BioMarin Pharmaceutical Inc. (Nasdaq: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.
Listing of Posters and Presentations at 2015 American
College of Medical Genetics and Genomics Annual
Conference
Phenylketonuria
TITLE |
AUTHORS |
Oral Presentation: A
Randomized, Placebo-Controlled, Double-Blind Study of Sapropterin
to Treat Symptoms of ADHD and Executive Dysfunction in Children and
Adolescents with Phenylketonuria |
Grant ML, Cohen-Pfeffer JL (co-first
authors), McCandless SE, Stahl SM, Bilder DA, Jurecki ER, Yu S,
Sanchez-Valle A, Dimmock D |
Evaluation of Multiple Dosing Regimens
in Phase 2 Studies of rAvPAL-PEG (BMN 165, Pegvaliase) for Control
of Blood Phenylalanine Levels in Adults with
Phenylketonuria |
Thomas JA, Longo N, Zori R, Burton BK,
Wasserstein M, Grange DK, Vockley J, Hillman R, Harding C, Shur N,
Adams D, Rice GM, Rizzo WB, Whitley C, Goodin KM, McBride KL,
Decker C, Merilainen M, Li M, Schweighardt B, Dimmock DP |
Evaluation of Long-term Safety and
Efficacy with rAvPAL-PEG (BMN 165, pegvaliase) for Control of Blood
Phenylalanine Levels in Adults with Phenylketonuria
(PKU) |
Longo N, Thomas JA, Wasserstein MP,
Burton BK, Vockley J, Grange DK, Hillman R, Harding C, Dimmock D,
Shur N, Adams D, Rizzo WB, Whitley C, Goodin KM, Decker C, Bolt K,
Chen Y, Schweighardt B, Zori R |
Neuropsychiatric Comorbidities in
Adults with Phenylketonuria: A Retrospective Cohort
Study |
Bilder DA, Kobori JA, Cohen-Pfeffer JL,
Johnson EM, Jurecki ER, Grant M |
Phase 2 Studies Contribute to
rAvPAL-PEG (BMN 165, pegvaliase) Phase 3 Trial Design |
Harding C, Longo N, Thomas JA, Burton
BK, Zori R, Bilder DA, Posner J, Lieberman P, Merilainen M, Gu Z,
Schweighardt B, Weng HH, Levy H |
Evaluation of an Induction, Titration,
and Maintenance Dosing Regimen in a Phase 2 Study of rAvPAL-PEG
(BMN165, pegvaliase) for Control of Blood Phenylalanine Levels in
Adults with Phenylketonuria (PKU) |
Zori R, Thomas JA, Shur N, Rizzo WB,
Decker C, Merilainen M, Li M, Schweighardt B, Longo N |
Mucopolysaccharidosis
TITLE |
AUTHORS |
Urine Keratan Sulfate (uKS) Elevation
in Lysosomal Storage Disorders (LSDs): Comparison of uKS levels in
Morquio/MPS IV versus non-Morquio LSDs |
Wood T, Fietz M, Auray-Blais C,
Ellsworth K, Giugliani R, Harmatz P, Lavoie P, Millington D,
Trinh M, van Vlies N, Wijburg F, Zhang H, Miller N |
Urine Keratan Sulfate (uKS) in Morquio
A Patients Measured via LC-MS/MS Method: Improved KS Detection as
Compared to Dye-Based Methods and Report of Age-Specific uKS
Reference Ranges |
Pasquali M, Wood T, Auray-Blais C,
Ellsworth K, Fietz M, Giugliani R, Harmatz P, Izzo E, Lavoie P, la
Marca G, Millington D, Trinh M, van Vlies N, Wijburg F, Zhang H,
Miller N |
Indication for Kuvan
Kuvan® (sapropterin dihydrochloride) Tablets for Oral Use and
Powder for Oral Solution are approved to reduce blood Phe levels in
people with a certain type of Phenylketonuria (PKU). Kuvan is to be
used with a Phe-restricted diet.
Important Safety Information
It is not possible to know if Kuvan will work for you without a
trial of the medicine. Your doctor will check your blood Phe levels
when you start taking Kuvan to see if the medicine is working.
Starting Kuvan does not eliminate the need for ongoing dietary
management. Any change to your diet may impact your blood Phe
level. Follow your doctor's instructions carefully. Your doctor and
dietitian will continue to monitor your diet and blood Phe levels
throughout your treatment with Kuvan to make sure your
blood Phe levels are not too high or too low. If you have
a fever, or if you are sick, your Phe level may go up. Tell your
doctor and dietitian as soon as possible so they can make any
necessary changes to your treatment.
Children younger than 7 years old treated with Kuvan doses of 20
mg/kg per day are at an increased risk for low levels of blood Phe
compared with children 7 years and older. Frequent blood monitoring
is recommended in this population to ensure that blood Phe levels
do not fall too low.
Tell your doctor if you have ever had liver or kidney problems,
have poor nutrition or have a loss of appetite, are pregnant or
plan to become pregnant, or are breastfeeding or plan to
breastfeed.
Kuvan is a prescription medicine and should not be taken by
people who are allergic to any of its ingredients. Kuvan and other
medicines may interact with each other. Tell your doctor about
all the medicines you take, including prescription
and over-the-counter medicines, vitamins, herbal and dietary
supplements.
If you forget to take your dose of Kuvan, take it as soon as you
remember that day. Do not take 2 doses in a day. If you take too
much Kuvan, call your doctor for advice.
The most common side effects reported when using Kuvan are
headache, runny nose and nasal congestion, sore throat, diarrhea,
vomiting, and cough. Additional adverse reactions reported in
connection with worldwide marketing include sore throat, heartburn
or pain in the esophagus, inflammation of the lining of the
stomach, indigestion, stomach pain, and nausea. These are not all
the possible side effects seen with Kuvan. Call your doctor for
medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
Kuvan can cause serious side effects, including:
- Severe allergic reactions. Stop taking Kuvan
and get medical help right away if you develop any
of these symptoms of a severe allergic reaction:
- Wheezing or trouble breathing
- Nausea
- Flushing
- Lightheadedness or fainting
- Coughing
- Rash
- Inflammation of the lining of the stomach
(gastritis). Gastritis can happen with Kuvan and may be
severe. Call your doctor right away if you have
any:
- Severe upper stomach-area discomfort or pain
- Blood in your vomit or stool
- Nausea and vomiting
- Black, tarry stools
- Too much or constant activity (hyperactivity) can
happen with Kuvan. Tell your doctor if
you have any signs of hyperactivity, including fidgeting, moving
around or talking too much.
For more information, call BioMarin Patient and Physician
Support (BPPS) at 1-866-906-6100. Please read the full Patient
Information online
(http://www.kuvan.com/downloads/KUVAN_Patient_Information.pdf).
About BioMarin
BioMarin develops and commercializes innovative
biopharmaceuticals for serious diseases and medical conditions. The
company's product portfolio comprises five approved products and
multiple clinical and pre-clinical product candidates. Approved
products include Vimizim® (elosulfase alfa) for MPS IVA, a product
wholly developed and commercialized by BioMarin; Naglazyme®
(galsulfase) for MPS VI, a product wholly developed and
commercialized by BioMarin; Aldurazyme® (laronidase) for MPS I, a
product which BioMarin developed through a 50/50 joint venture with
Genzyme Corporation; Kuvan® (sapropterin dihydrochloride) Powder
for Oral Solution and Tablets, for phenylketonuria (PKU), developed
in partnership with Merck Serono, a division of Merck KGaA of
Darmstadt, Germany and Firdapse® (amifampridine), which has been
approved by the European Commission for the treatment of Lambert
Eaton Myasthenic Syndrome (LEMS). Product candidates include
drisapersen, an exon skipping oligonucleotide, which is currently
undergoing regulatory submission for the treatment of Duchenne
muscular dystrophy (exon 51), pegvaliase (PEGylated recombinant
phenylalanine ammonia lyase, formerly referred to as BMN 165 or PEG
PAL), which is currently in Phase 3 clinical development for the
treatment of PKU, talazoparib (formerly referred to as BMN 673), a
poly ADP-ribose polymerase (PARP) inhibitor, which is currently in
Phase 3 clinical development for the treatment of germline BRCA
breast cancer, reveglucosidase alfa (formerly referred to as BMN
701), a novel fusion protein of insulin-like growth factor 2 and
acid alpha glucosidase (IGF2-GAA), which is currently in Phase 3
clinical development for the treatment of Pompe disease, BMN 111, a
modified C-natriuretic peptide, which is currently in Phase 2
clinical development for the treatment of achondroplasia, BMN 044,
BMN 045 and BMN 053, exon skipping oligonucleotides, which are
currently in Phase 2 clinical development for the treatment of
Duchenne muscular dystrophy (exons 44, 45 and 53), cerliponase alfa
(formerly referred to as BMN 190), a recombinant human tripeptidyl
peptidase-1 (rhTPP1) for the treatment of CLN2 disorder, a form of
Batten disease, which is currently in Phase 1, BMN 270, an
AAV-factor VIII vector, for the treatment of hemophilia A and BMN
250, a novel fusion of alpha-N-acetyglucosaminidase (NAGLU) with a
peptide derived from insulin-like growth factor 2 (IGF2), for the
treatment of MPS IIIB.
For additional information, please visit www.BMRN.com.
Information on BioMarin's website is not incorporated by reference
into this press release.
BioMarin®, Naglazyme®, Kuvan®, Firdapse® and VIMIZIM® are
registered trademarks of BioMarin Pharmaceutical Inc.
Aldurazyme® is a registered trademark of BioMarin/Genzyme
LLC.
CONTACT: Investors:
Traci McCarty
BioMarin Pharmaceutical Inc.
(415) 455-7558
Media:
Debra Charlesworth
BioMarin Pharmaceutical Inc.
(415) 455-7451
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