BioMarin Announces Kuvan Significantly Improves Inattentiveness in Kuvan Responding PKU Patients

BioMarin Announces Kuvan Significantly Improves Inattentiveness in Kuvan
Responding PKU Patients

SAN RAFAEL, Calif., Feb. 19, 2013 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical
Inc. (Nasdaq:BMRN) announced today results from the PKU-016 ASCEND study, the
largest randomized controlled trial evaluating neuropsychiatric outcomes in
phenylketonuria (PKU) patients treated with the approved drug Kuvan
(sapropterin dihydrochloride).

The study evaluated medically important symptoms similar to attention deficit
hyperactivity disorder (ADHD) in PKU patients whose blood levels of
phenylalanine (Phe) are reduced by Kuvan. 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), driven by a statistically significant change
in the inattention component of the score (p=0.036).PKU patients have a lower
degree of hyperactivity as compared to ADHD patients, which likely resulted in
the less prominent benefits in this domain. The neurocognitive benefit of
Kuvan in patients who respond to Kuvan was corroborated by the Behavior Rating
Inventory of Executive Function, or BRIEF, in children who were rated by their
parents. Moderate to severe inattention deficit affected approximately
one-third of patients in the study.Preliminary analysis of safety indicates
that it is consistent with the general experience with Kuvan.

"We are encouraged to see the positive trend in the predetermined ADHD
primary endpoint, which was driven by a statistically significant change in
the sub-domain of inattentiveness," said Hank Fuchs, M.D., Chief Medical
Officer of BioMarin."We believe these results will provide useful information
to the medical community on clinically relevant benefits of Kuvan and
facilitate adoption of the product.Further, the results will help inform the
design of the Phase 3 PEG-PAL program with key learnings about the measurement
tools.We are encouraged by the results and plan to discuss the submission of
this data with the FDA for possible inclusion in the Kuvan label."

In addition to the ADHD-RS and BRIEF instruments, other exploratory tests in
the PKU-016 study of neuropsychiatric deficit in PKU patients demonstrated a
higher level of impairment in PKU patients than the normal population.Further
analyses are underway to complete the evaluation of Kuvan on these outcome

Dr. Robert Hendren, Professor and Vice Chair of Psychiatry and Director of
Child and Adolescent Psychiatry at the University of California, San Francisco
commented, "These data document what has been known by PKU clinicians for a
long time; namely, mental health impairment is a prevalent and important
problem affecting PKU patients and that improved control of their metabolic
condition translates into improved control of the impairment in mental

Abstracts will be submitted to the International Congress of Inborn Errors of
Metabolism (ICIEM) and American Society of Human Genetics (ASHG) meetings this

Study Design

PKU-016 is 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 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.

                              Placebo Kuvan 
All patients (N)               108     98    Total= 206
Kuvan responders (N)           57      61    Total =118
ADHD-like Kuvan responders (N) 19      19    Total = 38
                                             Difference = -4.1 (in favor of
Change from baseline ADHD-RS   -5.4    -9.5  Kuvan) p=0.085, Kuvan versus
Change from baseline                         Difference -3.4 (in favor of
inattentiveness domain         -2.6    -6.0  Kuvan) p=0.036, Kuvan versus

About BioMarin

BioMarin develops and commercializes innovative biopharmaceuticals for serious
diseases and medical conditions. The company's product portfolio comprises
four approved products and multiple clinical and pre-clinical product
candidates. Approved products include Naglazyme® (galsulfase) for
mucopolysaccharidosis VI (MPS VI), a product wholly developed and
commercialized by BioMarin; Aldurazyme® (laronidase) for mucopolysaccharidosis
I (MPS I), a product which BioMarin developed through a 50/50 joint venture
with Genzyme Corporation; Kuvan® (sapropterin dihydrochloride) 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 BMN-110
(N-acetylgalactosamine 6-sulfatase), formally referred to as GALNS, which
successfully completed Phase III clinical development for the treatment of MPS
IVA, PEG-PAL (PEGylated recombinant phenylalanine ammonia lyase), which is
currently in Phase II clinical development for the treatment of PKU, BMN-701,
a novel fusion protein of insulin-like growth factor 2 and acid alpha
glucosidase (IGF2-GAA), which is currently in Phase I/II clinical development
for the treatment of Pompe disease, BMN-673, a poly ADP-ribose polymerase
(PARP) inhibitor, which is currently in Phase I/II clinical development for
the treatment of genetically-defined cancers, and BMN-111, a modified
C-natriuretic peptide, which is currently in Phase I clinical development for
the treatment of achondroplasia. For additional information, please visit Information on BioMarin's website is not incorporated by
reference into this press release.

The BioMarin Pharmaceutical Inc. logo is available at

Forward-Looking Statement

This press release contains forward-looking statements about the business
prospects of BioMarin Pharmaceutical Inc., including, without limitation,
statements about: regulatory actions related to Kuvan, the development of
BioMarin's PEG-PAL program generally, the design of the planed Phase 3 trial
of PEG-PAL, and expectations regarding the final results of the ASCEND trial
following final statistical analysis, the impact of the ASCEND trial on Kuvan
adoption. These forward-looking statements are predictions and involve risks
and uncertainties such that actual results may differ materially from these
statements. These risks and uncertainties include, among others:differences
in the final analysis of the data from the ASCEND trial, results and timing of
current and planned preclinical studies and clinical trials of PEG-PAL; the
content and timing of decisions by the U.S. Food and Drug Administration,
particularly as related to any amendment to the Kuvan label, the European
Commission and other regulatory authorities; physicians' interpretation of the
relevance of the final trial data and its impact on their prescribing
practices; and those factors detailed in BioMarin's filings with the
Securities and Exchange Commission, including, without limitation, the factors
contained under the caption "Risk Factors" in BioMarin's Quarterly Report on
Form 10-Q for the Quarter ended September 30, 2012. Stockholders are urged not
to place undue reliance on forward-looking statements, which speak only as of
the date hereof. BioMarin is under no obligation, and expressly disclaims any
obligation to update or alter any forward-looking statement, whether as a
result of new information, future events or otherwise.

BioMarin®, Naglazyme®, Kuvan® and Firdapse™ are registered trademarks of
BioMarin Pharmaceutical Inc.

Aldurazyme® is a registered trademark of BioMarin/Genzyme LLC.

CONTACT: Investors:
         Eugenia Shen
         BioMarin Pharmaceutical Inc.
         (415) 506-6570
         Debra Charlesworth
         BioMarin Pharmaceutical Inc.
         (415) 455-7451

BioMarin Pharmaceutical Inc. Logo
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