Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of SEL-302 (MMA-101 Following Administration of SEL-110) in Pediatric Subjects With Mut Subtype Isolated Methylmalonic Acidemia (MMA)
试验速览
- 阶段
- 1 期
- 状态
- 暂停
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Safety and tolerability of SEL-302
研究概览
简要总结
This Phase 1/2 study will evaluate the safety and pharmacodynamics (PD) of SEL-302, which consists of the gene transfer vector MMA-101 following administration of an immunomodulatory SEL-110 agent in pediatric subjects with Methylmalonyl-CoA Mutase (MMUT) MMA.
详细描述
MMA is a rare inborn error of branched chain amino acid metabolism. Despite strict dietary adherence and vigilant monitoring and care, affected individuals have recurrent episodes of severe illness and develop complications from different organ systems that can be life-threatening. Liver transplants can help, but gene transfer therapy could offer an alternative treatment option. This study will be an open-label, single dose, single center study of SEL-302 consisting of two investigative therapeutics: a gene transfer therapy that is using an inactive virus, called adeno-associated-virus 8 (AAV8), to deliver the MMUT gene to the liver, by itself called MMA-101, and an immunotherapy called SEL-110, a nano-encapsulated form of sirolimus.
The study will enroll two cohorts treating up to a total of 6 subjects.
Cohort 1: 3 adolescents (≥12 and <18 years of age) Cohort 2: 3 children (≥3 and <12 years of age, with a minimum body weight of 15 kg)
The dose of MMA-101 administered to each subject will be 1.0E13 vg/kg. Each progression to the next subject dosed in the study will be reviewed and approved by a data safety monitoring committee.
The first subject in Cohort 1 will receive only MMA-101. The second adolescent subject in Cohort 1 will be treated with 0.15 mg/kg of SEL-110 followed by MMA-101 on Day 1 and two repeat doses of 0.15 mg/kg of SEL-110 at Day 28 and Day 56. The dose of SEL-110 in the third subject in Cohort 1 may be increased up to 0.3 mg/kg depending on results from the second subject. After assessment of safety and efficacy of Cohort 1, Cohort 2 will be started in younger children.
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
- 3 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 3 to <18 years at time of consent (assent where possible)
- •Confirmed diagnosis of MMUT type methylmalonic acidemia by molecular genetic testing
- •Clinical and biochemical diagnosis of severe MMA as defined by:
- •sMMA level between 100 to 3,000 μmol/L
- •A clinical history consistent with severe MMA
- •Subjects must have fully recovered from any hospitalization for metabolic ketoacidosis or surgery at least 4 weeks prior to the start of the screening period.
- •Parent or legal guardian are willing and able to provide informed consent. Written assent will be obtained from minors older than age seven whenever possible.
- •Subject and caregiver must be willing to comply with study-related assessments and adhere to lifestyle considerations throughout study duration.
排除标准
- •History of any organ transplantation.
- •High MMUT liver enzymatic activity in the range seen in healthy subjects or MMA patients after corrective liver transplant, as demonstrated by POBT levels.
- •Presence of Nab against AAV8 or polyethylene glycol (PEG)
- •An estimated glomerular filtration rate (GFR)<45 mL/min/1.73 m2 (<chronic kidney disease stage 3a)
- •Hemoglobin <10 g/dL
- •Platelet count <100,000 per mm3
- •History of any malignancy or immunocompromising condition.
- •History of anaphylaxis or severe allergic reaction to drug therapy, foods, PEG or polysorbates.
- •Previously received gene therapy or messenger ribonucleic acid (mRNA) treatments for MMA.
- •Participated in a clinical trial of another (non-gene or mRNA therapy) investigational agent within 30 days prior to screening, or within 5 elimination half-lives of the investigational agent, whichever is longer.
- •Note: additional inclusion/exclusion criteria may apply, per protocol.
研究组 & 干预措施
Cohort 1 - Adolescents
IV infusion of MMA-101 in the first patient on Day 1 IV infusion of SEL-302 in the second and third patient on Day 1, followed by two repeat doses of SEL-110 on Day 28 and Day 56 Adolescents ages ≥12 and <18
干预措施: SEL-302 (Drug)
Cohort 2 - Children
IV infusion of SEL-302 in all patients on Day 1, followed by two repeat doses of SEL-110 on Day 28 and Day 56 Children ages ≥3 and <12
干预措施: SEL-302 (Drug)
结局指标
主要结局
Safety and tolerability of SEL-302
时间窗: From the initial administration of SEL-302 up to 5 years for long-term follow-up.
Incidence and severity of all adverse events (AEs), treatment emergent AEs (TEAEs), and serious adverse events (SAEs) and their relationship to SEL-302 (MMA-101 or SEL-110) Time Frame: From the initial administration of SEL-302 up to 5 years for long-term follow-up.
PD Activity of SEL-302
时间窗: From initial treatment with SEL-302 up to 5 years for long-term follow-up.
Measure the change in the 1-13C sodium POBT at Day 84 (interim endpoint for safety assessment) and at the end of the 1-year study period (primary endpoint) and assessed yearly during the 4 years of long-term follow-up.
Assess the change in Neutralizing antibody (Nab) titers for MMA-101 with treatment of SEL-110
时间窗: From initial treatment with SEL-302 up to 5 years for long-term follow-up.
Measure Nab serum titers from baseline at multiple timepoints following treatment on Day 28, Day 56, and Day 84.
次要结局
- World Health Organization Quality of Life Brief Version (WHOQoL-BREF)(From initial treatment with SEL-302 for up to 5 years for long-term follow-up.)
- Area Under Curve (AUC) of sirolimus(From initial treatment with SEL-302 up to 84 days following administration of SEL-110.)
- Zarit Burden Interview(From initial treatment with SEL-302 for up to 5 years for long-term follow-up.)
- Patient outcomes assessed by the frequency and severity of specified clinical events(From initial treatment with SEL-302 up to 5 years for long-term follow-up.)
- Maximum plasma concentration (Cmax) of sirolimus(From initial treatment with SEL-302 up to 84 days following administration of SEL-110.)