Development of PGN-EDODM1, a novel enhanced delivery oligonucleotide that targets the root cause of myotonic dystrophy type 1.

Topic:

Clinical Trials

Poster Number: 131 M

Author(s):

Jane Larkindale, D.Phil, PepGen Inc., Boston, MA, Johanna Hamel, MD, University of Rochester, Jean-Denis Brisson, MD, PhD, CIUSSS du Saguenay-Lac-Saint-Jean, Canada, Hanns Lochmüller, MD, PhD, Children’s Hospital of Eastern Ontario Research Institute, Thurman Wheeler, MD, Massachusetts General Hospital, Boston, MA, Jacinda Sampson, MD, PhD, Stanford, Namita Goyal, MD, University of California, Irvine, Jordi Diaz-Manera, MD, PhD, John Walton Muscular Dystrophy Research Centre, Newcastle University, UK, Gerald Pfeffer, PhD, MD, CM, FRCPC, University of Calgary, Canada, 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, Erin O'Ferrall, MD, McGill University, and Montreal Neurological Institute Hospital, Montreal, 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

PGN-EDODM1 is an investigational peptide-conjugated oligonucleotide (PPMO) in clinical trials for myotonic dystrophy type 1 (DM1), based on PepGen’s enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology. EDOs are engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. PGN-EDODM1 binds to pathogenic CUG trinucleotide repeat expansions in DMPK mRNA, liberating MBNL1 protein through steric blocking and is expected to restore splicing of downstream transcripts: a central cause of DM1 pathology. Delivery to target tissues and correction of mis-splicing have been demonstrated in nonclinical models and in the FREEDOM-DM1 clinical trial (NCT06204809).

The FREEDOM-DM1 Phase 1 single-ascending dose study demonstrated dose-dependent improvements in mean splicing correction 28 days postdose of 12.3%, 29.1% and 53.7% at 5 mg/kg, 10mg/kg and 15mg/kg, respectively (22-gene panel), substantially higher than previously reported in people with DM1. No significant changes in muscle function were observed after a single dose. PGN-EDODM1 was generally well-tolerated at 15 mg/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 were asymptomatic and resolved without intervention within 48 hours of dosing.

Further splicing improvement with repeat doses administered every 4 weeks may be anticipated. Dose dependent increases in muscle concentrations of PGN-EDODM1 were measured 28 days postdose in FREEDOM-DM1, offering potential for accumulation of oligonucleotide on repeat dosing. Single doses of PGN-EDODM1 to HSALR mice resulted in dose-dependent correction of mis-splicing and improvement in myotonia that was enhanced on repeat dosing every 4 weeks.

FREEDOM2-DM1 is an ongoing multiple ascending dose study of PGN-EDODM1 in adults with DM1 (NCT06667453). Three ascending dose levels will be studied (n=8, randomized 3:1); each cohort will receive 4 doses administered every 4 weeks. Endpoints include safety, tolerability, pharmacokinetics, pharmacodynamics (correction of mis-splicing), and multiple measures of function.