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, 2022
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 has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered
public accounting fi rm that prepared or issued its audit report. ☐
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the 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, 2022 was approximately $164.8 million.
As
of March 3, 2023, there were 217,264,526 shares 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, 2022
Table
of Contents
Page
PART I 1
Item 1. Business 3
Item 1A. Risk Factors 35
Item 2. Properties 63
Item 3. Legal Proceedings 64
Item 4. Mine Safety Disclosures 64
Item 6. Selected Financial Data 65
Item 7A. Quantitative And Qualitative Disclosures About Market Risk 71
Item 8. Financial Statements And Supplementary Data 71
Item 9A. Controls And Procedures 71
Item 9B. Other Information 72
PART III 72
Item 10. Directors, Executive Officers And Corporate Governance 72
Item 11. Executive Compensation 77
Item 14. Principal Accounting Fees And Services 87
Item 15. Exhibits And Financial Statement Schedules 88
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 delivering groundbreaking therapies using our lipid nanocrystal (LNC) platform
delivery technology (LNC Platform) to maximize global clinical impact and patient access. The Company is developing an internal portfolio
of products and strives to be the partner of choice for leading pharmaceutical companies seeking to develop novel formulations that capitalize
on the unique characteristics of the LNC Platform to facilitate, enhance and optimize the delivery of complex nucleic acids. Our current
internal pipeline consists of MAT2203 (oral amphotericin B), a highly potent antifungal drug which we have successfully made oral, safe,
and well-tolerated for patients. We also have internal discovery programs ongoing in the formulation and delivery of small oligonucleotides,
namely antisense oligonucleotides (ASOs) and silencing or short interfering RNAs (siRNAs). We are also intent on 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 of nucleic acids, particularly in the fields of mRNA and DNA.
We
are dedicated to maximizing the value associated with our unique LNC Platform. This proprietary platform technology, which partially
relies upon an exclusive worldwide license from Rutgers University to certain intellectual property, 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 due to the potential for cytotoxicity. The structure of an LNC is highly stable, protecting
the payload throughout formulation and following administration into the human body. This stability eliminates the need for the extreme
cold chain storage temperatures required to maintain the integrity of LNPs, and facilitates the oral administration of LNCs, which is
not possible with either AAV or LNP delivery as LNCs protect the vulnerable payload from the gastric environment and potential extracellular
degradation. LNCs can also be administered via IV or IM injection and intranasally. Because of their unique composition, we believe 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 an 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 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 for the treatment of cryptococcal meningitis (CM),
a deadly fungal infection located in the brain, and which primarily affects immunocompromised patients. This initial step-down indication
is a gateway indication, as we plan to expand the utilization of MAT2203 into the treatment of other invasive fungal infections (IFIs)
and potentially even for prophylaxis against IFIs 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 IFIs in patients who are on immunosuppressive
therapy, and, most recently with an Orphan Designation for the treatment of cryptococcosis. Upon approval, MAT2203 could be eligible
for up to 12 years of regulatory or marketing 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 recently completed enrollment and reported positive data. Cohort 2 of EnACT evaluated the safety and
efficacy of MAT2203 (administered with adjunctive flucytosine) as early step-down treatment, following two days of IV amphotericin B,
followed by consolidation treatment with MAT2203 in combination with 800 mg/day fluconazole for an additional 4 weeks. Cohort 4 of EnACT
evaluated the safety and efficacy of an all-oral regimen of MAT2203 (administered with adjunctive flucytosine) for the initial 14-day
induction period, with MAT2203 treatment continued for an additional four weeks into the consolidation phase, administered in combination
with 800 mg/day of fluconazole. The primary endpoint of EnACT was early fungicidal activity, a direct measurement of the quantitative
rate of antifungal activity at the site of infection in the cerebrospinal fluid (CSF) surrounding the brain, a well-recognized key surrogate
marker for survival. The pre-specified target threshold of 0.20 in EnACT is clinically meaningful and represents a robust degree of fungal
clearance that is associated with enhanced survival. Early fungicidal activity beyond the >0.20 threshold have not resulted in any
observed incremental benefit. EnACT also included secondary endpoints of overall survival, prevention of relapse, CSF sterilization,
and safety.
EnACT
Cohort 4 data from 40 MAT2203 treatment arm participants and 40 standard of care (SOC) controls were presented during the IDWeek 2022
conference. Data from Cohort 4 confirms the efficacy and safety observed in Cohort 2, which is clinically important given the lack of
any IV amphotericin B loading doses administered in this “all-oral” treatment cohort. Since the time of the data presentation
in October 2022, we continue to collect data for ongoing patients.
Interim
Results from Cohort 4
The
key interim results from Cohort 4 of EnACT include exceeding the prespecified early fungicidal activity threshold of >0.20 CFU/mL
CSF/day, survival, and the safety of longer-term use of an oral formulation of amphotericin B (MAT2203) for up to 6 weeks.
● Exceeding Key Early Fungicidal Activity Threshold
In
Cohort 4, the CSF yeast clearance rate exceeded the prespecified primary endpoint threshold target of >0.20, with a mean early fungicidal
activity achieved of 0.353 log10 CFU/mL/day with 95% confidence intervals from 0.22 – 0.49. Several participants with high baseline
fungal burdens had noteworthy antifungal activity within the MAT2203 treatment arm, including one patient with quantitative cryptococcal
culture as high as 915,000 CFU/mL at the time of screening with effective clearance during the induction period, a key demonstration
of potent antifungal activity, even in the most challenging of cases.
● Survival
In
Cohort 4, in 40 patients receiving MAT2203 treatment, interim 18 Week survival is currently 85%, while the survival rate at Week 2 was
95% (similar to SOC); note that Week 2 survival is the prespecified primary endpoint for the MAT2203 Phase 3 registration trial in cryptococcal
meningitis. No deaths were attributed to lack of effect of MAT2203.
● Safety
MAT2203
patients had fewer Grade ≥3 Clinical adverse events (AEs) (42%) vs. SOC treatment (59%). Importantly, the incidence of AEs events
relating to kidney function and anemia were significantly lower for MAT2203 compared with the SOC treatment, with no evidence of kidney
toxicity seen with 6 weeks of oral MAT2203 treatment. The favorable safety and tolerability data seen in Cohort 4 support the use of
oral MAT2203 for longer-term use, something not previously feasible due to associated toxicities with currently available IV formulations
of amphotericin B.
Phase
3 Key trial elements
With
guidance from multiple positive meetings with FDA based upon the data generated in EnACT, the Company has finalized the design of a single
pivotal Phase 3 registration trial for MAT2203 supporting submission of a New Drug Application (NDA) for a simplified indication for
the treatment of CM. The open-label trial involves a three arm non-inferiority design in HIV patients with CM: (A) step-down therapy
with MAT2203 with treatment continuing for 2 weeks; (B) step-down therapy with MAT2203 with treatment out to 6 weeks (mirroring Cohort
2 of EnACT); and (C) a SOC control arm of IV amphotericin B induction transitioning to fluconazole. The non-inferiority margin for both
the primary and key secondary endpoints will be 10% and total enrollment is expected to be approximately 270 patients, with an adaptive,
de-risking design allowing for the potential for additional patients once enrollment has reached 75%.
The
primary endpoint of the trial will be 2-week all-cause mortality, with a pooled analysis across the two MAT2203 treatment arms compared
with SOC control to support a potential indication for the treatment of CM for up to 2 weeks. To evaluate opportunities for extending
MAT2203 therapy, a key secondary analysis of 10-week relapse free survival of optimized treatment (2-weeks or 6-weeks) against SOC will
be evaluated for non-inferiority. Selection of the optimal treatment regimen will be based on predefined and protocolized clinical criteria
and will then form the basis for a final NDA submission.
We
have also received positive feedback from the European Medicines Agency (EMA) on both our Request for Scientific Advice and our Orphan
Drug Application; this provides alignment with FDA and positions MAT2203 for global registration in key commercial markets.
Data
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 IFIs. Furthermore, the demonstration that MAT2203 effectively crosses the blood-brain
barrier in humans positions our LNC Platform to potentially be used more broadly with many other types of molecules, potentially including
nucleic acids.
Platform
Collaborations
In
addition to advancing MAT2203, 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.
Strategy
We
are focused on redefining the intracellular delivery of nucleic acids and small molecules through our LNC 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
Safe,
efficient, and targeted intracellular delivery of medicines remains one of the biggest challenges in the pharmaceutical and biotech industry
today. An ever-growing understanding of the complex biology within cells has given rise to increasingly sophisticated therapeutic approaches
targeting the genetic machinery driving metabolic activity within cells. Unfortunately, the currently available options for intracellular
delivery – liposomes, lipid nanoparticles (LNPs) and viral vectors – although widely adopted, continue to have their own
well-recognized limitations, including inefficient delivery, undesirable and dangerous toxicity and immunogenicity, and unstable formulations
which necessitate challenging storage conditions (Figure 1).
Until
now, there have been limited options for intracellular delivery, and, despite these limitations, LNPs have emerged as a primary delivery
vehicle for mRNA, while viral vectors remain the mainstay of DNA delivery and gene therapy. We have developed our own proprietary lipid
nanocrystal (LNC) delivery platform that we believe may help overcome many of the limitations of both LNPs and viral vectors,
Figure
1: Current Delivery Technologies
LNCs
– Background
“Cochleate
lipid cylinders” were originally described in scientific literature as complex, cylindrical, multi-lamellar structures arising
from the addition of Ca++ to sonicated liposomal preparations of phosphatidylserine (PS) in an aqueous solution, with the
lamellae folded in a spiral, crystalline configuration that excludes water. When sufficient external calcium is present, these structures
remain in a crystalline state, while the addition of etheylenediaminetetraacetic acid (EDTA) to these preparations (removing the calcium)
results in the loss of the stable spiral crystalline structure (Figure 2).
Figure
2: Cochleate Formation
We
have developed techniques to embed cargo molecules within cochleates as they are assembled. These new cargo-carrying structures (termed
lipid nanocrystals, or LNCs) have been used to successfully deliver a number of different cargo molecules to cells in vitro
and to animals and humans in vivo. Because of their exceptional stability (an anhydrous crystalline structure) and unique
composition (PS-containing bilayers), we believe that LNCs are a promising alternative for the intracellular delivery of a variety of
small molecules – proteins, peptides, siRNA, ASOs – and, with modifications, large oligonucleotides such as DNA and RNA.
In addition, since the normal physiologic levels of calcium in the gut can maintain their crystalline structure, LNC formulations can
also potentially be delivered orally, as the encapsulated cargo is protected from degradation by harsh environmental conditions or enzymes
(Figure 3).
Figure
3: LNCs Encapsulate and Protect their Cargo in a Water-free Environment
Importance
of 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 and not normally exposed externally (Figure 4). However, when cells are injured
and/or apoptotic, PS moves from the inner layer to the outer layer and is the primary “eat me” signal driving efferocytotic
clearance of apoptotic cells by professional phagocytes.
Studies
with cargo carrying LNCs have documented both a lack of cargo accumulation in the tissues of normal, healthy animals, and significant
cargo delivery to involved tissues in infected animals. Another important aspect of the underlying stability of LNCs is that they do
not release their cargo within the blood (due to the presence of stabilizing levels of calcium), and delivery of cargo is confined to
involved cells and tissues.
Mechanistically,
the cellular entry of LNCs is driven by PS, which is an important participant in both efferocytotic clearance of apoptotic cells and
in physiologic cellular fusion processes (Figure 4). As noted, apoptotic cells expressing PS on their surface are recognized and
cleared by professional phagocytes, without eliciting the normal inflammatory responses that might otherwise be anticipated with cell
death. Professional phagocytes themselves have several very specific PS receptors that facilitate this clearance. Parenthetically this
mechanism is exploited by enveloped viruses to facilitate viral uptake by immune cells – “viral apoptotic mimicry”
– noting that the “envelope” of enveloped viruses is basically comprised of PS. Thus, phagocytosis of LNCs by professional
phagocytes (and some non-professional phagocytes) becomes one mechanism for intracellular delivery of LNCs.
Figure
4: Importance of Phosphatidylserine (PS) in apoptotic phagocytosis
As
described above, in addition to its role as an “eat-me” signal for uptake of apoptotic cells by phagocytes, PS also plays
a very important role in normal physiologic cellular fusion processes – as a “fuse-me” signal (such as with the formation
of myotubules from myoblasts, the formation of osteoclasts from osteoblasts, and the fertilization of an of egg by sperm to form a zygote)
or even as a “heal me” signal (as with axonal fusion after injury or repair of injured cell membranes). Consequently, the
presence of PS on both the surface of LNCs and on the surface of targeted somatic cells (which themselves may express PS because of injury
or inflammation) creates additional opportunities for intracellular delivery via direct cellular fusion (Figure 5).
Figure
5 – Importance of Phosphatidylserine (PS) in Cellular Fusion
LNC
Drug Delivery
Because
of their underlying stability, LNCs do not release cargo within the blood (due to the presence of stabilizing levels of calcium), and
the delivery of cargo is confined to involved cells and tissues. Studies utilizing an LNC formulation of radio-labeled amphotericin showed
no accumulation in normal healthy tissues, in contrast to multiple studies showing clinically meaningful tissue levels of amphotericin
when amphotericin-carrying LNCs were administered in the setting of systemic fungal infections.
After
oral administration, LNCs are transported across the cells lining the gastrointestinal tract (via transcytosis). Because of their size,
LNCs do not enter the portal circulation and thereby avoid first pass hepatic metabolism. Instead, they are transported through the gut
lymphatics to the thoracic duct and enter the circulatory system via the superior vena cava. Once they have entered the circulation,
LNCs are transported by professional phagocytes (as well as via other non-cellular mechanisms) to sites of injury or infection, where
they are avidly taken up by infected/injured cells that have PS on the outer layer of their cell membranes. Finally, when exposed to
the very low calcium environment in the interior of a cell, the forces responsible for maintaining the otherwise stable LNC structure
are no longer as strong, and the LNCs release their cargo.
Overcoming
limitations of LNPs and viral vectors
Conventional
LNPs in blood bind ApoE to their surface and are taken up into cells by clathrin-mediated endocytosis via the ApoE-recognizing LDL receptor.
From within early endosomes, LNPs then act to disrupt the endosomal membrane and gain entry to the cytosol. Endosomal escape of LNPs
is a very inefficient process, with endosomal escape rates of generally < 5%. Administration of LNPs can also be associated with injection
site reactions and other toxicities arising from the destruction of the endosomal membrane, which, ultimately, can limit their chronic
use. Finally, LNPs cannot be delivered orally.
Viral
vectors, including adeno-associated virus, attempt to utilize viral cellular entry 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 even deaths and similar to LNPs, viral vectors cannot be delivered orally.
Ways
in which LNCs can help overcome the limitations of LNPs and viral vectors include efficient cellular delivery, a breadth of payload capabilities,
extra-hepatic targeting, reduced toxicity and improved safety, multiple potential routes of administration (including oral) ,and improved
stability and shelf-life.
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 deliver many different molecules.
With
multiple potential mechanisms for getting into cells, unlike with LNPs, we believe that intracellular delivery via LNCs is not
primarily confined to the liver, and as noted, LNCs have been used to successfully deliver a wide range of therapeutic compounds –
including small molecules, proteins, ASOs, siRNA, DNA plasmids and DNA-protein complexes, both in vitro and in vivo.
Therapeutic
applications of our proprietary delivery technology have focused initially on the delivery of potent, highly effective anti-infective
agents that have treatment-limiting potential toxicities, including irreversible toxic effects on kidney and hearing function. For instance,
with MAT2203 we have developed a less toxic and orally deliverable formulation of the potent (but otherwise highly toxic) fungicidal
drug amphotericin that can be safely used for longer periods of time than currently possible with conventional amphotericin in the treatment
of deadly fungal infections. This, in turn, has created potential opportunities to use amphotericin in ways that were not previously
possible with conventional formulations, and endeavor to make amphotericin treatment possible in settings where conventional amphotericin
has proven to be too toxic.
More
recently, our research and development efforts using the LNC Platform have expanded to address additional therapeutic nucleic acid cargos
– both small oligonucleotides (ASOs, siRNA, etc.) and larger oligonucleotides like DNA and mRNA. The latter large complex molecules
have their own unique formulation challenges but can be successfully incorporated into a modified LNC structure and have been successfully
delivered in vitro in a variety of different cell types.
Our
LNC Clinical Stage Assets
We
have leveraged our LNC Platform to develop 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 Cohorts 2 and 4 of EnACT and following additional follow-up meetings
with the FDA, we believe we have a well-defined pathway to NDA submission for MAT2203 for an initial indication for the treatment of
cryptococcal meningitis. Our overall development strategy is to ultimately pursue a broader indication for MAT2203 for the treatment
of IFIs, building upon the efficacy bridge we have established with MAT2203 to IV amphotericin B based on the data from EnACT.
Cryptococcal
Meningitis History and Plan
Based
upon robust preclinical data, the NIH financially supported a grant application from the University of Minnesota to conduct EnACT 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
toxicology data for IV amphotericin B. Our 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 EnACT. We have received four qualified infectious disease (QIDP) designations
as well as an orphan designation for the treatment of cryptococcosis, which, if approved, could result in up to twelve years of regulatory
or marketing exclusivity for MAT2203 in the United States.
With
guidance from multiple positive meetings with FDA based upon the data generated in EnACT, we have finalized the design of a single pivotal
Phase 3 registration trial for MAT2203 supporting submission of a NDA for a simplified blanket indication for the treatment of CM. The
open-label trial involves a three arm non-inferiority design in HIV patients with CM: (A) step-down therapy with MAT2203 with treatment
continuing for two weeks; (B) step-down therapy with MAT2203 with treatment out to 6 weeks (mirroring Cohort 2 of EnACT); and (C) a SOC
control arm of IV amphotericin induction transitioning to fluconazole. The non-inferiority margin for both the primary and key secondary
endpoints will be 10% and total enrollment is expected to be approximately 270 patients, with an adaptive, de-risking design allowing
for the potential for additional patients once enrollment has reached 75%.
Invasive
Fungal Infection Background and Plan
MAT2203
is an oral LNC formulation of amphotericin B, intended for the treatment of serious life-threatening, invasive fungal infections (IFIs).
Because the active amphotericin B cargo is sequestered within a highly stable LNC crystalline structure, MAT2203 can be administered
orally and delivers amphotericin B directly to the site of infection. MAT2203 is orally absorbed and has been shown to target infected
tissues to deliver amphotericin B to sites of infection, where it is rapidly taken up by infected cells and fungal hyphae. The amphotericin
B cargo binds to ergosterol in the fungal cell wall, creating pores, and resulting in the death of the fungal cells. The use of an oral
LNC delivery system results in very low circulating plasma amphotericin B levels and thereby has the potential to markedly reduce the
risk of systemic amphotericin B toxicity.
MAT2203
has been shown to be effective in numerous nonclinical in vivo models of fungal infections (i.e., CM, aspergillosis, candidiasis,
and mucormycosis). In addition, results from Cohorts 2 and 4 of a Phase 2 clinical study of CM in HIV patients, demonstrated oral MAT2203
was effective and well-tolerated with a favorable safety profile. The overall efficacy from EnACT validates the hypothesis that the LNC
drug delivery platform can facilitate the oral administration of amphotericin B across the blood-brain barrier to target the central
nervous system (CNS) site of infection in CM and similarly to directly target other deadly IFIs (e.g., aspergillosis, candidiasis, mucormycosis)
at the sites of disease.
The
preliminary efficacy and safety results from Cohorts 2 and 4 of EnACT demonstrate that MAT2203 is reaching the intended target of infection,
with efficacy data comparable to the SOC (IV amphotericin B) arm of the trial. We believe these data (together with the anticipated data
from EnACT3) will provide a pharmacodynamic (PD) bridge to IV amphotericin B, thus supporting the conduct of a single-dose open-label
IFI Phase 3 study in patients with limited treatment options. The Company plans to leverage data from the proposed Phase 3 IFI registration
trial, together with the already established efficacy of IV amphotericin B to treat IFIs to support the registration of MAT2203 for an
expanded IFI treatment label leveraging a 505(b)(2) pathway and NDA.
We
will be meeting with the FDA in the second quarter of 2023 to discuss our plans for expanding our registration of MAT2203 for the treatment
of IFIs more broadly. We have submitted a formal Meeting Request to the FDA to discuss plans for a second Phase 3 study to assess the
efficacy, safety, and tolerability of MAT2203 in patients with serious, life-threatening IFIs with limited treatment options. The protocol
synopsis currently includes the treatment of four IFIs: invasive aspergillosis, invasive candidiasis, chronic coccidioidomycosis (Valley
Fever), and invasive mucormycosis. Our strategy is to leverage the success and data from EnACT to limit the required size of this study.
We currently plan to enroll approximately 100 patients in a single-arm design with no head-to-head active comparator, which we believe
should be acceptable to FDA given historical precedent and the challenges associated with the target patient population to be evaluated.
During our meeting we plan to discuss our proposed design and strategy for approval.
In
January 2023, we announced that we were focusing our resources and internal efforts on the upcoming FDA meeting and on potentially securing
non-dilutive funds from industry and/or governmental partners prior to commencing our Phase 3 program. We believe that FDA guidance on
the IFI Phase 3 study is important to prospective domestic and global partners and governmental sources of nondilutive capital available
to advance the development of MAT2203 based on feedback received to date.
Our
second potential 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. We have determined to pause development of MAT2501 to focus our existing resources
on MAT2203 and advancement of our LNC Platform into the field of nucleic acids. We are in communication with the Cystic Fibrosis Foundation,
which has committed up to $4.5 million dollars toward the preclinical development of MAT2501, regarding our decision and working with
them to wind up our current agreement.
MAT2203
Our
lead anti-fungal product candidate, MAT2203, is an application of our LNC Platform 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 to nano-encapsulate amphotericin B, we have created 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 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. This demonstration provides important data indicating that our LNC Platform could
become an important delivery solution for a variety of CNS-based disorders and diseases. These preclinical data have now been validated
in clinical data from Cohorts 2 and 4 of EnACT.
Fungal
pathogens and infections are an increasing global public health concern. IFIs are increasing globally due to advancements in the medical
management of critically ill and immunocompromised patients. The emergence of drug-resistant IFIs has resulted in prolonged hospitalizations
and the increased use of expensive and often highly toxic second-line antifungal agents.
Fungal
pathogens cause a wide variety of infections but there are only four currently available classes of systemic antifungal treatments (polyene,
azole, echinocandin, pyrimidine), and only two classes (azole, pyrimidine) are available in oral formulations. Use of these antifungal
agents typically require a considerable degree of expertise to manage potential toxicities and complex drug-drug interactions in these
vulnerable patients and effective polyene and echinocandins require prolonged hospitalization for intravenous administration. Therefore,
there is a critical unmet need for more effective, well-tolerated, and safe oral antifungal agents to treat patients with serious, life-threatening,
and often drug resistant IFIs.
The
World Health Organization (WHO) recently recognized IFIs to be a global public health concern. In late 2022, the WHO released their Fungal
Priority Pathogen List which designates Aspergillus fumigates, Candida auris, and Candida albicans to be in the Critical Priority group
(i.e., highest perceived public health threat), Mucorales, Candida tropicalis, and Candida parapsilosis in the High Priority group, and
Coccidioides species in the Medium Priority group. Aspergillus, Candida, Coccidioides, and Cryptococcus species are also qualified pathogens
that pose a serious and life-threatening risk and are on the qualified designation list according to 317.2 – CFR – Code of
Federal Regulations Title 21 – FDA.
We
believe that MAT2203 has the potential to become a best-in-class therapy for the treatment of CM and for other IFIs more broadly 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 IFIs 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 from the U.S. FDA
and EMA. 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, 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 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 in the
United States 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, may offer
a new and promising alternative for patients and doctors.
The
data from animal toxicity and human 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 Indications and Regulatory Interactions
The
early development strategy for MAT2203 is focused on the treatment of CM as the gateway indication, building upon the extensive preclinical
work conducted by the NIH early in the development of this product. EnACT provided critical proof of clinical efficacy which was the
basis for the agreement by FDA for the conduct of a single Phase 3 trial for the potential registration of MAT2203 for the treatment
of CM.
We
believe the true clinical value of MAT2203 is the potential benefit to patients suffering from IFIs more broadly. Building upon the positive
data generated in EnACT, we are pursuing the expanded development of MAT2203 for treatment of other deadly IFIs, (aspergillosis, mucormycosis,
coccidioidomycosis, or candidiasis), which will be treated with oral MAT2203 after an initial short course of treatment with IV amphotericin
B (or an IV echinocandin). We anticipate that the use of MAT2203 will maintain, and potentially improve upon, the clinical efficacy and
safety of the IV formulations of amphotericin B by targeting directly to the site of infection, reducing toxicity by lowering overall
systemic exposure, improving ease of use, and allowing for longer courses of outpatient treatment. Additionally, we intend to leverage
the pharmacodynamic bridge established in EnACT to IV amphotericin B and seek to leverage a 505(b)(2) pathway for a potentially expanded
indication for the treatment of IFIs.
We
have met with the FDA several times since 2018 to discuss development plans for MAT2203. Most recently, in April 2022 we held a clinical
guidance meeting with the FDA to discuss our Phase 3 pivotal, registrational study of MAT2203 in CM and thereafter agreed with FDA on
planned statistical analyses in June 2022.
Our
Phase 3 registration trial of MAT2203 in CM will assess MAT2203 as step-down therapy after only 2 loading doses of IV amphotericin B
(similar to EnACT Cohort 2), building upon the impressive results already documented in EnACT. This open-label randomized trial, which
we expect will be partially financially supported by the National Institutes of Health (NIH) National Institute of Neurological Disorders
and Stroke (NINDS), involves a three arm non-inferiority design in persons living with HIV who have cryptococcal meningitis: (A) step-down
therapy with MAT2203 with treatment continuing for 2 weeks; (B) step-down therapy with MAT2203 with treatment out to six weeks; and (C)
SOC control arm of IV amphotericin B induction transitioning to fluconazole. The non-inferiority margin for both the primary and key
secondary endpoints will be 10% and total enrollment is planned to be approximately 270 patients, with an adaptive, de-risking design
allowing for the potential for additional patients once enrollment has reached 75%. The primary endpoint will be 2-week all-cause mortality,