 g/day) from Day 15 to Week 6, oral fluconazole (800 mg/day) from
Day 15 to week 10, followed by oral fluconazole (200 mg/day).
Efficacy
and safety data from Cohort 1 of the study were reviewed by an Independent Data Safety Monitoring Board (DSMB) which voted unanimously
to progress into the second cohort of patients in the EnACT Study.
Enrollment
in the second cohort of patients has begun and Cohort 2.
Cohort
2 (or Stage 2) of the EnACT Study is designed to assess the potential to treat CM infections with oral MAT2203 as a step-down
treatment during the induction phase of treatment immediately following only 2 days of IV amphotericin treatment, with continued
treatment with MAT2203 for up to 6 weeks during early maintenance treatment. We believe that the clinical benefit of step-down
treatment from IV amphotericin to oral MAT2203 will provide compelling clinical evidence of efficacy in treating this deadly infection
with our oral agent. We believe that this Cohort of patients will also provide key data to support the further advancement of
the EnACT Study to ultimately test the potential to treat CM infections with an all-oral amphotericin dosing regimen in subsequent
cohorts (Stages 3 and 4 below).
The
read-out for Cohort 2 is expected in the second half of 2021.
Antifungal
Market Opportunity
The
overall global antifungal market accounted for approximately $11.9 billion in 2018 and is expected to reach approximately $13.9
billion by 2026. In 2018, the global invasive fungal infection market was valued at more than $6 billion. This includes therapies
used as active treatment or prophylaxis (preventative) in the inpatient and outpatient setting, therapies used for the treatment
of hospitalized patients and therapies used for the treatment of patients who are being discharged from the hospital. We estimate
that, each year, there are over 1.5 million cases of invasive fungal infections caused by various species of Candida, Aspergillus
and Cryptococcus, the three most common invasive fungal pathogens, globally. The estimated incidence in the U.S. for
these conditions is approximately 46,000 for invasive candidiasis, 15,000 for invasive aspergillosis, and 3,700 for CM. For example,
aspergillosis-associated hospitalizations in the U.S. alone came at an estimated treatment cost of more than $1 billion. The rapid
progression of disease and high mortality rates (20% - 50%) associated with documented invasive fungal infections often result
in antifungal therapy being administered in suspected (unconfirmed) cases or as a preventative measure in patients at high risk.
Also, the increasingly widespread use of immune suppressive drugs as cancer chemotherapy or for organ transplantation or treatment
of autoimmune disease has resulted in an increasing population of patients at risk for invasive fungal infections. Furthermore,
the limited number of systemic antifungal drug classes, consisting of azoles, echinocandins and polyenes, and their extensive
use, has led to increased numbers of infections with drug-resistant strains. The Centers for Disease Control and Prevention (CDC)
has listed fluconazole-resistant Candida as a serious threat requiring prompt and sustained action and has also identified
a rise in echinocandin resistance, especially among Candida glabrata. In June 2016, the CDC issued an extraordinary alert
for healthcare facilities and providers to be on the lookout for patients with Candida auris, a multidrug resistant strain
with high mortality (approximately 60%). Almost half of C. auris isolates are multidrug resistant to two or more antifungal
classes (large majority resistant to fluconazole, 40% resistant to echinocandins). We believe this underscores the urgent need
for new agents with demonstrated activity against resistant strains and that can be administered with significantly less toxicity
and the potential to discharge patients earlier to reduce hospital stays and associated costs.
Physicians’
options for the treatment of fungal infections are limited by a lack of innovative therapies. Several factors have contributed
to the low rate of antifungal drug development, including a previously challenging regulatory environment that necessitated large
and costly clinical trials. As a result of this regulatory environment and other factors, the number of antifungals in development
has decreased, while anti-microbial resistance has increased.
MAT2501
MAT2501
is an oral, LNC formulation of the broad-spectrum aminoglycoside antibiotic agent amikacin, which utilizes our proprietary LNC
platform to achieve oral bioavailability, limit toxicity, and enable targeted delivery to sites of infection. Currently, amikacin
can only be delivered parenterally or through inhalation and is used to treat a variety of chronic and acute bacterial infections,
including both NTM infections and various multi-drug resistant gram-negative bacterial infections. IV and inhaled amikacin, however,
are associated with major side-effects including nephrotoxicity and ototoxicity (permanent loss of hearing) with long-term use.
We believe that MAT2501’s ability to orally deliver high levels of amikacin directly to the lung and without use-limiting
toxicity, distinguishes it from all available therapies and could provide an important solution for patients and physicians. We
are currently developing MAT2501 for the treatment of NTM lung disease, including infections in patients with CF. MAT2501 has
been designated as a Qualified Infectious Disease Product (QIDP) and as an Orphan Drug for the treatment of NTM by the US FDA.
NTM
lung disease is a chronic, debilitating condition arising from an NTM infection in the lungs and is associated with significant
patient morbidity and mortality. The signs and symptoms of NTM lung disease often overlap with the underlying lung conditions
that increase the risk for NTM, like cystic fibrosis, bronchiectasis, COPD, and asthma. The most common pathogens for NTM infections
in the United States are Mycobacterium avium complex (MAC), which accounts for more than 80% of all NTM infections in the
US. Patients with NTM lung infections frequently require lengthy hospital stays and prolonged courses of antibiotics to manage
their disease. The prevalence of human disease attributable to NTM has increased over the past two decades and is now growing
at more than 8% per year and is even more prevalent than tuberculosis in the US. In 2018, it was estimated that between 75,000
and 100,000 patients were diagnosed with NTM lung disease in the US alone.
Non-tuberculous
mycobacterium (NTM) infections are extremely difficult to treat, especially so in patients with cystic fibrosis (Eikani, et.
al., 2018). The infecting organisms are frequently resistant to most antibiotics, and current treatment regimens require combination
therapies with highly toxic drugs for long periods of time, further complicated by challenges in delivering therapeutic levels
of these toxic drugs across plasma membranes of infected cells.
These
challenges are amplified in CF patients, with the thick buildup of pulmonary secretions that further impair treatment of infecting
organisms. Pulmonary infections represent the most frequent type of infection in CF patients, and are responsible for more than
90% of deaths in the CF population (Rowe SM, et.al. 2005). Mycobacterium avium complex (MAC) and Mycobacterium abscessus