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

Propionic Acidemia Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04159103
• Other study ID #: mRNA-3927-P101
• Secondary ID: 2022-502910-10
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: April 15, 2021
• Est. completion date: January 6, 2027

Study information

• Verified date: April 2024
• Source: ModernaTX, Inc.
• Contact: Moderna Clinical Trials Support Center
• Phone: 1-877-777-7187
• Email: clinicaltrials[@]modernatx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This First-in-Human (FIH) Phase 1/2 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 genetically confirmed propionic acidemia (PA). After establishing a dose with acceptable safety and pharmacodynamic (PD) response in a Dose Optimization Group (Part 1) in participants ≥1 year of age, additional participants will be enrolled into the study in a Dose Expansion Group (Part 2) to allow for further characterization 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).

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 acceptable safety and PD activity in a Dose Optimization Part (Part 1), additional participants (≥1 year of age) will be enrolled into the study in a Dose Expansion Part (Part 2) to allow for further characterization 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 68
• Est. completion date: January 6, 2027
• Est. primary completion date: March 5, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

• 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.

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.

• =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 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 (eg, 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 (decreased pH) with high anion gap, or compensated metabolic acidosis (reduced bicarbonate, or base deficit, or reduced PaCO2 or increased lactate) with high 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 achieving theresholds defined in the protocol

• 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.

Related Conditions & MeSH terms

• Acidosis
• Propionic Acidemia

Intervention

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

Locations

Country	Name	City	State
Canada	Stollery Children's Hospital University of Alberta	Edmonton	Alberta
Canada	Hospital For Sick Children	Toronto	Ontario
United Kingdom	University Hospital Birmingham NHS Foundation Trust	Birmingham
United Kingdom	Great Ormond Street Hospital (GOSH)	London
United Kingdom	Willink Biochemical Genetics Unit	Manchester
United States	University of Michigan	Ann Arbor	Michigan
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Texas Children's Hospital	Houston	Texas
United States	David Geffen School of Medicine UCLA	Los Angeles	California
United States	Icahn School of Medicine at Mount Sinai - Clinical Research Unit	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Stanford Medical Center	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
ModernaTX, Inc.

Countries where clinical trial is conducted

United States,  Canada,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	Part 2: Number of Metabolic Decompensation Events (MDEs)		Day 1 up to Week 53
Primary	Part 3: Number of Participants with Treatment- emergent Adverse Event (TEAEs), SAEs, AEs of Special Interest and TEAEs Leading to Discontinuation		Day 1 up to Week 82
Secondary	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	Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927	Baseline up to Week 40
Secondary	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
Secondary	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
Secondary	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
Secondary	Part 1: Maximum Observed Concentration (Cmax) of Propionyl-CoA Carboxylase Subunit a (PCCA) and Propionyl-CoA Carboxylase Subunit ß (PCCB) mRNAs	Baseline (predose levels) to postdose levels measured after single and after repeated administrations of mRNA-3927	Day 1 through Day 22
Secondary	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
Secondary	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
Secondary	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
Secondary	Part 1: Frequency of Anti-Polyethylene Glycol Antibodies		Day 1 (initial mRNA-3927 dose) up to Week 150 (End of Study)
Secondary	Part 2: Number of PA-related Hospitalizations		Day 1 up to Week 53
Secondary	Part 2: Change from Baseline in Pediatric Quality of Life Inventory (PedsQL) Physical Function Score		Baseline, Week 53
Secondary	Part 2: Change from Baseline in Methylmalonic Acidemia and Propionic Acidemia Questionnaire - Proximal Signs and Symptoms (MMAPAQ-PSS) Total Score		Baseline, Week 53
Secondary	Part 3: Change from Baseline in PedsQL Physical Function Score		Baseline, Week 53
Secondary	Part 3: Change from Baseline in MMAPAQ-PSS Total Score		Baseline, Week 53
Secondary	Part 3: Number of MDEs		Day 1 up to Week 53
Secondary	Part 3: Number of PA-related Hospitalizations		Day 1 up to Week 53