First-of-Its-Kind Study Suggests Importance of Routine Mental Health Screening in the Care of Patients Suffering From Genetic Disease PKU

Additional posters at ACMG describe ongoing studies designed to further examine the use of KUVAN® for PKU, with endpoints of neuropsychiatric effects and long-term safety in children

Mar 18, 2011, 09:00 ET from BioMarin Pharmaceutical Inc.

NOVATO, Calif., March 18, 2011 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (Nasdaq: BMRN) announced today preliminary results from ADAPT (A Diversified Approach for PKU Treatment) in an abstract (Abstract #91, Mental Health Screening in Phenylketoniuria (PKU) Clinic) presented by Barbara Burton, MD at the 2011 annual American College of Medical Genetics (ACMG) conference in Vancouver, Canada.  ADAPT, which was funded by a grant from BioMarin, is the first multi-center study suggesting the importance of mental health screening at clinics for patients suffering from PKU.  Although numerous studies have demonstrated a definite correlation between blood Phe (phenylalanine) levels -- currently the sole indicator used to assess PKU treatment -- and psychiatric impairment, very few PKU clinics in the U.S. screen patients for neuropsychiatric function.  As a result, PKU patients with psychiatric impairment may go undiagnosed and untreated.  

"The interim results from ADAPT are important to clinicians, patients and patients' families because neuropsychiatric impairment can have a devastating impact on the success of overall PKU treatment; yet, mental health screening is not a part of standard PKU treatment practice," said study investigator Barbara Burton, MD, Professor of Pediatrics, Northwestern University Feinberg School of Medicine, Director, PKU Clinic, Children's Memorial Hospital. "ADAPT is the first multi-center study to suggest the importance of routine mental health screening at clinics for patients with PKU.   By adding simple questionnaires to a routine PKU clinic visit, treating clinicians have the potential to assess psychiatric symptoms and neurocognitive function and, if appropriate, refer patients to a mental health professional. This new standard of care could improve not only the care and quality of life of patients but also adherence to a PKU treatment plan."  

To measure neuropsychiatric impairment, patients already treated at PKU clinics were screened for psychiatric distress and cognitive impairment using standard neuropsychiatric assessment tools.  Individual test results were then correlated to patients' blood Phe levels.  The study found that patients who screened positive for psychiatric deficiencies had significantly higher blood Phe levels than patients who screened negative.

"Up until now, lowering blood Phe levels has been the only success measure in the treatment of PKU.  We believe ADAPT study results are an important step toward improving the overall care of PKU patients.  The data indicate that physicians have the opportunity to more easily identify those patients with neuropsychiatric and cognitive impairments, and better understand the impact of the link between Phe and these deficits, by simply incorporating mental health screening into the current standard of care," said Hank Fuchs, M.D., Chief Medical Officer of BioMarin.

Additional KUVAN Poster Presentations at ACMG

Other presentations at ACMG describe ongoing studies designed to further examine the use of KUVAN® (sapropterin dihydrochloride) Tablets for PKU, with endpoints of neuropsychiatric effects and long-term safety in children. KUVAN is the first and only FDA approved treatment to reduce blood Phe levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin (BH4-) responsive PKU, and is to be used in conjunction with a Phe-restricted diet.

  • PKU-016 / ASCEND Outcomes Study: Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in PKU Subjects – Clinical Study Design (S Stahl, et al, University of California, San Diego, Calf.)  [Poster 189 – March 18, 10:30-11:30 am]. The ongoing double-blind, placebo-controlled, randomized (1:1) 26-week outcomes study is evaluating the safety and efficacy of Sapropterin Dihydrochloride (the active ingredient in KUVAN) on endpoints that include measures of global functioning and the symptoms of attention deficit hyperactivity disorder (ADHD), depression, anxiety and executive functioning in 200 individuals with PKU.  
  • PKU-015 Interim Report: A Phase IIIB Study of Sapropterin Dihydrochloride (KUVAN) in Young Children with PKU (N Longo, Pediatrics, University of Utah and A Feigenbaum, Hospital for Sick Children, Toronto, Ontario) [Poster 96 – March 19, 10:30 - 11:30 am].  The poster presentation included preliminary data from a Phase IIIb, open-label, clinical study evaluating the long-term efficacy and safety KUVAN in preserving neurocognitive function in young (age 0 to six years of age) children with PKU.  Data will include the first 80 patients, of the total expected approximately 100 patients, as the study is ongoing.

Copies of the scientific abstracts presented at the ACMG conference are available upon request by calling the BioMarin Corporate Communications Department.

ADAPT Study Design and Results

A total of 89 patients (42 adults and 47 children) over five years of age with a confirmed PKU diagnosis received screening for  psychiatric distress and cognitive impairment as part of the standard of care over a 10-month period. Results from this program demonstrate that 29 percent of patients screened positive for psychiatric distress (n=26 / 89), with more adults testing positive compared to children (43% vs.17%). In addition, those patients who screened positive had significantly higher mean blood Phe levels compared to those who screened negative (749+/-575 umol/L vs. 468+/-351 umol/L, P=.02).  Findings also showed that the older the patients, the higher the blood Phe levels (r2= .37; P<.001). 

The study also demonstrated that patients who were being treated with diet plus KUVAN (n=36) had a lower mean blood Phe level compared to those being treated with diet alone (n=53; 409+/-323μmol/L compared to 647+/-488 umol/L, P=.03).

The screening tools included standardized self- and parent-reported questionnaires and included both a Psychiatric Distress Assessment for patients ages 5 – 17 years of age (Pediatric Symptom Checklist) and adults (Brief Symptom Inventory) and a Cognitive Impairment Assessment (child or adult versions of the Behavioral Rating Inventory of Executive Function (BRIEF)). Patients with positive screening results were referred to a mental health care professional within the medical center.  BSI symptom dimensions most commonly flagged among adults were Interpersonal Sensitivity, Paranoid Ideation, and Psychoticism.  Thirty percent of the patients (n=22) scored  positive on at least one BRIEF executive function clinical scale and 68 percent of those patients also screened positive for psychiatric distress.

The company-sponsored study was conducted at the University of Chicago Children's Hospital in Chicago, Illinois; the University of Utah in Salt Lake City, Utah; and Johns Hopkins University School of Medicine in Baltimore, Maryland.  Results reported at ACMG include only data from the University of Chicago.  Overall data from ADAPT will be collected and analyzed over the next few months.  ADAPT was designed to support and improve the current standard of care for patients with PKU by fostering the development of practical treatment algorithms, referral patterns and communication among multidisciplinary healthcare providers including geneticists, psychiatrists, social workers, dieticians, nurses and genetic counselors.


KUVAN® (sapropterin dihydrochloride) Tablets is the first and only FDA approved medication for PKU. This treatment reduces blood Phe levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin (BH4-) responsive PKU.  The active ingredient in KUVAN, sapropterin dihydrochloride, is the synthetic form of 6R-BH4 (tetrahydrobiopterin), a naturally occurring enzyme cofactor that works in conjunction with phenylalanine hydroxylase (PAH) to metabolize Phe into tyrosine. KUVAN is to be used in conjunction with a Phe-restricted diet. KUVAN has received orphan drug designation from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA).

About PKU

Phenylketonuria (PKU), a genetic metabolic disorder affecting approximately 50,000 diagnosed patients in the developed world, is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH). PAH is required for the metabolism / breakdown of phenylalanine (Phe), an essential amino acid found in most protein-containing foods. If the active enzyme PAH is not present in sufficient quantities, Phe accumulates to abnormally high levels in the blood and tissues, and becomes toxic to the brain. The consequences of sustained high blood Phe levels may result in a variety of serious neurological complications including severe mental retardation and brain damage, mental illness, seizures, tremors, behavioral problems and limited cognitive ability. Blood Phe levels may be managed by adhering to a life-long Phe-restricted diet regimen. However, some patients may not respond to diet alone and for many, maintaining a Phe-restricted diet is extremely challenging, especially during adolescence and adulthood. As a result, blood Phe levels in many PKU patients remain high, which may cause problems with neurocognitive functioning. Because of newborn screening efforts implemented in the 1960s and early 1970s, virtually all PKU patients under the age of 40 in developed countries have been diagnosed at birth. To learn more about PKU, please visit

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 phosphate), which has been approved by the European Commission for the treatment of Lambert Eaton Myasthenic Syndrome (LEMS). Product candidates include GALNS (N-acetylgalactosamine 6-sulfatase), which is currently in 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, and 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. For additional information, please visit

Important Safety Information

Prolonged exposure to elevated blood Phe levels in PKU patients can result in severe neurologic damage. The initiation of KUVAN therapy does not eliminate the need for careful monitoring of blood Phe levels and ongoing dietary management.

Some patients receiving KUVAN can experience significant drops in blood Phe levels. Patients should be monitored closely to ensure that blood Phe levels do not fall too low. Not all patients with PKU respond to treatment with KUVAN. Response to treatment can only be determined by a therapeutic trial of KUVAN.

KUVAN has not been studied in patients with liver or renal impairment. Patients who have these conditions should be carefully monitored when receiving KUVAN. Caution should be used with the administration of KUVAN to patients who are receiving levodopa and drugs that affect nitric oxide-mediated vasorelaxation or folate metabolism.

The most serious adverse reactions reported during KUVAN administration (regardless of relationship to treatment) were gastritis, spinal cord injury, streptococcal infection, testicular carcinoma, and urinary tract infection. Mild to moderate neutropenia was also noted. The most common adverse reactions were headache, diarrhea, abdominal pain, upper respiratory tract infection, pharyngolaryngeal pain, vomiting, and nausea.

Forward-Looking Statement

This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including, without limitation, statements about: the expectations of revenue and sales related to Naglazyme, Kuvan, Firdapse, and Aldurazyme; the financial performance of the BioMarin as a whole; the timing of BioMarin's clinical trials of GALNS, Firdapse, PEG-PAL, BMN -673 , BMN -701 and other product candidates; the continued clinical development and commercialization of Aldurazyme, Naglazyme, Kuvan, Firdapse, and its product candidates; and actions by regulatory authorities. 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: our success in the continued commercialization of Naglazyme, Kuvan, and Firdapse; Genzyme Corporation's success in continuing the commercialization of Aldurazyme; results and timing of current and planned preclinical studies and clinical trials, particularly with respect to GALNS, Firdapse, PEG-PAL, BMN 673 and BMN 701; our ability to successfully manufacture our products and product candidates; the content and timing of decisions by the U.S. Food and Drug Administration, the European Commission and other regulatory authorities concerning each of the described products and product candidates; the market for each of these products and particularly Aldurazyme, Naglazyme, Kuvan and Firdapse; actual sales of Aldurazyme, Naglazyme Kuvan and Firdapse; Merck Serono's activities related to Kuvan; 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 2009 Annual Report on Form 10-K, and the factors contained in BioMarin's reports on Form 10-Q. 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® and KUVAN® are registered trademarks of BioMarin Pharmaceutical Inc.

Firdapse™ is a trademark of BioMarin Huxley Ltd.

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




Eugenia Shen

Bob Purcell

BioMarin Pharmaceutical Inc.

BioMarin Pharmaceutical Inc.

(415) 506-6570

(415) 506-3267

SOURCE BioMarin Pharmaceutical Inc.