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 |
Evaluate the safety and tolerability of mRNA-3705 administered via intravenous (IV) infusion to participants with isolated methylmalonic acidemia (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency. |
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E.2.2 | Secondary objectives of the trial |
- Characterize the pharmacodynamic (PD) response to mRNA-3705 as determined by changes from baseline in plasma methylmalonic acid measurement after single and repeated administrations of mRNA-3705 - Characterize the changes from baseline in plasma 2-methylcitric acid (2-MC) levels after single and repeated administrations of mRNA-3705 - Characterize the pharmacokinetics (PK) of human MUT (hMUT) messenger ribonucleic acid (mRNA) after single and repeated administrations of mRNA-3705 - Assess the presence and formation of anti-polyethylene glycol (PEG) antibodies (antidrug antibodies [ADAs]) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Participant is ≥ 1 year of age at the time of informed consent/assent. 2. Participant has a body weight of ≥ 11.0 kg at the Screening Visit 3. Participant has a diagnosis of isolated MMA due to MUT deficiency confirmed by molecular genetic testing. (see guidance in Section 8.1.1 for participants < 23.3 kg). 4. Participant has a serum/plasma 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 serum/plasma vitamin B12 level, the participant may enter if, in the opinion of the Investigator, the cause of the elevation is secondary to B12 supplementation. 5. Participant or his/her legally authorized representative is willing and able to provide informed consent and/or assent as mandated by local regulations and willing and able to comply with study-related assessments. 6. 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 (Section 11.4). 7. Participants with parameters that indicate MMA clinical severity as described in Section 11.2.3. |
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E.4 | Principal exclusion criteria |
1. Participant has a diagnosis of isolated MMA cb1A, cb1B, or cb1D enzymatic subtypes or methylmalonyl-CoA epimerase deficiency or combined MMA with homocystinuria. 2. Participant has any individual laboratory abnormalities achieving exclusionary thresholds defined in Table 16. 3. Participant has previously received gene therapy for the treatment of MMA. 4. Participant has an eGFR <30mL/min/1.73m2, as estimated by the Schwartz formula for participants<18years of age (Schwartz et al 2009), or by the Chronic Kidney Disease Epidemiology Collaboration creatinine-based formula for participants ≥ 18 years of age (Inker et al 2021), or receives long-term dialysis. 5. Participant has a corrected QT interval > 480 ms using Bazett’s correction. 6. For female participants of reproductive potential, the participant has a positive pregnancy test at the Screening Visit. 7. Participant is pregnant or breastfeeding. 8. Participant has a history of organ transplantation. 9. Participant has a history of hypersensitivity to any components of the study drug. 10. Participant has a history of hypersensitivity to acetaminophen/paracetamol and/or ibuprofen or H1/H2receptor blockers. 11. Participation in another clinical study of another investigational agent within 30 days before study entry or within 5 elimination half-lives of the investigational agent, whichever is longer. 12. Participant has undergone a major surgical procedure within 30 days before the Screening Visit (excludes central line, port, or feeding tube placement). 13. Participant has new uses or adjustments in dose within the last 2 weeks to antibiotic therapy used to reduce propionate production. Any participant whose new or adjusted dose in antibiotics conflicts with the rules described above may enter the Treatment Period after stabilization of the antibiotic regimen and reconfirmation of study eligibility. 14. 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. 15. Participant has received COVID-19 vaccination (generally 2 doses or a booster) within 6 weeks between their last COVID-19 vaccination dose and first study drug administration. 16. Participant has any individual vital sign abnormalities achieving exclusionary thresholds as defined in Table 17 .17. Participant has a history of anaphylaxis/anaphylactoid reaction or severe hypersensitivity with infusions. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence and severity of TEAEs, including study drug-related and not related TEAEs, SAEs, and TEAEs leading to treatment discontinuation |
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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) |
- Change in plasma methylmalonic acid levels from baseline (predose levels) to postdose levels measured after single and repeated administrations of mRNA-3705. - Estimation of PD parameters after single and repeated administrations of mRNA-3705, including maximum observed effect (Emax), area under the effect curve (AUEC), and duration of response. - Change in plasma 2-methylcitric acid (2-MC) levels from baseline (predose levels) to levels measured after single and repeated administrations of mRNA-3705. -Estimation of hMUT mRNA PK parameters including, but not limited to, maximum observed concentration (Cmax), time of Cmax (Tmax), , area under the concentration-time curve (AUC), terminal elimination half-life (t½), total body clearance (CL), and volume of distribution (Vz). - Presence and titers 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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
Australia |
Canada |
United States |
France |
Netherlands |
Spain |
United Kingdom |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
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 |