Objective:

The primary objective of this single-ascending dose (SAD) study is to evaluate the safety and tolerability of PGN-EDODM1 in adults living with DM1. Secondary and exploratory objectives include pharmacokinetics (PK), muscle distribution, pharmacodynamics (changes in splicing pattern of transcripts), and select functional outcome measures.

Background:

PepGen’s Enhanced Delivery Oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDODM1 is being evaluated for the treatment of DM1. PGN-EDODM1 binds to the pathogenic CUG repeat expansion in DMPK mRNA and reduces sequestration of Muscleblind (MBNL) proteins through a steric blocking mechanism. Release of MBNL proteins is hypothesized to correct DM1 spliceopathy; the root cause of DM1.

Design/Methods:

Males and females 18-50 years of age, inclusive, with genetically confirmed diagnosis of DM1 will be eligible to participate, and will be randomized 3:1 (6 active, 2 placebo) to receive PGN-EDODM1 or placebo in each dose cohort. A muscle needle biopsy (tibialis anterior) will be performed at baseline and at Weeks 4 and 16 post-dosing for measurement of splicing of selected transcripts. An independent data safety and monitoring committee will oversee dose escalation.

Results:

The doses to be assessed will be based on data from the preclinical data and data from the Phase 1 healthy volunteer safety study of our lead EDO, PGN-EDO51. A plan for analysis of safety measures such as vital signs, electrocardiograms, clinical chemistry, urinalysis, and biomarkers will be presented, along with details on proposed functional endpoints and biomarkers to be explored in this study.

Conclusions:

This Phase 1 SAD clinical study will support continued development of PGN-EDODM1 for the treatment of DM1, and will be initiated in 2023. Participants will be invited to enroll in a planned multiple-ascending dose study (MAD) and a subsequent open-label extension study.