8-K: PepGen Announces Positive Initial Results from FREEDOM-DM1 Trial, Showing Robust Splicing Correction in DM1 Patients

PepGen reports promising early data from its FREEDOM-DM1 trial, demonstrating significant splicing correction in patients with myotonic dystrophy type 1 (DM1) after a single dose of PGN-EDODM1.

Summary

• PepGen announced positive initial results from the FREEDOM-DM1 trial, a Phase 1 study evaluating PGN-EDODM1 in patients with myotonic dystrophy type 1 (DM1).
• The data showed a mean splicing correction of 12.3% in the 5 mg/kg cohort (n=6) and 29.1% in the 10 mg/kg cohort (n=4) at 28 days post-dosing.
• PGN-EDODM1 was observed to have a favorable emerging safety profile in the 5 and 10 mg/kg cohorts.
• The company expects to report results from the 15 mg/kg cohort in the second half of 2025 and from the FREEDOM2 5 mg/kg cohort in the first quarter of 2026.
• The CONNECT1-EDO51 10 mg/kg cohort is fully enrolled, with results expected in the third quarter of 2025.
• As of December 31, 2024, PepGen's cash, cash equivalents, and marketable securities were $120.2 million, anticipated to fund operations into 2026.
• Research and development expenses were $76.5 million for the year ended December 31, 2024, compared to $68.1 million for the same period in 2023.
• Net loss for the year ended December 31, 2024, was $90.0 million, or $(2.85) basic and diluted net loss per share, compared to $78.6 million, or $(3.30) basic and diluted net loss per share, for the same period in 2023.

Sentiment

Score: 8

Explanation: The document presents positive clinical data and financial stability, suggesting a favorable outlook for the company. However, the clinical hold on the CONNECT2 study and the serious adverse event temper the overall sentiment.

Positives

• The FREEDOM-DM1 trial showed significant mean splicing correction of 29.1% following a single dose of PGN-EDODM1 at 10 mg/kg.
• PGN-EDODM1 was observed to have a favorable emerging safety profile.
• Dose-dependent increase in muscle tissue concentrations of PGN-EDODM1 was observed.
• The company believes robust splicing correction with PGN-EDODM1 has the potential to lead to meaningful functional improvements with repeat dosing over time.
• Health Canada has allowed continued dosing of participants in the 5 and 10 mg/kg cohorts of CONNECT1-EDO51.

Negatives

• One participant's biopsy in the 10 mg/kg cohort was not collected due to a pseudoaneurysm in connection with the biopsy procedure.
• One participant's sample showed a splicing index outside the pre-specified assay range and was excluded from the analysis.
• There was one treatment-related serious adverse event of abdominal pain in the 10 mg/kg cohort that was potentially confounded by use of a prohibited, off-label drug.
• The Company received a clinical hold notice from the U.S. Food and Drug Administration (FDA) in December 2024 regarding its investigational new drug (IND) application to initiate the CONNECT2 study in the U.S.

Risks

• Delays or failure to successfully initiate or complete ongoing and planned development activities for product candidates.
• The company's ability to enroll patients in clinical trials.
• Incorrect interpretation of clinical and preclinical study results.
• Product candidates may not be safe and effective or otherwise demonstrate safety and efficacy in clinical trials.
• Adverse outcomes from regulatory interactions, including delays in regulatory review or approval.
• Unexpected increases in expenses associated with development activities.
• Dependence on third parties for product manufacturing, research, and preclinical and clinical testing.

Future Outlook

PepGen anticipates numerous key data milestones in the coming year, including clinical results from the 15 mg/kg cohort of FREEDOM and the 10 mg/kg cohort of CONNECT1-EDO51.

Management Comments

• We believe these data contribute to the growing evidence of our novel EDO platform's potential to deliver the drug to the nucleus, the site of action, said James McArthur, PhD, President and CEO of PepGen.
• We remain dedicated to our mission of developing life-changing therapeutics for patients with neuromuscular diseases and are committed to demonstrating the ability of our investigational candidates to address the root cause of disease for improved patient outcomes, said James McArthur, PhD, President and CEO of PepGen.
• Mis-splicing is the underlying cause of DM1 pathology, and we believe the mean splicing correction observed at 28 days following a single dose of PGN-EDODM1 at 10 mg/kg in the FREEDOM clinical trial surpasses those reported to date in multi-dose clinical trials of up to nine months in duration in patients with DM1, said James McArthur, PhD, President and CEO of PepGen.

Industry Context

These results position PepGen as a key player in the development of oligonucleotide therapies for neuromuscular diseases, particularly DM1 and DMD, addressing significant unmet medical needs.

Comparison to Industry Standards

• The reported splicing correction of 29.1% following a single dose of PGN-EDODM1 at 10 mg/kg in the FREEDOM clinical trial surpasses those reported to date in multi-dose clinical trials of up to nine months in duration in patients with DM1.
• Companies like Biogen, Sarepta Therapeutics, and Ionis Pharmaceuticals are also developing therapies for neuromuscular diseases, but PepGen's EDO platform offers a unique approach to oligonucleotide delivery.
• Sarepta's exon-skipping therapies for DMD, such as Exondys 51, provide a benchmark for regulatory approval and market access in the neuromuscular disease space.

Stakeholder Impact

• Positive results from clinical trials could lead to improved treatment options for patients with DM1 and DMD.
• The company's financial stability ensures continued investment in research and development.
• Regulatory hurdles and clinical trial outcomes will impact investor confidence and stock price.

Next Steps

• Report results from the 15 mg/kg cohort of the FREEDOM-DM1 trial in the second half of 2025.
• Report clinical data from the 10 mg/kg cohort of the CONNECT1-EDO51 trial in the third quarter of 2025.
• Report results from the 5 mg/kg cohort of the FREEDOM2-DM1 trial in the first quarter of 2026.
• Work with the FDA to address questions regarding the CONNECT2 study and resolve the clinical hold.

Key Dates

Keywords

PepGen, PGN-EDODM1, PGN-EDO51, Myotonic Dystrophy Type 1, DM1, Duchenne Muscular Dystrophy, DMD, Splicing Correction, Oligonucleotide Therapies, Clinical Trial, FREEDOM-DM1, CONNECT1-EDO51, EDO Platform