Pharmacology Update

Sapropterin Dihydrochloride Tablets (Kuvan™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The FDA has approved, by priority review, the first drug to help manage patients with phenylketonuria (PKU). PKU is an inherited disorder in the activity of phenylalanine hydroxylase (PAH). Sapropterin is a synthetic version of the naturally occurring tetrahydrobiopterin (BH4), which is the catalytic cofactor for PAH. Sapropterin will be marketed by BioMarin Pharmaceuticals Inc. as Kuvan.


Sapropterin is indicated to reduce blood levels of phenylalanine in patients with hyperphenylalaninemia due to tetrahydrobiopterin responsive phenyketonuria in conjunction with a phenylalanine-restricted diet.1


The recommended starting dose is 10 mg/kg/day taken once daily. Phenylalanine levels should be checked after 1 week of treatment and periodically up to one month. If the levels do not decrease from baseline the dose may be increased to 20 mg/kg/day. If no change occurs the patient should be considered to be non-responsive and treatment should be discontinued. For responders, the dose may be titrated between 5 and 20 mg/kg/day.1

Sapropterin is available as 100 mg tablets each containing 76.8 mg of sapropterin base.

Potential Advantages

Sapropterin is the first drug approved to lower phenylalanine levels in some patients with PKU. In those who respond, easing or possible elimination of dietary restrictions may be possible.2

Potential Disadvantages

Sapropterin is only effective in patients with residual PAH activity (ie, mild to moderate disease). This is estimated to represent 20 to 56% of PKU patients.1-3 Common adverse events (>10%) include headache, upper respiratory tract infections, pharyngolaryngeal pain, and rhinorrhea.1


PKU is an autosomal recessive disorder caused by mutation in both alleles of the gene for phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine. Deficiency of this enzyme results in a spectrum of the disorder from classic PKU to hyperphenylalaninemia. Accumulation of phenylalanine leads to mental retardation, smaller brain size, behavioral abnormalities, seizures, and neurological complications.

Sapropterin is believed to stimulate PAH activity in those with residual activity. The efficacy and safety of sapropterin was evaluated in four clinical studies.1,4 Study 1 was an open label study in patients not on a phenylalanine diet who had phenylalanine levels ³450 mmols/L and treated at 10 mg/kg/day (n = 489). Study 2 was a randomized placebo-controlled study involving patients who responded in the first study (n = 88). Study 3 was a forced dose titration study involving those who completed study 2 (n = 80). Study 4 was an open label study in children (ages 4-12) with phenylalanine-restricted diets and phenylalanine levels £480 mmole/l and treated at 20 mg/kg/day (n = 50). Response was defined as a 30% or greater decrease in phenylalanine blood levels. In study 1, 20% of patients were responders at Day 8. In study 2, patients randomized to sapropterin 10 mg/kg/day had a mean reduction of 29% compared to an increase of 3% for placebo at week 6. Forty-four percent of patients had at least a 30% reduction compared to 9% for placebo. Forced titration of 5 mg to 20 mg/kg every 2 weeks, in study 3, showed a dose response effect. In study 4, 56% of patients responded at Day 8. Sapropterin is expected to cost about $57,000 per year for children and up to $200,000 per year for adults.

Clinical Implications

PKU occurs in one out of 12,000 to 15,000 live births.5 Current treatment is limited to eating a special diet low in phenylalanine. Sapropterin is the first drug to be approved and may be beneficial to 20-56% of PKU patients. However, responders cannot be determined a priori by laboratory or PAH genotyping but only by a therapeutic trial. The least costly way consists of two doses of sapropterin at 20 mg/kg/day given over 24 hours and blood levels of phenylalanine followed over 48 hours.6 Responsiveness is defined as a 30% or greater reduction in phenylalanine blood levels. Some have suggested that younger patients on diets but not optimally controlled, and those with mild disease be tested first for responsiveness.7 It is unknown if sapropterin will improve long-term outcome of PKU or whether any potential improvement in quality of life or easing dietary restriction or elimination in a few patients justifies the high cost of the drug.


1. Kuvan Product Information. BioMarin Pharmaceutical Inc. December 2007.

2. Shintaku H et al. Pediatr Res. 2004;55:425-30.

3. Burnett JR. Idrugs. 2007;10(11);805-813.

4. Levy HL, et al. Lancet. 2007;370:504-510.

5. Accessed 12/24/07.

6. Fiege B, et al. Mol Genet Metab. 2005;86 (suppl 1):S91-95.

7. Levy H, et al. Mol Genet Metab. 2007;92(4):287-291.