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Item 1. Business

2024-03-27 compared with 2023-03-15 · 906 added, 787 removed, 889 unchanged (66% of the section changed)

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.

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.

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).

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.

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.

internal discovery programs are currently directed at:

safe and effective delivery of chemotherapeutic agents for oncology applications;

formulation and delivery of small oligonucleotides, such as antisense oligonucleotides (ASOs) and silencing or short interfering

RNAs (siRNAs), with a primary therapeutic focus on inflammation.

are dedicated to maximizing the value associated with our unique LNC Platform.

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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.

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

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.

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.

payloads in a manner that facilitates safe, efficient, and targeted intracellular delivery for a wide variety of molecules.

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.

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.

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

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.

lead drug candidate based on the LNC Platform is MAT2203, an oral formulation of amphotericin B, a well-known and highly effective antifungal

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

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 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.

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’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.

has been developed to date with the assistance and financial support of the National Institutes of Allergy and Infectious Disease (NIAID)

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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.

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,

Cohort 4 data from 40 MAT2203 treatment arm participants and 40 standard of care (SOC) controls were presented during the IDWeek 2022

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.

Results from Cohort 4

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.

Key Early Fungicidal Activity Threshold

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.

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

No deaths were attributed to lack of effect of 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.

3 Key trial elements

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

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%.

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.

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.

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.

Collaborations

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

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

We have ongoing collaborations with third parties which have successfully broadened the application of our LNC Platform and remain

December 2019, we announced a feasibility collaboration with Genentech relating to the development of oral formulations of up to

three Genentech proprietary compounds applying the LNC Platform.

This collaboration has resulted in the successful formulation of

two Genentech compounds and the agreement was recently extended through 2023.

April 2022, we announced that we entered an exclusive research collaboration with BioNTech to evaluate the combination of mRNA formats

utilizing our proprietary LNC Platform.

The parties expect to collaborate closely on formulation, optimization, and in vitro

Under the terms of the agreement with BioNTech, we received an exclusivity fee in the amount of $2.75 million, and BioNTech

is funding certain of our research expenses related to the collaboration.

We remain in discussions with BioNTech on a potential license

agreement for our LNC Platform.

January 2023 we announced a strategic collaboration with National Resilience, Inc.

(Resilience).

The parties entered into a Material

Transfer and Evaluation Agreement focused on exploring the potential for oral delivery of identified nucleic acids pursuant to which

the parties will collaborate on a research program comprising the design, formulation, optimization, and in vitro and in

vivo testing of these nucleic acid formats in combination with the Company’s proprietary LNC Platform.

continue to evaluate additional potential strategic collaborations with other interested biotechnology and pharmaceutical partners.

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.

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.

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.

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

Cohorts 1 and 3 were safety lead-ins to Cohorts 2 and 4, respectively, which were the key efficacy cohorts for EnACT.

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 log 10

Cryptococcus colony forming units (CFUs) per mL CSF per day are associated with significantly higher mortality and worse clinical

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 log 10 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.

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 log 10 CFU/mL/day, with a mean EFA achieved of 0.30 log 10 CFU/mL/day with 95% confidence

intervals from 0.22 – 0.38.

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.

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).

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.

secondary objectives include:

2020;71(5):e45-49

demonstration

of superiority of oral-step down treatment with MAT2203 compared with AmBisome for treatment-related toxicities leading to changes

in treatment (i.e., dose adjustment/discontinuations or changes to treatment regimens);

survival benefit of MAT2203 using all-cause mortality at study day 84;

of the impact of MAT2203 on healthcare resource utilization and quality of life impact.

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.

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.

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.

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.

will be conducted at approximately 65 investigator sites in the U.S., Europe, South America, Middle East, and Asia Pacific.

is expected to commence in the second half of 2024 and is expected to require approximately 24 months.

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.

addition to conducting the EnACT trial, a MAT2203 Compassionate/Expanded Use Access Program was established to provide MAT2203 on a compassionate

Enrollment into the Program requires that patient applicants meet certain criteria for eligibility, including:

patient has no other treatment options.

invasive fungal infection is serious and/or life-threatening.

patient is expected to benefit from oral MAT2203 treatment and can tolerate oral medication;

patient has a reasonable life expectancy, and their underlying conditions are under control.

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.

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

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.

the 19 patients enrolled in the Program, 15 have available follow-up and 4 recently initiated or will soon commence treatment with MAT2203.

of the 15 patients had either complete clinical resolution or objective improvement in clinical markers of infection (including radiologic

and mycologic).

the 5 patients who completed their full individually specified course of treatment (ranging from 2 weeks to 1 year, depending on

the infection) - all have had complete clinical resolution with no relapses or recurrence of their infection.

additional patients have shown objective improvement in clinical markers and are continuing treatment with MAT2203 as planned.

of the 15 patients were unable to complete their individually specified course of treatment, although 2 saw significant clinical

improvement of their fungal infection and are included in the 12 overall successful cases.

patients transitioned to palliative care shortly after starting therapy with MAT2203 because of unanticipated progression of their

malignant disease.

patient discontinued therapy after two days due to underlying GI issues (i.e., Crohn’s disease).

patient passed away due to progression of their underlying disease approximately 8 weeks into therapy (but previously experienced

significant clinical improvement of their fungal infection).

patient discontinued MAT2203 treatment following 10 weeks of therapy due to underlying GI issues (long-standing nausea/vomiting),

but with improvement in their fungal infection.

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.

Platform Work

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.

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.

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.

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.

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.

Colitis Study (“TNFα”)

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.

Psoriasis Study (“IL-17A”)

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.

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

Body weight was stable over treatment duration and hematologic parameters were similar to untreated controls.

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.

takeaways included the following:

Day 22, the total amount of docetaxel administered with the oral LNC-docetaxel formulation was more than 8x greater than with IV-docetaxel

(the final IV dose was used to measure pharmacokinetics).

mice treated with IV-docetaxel lost a significant amount of weight (toxicity), with an average peak loss of 20% of their

original body weight.

treated with oral LNC-docetaxel maintained their body weight, which was statistically no different than the weight of control mice

treated with oral saline.

mouse in the IV-docetaxel group died prior to the conclusion of the study and was censored from the analysis (last measurement was

-32% body weight loss);

the curve of the IV-docetaxel group also reflects the expected 7-day recovery following an IV dose of docetaxel.

daily administered oral LNC-docetaxel dose was 50% higher, and the total amount of drug administered was 3.5 times greater, than

the LNC-docetaxel dose administered in a previous study that demonstrated anti-tumor activity comparable to IV-docetaxel in a syngeneic

mouse melanoma model.

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.

are focused on redefining the intracellular delivery of nucleic acids and small molecules through our LNC Platform and its application

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elements of our strategy include:

Advancing our

LNC Platform and expanding the utilization of this promising technology into areas of innovative medicine beyond small molecules,

including nucleic acids (e.g., mRNA, DNA, ASOs) and proteins.

Positioning MAT2203 for

an NDA filing for various indications for the treatment of serious IFIs, including cryptococcal meningitis.

We are seeking non-dilutive

funds from prospective third-party pharmaceutical partners and various governmental sources of capital, such as the Biomedical Advanced

Research and Development Authority (BARDA) and the NIH to continue the development of MAT2203 into Phase 3.

We are also seeking the

input and guidance of the FDA for an additional Phase 3 study of various IFIs.

Building an external pipeline

of collaborations focused on our LNC Platform with leading pharmaceutical companies like BioNTech, Genentech and National Resilience

to provide delivery solutions for their complex nucleic acid drug products.

MAT2203 into the ORALTO trial for the treatment of invasive aspergillosis in patients with limited treatment options by securing

a development and/or commercial partner.

This initial indication is designed to be a gateway indication to establish the pharmacodynamic

bridge necessary to expand the use of MAT2203 into other indications to treat deadly invasive fungal infections (e.g., mucormycosis,

candidiasis and the endemic mycoses) through limited additional clinical work under a 505(b)(2) pathway, thereby making MAT2203 a

pipeline in a product.

the utilization of our LNC Platform with other small molecules and small oligonucleotides into inflammation and oncology in order

to develop an internal pipeline of differentiated drug candidates.

Oral, extrahepatic and non-toxic intracellular delivery of these

molecules would represent a significant advancement.

an external pipeline of collaborations focused on our LNC Platform with leading pharmaceutical companies to provide delivery solutions

for their complex small molecules and small oligonucleotides, including ASOs and siRNAs.

Lipid Nanocrystal (LNC) Platform

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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 ).

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,

Current Delivery Technologies

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.

lipid cylinders” were originally described in scientific literature as complex, cylindrical, multi-lamellar structures arising

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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 ).

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 ).

LNCs Encapsulate and Protect their Cargo in a Water-free Environment

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are no longer as strong, and the LNCs release their cargo.

limitations of LNPs and viral vectors

Differentiation

LNPs in blood bind ApoE to their surface and are taken up into cells by clathrin-mediated endocytosis via the ApoE-recognizing LDL receptor.

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site reactions and other toxicities arising from the destruction of the endosomal membrane, which, ultimately, can limit their chronic

Finally, LNPs cannot be delivered orally.

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.

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.

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.

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 .

applications of our proprietary delivery technology have focused initially on the delivery of potent, highly effective anti-infective

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 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.

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.

LNC Clinical Stage Assets

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.

Meningitis History and Plan

upon robust preclinical data, the NIH financially supported a grant application from the University of Minnesota to conduct EnACT in

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.

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.

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%.

Fungal Infection Background and Plan

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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:

for reduced toxicity because of tissue-targeted delivery and low blood levels

for enhanced efficacy through more efficient delivery

began initial formulation work with a number of chemotherapeutic agents, and ultimately chose to move forward with docetaxel.

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%.

LNC Clinical Stage Asset:

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

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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.

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.

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.

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.

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:

LNC is a solid crystal that does not significantly “leak” its drug content while circulating.

The crystal releases its

medication pay-load only when inside the target cells, and thus appears that the use of MAT2203 does not result in off-organ toxicities

normally seen in the kidneys when using current formulations of amphotericin B.

of this targeted delivery, we have been able to increase the therapeutic window on a mg/kg basis as compared to IV amphotericin B

formulations.

We have observed equivalent efficacy at lower doses as well as been able to use oral doses of up to 10x the highest

tolerable IV dose in animal model studies.

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.

Increasing Problem of Fungal Pathogens

pathogens and infections are an increasing global public health concern.

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Federal Regulations Title 21 – FDA.

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

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:

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at the site of infection early during therapy.

Enabling an all-oral

The ability to step-down to an oral amphotericin B product during treatment of an invasive fungal infection will offer

significant benefit to patients for whom there are only limited oral treatment options that carry significant issues of safety, tolerability,

and high propensity of resistance, as seen with the azole class of antifungals.

Shorter and less costly

hospital stays and lower outpatient costs .

By providing physicians and patients with access to an orally available, broad spectrum

fungicidal agent in MAT2203, we believe that there is significant potential to reduce hospital costs, which account for over 70%

of the overall treatment cost of IFIs.

an all-oral therapy.

The ability to step-down to an oral amphotericin B product early during treatment of an invasive fungal

infection will offer significant benefit to patients for whom there are only limited oral treatment options that carry significant

issues of safety, tolerability, and high propensity of resistance, as seen with the azole class of antifungals.

and less costly hospital stays and lower outpatient costs .

By providing physicians and patients with access to an orally available,

broad spectrum fungicidal agent in MAT2203, we believe that there is significant potential to reduce hospital costs, which account

for over 70% of the overall treatment cost of IFIs.

Development History and Plan

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.

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.

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.

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.

circinelloide s 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.

Phase 2 Trial

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

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.

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.

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.

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

six weeks during early maintenance treatment.

The primary efficacy endpoint for Part 2 of EnACT was early fungicidal activity (EFA) defined

as rate of clearance of Cryptococcus from the cerebrospinal fluid (CSF) (log 10 colony forming units [CFU]/mL/day) as measured

by serial quantitative fungal cultures over the first two weeks of treatment.

Cohort 2 of EnACT, we reported the following results:

Early Fungicidal Activity (EFA), Cerebrospinal Fluid (CSF) Sterilization, with No Evidence of Breakthrough Infections During Treatment

primary endpoint in EnACT was 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 outcomes 2 .

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.

patients treated with MAT2203 who completed the induction phase achieved sterile CSF cultures during treatment (either during induction

or early consolidation phases).

was no evidence of breakthrough or relapsed cryptococcal infections observed in any of the patients during treatment with MAT2203

through 10 weeks.

survival was 95% in 40 patients randomized to receive MAT2203.

2020;71(5):e45-49

showed no evidence of renal toxicity or electrolyte abnormalities attributable to MAT2203, no major safety signals, and no use-limiting

tolerability issues, even with longer-term treatment with MAT2203 extended beyond induction into the consolidation phase, from week

Cohort 4 of EnACT, we reported the following results:

CSF yeast clearance rate exceeded the prespecified primary endpoint threshold target of >0.20, with a mean EFA achieved of 0.30

log 10 CFU/mL/day with 95% confidence intervals from 0.22 – 0.38.

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.

40 patients receiving MAT2203 treatment, interim survival is currently 90%, while the survival rate at Week 2 was 95%.

patients had fewer Grade ≥3 Clinical Adverse Events (42%) vs.

SOC treatment (59%).

incidence of adverse 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 six weeks of oral MAT2203 treatment.

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.

EnACT trial results were published in the Journal of Clinical Infectious Diseases in August 2023 as an Editor’s Choice manuscript.

Expanded/Compassionate

Use Access Program

completion of the EnACT Trial, we initiated our Expanded/Compassionate Use Access Program in 2022 to demonstrate that MAT2203 could have

a significant impact in treating patients with invasive fungal infections with limited or no treatment options, which are very similar

to the patients we believed we would be enrolling in a Phase 3 clinical trial.

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.

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

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.

the 19 patients enrolled in the Program, 15 have available follow-up and 4 recently initiated or will soon commence treatment with MAT2203.

of the 15 patients had either complete clinical resolution or objective improvement in clinical markers of infection (including radiologic

and mycologic).

the 5 patients who completed their full individually specified course of treatment (ranging from 2 weeks to 1 year, depending on

the infection) - all have had complete clinical resolution with no relapses or recurrence of their infection.

additional patients have shown objective improvement in clinical markers and are continuing treatment with MAT2203 as planned.

of the 15 patients were unable to complete their individually specified course of treatment, although 2 saw significant clinical

improvement of their fungal infection and are included in the 12 overall successful cases.

patients transitioned to palliative care shortly after starting therapy with MAT2203 because of unanticipated progression of their

malignant disease.

patient discontinued therapy after two days due to underlying GI issues (i.e., Crohn’s disease).

patient passed away due to progression of their underlying disease approximately 8 weeks into therapy (but previously experienced

significant clinical improvement of their fungal infection).

patient discontinued MAT2203 treatment following 10 weeks of therapy due to underlying GI issues (long-standing nausea/vomiting),

but with improvement in their fungal infection.

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.

plan to continue to evaluate opportunities to provide MAT2203 on a compassionate use basis for patients as we believe these are opportunities

to showcase the safety and efficacy of MAT2203 outside clinical trial settings which represent important additional patient data for

both FDA and prospective partners to review.

ORALTO Phase 3 Trial

February 2024, the Company announced that it has reached agreement with the FDA on the design of a the ORALTO trial, including consensus

on all critical elements of the registrational path for MAT2203.

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.