Ataluren for Nonsense Mutation Methylmalonic Acidemia

NCT01141075 | Terminated Phase 2 Results

• 1 other identifier: PTC124-GD-012-MMA
• Study Type: interventional
• Target: 11
• Locations: 6 countries
• Sites: 9

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.

Conditions

Amino Acid Metabolism, Inborn Errors

Outcome Measures

Primary Outcomes (1)

• Plasma Methylmalonic Acid (MMacid) Levels

  Normal plasma MMacid level is \<0.27 micromole/liters (umol/L). Plasma samples for MMacid levels were collected after a 2- to 4-hour fast. Plasma MMacid levels were measured by a standard gas chromatography/mass spectroscopy (GC/MS) stable-isotope dilution method. Individual participant values in plasma MMacid levels at Baseline and end-to-treatment (Day 28 and Day 29 \[last day of dosing\]) in each cycle were recorded.

  Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2

Secondary Outcomes (8)

• Urinary MMacid Levels

  Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2

• Plasma Propionylcarnitine Levels

  Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2

• Urine Methylcitric Acid Levels

  Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2

• Number of Participants With Adverse Events (AEs)

  Baseline up to Day 112 (end of study follow-up)

• Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results

  Baseline up to Day 112 (end of study follow-up)

Study Arms (1)

Ataluren

EXPERIMENTAL

Cycle 1: Ataluren treatment will be taken 3 times per day with meals for 28 days at doses of 5 mg/kg (morning), 5 mg/kg (midday), and 10 mg/kg (evening); there will then be an interval of 21 up to 42 days without treatment. Cycle 2: Ataluren treatment 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 14 days without treatment.

Drug: Ataluren

Interventions

Ataluren DRUG

Ataluren will be provided as a vanilla-flavored powder to be mixed with water.

Also known as: PTC124

Ataluren

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• PTC Therapeutics: lead
• Genzyme, a Sanofi Company: collaborator

Study Sites (9)

ZNA Queen Paola Child Hospital and Provincial Centre for Metabolic Disorders

Antwerp, Belgium

Location

Hôpital Edouard Herriot

Lyon, France

Location

Necker-Enfants Malades Hospital

Paris, France

Location

University Children's Hospital

Düsseldorf, Germany

Location

Istituti Clinici di Perfezionamento, Milano

Milan, Italy

Location

Federico II University

Naples, Italy

Location

University Hospital, Department of Pediatrics

Padua, Italy

Location

University Children's Hospital

Zurich, Switzerland

Location

Great Ormand Street Hospital

London, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 17450125 BACKGROUND

• 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.

  PMID: 17389552 BACKGROUND

Related Links

• PTC Therapeutics' website

MeSH Terms

Conditions

Amino Acid Metabolism, Inborn Errors

Interventions

ataluren

Condition Hierarchy (Ancestors)

Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Patient Advocacy
• Organization: PTC Therapeutics, Inc.

medinfo@ptcbio.com

1-866-562-4620

Study Officials

• Jay Barth, MD

  PTC Therapeutics

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 7, 2010
• First Posted: June 10, 2010
• Study Start: July 19, 2010
• Primary Completion: November 3, 2011
• Study Completion: November 3, 2011
• Last Updated: July 7, 2020
• Results First Posted: July 7, 2020

Record last verified: 2020-06

Locations

DE (1); FR (2); GB (1); IT (3); CH (1); BE (1)