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

Nature volume 628, pages 872–877 (2024)Cite this article

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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.

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Fig. 1: PCCA and PCCB genes, the propionate pathway and the mechanism of action of mRNA-3927.
Fig. 2: Dose-optimization study design and participant information.
Fig. 3: PK exposure to PCCA mRNA after dose 1 (PK analysis population).
Fig. 4: MDE profiles (intention-to-treat population).

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Access to patient-level data and supporting clinical documents with qualified external researchers may be available upon request and subject to review once the trial is complete.

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Acknowledgements

We thank all research teams and nurses, including M. Xu, E. Raffman, K. Ha and H. Meghari. Medical writing and editorial support were provided by L. Watts and were funded by Moderna.

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Authors and Affiliations

  1. Duke University School of Medicine, Durham, NC, USA

    Dwight Koeberl

  2. Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada

    Andreas Schulze & Neal Sondheimer

  3. University of California at Los Angeles (UCLA), Los Angeles, CA, USA

    Gerald S. Lipshutz

  4. University of Birmingham, Birmingham, UK

    Tarekegn Geberhiwot

  5. Moderna, Inc., Cambridge, MA, USA

    Lerong Li, Rajnish Saini, Junxiang Luo, Vanja Sikirica, Ling Jin, Min Liang & Mary Leuchars

  6. Great Ormond Street Hospital for Children and Institute for Child Health, NIHR Biomedical Research Centre, London, UK

    Stephanie Grunewald

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Contributions

D.K. and A.S. conducted the study, acquired data and reviewed and edited the manuscript. N.S. acquired data and edited the manuscript. G.S.L. and T.G. conducted the study, acquired the data and reviewed and edited the manuscript. L.L., R.S., J.L., L.J. and M. Leuchars conducted the study, analysed the data and reviewed and edited the manuscript. V.S. contributed to the conceptualization and design of the study, endpoint development and selection, data interpretation, and review and editing of the manuscript. M. Liang analysed the data and reviewed and edited the manuscript. S.G. consulted on the design of the study, conducted the study, acquired data and reviewed and edited the manuscript. All authors approved the final version of the manuscript and vouch for the accuracy and completeness of the data.

Corresponding author

Correspondence to Stephanie Grunewald.

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Competing interests

D.K. is a consultant for Amicus, Genzyme Sanofi, Sangamo Therapeutics, Takeda and Vertex; is a grant support recipient from Amicus, Genzyme Sanofi, Roivant Rare Diseases and Viking Therapeutics; and has equity in AskBio–Bayer. A.S. is an investigator and consultant for Moderna, Ultragenyx and iEcure; and is a consultant and/or advisory board member for Aeglea, Beam, Ceres Brain, Horizon, iEcure, MTPharma, Recordati and Satellite Bio. N.S. was an investigator and consultant for Moderna at the time of the study and is a current employee of Synlogic. G.S.L. has research grants from Moderna and has served as a consultant for Audentes Therapuetics, Taysha Therapeutics and Tenaya Therapeutics. T.G. is an investigator for Moderna. L.L., R.S., J.L., V.S., L.J. and M. Liang are employees of Moderna and hold stock or stock options in the company. At the time of the study, M. Leuchars was an employee of Moderna and held stock or stock options in the company. S.G. is an investigator, consultant, advisory board member and recipient of travel reimbursements for Moderna, and consults for BridgeBio, Glycomine, Jaguar, Orphazyme and Ultragenyx.

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Nature thanks Cary Harding and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Table 1 Participant exposure (safety population)
Full size table
Extended Data Table 2 PK parameter summary statistics of serum PCCA mRNA after dose 1 (PK analysis population)
Full size table
Extended Data Table 3 Biomarker percentage change from baseline after the third dose
Full size table
Extended Data Table 4 Summary of MDEs (intention-to-treat population)
Full size table

Supplementary information

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Koeberl, D., Schulze, A., Sondheimer, N. et al. Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia. Nature 628, 872–877 (2024). https://doi.org/10.1038/s41586-024-07266-7

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