BioMarin Pharmaceutical announces FDA approval for Kuvan

BioMarin Pharmaceutical Inc. has announced that the U.S. Food and Drug Administration (FDA) has granted marketing approval for Kuvan(TM) (sapropterin dihydrochloride) Tablets, the first specific drug therapy approved for the treatment of phenylketonuria (PKU).

Shipments to the distribution channel will commence tomorrow, and BioMarin will begin promotion of Kuvan immediately.

"The approval of Kuvan represents an important milestone for PKU patients and their families and also for BioMarin. We are extremely pleased to bring this promising treatment option to market in just a little over three years since the IND filing, and we are now ready for an immediate launch," said Jean-Jacques Bienaime, Chief Executive Officer of BioMarin. "We would like to thank all the patients, their families and physicians, our corporate partners, the FDA, and BioMarin employees for their hard work and dedication in making Kuvan a reality."

"In clinical trials, Kuvan has been shown to help control blood Phe levels in PKU patients, and I am thrilled that this new therapy is now commercially available to the PKU community," stated Dr. Barbara Burton, Professor of Pediatrics, Northwestern University Feinberg School of Medicine; Director, PKU Clinic at Children's Memorial Hospital; and Clinical Investigator in the Kuvan Phase 2 and Phase 3 trials. "With Kuvan now approved, physicians and patients have, for the first time, a drug therapy option to manage the disease."

Kuvan is indicated to reduce blood phenylalanine (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. To determine if there is a response to Kuvan, the recommended starting dose of Kuvan is 10 mg/kg/day taken once daily for up to a month. If there is no response, the drug dose may be increased to 20 mg/kg/day for up to a month. The dose may be adjusted within a range of 5 to 20 mg/kg/day in patients who respond to Kuvan. Kuvan is developed in partnership with Merck Serono, a division of Merck KGaA, Darmstadt, Germany.

Clinical Trial Study Results

The efficacy and safety of Kuvan were evaluated in four clinical studies in patients with PKU.

Study 1 -- A multicenter, open-label, uncontrolled clinical trial of 489 patients with PKU, ages 8 to 48 years (mean 22 years), who had baseline blood Phe levels greater than or equal to 450 umol/L and who were not on Phe- restricted diets. All patients received treatment with Kuvan 10 mg/kg/day for 8 days. Response to Kuvan treatment was defined as a greater than or equal to 30% decrease in blood Phe from baseline. Results: At Day 8, 96 patients (20%) were identified as responders.

Study 2 -- A multicenter, double-blind, placebo-controlled study of 88 patients with PKU who responded to Kuvan in Study 1. After a washout period from Study 1, patients were randomized equally to either Kuvan 10 mg/kg/day (N=41) or placebo (N=47) for 6 weeks. Efficacy was assessed by the mean change in blood Phe level from baseline to Week 6 in the Kuvan-treated group as compared to the mean change in the placebo group. Results: At baseline, the mean (+/-SD) blood Phe level was 843 (+/-300) umol/L in the Kuvan-treated group and 888 (+/-323) umol/L in the placebo group. At Week 6, the Kuvan-treated group had a mean (+/-SD) blood Phe level of 607 (+/-377) umol/L, and the placebo group had a mean blood Phe level of 891 (+/-348) umol/L. At Week 6, the Kuvan- and placebo-treated groups had mean changes in blood Phe level of -239 and 6 umol/L, respectively (mean percent changes of -29% (+/-32) and 3% (+/-33), respectively). The difference between the groups was statistically significant (p < 0.001). Change in blood Phe was noted in the Kuvan-treated group at Week 1 and sustained through Week 6.

Study 3 -- A multicenter, open-label, extension study in which 80 patients who responded to Kuvan treatment in Study 1 and completed Study 2 underwent 6 weeks of forced dose-titration with 3 different doses of Kuvan. Treatments consisted of 3 consecutive 2-week courses of Kuvan at doses of 5, then 20, and then 10 mg/kg/day. Blood Phe level was monitored after 2 weeks of treatment at each dose level. Results: At baseline, mean (+/-SD) blood Phe was 844 (+/-398) umol/L. At the end of treatment with 5, 10, and 20 mg/kg/day, mean (+/-SD) blood Phe levels were 744 (+/-384) umol/L, 640 (+/-382) umol/L, and 581 (+/-399) umol/L, respectively.

Study 4 -- A multicenter study of 90 children with PKU, ages 4 to 12 years, who were on Phe-restricted diets and who had blood Phe levels less than or equal to 480 umol/L at screening. All patients were treated with open-label Kuvan 20 mg/kg/day for 8 days. Response to Kuvan was defined as a greater than or equal to 30% decrease in blood Phe from baseline at Day 8. Results: At Day 8, 50 patients (56%) had a greater than or equal to 30% decrease in blood Phe.

Post-marketing commitments include a PKU registry program, a 2-year extension study for pivotal study patients (ending in mid-2008 for U.S. patients), a single-dose QT cardiovascular study in healthy volunteers, and a 7-year open-label clinical study in an estimated 50 PKU patients less than or equal to 8 years of age. The latter study will verify that control of Phe levels with Kuvan provides a similar benefit on intellectual function as expected with dietary Phe restriction. It will also provide requested safety, efficacy, and pharmacokinetic data in PKU patients less than or equal to 4 years of age.