Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia (HERO)

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

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.

Study Overview

• Status: Terminated
• Conditions: Propionic Acidemia; Methylmalonic Acidemia
• Intervention / Treatment: Drug: HST5040; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital Melbourne
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11211
    • King Faisal Specialist Hospital and Research Centre
• United States
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Health System
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital Kansas City
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center - Children's Hospital of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • John P. and Kathrine G. McGovern Medical School
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Drug; 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; Liquid solution
Experimental: Placebo; Placebo in addition to standard of care.	Drug: Placebo; Liquid solution

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: HemoShear Therapeutics
• Investigators: Study Chair: Patrick Horn, MD PhD, HemoShear Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2021
• Primary Completion (Actual): October 20, 2023
• Study Completion (Actual): October 20, 2023

Study Registration Dates

• First Submitted: January 21, 2021
• First Submitted That Met QC Criteria: January 26, 2021
• First Posted (Actual): February 1, 2021

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Propionic Acidemia; Genetic disease; Inborn errors of metabolism; Organic Acidemia; Methylmalonic Acidemia; Metabolic disease; PCCA; PCCB; Propionyl-coenzyme A carboxylase; MMUT; Methylmalonyl-CoA mutase; HemoShear
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Acid-Base Imbalance; Acidosis; Propionic Acidemia; Amino Acid Metabolism, Inborn Errors
• Other Study ID Numbers: HST20-CL01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No