8-K: PepGen Provides Update on Duchenne Muscular Dystrophy Program, Faces Regulatory Hurdles

PepGen Inc. announces updates on its CONNECT clinical program for PGN-EDO51 in Duchenne muscular dystrophy (DMD), including progress in CONNECT1 and challenges with FDA hold on CONNECT2.

Summary

• PepGen Inc. provided updates on its CONNECT clinical program, which is investigating PGN-EDO51 for Duchenne muscular dystrophy (DMD) patients amenable to exon-51 skipping.
• The CONNECT1 trial, a Phase 2 open-label study in Canada, has fully enrolled the 10 mg/kg cohort (n=4) and the 5 mg/kg cohort (n=3) is continuing to dose in the long-term extension.
• Clinical data from the 10 mg/kg cohort of CONNECT1 is expected by year-end 2025.
• Two participants in the 10 mg/kg cohort experienced asymptomatic hypomagnesemia, which has returned to baseline levels with oral magnesium supplementation.
• One participant's dosing was paused due to a reduction in estimated glomerular filtration rate (eGFR), but a subsequent scan indicated normal range and the eGFR is improving.
• Health Canada has requested additional information from PepGen regarding safety concerns before further dose escalation or enrollment in the CONNECT1 trial.
• The CONNECT2 trial, a Phase 2 multinational, double-blind, placebo-controlled study in the UK, is open.
• The FDA placed a clinical hold on the Investigational New Drug application to initiate the CONNECT2 trial in the US due to questions regarding dosing levels.
• PepGen is working with both Health Canada and the FDA to address their respective questions.
• Initial data from the FREEDOM-DM1 study in myotonic dystrophy type 1 is expected during the first quarter of 2025.

Sentiment

Score: 5

Explanation: The sentiment is neutral. While there is progress in the CONNECT1 trial and positive comments on the safety profile, the FDA clinical hold on CONNECT2 and Health Canada's request for additional information introduce uncertainty and potential delays.

Positives

• The CONNECT1 trial is progressing, with the 10 mg/kg cohort fully enrolled and the 5 mg/kg cohort continuing to dose.
• Hypomagnesemia in two participants in the 10 mg/kg cohort has been resolved with oral magnesium supplementation.
• The eGFR of one participant who experienced a reduction has improved and is normalizing.
• Health Canada is allowing dosing to continue at current levels in the CONNECT1 trial.
• All treatment related adverse events in CONNECT1 have been mild as of January 23, 2025.

Negatives

• The FDA has placed a clinical hold on the CONNECT2 trial in the US, delaying its initiation.
• Health Canada has requested additional information regarding safety concerns before allowing further dose escalation or enrollment in the CONNECT1 trial.
• One participant in the CONNECT1 trial experienced a reduction in eGFR, leading to a temporary pause in dosing.

Risks

• The FDA clinical hold on the CONNECT2 trial could delay or prevent its initiation in the US.
• Health Canada's request for additional safety information could delay further dose escalation or enrollment in the CONNECT1 trial.
• Unexpected adverse events or safety concerns could arise in the ongoing clinical trials.
• Regulatory interactions may lead to adverse outcomes, including delays in regulatory review or modifications to development programs.
• Delays or failure to successfully complete development activities for product candidates, including PGN-EDO51 and PGN-EDODM1, could occur.

Future Outlook

PepGen anticipates providing clinical data updates from both CONNECT1 and the FREEDOM-DM1 study during 2025, including initial data from FREEDOM during the first quarter, as well as an update on the status of CONNECT2.

Management Comments

• Paul Streck, MD, Head of R&D, stated that as of January 23, 2025, all treatment related adverse events in CONNECT1 have been mild, and the emerging safety profile of PGN-EDO51 remains favorable.
• He also mentioned that the decreased eGFR reported for one of the CONNECT1 10 mg/kg cohort patients has improved during his brief pause in dosing.

Industry Context

The development of oligonucleotide therapies for neuromuscular and neurological diseases is a competitive field, with companies like Sarepta Therapeutics already having approved exon-skipping drugs for DMD. PepGen's EDO technology aims to improve the delivery and efficacy of these therapies, potentially offering advantages over existing treatments.

Comparison to Industry Standards

• Sarepta Therapeutics' Exondys 51 is an approved exon-51 skipping drug for DMD, serving as a benchmark for dystrophin production and clinical efficacy.
• The FDA's clinical hold on PepGen's CONNECT2 trial highlights the agency's scrutiny of dosing levels and safety data, consistent with its approach to other DMD therapies.
• The prevalence of hypomagnesemia as an adverse event is not uncommon in oligonucleotide therapies, requiring careful monitoring and management, similar to other drugs in this class.

Stakeholder Impact

• The FDA clinical hold on CONNECT2 and Health Canada's request for information could delay the availability of a potential treatment for DMD patients.
• Positive data from the CONNECT1 trial could provide hope for DMD patients amenable to exon-51 skipping.
• The company's stock price may be affected by the regulatory updates and clinical trial results.

Next Steps

• PepGen will work with the FDA to address its questions regarding dosing levels for the CONNECT2 trial.
• PepGen will work with Health Canada to address its safety concerns and provide additional information for the CONNECT1 trial.
• PepGen will continue to monitor the safety and efficacy of PGN-EDO51 in the CONNECT1 trial.
• PepGen will report clinical data from the 10 mg/kg cohort of CONNECT1 by year-end 2025.
• PepGen will provide initial data from the FREEDOM-DM1 study in the first quarter of 2025.

Key Dates