Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia

Phase 2

Terminated

• Conditions: Methylmalonic Acidemia; Propionic Acidemia
• Interventions: Drug: Placebo; Drug: HST5040

• Registration Number: NCT04732429
• Lead Sponsor: HemoShear Therapeutics

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-01-21
• Study First Submitted QC: 2021-01-26
• Study First Posted: 2021-02-01
• Study Start: 2021-03-15
• Primary Completion: 2023-10-20
• Study Completion: 2023-10-20
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-03
• Last Update Posted: 2024-01-05

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 26

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo in addition to standard of care.
Active Drug	HST5040	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).

Primary Outcome Measures

Name	Time	Method
Change in plasma 2-methylcitric acid (MCA) levels	6 months	nmol/mL

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics parameters - Tmax	6 months	Time of maximum concentration (Tmax)
Change in Methylmalonic acid (in MMA subjects)	6 months	nmol/L
Change in plasma propionyl-carnitine (3)	6 months	µmol/L
Change in C3 to acetyl-carnitine ratio (C3:C2)	6 months	µmol/L
Change in 3-OH propionate	6 months	g/mol
Pharmacokinetics parameters - Cmax	6 months	Maximum concentration (Cmax) after administration of HST5040
Pharmacokinetics parameters - AUC	6 months	Area under the concentration time curve (AUC)
Anion Gap	6 months	mEq/L
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
Change in NH3	6 months	nmol/L

Trial Locations

Locations (16)

Rady Children's Hospital; 🇺🇸 San Diego, California, United States

Ann & Robert H. Lurie Children's Hospital of Chicago; 🇺🇸 Chicago, Illinois, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

University Hospitals Cleveland Medical Center; 🇺🇸 Cleveland, Ohio, United States

John P. and Kathrine G. McGovern Medical School; 🇺🇸 Houston, Texas, United States

University of Utah Hospital; 🇺🇸 Salt Lake City, Utah, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

University of Pittsburgh Medical Center - Children's Hospital of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Yale; 🇺🇸 New Haven, Connecticut, United States

Children's National Health System; 🇺🇸 Washington, District of Columbia, United States

King Faisal Specialist Hospital and Research Centre; 🇸🇦 Riyadh, Saudi Arabia

Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Emory University School of Medicine; 🇺🇸 Atlanta, Georgia, United States

Children's Mercy Hospital Kansas City; 🇺🇸 Kansas City, Missouri, United States

Royal Children's Hospital Melbourne; 🇦🇺 Parkville, Victoria, Australia