BioMarin Reports One Oral, Seven Poster Presentations at ACMGG Annual Meeting

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BioMarin Pharmaceutical Inc.
BMRN
today announced the results of a post-hoc sub-analysis of the PKU-016 or ASCEND study, the largest randomized controlled trial evaluating neurocognitive outcomes in patients with phenylketonuria (PKU) treated with the approved therapy Kuvan® (sapropterin dihydrochloride)at the 2015 American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting. The sub-analysis included 86 subjects 8 to 17 years of age with PKU who were randomized to blinded treatment with Kuvan (N = 43) or placebo (N = 43) for 13 weeks, after which all individuals received open label Kuvan for an additional 13 weeks. This analysis evaluated the effects of Kuvan treatment on blood phenylalanine (Phe) concentration, attention deficit hyperactivity disorder–like symptoms, and executive function defects in children and adolescents with PKU. Symptoms of ADHD were evaluated by using the attention deficit hyperactivity rating scale (ADHD-RS) commonly used to evaluate symptoms of inattentiveness and hyperactivity. There was a statistically significant difference between the baseline and week 13 ADHD-RS total score with Kuvan compared with placebo (p = 0.01). "This sub-analysis of our larger data set helps us further understand how we can help with the care of children with PKU and symptoms of inattentiveness and hyperactivity," said Hank Fuchs, M.D., Chief Medical Officer at BioMarin. "This new information emphasizes the importance of neurocognitive assessments in this population and its apparent link to higher Phe levels, which may be reversible." In addition to the total ADHD-RS score, the sub-analysis showed a statistically significant (p= 0.04) improvement in the inattention subscale score and statistically significance (p= 0.016) improvement in the hyperactivity subscale score for the Kuvan group compared with placebo from baseline to week 13. The Behavior Rating Inventory of Executive Function (BRIEF) assessment for School-Aged Children (5 to18 years of age) is a validated instrument used to assess executive function. The BRIEF is composed of two indices, the Behavioral Regulation Index (BRIEF-BRI) and Metacognition Index (BRIEF-MI), and the overall score makes up the Global Executive Composite (BRIEF-GEC). The BRIEF-GEC score (p= 0.04) in the Kuvan group showed statistically significant improvements. The Metacognition Index (MI) score was not statistically significantly (p= 0.051). Study Design PKU-016 or ASCEND was a double-blind, placebo-controlled, randomized study to evaluate the safety and therapeutic effects of Kuvan on neuropsychiatric symptoms in subjects with PKU. The study enrolled 206 patients, 118 of whom are responders to Kuvan as determined by a drop in blood Phe levels. The study includes a two-week screening period, a 13-week double-blind randomized treatment period and a 13-week open-label treatment period at a dose of 20 mg/kg/day. The primary endpoint of the study was evaluated using an attention deficit hyperactivity rating scale (ADHD-RS), commonly used to evaluate symptoms of inattentiveness and hyperactivity. Kuvan improved the ADHD-RS (p=0.085), but did not reach statistical significance. However, the study did show a statistically significant change in the inattention component of the score (p=0.036). The sub-analysis evaluated the impact of Kuvan on ADHD symptoms and executive function deficits in a pediatric PKU population. The Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) is an instrument for assessing treatment response in patients who do not have metabolic disorders causing inattention and hyperactivity. The scale has been widely used to evaluate therapies approved for ADHD in patients without metabolic brain disease. Because inattention observed in PKU patients is similar in clinical presentation, the ADHD-RS was used to measure outcomes. The Behavior Rating Inventory of Executive Function (BRIEF) rating scale is an instrument to assess executive function behaviors. The 86-item questionnaire forms a Global Executive Composite, which is comprised of two indices: Behavioral Regulation and Metacognition and eight sub-domains exploring specific deficits in executive functioning.
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