E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency |
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E.1.1.1 | Medical condition in easily understood language |
Deficiency of the enzyme methylmalonyl-coenzyme A (CoA) mutase (MUT) |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives of the study are:
• To evaluate the safety and tolerability of mRNA-3704 administered via IV infusion to patients with isolated MMA due to MUT deficiency.
• To characterize the PD response to mRNA-3704 as determined by plasma methylmalonic acid measurement after single and repeated administrations of mRNA-3704. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To characterize the single-dose and repeat-dose PK of mRNA-3704.
• To characterize the changes in plasma 2-methylcitrate levels after single and repeated administrations of mRNA-3704.
• To assess for the presence of anti-drug antibodies (ADAs). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if all of the following criteria apply:
1. Confirmed diagnosis of isolated MMA due to MUT deficiency based on the following criteria:
o Elevated plasma methylmalonic acid concentrations of ≥100 μmol/L, confirmed by 2 values drawn at least 24 hours apart during the Screening Period or within the past 6 months;
o 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
o Confirmed diagnosis by molecular genetic testing.
2. Patient must be ≥1 years of age at the time of consent/assent. (inclusion of the first three patients will be restricted to individuals 8 years of age or older).
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 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. |
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E.4 | Principal exclusion criteria |
Patients are excluded from the study if any of the following criteria apply:
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.
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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Incidence and severity of treatment-emergent adverse events (TEAEs; including study drugrelated and not related TEAEs regardless of causality), treatment-emergent serious adverse events (SAEs), and TEAEs leading to treatment discontinuation.
- Change in plasma methylmalonic acid levels from baseline (pre-dose levels) to post-dose levels measured after single and after repeated administrations of mRNA-3704. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoints will be evaluated over the entire period of the trial |
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E.5.2 | Secondary end point(s) |
- Pharmacokinetic parameters of hMUT mRNA including, but not limited to, maximum observed concentration (Cmax), time of Cmax (Tmax), area under the plasma concentration-time curve (AUC), terminal elimination half-life (t1/2), clearance (CL), and volume of distribution (Vz).
- Change in plasma 2-methylctirate levels from baseline (pre-dose levels) to levels measured after single and after repeated administrations of mRNA-3704.
- Measurement of anti-PEG antibodies |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be evaluated over the entire period of the trial |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |