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 ACTOF 1934
For
the fiscal year ended December 31, 2021
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)
908-484-8805
(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 every Interactive Data
File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding
12 months (or for such shorter period that the registrant was required to submit such files).
Yes
☒ No ☐
Indicate
by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting
company, or 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 voting and non-voting common equity held by non-affiliates computed by reference to the price at
which the common equity was sold on June 30, 2021 was approximately $160.0million.
As
of March 4, 2022, there were 216,864,526shares
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, 2021
Table
of Contents
Page
PART I 1
Item 1. Business 2
Item 1A. Risk Factors 33
Item 2. Properties 62
Item 3. Legal Proceedings 62
Item 4. Mine Safety Disclosures 62
Item 6. Selected Financial Data 62
Item 7A. Quantitative And Qualitative Disclosures About Market Risk 69
Item 8. Financial Statements And Supplementary Data 69
Item 9A. Controls And Procedures 69
Item 9B. Other Information 70
PART III 70
Item 10. Directors, Executive Officers And Corporate Governance 70
Item 11. Executive Compensation 76
Item 14. Principal Accounting Fees And Services 85
Item 15. Exhibits And Financial Statement Schedules 86
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 clinical-stage biopharmaceutical company focused on redefining the intracellular delivery of nucleic acids and small molecules
through our lipid nanocrystal (LNC) delivery platform technology. Our current pipeline consists of two potent anti-infective small molecules,
MAT2203 (oral amphotericin B) and MAT2501 (oral amikacin). We are also expanding the application of our LNC platform through collaborations
with well-respected pharmaceutical companies whose molecules and compounds benefit from the unique capabilities of our delivery technology,
which can provide oral bioavailability and facilitate non-toxic and efficient intracellular delivery. We are intent on further expansion
of our LNC platform, both internally and through external partnerships, into the field of nucleic acids where delivery into cells remains
a critical element of therapeutic effect.
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 chemical and biological payloads in a
way that facilitates safe, efficient, and targeted intracellular delivery for a wide variety of molecules, including nucleic acids (mRNA,
DNA, siRNA, antisense oligonucleotides (ASOs)), proteins and small molecules. Our LNCs are primarily comprised of phospholipids, like
phosphatidylserine (PS), and calcium (which is required to keep LNCs intact), and are well differentiated from other viral and lipid
nano-particle delivery technologies. LNCs have a novel targeting profile utilizing PS fusion and PS-receptor mediated endocytosis. LNCs
have a neutral immunogenic profile enabling repeated administration, which is a significant drawback associated with both viral vector
(AAV) and lipid nanoparticle (LNP) delivery. The structure of an LNC is highly stable, protecting the payload throughout formulation
and following administration into the human body. This stability allows for the avoidance of extreme cold chain storage temperatures
required for maintaining the integrity of LNPs and facilitates the oral administration of LNCs, which is not possible with either AAV
or LNP delivery as they protect the vulnerable payload from the gastric environment and potential extracellular degradation. LNCs can
also be administered via IV injection and intranasally. Because of their unique composition, LNCs can be delivered into a cell
through both endocytosis and membrane fusion. Once LNCs gain access to the inside of a cell, they naturally unwind due to the necessarily
low calcium concentrations inside a cell. Thereafter, depending on the target, payloads either have their desired impact inside a cell,
or utilize the cell as a vehicle to target tissues, in the case of infection or inflammation.
Clinical
and preclinical studies have demonstrated success in delivering LNCs to professional phagocytes, including macrophages, sites of infection
and inflammation, and tumors. Each of these target cells either have exposed PS, enabling cellular fusion, or specific and dedicated
PS receptors which facilitate receptor mediated cellular uptake. This tissue targeting, coupled with 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., mRNA,
DNA , ASOs, and siRNA,) provide a broad array of potential targets and modalities from which to create a broad pipeline of internal product
candidates and partnerships.
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. Amphotericin B is currently only available in IV formulations which are associated with significant
renal toxicity and labeled restrictions on its use for up to 2 weeks in the United States and only 1 week in most parts of the world
due to its toxicities, the most prevalent of which is severe nephrotoxicity. Despite these limitations, amphotericin B is currently used
and approved to treat a variety of invasive, and potentially deadly, fungal infections due to its potency. MAT2203, which is formulated
using our LNC delivery technology, has the potential to preserve the efficacy of amphotericin B while eliminating the risk of nephrotoxicity
and providing more convenient and cost-effective oral administration. MAT2203’s product profile could potentially allow physicians
and patients to use MAT2203 for longer periods of time and more broadly than amphotericin B could ever have been used previously.
The
initial planned indication for MAT2203 is as step-down therapy from IV amphotericin B during induction treatment in patients with cryptococcal
meningitis (CM), a deadly fungal infection located in the brain, and which primarily affects immunocompromised patients. The induction
treatment period is typically 14 days and step-down therapy with MAT2203 would begin following an initial, short 1–2-day treatment
course with IV amphotericin followed by 12-13 days of MAT2203. This initial step-down indication is a gateway indication, as we plan
to expand the utilization of MAT2203 into consolidation therapy in CM patients (weeks 3-6) and then into the treatment of other invasive
fungal infections and even for prophylaxis against invasive fungal infections in immunocompromised patients, such as transplant patients.
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. MAT2203 has also received an Orphan drug designation
from FDA. Upon approval, MAT2203 could be eligible for up to 12 years of regulatory exclusivity in the United States.
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, the Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial (EnACT), initiated
in 2019 and currently enrolling patients in Cohort 4 of the trial. In this trial we are exploring the use of MAT2203 for both induction
(step-down and all oral) and consolidation therapy, and we believe that, if positive, this trial could form the foundation for the filing
of a New Drug Application for MAT2203. The first three cohorts of EnACT have been completed, with the data from each of the cohorts reviewed
by an independent Data Safety Monitoring Board (DSMB) prior to progression from one cohort to the next. EnACT is currently enrolling
patients in Cohort 4, which is designed to test an all-oral regimen of MAT2203 during the induction period. Results from Cohort 4 are
expected in the third quarter of 2022.
Based
upon the data from the first two cohorts of EnACT, we held a meeting with the FDA in December of 2021 to discuss potential registration
pathways for MAT2203. Following feedback from FDA, we plan to expand the EnACT trial to include a new, Cohort 5, which will replicate
the design from Cohort 2, and include more patients where MAT2203 will be evaluated as step-down treatment to IV amphotericin. We anticipate
meeting again with FDA in the first half of 2022 to finalize the protocol for Cohort 5 and agree on the requirements for NDA filing for
this initial indication.
Data
to date from EnACT validates the use of MAT2203 in difficult-to-treat fungal infections, and we believe positions MAT2203 to become
a best-in-class antifungal drug for the treatment of additional invasive fungal infections. Furthermore, the demonstration that MAT2203
effectively crosses the blood-brain barrier in humans positions our LNC platform delivery technology to potentially be used more
broadly with many other types of molecules, potentially including nucleic acids.
Our
second clinical-stage program is the development of MAT2501, our oral amikacin development program, which also utilizes our LNC platform
technology. MAT2501 is currently being studied in a Phase 1, single ascending dose (SAD) pharmacokinetic study in healthy volunteers,
with results expected late in the first half of 2022. This program is funded in large part by the Cystic Fibrosis Foundation (CFF) and
together we are developing MAT2501 initially for the treatment of non-tuberculous mycobacterial (NTM) infection, a serious lung infection
which can be especially problematic in patients with cystic fibrosis (CF). To date, we have received commitments totaling approximately
$4.6 million from the CFF based, in part, 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
plan to establish a broad internal and external pipeline of drug candidates utilizing our LNC platform. Internally, we have increased
our efforts to demonstrate, validate and optimize the formulation and intracellular delivery of nucleic acids. We also are in active
discussions with third parties concerning the formulation of proprietary nucleic acids utilizing our LNC platform and are concentrating
on those parties with demonstrated scientific expertise and competitive advantages in the nucleic acid space. We have ongoing collaborations
with third parties which have successfully broadened the application of our LNC platform and remain ongoing.
We
continue to evaluate additional potential strategic collaborations with other interested biotechnology and pharmaceutical partners. These
collaborations could enable us to grow our external pipeline and generate upfront, license, milestone and royalty payments as we maximize
the value of the overall LNC platform delivery technology.
Strategy
We
are focused on redefining the intracellular delivery of nucleic acids and small molecules through our 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.
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 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 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 intranasally. 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 endocytosis (through a variety of pathways including phagocytosis, clathrin-mediated
endocytosis (CME), caveolin-mediated endocystosis, and macro- and micropinocytosis), or through membrane fusion. LNPs are limited
in that they can typically only access a cell via CME, 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 (AEs) and other
toxicities associated with LNPs, thereby limiting chronic use. LNPs also cannot be delivered orally. Viral vectors, including
adeno-associated virus, attempt 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 both endocytosis and membrane
fusion, in addition to having great flexibility with the desired route of administration.
We
believe that LNC’s unique ability to enter a cell through endocytosis (including phagocytosis and macropinocytosis), membrane
fusion, 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. Professional phagocytes, with drug-loaded
LNCs inside, are believed to 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 advance 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.
Safety:
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 nanometers. 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, in animal studies we have orally delivered vaccines, siRNAs, 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 product candidate, MAT2203, is an orally-administered LNC formulation
of a broad spectrum anti-fungal drug called amphotericin B. Based on the data generated in Cohort 2 of the EnACT Trial and following
an End of Phase 2 Meeting with FDA, we believe we have a pathway to NDA submission for MAT2203 following confirmatory data to
be generated in an additional cohort (Cohort 5) in the ongoing EnACT Trial. We additionally believe there are opportunities for approval
of MAT2203 for the treatment of additional invasive fungal infections in areas of high unmet medical need, which we will be evaluating
in a number of preclinical animal models in Candida auris and mucormycosis in 2022.
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 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 safety based upon the available preclinical tox data for 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 4 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 market exclusivity for MAT2203.
We met with the FDA in an End of Phase 2 Meeting in December 2021 to review the Cohort 2 data from the EnACT Trial and discuss a potential
path to NDA filing. Following our meeting with FDA, we now have a pathway to NDA submission following confirmatory data to be generated
in an additional cohort (Cohort 5) in the ongoing EnACT Trial. We will be meeting with FDA early in the second quarter of 2022 to gain
agreement on the design of this confirmatory cohort.
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 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 AEs 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 CFF to complete preclinical
studies with Colorado State University which further demonstrated the potential for MAT2501 in treating CF-associated NTM lung infections.
In November 2020, we received an additional grant from the CFF in the amount of $3.75 million to support the continued development of
MAT2501 through a comprehensive preclinical toxicology program and a SAD study in healthy volunteers with our new and improved formulation
of MAT2501. The grant was later increased by $0.3 million in November 2021 to bring the CFF’s total commitment towards the development
of MAT2501 to $4.6 million. 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. We are currently conducting
key acute and long-term toxicology studies to support Phase 2 clinical trials as well as an ongoing Single Ascending Dose (SAD) Trial.
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 reported 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 amphotericin B at the site of infection and a lower level of free circulating drug.
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 drug-carrying phagocytes to inflammatory regions. Based upon data
generated 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. These preclinical data have now been born-out in clinical data from Cohort
2 of the EnACT Trial.
We
believe that MAT2203 has the potential to become a best-in-class induction and consolidation therapy for the treatment of CM in HIV patients
by offering the following key potential 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 a new drug application (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 drug; however, it also has significant treatment-limiting side effects,
most notably nephrotoxicity. We believe that the ability to provide amphotericin B orally using our proprietary 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 substantial advantage over other amphotericin B formulations in observed toxicities
and side effects, which we believe is driven by two primary factors:
Development
History of MAT2203 and Initial Target Indication
Preclinical
Data:
Oral
MAT2203 has demonstrated antifungal activity when administered orally in several animal models for Cryptococcus, Candida,
and Aspergillus infection [Zarif et al, 2000; Perlin, 2004; Lu et al, 2019]. The efficacy in these animal
models have shown to demonstrate comparable or superior antifungal activity compared to IV amphotericin B but with reduced toxicity.
The
in vivo efficacy of MAT2203 has been shown in multiple mouse models infected with Cryptococcus neoformans; these studies
were conducted by Dr Peter Williamson at NIH [Lu et al, 2019]. Multiple studies demonstrated the potential for MAT2203 administered
in combination with 5FC to provide an effective oral formulation for treatment of cryptococcal meningitis. Using a 3-day delayed model
of murine cryptococcal meningoencephalitis and a large inoculum of a highly virulent strain of serotype A C. neoformans, MAT2203,
administered in combination with 5FC, was found to have efficacy equivalent to administered amphotericin B deoxycholate with 5FC and
superior to oral fluconazole without any observed toxicity. Transport of fluorescent MAT2203 particles to the brain as well as significant
brain levels of amphotericin drug was demonstrated in treated mice, and immunological profiles were similar to those of mice treated
with conventional amphotericin B. These studies offer the potential for an efficacious oral formulation of a known fungicidal drug against
intrathecal cryptococcal disease. MAT2203 therefore provides a promising therapeutic option for CM.
Additional
preclinical studies of MAT2203 are planned to investigate the treatment of invasive fungal infections, such as Candida auris and
mucormycosis (black fungus), to position MAT2203 for label expansion. Data is expected in late 2022.
Clinical
Data:
Clinical
studies conducted and previously completed with MAT2203 include 2 Phase 1 studies in healthy subjects (Study CAM-102 and Study
MB-70011), and 2 Phase 2 studies: 1 completed study in patients with moderate to severe vulvovaginal candidiasis (VVC) (Study
MB-70005) and 1 study in patients with mucocutaneous candidiasis who are refractory or intolerant to standard non-IV therapies (MB-70004).
As
of the end of January 2022, MAT2203 has been administered to a total of 247 subjects in 5 clinical trials as follows: 52 healthy subjects
(Studies CAM-102 and MB-70011), 36 patients with HIV and 65 patients with cryptococcal meningitis (in EnACT Trial MB-70007), 91 patients
with VVC (MB-70005), and 4 patients with mucocutaneous (esophageal and oropharyngeal) candidiasis (MB-70004). In these studies, single
doses of MAT2203 up to 2.0 g and repeated doses of MAT2203 up to 2.0 g/day and as long as 60 months have been safe and well-tolerated.
Results of these studies support efficacy of oral MAT2203 against Cryptococcus and overall safety of longer-term MAT2203 treatment.
The
EnACT Trial (MB-70007) consists of 2 parts. Part 1 of the EnACT Trial was conducted in HIV-positive patients with a history of cryptococcosis
evaluated ascending oral doses of MAT2203, and identified a safe maximum tolerated dose for Part 2 of the trial.
Part
2 of the EnACT Trial is a prospective, randomized, open-label clinical trial to investigate the safety, tolerability, and
efficacy of oral MAT2203 compared to Standard of Care (SoC) for the treatment of CM in patients with HIV and was originally divided into
four distinct patient cohorts. Cohort 2 of the EnACT Study was 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. This cohort of patients also provided 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 (Cohorts 3 and 4). The primary
efficacy endpoint for Part 2 of EnACT is early fungicidal activity (EFA) defined as rate of clearance of Cryptococcus from the cerebrospinal
fluid (CSF) (log10 colony forming units [CFU]/mL/day) as measured by serial quantitative fungal cultures over the first 2
weeks of treatment.
In
Part 2, cohorts 1, 2, and 3 have been completed and Cohort 4 is ongoing. Enrollment in Cohort 3 has completed with 14 subjects enrolled,
8 of whom are still active in the trial; 10 of the 14 patients received at least 1 dose of MAT2203. Eight patients have been enrolled
in Cohort 4 as of 26 January 2022; 5 of these 7 patients received at least 1 dose of MAT2203.
In
Part 2, Cohort 2 of the EnACT Trial (MB-70007), 40 patients with active CM were treated with MAT2203. The mean EFA for these 40 patients
who received MAT2203 during induction was 0.422 log10 CFU/mL/day (95% CI: 0.294, 0.550). The primary efficacy endpoint for
the trial was met because the lower bound of the 95% CI for the mean EFA excluded 0.20 log10 CFU/mL/day. In addition, among
patients treated with MAT2203, CSF sterilization rates were greater than 90% and all patients who completed the induction phase achieved
sterile CSF cultures at end of induction or during consolidation treatment. Survival rates in Cohort 2 were high and there were no relapses
in patients receiving MAT2203 during consolidation. Additional analysis of final data from Cohort 2 demonstrated survival at Day 30 of
98% in patients receiving MAT2203 vs. 88% in patients receiving IV amphotericin B and culture conversion (sterility) assessed at any
time during the trial of 97% in patients receiving MAT2203 and 76% in patients receiving IV amphotericin B.
MAT2203
was demonstrated to be safe and well-tolerated over 6 weeks of treatment in Part 2, Cohort 2 of EnACT. The majority of SAEs and AEs reported
were considered to be expected in this HIV patient population and there was no evidence of MAT2203-associated renal toxicity or electrolyte
abnormalities in patients who received MAT2203. Additionally, GI AEs reported were generally transient, moderate in severity, and did
not have an impact on the ability of patients to tolerate the planned treatment course.
Health
Authority Interactions:
In
December 2021, the Company had a meeting with FDA to discuss a potential registration pathway for MAT2203. The
outcome of the meeting reinforced the FDA’s ongoing commitment to anti-infective drug development generally and to MAT2203 specifically.
During the meeting, the FDA expressed no concerns with any data generated to date related to the efficacy, safety, or tolerability of
MAT2203. Additional confirmatory evidence was requested for an indication for step-down therapy during induction treatment, but there
was no requirement for a separate stand-alone study or enrollment of U.S. patients. The FDA expressed openness to an expansion of EnACT
to include a new Cohort 5 to run alongside Cohort 4 in Uganda, increasing the number of clinical sites from two to five to streamline
the development program in support of an accelerated NDA submission. The Company is planning to meet with FDA in April 2022 to finalize
cohort design, including sample size required for non-inferiority and to discuss a potential primary endpoint of 30-day survival. NIH
financial support of EnACT expansion to Cohort 5 is anticipated and the Company continues to evaluate the timing for submission of an
application for Breakthrough Designation. A key chemistry, manufacturing, and controls (CMC) meeting with FDA is scheduled late in the
first quarter of 2022 to discuss and evaluate our MAT2203 formulation in support of a potential NDA submission in late 2023. The Company
also plans to submit a formal Request for Scientific Advice to the European Medicines Agency (EMA) in 2022 to align and plan for expanding
the regulatory footprint for MAT2203 globally.
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 Candida 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 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 CF, 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.
NTM
infections are extremely difficult to treat, especially so in patients with CF (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). MAC and Mycobacterium abscessus complex (MABSC) are NTM species that have emerged in
recent years as important opportunistic pathogens frequently responsible for pulmonary infections in CF patients (Brode SK, et. al.
2014). Infections due to MAC and MABSC are difficult to treat and to eradicate since these organisms are naturally resistant to most
antibiotics. The recommended treatment for MAC and MABSC pulmonary infections includes a combination of a macrolide (clarithromycin or
azithromycin), an aminoglycoside (amikacin), and an antimycobacterial antibiotic for MAC (rifampin and ethambutol), while MABSC many