Open-Label Study of mRNA-3927 in Participants With Propionic Acidemia

Official title

A Global, Phase 1/2, Open-Label, Dose Optimization Study to Evaluate the Safety, Pharmacodynamics, and Pharmacokinetics of mRNA-3927 in Participants With Propionic Acidemia

Overview

This 3-part, Phase 1/2 study is designed to characterize the safety, tolerability, and pharmacological activity (as assessed by biomarker measurements) and to determine the selected dose of mRNA-3927 in participants with genetically confirmed propionic acidemia (PA). After establishing a dose with an acceptable safety and pharmacodynamic (PD) response for participants ≥1 year of age in Part 1, participants will be enrolled in Part 2 (which will serve as the pivotal study) to allow for determination of the efficacy, safety, and PD of mRNA-3927. Part 3 will evaluate the safety, efficacy and PD response of mRNA-3927 in infants (\<1 year of age).

Detailed description

During the Dose Optimization Stage, after each dose cohort is fully enrolled (≥1 year of age), and the dose-limiting toxicity (DLT) observation window of at least 14 days is complete for the final participant in that cohort, the Sponsor will review the totality of available safety data in conjunction with all available PK/PD data. Based on this review, the Sponsor will recommend a revised dose and/or dosing interval. The Sponsor will abide by predefined constraints as to the maximum percentage change in dose and dose interval. A maximum of 9 cohorts will be enrolled in Part 1 (Dose Optimization).

Upon establishment of a dose with an acceptable safety and PD activity in Part 1 (participants ≥1 year of age), additional participants will be enrolled into the study in Part 2 (participants ≥1 year of age) to allow for determination of the safety, efficacy, and PD of mRNA-3927. Part 3 will evaluate the safety, efficacy and PD response in infants (\<1 year of age).

Participants in all the phases will participate in a predosing observational period, followed by a treatment period, and then a follow-up period after withdrawal of treatment.

Interventions

• Biological mRNA-3927
  mRNA-3927 dispersion for IV infusion

Primary outcome measures

• Part 1: Number of Participants with Treatment-emergent Adverse Event (TEAE), Serious Adverse Events (SAE) and TEAEs Leading to Discontinuation [Time frame: Day 1 (initial mRNA-3927 dose) up to Week 150 (End of Study)]
• Part 2: Change in Annualized Frequency of Clinical Event Committee (CEC)-adjudicated Metabolic Decompensation Events (MDEs) During 12-month Treatment Period With mRNA-3927 Compared to Annualized Frequency of CEC-adjudicated MDE During Pretreatment Period [Time frame: Pretreatment period (12 months before consent to first mRNA-3927 dose in the study) up to Month 12]
• Part 3: Number of Participants with TEAEs, SAEs, Adverse Events (AEs) of Special Interest (AESIs) and TEAEs Leading to Discontinuation [Time frame: Day 1 up to Week 73]

Secondary outcome measures (12)

• Part 1: Change From Baseline in Plasma 2-Methylcitrate (2-MC) and 3-Hydroxypropionic Acid (3-HP) Levels After Single and Repeated Administrations of mRNA-3927 [Time frame: Baseline up to Week 40]
• Part 1: Maximum Observed Effect (Emax) of 2-MC and 3-HP After Single and Repeated Administrations of mRNA-3927 [Time frame: Baseline up to Week 40]
• Part 1: Area Under the Effect Versus Time Curve (AUEC) of 2-MC and 3-HP After Single and Repeated Administrations of mRNA-3927 [Time frame: Baseline up to Week 40]
• Part 1: Duration of Response (DOR) After Single and Repeated Administrations of mRNA-3927 [Time frame: Baseline up to Week 40]
• Part 1: Maximum Observed Concentration (Cmax) of Propionyl-CoA Carboxylase Subunit α (PCCA) and Propionyl-CoA Carboxylase Subunit β (PCCB) mRNAs [Time frame: Baseline up to Week 40]
• Part 1: Time of Cmax (Tmax) of PCCA and PCCB mRNAs [Time frame: Baseline up to Week 40]
• Part 1: Area Under the Plasma Concentration-Time Curve (AUC) of PCCA and PCCB mRNAs [Time frame: Baseline up to Week 40]
• Part 1: SM-86 Concentration After Single and Repeated Administrations of mRNA-3927 [Time frame: Baseline up to Week 40]
• Part 1: Frequency of Anti-Polyethylene Glycol and Anti-Propionyl-CoA Carboxylase Antibodies [Time frame: Day 1 (initial mRNA-3927 dose) up to Week 150 (End of Study)]
• Part 2: Change in Annualized Frequency of CEC-adjudicated MDE-related Hospitalizations During the 12-month Treatment Period With mRNA-3927 Compared to the Annualized Frequency of CEC-adjudicated MDE-related Hospitalizations During the Pretreatment Period [Time frame: Pretreatment period (12 months before consent to first mRNA-3927 dose in the study) up to Month 12]
• Part 2: Change in Annualized Frequency of CEC-adjudicated PA-related Hospitalizations During the 12-month Treatment Period With mRNA-3927 Compared to the Annualized Frequency of CEC-adjudicated PA-related Hospitalizations During the Pretreatment Period [Time frame: Pretreatment period (12 months before consent to first mRNA-3927 dose in the study) up to Month 12]
• Part 2: Change in Annualized Frequency of CEC-adjudicated MDEs During 12-month Treatment Period With mRNA-3927 Compared to Annualized Frequency of CEC-adjudicated MDE During Pretreatment Period by the Following Severity Grades: Grade 1, Grade 2, Grade 3 [Time frame: Pretreatment period (12 months before consent to first mRNA-3927 dose in the study) up to Month 12]

Eligibility criteria

Inclusion criteria

Participants ≥1 year of age are eligible to be included in the study only if all of the following criteria apply:

• ≥ 8 years of age at the time of consent/assent if enrolled as 1 of the first 2 participants in Part 1.
• ≥1 year of age at the time of consent/assent if enrolled after the first 2 participants in Part 1.
• Confirmed diagnosis of PA based on diagnosis by molecular genetic testing via central laboratory (PCCA and/or PCCB mutations).
• Part 2 only: At least one documented MDE in the 12-month period before consent.

Participants <1 Year of Age :

• Identification by newborn screening shortly after birth or having suspected PA by presenting with a spectrum of metabolic symptoms, and having a sibling diagnosed with PA. Participant may enter the Screening Period while awaiting genetic testing results, provided that all other eligibility criteria are met but would not be enrolled until diagnosis of PA is confirmed.
• For infants in the neonatal intensive care unit (NICU) only: ≥37 weeks gestational age at the time of birth without other conditions/comorbidities that in the opinion of the Investigator may interfere with the interpretation of study results.
• Body weight ≥3 kilograms (kg) at Screening.
• At least 1 documented PA-related event prior to Screening defined as the following criteria:

• Clinical signs of metabolic deterioration consistent with PA (for example, vomiting, not feeding well/poor suck, heavy breathing, lethargy, absence of proper perfusion, abnormal movements including bicycling, abnormal tone, low body temperature, seizure\[s\]), OR
• Meeting the criteria of MDE definition, OR
• Evidence of laboratory abnormalities as evidenced by at least one of the following:
• Metabolic acidosis with elevated anion gap.
• Acute hyperammonemia.
• Neutropenia or thrombocytopenia.

Exclusion criteria

Participants of all ages are excluded from the study if during Screening any of the following criteria apply:

• Any individual with laboratory abnormalities considered to be clinically significant (for example, markedly out of range, associated with clinical symptoms) in the Investigator or Sponsor's opinion that could interfere with or limit the participation in the study.
• Estimated glomerular filtration rate (eGFR) <30 milliliters (mL)/minute/1.73 square meter (m\^2) for participants of all ages receiving chronic dialysis.
• History of organ transplantation or planned organ transplantation during the period of study participation.
• Corrected QT interval (QTc) >480 milliseconds (ms) using Bazett's correction.
• Grade 3 or 4 heart failure according to the Modified Ross Heart Failure Classification for Children or the New York Heart Association Classification.
• Pregnant or breastfeeding.
• Other clinically significant conditions that in the Investigator's opinion could interfere with the safety of the participant, the interpretation of study results, or limit the participation in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 15 centers

• UCSD Altman Clinical and Transalational Research Institute Building — Los Angeles
• Ronald Reagan UCLA Medical Center — Los Angeles
• Lucile Packard Children's Hospital Stanford — Stanford
• Nicklaus Children's Hospital — Miami
• University of South Florida - 12901 Bruce B Downs — Tampa
• Ann and Robert H Lurie Childrens Hospital of Chicago — Chicago
• Johns Hopkins Hospital, Adult Outpatient Clinical Research Unit — Baltimore
• Boston Children's Hospital — Boston
• … and 7 more centers

Spain · 4 centers

• Hospital Sant Joan de Deu - PIN — Esplugues de Llobregat
• Hospital Universitario Cruces — Barakaldo
• Hospital Universitario 12 de Octubre — Madrid
• Hospital Universitario Virgen del Rocio - PPDS — Seville

United Kingdom · 4 centers

• University Hospital Birmingham NHS Foundation Trust — Birmingham
• Birmingham Children's Hospital — Birmingham
• Great Ormond Street Hospital for Children NHS Foundation Trust — London
• Willink Biochemical Genetics Unit - PPDS — Manchester

Japan · 3 centers

• Fujita Health University Hospital — Toyoake-shi
• Tohoku University Hospital — Sendai
• National Center for Child Health and Development — Tokyo

Saudi Arabia · 3 centers

• King Faisal Specialist Hospital & Research Center - Riyadh — Riyadh
• King Fahad Medical City — Riyadh
• King Abdullah Children's Specialist Hospital — Riyadh

Canada · 2 centers

• Stollery Children's Hospital University of Alberta — Edmonton
• Hospital For Sick Children — Toronto

France · 2 centers

• CHU de Marseille - Hôpital de la Timone — Marseille
• Hôpital Necker - Enfants Malades — Paris

Netherlands · 2 centers

• Erasmus MC — Rotterdam
• Universitair Medisch Centrum Utrecht - PPDS — Utrecht

Publications

• Attarwala H, Lumley M, Liang M, Ivaturi V, Senn J. Translational Pharmacokinetic/Pharmacodynamic Model for mRNA-3927, an Investigational Therapeutic for the Treatment of Propionic Acidemia. Nucleic Acid Ther. 2023 Apr;33(2):141-147. doi: 10.1089/nat.2022.0036. Epub 2022 Dec 27. PMID 36577040

Identifiers

NCT: NCT04159103 · mRNA-3927-P101 · 2022-502910-10-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗