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
Adverse events associated with the use of Kuvan may include, but are not limited to, the following:
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.
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
For additional information regarding Kuvan or hyperphenylalaninemia, please visit the Kuvan web page.