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, 2023
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, 2023 was approximately $75.9 million.
As
of March 18, 2024, there were 217,482,830 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, 2023
Table
of Contents
Page
PART I 1
Item 1. Business 2
Item 1A. Risk Factors 40
Item 1B. Cybersecurity 68
Item 2. Properties 69
Item 3. Legal Proceedings 69
Item 4. Mine Safety Disclosures 69
Item 6. [Reserved] 69
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 75
Item 8. Financial Statements and Supplementary Data 76
Item 9A. Controls and Procedures 76
Item 9B. Other Information 77
PART III 77
Item 10. Directors, Executive Officers and Corporate Governance 77
Item 11. Executive Compensation 82
Item 14. Principal Accounting Fees and Services 91
Item 15. Exhibits and Financial Statement Schedules 92
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). We are seeking to develop an internal pipeline of products utilizing the LNC Platform to successfully
encapsulate small molecules and small oligonucleotides and facilitate targeted and extrahepatic delivery to desired cells and tissues
without toxicity. In addition, we believe the LNC Platform can also support building an external pipeline of products 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 molecules, including small molecules, antisense oligonucleotides (ASOs) and silencing or short interfering
RNAs (siRNAs).
Our
current lead product candidate is MAT2203 (oral amphotericin B), a highly potent antifungal drug which, by virtue of LNC delivery, has
been made oral, safe, and well-tolerated for prolonged administration in patients with life-threatening invasive fungal infections. Following
the successful EnACT Phase 2 trial in the treatment of cryptococcal meningitis, MAT2203 is now positioned for a single, Phase 3 registration
trial (the ORALTO trial) in support of a New Drug Application (NDA) for the treatment of invasive aspergillosis in patients with limited
treatment options.
Additional
internal discovery programs are currently directed at:
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 manner that facilitates safe, efficient, and targeted intracellular delivery for a wide variety of molecules. LNCs have
been used to successfully deliver a variety of therapeutic compounds in vivo, including small molecules, peptides, proteins, and small
oligonucleotides. Importantly, LNCs are well differentiated from other lipid nanoparticle delivery technologies.
Our
LNCs are primarily comprised of phospholipids, like phosphatidylserine (PS), calcium (which is required to keep LNCs intact) and a designated
therapeutic cargo, which is trapped inside or between the bilayers of the LNC, resulting in a highly stable, crystalline structure which
protects the cargo and allows for oral administration surviving gastrointestinal conditions. Outside of cells, such as in gastrointestinal
fluid and in blood, normal extracellular levels of calcium maintain this crystalline structure, whereas in tissues LNCs are avidly taken
up by professional phagocytes, as well as infected, inflamed, and malignant cells. In the much lower calcium environment of the cytosol,
LNCs lose their crystalline structure and release their cargo intracellularly.
LNCs
have a novel targeting profile utilizing PS to facilitate both membrane fusion and PS-receptor mediated endocytosis. Depending on the
therapeutic target being approached, the cargo may either have a direct impact inside that particular cell, or, alternatively blood cells
such as neutrophils can act as a vehicle to indirectly deliver cargo to target tissues, as in the case of infection or inflammation.
LNCs also have a neutral immunogenic profile enabling repeated administration, unlike lipid nanoparticle (LNP) delivery, which because
of inherent cytotoxicity may also not be amenable to repeat administration. Uniquely, the highly stable structure of LNCs permits oral
administration (not possible with LNPs) since the cargo is protected within the LNC structure from the harsh environment of the gastrointestinal
tract.
Preclinical
and clinical studies have consistently demonstrated that orally administered LNCs can successfully deliver therapeutic cargos in vivo,
to sites of infection, to areas of inflammation, and to tumors. All these target tissues have cells with PS exposed on their surface
(which creates opportunities for direct fusion with the cell membrane), as well as specific PS-recognizing receptors on tissue-resident
professional phagocytes (which facilitates additional cellular uptake via endocytosis). The ability to target diseased tissues –
and potentially avoid off-target effects - the capability to enter cells via both fusion and endocytic mechanisms, and the ability of
LNCs to encapsulate – and deliver - a broad range of therapeutic agents provides a solid foundation from which to create a broad
pipeline of internal product candidates and external partnerships. While the delivery of therapeutic nucleic acids has advanced considerably
in recent years, to date there has been little progress in orally delivered oligonucleotide therapeutics beyond conjugated oligos specifically
targeting the liver. Similarly, there are also significant potential opportunities for both small molecules (with potential for both
enhanced safety and increased efficacy) and small oligonucleotides in the oncology area.
MAT2203
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 have labeled
restrictions on their use for up to 2 weeks in the United States and only 1 week in most parts of the world due to 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 Platform, has the
potential to preserve or even increase the efficacy of amphotericin B, while eliminating the risk of nephrotoxicity and providing more
convenient and cost-effective oral administration. MAT2203’s product profile has allowed physicians and patients to use MAT2203
for longer periods of time and more broadly than amphotericin B has ever have been used previously and in an outpatient setting.
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. We plan to pursue additional orphan designations
for the treatment of aspergillosis, the treatment of invasive candidiasis and the treatment of certain endemic mycoses. Upon approval,
MAT2203 could be eligible for up to 12 years of regulatory or marketing exclusivity in the United States.
The
initial indication for MAT2203 is early step-down therapy from IV amphotericin B for the treatment of invasive aspergillosis in patient
with limited treatment options. Invasive aspergillosis is a serious and life-threatening invasive fungal infection that occurs primarily
in severely immunocompromised patients with hematological malignancies and in transplant recipients. 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.
The
EnACT (Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial) Phase 2 study was a Phase 2 prospective, randomized,
open-label, sequential cohort study, financially supported by the NIH NINDS, evaluating the safety, tolerability, and efficacy of MAT2203
in 100 HIV-positive persons with cryptococcal meningitis. The EnACT trial included a total of four cohorts of patients, with the first
two cohorts testing MAT2203 as early step-down therapy following initial treatment with IV amphotericin B during the 14-day induction
period, and the second two cohorts testing MAT2203 as potentially all oral therapy. The induction period for all patients in each cohort
(active or control) is 14 days, followed by an additional four weeks of treatment (active or control) during a consolidation/maintenance
period. Cohorts 1 and 3 were safety lead-ins to Cohorts 2 and 4, respectively, which were the key efficacy cohorts for EnACT.
The
primary endpoint in EnACT was Early Fungicidal Activity (EFA), a measurement of cerebrospinal fluid fungal clearance. EFA is a well-validated
quantitative measure of the efficacy of antifungal agents and is a key surrogate marker for survival. EFAs of less than 0.20 log10
Cryptococcus colony forming units (CFUs) per mL CSF per day are associated with significantly higher mortality and worse clinical
outcomes1. EFA measured above this threshold is clinically meaningful and represents robust fungal clearance. In the second
cohort of EnACT, the mean EFA achieved with patients treated with MAT2203 was 0.38 log10 CFU/mL/day, with 95% confidence intervals
(0.30 to 0.46) significantly higher than the prespecified primary endpoint threshold of >0.20. All patients treated with MAT2203 who
completed the induction phase achieved sterile CSF cultures during treatment (either during induction or early consolidation phases).
There was no evidence of breakthrough or relapsed cryptococcal infections observed in any of the patients during treatment with MAT2203
through 10 weeks. In Cohort 2, overall survival was 90% after 18 weeks in 40 patients randomized to receive MAT2203.
Interim
data from Cohort 4 of the Phase 2 EnACT study of MAT2203 (oral amphotericin B) for the treatment of cryptococcal meningitis (CM) were
presented at IDWeek in October 2022. As part of IDWeek, the EnACT abstract was the recipient of the Outstanding Abstract and IDSA Awardee
by the Infectious Diseases Society of America. In the EnACT trial, MAT2203 exceeded the primary endpoint threshold for early fungicidal
activity (EFA) of 0.20 log10 CFU/mL/day, with a mean EFA achieved of 0.30 log10 CFU/mL/day with 95% confidence
intervals from 0.22 – 0.38.
Cohort
4 also yielded key secondary endpoints, including overall survival and safety. For 40 patients receiving MAT2203 treatment, overall survival
remained at 90% through 18 weeks, while the survival rate at Week 2 was 95% (the primary endpoint for the upcoming Phase 3 registration
trial in cryptococcal meningitis). Importantly, the incidence of adverse events relating to kidney function and anemia were significantly
lower for MAT2203 compared to the conventional IV amphotericin B standard of care treatment across the entirety of the EnACT trial, with
no evidence of kidney toxicity even with up to 6 weeks of oral MAT2203 treatment.
In
February 2024, we announced agreement with the United States Food and Drug Administration (FDA) on the design of a single Phase 3 registration
trial of MAT2203 in patients with invasive aspergillosis who have limited treatment options, including consensus on all critical elements
of the registrational path for MAT2203 (the ORALTO trial).
ORALTO
is a Phase 3, randomized, multicenter, open-label, adjudicator-blinded study to evaluate the efficacy and safety of MAT2203 as an oral
step-down treatment following treatment with AmBisome® (liposomal IV-amphotericin B) compared with the standard of care in patients
with invasive aspergillosis who have limited treatment options. The primary efficacy endpoint is all-cause mortality at study day 42.
Key
secondary objectives include:
1*Clin
Infect Dis. 2020;71(5):e45-49
Enrollment
is expected to include approximately 216 adults with recently diagnosed probable or proven invasive aspergillosis who are being treated
with AmBisome due to their inability to receive an IV mold-active azole and with limited alternative treatment options. Following up
to two days of initial treatment with AmBisome, eligible study participants will be entered into the study and randomized in a 2:1 ratio
to receive either oral MAT2203 or continued AmBisome treatment followed by standard of care.
All
study participants will receive up to 12 weeks of treatment starting from the first day of treatment with AmBisome. It is anticipated
that all study participants will be hospitalized during the initial AmBisome treatment period. After step-down to oral MAT2203, study
participants may be discharged from the hospital to continue treatment on an outpatient basis, as clinically appropriate.
An
independent Data Review Committee, who will be blinded to treatment, will adjudicate primary and secondary endpoints, including clinical,
radiological, and mycological responses. Once approximately 75% of participants are enrolled, an independent Data Safety Monitoring Board
will review the overall pooled all-cause mortality rate in a blinded fashion to ensure that the sample size assumptions are reasonable
and that the study is adequately powered. Should the pooled event differ substantially from expected levels, a sample size adjustment
can be made to the trial.
ORALTO
will be conducted at approximately 65 investigator sites in the U.S., Europe, South America, Middle East, and Asia Pacific. Enrollment
is expected to commence in the second half of 2024 and is expected to require approximately 24 months.
We
are actively engaged in an ongoing partnership process for MAT2203, seeking one or more development and/or commercialization partners.
We will require either (i) the consummation of a partnership transaction, or (ii) raising additional capital, prior to commencing the
ORALTO trial.
In
addition to conducting the EnACT trial, a MAT2203 Compassionate/Expanded Use Access Program was established to provide MAT2203 on a compassionate
use basis. Enrollment into the Program requires that patient applicants meet certain criteria for eligibility, including:
● the patient has no other treatment options.
● the invasive fungal infection is serious and/or life-threatening.
19
patients to date have been enrolled in the Program at multiple healthcare institutions, including the University of Michigan, Johns Hopkins,
Nationwide Children’s Hospital, City of Hope, Vanderbilt University Medical Center, the National Institutes of Health, Children’s
Hospital of Philadelphia, Memorial Sloan Kettering Cancer Center, and the University of California, San Diego School of Medicine. The
majority of enrolled patients are post-transplant or are undergoing treatment for underlying malignancies. The infections being treated
with MAT2203 include a variety of micro-organisms (including Aspergillus, Mucorales species, Candidiasis, Fusarium
and suspected Coccidioides) occurring at multiple sites of infection, including brain, bladder/colon, bone, lung, sinus, and
skin. Most patients were receiving AmBisome® prior to enrollment but developed treatment-limiting nephrotoxicity and most also required
treatment for either azole-resistant organisms or had clinically failed azole therapy and had no other treatment options.
Of
the 19 patients enrolled in the Program, 15 have available follow-up and 4 recently initiated or will soon commence treatment with MAT2203.
Importantly,
all patients who experienced renal toxicity following treatment with AmBisome saw their renal function return to baseline after transitioning
to MAT2203 therapy and suffered no further renal side effects over the course of extended treatment with MAT2203.
LNC
Platform Work
In
addition to advancing MAT2203 into the ORALTO Phase 3 trial, we continue to expand the utilization of the LNC Platform with small molecules
and small oligonucleotides outside of infectious disease, targeting inflammation and oncology.
Inflammation
We
are investigating a variety of LNC formulations of two small oligonucleotides designed to target inflammatory cytokines IL-17A and TNFα
and have conducted a series of in vitro and in vivo studies evaluating the biological activity associated with oral delivery
as well as the corresponding associated clinical benefit of IL-17A knockdown in an imiquimod (IMQ) induced murine psoriasis disease model.
These
preliminary studies have documented biological activity in the form of cytokine knockdown and have also provided some evidence of associated
tangible clinical benefit with improvements in skin lesion appearance (redness, scaling) in this qualitative psoriasis model. These data
remain under evaluation and the analyses are focused on (a) clarifying the strength and time course of cytokine inhibition, and (b) evaluating
cytokine mRNA levels and specific tissue responses in these models to better understand and interpret these data.
In
December 2023, we announced results from a series of in vivo studies demonstrating successful oral delivery of two LNC-formulated
small single-strand oligonucleotides that specifically target key inflammatory cytokines TNFα and IL-17A in well-established and
validated animal models that mimic acute inflammatory responses seen in human diseases.
Acute
Colitis Study (“TNFα”)
A
dextran sulfate sodium (“DSS”)-induced murine colitis model was used to evaluate an orally administered LNC-delivered small
oligonucleotide that specifically targets TNFα mRNA synthesis. Colon tissue TNFα mRNA levels, as assessed by quantitative
real-time PCR analysis, were lower following orally administered active LNCs, resulting in statistically significant reductions of serum
TNFα levels by 37% compared with diseased, but untreated animals. Importantly, clinical disease activity scores at key time points
in the studies were also significantly improved with an active LNC formulation.
Acute
Psoriasis Study (“IL-17A”)
An
imiquimod (“IMQ”)-induced murine psoriasis model was used to evaluate an orally administered, LNC-delivered small oligonucleotide
designed to inhibit IL-17A mRNA synthesis, which contributes significantly to the progression of psoriatic skin lesions. Similar to the
DSS colitis model, skin tissue levels of IL-17A mRNA in the IMQ psoriasis model were lower with orally administered active LNCs compared
with IMQ alone. In this model, while IL-17A serum levels were not expected to change, improvement was demonstrated in clinical disease
markers of skin redness and scaling, further validating the biological activity of these small oligonucleotides.
Oncology
In
November of 2023 we announced positive results from an in vivo animal study of an oral LNC formulation of docetaxel, a well-known
chemotherapeutic agent used in the management of multiple metastatic and unresectable tumors. Anti-tumor effects of daily oral LNC-docetaxel
were comparable to IV-docetaxel with statistically significant reductions in tumor volume compared with untreated controls at Day 14
(high dose oral LNC -63%; low dose oral LNC -57%; IV docetaxel -68%), and similar reductions in tumor weight at Day 14. No systemic toxicities
were noted. Body weight was stable over treatment duration and hematologic parameters were similar to untreated controls.
In
March 2024 we announced positive results from an additional in vivo study of LNC-docetaxel in healthy mice. The goal of the study was
to determine whether an oral LNC formulation of docetaxel could improve the overall safety profile of conventional IV-administered docetaxel.
The study included 24 healthy BALB/c mice divided into three treatment groups: (1) control animals treated with oral saline, (2) IV-docetaxel
(30 mg/kg, or 0.6 mg/dose) administered once a week for three weeks, and (3) oral LNC-docetaxel (37.5 mg/kg, or 0.75 mg/dose) administered
once daily over three weeks. The primary endpoint of the study was change in body weight over the treatment period which how toxicity
is primarily manifested in this model.
Key
takeaways included the following:
Next
steps include evaluating the efficacy of the current LNC-docetaxel formulation in other tumor models. Additionally, we plan to evaluate
the potential anti-tumor activity of LNC formulations of small oligonucleotides.
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. However, challenges remain, especially for small molecules causing
significant toxicity and for therapeutic oligonucleotides in areas including safely and efficiently delivering cargo to the interior
of a cell, delivering to targets beyond the liver and in providing opportunities for longer-term oral delivery to increase convenience
and resulting in a potentially significant pharmacoeconomic impact.
Strategically,
we are seeking to leverage the unique features of the LNC Platform and the biology of phosphatidylserine to extend potential applications
for the intracellular delivery of highly potent, but highly toxic small molecules as well as the oral, target delivery of small oligonucleotides.
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 1).
Figure
1: 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 several 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 – and small oligonucleotides such as ASOs and siRNA. 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 2).
Figure
2: 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 3). 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 3). 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
3: 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 4).
Figure
4 – 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.
Differentiation
from LNPs
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. Additionally, LNPs cannot be delivered orally. LNC delivery can overcome many of the limitations of LNPs with oral administration,
extra-hepatic targeting, multiple potential cellular entry mechanisms, a breadth of payload capabilities, the ability to target both
immune and somatic cells, reduced toxicity/improved safety, and opportunities for safe, chronic long-term administration. Each of these
have been validated with the clinical success of MAT2203 in the treatment of deadly invasive fungal infections.
Therapeutic
Targets
Infection
The
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. In MAT2203,
we have developed a less toxic and orally bioavailable formulation of the potent (but otherwise highly toxic) fungicidal drug amphotericin
B 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 B in ways that were not previously possible
with conventional formulations, and create opportunities for amphotericin treatment in settings where conventional amphotericin has proven
to be too toxic, and open the possibilities for much longer-term treatment which should result in overall improved outcomes for patients
with a significant pharmacoeconomic impact.
Inflammation
With
the observation that LNCs are avidly taken up by innate immune cells (monocytes, neutrophils, and dendritic cells) we believe that
LNCs could become very useful in treating inflammatory diseases. We have gained access to a number of small oligonucleotides that
are capable of very selectively knocking down individual cytokines – specifically IL-17A and TNFɑ. We have
successfully advanced the program with these small oligos, first with successful, efficiently encapsulated LNC formulations, and
next with in vitro validation of the efficacy of the LNC formulations. More recently, we have progressed two of these
LNC-formulated small oligos into in vivo studies in animal disease models, with successful demonstration of both measurable
biological activity and potential therapeutic efficacy in two different models. In a murine imiquimod-induced psoriasis model we
observed reductions of tissue IL-17A mRNA, accompanied by improvement in skin redness and scaling. Similarly, in a murine DSS model
of inflammatory bowel disease, daily oral administration of an oral LNC formulation of the TNFɑ targeted oligonucleotide
resulted in reductions of colon TNFɑ mRNA, significant reductions in serum TNFɑ levels, and significant improvements in
disease activity scores.
Cancer
Building
on the success of MAT2203 in creating a safe, effective formulation of amphotericin that can be administered orally for much longer periods
of time for the treatment of deadly fungal infections, and having seen how avidly tumor cells can take up LNCs in vitro, we have extended
the application of LNC technology to oncology applications. Some tumors cell lines are also known to have relatively high levels of surface
PS expression, which provides potential directionality for those tumors which may respond positively to treatment with LNC-mediated chemotherapies.
Building upon our experience with MAT2203, there are two specific areas where we believe that LNCs could provide major advances:
2) potential for enhanced efficacy through more efficient delivery
We
began initial formulation work with a number of chemotherapeutic agents, and ultimately chose to move forward with docetaxel. We have
shown in vitro therapeutic efficacy that proved even better than conventional docetaxel, and moved rapidly to in vivo studies
and into a syngeneic mouse melanoma model (with known high surface PS expression). In this model, our oral LNC formulation of docetaxel
proved to be equally effective as conventional intravenous docetaxel. Moreover, despite daily oral administration of the LNC formulation,
there was no adverse impact on body weight, and no indications of any hematologic toxicity. Through this work, we have demonstrated that
an oral LNC formulation of docetaxel, administered daily, can deliver levels of drug to tumors provide a comparable therapeutic response
to that of conventional IV docetaxel, without any indications of toxicity. Additional in vivo work in healthy mice has shown that
even higher doses of LNC docetaxel (50% greater) were equally free from toxicity, while similar increases in the IV docetaxel dose were
accompanied by indications of toxicity, with a mean weight loss of approximately 20%.
Our
LNC Clinical Stage Asset: MAT2203
Our
lead product candidate, MAT2203, is an orally administered LNC formulation of a broad spectrum 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 and tissues, which we believe may have fewer side effects than the currently
available IV-formulations of amphotericin B, and potentially result in greater efficacy due to the ability to administer amphotericin
B safely for longer periods of time.
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.
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:
The
profile of MAT2203, which facilitates the oral, targeted, and non-toxic delivery of amphotericin B has the potential to fundamentally
change the treatment paradigm for IFIs, which are a rapidly growing global threat.
The
Increasing Problem of Fungal Pathogens
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 IA and for other IFIs more broadly by offering
the following key potential benefits:
MAT2203
Development History and Plan
Preclinical
Data
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 has been 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 to be
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. The 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 suggest 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 have been conducted to investigate the treatment of other IFIs. Oral MAT2203 was demonstrated to be effective
in multiple nonclinical studies. In vitro studies have demonstrated that the MAT2203 LNC formulation did not have an impact on
the antifungal activity of amphotericin B. Oral MAT2203 was demonstrated to be effective in several mouse models of systemic fungal infection
with Candida, Aspergillus, and Mucor. In the Candida infection models in both immunocompromised and immunocompetent mice, the efficacy
of oral MAT2203 was comparable to intraperitoneal (IP) amphotericin B in terms of survival and reduction of tissue burden in target organs
of lung, liver, and kidneys of infected animals. In the Aspergillus mouse models of infection, the efficacy of oral MAT2203 was comparable
to intraperitoneal amphotericin B in terms of survival, with dose-dependent reduction of fungal tissue burden. Oral MAT2203 also demonstrated
in vivo efficacy in treating R. delemar or M. circinelloides pulmonary infections in immunosuppressed mice and led
to a reduction in fungal spores in lung and brain comparable to results achieved with the liposomal intravenous amphotericin B.
EnACT
Phase 2 Trial
Based
a comprehensive preclinical data package, the NIH financially supported a grant application from the University of Minnesota to conduct
the EnACT Phase 2a/b trial in Uganda. This study was initiated in October 2019 and explored the use of MAT2203 for both induction and
maintenance therapy in the treatment of cryptococcal meningitis, 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.
EnACT
consisted of two parts. Part 1 of EnACT 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 EnACT was a prospective, randomized, open-label sequential cohort clinical trial to investigate the safety, tolerability, and efficacy
of oral MAT2203 in 100 HIV-positive persons with cryptococcal meningitis compared to SOC. The EnACT trial included a total of four cohorts
of patients, with the first two cohorts testing MAT2203 as early step-down therapy following initial treatment with IV amphotericin B
during the 14-day induction period, and the second two cohorts testing MAT2203 as potentially all oral therapy. The induction period
for all patients in each cohort (active or control) is 14 days, followed by an additional four weeks of treatment (active or control)
during a consolidation/maintenance period. Cohorts 1 and 3 were safety lead-ins to Cohorts 2 and 4, respectively, which were the key
efficacy cohorts for EnACT.
Cohort
2 of EnACT 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 two days of IV amphotericin treatment, with continued treatment with MAT2203 for up to