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

Clinicaltrials.gov ID# 04732429

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:

Inclusion Criteria:

• Confirmed diagnosis of symptomatic PA or MMA defined by:

• Biochemical testing Or Enzymatic testing

• Biochemical: Marked elevations in C3, MCA, &/or methylmalonic acid with a normal homocysteine level

• Enzymatic: Deficient activity of propionyl-coenzyme A [P-CoA] carboxylase for PA and methylmalonyl-coenzyme A [M-CoA] mutase for MMA

• And Genetic Testing

• Biallelic mutations in propionyl-coenzyme A carboxylase subunits A or B (PCCAor PCCB) for PA and L-methylmalonyl-coenzyme A mutates (MMUT) for MMA

• And History of metabolic decompensations

• Ages ≥2 years old

• Inadequate metabolic control while receiving standard of care (SoC) within the past 4 years, as evidenced by:

• Plasma NH 3 >50µM on 2 occasions at least 1 week apart -OR-

• Plasma methylmalonic acid >150 µM (MMA only) -OR-

• A metabolic decompensation requiring hospitalization &/or an ER visit (Part A only)

• Plasma MCA concentration >3x ULN of reference rage at screening

• Stable supplementation dose of carnitine for at least 1 week prior to entry in the study and have a free carnitine level >10nmol/ mL.

• Subject or subject’s parent/legal guardian consents to participate in the study and provides informed consent prior to any study procedures being performed. If  he subject is of a minor age, he/she is willing to provide assent where required per local regulations and if deemed able to do so.

Exclusion Criteria:

• Serologic evidence of human immunodeficiency virus (HIV) infection.

• Serologic evidence of Hepatitis B or C infection.

• Plasma vitamin B5 below LLN

• Moderate to severely impaired cardiac function with LVEF <45% by ECHO.

• Clinically significant arrythmia by Holter monitor.

• Marked prolongation of QT/correct QT (QTc) interval (>450 msec by Fridericia method; QTcF); a history of additional risk factors for Torsades de pointes [e.g., heart failure, hypokalemia, family history of Long QT Syndrome]; and the use of concomitant medications that prolong the QT/QTc interval.

Recruitment Status: 

Not yet recruiting, anticipated site activation in February

Primary Investigator:

Michele Spencer-Manzon, MD

Contact Information:

PI: michele.spencer-manzon@yale.edu

Coordinator: michele.jasne@yale.edu

(203) 785-6351 (voicemail)