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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1/2 Open-label Clinical Study of hLB-001 Gene Therapy in Pediatric Patients With Methylmalonic Acidemia Characterized by MMUT Mutations

Conditions
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Methylmalonic Acidemia

Intervention / Treatment
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* Biological: hLB-001


Participation Criteria
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Eligibility Criteria
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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; Isolated MMA with genetically confirmed, pathogenic mutations in the MMUT gene Screening serum/plasma methylmalonic acid level of >100 µmol/L 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 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

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1 Part A<br>3 year-olds to 12 year-olds | Biological: hLB-001<br>* hLB-001 via IV infusion<br>|
| Experimental: Dose Level 1 Part B<br>6 month to 2 year-olds | Biological: hLB-001<br>* hLB-001 via IV infusion<br>|
| Experimental: Dose Level 1 Part C<br>6 month to 12 year-olds | Biological: hLB-001<br>* hLB-001 via IV infusion<br>|
| Experimental: Dose Level 2 Part A<br>3 year-olds to 12 year-olds | Biological: hLB-001<br>* hLB-001 via IV infusion<br>|
| Experimental: Dose Level 2 Part B<br>6 month to 2 year-olds | Biological: hLB-001<br>* hLB-001 via IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (AEs) |  | 52 weeks | 
| Incidence of infusional toxicities |  | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum methylmalonic acid and methylcitrate |  | 52 weeks | 
| Change in serum fibroblast growth factor 21 (FGF21) level |  | 52 weeks | 
| Change in propionate oxidation rate |  | 52 weeks | 
| Change in serum albumin-2A level |  | 52 weeks | 
| Overall Survival: deaths of patients occurring during the study period will be collected |  | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inborn errors of metabolism, mut0, mut-, mut deficiency, organic acidemia, SUNRISE