Methylmalonic Acidemia, Propionic Acidemia
Conditions
Keywords
Methylmalonic Acidemia, Propionic Acidemia, Organic Acidemia, Inborn errors of metabolism, PCCA, PCCB, Propionyl-coenzyme A carboxylase, MMUT, Methylmalonyl-CoA mutase, Metabolic disease, Genetic disease, HemoShear
Brief summary
This is an interventional study to assess the safety, PK, and efficacy of HST5040 in 12 subjects - 6 with Methylmalonic Acidemia (MMA) and 6 with Propionic Acidemia (PA). The study consists of 3 parts: * Part A: Open-label, within-subject, dose escalation study in PA and MMA subjects ≥ 2 years old to identify a safe and pharmacologically active (optimal) dose of HST5040 for use in Part B. Subjects will continue in a Part A open-label extension until all subjects complete Part A and the optimal dose of HST5040 is identified for use in Part B. * Part B: 6-month, randomized, double-blind, placebo-controlled, 2-period crossover in the same subjects from Part A to evaluate safety and efficacy of the optimal dose of HST5040 in addition to standard of care (SoC). * Part C: open-label long-term extension study in PA and MMA subjects ≥ 2 years old (N = approximately 12, 6 each) to evaluate the long-term safety and efficacy of the optimal dose of HST5040. This study will determine whether HST5040 can improve levels of disease-associated toxins that accumulate in patients with PA and MMA.
Interventions
DRUGHST5040
Liquid solution
DRUGPlacebo
Liquid solution
Sponsors
HemoShear Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of symptomatic PA or MMA (Mutase) * Ages ≥ 2 years old. * History of Inadequate metabolic control while receiving standard of care (SoC). * Plasma MCA concentration \> 3x upper limit of normal of the reference range at screening. * Stable supplementation dose of carnitine for at least 1 week prior to the entry in the study.
Exclusion criteria
* Moderate-to-severely impaired cardiac function with LVEF \< 45% by ECHO. * Clinically significant arrhythmia by Holter monitor. * QTcF \> 450 msec * Moderate to severe chronic kidney disease with estimated glomerular filtration rate (eGFR) \< 60 mL/min/1.73m2. * Exposure to any investigational therapy, apart for a COVID-19 vaccine, within the past 6 months prior to study entry. * Exposure to gene therapy for PA or MMA at any time prior to study entry. * History of organ transplantation (Part A and B only) * History of severe allergic or anaphylactic reactions to any of the components of HST5040.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in plasma 2-methylcitric acid (MCA) levels | 6 months | nmol/mL |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in C3 to acetyl-carnitine ratio (C3:C2) | 6 months | µmol/L |
| Change in 3-OH propionate | 6 months | g/mol |
| Change in Methylmalonic acid (in MMA subjects) | 6 months | nmol/L |
| Change in NH3 | 6 months | nmol/L |
| Anion Gap | 6 months | mEq/L |
| Pharmacokinetics parameters - Cmax | 6 months | Maximum concentration (Cmax) after administration of HST5040 |
| Change in plasma propionyl-carnitine (3) | 6 months | µmol/L |
| Pharmacokinetics parameters - AUC | 6 months | Area under the concentration time curve (AUC) |
| Oral Intake | 6 months | Food diary - change from baseline to end of each dose level interval in oral intake |
| Acute Metabolic Decompensations | 6 months | Change in the total number of metabolic decompensation events requiring an emergency room (ER) visit of hospitalization |
| MetabQoL 1.0 - Health Related Quality of Life (HRQOL) | 6 months | Score 0-100 Scale. Higher Score indicates better HRQOL |
| PedsQL 1.0 Family Impact Score - Health Related Quality of Life (HRQOL) | 6 months | Score 0-100 Scale. Higher Score indicates better HRQOL |
| Pharmacokinetics parameters - Tmax | 6 months | Time of maximum concentration (Tmax) |
Countries
Australia, Saudi Arabia, United States
Outcome results
None listed