Clinical trial NCT04899310: A Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of mRNA-3705 in Participants With Isolated Methylmalonic Acidemia
Official title: A Global, Phase 1/2, Open-Label, Dose Optimization Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of mRNA-3705 in Participants With Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Methylmalonic Acidemia
Keywords: Isolated Methylmalonic acidemia
Isolated methylmalonic aciduria
elevated methylmalonic acid (MMA)
Metabolism, Inborn Errors
Genetic Diseases
Moderna
mRNA
mRNA-3705
Lead sponsor: ModernaTX, Inc.
Sponsor class: INDUSTRY
First posted: 2021-05-24
Enrollment: 63
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a study of mRNA-3705 in participants with isolated elevated methylmalonic acid (MMA) due to methylmalonyl-coenzyme A (CoA) mutase (MUT) deficiency. The main goal of the study is to assess safety, pharmacokinetics, and pharmacodynamics of mRNA-3705.

Detailed description: This study comprises 2 parts: Dose Optimization part (Part 1) followed by a Dose Expansion part (Part 2). The study is designed to evaluate multiple doses and dosing intervals of mRNA-3705.

In both parts, after confirmation of eligibility, participants will enter an Observation Period (48 to 72 hours pre-dose) in Part 1 and 24 hours before dose 1 in Part 2), followed by the Treatment Period. Participants who complete the Treatment Period, including the End of Treatment (EOT) Visit, are offered participation in the mRNA-3705 extension study. If the participant chooses to participate and meets eligibility criteria, they will be enrolled in the extension study; otherwise, they will transition to the follow-up part of the study (approximately 2-year follow-up in Part 1 and 6-months follow-up in Part 2).

Eligibility criteria: Key Inclusion Criteria:

* Participant has a body weight of ≥11.0 kilograms (kg) at the Screening Visit.
* Participant has a diagnosis of isolated MMA due to MUT deficiency confirmed by molecular genetic testing.
* Participant has a blood vitamin B12 level equal to or above the lower limit of normal (based on laboratory reference range) confirmed in the Screening Period. For those participants found to have an elevated blood vitamin B12 level, the participant may enter if, in the opinion of the Investigator, the cause of the elevation is secondary to B12 supplementation.
* Participant or their legally authorized representative is willing and able to provide informed consent and/or assent as mandated by local regulations and is willing and able to comply with study-related assessments.
* Sexually active females of childbearing potential and sexually active males of reproductive potential agree to use a highly-effective method of contraception during the study and for 3 months after the last administration of study drug.
* (Part 2 only) At least 1 documented MDE in the 12-month period before consent.

Key Exclusion Criteria:

* Participant has a diagnosis of isolated MMA cb1A, cb1B, or cb1D enzymatic subtypes or methylmalonyl-CoA epimerase deficiency or combined MMA with homocystinuria.
* Participant has previously received gene therapy for the treatment of MMA.
* Participant has a history of organ transplantation or planned organ transplantation during the period of study participation.
* Participant has an active, unstable, or clinically significant medical condition not related to MMA or history of noncompliance that, in the Investigator's opinion, could potentiate the risk while participating in this study, interfere with the interpretation of study results, or limit the participant's participation in the study. This may include, but is not limited to, history of relevant food or drug allergies; history of cardiovascular, central nervous, gastrointestinal, or infectious disease; history of clinically significant pathology; and/or history of cancer.
* (Part 2 only) History of hepatitis B (known positive hepatitis B surface antigen \[HbsAg\]), hepatitis C virus (HCV), or HIV (positive HIV1/HIV-2 antibodies). Participants with a past or resolved hepatitis virus B (HBV) infection (defined as the presence of hepatitis B core antibody and absence of HbsAg) are eligible. Participants with history of positive results for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

Primary outcomes:
measure: Part 1: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Study Drug-related TEAES, Serious Adverse Events (SAEs), and TEAEs Leading to Treatment Discontinuation
timeFrame: Up to 144 weeks
measure: Part 2: Annualized Frequency of Metabolic Decompensation Events (MDEs)
timeFrame: Baseline up to Week 52
Secondary outcomes:
measure: Change in Blood Methylmalonic Acid Level
timeFrame: Baseline up to Week 40
measure: Maximum Observed Effect (Emax) for Plasma Methylmalonic Acid Measurement after Single and Repeated Administrations of mRNA-3705
timeFrame: Baseline up to Week 40
measure: Area Under the Effect Curve (AUEC) for Plasma Methylmalonic Acid Measurement after Single and Repeated Administrations of mRNA-3705
timeFrame: Baseline up to Week 40
measure: Duration of Response for Plasma Methylmalonic Acid Measurement after Single and Repeated Administrations of mRNA-3705
timeFrame: 0 (predose) up to 336 hours postdose
measure: Change in Blood 2-Methylcitric Acid (2-MC ) Levels
timeFrame: Baseline up to Week 40
measure: Maximum Observed Concentration (Cmax) of human Methylmalonyl-Coenzyme A Mutase (hMUT) mRNA-3705
timeFrame: 0 (predose) to 336 hours postdose
measure: Area Under the Concentration-Time Curve (AUC) of hMUT mRNA-3705
timeFrame: 0 (predose) to 336 hours postdose
measure: Titer of Anti-Polyethylene Glycol (PEG) Antibodies
timeFrame: 0 (predose) to 336 hours postdose
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital at Stanford
state: California
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
state: New South Wales
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne
state: Victoria
city: Edmonton
country: Canada
facility: Stollery Children's Hospital University of Alberta
state: Alberta
city: Toronto
country: Canada
facility: Hospital For Sick Children
state: Ontario
city: Paris
country: France
facility: Hôpital Necker - Enfants Malades
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan de Deu - PIN
state: Barcelona
city: Barakaldo
country: Spain
facility: Hospital Universitario Cruces
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Santiago de Compostela
country: Spain
facility: CHUS - H. Clinico U. de Santiago
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio - PPDS
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Royal Manchester Childrens Hospital
Study officials:
References: