Clinical trial NCT01141075: Ataluren for Nonsense Mutation Methylmalonic Acidemia
Official title: A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Amino Acid Metabolism, Inborn Errors
Lead sponsor: PTC Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Genzyme, a Sanofi Company
First posted: 2010-06-10
Enrollment: 11
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Methylmalonic acidemia (MMA) is a rare genetic disorder caused by mutations in the gene for mitochondrial enzyme methylmalonyl-CoA mutase (MCM) or in one of the genes for adenosylcobalamin (AdoCbl). Lack of these proteins causes toxic elevations of methylmalonic acid (MMacid) in blood, urine, and other tissues. A specific type of mutation, called a nonsense (premature stop codon) mutation, is the cause of the disease in approximately 5% to 20% of participants with mutations in the MCM gene, and approximately 20% to \>50% of participants with mutations in one of the AdoCbl genes. Ataluren is an orally delivered, investigational drug that acts to overcome the effects of the premature stop codon, potentially enabling the production of functional MCM/AdoCbl. This study is a Phase 2a trial evaluating the safety and activity of ataluren in participants with MMA due to a nonsense mutation. The main purpose of this study is to understand whether ataluren can safely decrease MMacid levels.

Detailed description: In this study, participants with MMA due to a nonsense mutation will be administered an investigational drug called ataluren. Evaluation procedures to determine if a participant qualifies for the study will be performed within 14 days prior to the start of drug administration. Eligible participants who elect to enroll in the study will then participate in 2 drug administration and follow-up periods. Within the first period, ataluren will be taken 3 times per day with meals for 28 days at doses of 5 milligrams/kilograms (mg/kg) (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there will then be an interval of approximately 21 days without ataluren. Within the second period, ataluren will be taken 3 times per day with meals for 28 days at doses of 10 mg/kg (morning), 10 mg/kg (midday), and 20 mg/kg (evening); there will then be an interval of approximately 14 days without ataluren. During the study, ataluren activity, safety, and pharmacokinetics will be evaluated, and MMacid levels in blood and urine will be measured periodically.

Eligibility criteria: Major Inclusion Criteria:

* Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if applicable)
* Age ≥2 years
* Phenotypic evidence of methylmalonic acidemia (MMA) based on the presence of characteristic clinical symptoms or signs and an elevated plasma MMacid level (\>0.27 micromole/liter (umol/L)
* Presence of a nonsense mutation in at least 1 allele of the mutase (mut), Cobalamin A (cblA), or Cobalamin B (cblB) gene
* Glomerular filtration rate ≥30 milliliters (mL)/minutes/1.73 meters squared (m\^2), serum aminotransferase values ≤2.5\*the upper limit of normal, serum bilirubin ≤1.5\*the upper limit of normal, plasma adrenocorticotropic (ACTH) within normal limits
* Willingness and ability to comply with scheduled visits, drug administration plan, study restrictions, and study procedures

Major Exclusion Criteria:

* Known hypersensitivity to any of the ingredients or excipients of the study drug
* Any change in chronic treatment for MMA within 2 months prior to start of screening laboratory assessments
* Episode of metabolic decompensation within 1 month prior to start of Screening laboratory assessments
* History of organ transplantation
* Ongoing dialysis for renal dysfunction

Primary outcomes:
measure: Plasma Methylmalonic Acid (MMacid) Levels
timeFrame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
Secondary outcomes:
measure: Urinary MMacid Levels
timeFrame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
measure: Plasma Propionylcarnitine Levels
timeFrame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
measure: Urine Methylcitric Acid Levels
timeFrame: Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Baseline up to Day 112 (end of study follow-up)
measure: Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results
timeFrame: Baseline up to Day 112 (end of study follow-up)
measure: Number of Participants With a Metabolic Decompensation Episode
timeFrame: Baseline up to Day 112 (end of study follow-up)
measure: Number of Participants Compliant With Study Treatment
timeFrame: Baseline up to Day 29 of Cycles 1 and 2
measure: Ataluren Plasma Exposure
timeFrame: Baseline on Day 0 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning dose and 0 (predose) of the midday dose]; Day 28 of Cycles 1 and 2 [0 (predose), 1, 2, 3, and 4 hours postdose of the morning, midday, and evening doses]
Other outcomes:
Locations:
city: Antwerp
country: Belgium
facility: ZNA Queen Paola Child Hospital and Provincial Centre for Metabolic Disorders
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Paris
country: France
facility: Necker-Enfants Malades Hospital
city: Duesseldorf
country: Germany
facility: University Children's Hospital
city: Milan
country: Italy
facility: Istituti Clinici di Perfezionamento, Milano
city: Naples
country: Italy
facility: Federico II University
city: Padova
country: Italy
facility: University Hospital, Department of Pediatrics
city: Zürich
country: Switzerland
facility: University Children's Hospital
city: London
country: United Kingdom
facility: Great Ormand Street Hospital
Study officials:
affiliation: PTC Therapeutics
name: Jay Barth, MD
role: STUDY_DIRECTOR
References:
citation: Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3;447(7140):87-91. doi: 10.1038/nature05756. Epub 2007 Apr 22.
citation: Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol. 2007 Apr;47(4):430-44. doi: 10.1177/0091270006297140.