FDA Lifts Clinical Hold on FREEDOM-DM1 Study of Antisense Agent PGN-EDODM1
In preclinical data, treatment with PGN-EDODM reduced pathogenic nuclear foci by 54% per nuclei and liberated muscleblind like splicing regulator 1, resulting in a greater than 68% correction of downstream transcript missplicing events.
James McArthur, PhD
According to an announcement from PepGen, the FDA has lifted a clinical hold on its investigational new drug application (IND) for its phase 1 study assessing PGN-EDODM1, an investigational antisense oligonucleotide (ASO), in patients with myotonic dystrophy type 1 (DM1). The company expects to obtain proof-of-concept data, including transcript splicing and clinical outcome measures, as well as safety data, for treated patients in the study in 2024.1
Originally started in Canada, FREEDOM-DM1 is a randomized, double-blind, placebo-controlled, single-ascending dose study assessing the safety and tolerability of the ASO in 3 cohorts of 5 mg/kg, 10 mg/kg, and 20 mg/kg dose levels. The study also will look at correction of mis-splicing of transcripts and other clinical functional outcome measures throughout.
"We have worked closely with the FDA to resolve their questions expeditiously and are pleased that the clinical hold on our DM1 program in the United States has been lifted,” James McArthur, PhD, president and chief executive officer, PepGen, said in a statement.1 "Our novel PGN-EDODM1 approach targets the toxic RNA species responsible for the disease, and the strength of our Enhanced Delivery Oligonucleotide (EDO) safety preclinical package has enabled us to launch this study in both the U.S. and internationally at doses that we believe could provide a clinically meaningful benefit to patients."
He added, "We are very pleased after review of our existing safety data that the FDA agreed with our proposed starting dose of 5 mg/kg, moving up to 10 mg/kg and 20 mg/kg."1
An ASO therapy, PGN-EDODM1 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. DM1, also known as Steinert’s disease, affects an estimated 40,000 people in the US and 70,000 in the EU.
In its announcement, PepGen noted that it anticipates proof-of-concept data, as well as safety data for PGN-EDO51, the company’s lead candidate for the treatment of Duchenne muscular dystrophy (DMD), in mid-2024. Designed to deliver a peptide-conjugated ASO to restore cellular function, the agent is currently being assessed in the phase 2 CONNECT1-EDO51 clinical trial of patients with DMD amenable to exon 51 skipping. Earlier this year, PepGen received a No Objection Letter from Health Canada to initiate the study.
READ MORE: RAINBOWFISH Results Highlight Risdiplam as Effective Treatment for Presymptomatic SMA
Designed as a multiple-ascending dose trial, CONNECT1-EDO51 will evaluate 3 cohorts of ambulatory and non-ambulatory boys and young men with DMD, 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 The anticipated data release from that study is expected to be for the 5 mg/kg dose level, and will include outcomes of exon skipping and dystrophin data.
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.
"This was increased to 99% correction of both measures following multiple doses," McArthur added, regarding the correction of downstream events.1 "Based on these preclinical results, we anticipate proof-of-concept data in patients in 2024, including transcript splicing and clinical outcome measures, at the 5 mg/kg PGN-EDODM1 dose level in DM1 patients. With clearance of our IND from the FDA, we are eager to open study sites in the U.S. to accelerate the development of PGN-EDODM1 for individuals worldwide living with DM1."
