PepGen Inc.

PepGen disclosed that two patients in the 10-mg/kg cohort had reported asymptomatic magnesium deficiency.\n While PepGen works to persuade the FDA to let it launch a phase 2 trial of its Duchenne muscular dystrophy (DMD) therapy in the U.S., the biotech has decided to pause the U.K. arm of the study.The CONNECT2-EDO51 trial, which is designed to test PepGen’s PGN-EDO51 exon-skipping therapy over 25 weeks in patients with DMD, was placed on hold by the FDA in December. The following month, PepGen disclosed that two patients in the 10-mg/kg cohort had reported asymptomatic magnesium deficiency, although their magnesium levels had since returned to baseline levels after receiving oral magnesium supplements.Now, PepGen has decided to pause the U.K. arm of the study while it considers any lessons from a separate phase 2 study, dubbed CONNECT1, that’s ongoing in Canada. The first two cohorts of the Canadian study have been fully enrolled, with a readout expected in the third quarter. Health Canada has previously been in touch with PepGen to ensure it addressed the regulator’s safety concerns. The company said today that it hasn’t observed any new safety issues in its trials.“With our 10 mg/kg cohort of CONNECT1 study fully enrolled and data expected later this year, we decided to pause CONNECT2 until we are able to review results from the 10 mg/kg cohort in patients with DMD,” PepGen CEO James McArthur, Ph.D., said in the March 4 release.“This will allow us to gather additional safety data, assess the impact of this dose of PGN-EDO51 on dystrophin levels, and potentially improve the design of CONNECT2,” McArthur continued.PepGen will also “rapidly advance” studies of its antisense oligonucleotide therapy PGN-EDODM1 in myotonic dystrophy type 1. A phase 1 trial of the therapy endured its own FDA hold back in 2023 but has since gone on to post what PepGen described last week as “encouraging initial clinical data.” 

PepGen is “temporarily pausing” a Phase 2 study of its exon 51 skipping drug for Duchenne muscular dystrophy, it said Tuesday. PepGen told Endpoints News via email that no patients have been enrolled in the paused study, which is recruiting at two sites in the UK, according to a federal clinical trials database . The neuromuscular disease biotech said it is planning to first review safety data for a cohort of patients enrolled in a separate, open-label study known as CONNECT1 that’s being conducted in Canada. It expects to have results from that group of four patients receiving a 10 mg/kg dose of PepGen’s drug, PGN-EDO51, in the third quarter. PepGen is currently facing queries from US and Canadian drug authorities on its Duchenne program, which is now further delayed. “This will allow us to gather additional safety data, assess the impact of this dose of PGN-EDO51 on dystrophin levels, and potentially improve the design of CONNECT2,” PepGen president and CEO James McArthur said in a statement. PepGen’s shares $PEPG fell 25% on Tuesday morning after announcing the pause. Exon skipping drugs are developed for patients with specific mutations and are meant to help “skip” over the faulty section of the RNA transcript for the muscle protein dystrophin to make a shorter but functional version of it. PepGen previously reported that two participants who received the 10 mg/kg dose of its drug in the CONNECT1 trial experienced abnormally low levels of magnesium. Then, in January, it said that those two patients returned to baseline magnesium levels after receiving supplements. One of the patients also experienced a decrease in a measure of kidney function called estimated glomerular filtration rate, and a subsequent scan indicated their eGFR was in the normal range. Canadian health authorities said then that the biotech can continue dosing at 5 and 10 mg/kg but have asked for additional safety information before any new patients at current or higher doses are enrolled in the CONNECT1 study. In December, the FDA put a clinical hold on PepGen’s request to start the CONNECT2 study in the US. The FDA had questions about the data behind the planned dosing levels for the study, according to PepGen. The company hopes to use the CONNECT2 study to ask for accelerated approval from the FDA, though those plans are now being delayed. PepGen said Tuesday that no new safety issues have been seen with its exon 51 skipping program. McArthur said in his statement that the study pause will let PepGen “focus resources” on its open-label study and its myotonic dystrophy type 1 program. As of the end of 2024, the biotech had $120.2 million in cash, which it said could fund its operations into 2026. In 2016, Sarepta Therapeutics won the first and widely controversial accelerated approval for an exon 51 skipping drug, Exondys 51. Biotechs like PepGen and Dyne Therapeutics are developing new exon 51 skipping drugs that they hope can be better than Sarepta’s therapy.

A PepGen drug in development for myotonic dystrophy type 1 (DM1) has encouraging early human data that suggest it could be a better treatment than other medicines in clinical testing for this rare, inherited neuromuscular disorder that currently has no FDA-approved therapies. PepGen said its drug candidate, PGN-EDODM1, led to a dose-dependent increase in splicing correction, which is the fixing of errors in a gene sequence. In the four evaluable patients who received a single 10 mg intravenous infusion, the higher of the two doses tested so far, the results released Monday show the average splicing correction was 29.1% measured at 28 days. Boston-based PepGen expects these results will get even better. “Mis-splicing is the known cause of DM1, and we believe that with repeat and higher dosing, PGN-EDODM1 has the potential to produce greater splicing correction levels, which could lead to improved functional outcomes for patients,” the company said in an investor presentation. presented by Artificial Intelligence What Keeps Healthcare CIOs Up at Night: Balancing Technology Investments with Consumer Expectations When it comes to managing inbound phone calls, underperformance has devastating cost implications. By Stephanie Baum DM1 leads to progressive weakening of muscles. This disease stems from a mutation to the DMPK gene that results in toxic RNA. Antisense oligonucleotides (ASOs) offer one approach to treating genetic diseases. While ASOs can be used to degrade RNA that drives a disease, PepGgen is developing drugs that block it. These drugs are made with Enhanced Delivery Oligonucleotide (EDO), PepGen’s technology for engineering peptides to deliver ASO cargos to destinations in the body. The Phase 1 single-ascending dose study is designed to enroll up to 32 adults with DM1. The study is starting with 5 mg per kilogram of patient weight and 10 mg/kg doses, escalating to 15 mg/kg and potentially 20 mg/kg if safety data support higher dosing. Patients receive muscle biopsies at baseline, day 28, and week 16. Functional outcome measures at day 28 include a 10 meter walk/run test measure and assessment of myotonia, or muscle stiffness. The company said the early results show positive early trends in these functional measures. Leerink Partners analyst Joseph Schwartz said in a research note that the Pepgen DM1 data so far are competitive with ASO degrading therapies in development by Avidity Biosciences and Dyne Therapeutics. For context, Avidity’s del-desiran showed 3% splicing correction after a single 1 mg dose while Dyne’s DYNE-101 showed 13% splicing correction at the lowest dose measured at three months. Pepgen’s preliminary results also top the 25% splicing correction mark achieved by the Dyne therapy’s highest dose, which is the dose continuing through Phase 1/2 development. While the early signs of efficacy are encouraging, safety was a major concern in light of the December clinical hold placed on PepGen’s plans to advance a Duchenne muscular dystrophy therapy to Phase 2 testing. Pepgen said the DM1 drug continues to show a favorable safety profile. As of a Dec. 3 data cutoff, the company said there were no adverse events related to electrolytes or renal biomarkers, which were concerns for the Duchenne study. presented by Health IT Transforming Patient Care: The Role of AI-Powered Assistants The progress in artificial intelligence (AI) is reshaping patient care, across various dimensions, from facilitating faster discharge to curating treatment plans and suggesting lifestyle changes. By IT Medical Schwartz said Leerink is encouraged that safety appears to be cleaner than what has been observed for PepGen’s Duchenne therapy. He added that the firm hasn’t written off the Duchenne program, which may be able to thread the needle between safety and efficacy. In its report of fourth quarter and full year 2024 financial results released Monday, PepGen said it is working with the FDA to address questions about supportive data for dosing levels in the study’s planned patient population. More data from the Phase 1 test of the PepGen DM1 drug are coming. The company expects data from the 15 mg/kg cohort will become available in the second half of this year. Meanwhile, a separate study is underway to see whether multiple doses over longer periods of time lead to better patient outcomes. This placebo-controlled multiple-ascending Phase 2 test will evaluate the study drug in about 24 adults. The company said it expects to report results from the 5 mg 15 mg/kg cohort in the first quarter of next year. As of the end of 2024, PepGen said its cash position was $120.2 million, which it estimates is sufficient to last into 2026. Public domain image by Flickr user Berkshire Community College Bioscience Image Library