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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