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.

BioMarin will offer support to PKU patients through its BioMarin Patient and Physician Support (BPPS) program. BPPS currently provides support for MPS VI patients treated with Naglazyme, and a similar support program will be available for PKU patients. For more information about the BioMarin Patient and Physician Support Program, please call 877-MY-KUVAN (877.695.8826). For more information about Kuvan, please visit http://www.Kuvan.com.

Conference Call

BioMarin will host a conference call and webcast to discuss the Kuvan approval today, Thursday, December 13, 2007, at 5:00 p.m. ET. This event can be accessed on the investor section of the BioMarin website at http://www.BMRN.com.

Date: December 13, 2007
Time: 5:00 p.m. ET
U.S. / Canada Dial-in Number:  800.510.9661
International Dial-in Number:  617.614.3452
Participant Code: 95299072
Replay Dial-in Number: 888.286.8010
Replay International Dial-in Number: 617.801.6888
Replay Code: 61294597

About Kuvan

Kuvan(TM) (sapropterin dihydrochloride) Tablets is indicated to reduce blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive phenylketonuria (PKU). Kuvan is to be used in conjunction with a Phe-restricted diet.

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. BioMarin and Merck Serono estimate that Kuvan could be a potential treatment option for approximately 30 percent to 50 percent of the estimated 50,000 identified PKU patients in the developed world.

Kuvan has received orphan drug designation from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Kuvan has received seven years of market exclusivity in the United States. In November 2007, Merck Serono submitted a Marketing Authorization Application (MAA) to the EMEA for sapropterin dihydrochloride as an oral treatment for patients suffering from HPA due to PKU or BH4 deficiency. If approved in the EU, it will receive 10 years of market exclusivity for this indication.

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.

To learn more about Kuvan and to access a copy of the full prescribing information, please visit http://www.Kuvan.com. Information on this website is not incorporated by reference into this press release.

About PKU

PKU, a genetic disorder affecting approximately 50,000 diagnosed patients in the developed world, is caused by a deficiency of the enzyme phenylalanine hydroxylase. PAH is required for the metabolism of phenylalanine, an essential amino acid found in most protein-containing foods. If the active enzyme is not present in sufficient quantities, Phe accumulates to abnormally high levels in the blood and becomes toxic to the brain, resulting in a variety of complications including severe mental retardation and brain damage, mental illness, seizures, tremors, and limited cognitive ability. As a result 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. Currently, PKU can only be managed by a Phe-restricted diet, which is supplemented by nutritional replacement products, like formulas and specially-manufactured foods; however, the strict diet is difficult for most patients to adhere to the extent needed for achieving adequate control of blood Phe levels. To learn more about PKU, please visit http://www.PKU.com. Information on this website is not incorporated by reference into this press release.

四氢生物蝶呤缺乏症治疗新药“科望”（Kuvan）获国家药监局批准

近日，默克雪兰诺公司研发的罕见病治疗新药科望（Kuvan）获得国家食品药品监督管理局（SFDA）批准。目前科望为国内首个可用于治疗四氢生物蝶呤（BH4）缺乏症的药物。

科望在中国获准上市，弥补了我国BH4缺乏症临床治疗的空白，为患儿及其家庭带来新希望。

研究结果表明，科望可有效控制BH4缺乏症患儿血液中的苯丙氨酸水平，减少脑部持续受损的风险，显著提升患儿的生活质量。在国外进行的600多例临床试验中效果良好。

BH4缺乏症是一种常染色体遗传性疾病，是迄今得以确认的5000～6000种人类的罕见病之一，也是当今少数的几种可控制的遗传性疾病之一。BH4缺乏症可通过对新生儿进行疾病筛查，检出高苯丙氨酸血症（HPA）后得到确诊。BH4缺乏症主要会对人的神经系统造成损害，导致患儿出现智力低下、癫痫等症状。 

据估算，我国每年约2000万新生儿中约100～200人可能罹患BH4缺乏症，即平均每两天就可能有1个BH4缺乏症的孩子降生。由于BH4缺乏症是高苯丙氨酸血症的一个亚类，其发病率则更为罕见。

科望分别于2007年12月和2008年12月获得了美国FDA及欧盟EMA的快速批准，并被授予了孤儿药的身份。

注册证号 H20100663
原注册证号 
产品名称（中文） 盐酸沙丙蝶呤片
产品名称（英文） Sapropterin Dihydrochloride Tablets
商品名（中文） 科望
商品名（英文） Kuvan
剂型（中文） 片剂
规格（中文） 100mg（以C9H15N5O3·2HCl计）
注册证号备注 
包装规格（中文） 30片/瓶、120片/瓶
生产厂商（中文） 
生产厂商（英文） Lyne Laboratories
厂商地址（中文） 
厂商地址（英文） 10 Burke Drive,Brockton，MA 02301，USA
厂商国家（中文） 美国
厂商国家（英文） U.S.A.
分包装批准文号 
发证日期 2010-09-25
有效期截止日 2015-09-24
分包装企业名称 
分包装企业地址 
分包装文号批准日期 
分包装文号有效期截止日 
产品类别 化学药品
药品本位码 86978635000200
药品本位码备注 
公司名称（中文） 
公司名称（英文） Merck KGaA
地址（中文） 
地址（英文） Frankfurter Strasse 250, Darmstadt, D-64293 Germany
国家（中文） 德国
国家（英文） Germany