Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: BioMarin International Limited, Shanbally, Ringaskiddy, County Cork, Ireland
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract and metabolism products
ATC code: A16AX07
Hyperphenylalaninaemia (HPA) is diagnosed as an abnormal elevation in blood phenylalanine levels and is usually caused by autosomal recessive mutations in the genes encoding for phenylalanine hydroxylase enzyme (in the case of phenylketonuria, PKU) or for the enzymes involved in 6R-tetrahydrobiopterin (6R-BH4) biosynthesis or regeneration (in the case of BH4 deficiency). BH4 deficiency is a group of disorders arising from mutations or deletions in the genes encoding for one of the five enzymes involved in the biosynthesis or recycling of BH4. In both cases, phenylalanine cannot be effectively transformed into the amino acid tyrosine, leading to increased phenylalanine levels in the blood.
Sapropterin is a synthetic version of the naturally occurring 6R-BH4, which is a cofactor of the hydroxylases for phenylalanine, tyrosine and tryptophan.
The rationale for administration of Kuvan in patients with BH4-responsive PKU is to enhance the activity of the defective phenylalanine hydroxylase and thereby increase or restore the oxidative metabolism of phenylalanine sufficient to reduce or maintain blood phenylalanine levels, prevent or decrease further phenylalanine accumulation, and increase tolerance to phenylalanine intake in the diet. The rationale for administration of Kuvan in patients with BH4 Deficiency is to replace the deficient levels of BH4, thereby restoring the activity of phenylalanine hydroxylase.
The Phase III clinical development program for Kuvan included 2, randomised placebo-controlled studies in patients with PKU. The results of these studies demonstrate the efficacy of Kuvan to reduce blood phenylalanine levels and to increase dietary phenylalanine tolerance.
In 88 subjects with poorly controlled PKU who had elevated blood phenylalanine levels at screening, sapropterin dihydrochloride 10 mg/kg/day significantly reduced blood phenylalanine levels as compared to placebo. The baseline blood phenylalanine levels for the Kuvan-treated group and the placebo group were similar, with mean ± SD baseline blood phenylalanine levels of 843 ± 300 μmol/l and 888 ± 323 μmol/l, respectively. The mean ± SD decrease from baseline in blood phenylalanine levels at the end of the 6 week study period was 236 ± 257 μmol/l for the sapropterin treated group (n=41) as compared to an increase of 2.9 ± 240 μmol/l for the placebo group (n=47) (p<0.001). For patients with baseline blood phenylalanine levels ≥600 μmol/l, 41.9% (13/31) of those treated with sapropterin and 13.2% (5/38) of those treated with placebo had blood phenylalanine levels <600 μmol/l at the end of the 6-week study period (p=0.012).
In a separate 10-week, placebo-controlled study, 45 PKU patients with blood phenylalanine levels controlled on a stable phenylalanine-restricted diet (blood phenylalanine ≤480 μmol/l on enrolment) were randomised 3:1 to treatment with sapropterin dihydrochloride 20 mg/kg/day (n=33) or placebo (n=12). After 3-weeks of treatment with sapropterin dihydrochloride 20 mg/kg/day, blood phenylalanine levels were significantly reduced; the mean ± SD decrease from baseline in blood phenylalanine level within this group was 149 ± 134 μmol/l (p<0.001). After 3 weeks, subjects in both the sapropterin and placebo treatment groups were continued on their phenylalanine-restricted diets and dietary phenylalanine intake was increased or decreased using standardised phenylalanine supplements with a goal to maintain blood phenylalanine levels at <360 μmol/l. There was a significant difference in dietary phenylalanine tolerance in the sapropterin treatment group as compared to the placebo group. The mean ± SD increase in dietary phenylalanine tolerance was 17.5 ± 13.3 mg/kg/day for the group treated with sapropterin dihydrochloride 20 mg/kg/day, compared to 3.3 ± 5.3 mg/kg/day for the placebo group (p=0.006). For the sapropterin treatment group, the mean ± SD total dietary phenylalanine tolerance was 38.4 ± 21.6 mg/kg/day during treatment with sapropterin dihydrochloride 20 mg/kg/day compared to 15.7 ± 7.2 mg/kg/day before treatment.
The safety, efficacy and population pharmacokinetics of Kuvan in paediatric patients aged <7 years were studied in two open-label studies.
The first study was a multicentre, open-label, randomised, controlled study in children <4 years old with a confirmed diagnosis of PKU. 56 paediatric PKU patients <4 years of age were randomised 1:1 to receive either 10 mg/kg/day Kuvan in conjunction with a phenylalanine-restricted diet (n=27), or just a phenylalanine-restricted diet (n=29) over a 26-week Study Period.
It was intended that all patients maintained blood phenylalanine levels within a range of 120-360 μmol/l (defined as ≥120 to <360 μmol/l) through monitored dietary intake during the 26-week Study Period. If after approximately 4 weeks, a patient’s phenylalanine tolerance had not increased by >20% versus baseline, the Kuvan dose was increased in a single step to 20 mg/kg/day.
The results of this study demonstrated that daily dosing with 10 or 20 mg/kg/day of Kuvan in conjunction with a phenylalanine-restricted diet led to statistically significant improvements in dietary phenylalanine tolerance compared with dietary phenylalanine restriction alone while maintaining blood phenylalanine levels within the target range (≥120 to <360 μmol/l). The adjusted mean dietary phenylalanine tolerance in the Kuvan in conjunction with a phenylalanine-restricted diet group was 80.6 mg/kg/day and was statistically significantly greater (p<0.001) than the adjusted mean dietary phenylalanine tolerance in dietary phenylalanine therapy alone group (50.1 mg/kg/day). In the clinical trial extension period, patients maintained dietary phenylalanine tolerance while on Kuvan treatment in conjunction with a Phe-restricted diet, demonstrating sustained benefit over 3.5 years.
The second study was a multicenter, uncontrolled, open-label study designed to evaluate the safety and effect on preservation of neurocognitive function of Kuvan 20 mg/kg/day in combination with a phenylalanine- restricted diet in children with PKU less than 7 years of age at study entry. Part 1 of the study (4 weeks) assessed patients' response to Kuvan; Part 2 of the study (up to 7 years of follow-up) evaluated neurocognitive function with age-appropriate measures, and monitored long-term safety in patients responsive to Kuvan. Patients with pre-existing neurocognitive damage (IQ<80) were excluded from the study. Ninety-three patients were enrolled into Part 1, and 65 patients were enrolled into Part 2, of whom 49 (75%) patients completed the study with 27 (42%) patients providing Full Scale IQ (FSIQ) data at year 7.
Mean Indices of Dietary Control were maintained between 133 μmol/L and 375 μmol/L blood Phe for all age groups at all time points. At baseline, mean Bayley-III score (102, SD=9.1, n=27), WPPSI-III score (101, SD=11, n=34) and WISC-IV score (113, SD=9.8, n=4) were within the average range for the normative population.
Among 62 patients with a minimum of two FSIQ assessments, the 95% lower limit confidence interval of the mean change over an average 2-year period was -1.6 points, within the clinically expected variation of ±5 points. No additional adverse reactions were identified with long-term use of Kuvan in children less than 7 years of age.
Limited studies have been conducted in patients under 4 years of age with BH4 deficiency using another formulation of the same active substance (sapropterin) or an un-registered preparation of BH4.
Sapropterin is absorbed after oral administration of the dissolved tablet, and the maximum blood concentration (Cmax) is achieved 3 to 4 hours after dosing in the fasted state. The rate and extent of absorption of sapropterin is influenced by food. The absorption of sapropterin is higher after a high-fat, high-calorie meal as compared to fasting, resulting, in average, in 40-85% higher maximum blood concentrations achieved 4 to 5 hours after administration.
Absolute bioavailability or bioavailability for humans after oral administration is not known.
In non-clinical studies, sapropterin was primarily distributed to the kidneys, adrenal glands, and liver as assessed by levels of total and reduced biopterin concentrations. In rats, following intravenous radiolabeled sapropterin administration, radioactivity was found to distribute in foetuses. Excretion of total biopterin in milk was demonstrated in rats by intravenous route. No increase in total biopterin concentrations in either foetuses or milk was observed in rats after oral administration of 10 mg/kg sapropterin dihydrochloride.
Sapropterin dihydrochloride is primarily metabolised in the liver to dihydrobiopterin and biopterin. Since sapropterin dihydrochloride is a synthetic version of the naturally occurring 6R-BH4, it can be reasonably anticipated to undergo the same metabolism, including 6R-BH4 regeneration.
Following intravenous administration in rats, sapropterin dihydrochloride is mainly excreted in the urine. Following oral administration it is mainly eliminated through faeces while a small proportion is excreted in urine.
Population pharmacokinetic analysis of sapropterin including patients from birth to 49 years of age showed that body weight is the only covariate substantially affecting clearance or volume of distribution.
In vitro, sapropterin did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5, nor induce CYP1A2, 2B6, or 3A4/5.
Based on an in vitro study, there is potential for sapropterin dihydrochloride to inhibit p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in the gut at the therapeutic doses. A higher intestinal concentration of Kuvan is needed to inhibit BCRP than P-gp, as inhibitory potency in intestine for BCRP (IC50=267 μM) is lower than P-gp (IC50=158 μM).
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. Based on the in vitro and in vivo results, co-administration of Kuvan is unlikely to increase systemic exposure to drugs that are substrates for BCRP.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology (CNS, respiratory, cardiovascular, genitourinary), and toxicity to reproduction.
An increased incidence of altered renal microscopic morphology (collecting tubule basophilia) was observed in rats following chronic oral administration of sapropterin dihydrochloride at exposures at or slightly above the maximal recommended human dose.
Sapropterin was found to be weakly mutagenic in bacterial cells and an increase in chromosome aberrations was detected in Chinese hamster lung and ovary cells. However, sapropterin has not been shown to be genotoxic in the in vitro test with human lymphocytes as well as in in vivo micronucleus mouse tests.
No tumorigenic activity was observed in an oral carcinogenicity study in mice at doses of up to 250 mg/kg/day (12.5 to 50 times the human therapeutic dose range).
Emesis has been observed in both the safety pharmacology and the repeated-dose toxicity studies. Emesis is considered to be related to the pH of the solution containing sapropterin.
No clear evidence of teratogenic activity was found in rats and in rabbits at doses of approximately 3 and 10 times the maximum recommended human dose, based on body surface area.
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