Patient Dosing Commenced in Phase 2 CONNECT1-EDO51 Trial for DMD Amenable to Exon 51 Skipping


PepGen has begun its phase 2 CONNECT1-EDO51 trial, dosing the first patient with PGN-EDO51, an agent for Duchenne muscular dystrophy amendable to an exon 51 skipping.

James McArthur, PhD, president and chief executive office at PepGen

James McArthur, PhD

Credit: PepGen

Months after PepGen received a No Objection Letter from Health Canada, the company announced that the first patient has been dosed in the phase 2, open-label multiple ascending dose (MAD) CONNECT1-EDO51 trial (NCT06079736) assessing PGN-EDO51, an investigational antisense oligonucleotide (ASO), for the treatment of individuals with Duchenne muscular dystrophy (DMD) amendable to an exon 51 skipping therapy.1,2

CONNECT1-EDO51 is an open-label study enrolling approximately 10 patients at least 8 years old with DMD amenable to an exon 51 skipping approach to investigate the safety and tolerability of PGN-EDO51. The trial will also assess oligonucleotide muscle concentrations, exon skipping and dystrophin protein production in muscle at week 12 following 4 monthly doses of PGN-EDO51. Following protocol, the starting dose for patients will increase from 5 mg/kg to 10 mg/kg and further escalation will be determined based on evaluation of safety data from prior cohorts.

“We are pleased to have dosed the first patient in our CONNECT1-EDO51 clinical trial, which marks another milestone in our commitment to developing therapies with the potential to truly improve the lives of patients living with DMD,” James McArthur, PhD, president and chief executive office at PepGen, said in a statement.1 “Based on the levels of exon skipping achieved following a single dose of PGN-EDO51 in our phase 1 healthy volunteer trial, we are looking forward to our initial planned data readout in patients with DMD at the 5 mg/kg PGN-EDO51 dose level for CONNECT1-EDO51 in the middle of 2024.”

Top Clinical Takeaways

  • PepGen has initiated the phase 2 trial for PGN-EDO51 in the treatment of Duchenne muscular dystrophy, following Health Canada's No Objection Letter.
  • The CONNECT1-EDO51 trial aims to assess the safety, tolerability, and efficacy of PGN-EDO51 in approximately 10 patients with DMD amenable to exon 51 skipping therapy.
  • The trial's dose escalation strategy, starting from 5 mg/kg and increasing to 10 mg/kg, reflects a cautious approach based on the evaluation of safety data from earlier cohorts.

PGN-EDO51 had oligonucleotide tissue concentration and exon skipping assessed in a phase 1 trial that included 32 healthy adult males.3 All told, the trial met its primary end point, providing evidence that PGN-EDO51 was generally well tolerated at pharmacologically relevant doses.3 After 28 days of treatment, the majority of treatment-emergent adverse events (AEs) observed were mild and resolved without any intervention.

READ MORE: FDA Grants Priority Review to Efficacy Supplement for Sarepta Therapeutics’ SRP-9001 Indication Expansion

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."3

Presented at the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 19-22, in Dallas, Texas, preclinical data from in vitro and in vivo studies of DMD 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 DMD patient cells with 2600 CTG repeats.4

1. PepGen Announces First Patient Dosed in CONNECT1-EDO51 Phase 2 Clinical Trial of PGN-EDO51 for Duchenne Muscular Dystrophy Patients Amenable to Exon 51 Skippin. News Release. PepGen. Published January 8, 2024. Accessed Febrauary 22, 2024.
2. 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. News Release. PepGen. Published May 18, 2023. Accessed February 22, 2024.
3. PepGen Reports Positive Data from Phase 1 Trial of PGN-EDO51 for the Treatment of Duchenne Muscular Dystrophy. News Release. PepGen. Published September 28, 2022. Accessed February 22, 2024.
4. PepGen presents clinical and nonclinical data at the 2023 Annual Muscular Dystrophy Association Clinical and Scientific Conference. News release. March 22, 2023. Accessed February 22, 2024.
Recent Videos
David T. Jones, MD
Clifford R. Jack Jr., MD
 Lisa Mosconi, PhD
Emma Ciafaloni, MD, an expert on Duchenne muscular dystrophy
 Justin Davanzo, MD
1 KOL is featured in this series.
Aliza Ben-Zacharia, PhD, DNP, ANP-BC, FAAN
5 KOLs are featured in this series.
5 KOLs are featured in this series.
Kathy Zackowski, PhD, OTR
© 2024 MJH Life Sciences

All rights reserved.