FDA Places Hold on Phase 1 Study of Exon Skipping Therapy PGN-EDODM1 in Myotonic Muscular Dystrophy


The hold comes nearly a month after Health Canada sent PepGen a No Objection Letter to start its phase 2 CONNECT1-EDO51 trial in patients with Duchenne muscular dystrophy.

James McArthur, PhD, president and chief executive officer, PepGen

James McArthur, PhD

According to a recent announcement, the FDA has placed a clinical hold on PepGen’s investigational new drug application (IND) for its phase 1 study assessing PGN-EDODM1 in individuals with myotonic dystrophy type 1 (DM1). The agency plans to provide an official clinical hold letter to the company stating the reasons for its decision within 30 days.1

PGN-EDODM1, an antisense oligonucleotide, is designed to deliver a small molecule that binds to CUG repeats and corrects defects in RNA processing. In turn, this restores the production of DMPK, the gene responsible for DM1, and allows the muscles to function properly again.

"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 U.S. 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."

The news comes weeks after the company received a No Objection Letter from Health Canada for its clinical trial application to initiate a phase 2 open-label trial of PGN-EDO51 in patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. Also called CONNECT1-EDO51, the multiple-ascending dose trial will not be impacted by the clinical hold placed by the FDA. CONNECT1-EDO51 is expected to evaluate the agent in 3 cohorts of ambulatory and non-ambulatory boys and young men, with doses starting at 5 mg/kg and plans to escalate to 10 mg/kg and potentially other doses following Drug Safety Monitoring Board review.2

Earlier this year, at the 2023 Muscular Dystrophy Association’s Clinical and Scientific Conference, preclinical data from in vitro and in vivo studies of DM1 showed that treatment with PGN-EDODM reduced pathogenic nuclear foci by 54% per nuclei and liberated muscleblind like spicing regulator 1. Ultimately, this resulted in a greater than 68% correction of downstream transcript missplicing events in in vitro DM1 patient cells with 2600 CTG repeats.3

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PGN-EDO51 had oligonucleotide tissue concentration and exon skipping also assessed in a phase 1 trial that included 32 healthy adult males. All told, the trial met its primary end point, providing evidence that PGN-EDO51 was generally well tolerated at pharmacologically relevant doses. After 28 days of treatment, the majority of treatment-emergent adverse events (AEs) observed were mild and resolved without any intervention.4

In the 10 mg/kg dose cohort, PGN-EDO51 exhibited mean oligonucleotide concentrations of 19 nM and 11 nM in biceps biopsies taken at day 10 (n = 6) and day 28 respectively (n = 6), while those in the 15 mg/kg cohort showed mean concentrations of 50 nM and 50 nM at the same time points. Additionally, at day 10 and 28, treatment with 10 mg/kg PGN-EDO51 resulted in mean skipping of 1.1% and 1.4% in biceps biopsies, respectively. In the 15 mg/kg dose cohort, PGN-EDO51 exhibited mean exon skipping of 1.4% and 2.0% in biceps biopsies at day 10 (n = 5) and day 28 (n = 6), respectively.

At the time of the announced results, McArthur said in a statement that, "We are particularly pleased with the high levels of exon skipping observed for PGN-EDO51 at 28 days. Exon skipping was higher on Day 28 than at Day 10, which we believe, in conjunction with our tissue concentration data, suggests both sustained drug exposure and pharmacodynamic effect. Furthermore, we believe that these results could signal the potential for the accumulation of exon 51 skipped transcript and dystrophin protein in muscle tissue with repeated doses of PGN-EDO51 in people living with DMD."4

1. PepGen announces clinical hold in the US on IND application to initiate a phase 1 study of PGN-EDODM1 for myotonic dystrophy. News release. PepGen. May 30, 2023. Accessed June 8, 2023. https://www.globenewswire.com/news-release/2023/05/30/2678819/0/en/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.html

2. PepGen announces clearance by Health Canada for PGN-EDO51 to begin the phase 2 clinical trial, CONNECT1-EDO51, for the treatment of Duchenne muscular dystrophy. May 18, 2023. Accessed June 8, 2023. https://www.biospace.com/article/releases/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/

3. PepGen presents clinical and nonclinical data at the 2023 Annual Muscular Dystrophy Association Clinical and Scientific Conference. News release. March 22, 2023. Accessed June 8, 2023. https://investors.pepgen.com/news-releases/news-release-details/pepgen-presents-clinical-and-nonclinical-data-2023-annual

4. PepGen reports positive data from phase 1 trial of PGN-EDO51 for the treatment of Duchenne muscular dystrophy. News release. September 28, 2023. Accessed June 8, 2023. https://investors.pepgen.com/news-releases/news-release-details/pepgen-reports-positive-data-phase-1-trial-pgn-edo51-treatment

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