297 - MaP Natural History Study: Clinical and Biomarker Findings in Methylmalonic Acidemia Due to Mut Deficiency

Monday, May 1, 2023

9:30 AM – 11:30 AM ET

Poster Number: 297
Publication Number: 297.407

Manuel Schiff, Assistance Publique Hôpitaux de Paris, Paris, Ile-de-France, France; Bernd Schwahn, Manchester Centre for Genomic Medicine, Manchester, England, United Kingdom; Brigitte Chabrol, AP-HM, CHU Timone, Marseille Cedex 05, Provence-Alpes-Cote d'Azur, France; J Lawrence Merritt, University of Washington School of Medicine, Seattle, WA, United States; Jerry Vockley, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Hilary Vernon, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Gerard T. Berry, Boston Children's Hospital, Boston, MA, United States; Saikat Santra, Birmingham Children's Hospital, Birmingham, England, United Kingdom; Chung Lee, Stanford University School of Medicine, Palo Alto, CA, United States; Dwight Koeberl, Duke University School of Medicine, Durham, NC, United States; Hong li, Emory University School of Medicine, Atlanta, GA, United States; Barbara K. Burton, Northwestern University The Feinberg School of Medicine, Chicago, IL, United States; Javier De las Heras, Hospital Universitario Cruces, Bilbao, Pais Vasco, Spain; George A. Diaz, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Mariana Faria-Urbina, Moderna, Hopkinton, MA, United States; Junxiang Luo, Moderna, Basking Ridge, NJ, United States; Husain Z. Attarwala, Moderna, Cambridge, MA, United States; Vanja Sikirica, Moderna, Devon, PA, United States; Min Liang, Moderna, Belmont, MA, United States; Lin Guey, Moderna, Cambridge, MA, United States; Christine Lukacs, Moderna, Cambridge, MA, United States; Paolo GV. martini, Moderna Inc, Cambridge, MA, United States; Ruchira Glaser, Moderna, Haverford, PA, United States; Nuria Carrillo, Moderna, Inc., Cambridge, MA, United States

Presenting Author(s)

NC

Nuria Carrillo, MD (she/her/hers)

Moderna, Inc.
Cambridge, Massachusetts, United States

Background: Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency (MMA-MUT) is a rare inherited metabolic disorder typically diagnosed in infants and characterized by accumulation of methylmalonic acid and other toxic metabolites and recurrent, life-threatening, acute metabolic decompensation events (MDEs). No effective therapy for MMA-MUT is currently available and outcomes remain poor.

Objective: To characterize the natural history of MMA-MUT.

Design/Methods: The MaP study (NCT03484767) was an observational, longitudinal, exploratory, natural history study of patients in North America and Europe with MMA-MUT or propionic acidemia. The MMA-MUT cohort included patients of any age with a confirmed diagnosis of MMA with complete (mut⁰) or partial (mut^–) MUT deficiency. Data were collected prospectively from time of enrollment to 36 months and retrospectively from medical records from the previous 12 months.

Results: Of 45 patients in the MMA-MUT cohort, 32 (71%) had mut⁰ and 10 (22%) had mut^– subtype; 3 (7%) were missing subtype data. Median age at enrollment was 9.30 (range, 0.3-35.2) years; 60% of patients were female. Median age at disease onset was 0.51 (0.0-65.2) months and at time of diagnosis was 4.63 (0.0-122.9) months. One patient (2%) died during the study due to respiratory arrest and chronic renal failure. Most patients (93%) reported MDEs; overall mean annualized MDE frequency was 0.76 (standard deviation [SD], 1.1) and was lower in patients with mut^– (0.53) than mut⁰ (0.89) subtype. Mean annualized frequency of MDEs decreased with age, from 1.82 (SD, 1.6) in patents aged ≤1 year to 0.47 (SD, 0.2) in those aged >18 years. Median plasma methylmalonic acid levels were higher for patients without transplant (398.5 µmol/L) vs with liver (228.5 µmol/L) or combined liver/kidney (292.0 µmol/L) transplant, and higher during MDE (4975.0 µmol/L) vs non-MDE (371.0 µmol/L) visits. Higher levels of plasma 2-methylcitrate (2-MC) and propionylcarnitine (C3) were associated with more frequent MDEs. Relative risk (RR) of MDE was reduced by 41% with a 50% decrease in 2-MC level (RR, 0.60; 95% CI, 0.42-0.84; P< 0.01) and by 37% with a 50% reduction in C3 level (RR, 0.63; 95% CI, 0.47-0.86; P< 0.01). The RR of hospitalization was reduced by 35% with a 50% reduction in 2-MC level (RR, 0.66; 95% CI, 0.52-0.82; P< 0.001), and by 31% with a 50% reduction in C3 level (RR, 0.69; 95% CI, 0.54-0.89; P< 0.01).

Conclusion(s):

This study highlights the clinical course of MMA-MUT and potential MDE biomarkers. The findings can inform future interventional studies. Funded by Moderna, Inc.