FDA approved sapropterin on December 13, 2007, to reduce blood Phe levels in patients with hyperphenylalaninemia (HPA) due ro BH4-responsive phenylketonuria (PKU).
Sapropterin is a synthetic preparation of tetrahydrobiopterin (BH4), the cofactor for phenylalanine hydroxylase (PAH). PAH is responsible for hydroxylating phenylalanine (Phe) to form tyrosine. In patients with phenylketonuria (PKU), the activity of PAH is absent or deficient. Sapropterin activates residual PAH, thus improving the metabolism of Phe. This agent was approved on December 13, 2007, to reduce blood Phe levels in patients with hyperphenylalaninemia (HPA) due to BH4-responsive PKU.
Efficacy. The efficacy of sapropterin was evaluated in 4 multicenter trials. The first study was an open-label, uncontrolled trial that included 489 patients aged 8 to 48 years who were not on a Phe-restricted diet. Patients were treated with sapropterin 10 mg/kg/d for 8 days. At the end of the study, 96 patients were identified as responders (≥30% decrease in blood Phe from baseline). The second study was a double-blind, placebo-controlled trial in 88 responders from the first study. Patients were randomized to receive sapropterin 10 mg/kg/d or placebo for 6 weeks. At Week 6, sapropterin-treated patients demonstrated an adjusted mean change in blood Phe level of –239 mcmol/L versus +6 mcmol/L in placebo-treated patients (P<.001). The third study was an open-label extension trial in 80 responders from the first study who had completed the second study. These patients were treated with 3 consecutive 2-week courses of sapropterin 5, 20, and 10 mg/kg/d. Blood Phe levels were monitored at each 2-week interval. After treatment with sapropterin 5, 20, and 10 mg/kg/d, patients demonstrated mean changes in blood Phe levels of –100, –263, and –204 mcmol/L, respectively. In the fourth study, 90 patients aged 4 to 12 years who were on Phe-restricted diets were treated with open-label sapropterin 20 mg/kg/d for 8 days. At Day 8, 50 patients were identified as responders.
Safety. Patients with prolonged elevations in blood Phe levels may experience severe neurologic damage. Blood Phe levels that are too low for prolonged periods may result in catabolism and protein breakdown. Sapropterin-treated patients should follow a Phe-restricted diet. The most common adverse events associated with sapropterin treatment include headache, upper respiratory tract infection, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, pyrexia, contusion, abdominal pain, rash, and nasal congestion.