Kuvan

Studies in healthy subjects 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 C_maxof 84% and AUC of 87% (dissolved in water). However, there was extensive variability in individual subject values for C_maxand 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 hours), comparable with values seen in healthy subjects (range 3.0 to 5.3 hours).

A study in healthy adults with 10 mg/kg of KUVAN demonstrated that the absorption via intact tablet administration was 40% greater than via dissolved tablet administration under fasted conditions based on AUC_0-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 AUC_0-t

.

Population pharmacokinetic analysis of sapropterin including patients from 1 month to 49 years of age showed that body weight is the only covariate substantially affecting clearance or distribution volume (see Table 5). Pharmacokinetics in patients >49 years of age have not been studied.

Parameter	0 to <1 yr* (N=10)	1 to <6 yr* (N=57)	6 to <12 yr† (N=23)	12 to <18 yr† (N=24)	≥18 yr† (N=42)
CL/F (L/hr/kg) Mean ± SD (Median)	81.5 ± 92.4 (53.6)	50.7 ± 20.1 (48.4)	51.7 ± 21.9 (47.4)	39.2 ± 9.3 (38.3)	37.9 ± 20.2 (31.8)

^*Evaluated at 20 mg/kg per day dose.

^†Evaluated at 5, 10, or 20 mg/kg per day doses.

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.

In healthy subjects, administration of a single dose of KUVAN at the maximum therapeutic dose of 20 mg/kg had no effect on the pharmacokinetics of a single dose of digoxin (P-gp substrate) administered concomitantly.

The potential for sapropterin to induce or inhibit cytochrome P450 enzymes was evaluated in in vitro studies which showed sapropterin did not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5, nor induce CYP 1A2, 2B6, or 3A4/5.

In vitro sapropterin did not inhibit OAT1, OAT3, OCT2, MATE1, and MATE2-K transporters. The potential for sapropterin to inhibit OATP1B1 and OATP1B3 has not been adequately studied. In vitro, sapropterin inhibits breast cancer resistance protein (BCRP) but the potential for a clinically significant increase in systemic exposure of BCRP substrates by KUVAN appears to be low.

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).

	Sapropterin (N=41)	Placebo (N=47)
Baseline Blood Phe Level * (μ 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).

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 per 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 per day, mean (±SD) blood Phe levels were 744 (±384) μmol/L, 640 (±382) μmol/L, and 581 (±399) μmol/L, respectively (Table 7).

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)

.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of KUVAN was evaluated in 7 clinical studies in patients with PKU (aged 1 month to 50 years)

.

In Studies 1-4 (controlled and uncontrolled studies), 579 patients with PKU aged 4 to 49 years received KUVAN in doses ranging from 5 to 20 mg/kg per day for lengths of treatment ranging from 1 to 164 weeks. The patient population was evenly distributed in gender, and approximately 95% of patients were Caucasian. The most common adverse reactions (≥4% of patients) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion.

The data described in Table 3 reflect exposure of 74 patients with PKU to KUVAN at doses of 10 to 20 mg/kg per day for 6 to 10 weeks in two double-blind, placebo-controlled clinical trials (Studies 2 and 4).

Table 3 enumerates adverse reactions occurring in at least 4% of patients treated with KUVAN in the double-blind, placebo-controlled clinical trials described above.

MedDRA Preferred Term	Treatment
	KUVAN (N=74)	Placebo (N=59)
	No. Patients (%)	No. Patients (%)
Headache	11 (15)	8 (14)
Rhinorrhea	8 (11)	0
Pharyngolaryngeal pain	7 (10)	1 (2)
Diarrhea	6 (8)	3 (5)
Vomiting	6 (8)	4 (7)
Cough	5 (7)	3 (5)
Nasal congestion	3 (4)	0

In open-label, uncontrolled clinical trials (Studies 1 and 3) all patients received KUVAN in doses of 5 to 20 mg/kg per day, and adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials

.

In Study 5, 65 pediatric patients with PKU aged 1 month to 6 years received KUVAN 20 mg/kg per day for 6 months. Adverse reactions in these patients were similar in frequency and type as those seen in other KUVAN clinical trials except for an increased incidence of low Phe levels. Twenty-five percent (16 out of 65) of patients developed Phe levels below normal for age

.

In Study 6, a long term, open-label, extension study of 111 patients aged 4 to 50 years, receiving KUVAN in doses ranging from 5 to 20 mg/kg per day, adverse reactions were similar in type and frequency to those reported in the previous clinical studies. Fifty-five patients received KUVAN both as dissolved and intact tablets. There were no notable differences in the incidence or severity of adverse reactions between the two methods of administration. The mean (± SD) exposure to sapropterin for the entire study population was 659 ± 221 days (maximum 953 days).

In Study 7, 27 pediatric patients with PKU aged 0 to 4 years received KUVAN 10 mg/kg per day or 20 mg/kg per day. Adverse reactions were similar in type and frequency to those observed in other clinical trials, with the addition of rhinitis, which was reported in 2 subjects (7.4%).

Approximately 800 healthy subjects and patients with disorders other than PKU, some of whom had underlying neurologic disorders or cardiovascular disease, have been administered a different formulation of the same active ingredient (sapropterin) in approximately 19 controlled and uncontrolled clinical trials. In these clinical trials, subjects were administered sapropterin at doses ranging from 1 to 100 mg/kg per day for lengths of exposure from 1 day to 2 years. Serious and severe adverse reactions (regardless of causality) during sapropterin administration were seizures, exacerbation of seizures

, dizziness, gastrointestinal bleeding, post-procedural bleeding, headache, irritability, myocardial infarction, overstimulation, and respiratory failure. Common adverse reactions were headache, peripheral edema, arthralgia, polyuria, agitation, dizziness, nausea, pharyngitis, abdominal pain, upper abdominal pain, and upper respiratory tract infection.

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).

	Sapropterin (N=41)	Placebo (N=47)
Baseline Blood Phe Level * (μ 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).

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 per 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 per day, mean (±SD) blood Phe levels were 744 (±384) μmol/L, 640 (±382) μmol/L, and 581 (±399) μmol/L, respectively (Table 7).

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)

.