Ataluren for Nonsense Mutation Methylmalonic Acidemia

Study Description

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Brief Summary:

Methylmalonic acidemia 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 patients with mutations in the MCM gene, and approximately 20 to >50% of patients with mutations in one of the AdoCbl genes. Ataluren (PTC124) 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 patients with methylmalonic acidemia due to a nonsense mutation. The main purpose of this study is to understand whether ataluren can safely decrease MMacid levels.

Condition or disease	Intervention/treatment	Phase
Amino Acid Metabolism, Inborn Errors	Drug: Ataluren (PTC124)	Phase 2

Detailed Description:

In this study, patients with methylmalonic acidemia due to a nonsense mutation will be administered an investigational drug called ataluren (PTC124). Evaluation procedures to determine if a patient qualifies for the study will be performed within 14 days prior to the start of drug administration. Eligible patients who elect to enroll in the study will then participate in 2 drug administration and follow-up periods. Within the first period, ataluren (PTC124) 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 approximately 21 days without ataluren (PTC124). Within the second period, ataluren (PTC124) 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 (PTC124). During the study, ataluren (PTC124) activity, safety, and pharmacokinetics will be evaluated, and MMacid levels in blood and urine will be measured periodically.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	11 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia
Study Start Date :	June 2010
Actual Primary Completion Date :	July 2012
Actual Study Completion Date :	October 2012

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Ataluren (PTC124)

Drug: Ataluren (PTC124); Ataluren (PTC124) will be provided as a vanilla-flavored powder to be mixed with water. Ataluren (PTC124) will be taken 3 times per day, with dosing based on the patient's body weight. Ataluren (PTC124) will be taken at two different dose levels. In Cycle 1, the dose level is 5 mg/kg in the morning, 5 mg/kg at midday, and 10 mg/kg in the evening for 28 days. In Cycle 2, the dose level is 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening for 28 days.

Outcome Measures

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Primary Outcome Measures :

1. Change in plasma MMacid levels [ Time Frame: Baseline and 4 weeks in each cycle ]

Secondary Outcome Measures :

1. Change in urinary MMacid levels [ Time Frame: Baseline and 4 weeks in each cycle ]
2. Effects of ataluren (PTC124) on additional markers of disease activity [ Time Frame: Baseline and 4 weeks in each cycle ]
3. Safety profile of ataluren (PTC124) as assessed by adverse events and laboratory data [ Time Frame: Baseline and 4 weeks in each cycle ]
4. Compliance with study drug administration [ Time Frame: Baseline and 4 weeks in each cycle ]
5. Ataluren (PTC124) plasma exposure [ Time Frame: Baseline and 4 weeks in each cycle ]

Eligibility Criteria

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Ages Eligible for Study:	2 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Major Inclusion Criteria:

• Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if applicable)
• Age ≥2 years
• Phenotypic evidence of MMA based on the presence of characteristic clinical symptoms or signs and an elevated plasma MMacid level (>0.27 μmol/L)
• Presence of a nonsense mutation in at least 1 allele of the mut, cblA, or cblB gene
• Glomerular filtration rate ≥30 mL/min/1.73 m², serum aminotransferase values ≤2.5 x the upper limit of normal, serum bilirubin ≤1.5 x the upper limit of normal, plasma 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 methylmalonic acidemia 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

Contacts and Locations

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Locations

Belgium
ZNA Queen Paola Child Hospital and Provincial Centre for Metabolic Disorders
Antwerp, Belgium
France
Hôpital Edouard Herriot
Lyon, France
Necker-Enfants Malades Hospital
Paris, France
Germany
University Children's Hospital
Duesseldorf, Germany
Italy
Istituti Clinici di Perfezionamento, Milano
Milan, Italy
Federico II University
Naples, Italy
University Hospital, Department of Pediatrics
Padova, Italy
Switzerland
University Children's Hospital
Zürich, Switzerland
United Kingdom
Great Ormand Street Hospital
London, United Kingdom

Sponsors and Collaborators

PTC Therapeutics

Genzyme, a Sanofi Company

Investigators

Study Director:	Jay Barth, MD	PTC Therapeutics

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

PTC Therapeutics' website 

Publications:

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. Epub 2007 Apr 22.

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.

Responsible Party:	PTC Therapeutics
ClinicalTrials.gov Identifier:	NCT01141075 History of Changes
Other Study ID Numbers:	PTC124-GD-012-MMA
First Posted:	June 10, 2010
Last Update Posted:	January 18, 2018
Last Verified:	January 2018

Additional relevant MeSH terms:

Metabolism, Inborn Errors; Amino Acid Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases