February 9, 2016
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Mechanism Of Action

Kuvan is a synthetic form of BH4, the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with PKU, PAH activity is absent or deficient. Treatment with BH4 can activate residual PAH enzyme, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.


In PKU patients who are responsive to BH4 treatment, blood Phe levels decrease within 24 hours after a single administration of sapropterin dihydrochloride, although maximal effect on Phe level may take up to a month, depending on the patient. A single daily dose of Kuvan is adequate to maintain stable blood Phe levels over a 24-hour period. Twelve patients with blood Phe levels ranging from 516 to 986 μmol/L (mean 747 ± 153 μmol/L) were assessed with 24-hour blood Phe level monitoring following a daily morning dose of 10 mg/kg/day. The blood Phe level remained stable during a 24-hour observation period. No substantial increases in blood Phe levels were observed following food intake throughout the 24-hour period.

Effects of Kuvan on the QTc interval

A thorough QTc study was performed in 56 healthy adults. This randomized, placebo and active controlled crossover study was conducted to determine if a single supra-therapeutic (100 mg/kg) of Kuvan, or a single therapeutic dose (20 mg/kg) of Kuvan had an effect on cardiac repolarization. In this study, Kuvan was administered after dissolving tablets in water under fed condition. This study demonstrated a dose-dependent shortening of the QT interval. The maximum placebo-subtracted mean change from baseline of the QTc interval was -3.69 and 8.32 ms (lower bound of 90% CI: -5.3 and -10.6 ms) at 20 and 100 mg/kg, respectively.


Studies in healthy volunteers have shown comparable absorption of sapropterin when tablets are dissolved in water or orange juice and taken under fasted conditions. Administration of dissolved tablets after a high-fat/high-calorie meal resulted in mean increases in Cmax of 84% and AUC of 87% (dissolved in water). However, there was extensive variability in individual subject values for Cmax and AUC across the different modes of administration and meal conditions. In the clinical trials of Kuvan, drug was administered in the morning as a dissolved tablet without regard to meals. The mean elimination half-life in PKU patients was approximately 6.7 hours (range 3.9 to 17 hr), comparable with values seen in healthy subjects (range 3.0 to 5.3 hr).

A study in healthy adults with 10 mg/kg of Kuvan demonstrated the absorption via intact tablet administration was 40% greater than via dissolved tablet administration under fasted conditions based on AUC0-t. The administration of intact tablets under fed conditions resulted in an approximately 43% increase in the extent of absorption compared to fasted conditions based on AUC0-t.

A population pharmacokinetic analysis of sapropterin including patients between 9 and 49 years of age showed no effect of age on sapropterin pharmacokinetics. Pharmacokinetics in patients < 9 years and > 49 years of age have not been studied.


Sapropterin is a synthetic form of tetrahydrobiopterin (BH4) and is expected to be metabolized and recycled by the same endogenous enzymes. In vivo endogenous BH4 is converted to quinoid dihydrobiopterin and is metabolized to dihydrobiopterin and biopterin. The enzymes dihydrofolate reductase and dihydropteridine reductase are responsible for the metabolism and recycling of BH4.

Clinical Studies

Clinical Studies In PKU

The efficacy and safety of Kuvan were evaluated in 5 clinical studies in patients with PKU.

Study 1 was 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 ≥ 450 μmol/L and who were not on Phe-restricted diets. All patients received treatment with Kuvan 10 mg/kg/day for 8 days. For the purposes of this study, response to Kuvan treatment was defined as a ≥ 30% decrease in blood Phe from baseline. At Day 8, 96 patients (20%) were identified as responders.

Study 2 was 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.

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) (Table 2).

Table 2: Blood Phe Results in Study 2

Baseline Blood Phe Level1 (μmol/L)
  Mean (±SD) 843 (±300) 888 (±323)
  Percentiles (25th, 75th) 620, 990 618, 1141
Week 6 Blood Phe Level (μmol/L)
  Mean (±SD) 607 (±377) 891 (±348)
  Percentiles (25th, 75th) 307, 812 619, 1143
Mean Change in Blood Phe From Baseline to Week 6 (μmol/L)
  Adjusted Mean (±SE)2 -239 (±38) 6 (±36)
  Percentiles (25th, 75th) -397, -92 -96, 93
Mean Percent Change in Blood Phe From Baseline to Week 6
  Mean (±SD) - 29 (±32) 3 (±33)
  Percentiles (25th, 75th) -61, -11 -13, 12
1The mean baseline levels shown in this table represent the mean of 3 pretreatment levels (Wk -2, Wk -1, and Wk 0). Treatment with Kuvan or placebo started at Wk 0.
2p-value < 0.001, adjusted mean and standard error from an ANCOVA model with change in blood Phe level from baseline to Week 6 as the response variable, and both treatment group and baseline blood Phe level as covariates.

Change in blood Phe was noted in the Kuvan-treated group at Week 1 and was sustained through Week 6 (Figure 1).

Figure 1: Mean Blood Phenylalanine (Phe) Level Over Time1

Mean Blood Phenylalanine (Phe) Level Over Time - Illustration

Study 3 was 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. 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 744 (±384) μmol/L, 640 (±382) μmol/L, and 581 (±399) μmol/L, respectively (Table 3).

Table 3: Blood Phe Results From Forced Dose-Titration in Study 3

Kuvan Dose Level (mg/kg/day) No. of Patients Mean (±SD) Blood Phe Level (μmol/L) Mean Changes (±SD) in Blood Phe Level From Week 0 (μmol/L)
Baseline (No Treatment) 80 844 (±398)
5 80 744 (±384) -100 (±295)
10 80 640 (±382) -204 (±303)
20 80 581 (±399) -263 (±318)

Study 4 was 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 ≤ 480 μmol/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 ≥ 30% decrease in blood Phe from baseline at Day 8. At Day 8, 50 patients (56%) had a ≥ 30% decrease in blood Phe.

Study 5 demonstrated the long-term safety of Kuvan in patients with PKU. The study was a multicenter, open-label extension study of 111 patients with PKU who participated in Study 3 or Study 4. Doses ranged in this study between 5-20mg/kg. The mean ± SD exposure to sapropterin for the entire study population was 659 ± 221 days (maximum 953) and 799 + 237 days (maximum 1151) including the previous studies.

Last reviewed on RxList: 1/6/2014
This monograph has been modified to include the generic and brand name in many instances.

Report Problems to the Food and Drug Administration


You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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