PepGen’s Myotonic Dystrophy Oligonucleotide Trial Stalls


In more positive news, the company’s phase 2 trial for treating DMD will enroll patients in the second half of 2023.

The FDA has placed a clinical hold on PepGen’s investigational new drug (IND) application for a phase 1 study of PGN-EDODM1, an enhanced delivery oligonucleotide for the potential treatment of Myotonic Dystrophy Type 1 (DM1).1 An official clinical hold letter that will detail the reasons for the hold will be sent by the FDA within 30 days.

“We are disappointed to receive a clinical hold notice on our planned PGN-EDODM1 study in the U.S., and we will work closely with the FDA to lift the hold as quickly as possible,” James McArthur, PhD, president and chief executive officer, PepGen, said in a statement.1 “In parallel, we continue to pursue the advancement of PGN-EDODM1 into the clinic outside the US. We remain well-capitalized to fund the continued development of both EDO51 and EDODM1, investigational treatments that may have life-changing impact on individuals with neuromuscular disorders.”

Earlier this month, PepGen announced that they had received a No Objection Letter (NOL) for its Clinical Trial Application (CTA) from Health Canada for its Phase 2 CONNECT1-EDO51 study to initiate an open label, multiple ascending dose trial of its lead candidate, PGN-EDO51, a similar enhanced delivery oligonucleotide, being investigated for the treatment of patients with Duchenne muscular dystrophy amenable to an exon 51 skipping approach. PepGen expects to begin dosing patients in the trial in the second half of 2023.

“Today is the next step in our development of PGN-EDO51, a potentially transformative treatment candidate for people living with DMD. Building upon the encouraging safety, tolerability, and exon skipping data from our Phase 1 healthy volunteer (HV) study reported last year showing promising tolerability and exon-skipping activity, we are pleased to continue our work with the DMD community to develop a therapy that we hope will produce meaningful levels of a functional, skipped dystrophin protein,” McArthur said in a statement at that time.2 “In addition to our most advanced program, PGN-EDO51, we eagerly anticipate providing the community with updates on our progress to develop transformational therapies for myotonic dystrophy type one (DM1), and other exon skippable mutations for people living with DMD, including 53, 45 and 44. We are leveraging the power of our EDO technology to work to change the future for people living with these devastating diseases.”

READ MORE: John Leonard, PhD, on an AAV Approach to Exon 51 Skipping in DMD

The CONNECT1-EDO51 study will evaluate safety and tolerability, as well as pharmacokinetics, clinical assessments, and dystrophin levels.2 The phase 2 trial plans to enroll 3 cohorts of ambulatory and non-ambulatory boys and young men to be dosed with PGN-EDO51 starting with 5 mg/kg, with plans to escalate to 10 mg/kg. After Drug Safety Monitoring Board (DSMB) review, more doses may be added.

“PGN-EDO51 exhibited the highest levels of oligonucleotide delivery and exon 51 skipping in a clinical study following a single dose of 5, 10 and 15 mg/kg in healthy volunteers when compared to publicly available clinical data for other exon 51 skipping approaches,” Michelle Mellion, MD, senior vice president and head, Clinical Development, PepGen, added.2 “At these dose levels, the majority of treatment emergent adverse events (TEAE) were assessed as mild and resolved without any intervention. Looking ahead, and based on our nonclinical data, we believe CONNECT1-EDO51 may support a differentiated profile for PGN-EDO51relative to other investigational and approved therapies based on previouslyobserved meaningful and durable data on dystrophin production, as well as clinical assessments. In summary, we believe PGN-EDO51 offers the hope of a more complete correction of the disease pathology and look forward to sharing updates on the progress of our planned trial.”

1. PepGen Inc. announces clinical hold in the U.S. on IND application to initiate a phase 1 study of PGN-EDODM1 for myotonic dystrophy type 1 (DM1). News release. PepGen. MAy 30, 2023.
2. PepGen announces clearance by Health Canada of CTA for PGN-EDO51 to begin the phase 2 clinical trial, CONNECT1-EDO51, for the treatment of Duchenne muscular dystrophy. News release. May 18, 2023.
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