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

Study Overview
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Brief Summary
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This First-in-Human (FIH) Phase 1/2 study will evaluate the safety, pharmacological activity, and efficacy of mRNA-3927 in participants 1 year of age and older with genetically confirmed propionic acidemia (PA). This study is designed to characterize the safety, tolerability, and pharmacological activity (as assessed by biomarker measurements) and to determine the optimal dose of mRNA-3927 in participants with PA. After establishing a dose with acceptable safety and pharmacodynamic (PD) response in a Dose Optimization Part (Part 1), additional participants will be enrolled into the study in a Dose Expansion Part (Part 2) to allow for further characterization of the efficacy, safety, and PD of mRNA-3927.

Detailed Description
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During the Dose Optimization Stage, after each dose cohort is fully enrolled, 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 acceptable safety and pharmacodynamic activity in a Dose Optimization Part (Part 1), additional participants will be enrolled into the study in a Dose Expansion Part (Part 2) to allow for further characterization of the safety, efficacy, and pharmacodynamics of mRNA-3927. Participants in both phases of study will participate in a predosing observational period, followed by a treatment period, and then a follow-up period after withdrawal of treatment.

Official Title
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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

Conditions
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Propionic Acidemia

Intervention / Treatment
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* Biological: mRNA-3927


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be ≥ 8 years of age at the time of consent/assent if enrolled as 1 of the first 2 participants in Part 1. Participant must be ≥1 year of age at the time of consent/assent if enrolled after the first 2 participants. Confirmed diagnosis of PA based on diagnosis by molecular genetic testing (PCCA and/or PCCB mutations). Part 2 only: At least one documented MDE in the 12-month period before consent. Exclusion Criteria: Estimated glomerular filtration rate <30 milliliters (mL)/minute/1.73 square meter (m^2) as estimated by Schwartz formula for participants < 18 years of age or the Chronic Kidney Disease Epidemiology Collaboration creatinine based formula for participants ≥ 18 years of age or 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. COVID-19 vaccination (generally 2 doses or a booster) within 6 weeks between their last COVID-19 vaccination dose and first study drug administration.

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Optimization and Part 2: Dose Expansion<br>Part 1 (Dose Optimization): Participants will receive single dose of mRNA-3927 by intravenous (IV) infusion every 2 weeks (Q2W) or every 3 weeks (Q3W) or every 4 weeks (Q4W) for up to 10 doses. Part 2 (Dose Expansion): Participants will receive single dose of mRNA-3927 (identified during Dose Optimization Phase) by IV infusion Q2W or Q3W or Q4W for up to 12 months. | Biological: mRNA-3927<br>* mRNA-3927 dispersion for IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants with an Adverse Event (AE), Serious AE (SAE) and AE Leading to Discontinuation |  | Day 1 (initial mRNA-3927 dose) up to Week 150 (End of Study) | 
| Part 2: Number of Metabolic Decompensation Events (MDEs) |  | Up to 53 Weeks (14 days after the last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Change in Plasma 2-Methylcitrate (2-MC) Level and Plasma 3-Hydroxypropionic Acid (3-HP) Level After Single and Repeated Administrations of mRNA-3927 | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | 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 | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | 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 | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | Baseline up to Week 40 | 
| Part 1: Duration of Response (DOR) after Single and Repeated Administrations of mRNA-3927 | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | 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 | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | Day 1 through Day 22 | 
| Part 1: Time of Cmax (Tmax) of PCCA and PCCB mRNAs | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | Day 1 through Day 22 | 
| Part 1: Area Under the Plasma Concentration-Time Curve (AUC) of PCCA and PCCB mRNAs | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | Day 1 through Day 22 | 
| Part 1: SM-86 Concentration after Single and Repeated Administrations of mRNA-3927 | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | Day 1 through Day 8 | 
| Part 1: Frequency of Anti-Polyethylene Glycol Antibodies |  | Up to Week 150 (End of Study) | 
| Part 2: Duration of MDEs |  | Up to 53 Weeks (14 days after the last dose) | 
| Part 2: Number of PA-related Hospitalizations |  | Up to 53 Weeks (14 days after the last dose) | 
| Part 2: Number of PA-related Complications |  | Baseline up to Week 53 (14 days after last dose) | 
| Part 2: Change from Baseline in Prescribed Protein Intake up to Week 54 |  | Baseline up to Week 53 (14 days after last dose) | 
| Part 2: Change from Baseline in Pediatric Quality of Life Inventory (PedsQL) Score up to Day 180 |  | Baseline up to Week 53 (14 days after last dose) | 
| Part 2: Change from Baseline in PedsQL Family Impact Module Score up to Day 180 |  | Baseline up to Week 53 (14 days after last dose) | 
| Part 2: Change from Baseline in Investigator Global Assessment of Improvement (IGA-I) Score up to Day 180 |  | Baseline up to Week 53 (14 days after last dose) | 
| Part 2: Change from Baseline in Investigator Global Assessment of Severity (IGA-S) Score up to Day 180 |  | Baseline up to Week 53 (14 days after last dose) | 
| Part 2: Change in 3-HP Level After Administrations of mRNA-3927 |  | Baseline up to Week 40 | 
| Part 2: Change in 2-MC Level After Administrations of mRNA-3927 |  | Baseline up to Week 40 | 
| Part 2: Change from Baseline in Metabolic Biomarkers up to Week 40 | Metabolic biomarkers will include C3, Glycine and Propionylglycine. | Baseline up to Week 40 | 
| Part 2: Emax of 2-MC and 3-HP after Administrations of mRNA-3927 |  | Baseline up to Week 40 | 
| Part 2: AUEC of 2-MC and 3-HP after Administrations of mRNA-3927 |  | Baseline up to Week 40 | 
| Part 2: DOR after Administrations of mRNA-3927 |  | Baseline up to Week 40 | 
| Part 2: Cmax of PCCA and PCCB mRNAs | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | Day 1 through Day 22 | 
| Part 2: Tmax of PCCA and PCCB mRNAs | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | Day 1 through Day 22 | 
| Part 2: AUC of PCCA and PCCB mRNAs | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | Day 1 through Day 22 | 
| Part 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs), SAEs, AESIs and TEAEs Leading to Treatment Discontinuation |  | Day 1 (initial mRNA-3927 dose) up to Week 82 (End of Study) | 
| Part 2: Frequency of Anti-Polyethylene Glycol Antibodies |  | Day 1 (initial mRNA-3927 dose) up to Week 82 (End of Study) | 
| Part 2: SM-86/Polyethylene Glycol Conjugate (OL-56) Concentration | Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927 | Day 1 through Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mRNA-3927, Propionic Aciduria, Metabolism, Inborn Errors, Genetic Diseases, Inborn Amino Acid Metabolism, Inborn Errors, Acidosis, Acid-Base Imbalance, Metabolic Diseases, Organic Acidemias, Moderna, mRNA