Duchenne muscular dystrophy (DMD) devastates young lives. This progressive disease, stemming from mutations in the gene that encodes the protein dystrophin, weakens muscles and strips away mobility. DMD is a rare genetic disease that affects approximately one in every 3,500 male births worldwide. Marked by progressive muscle weakness, DMD leads to patients losing the ability to walk and control the upper body, as well as cardiac issues and difficulty breathing. Boston-based biotech company PepGen now offers a glimmer of hope with its lead candidate, PGN-EDO51, which uses PepGen’s Enhanced Delivery Oligonucleotide (EDO) platform.
Exon Skipping Strategy
A common type of mutation in the dystrophin gene involves missing or deleted sections of code in the middle of the gene. Skipping additional segments, known as exons, can shift the mutation from an out-of-frame deletion to an in-frame deletion. Skipping exon 51 of the dystrophin transcript produces an in-frame deletion, typically leading to a smaller but functional dystrophin protein. This shortened protein can mimic the function of normal dystrophin. Exon 51 is an established therapeutic target for approximately 13% of DMD patients.
The Enhanced Delivery Oligonucleotide platform helps PGN-EDO51 reach the target muscle cells by utilizing cell-penetrating peptides. This technology allows for more efficient delivery and activity within muscle tissue. The US Food and Drug Administration has granted PGN-EDO51 both Orphan Drug and Rare Pediatric Disease Designations for treating patients with DMD who are candidates for the exon-51 skipping therapeutic approach.
Encouraging Results and Safety Profile
Early results from PepGen’s CONNECT1-EDO51 Phase II trial, which tested a starting dose of 5 mg/kg in three participants, show promising outcomes. The participants received four doses of PGN-ED051 over 12 weeks. Compared to the baseline, the treatment produced a mean exon skipping level of 2.15% in bicep tissue at week 13 and a 0.70% increase in mean muscle-adjusted dystrophin level.
“We are encouraged by the early data,” said James McArthur, PepGen’s President and CEO, in a statement. “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,” he added.
PGN-EDO51 has demonstrated safety alongside its efficacy. No participants discontinued the trial due to adverse effects. The only related adverse event was mild and resolved on its own. There were no severe issues with kidney biomarkers, liver function or blood health.
The Path Forward
The CONNECT1 trial sets the stage for further investigation. PepGen plans to explore higher doses, including 10 mg/kg, in both the ongoing CONNECT1 and the multinational, double-blind CONNECT2 trial. The CONNECT2 trial aims to test PGN-EDO51 across various dose levels for longer periods and evaluate safety, efficacy and patient quality of life.
PepGen plans to present more data later this year. If higher doses yield similarly positive results, PGN-EDO51 could change the landscape of DMD treatment. Hugh McMillan, a Pediatric Neurologist at the Children’s Hospital of Eastern Ontario and Professor in the Department of Pediatrics at the University of Ottawa, expressed cautious optimism. “People with DMD and their families constantly hope for effective therapies with the potential to change the course of this relentlessly progressive neuromuscular disease. I look forward to seeing the results of exon skipping and dystrophin production at 10 mg/kg in both CONNECT1 and CONNECT2.”
For families grappling with the harsh reality of DMD, these advances offer a reason to hope. PepGen’s progress marks an encouraging step in the fight against this devastating disease.
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