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.
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. The dose of SEL-110 in Cohort 2 for the first subject will be 0.15 mg/kg of SEL-110 immediately prior to the dose of 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 second and third subject in Cohort 2 may be increased up to 0.3 mg/kg at one or more of the three doses depending on results of all previously treated subjects. The primary efficacy endpoints of reduction in serum methylmalonic acid (sMMA) levels and increases in the 1-13C sodium propionate oxidation breath test (POBT) will be assessed at an interim timepoint for safety evaluation (Day 84) and at the primary endpoint of 1 year. All subjects will be monitored closely for safety for the first year of the study and then annually for an additional 4 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
SEL-302 Drug: MMA-101 (1.0E13 vg/kg) Drug: SEL-110 (0.15 mg/kg or up to 0.3 mg/kg) Other Names: SEL-110.36, ImmTOR
National Human Genome Research Institute, National Institutes of Health
Bethesda, Maryland, United States
Safety and tolerability of SEL-302
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.
Time frame: From the initial administration of SEL-302 up to 5 years for long-term follow-up.
PD Activity of SEL-302
Measure the change in sMMA levels 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.
Time frame: From initial treatment with SEL-302 up to 5 years for long-term follow-up.
PD Activity of SEL-302
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.
Time frame: From initial treatment with SEL-302 up to 5 years for long-term follow-up.
Assess the change in Neutralizing antibody (Nab) titers for MMA-101 with treatment of SEL-110
Measure Nab serum titers from baseline at multiple timepoints following treatment on Day 28, Day 56, and Day 84.
Time frame: From initial treatment with SEL-302 up to 5 years for long-term follow-up.
Maximum plasma concentration (Cmax) of sirolimus
Measuring the Cmax of sirolimus at the first, second, and third dose of SEL-110. Time Frame: From initial treatment with SEL-302 up to 84 days following administration of SEL-110.
Time frame: From initial treatment with SEL-302 up to 84 days following administration of SEL-110.
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Area Under Curve (AUC) of sirolimus
Measuring the AUC of sirolimus at the first, second, and third dose of SEL-110.
Time frame: From initial treatment with SEL-302 up to 84 days following administration of SEL-110.
Patient outcomes assessed by the frequency and severity of specified clinical events
Recording of patient outcomes regarding metabolic crisis in need of sick-day dietary modifications, hospitalization, and need for referral for liver, kidney, or liver/kidney transplant.
Time frame: From initial treatment with SEL-302 up to 5 years for long-term follow-up.
World Health Organization Quality of Life Brief Version (WHOQoL-BREF)
Assess the change from baseline in patient-reported quality of life measures using the WHOQoL-BREF (on a number scale of 0 to 100, with lower indicating a worse outcome).
Time frame: From initial treatment with SEL-302 for up to 5 years for long-term follow-up.
Zarit Burden Interview
Assess the change from baseline in patient-reported quality of life measures using the Zarit Burden Interview (on a number scale from 0 to 48, with higher indicating a greater burden)
Time frame: From initial treatment with SEL-302 for up to 5 years for long-term follow-up.