Gene Therapy With hLB-001 in Pediatric Patients With Severe Methylmalonic Acidemia

Phase 1

Terminated

Brief Summary: The SUNRISE trial is a first-in-human (FIH), open-label, Phase 1/2 clinical trial designed to assess the safety, tolerability and preliminary efficacy of a single intravenous infusion of hLB-001 in pediatric patients with MMA characterized by methylmalonyl-CoA mutase gene (MMUT) mutations. hLB-001 is a liver-targeted, recombinant engineered adeno-associated viral (rAAV) vector utilizing the LK03 capsid (rAAV-LK03), designed to non-disruptively integrate the human methylmalonyl-CoA mutase gene at the albumin locus.

The trial is expected to enroll pediatric patients with ages ranging from 6 months to 12 years, initially starting with 3 to 12 year-old patients and then adding patients aged 6 months to 2 years.

Recruitment & Eligibility

Inclusion Criteria

At the time of dosing, participants must be 6 months to 12 years of age
Males and females with diagnosis of severe MMA meeting all the following;
1. Isolated MMA with genetically confirmed, pathogenic mutations in the MMUT gene
2. Screening serum/plasma methylmalonic acid level of >100 µmol/L
3. One or more of the following considered by the PI to be MMA-related: (i) An unscheduled ER visit, hospitalization or requirement for sick day diet in the year prior to screening visit (ii) Developmental delay, movement disorder, optic neuropathy or feeding disorder with tube feeding requirement
4. Medically stable for the 2 months prior to the start of screening

Exclusion Criteria

Participants with organic acidemias other than isolated MMA, or with any other causes of hyperammonemia
Having received MMA-targeted gene therapy or nucleic acid therapy
Participants on insulin or high dose hydroxocobalamin (> 1 mg/day OHB12 parenteral)
Kidney or liver transplant, including hepatocyte cell therapy
Estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2 based on age appropriate equations, or ongoing dialysis for renal disease
Participant tests positive for anti-rAAV-LK03-neutralizing antibodies

Arm && Interventions

Primary Outcome Measures

Name	Time	Method
Number of Participants With Infusional Toxicities	Baseline up to Week 52	An infusional toxicity was a hLB-001-related AE that limits, delays, or requires medical intervention during administration. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	From first dose of study drug up to Week 52	An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAE was an AE that was not present prior to administration of hLB-001, or an event already present that worsened in either severity or frequency following hLB-001administration. A summary of serious adverse events (SAEs) and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Propionate Oxidation Rate at Week 52	Baseline, Week 52
Change From Baseline in Serum Albumin-2A Level at Week 52	Baseline, Week 52	Below the limit of quantification (BLQ) value was 2.44 nanograms (ng)/milliliter (mL).
Change From Baseline in Serum Fibroblast Growth Factor 21 (FGF21) Level at Week 52	Baseline, Week 52
Change From Baseline in Serum Methylmalonic Acid Level at Week 52	Baseline, Week 52
Change From Baseline in Serum Methylcitrate Level at Week 52	Baseline, Week 52