296 - MaP Natural History Study: Clinical and Biomarker Findings in Propionic Acidemia

Monday, May 1, 2023

9:30 AM – 11:30 AM ET

Poster Number: 296
Publication Number: 296.407

Bernd Schwahn, Manchester Centre for Genomic Medicine, Manchester, England, United Kingdom; Gerard T. Berry, Boston Children's Hospital, Boston, MA, United States; Saikat Santra, Birmingham Children's Hospital, Birmingham, England, United Kingdom; Hilary Vernon, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Hong li, Emory University School of Medicine, Atlanta, GA, United States; J Lawrence Merritt, University of Washington School of Medicine, Seattle, WA, United States; Manuel Schiff, Assistance Publique Hôpitaux de Paris, Paris, Ile-de-France, France; Brigitte Chabrol, AP-HM, CHU Timone, Marseille Cedex 05, Provence-Alpes-Cote d'Azur, France; Javier De las Heras, Hospital Universitario Cruces, Bilbao, Pais Vasco, Spain; Jerry Vockley, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Chung Lee, Stanford University School of Medicine, Palo Alto, CA, United States; Dwight Koeberl, Duke University School of Medicine, Durham, NC, United States; Barbara K. Burton, Northwestern University The Feinberg School of Medicine, Chicago, IL, United States; Stephanie Grunewald, Great Ormond Street Hospital, London, England, United Kingdom; George A. Diaz, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Can Ficicioglu, The Children's Hospital of Philadelphia, Philadelphia, PA, 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: Propionic acidemia (PA) is a rare, inherited metabolic disorder caused by deficiency in the propionyl CoA carboxylase (PCC) enzyme that typically presents in infants. PA is characterized by accumulation of toxic metabolites, including 2-methylcitrate (2-MC), 3-hydroxypropionate (3-HP), and propionylcarnitine (C3) and recurrent life-threatening acute metabolic decompensation events (MDEs). No effective targeted therapy for PA is currently available.

Objective:

To characterize the natural history of PA.

Design/Methods: The MaP study (NCT03484767) was an observational, longitudinal, exploratory, natural history study of patients in North America and Europe with PA or methylmalonic acidemia due to MUT deficiency. The PA cohort included patients of any age with a confirmed diagnosis of PA with variants in PCCA or PCCB genes. Data were collected prospectively from time of enrollment up to 36 months and retrospectively from medical records from the previous 12 months.

Results: Of 50 patients with PA, 22 had PCCA variants and 28 had PCCB variants. Median age at enrollment was 9.15 (range, 0.2-35.6) years; 52% were female. Median age at disease onset was 0.53 (0.0-145.8) months; 78% of patients had early-onset disease (first MDE at age ≤3 months). Median age at diagnosis was 2.92 (0.0-285.5) months; diagnosis was based on clinical presentation (78%), newborn screening (16%), and family history (6%). Most patients (98%) reported MDEs; overall mean annualized MDE frequency was 1.01 (standard deviation [SD], 1.6). Patients with early-onset disease had a higher mean annualized MDE frequency (1.17 [SD, 1.8]) than patients with late-onset disease (first MDE at age >3 months; 0.34 [SD, 0.4]). Mean annualized frequency of MDEs decreased with age, from 2.58 (SD, 2.7) in patients aged ≤1 year to 0.63 (SD, 0.7) in patients aged >18 years. Mean annualized MDE frequency was lower in patients who received a liver transplant (n=8; 0.51 [SD, 0.8]) than those who did not (n=41; 1.05 [SD, 1.7]). While there was no association between disease biomarkers and hospitalization for all causes, higher levels of plasma 3-HP and C3 were associated with more frequent MDEs. The frequency of MDEs was significantly higher among patients with the highest tertile of 3-HP compared with the lowest tertile (relative risk [RR], 2.80; 95% confidence interval [CI], 1.09-7.21; P</em>< 0.05). The RR of MDE was reduced by 38% with a 50% reduction in C3 level (RR, 0.62; 95% CI, 0.42-0.92; P< 0.05).

Conclusion(s):

This study highlights the clinical course of PA and potential MDE biomarkers; findings can inform future interventional studies. Funded by Moderna, Inc.