Regulatory After a 5-month hold FDA finally clears PepGen’s myotonic...

After a 5-month hold FDA finally clears PepGen’s myotonic dystrophy therapy


PepGen’s achievement in receiving FDA clearance to proceed with the phase 1 study for their myotonic dystrophy type 1 (DM1) therapy represents a momentous breakthrough. The FDA had placed the study on hold for a period of five months, but now, this obstacle has been overcome, signaling a crucial development in the quest to combat this debilitating genetic disorder that affects 40,000 individuals in the United States alone.

Myotonic dystrophy type 1 is a hereditary muscular dystrophy condition that arises from a mutation in the DMPK gene. It results in a spectrum of symptoms, including muscle weakness, muscle wasting, cardiac and respiratory abnormalities, and a potentially reduced lifespan. The impact of DM1 is profound, not only affecting the individual diagnosed with the ailment but also significantly impacting their families and caregivers. 

The green light for the investigational new drug application for PGN-EDODM1 now sets the stage for the commencement of the FREEDOM-DM1 trial. PGN-EDODM1 represents a promising approach to address the fundamental causes of DM1. It is a compound consisting of PepGen’s cell-penetrating peptide combined with a steric-blocking oligonucleotide cargo, strategically designed to target and rectify the genetic anomalies underlying the condition.

PepGen faced regulatory challenges back in May when the FDA imposed a clinical hold on the development of PGN-EDODM1. The specifics of the agency’s concerns were not initially disclosed, but it later came to light that dosing was at the crux of the matter. 

The CEO of PepGen, James McArthur, Ph., stressed the pivotal role of a comprehensive review of existing safety data in persuading the FDA to endorse the proposed dosing strategy. This strategy entails an initial dose of 5 mg/kg, followed by escalations to 10 mg/kg and eventually 20 mg/kg. The company firmly believes that this dosing regimen has the potential to deliver significant clinical benefits for DM1 patients.

While addressing the FDA’s concerns, PepGen proactively moved ahead with the FREEDOM-DM1 trial in Canada, where regulatory authorities granted approval in September. The trial’s design is rigorous, featuring a randomized, double-blind, placebo-controlled, single ascending dose study. It aims to evaluate the safety and tolerability of PGN-EDODM1, assess the correction of mis-splicing of transcripts, and gauge clinical functional outcomes.

Encouraging results from preclinical mouse studies showed a promising 76% reversal of myotonia, a condition characterized by impaired muscle relaxation, and a 68% correction of mis-splicing. DM1 primarily arises from mis-splicing events driven by the sequestration of a key RNA processing factor. PGN-EDODM1’s objective is to liberate the MBNL1 protein, consequently restoring proper splicing and, in turn, improving impaired muscular and systemic functions.

PepGen’s dedication to advancing treatments for muscular dystrophies extends beyond DM1. Simultaneously, the company is developing PGN-EDO51 for individuals with exon 51 amenable Duchenne muscular dystrophy. A phase 2 study, known as CONNECT1-EDO51, is currently underway in Canada and is expected to furnish valuable proof-of-concept and safety data by mid-2024.

As of the end of the second quarter, PepGen reported having $147 million in cash and equivalents. This financial stability positions the company to continue its research and development efforts well into 2025, further underscoring its commitment to advancing therapies for individuals affected by these debilitating neuromuscular disorders.

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