Ataluren for Nonsense Mutation Methylmalonic Acidemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2 Study of Ataluren (PTC124®) as an Oral Treatment for Nonsense Mutation Methylmalonic Acidemia

Conditions
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Amino Acid Metabolism, Inborn Errors

Intervention / Treatment
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* Drug: Ataluren


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ataluren<br>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<br>* Ataluren will be provided as a vanilla-flavored powder to be mixed with water.<br>* Other names: PTC124;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary MMacid Levels | The normal urinary MMacid level is <4 millimole/mole (mmol/mol) creatinine. Urinary samples for MMacid levels were collected after a 2- to 4-hour fast. Urinary MMacid levels were measured by a standard GC/MS stable-isotope dilution method. | Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 | 
| Plasma Propionylcarnitine Levels | Plasma samples for propionylcarnitine levels were evaluated to detect disease activity. The level of propionylcarnitine was measured using gas chromatography and LC/MS-MS. An increase in propionylcarnitine values indicates greater disease activity. | Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 | 
| Urine Methylcitric Acid Levels | Urine methylcitric acid levels were evaluated to detect disease activity. An increase in methylcitric acid values indicates greater disease activity. | Baseline and Day 28 and Day 29 (last day of dosing) of Cycles 1 and 2 | 
| Number of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Day 112 (end of study follow-up) | 
| Number of Participants With Potentially Clinically Significant Laboratory (Hematology and Biochemistry) Abnormal Results | Hematological and biochemistry data graded according to Common Terminology Criteria for Adverse Events (CTCAE) severity grade (Grade 1 [mild], Grade 2 [moderate], Grade 3 [severe], Grade 4 [life-threatening], or Grade 5 [fatal]). Life-threatening (Grade 4) or severe (Grade 3) laboratory abnormalities were considered clinically significant. Recurrent or persistent moderate (Grade 2) abnormalities were also considered clinically significant in certain circumstances. Hematology assessments: white blood cell count with differential, hemoglobin, hematocrit, other red cell parameters, and platelet count. Biochemistry assessments: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, magnesium, calcium, phosphorus, uric acid, glucose, total protein, albumin, bilirubin (direct and indirect), aspartate aminotransferase, alanine aminotransferase, glutamyl transferase, creatine kinase, lactate dehydrogenase, alkaline phosphatase, total cholesterol, and triglycerides. | Baseline up to Day 112 (end of study follow-up) | 
| Number of Participants With a Metabolic Decompensation Episode | A metabolic decompensation episode is characterized by vomiting, hypotonia, and alteration of consciousness associated with metabolic acidosis and hyperammonemia. | Baseline up to Day 112 (end of study follow-up) | 
| Number of Participants Compliant With Study Treatment | For each participant, compliance was described in terms of the proportion of drug actually taken relative to the amount that should have been taken during the time the participant was on study (both Cycle 1 and Cycle 2). | Baseline up to Day 29 of Cycles 1 and 2 | 
| Ataluren Plasma Exposure | Validated quantitative methods employing high performance liquid chromatography with tandem mass spectroscopy (HPLC-MS-MS) were used to determine plasma concentrations of unchanged ataluren. The median and full range of the total of all of the ataluren plasma concentrations collected at Baseline and at Day 28 are reported. | 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] |