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Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia

Author

Listed:
  • Dwight Koeberl

    (Duke University School of Medicine)

  • Andreas Schulze

    (Hospital for Sick Children and University of Toronto)

  • Neal Sondheimer

    (Hospital for Sick Children and University of Toronto)

  • Gerald S. Lipshutz

    (University of California at Los Angeles (UCLA))

  • Tarekegn Geberhiwot

    (University of Birmingham)

  • Lerong Li

    (Inc.)

  • Rajnish Saini

    (Inc.)

  • Junxiang Luo

    (Inc.)

  • Vanja Sikirica

    (Inc.)

  • Ling Jin

    (Inc.)

  • Min Liang

    (Inc.)

  • Mary Leuchars

    (Inc.)

  • Stephanie Grunewald

    (NIHR Biomedical Research Centre)

Abstract

Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we report interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. As of 31 May 2023, 16 participants were enrolled across 5 dose cohorts. Twelve of the 16 participants completed the dose-optimization study and enrolled in the extension study. A total of 346 intravenous doses of mRNA-3927 were administered over a total of 15.69 person-years of treatment. No dose-limiting toxicities occurred. Treatment-emergent adverse events were reported in 15 out of the 16 (93.8%) participants. Preliminary analysis suggests an increase in the exposure to mRNA-3927 with dose escalation, and a 70% reduction in the risk of metabolic decompensation events among 8 participants who reported them in the 12-month pretreatment period.

Suggested Citation

  • Dwight Koeberl & Andreas Schulze & Neal Sondheimer & Gerald S. Lipshutz & Tarekegn Geberhiwot & Lerong Li & Rajnish Saini & Junxiang Luo & Vanja Sikirica & Ling Jin & Min Liang & Mary Leuchars & Steph, 2024. "Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia," Nature, Nature, vol. 628(8009), pages 872-877, April.
    • Handle: RePEc:nat:nature:v:628:y:2024:i:8009:d:10.1038_s41586-024-07266-7
    DOI: 10.1038/s41586-024-07266-7
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