FREEDOM-DM1: Final results from a Phase 1, placebo-controlled SAD study to evaluate PGN-EDODM1 in people with myotonic dystrophy type 1 (DM1)

Topic:

Clinical Trials

Poster Number: 413 O

Author(s):

Johanna Hamel, MD, University of Rochester, Rochester, NY, Thurman Wheeler, MD, Massachusetts General Hospital, Boston, MA, Jean-Denis Brisson, MD, PhD, CIUSSS du Saguenay-Lac-Saint-Jean, Canada, Hanns Lochmüller, MD, PhD, Children’s Hospital of Eastern Ontario Research Institute, Jacinda Sampson, MD, PhD, Stanford, Namita Goyal, MD, University of California, Irvine, Han Phan, MD, Rare Disease Research, Atlanta, Georgia, USA, Nicholas Johnson, MD, Virginia Commonwealth University, Richmond, Virginia, USA , Jeffrey Statland, MD, University of Kansas Medical Center, Kansas City, Kansas, USA, James Lilleker, MD, MBChB, MRCP, PhD, Northern Care Alliance NHS Trust, Christopher Turner, MD, PhD, University College London Hospitals, London, UK, Gerald Pfeffer, PhD, MD, CM, FRCPC, University of Calgary, Canada, Brijesh Garg, PhD, PepGen Inc., Boston, MA, GREGORY SONG, PhD, PepGen, Pallavi Lonkar, PhD, PepGen Inc., Boston, MA, Sarah Vacca, BS, PepGen Inc., Boston, MA, Stephen Babcock, MS, PepGen, Sejal Batra, MS, PepGen Inc., Boston, MA, Shaoxia Yu, MS, PepGen Inc., Boston, MA, Paul Streck, MD, MBA, PepGen Inc., Boston, MA, Ann Barbier, MD, PhD, PepGen Inc., Boston, MA, Jane Larkindale, D.Phil, PepGen Inc., Boston, MA

FREEDOM-DM1 is a Phase 1 randomized, double-blind, placebo-controlled, single ascending dose (SAD) study of PGN-EDODM1 in people with myotonic dystrophy type 1 (DM1) (NCT06204809). Three cohorts of 5, 10 and 15mg/kg (n=8, 3:1 randomization) were investigated in adults with confirmed DM1. The study was designed to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics (correction of mis-splicing), and to explore functional endpoints. Unblinded results of this study will be shared.

Data showed dose-dependent increases in PGN-EDODM1 concentration in muscle 28 days after a single dose. This correlates with correction of mis-splicing, a pharmacodynamic biomarker of PGN-EDODM1 activity that demonstrates potential activity on the central cause of DM1 pathology. Splicing correction of 12.3%, 29.1% and 53.7% was measured at 5mg/kg, 10mg/kg and 15mg/kg, respectively (22-gene panel), substantially higher than any previously reported splicing correction in people with DM1. PGN-EDODM1 was generally well-tolerated at 15mg/kg with no serious treatment-related adverse events. Transient mild-moderate changes in renal biomarkers were observed, which met the dose limiting toxicity criteria in one participant. These resolved without intervention within 48 hours of dosing with no associated symptoms. High levels of splicing correction after single doses of PGN-EDODM1 demonstrate PGN-EDODM1’s potential to affect the symptoms of DM1. Studies in animal models demonstrated further improvement in correction of mis-splicing after repeat dosing compared to single doses, which correlated with greater improvement in a functional measure (myotonia) on repeat dosing. Correction of mis-splicing over time with repeat dosing is therefore anticipated to improve functional measures in people with DM1.

The emerging benefit/risk profile for PGN-EDODM1 supports further clinical development. FREEDOM2-DM1, a multiple ascending dose study of 4 monthly doses of PGN-EDODM1 is ongoing (NCT06667453).