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General Information

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.

Clinical Results

FDA Approval
FDA approval of Kuvan was based on the results of four clinical studies.

Study One
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.

Study Two
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).

Study Three
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.

Study Four
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 period.
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 69,708.
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 portion.
Final Report Submission: June 14, 2008

Side Effects

Adverse events associated with the use of Kuvan may include, but are not limited to, the following:

Headache
Upper respiratory tract infection
Rhinorrhea
Pharyngolaryngeal pain
Diarrhea
Vomiting
Cough
Pyrexia

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.

Literature References

Burton BK, Grange DK, Milanowski A, Vockley G, Feillet F, Crombez EA, Abadie V, Harding CO, Cederbaum S, Dobbelaere D, Smith A, Dorenbaum A The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. Journal of inherited metabolic disease 2007 Oct;30(5):700-7

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

Matalon R, Michals-Matalon K, Koch R, Grady J, Tyring S, Stevens RC Response of patients with phenylketonuria in the US to tetrahydrobiopterin. Molecular genetics and metabolism 2005 Dec;86 Suppl 1:S17-21

Trefz FK, Scheible D, Frauendienst-Egger G, Korall H, Blau N Long-term treatment of patients with mild and classical phenylketonuria by tetrahydrobiopterin. Molecular genetics and metabolism 2005 Dec;86 Suppl 1:S75-80

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