BioMarin Announces One Oral and 7 Poster Presentations at the 2015 American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting

SAN RAFAEL, Calif., March 30, 2015 (GLOBE NEWSWIRE) -- 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


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


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 (

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 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

Source:BioMarin Pharmaceutical Inc.