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E - Disease Models and Clinical Applications -> Metabolic, Storage, Endocrine, Liver and Gastrointestinal Diseases

190: mRNA-3927 Therapy for Propionic Acidemia: Interim Data from a Phase 1/2 Study

Type: Oral Abstract Session

Presentation Details
Session Title: Metabolic, Storage, Endocrine, Liver and Gastrointestinal Diseases II
Location: Room 403 AB
Start Time: 5/18/2023 16:45
End Time: 5/18/2023 17:00

Background: Propionic acidemia (PA) is a rare and severe inherited metabolic disorder caused by pathogenic variants in the propionyl-coenzyme A carboxylase (PCC) α or β subunits (PCCA and PCCB genes, respectively) leading to PCC deficiency and subsequent accumulation of toxic metabolites. PA is characterized by recurrent life-threatening metabolic decompensation events (MDEs) and multisystemic complications. Currently, there are no effective therapies for PA that target the underlying enzyme defects. mRNA-3927 is an investigational dual mRNA therapy that encodes for PCCA and PCCB that has shown to restore functional PCC activity in preclinical models. Results from an interim analysis of the first-in-human trial of mRNA-3927 are reported here.
Methods: This ongoing global, phase 1/2, open-label, multicenter, dose-optimization trial (NCT04159103) evaluates the safety, tolerability, and pharmacology of mRNA-3927 in participants aged ≥1 year with genetically confirmed PA. The trial uses a staggered enrollment, dose-escalation approach to evaluate the intravenous administration of mRNA-3927. The initial dosing regimen was 0.3 mg/kg administered every 3 weeks (Q3W); subsequent doses were administered every 2 weeks (Q2W). Participants who complete the dose optimization trial (10 doses) are eligible to continue treatment in an open-label extension study (NCT05130437). Primary outcomes are safety and tolerability; secondary and exploratory outcomes include pharmacology and evaluation of potential plasma biomarkers and frequency and duration of MDEs, respectively.
Results: As of January 5, 2023, 14 participants were enrolled across 5 dose cohorts: 0.3 mg/kg Q3W (n=4), 0.3 mg/kg Q2W (n=3), 0.45 mg/kg Q2W (n=3), 0.6 mg/kg Q2W (n=3), and 0.9 mg/kg (n=1). Nine participants completed the study and enrolled in the open-label extension (0.3 mg/kg Q3W [n=3], 0.3 mg/kg Q2W [n=3], 0.45 mg/kg Q2W [n=3]). A total of 214 doses were administered across both studies with a median treatment duration of 27.3 weeks (range, 3.0-85.6). No dose-limiting toxicities or study discontinuations due to drug-related treatment-emergent adverse events (TEAEs) have occurred. Across both studies, drug-related TEAEs were reported in 5 patients; all were grade 1 or 2. Preliminary analyses for patients administered mRNA-3927 suggest reductions in plasma biomarker levels. Additionally, in participants who reported MDEs in the 12 months prior to dosing, reductions in number and duration of MDEs were observed after the start of treatment with mRNA-3927.
Conclusion: To date, mRNA-3927 has been well-tolerated at the doses administered, with encouraging early signs of dose-dependent pharmacology and potential clinical benefit.

Stephanie Grunewald1, Saikat Santra2, Dwight Koeberl3, Andreas Schulze4, Neal Sondheimer4, Ayesha Ahmad5, Gerald S. Lipshutz6, Tarekegn Geberhiwot7, Min Liang8, Lerong Li8, Ruchira Glaser8, Nuria Carrillo8

1Great Ormond Street Hospital for Children and Institute for Child Health, NIHR Biomedical Research Center, London, United Kingdom,2Birmingham Women’s and Children's NHS Foundation Trust, Birmingham, United Kingdom,3Duke University Medical Center, Durham, NC,4Hospital for Sick Children and University of Toronto, Toronto, ON, Canada,5University of Michigan, Ann Arbor, MI,6David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA,7University of Birmingham, Birmingham, United Kingdom,8Moderna, Inc., Cambridge, MA
  G.S. Lipshutz: 1; Commercial Interest i.e. Company X; Moderna, Inc.. 1; What was received? i.e. Honorarium; Research Grants. 1; For what role? i.e. Speaker; Research.

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