A Global, Phase 1/2, Open Label, Dose Escalation Study to Evaluate the Safety, Pharmacodynamics, and Pharmacokinetics of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Change in plasma methylmalonic acid levels
研究概览
简要总结
This First-in-Human (FIH) Phase 1/2 study will evaluate mRNA-3704 in patients with methylmalonic acidemia/aciduria (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency between 1 to 18 years of age with elevated plasma methylmalonic acid. The study is designed to characterize baseline biomarker levels followed by assessment of safety, pharmacokinetics, and pharmacodynamics of different doses of mRNA-3704 in patients affected by MMA as part of the Dose Escalation phase.
During the Dose Escalation phase, three dose levels of mRNA-3704 are planned to be investigated in this study among patients with MMA due to MUT deficiency: low dose, mid dose, and high dose. An additional cohort to evaluate a fourth dose level may be considered jointly by the independent SMC and the Sponsor.
Upon establishment of a dose with acceptable safety and pharmacodynamic activity, additional patients will be enrolled in a Dose Expansion phase to allow for further characterization of the safety and pharmacodynamics of mRNA-3704.
Patients in both phases of study will participate in a pre-dosing observational period, followed by a treatment period, and then a follow-up period after withdrawal of treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients are eligible to be included in the study only if all of the following criteria apply:
- •Confirmed diagnosis of isolated MMA due to MUT deficiency based on the following criteria:
- •Elevated plasma methylmalonic acid concentrations (≥ 100 µmol/L)
- •Presence of normal serum/plasma Vitamin B12 and plasma homocysteine levels
- •Confirmed diagnosis by molecular genetic testing
- •Patient must be ≥ 1 year of age at the time of consent/assent (Inclusion of the first three patients will be restricted to individuals age ≥ 8 years)
排除标准
- •Patients are excluded from the study if any of the following criteria apply:
- •Diagnosis of isolated MMA cblA, cblB, or cblD enzymatic subtypes or methylmalonyl-CoA epimerase deficiency or combined MMA with homocystinuria
- •History of organ transplantation
- •Previously received gene therapy for the treatment of MMA.
- •Estimated glomerular filtration rate (GFR) < 30 mL/min/1.73 m2; or patients who receive chronic dialysis
结局指标
主要结局
Change in plasma methylmalonic acid levels
时间窗: Week -4 through 36 weeks after initial mRNA-3704 dose
Baseline (pre-dose levels) to post-dose levels measured after single and after repeated administrations of mRNA-3704
Incidence of treatment-emergent adverse events
时间窗: Day 1 (initial mRNA-3704 dose) through 52 weeks after final mRNA-3704 dose
次要结局
- Measurement of anti-PEG antibodies(Pre-dose through up to 52 weeks after final mRNA-3704 dose)
- Maximum observed concentration (Cmax) after administration of mRNA-3704(Baseline through 36 weeks after initial mRNA-3704 dose)
- Area under the plasma concentration-time curve (AUC)(Baseline through 36 weeks after initial mRNA-3704 dose)
- Time of Cmax (Tmax)(Baseline through 36 weeks after initial mRNA-3704 dose)
- Change in plasma 2-methylcitrate levels(Week -4 through 36 weeks after initial mRNA-3704 dose)