Matinas BioPharma Holdings, Inc. announced positive interim data from Cohort 4, the fourth and final cohort of the Phase 2 EnACT trial evaluating MAT2203, an oral LNC formulation of amphotericin B, for the treatment of cryptococcal meningitis. Interim EnACT Cohort 4 data from 40 MAT2203 treatment arm participants and 40 standard of care (SOC) controls will be presented by Drs. Mucunguzi Atukunda, MBChB, MPH of the Infectious Diseases Institute of Makarere University in Uganda and David Boulware, MD, MPH of the University of Minnesota Medical School during the IDWeek 2022 conference, currently taking place in Washington DC.

Importantly, Cohort 4 (an all-oral treatment regimen with MAT2203) met its prespecified primary endpoint, exceeding the target rate of CSF yeast clearance threshold of >0.20 colony forming units (CFUs) per mL of cerebrospinal fluid per day. Overall survival in Cohort 4, a key secondary endpoint of the study, is 95 % at two weeks and currently 90% overall, with ongoing final follow-up through 18 weeks. Matinas plans to initiate the Phase 3 registration trial of MAT2203 as step-down therapy in cryptococcal meningitis in the first quarter of 2023.

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.

Treatment early fungicidal activity beyond the >0.20 threshold have not resulted in any observed incremental benefit. Cohort 4 also included secondary endpoints of overall survival, prevention of relapse, CSF sterilization, and safety. Interim Results from Cohort 4 The key interim results from Cohort 4 of EnACT include exceeding the prespecified early fungicidal activity threshold of >0.20 CFU/mL CSF/day, survival, and the safety of longer-term use of an oral formulation of amphotericin B (MAT2203) for up to 6 weeks.

Exceeding Key Early Fungicidal Activity Threshold In Cohort 4, the CSF yeast clearance rate exceeded the prespecified primary endpoint threshold target of >0.20, with a mean early fungicidal activity achieved of 0.30 log10 CFU/mL/day with 95% confidence intervals from 0.22 – 0.38. Several participants with high baseline fungal burdens had noteworthy antifungal activity within the MAT2203 treatment arm, including one patient with quantitative cryptococcal culture as high as 915,000 CFU/mL at the time of screening with effective clearance during the induction period, a key demonstration of potent antifungal activity, even in the most challenging of cases. Survival In Cohort 4, in 40 patients receiving MAT2203 treatment, interim survival is currently 90%, while the survival rate at Week 2 was 95%; note that Week 2 survival is the prespecified primary endpoint for the MAT2203 Phase 3 registration trial in cryptococcal meningitis.

Safety MAT2203 patients had fewer Grade =3 Clinical adverse events (AEs) (42%) vs. SOC treatment (59%). Importantly, the 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 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. The pivotal Phase 3 registration trial of MAT2203 in cryptococcal meningitis will be initiated early in the first quarter of 2023 and will assess MAT2203 as step-down therapy after only 2 loading doses of IV amphotericin B (similar to EnACT Cohort 2), building upon the impressive results already documented in EnACT Phase 2 trial. This open-label randomized trial, which will be partially financially supported by the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS), involves a three arm non-inferiority design in persons living with HIV who have cryptococcal meningitis: (A) step-down therapy with MAT2203 with treatment continuing for 2 weeks; (B) step-down therapy with MAT2203 with treatment out to 6 weeks; and (C) 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 planned to be approximately 270 patients, with an adaptive, de-risking design allowing for the potential for additional patients once enrollment has reached 75%.

The primary endpoint will be 2-week all-cause mortality, with a pooled analysis across the two MAT2203 treatment arms compared with SOC control to support a potential indication for the treatment of cryptococcal meningitis. To evaluate opportunities to improve survival by extending MAT2203 therapy, a key secondary endpoint is 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.

Following substantial collaboration with the U.S. Food and Drug Administration (FDA) and written feedback from the European Medicines Agency (EMA) in the form of Scientific Advice, as well as external NIH peer-review, the planned Phase 3 study design, including endpoints, is well-positioned to potentially support registration of MAT2203 in both the US and Europe. FDA has designated MAT2203 as a Qualified Infectious Disease Product (QIDP) with Fast Track status for four indications, specifically, the prevention of invasive fungal infections due to immunosuppressive therapy, and the treatment of invasive candidiasis, invasive aspergillus and cryptococcal meningitis. In addition, the FDA and EMA have granted orphan drug designation to MAT2203 for the treatment of cryptococcosis.

If approved, MAT2203 would be eligible for up to 12 years of regulatory exclusivity.