PepGen Reports Encouraging Phase 2 Data for PGN-EDODM1 in Myotonic Dystrophy Type 1, Advances Higher-Dose Cohort in FREEDOM2 Trial
PepGen Inc., a clinical-stage biotechnology company focused on advancing next-generation oligonucleotide therapeutics, has announced new clinical data from the 5 mg/kg multiple ascending dose (MAD) cohort of its ongoing Phase 2 FREEDOM2-DM1 trial. The study is evaluating PGN-EDODM1, the company’s investigational therapy for myotonic dystrophy type 1 (DM1), a rare and progressive neuromuscular disorder characterized by muscle weakness, myotonia, and multisystem complications.
The newly released results provide early insights into the safety, tolerability, and biological activity of PGN-EDODM1 at the lowest dose level tested in the MAD portion of the trial. While efficacy signals remain preliminary, the overall dataset suggests a favorable safety profile and encouraging trends in molecular and functional measures, supporting continued dose escalation and further evaluation at higher dose levels.
Advancing a Novel Therapeutic Approach for DM1
Myotonic dystrophy type 1 is caused by a genetic mutation leading to toxic RNA transcripts that disrupt normal cellular function, particularly affecting RNA splicing. There are currently no approved disease-modifying therapies that directly target the underlying cause of DM1, representing a significant unmet medical need.
PepGen’s investigational candidate, PGN-EDODM1, is designed to address this root cause by improving RNA splicing and restoring more normal cellular processes. The FREEDOM2 trial represents a key step in translating this mechanism into clinical benefit.
The Phase 2 FREEDOM2 study is a randomized, placebo-controlled, multiple ascending dose trial, with planned dose escalation up to 12.5 mg/kg. Patients enrolled in the study receive treatment every four weeks over a 12-week period, with follow-up assessments to evaluate both safety and efficacy endpoints.
Study Design and Cohort Overview
The 5 mg/kg dose cohort included a total of eight patients, randomized in a 6:2 ratio to receive either PGN-EDODM1 or placebo. The data cutoff for the analysis was March 4, 2026.
The study is designed to evaluate several key endpoints, including safety and tolerability, molecular measures such as RNA splicing correction, and functional outcomes relevant to patient mobility and muscle strength.
Although the cohort size is small, as expected in early-stage clinical trials, the results provide valuable information to guide dose selection and future study design.
Splicing Correction and Biological Activity
One of the primary objectives of the FREEDOM2 trial is to assess the ability of PGN-EDODM1 to improve RNA splicing abnormalities associated with DM1. In the 5 mg/kg cohort, patients treated with the investigational therapy demonstrated a mean splicing correction of 7.3%, compared to 6.8% observed in placebo-treated patients.
At first glance, the difference between treatment and placebo groups appears modest. However, further analysis revealed that the overall mean was significantly influenced by an outlier patient who experienced a worsening in splicing correction of 70.8%. When this outlier was excluded, the treated group demonstrated a substantially higher mean splicing correction of 22.9%, suggesting a more meaningful biological effect in the majority of patients.
These findings highlight both the variability inherent in early clinical datasets and the importance of continued evaluation in larger cohorts. They also provide preliminary evidence that PGN-EDODM1 is engaging its intended molecular target.
Functional Outcomes and Early Signals
In addition to molecular endpoints, the study evaluated functional measures to assess potential clinical benefit. One such measure, the middle finger velocity of hand opening time (vHOT), showed a positive trend in patients receiving PGN-EDODM1, while those in the placebo group experienced worsening over the same period.
Although both groups returned to baseline by Week 16, the observed trend suggests a potential early signal of functional improvement that may become more pronounced with higher doses or longer treatment duration.
Other functional endpoints, including the 10-meter walk/run test (10MWRT) and handgrip strength, did not show meaningful improvements at the 5 mg/kg dose level. This outcome is not unexpected, as lower doses in early-phase studies are often insufficient to produce measurable clinical changes, particularly in complex neuromuscular conditions like DM1.
Drug Exposure and Tissue Penetration
An important aspect of evaluating oligonucleotide therapies is understanding their distribution and concentration within target tissues. In the FREEDOM2 trial, muscle tissue concentrations of PGN-EDODM1 were measured in five of the six treated patients.
The mean concentration was reported at 158 ng/g, measured approximately one week after the fourth dose. This finding indicates that the drug is successfully reaching muscle tissue, a critical requirement for achieving therapeutic effects in DM1.
One additional concentration measurement remains pending, which may further inform the pharmacokinetic profile of the therapy.
Favorable Safety and Tolerability Profile
A key highlight of the 5 mg/kg cohort data is the favorable safety and tolerability profile of PGN-EDODM1. The therapy was generally well tolerated, with no serious adverse events (SAEs) reported during the study period.
All treatment-emergent adverse events (TEAEs) considered related to the therapy were mild in severity, while non-related TEAEs were either mild or moderate. Importantly, there were no treatment-related discontinuations, suggesting good overall tolerability.
Nausea was the most commonly reported adverse event, but it was manageable and did not lead to treatment interruption. Additionally, no adverse events related to renal function were observed, and there were no signs of cumulative toxicity, which is particularly important for therapies intended for chronic use.
These safety findings are encouraging, especially given the challenges associated with developing oligonucleotide-based therapies, where off-target effects and toxicity have historically been concerns.
Progressing to Higher Dose Cohorts
Building on the results from the 5 mg/kg cohort, PepGen is actively advancing the next stage of the FREEDOM2 trial. The 10 mg/kg multiple ascending dose cohort is currently underway, with more than half of the planned patients already enrolled.
As of the latest update, five out of eight patients in this cohort have received up to three doses of PGN-EDODM1. The company expects to report data from this higher-dose group in the second half of 2026.
The decision to proceed with dose escalation reflects confidence in the safety profile observed at the lower dose, as well as the potential for enhanced efficacy at higher exposure levels. Dose-response relationships are a critical component of drug development, and the upcoming data will play a key role in determining the optimal dosing strategy for future studies.
Open-Label Extension and Long-Term Evaluation
In addition to the randomized portion of the trial, PepGen has initiated an open-label extension (OLE) study to evaluate the longer-term safety and potential efficacy of PGN-EDODM1.
To date, 12 patients have enrolled in the OLE at the 5 mg/kg dose level, including five patients who transitioned from the FREEDOM2 trial. This extension phase will provide valuable data on sustained treatment effects and long-term tolerability, which are essential for therapies targeting chronic conditions like DM1.
Outlook and Future Development
The data from the 5 mg/kg cohort of the FREEDOM2 trial represent an important early milestone in the development of PGN-EDODM1. While efficacy signals remain preliminary, the combination of favorable safety, evidence of target engagement, and encouraging functional trends supports continued clinical advancement.
The upcoming results from the 10 mg/kg cohort are expected to provide further clarity on the therapeutic potential of PGN-EDODM1, particularly with respect to dose-dependent effects on splicing correction and clinical outcomes.
As PepGen continues to advance its pipeline, the company remains focused on addressing the significant unmet needs of patients with myotonic dystrophy type 1. With no approved disease-modifying treatments currently available, the development of therapies targeting the underlying genetic cause of the disease has the potential to transform patient care.
PepGen’s latest update underscores steady progress in its mission to develop innovative oligonucleotide therapies for severe neuromuscular disorders. The FREEDOM2 trial continues to generate important clinical insights, laying the groundwork for future development stages.
With a favorable safety profile established at the initial dose level and higher-dose data on the horizon, PGN-EDODM1 remains a promising candidate in the evolving landscape of DM1 therapeutics. The coming months, particularly the anticipated data readout in the second half of 2026, will be critical in determining the next steps for this novel treatment approach.
About PGN-EDODM1
PGN-EDODM1, PepGen’s investigational candidate in development for the treatment of DM1, utilizes the Company’s proprietary EDO technology to deliver a therapeutic oligonucleotide that is designed to restore the normal splicing function of MBNL1, a key RNA splicing protein. PGN-EDODM1 addresses the deleterious effects of cytosine-uracil-guanine (CUG) repeat expansion in the dystrophia myotonica protein kinase (DMPK) transcripts which sequester MBNL1, by binding to the pathogenic CUG trinucleotide repeat expansion present in the DMPK transcripts, and disrupting the binding between the CUG repeat expansion and MBNL1.
PepGen believes this innovative therapeutic approach may have considerable advantages over oligonucleotide modalities that rely on knockdown or degradation of the DMPK transcripts as it will allow the DMPK transcripts to continue to perform their normal function within the cell, while also liberating MBNL1 to correct downstream mis-splicing events. The U.S. Food and Drug Administration has granted PGN-EDODM1 both Orphan Drug and Fast Track Designations for the treatment of patients with DM1. The European Medicines Agency (EMA) has recently granted Orphan Designation for PGN-EDODM1.
About PepGen
PepGen Inc. is a clinical-stage biotechnology company developing the next generation of oligonucleotide therapies with the goal of transforming the treatment of severe neuromuscular and neurological diseases. PepGen’s Enhanced Delivery Oligonucleotide (EDO) platform is founded on over a decade of research and development and leverages cell-penetrating peptides to improve the uptake and activity of conjugated oligonucleotide therapeutics. Using these EDO peptides, the Company is generating a pipeline of oligonucleotide therapeutic candidates designed to target the root cause of serious diseases.
Source Link:https://www.businesswire.com/
