RARE Daily

FDA Lifts Clinical Hold on PepGen’s NDA Phase 1 Study in Myotonic Dystrophy Type 1

October 12, 2023

Rare Daily Staff

The U.S. Food and Drug Administration lifted the clinical hold and cleared PepGen’s application to begin human clinical studies of its experimental therapy PGN-EDODM1 in patients with myotonic dystrophy type 1.

Myotonic dystrophy type 1, or DM1 (also known as Steinert’s disease), is a progressively disabling, life-shortening genetic disorder. DM1 is the most prevalent form of the disease and generally the most severe, affecting an estimated 40,000 people in the U.S., and 70,000 in the EU. The average life expectancy for people living with DM1 is 45-60 years old. People living with DM1 typically present with myotonia (stiff or contracted muscles), muscle weakness, and cardiac and respiratory abnormalities. Many people living with DM1 also experience excessive daytime sleepiness, fatigue, and issues with gastrointestinal or cognitive dysfunction that significantly affect their quality of life.

PGN-EDODM1 is an investigational candidate designed to deliver a peptide-conjugated antisense oligonucleotide (ASO) to restore cellular function. DM1 is caused by an expansion of CUG repeats that form hairpin loops in the DMPK RNA, resulting in sequestration of the MBNL1 protein, a key RNA processing factor. The sequestration of MBNL1 results in downstream mis-splicing events and aberrant expression of many proteins that play a critical role in muscle and other systemic functions (e.g., endocrine, gastrointestinal, central nervous system). By specifically blocking the toxic CUG repeats, the goal of PGN-EDODM1 is to liberate MBNL1 protein and to restore functional downstream splicing and muscle and other systemic functions.

“Our novel PGN-EDODM1 approach targets the toxic RNA species responsible for the disease, and the strength of our Enhanced Delivery Oligonucleotide safety preclinical package has enabled us to launch this study in both the United States and internationally at doses that we believe could provide a clinically meaningful benefit to patients,” said James McArthur, president and CEO of PepGen.

PepGen opened FREEDOM-DM1 in Canada in September of this year. FREEDOM-DM1 is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) study, designed to assess PGN-EDODM1 safety and tolerability, correction of mis-splicing of transcripts, and clinical functional outcome measures. Sites in both the U.S. and Canada will evaluate PGN-EDODM1 in 3 cohorts of 5 mg/kg, 10 mg/kg, and 20 mg/kg dose levels. The decision to advance to the next dose level will be contingent upon the evaluation of safety data derived from previous dose cohorts.

In a preclinical DM1 mouse model, PepGen observed 76 percent reversal of myotonia and 68 percent correction of mis-splicing. This was increased to 99 percent correction of both measures following multiple doses.

PepGen expects to obtain proof-of-concept data, including transcript splicing and clinical outcome measures, as well as safety data, for DM1 patients in the FREEDOM-DM1 clinical study in 2024.

Photo: James McArthur, president and CEO of PepGen

Stay Connected

Sign up for updates straight to your inbox.