Recent Developments in PepGen's CONNECT Program for DMD

PepGen's Latest Advancements in Clinical Trials

PepGen Inc. (Nasdaq: PEPG), a clinical-stage biotechnology company dedicated to innovating oligonucleotide therapies, has recently announced pivotal updates regarding its CONNECT clinical program. This program primarily investigates PGN-EDO51 as a treatment option for Duchenne muscular dystrophy (DMD), focusing on patients suited for an exon-51 skipping approach.

CONNECT1-EDO51 Clinical Trial Overview

The CONNECT1 study is a Phase 2, open-label, multiple ascending dose (MAD) clinical trial with ongoing enrollment in Canada. This trial has two cohorts comprised of boys and young men diagnosed with DMD who are eligible for the exon 51 skipping treatment. Its key objectives target safety, tolerability, and various efficacy endpoints including dystrophin production and muscle tissue concentration.

Currently, the 10 mg/kg cohort has reached full enrollment with four participants, while three are still active in the ongoing dosing regimens at the 5 mg/kg level during the long-term extension component of the study. The company has outlined plans to share clinical data from the 10 mg/kg cohort by the end of 2025.

Safety Monitoring and Regulatory Compliance

Recent developments have indicated a return to baseline magnesium levels in two subjects from the 10 mg/kg cohort, who had previously exhibited asymptomatic hypomagnesemia. One of the participants experienced a temporary pause in dosing due to a drop in his estimated glomerular filtration rate (eGFR), although this did not cause a dose-limiting toxicity according to pre-established safety criteria. Subsequent evaluations confirmed improvements in the participant’s eGFR, with ongoing reviews by the investigator to determine when dosing can safely resume.

Moreover, PepGen has received communication from Health Canada permitting continued dosing for the 5 mg/kg and 10 mg/kg cohorts, albeit with requests for further information to address safety inquiries before advancing to increased dosing or additional participant enrollment. The company is actively collaborating with regulatory authorities to clarify their questions.

CONNECT2-EDO51 Clinical Trial Status

As for the CONNECT2-EDO51 trial, this Phase 2 study is a multinational, double-blind, placebo-controlled investigation that is currently open for enrollment in the United Kingdom. Similar to CONNECT1, this trial targets boys and young men amenable to the exon 51 skipping treatment, with monitoring focusing on safety, tolerability, dystrophin production, and functional outcomes.

However, in a setback, PepGen was notified by the US Food and Drug Administration (FDA) of a clinical hold on its Investigational New Drug application to initiate CONNECT2 in the US, despite prior authorization from the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). The team is diligently addressing the FDA’s inquiries regarding their planned dosing levels and supporting data.

Expert Commentary from PepGen’s Leadership

Dr. Paul Streck, Head of Research and Development at PepGen, expressed optimism regarding the findings in CONNECT1, noting that treatment-related adverse events have generally been mild. He reassured stakeholders about the favorable emerging safety profile of PGN-EDO51 and highlighted the improving eGFR levels documented in one participant following a pause in dosing. He emphasized the importance of continued safety evaluations and eagerly anticipates sharing clinical data updates from both CONNECT1 and another significant study, FREEDOM-DM1, targeting myotonic dystrophy type 1.

Understanding PGN-EDO51 and PGN-EDODM1

PGN-EDO51 represents PepGen's cutting-edge investigational therapy aimed at DMD treatment. The design leverages the proprietary Enhanced Delivery Oligonucleotide (EDO) technology to facilitate effective oligonucleotide delivery, specifically targeting the root cause of DMD by achieving exon 51 skipping in the dystrophin transcript. Substantial efforts are implemented to restore reading frames for approximately 13% of DMD patients, enhancing dystrophin protein production.

Additionally, the company is advancing PGN-EDODM1, a candidate for treating myotonic dystrophy type 1 (DM1). Leveraging similar EDO technology, PGN-EDODM1 focuses on reinstating the splicing functions of MBNL1, a pivotal RNA splicing protein, ultimately benefiting thousands suffering from DM1, a progressive genetic disorder that significantly impacts quality of life.

About PepGen and Its Vision

PepGen’s mission is to revolutionize treatment methodologies for severe neuromuscular and neurological disorders through innovative oligonucleotide therapies. Their sophisticated EDO platform results from over ten years of intensive research, establishing a robust pipeline aimed at confronting the underpinnings of serious diseases. The company’s commitment to enhancing therapeutic effectiveness through improved cellular uptake mechanisms showcases its dedication to addressing pressing healthcare challenges.

Frequently Asked Questions

What is PepGen's CONNECT program?

The CONNECT program focuses on developing PGN-EDO51 for treating Duchenne muscular dystrophy, particularly using an exon-51 skipping approach.

What are the primary goals of the CONNECT1 trial?

CONNECT1 aims to evaluate safety, tolerability, and efficacy measures such as dystrophin production in participants with DMD.

What recent updates were made regarding safety in the trials?

Recent safety monitoring indicated improvements in magnesium levels and renal function in some participants, with no significant adverse effects noted.

How is PepGen addressing the regulatory hold from the FDA?

PepGen is working closely with the FDA to resolve concerns and provide necessary data to proceed with the CONNECT2 trial in the US.

What other conditions does PepGen's research focus on?

In addition to DMD, PepGen is also developing PGN-EDODM1 for myotonic dystrophy type 1, aiming to restore RNA splicing functions effectively.

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