Clinical trial NCT04732429: Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Methylmalonic Acidemia
Propionic Acidemia
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
Lead sponsor: HemoShear Therapeutics
Sponsor class: INDUSTRY
First posted: 2021-02-01
Enrollment: 26
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change in plasma 2-methylcitric acid (MCA) levels
timeFrame: 6 months
Secondary outcomes:
measure: Change in plasma propionyl-carnitine (3)
timeFrame: 6 months
measure: Change in C3 to acetyl-carnitine ratio (C3:C2)
timeFrame: 6 months
measure: Change in 3-OH propionate
timeFrame: 6 months
measure: Change in Methylmalonic acid (in MMA subjects)
timeFrame: 6 months
measure: Change in NH3
timeFrame: 6 months
measure: Anion Gap
timeFrame: 6 months
measure: Pharmacokinetics parameters - Cmax
timeFrame: 6 months
measure: Pharmacokinetics parameters - Tmax
timeFrame: 6 months
measure: Pharmacokinetics parameters - AUC
timeFrame: 6 months
measure: Oral Intake
timeFrame: 6 months
measure: Acute Metabolic Decompensations
timeFrame: 6 months
measure: MetabQoL 1.0 - Health Related Quality of Life (HRQOL)
timeFrame: 6 months
measure: PedsQL 1.0 Family Impact Score - Health Related Quality of Life (HRQOL)
timeFrame: 6 months
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
city: New Haven
country: United States
facility: Yale
state: Connecticut
city: Washington
country: United States
facility: Children's National Health System
state: District of Columbia
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital Kansas City
state: Missouri
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Children's Hospital of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: John P. and Kathrine G. McGovern Medical School
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne
state: Victoria
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital and Research Centre
Study officials:
affiliation: HemoShear Therapeutics, Inc.
name: Patrick Horn, MD PhD
role: STUDY_CHAIR
References: