Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2 Open-label, Dose Escalation Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia Followed by a Randomized, Double-blind, Placebo-controlled, 2-period Crossover Study and an Open-label, Long-term Extension Study

Conditions
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Methylmalonic Acidemia, Propionic Acidemia

Intervention / Treatment
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* Drug: HST5040
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 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: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Drug<br>Part B is the 6-month, randomized, double-blind (Subject/Investigator/Sponsor), placebo-controlled, 2-period crossover study consisting of 2 intervention periods of 12 weeks each to evaluate the safety and efficacy of the optimal dose of HST5040 in PA and MMA subjects ≥ 2 years old (N = minimum 12) in addition to SoC determined in Part A (within-subject dose escalation). | Drug: HST5040<br>* Liquid solution<br>|
| Experimental: Placebo<br>Placebo in addition to standard of care. | Drug: Placebo<br>* Liquid solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma 2-methylcitric acid (MCA) levels | nmol/mL | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma propionyl-carnitine (3) | µmol/L | 6 months | 
| Change in C3 to acetyl-carnitine ratio (C3:C2) | µmol/L | 6 months | 
| Change in 3-OH propionate | g/mol | 6 months | 
| Change in Methylmalonic acid (in MMA subjects) | nmol/L | 6 months | 
| Change in NH3 | nmol/L | 6 months | 
| Anion Gap | mEq/L | 6 months | 
| Pharmacokinetics parameters - Cmax | Maximum concentration (Cmax) after administration of HST5040 | 6 months | 
| Pharmacokinetics parameters - Tmax | Time of maximum concentration (Tmax) | 6 months | 
| Pharmacokinetics parameters - AUC | Area under the concentration time curve (AUC) | 6 months | 
| Oral Intake | Food diary - change from baseline to end of each dose level interval in oral intake | 6 months | 
| Acute Metabolic Decompensations | Change in the total number of metabolic decompensation events requiring an emergency room (ER) visit of hospitalization | 6 months | 
| MetabQoL 1.0 - Health Related Quality of Life (HRQOL) | Score 0-100 Scale. Higher Score indicates better HRQOL | 6 months | 
| PedsQL 1.0 Family Impact Score - Health Related Quality of Life (HRQOL) | Score 0-100 Scale. Higher Score indicates better HRQOL | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCCA, Methylmalonic Acidemia, Propionic Acidemia, Organic Acidemia, Inborn errors of metabolism, PCCB, Propionyl-coenzyme A carboxylase, MMUT, Methylmalonyl-CoA mutase, Metabolic disease, Genetic disease, HemoShear