PepGen Inc., announced on July 30th 2024, positive clinical data from the first dose cohort (5 mg/kg) of PGN-EDO51, its lead investigational candidate for patients with Duchenne muscular dystrophy (DMD) whose mutations are amenable to an exon 51-skipping approach. In the ongoing CONNECT1-EDO51 Phase 2 open-label trial, PGN-EDO51 demonstrated higher levels of exon skipping than previously reported studies with other oligonucleotide therapies at similar PMO dose levels in DMD patients.
The CONNECT1 results for the 5mg/kg starting dose were analysed from a cohort of 3 individuals.
- 2.15% increase in exon skipping in bicep muscle tissue at week 13 compared to baseline recordings.
- Achieved a mean muscle adjusted dystrophin level of 1.49% of normal and 0.70% change from baseline after 4 doses, measured at 13 weeks.
- Mean absolute dystrophin level of 0.6% of normal and a 0.26% change from baseline after 4 doses, measured at 13 weeks.
- Western blot analysis was used to determine dystrophin levels in muscle.
- One reported treatment-emergent adverse event was mild and resolved.
- No sustained elevation in kidney biomarkers, and no cases of hypomagnesemia or hypokalemia. No cases of anaemia or thrombocytopenia.
- All three patients are continuing the dosage of PGN-EDO51 in a long term extension, and is currently well tolerated at the time of reporting.
PepGen Inc. plans to present additional results from the 5 mg/kg cohort at a medical meeting later in the year.
We are encouraged by the early data from our CONNECT1 clinical trial of PGN-EDO51 in people with DMD. In three 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 Enhanced Delivery Oligonucleotide technology is delivering higher levels of oligonucleotide to the nuclei. Importantly, PGN-EDO51 has demonstrated a favourable 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 optimise 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.
James McArthur, Ph.D., President and CEO of PepGen.
CONNECT1-EDO51 Clinical Trial
An open-label, multiple ascending dose Phase 2 trial designed to evaluate PGN-EDO51 at up to three different dose levels starting with 5 mg/kg administered intravenously once every four weeks for 12 weeks in patients with DMD amenable to an exon 51-skipping approach. The key endpoints for this trial are safety, dystrophin production and exon skipping. Multiple pharmacokinetic parameters are also being assessed as part of the trial protocol.
PGN-EDO51
PepGen’s lead clinical candidate for the treatment of Duchenne muscular dystrophy (DMD), utilises the Company’s proprietary Enhanced Delivery Oligonucleotide (EDO) technology to deliver a therapeutic phosphorodiamidate morpholino oligomer (PMO) that is designed to target the root cause of this devastating disease. PGN-EDO51 is designed to skip exon 51 of the dystrophin transcript, an established therapeutic target for approximately 13% of DMD patients, thereby aiming to restore the open reading frame and enabling the production of a truncated, yet functional dystrophin protein. The U.S. Food and Drug Administration has granted PGN-EDO51 both Orphan Drug and Rare Pediatric Disease Designations for the treatment of patients with DMD amenable to an exon-51 skipping approach.
CONNECT2-EDO51 Clinical Trial
Based on the data from CONNECT1, including PGN-EDO51’s emerging safety profile to date, the Company is working to optimise the design of the CONNECT2 Phase 2 double-blind, placebo-controlled 25-week multinational trial. The CONNECT2 clinical trial is open in the United Kingdom. The Company continues to engage with regulators in the European Union and expects to open the clinical trial in the United States by year-end.
Would you like to know more about Duchenne muscular dystrophy? Increase your knowledge and understanding of Duchenne with our bite-sized science video series.
Section 1 – Facts about Duchenne muscular dystrophy
Section 2 – Signs and Symptoms of Duchenne muscular dystrophy
Section 3 – Diagnosis of Duchenne muscular dystrophy
Section 4 – Crucial Genetic Terminology
Section 5 – Genetics – Blueprint of Duchenne muscular dystrophy
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