Currently Enrolling Trials
Kuvan (sapropterin dihydrochloride) is an enzyme cofactor and oral form of tetrahydrobiopterin. Tetrahydrobiopterin (BH4) works with phenylalanine hydroxylase to metabolize phenylalanine (Phe).
Kuvan is specifically 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.
Kuvan is supplied as a tablet for oral administration. The recommended initial dose of the drug is 10 mg/kg/day taken once daily with food. Response to therapy is determined by change in blood Phe following treatment with Kuvan at 10 mg/kg/day for a period of up to 1 month. Blood Phe levels should be checked after 1 week of Kuvan treatment and periodically for up to a month. If the blood Phe level does not decrease from baseline at 10 mg/kg/day, the dose may be increased to 20 mg/kg/day. If the blood Phe does not decrease after 1 month of treatment at 20 mg/kg/day the subjects are non-responders, and treatment with Kuvan should be discontinued.
FDA approval of Kuvan was based on the results of four clinical studies.
This multicenter, open-label, uncontrolled clinical trial enrolled 489 subjects with PKU ages 8 to 48 years, who had baseline blood Phe levels =450 µmol/L and who were not on Phe-restricted diets. All subjects received Kuvan 10 mg/kg/day for 8 days. Response was defined as a greater than or equal to 30% decrease in blood Phe from baseline. At Day 8, 96 subjects (20%) were identified as responders.
This multicenter, double-blind, placebo-controlled study enrolled 88 subjects with PKU who responded to Kuvan in Study 1. After a washout period from Study 1, subjects 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. The results showed that at baseline, the mean (±SD) blood Phe level was 843 (±300) µmol/L in the Kuvan-treated group and 888 (±323) µmol/L in the placebo group. At Week 6, the Kuvan-treated group had a mean (±SD) blood Phe level of 607 (±377) µmol/L, and the placebo group had a mean blood Phe level of 891 (±348) µmol/L. At Week 6, the Kuvan- and placebo-treated groups had mean changes in blood Phe level of -239 and 6 µmol/L, respectively (mean percent changes of -29% (±32) and 3% (±33), respectively). The difference between the groups was statistically significant (p < 0.001).
This multicenter, open-label, extension study enrolled 80 subjects who responded to Kuvan treatment in Study 1 and completed Study 2. The subjects 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. At baseline, mean (±SD) blood Phe was 844 (±398) µmol/L. At the end of treatment with 5, 10, and 20 mg/kg/day, mean (±SD) blood Phe levels were 408 (±384) µmol/L, 640 (±382) µmol/L, and 581 (±399) µmol/L, respectively.
This multicenter study enrolled 90 pediatric subjects with PKU, ages 4 to 12 years, who were on Phe-restricted diets and who had blood Phe levels =480 µmol/L at screening. The subjects 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. At Day 8, 50 subjects (56%) had a greater than or equal to 30% decrease in blood Phe.
Ongoing Study Commitments
- BioMarin has agreed to design and implement a safety, efficacy,
and pharmacokinetics study with Kuvan in patients with PKU who are
four years of age or younger at study entry. Efficacy is to be
assessed by the pharmacodynamic outcome measure of blood
phenylalanine levels over a six-month period of treatment.
Protocol Submission: June 14, 2008
Study Start: December 14, 2008
Final Report Submission: June 14, 2010
- BioMarin has agreed to design and implement a long-term study
designed to assess growth and neurocognitive development with
treatment with Kuvan in patients who are eight years of age or
younger at study entry. This study is to include blinded
assessments of growth (including standardized measurements of
recumbent length or height, weight, and head circumference), and
developmental testing (the scales used need to be prospectively
agreed upon) at six- to twelve-month intervals over a seven-year
Protocol Submission: June 14, 2008
Study Start: December 14, 2008
Final Report Submission: June 14, 2017
- BioMarin has agreed to complete the open-label extension study
PKU-008, entitled "A Phase 3b, Multicenter, Open-Label
Extension Study of Phenoptin in Subjects with Phenylketonuria Who
Participated in Studies PKU004 or PKU006. Patients who participated
in the extension study PKU-004 will be treated under PKU-008 for a
minimum of two years of total treatment with Kuvan. Patient accrual
is complete, the two-year cutoff period is to be completed on May
30, 2008, and an interim study report will be submitted to CDER by
September 30, 2008.
Final Report Submission: March 30, 2010
- BioMarin has agreed to design and implement a registry of
patients with PKU being treated with Kuvan that will be established
to obtain long-term clinical status information. Information will
be collected on patient demographics, specifics of treatment with
Kuvan (sapropterin dihydrochloride), clinical status,
neurocognitive assessments, growth and development (for patients
who are pre-pubertal at the start of treatment), and adverse
events. This registry will be designed so that detailed clinical
status information is collected at registry entry and on a six- to
twelve-month basis for at least 15 years. BioMarin commits to
conducting one sub-study within the registry that will evaluate the
effect of Kuvan (sapropterin dihydrochloride) on pregnancy and
lactation. The registry data will be analyzed at yearly intervals
and the results will be submitted in annual reports for IND
Protocol Submission: May 25, 2008
Study Start: November 25, 2008
Final Report Submission: May 25, 2025
- BioMarin has agreed to design and implement a thorough QT (TQT)
study with Kuvan that complies with International Conference on
Harmonisation (ICH) E14. The dose of Kuvan administered in the TQT
study is to be selected so that it results in plasma concentrations
that cover the expected high clinical exposure scenario in patients
with BH4-responsive PKU, without compromising study subject safety.
This study may be a single-dose, positive- and placebo-controlled,
cross-over study in healthy volunteers.
Protocol Submission: June 14, 2008
Study Start: October 14, 2008
Final Report Submission: October 14, 2009
- BioMarin has agreed to analyze the whole blood samples for PAH
gene mutations that were collected during the PKU-001 study,
entitled "A Phase 2, multicenter, open-label study to evaluate
the response to and safety of an 8-day course of Phenoptin
treatment in subjects with phenylketonuria who have elevated
phenylalanine levels". These samples are to be analyzed for
the purpose of determining whether patients with PKU with specific
PAH mutations are likely to be responders (by change in blood
phenylalanine levels) to treatment with Kuvan.
Final Report Submission: December 14, 2008
- BioMarin has agreed to complete the open-label study PKU-007,
entitled "A Phase 2, Multicenter, Open-label Study to Evaluate
the Safety and Efficacy of Phenoptin in Subjects with
Hyperphenylalaninemia Due to Primary BH4 Deficiency". Patient
accrual is complete. The core safety and efficacy portion of this
study is complete and patients are continuing in an extension
Final Report Submission: June 14, 2008
Adverse events associated with the use of Kuvan may include, but are not limited to, the following:
- Upper respiratory tract infection
- Pharyngolaryngeal pain
Mechanism of Action
Kuvan (sapropterin dihydrochloride) is a synthetic form of BH4, the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates Phe through an oxidative reaction to form tyrosine. BH4 can activate residual PAH enzyme, improve the normal oxidative metabolism of Phe, and decrease Phe levels.
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Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FK, Whitley CB, Feillet F, Feigenbaum AS, Bebchuk JD, Christ-Schmidt H, Dorenbaum A; Sapropterin Research Group Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 2007 Aug 11;370(9586):504-10
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Pérez-Dueñas B, Vilaseca MA, Mas A, Lambruschini N, Artuch R, Gómez L, Pineda J, Gutiérrez A, Mila M, Campistol J Tetrahydrobiopterin responsiveness in patients with phenylketonuria. Clinical biochemistry 2004 Dec;37(12):1083-90
Steinfeld R, Kohlschütter A, Ullrich K, Lukacs Z Efficiency of long-term tetrahydrobiopterin monotherapy in phenylketonuria. Journal of inherited metabolic disease 2004;27(4):449-53
For additional information regarding Kuvan or hyperphenylalaninemia, please visit the Kuvan web page.