Kuvan (Page 5 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year carcinogenicity study was conducted in F-344 rats, and a 78-week carcinogenicity study was conducted in CD-1 mice. In the 104-week oral carcinogenicity study in rats, sapropterin dihydrochloride doses of 25, 80, and 250 mg/kg per day (0.2, 0.7, and 2 times the maximum recommended human dose of 20 mg/kg per day, respectively, based on body surface area) were used. In the 78-week oral carcinogenicity study in mice, sapropterin dihydrochloride doses of 25, 80, and 250 mg/kg per day (0.1, 0.3, and 2 times the recommended human dose, respectively, based on body surface area) were used. In the 2‑year rat carcinogenicity study, there was a statistically significant increase in the incidence of benign adrenal pheochromocytoma in male rats treated with the 250 mg/kg per day (about 2 times the maximum recommended human dose, based on body surface area) dose, as compared to vehicle treated rats. The mouse carcinogenicity study showed no evidence of a carcinogenic effect, but the study was not ideal due to its duration of 78 instead of 104 weeks.

Sapropterin dihydrochloride was genotoxic in the in vitro Ames test at concentrations of 625 µg (TA98) and 5000 µg (TA100) per plate, without metabolic activation. However, no genotoxicity was observed in the in vitro Ames test with metabolic activation. Sapropterin dihydrochloride was genotoxic in the in vitro chromosomal aberration assay in Chinese hamster lung cells at concentrations of 0.25 and 0.5 mM. Sapropterin dihydrochloride was not mutagenic in the in vivo micronucleus assay in mice at doses up to 2000 mg/kg per day (about 8 times the maximum recommended human dose of 20 mg/kg per day, based on body surface area). Sapropterin dihydrochloride, at oral doses up to 400 mg/kg per day (about 3 times the maximum recommended human dose, based on body surface area) was found to have no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

The efficacy of Kuvan was evaluated in five 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 per 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 per 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 6).

Table 6: Blood Phe Results in Study 2

Sapropterin (N=41)

Placebo (N=47)

Baseline Blood Phe Level * mol/L)

Mean (±SD)

843 (±300)

888 (±323)

Percentiles (25th , 75th)

620, 990

618, 1141

Week 6 Blood Phe Level (μ mol/L)

Mean (±SD)

607 (±377)

891 (±348)

Percentiles (25th , 75th)

307, 812

619, 1143

Mean Change in Blood Phe From Baseline to Week 6 (μ mol/L)

Adjusted Mean (±SE)†

-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

* The 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.

p-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 2).

Figure 2
(click image for full-size original)

Figure 2

Table 7: Blood Phe Results From Forced Dose-Titration in Study 3

Kuvan Dose Level (mg/kg per day)

No. of Patients

Mean ( ±SD) Blood Phe Level (μ mol/L)

Mean Changes ( ±SD) in Blood Phe Level From Week 0 (μ mol/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 pediatric patients 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 per 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 was an open label, single arm, multicenter trial in 93 pediatric patients with PKU, aged 1 month to 6 years, who had Phe levels greater than or equal to 360 μmol/L at screening. All patients were treated with Kuvan at 20 mg/kg per day and maintained on a Phe-restricted diet. At Week 4, 57 patients (61%) were identified as responders (defined as ≥ 30% decreased in blood Phe from baseline) (see Figure 1 section 8.4).

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