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2595 Erythropoietic Protoporphyria: Phase 2 Clinical Trial Results Evaluating the Safety and Effectiveness of Dersimelagon (MT-7117), an Oral MC1R Agonist

Program: Oral and Poster Abstracts
Session: 102. Regulation of Iron Metabolism: Poster III
Hematology Disease Topics & Pathways:
Diseases, Non-Biological, Therapies, Genetic Disorders, Clinically relevant, pharmacology, Quality Improvement
Monday, December 7, 2020, 7:00 AM-3:30 PM

Manisha Balwani1*, Herbert L. Bonkovsky, MD2*, Kirstine J Belongie, PhD3*, Karl E Anderson, MD4*, Fumihiro Takahashi, PhD5*, Antonio Irizarry, MBA6*, Mark Amster, MD7*, D. Montgomery Bissell, MD8*, Bruce Wang, MD9*, Lydie Hazan, MD10*, Charles J. Parker, MD11, Edward Cordasco, MD12*, Cynthia Levy, MD13* and Robert J. Desnick, MD, PhD14*

1Icahn School of Medicine at Mount Sinai, New York
2University of Connecticut, Farmington, CT
3Mitsubishi Tanabe Pharma Development America, Jersey city, NJ
4University of Texas Medical Branch, Galveston
5Mitsubishi Tanabe Pharma Cooperation, Tokyo, Japan
6Mitsubishi Tanabe Pharma Development America, Jersey city
7Dermatology Associates Rogers Outpatient Center, Mashpee
8UCS, San Francisco, CA
9University of California, san francisco
10Axis Clinical Trials, Los Angeles
11University of Utah School of Medicine, Salt Lake City, UT
12Remington Davis clinical research, Columbus
13University of Miami, Miami
14Mount Sinai School of Medicine, New York, NY

Introduction

Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) are inborn errors of heme biosynthesis caused by the abnormal accumulation of erythrocyte protoporphyrin IX (ePPIX). These protoporphyrias are characterized by excruciating painful attacks on prolonged sunlight exposure. Before the onset of phototoxic pain, patients experience characteristic prodromal symptoms which serves as a warning signal to avoid further sun exposure. Of note, patients with higher ePPIX levels report shorter times to symptoms compared to patients with lower median ePPIX levels (JAMA Derm, 2017; 153). Here we report the safety and effectiveness of Dersimelagon (MT-7117), a novel, orally-administered, small molecule, selective melanocortin-1 receptor (MC1R) agonist that increases skin melanin without sun exposure and is being developed to increase light tolerance in EPP/XLP patients. Results of the primary, secondary efficacy endpoints, and post-hoc subgroup analyses evaluating effects of baseline ePPIX levels on treatment response will be presented.

Methods

The MT-7117-A01 (ENDEAVOR) study was a Phase 2, multi-center, randomized, placebo-controlled study with a 16-week double-blind treatment period. A total of 102 EPP/XLP patients were randomized to 3 groups: placebo once daily (QD) (n=35 [31 EPP/4 XLP]), MT-7117 100 mg QD (n=33 [31 EPP/2 XLP]), and MT-7117 300 mg QD (n=34 [31 EPP/3 XLP]). Results of the primary endpoint, increase in the average daily time (min) to first prodromal symptom during sunlight exposure, and secondary endpoints including 1) average daily duration of sunlight exposure without prodromal symptoms, 2) total number of sunlight exposure episodes with prodromal symptoms, and 3) total number of pain events, and post-hoc subgroup analyses evaluating baseline median ePPIX levels are presented here. Safety and tolerability were also assessed.

Results

There was a significant improvement in average daily time (>50 min) to first prodromal symptom [the primary endpoint] associated with sunlight exposure in subjects treated with MT-7117 100 mg (p=0.008) or 300 mg (p=0.003) compared to placebo at Week 16. Multiple secondary endpoints supported primary endpoint. There was a significant increase in average daily minutes of sunlight exposure without prodromal symptoms at Week 16 in 100 mg (p=0.009) and 300 mg (p=0.004) treated subjects compared to placebo, with an increased average exposure time without prodromal symptoms of ~50 min in MT-7117 subjects at both doses compared to placebo. There was also a 40% reduction in the total number of sunlight exposure episodes with prodromal symptoms in 100 mg (p=0.019) and 300 mg (p=0.006) subjects compared to placebo. There was a significant decrease in the total number of pain events reported in 100 mg (p=0.027, 60% reduction) and 300 mg (p=0.028, 50% reduction) subjects compared to placebo.

The post-hoc subgroup analysis evaluating the effects of baseline ePPIX levels in subjects grouped based on the baseline median ePPIX level of 1981 µg/dL. There was a statistically significant increase in average daily time to first prodromal symptom in the subgroup with ePPIX levels ≥1981 µg/dL receiving 100 mg (p=0.020) and 300 mg (p=0.003) compared to placebo. A trend to beneficial effect was also observed for the subgroup of subjects with ePPIX levels <1981 µg/dL receiving 100 mg (p=0.180) and 300 mg (p=0.216) compared to placebo.

MT-7117 had an acceptable safety and tolerability profile. The most common treatment-related treatment emergent adverse reactions were nausea (27.9%), ephelides (23.5%), and skin hyperpigmentation (20.6%).

Conclusion

The results of the primary efficacy endpoint and multiple secondary endpoints in this Phase 2 study indicate that the oral, MC1R agonist dersimelagon was efficacious after 16 weeks of treatment in increasing symptom-free light exposure in patients with EPP or XLP at doses of 100 and 300 mg QD and showed an acceptable safety and tolerability profile. The post-hoc analyses showed more profound and statistically significant efficacy at both doses for the subgroup with higher baseline median ePPIX levels.

Disclosures: Balwani: Alnylam Pharmaceuticals: Consultancy, Honoraria, Research Funding; Recordati Rare Diseases: Consultancy, Honoraria, Other: Disease information video recording. Anderson: Alnylam Pahrmaceuticals: Consultancy; Recordati Rare Diseases: Consultancy; Mitsubishi Tanabe Pharma: Consultancy.

*signifies non-member of ASH