Methylmalonic Acidemia
Conditions
Keywords
inborn errors of metabolism, mut0, mut-, mut deficiency, organic acidemia, SUNRISE
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.
Interventions
BIOLOGICALhLB-001
hLB-001 via IV infusion
Sponsors
Alexion Pharmaceuticals, Inc.
LogicBio Therapeutics, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 12 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 Albumin-2A Level at Week 52 | Baseline, Week 52 | Below the limit of quantification (BLQ) value was 2.44 nanograms (ng)/milliliter (mL). |
| Percent Change From Baseline in Propionate Oxidation Rate at Week 52 | Baseline, Week 52 | — |
| Change From Baseline in Serum Methylcitrate Level at Week 52 | Baseline, Week 52 | — |
Countries
United States
Participant flow
Pre-assignment details
The study was planned to enroll participants in 2 Cohorts. Cohort 1 consisted of 2 parts: Part A enrolled participants aged 3 to 12 years, and Part B enrolled participants aged 6 months to 36 months. Part C was to enroll participants aged 6 months to 12 years for further safety evaluation prior to enrolling participants in Cohort 2. No participants were enrolled in Part C and thus Cohort 2 was not initiated.
Participants by arm
| Arm | Count |
|---|---|
| Overall Participants (Cohort 1 Part A and Part B) Participants received a single IV infusion of hLB-001. | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | Overall Participants (Cohort 1 Part A and Part B) |
|---|---|
| Age, Continuous | 48.5 months |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 1 / 2 | 2 / 2 |
Outcome results
Primary
Number of Participants With Infusional Toxicities
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.
Time frame: Baseline up to Week 52
Population: The safety population included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 Part A: 3- to 12-years Old | Number of Participants With Infusional Toxicities | 0 Participants |
| Cohort 1 Part B: 6- to 36-months Old | Number of Participants With Infusional Toxicities | 0 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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.
Time frame: From first dose of study drug up to Week 52
Population: The safety population included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 Part A: 3- to 12-years Old | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
| Cohort 1 Part B: 6- to 36-months Old | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
Secondary
Change From Baseline in Serum Albumin-2A Level at Week 52
Below the limit of quantification (BLQ) value was 2.44 nanograms (ng)/milliliter (mL).
Time frame: Baseline, Week 52
Population: The ITT population included all participants receiving hLB-001 who had baseline data and at least 1 postdose measurement.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Part A: 3- to 12-years Old | Change From Baseline in Serum Albumin-2A Level at Week 52 | NA µmol/L |
| Cohort 1 Part B: 6- to 36-months Old | Change From Baseline in Serum Albumin-2A Level at Week 52 | NA µmol/L |
Secondary
Change From Baseline in Serum Fibroblast Growth Factor 21 (FGF21) Level at Week 52
Time frame: Baseline, Week 52
Population: The ITT population included all participants receiving hLB-001 who had baseline data and at least 1 postdose measurement.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Part A: 3- to 12-years Old | Change From Baseline in Serum Fibroblast Growth Factor 21 (FGF21) Level at Week 52 | -4.75 µmol/L |
| Cohort 1 Part B: 6- to 36-months Old | Change From Baseline in Serum Fibroblast Growth Factor 21 (FGF21) Level at Week 52 | 1.57 µmol/L |
Secondary
Change From Baseline in Serum Methylcitrate Level at Week 52
Time frame: Baseline, Week 52
Population: The ITT population included all participants receiving hLB-001 who had baseline data and at least 1 postdose measurement.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Part A: 3- to 12-years Old | Change From Baseline in Serum Methylcitrate Level at Week 52 | 2.35 µmol/L |
| Cohort 1 Part B: 6- to 36-months Old | Change From Baseline in Serum Methylcitrate Level at Week 52 | 4.66 µmol/L |
Secondary
Change From Baseline in Serum Methylmalonic Acid Level at Week 52
Time frame: Baseline, Week 52
Population: The intent-to-treat (ITT) population included all participants receiving hLB-001 who had baseline data and at least 1 postdose measurement.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Part A: 3- to 12-years Old | Change From Baseline in Serum Methylmalonic Acid Level at Week 52 | 286.90 micromoles (µmol)/liter (L) |
| Cohort 1 Part B: 6- to 36-months Old | Change From Baseline in Serum Methylmalonic Acid Level at Week 52 | 122.72 micromoles (µmol)/liter (L) |
Secondary
Percent Change From Baseline in Propionate Oxidation Rate at Week 52
Time frame: Baseline, Week 52
Population: The ITT population included all participants receiving hLB-001 who had baseline data and at least 1 postdose measurement.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 Part A: 3- to 12-years Old | Percent Change From Baseline in Propionate Oxidation Rate at Week 52 | 6.28 percent change |
| Cohort 1 Part B: 6- to 36-months Old | Percent Change From Baseline in Propionate Oxidation Rate at Week 52 | 2.16 percent change |