MAT2203: Encochleated Formulation of Amphotericin B
|Candidate & Indication||Development Stage|
|MAT2203 Prevention of IFI in Acute Lymphoblastic Leukemia||
IND Preparation Phase complete
Phase 1 Development Phase complete
Phase 2 Development Phase in progress
Phase 3 Development Phase not started
Market Phase not started
MAT2203 is an orally-administered, cochleate formulation of amphotericin B (a broad spectrum fungicidal agent). Little to no clinical resistance has been reported to date with amphotericin B as compared to the rapidly emerging drug resistance seen in other antifungal therapies. Currently, IV-only administered amphotericin B is the only broad spectrum fungicidal; however, it has significant treatment-limiting side effects, most notably nephrotoxicity. The ability to provide amphotericin B orally using our proprietary and novel oral formulation may offer a new and promising alternative for patients and doctors. In a clinical Phase 1 single-dose, double-blind, dose-escalating, pharmacokinetic study of 48 healthy volunteers, oral MAT2203 demonstrated a good safety and tolerability profile with no serious adverse events reported, without any observed nephrotoxicity. More recently, in our Phase 2 trial of MAT2203 conducted by the National Institutes of Health, three of three enrolled patients met their primary efficacy endpoint and two of these patients have been successfully taking MAT2203 for more than a year with no evidence of kidney or other toxicity frequently associated with the use of amphotericin B.
We believe that MAT2203 has the potential to be a best-in-class therapy for both prophylaxis (preventive) and treatment of invasive fungal infections by offering the following key benefits.
- Potential to treat resistant pathogens. We believe that MAT2203 can be used to prevent and treat fungal infections caused by drug resistant fungi, including those resistant to existing azoles and echinocandins, due to amphotericin B's fungicidal (i.e. killing the fungi) nature and potency against resistant strains and the ability of our cochleate drug delivery platform to provide higher and safer drug exposure early in the course of therapy.
- Enabling prophylaxis regimens. Many patients cannot receive azole prophylactic therapy due to drug to drug interactions or poor tolerability, while the long-term preventative use (6-14 weeks) of IV echinocandins is impractical and expensive. Amphotericin B is known to have limited drug to drug interactions. We therefore expect that our orally available MAT2203 could provide for better prophylactic therapy on an inpatient and outpatient basis, particularly for those patients with a hematologic malignancy, such as leukemia.
- 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, there is the potential to significantly reduce hospital costs, which account for over 70% of the overall treatment cost of invasive candidiasis.
The FDA has granted MAT2203 designations for Qualified Infectious Disease Product, or QIDP, and Fast Track for the treatment of invasive candidiasis and aspergillosis and for the prevention of IFIs in patients on immunosuppressive therapy. We have also applied for Orphan Drug Designation for MAT2203. The orphan drug designation provides eligibility for seven years of market exclusivity in the United States upon FDA approval, a waiver from payment of user fees, an exemption from performing clinical studies in pediatric patients, and tax credits for the cost of the clinical research. The QIDP designation, provided under the Generating Antibiotic Incentives Now Act, or the GAIN Act, offers certain incentives for the development of new antibacterial or antifungal drugs, including eligibility for Fast Track designation, priority review and, if approved by the FDA, eligibility for an additional five years of marketing exclusivity. Fast Track designation enables more frequent interactions with FDA to expedite drug development and review. Fast Track designation does not change the standards for approval and we can provide no assurances that we can maintain Fast Track designation for MAT2203 or that such designation will result in faster regulatory review. The seven-year period of marketing exclusivity provided through orphan designation, if granted, combined with an additional five years of marketing exclusivity provided by the QIDP designation positions MAT2203 with a potential for a total of 12 years of marketing exclusivity to be granted at the time of FDA approval.
We are pursuing a first indication for the prevention of invasive fungal infections in patients with ALL because the risk for invasive fungal infections (IFIs) in patients being treated for ALL is high, with an associated high risk of lethality. Currently, there is no standard of care for preventing these high risk IFIs in ALL patients. The established treatment regimens for ALL are highly sensitive to liver-metabolized drug-drug interactions, causing serious concerns for drug-drug interaction induced side-effects. Amphotericin B is not liver metabolized and when incorporated in the lipid-crystal nano-particle structure of MAT2203, this otherwise toxic IV only compound can now be safely orally administered (providing patient convenience over ~12 weeks prophylactic treatment duration), without the typical kidney and liver toxicity associated with other Amphotericin B formulations.
We are currently partnering with the National Institutes of Health (NIH) on a NIH -funded Phase 2a clinical study with MAT2203 (CAMB) in patients with refractory mucocutaneous candidiasis. This study is ongoing and enrolling patients and is an open-label, dose-titration trial in up to 16 patients to study the efficacy, safety, and pharmacokinetics of oral CAMB in the treatment of mucocutaneous candidiasis (esophageal, oropharyngeal, or vulvovaginal). In early June 2017, the Company reported interim data from the NIH-Conducted Phase 2a Clinical Study of Orally-Administered MAT2203 for the Treatment of Chronic Refractory Mucocutaneous Candidiasis. At that time, two out of the two patients with long-standing azole resistant mucocutaneous candidiasis met the primary endpoint of the Phase 2a study, achieving ≥ 50% clinical response with treatment of MAT2203. Patient #01 achieved a 57% reduction in clinical symptoms after 8 weeks on therapy while patient #02 achieved an 85% reduction in such clinical symptoms after 6 weeks of treatment. MAT2203 was well tolerated with majority of adverse events observed being mild in severity and mostly unrelated to study drug. Importantly, for both patients renal and liver function parameters remained well within normal ranges during the core study as well as during the first 6-month extension of this study. In July 2017, the NIH/NIAID institutional review board approved continuation of treatment of patients in the study-extension for an additional 6 months, for total extension of up to one year.
In January 2018, the National Institutes of Health (“NIH”) reported positive data from a third patient enrolled in this study. This third patient, with long-standing azole resistant mucocutaneous candidiasis, met the primary endpoint of the Phase 2a study in achieving ≥ 50% clinical response with treatment of MAT2203. MAT2203 was well tolerated with any adverse events observed being mild in severity and unrelated to study drug. With this third positive response, the study has met its statistical hurdle for success. The third patient in this study was diagnosed with a dual Candida albicans and C. glabrata infection with azole resistance. The predominant manifestation was esophageal candidiasis, which had been refractory to treatment for a prolonged period. Patient 3 achieved a reduction in clinical symptoms at an efficacious orally administered dosage of 800 mg MAT2203 per day, meeting the response criterium of ≥ 50% reduction in clinical symptoms. MAT2203 was generally well tolerated by Patient 3 and there were no signs of nephrotoxicity, hypokalemia or hepatoxicity (measured by ALT and AST). Indicators of kidney and liver toxicity remained within normal limits throughout the treatment period. For this patient, no underlying immunocompromising condition was diagnosed. Patients 1 and 2, both with an underlying hereditary immunodeficiency called Job’s Syndrome, also known as Autosomal Dominant Hyper IgE Syndrome (AD-HIES), enrolled earlier in this trial and achieved reduction in clinical symptoms of 57% (at 800mg/day) and 85% (at 400mg/day). The first two patients have enrolled in a long-term study extension and have shown no signs of kidney or liver toxicity over the approximately twelve months of being administered MAT2203. Furthermore, the clinical response to MAT2203 seen in these patients has been maintained and/or improved during the extension period in addition to patients reporting meaningful quality-of-life improvements. This third patient has also enrolled in the long-term study extension.
In late June 2017, we announced the topline data from our Phase 2 study in Vulvovaginal Candidiasis (VVC) using MAT2203. In the context of our overall program for MAT2203 with the aim to develop our lead product for the prevention of invasive fungal infections in patients who are immunocompromised due to immunosuppressive therapy, our goal was, in addition to further establishing the safety and tolerability of MAT2203, to demonstrate efficacy of MAT2203 through a mechanism involving systemic absorption in a non-life threatening fungal infection. This study concept is consistent with early human efficacy studies in the development of other anti- fungal therapies. This Phase 2 study was not designed or powered to support an indication for the treatment of VVC and therefore supplant fluconazole as the standard of care. The key data generated from this study includes additional safety and tolerability data.
In this VVC study, the primary endpoint of safety was met, and it was demonstrated that oral delivery of encochleated amphotericin B is safe and well tolerated without the renal and hepatic toxicities that can be seen with administration of intravenous amphotericin B. Drug-related treatment emergent adverse events in this study were mostly of mild and gastro-intestinal nature and were seen at a rate of 20%, 18% and 2% respectively for MAT2203 200mg, MAT2203 400mg, and fluconazole. Consistent with the safety observations in the NIH study, in this VVC study no drug-related effects on liver function were observed and kidney function parameters stayed within normal ranges during the entire study for all 91 patients treated with MAT2203 for 5 days.
In January 2018, Matinas met with the FDA to discuss its clinical development and toxicology plans for MAT2203 in Phase 2 and Phase 3 in support of an NDA submission for approval in prevention of invasive fungal infections in patients with ALL. The Company plans to conduct a Phase 2 trial using an adaptive trial design which we believe will position MAT2203 for approval with a limited indication for prevention of invasive fungal infections in ALL patients. We are in the process of conducting animal efficacy, pharmacokinetic / pharmacodynamic studies and dynamic pharmacokinetic / pharmcodynamic modeling to establish the optimal dosing for our adaptive pivotal trial. We believe that by optimizing the dose and implementing this streamlined development plan, we could decrease the time and cost of our overall development program for MAT2203. We expect to be in position to commence a pivotal Phase 2 adaptive-designed study in the first half of 2019. The first aspect of this pivotal Phase 2 trial will be an evaluation of the PK/PD and tolerability of MAT2203 in patients with either ALL or AML. The second part of this study will evolve to become an evaluation of PK/PD, efficacy and safety of MAT2203 versus placebo in ALL patients alone, where there is no standard of care. We believe this overall development program will position MAT2203 for an initial, limited use approval indication for prevention of invasive fungal infections in ALL patients by 2022. Based on limited utility of currently approved antifungal therapies for the prevention of IFI due to significant drug-drug interactions or lack of oral dosing mode, we believe that our orally administered MAT2203 has the potential to become a highly differentiated therapy in the antifungal field upon FDA approval in the prevention of invasive fungal infections in patients with ALL.