|Principal Investigator: Nicola Longo|
|Keywords: MMA , mRNA-3704 , Methylmalonic Acidemia , Methylmalonyl-CoA Mutase Deficiency||Department: Pediatric Genetics|
|IRB Number: 00120894|
|Specialty: Pediatric Genetics|
|Sub Specialties: Medical Genetics|
|Recruitment Status: Recruiting|
Evaluate the safety and tolerability of mRNA-3704 administered via IV infusion to patients with isolated MMA due to MUT deficiency.
Characterize the pharmacodynamic (PD) response to mRNA-3704 as determined by plasma methylmalonic acid measurement after single and repeated administrations of mRNA-3704.
Characterize the single-dose and repeated dose pharmacokinetics (PK) of mRNA-3704.
Characterize the changes in plasma 2-methylcitrate levels after single and repeated administrations of mRNA-3704.
Assess for the presence of anti-drug antibodies (ADAs).
Assess incidence and severity of MMA-related clinical events.
Assess quality of life (QoL) measures.
Evaluate the incidence of healthcare utilization and health economic outcomes.
Assess the relationships between PK, PD, safety, and disease-related parameters.
Characterize the PD response to mRNA-3704 as determined by other biomarkers after single and repeated administrations.
Assess for the presence of antibodies to MUT protein.
To assess for changes in inflammatory markers in the Dose Escalation Phase
1. Confirmed diagnosis of isolated MMA due to MUT deficiency based on the following criteria:
•Elevated plasma methylmalonic acid concentrations of ≥100 μmol/L, confirmed by 2 values drawn at least 24 hours apart during the Screening Period;
•Presence of normal serum/plasma vitamin B12 and plasma homocysteine levels (local laboratory reference range) confirmed in the Screening Period (values may be from historical data); and
•Confirmed diagnosis by molecular genetic testing.
2. Patient must be ≥1 years of age at the time of consent/assent.
3. Patient or legally authorized representative is willing and able to provide informed consent and/or assent as mandated by local regulations.
4. The patient’s caregiver (and the patient) must be willing and able to comply with study-related assessments.
5. Values for ALT, AST, and direct serum bilirubin ≤1.25x of ULN.
6. Platelet count within a range of ≥150,000/mm3 to 450,000/mm3.
7. Hemoglobin levels> 9.0 g/dL
8. 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 12 weeks following study participation.
1. Diagnosis of isolated MMA cblA, cblB, or cblD enzymatic subtypes or methylmalonyl-CoA epimerase deficiency or combined MMA with homocystinuria.
2. Previously received gene therapy for the treatment of MMA.
3. Estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2, as estimated by the Schwartz formula (based on serum creatinine); or patients who receive chronic dialysis (Fadem and Rosenthal, 2012).
4. QTc including Bazett's correction >450 msec.
5. In female patients of reproductive potential: a positive pregnancy test at Screening or at the end of the Observational Period.
6. Pregnant or lactating.
7. aPTT, PT, or INR greater than ULN or history of clinically significant bleeding abnormality.
8. Absolute neutrophil count (ANC) below the following:
• 1000/mm3 for patients ≥1 year of age to <2 years of age
• 1500/mm3 for patients ≥2 years of age
9. History of organ transplantation.
10. History of hypersensitivity to any components of the study drug.
11. Participated in another clinical trial of another investigational agent within 30 days prior to study entry (or within 5 elimination half-lives of the investigational agent), whichever is longer.
12. Major surgical procedure within 30 days prior to study entry (excludes central line, port, or feeding tube placement).
13. Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection.
14. Have any other clinically significant medical condition that in the Investigator’s opinion could interfere with the interpretation of study results or limit the patient’s participation in the study.