PepGen’s IND for Duchenne Muscular Dystrophy PMO PGN-EDO51 Placed on Clinical Hold by the FDA
The trial for the exon-51 skipping therapy is already active in the United Kingdom.
James McArthur, PhD
PepGen’s investigational new drug (IND) application for PGN-EDO51, an investigational phosphorodiamidate morpholino oligomer (PMO) intended to treat Duchenne muscular dystrophy (DMD), has been placed on hold by the FDA.1
As such, the phase 2 CONNECT2-EDO51 clinical trial for PGN-EDO51, which is already active in the United Kingdom, may not yet go forward to with activities in the United States. PepGen pointed out that it has not yet received an official clinical hold letter from the FDA, but that the agency stated the letter will be provided within 30 days. The reason(s) for the clinical hold were not made clear in the company’s announcement of the FDA's decision. CONNECT2-EDO51 is a double-blind, placebo-controlled, multiple ascending dose study. PGN-EDO51 is also being evaluated in Canada in the separate open-label phase 2 CONNECT1-EDO51 clinical trial (NCT06079736).
“We intend to work closely with the FDA to address their questions on our application to initiate CONNECT2 as expeditiously as possible,” Paul Streck, MD, MBA, the head of research & development at PepGen, said in the press release.1 “Our open-label CONNECT1-EDO51 multiple ascending dose study of PGN-EDO51 in boys and young men living with DMD continues as planned in Canada. We have completed enrollment of the 10 mg/kg dose cohort; all 4 patients in this cohort have received at least 1 dose.”
CONNECT1-EDO51 dosed its first patient in January 2024.2 PGN-EDO51, which uses PepGen’s Enhanced Delivery Oligonucleotide (EDO) and is intended to function by skipping exon 51 in dystrophin transcripts, is being assessed in patients with DMD who are amenable to exon 51-skipping therapy, who comprise roughly 13% of the DMD patient population. CONNECT1-EDO51 is seeking to enroll an estimated 10 boys aged at least 8 years with DMD to assess the safety and tolerability of the therapy, with the primary end point being adverse events (AEs) and serious AEs from baseline to week 16 of treatment. Additionally, the trial will evaluate key pharmacokinetic parameters, namely the maximum observed plasma concentration, the time to maximum plasma concentration, the terminal half-life, and the area under the curve for concentration time—all measured from baseline to week 12, after 4 monthly doses of PGN-EDO51.
Interim data from patients treated in CONNECT1-EDO51 were announced in July 2024.3 Among 3 patients who were treated at the study’s starting dose level (5 mg/kg), mean exon skipping of 2.15% in biceps tissue compared to baseline was reported at 13 weeks posttreatment, at which point 4 doses of the therapy had been administered. Furthermore, a mean muscle-adjusted dystrophin level of 1.49% of normal and a 0.70% change from baseline was recorded at 13 weeks posttreatment, along with a mean absolute dystrophin level of 0.61% of normal and a 0.26% change from baseline.
“We are encouraged by the early data from our CONNECT1 clinical trial of PGN-EDO51 in people with DMD,” James McArthur, PhD, the president and CEO of PepGen, said in a July 2024 statement.3 “In 3 months, the starting monthly dose of 5 mg/kg achieved high levels of exon skipping and all patients showed increases in dystrophin. PGN-EDO51 produced meaningfully higher levels of exon skipped transcript at lower doses and in a shorter time period compared to other exon 51 therapies, approved and in development, indicating that our EDO technology is delivering higher levels of oligonucleotide to the nuclei. Importantly, PGN-EDO51 has demonstrated a favorable safety profile, supporting our ongoing evaluation of the 10 mg/kg monthly dose cohort in CONNECT1. We intend to leverage the early observations from CONNECT1 to optimize our CONNECT2-EDO51 phase 2 trial. Based on these initial results, we are optimistic about the possibility that higher levels of dystrophin production will be observed in the 10 mg/kg cohort of CONNECT1. We also look forward to reporting data from the first cohort of our placebo-controlled multinational study CONNECT2.”
