, Volume 69, Issue 4, pp 461–476


A Review of its Use in the Treatment of Primary Hyperphenylalaninaemia
Adis Drug Evaluation



Sapropterin dihydrochloride (Kuvan®), hereafter referred to as sapropterin, is a synthetic formulation of the active 6R-isomer of tetrahydrobiopterin, a naturally occurring cofactor for phenylalanine hydroxylase. In the EU, sapropterin is approved for the treatment of hyperphenylalaninaemia in patients ≥4 years of age with tetrahydrobiopterin-responsive phenylketonuria (PKU) and in adults and children with tetrahydrobiopterin deficiency who have been shown to be responsive to such treatment. In the US, it is approved to reduce blood phenylalanine levels in patients with hyperphenylalaninaemia due to tetrahydrobiopterin-responsive PKU.

Oral sapropterin effectively lowers blood phenylalanine levels in a proportion of patients with PKU; to date, there are no published efficacy trials of the specific sapropterin formulation under review in patients with tetrahydrobiopterin deficiency. Sapropterin was well tolerated in patients with PKU, although longer-term tolerability data are required. Sapropterin is the first non-dietary treatment for patients with PKU that has been shown in randomized, double-blind trials to be effective in lowering blood phenylalanine levels. Thus, sapropterin provides a promising treatment option for patients with PKU who are tetrahydrobiopterin-responsive.

Pharmacological Properties

The mechanism of action of sapropterin in lowering blood phenylalanine levels in patients with PKU has not been fully elucidated, but appears to be related, in part, to its effect in augmenting and stabilizing mutant phenylalanine hydroxylases, resulting in increased clearance of phenylalanine from the body. In tetrahydrobiopterin deficiency, its mechanism of action is presumed to be secondary to replacement of endogenous tetrahydrobiopterin.

In healthy adults, orally-administered sapropterin is absorbed into the bloodstream,reaching maximum concentrations in 3–4 hours. It has a mean elimination half-life of ≈4 hours in healthy adults and, based on a population pharmacokinetic study, 6.7 hours in patients with tetrahydrobiopterin-responsive PKU. Age, from 9 to 49 years, had no effect on key pharmacokinetic parameters.

Therapeutic Efficacy

In an 8-day screening study in patients aged ≥8 years with PKU, ≈20% of patients responded to sapropterin 10mg/kg/day (i.e. were tetrahydrobiopterin responsive). Tetrahydrobiopterin-responsive patients from this study were entered into a randomized, double-blind, placebo-controlled trial in which they received sapropterin 10mg/kg/day or placebo. At the end of 6 weeks of treatment, sapropterin recipients experienced a significant 28% decrease from baseline in mean blood phenylalanine level, while there was no significant change in placebo recipients. The difference in mean blood phenylalanine level between sapropterin and placebo groups was statistically significant at −245 μmol/L. In an extension of this trial, significantly greater reductions in blood phenylalanine levels were observed with sapropterin dosages of 10 and 20 mg/kg/day than with sapropterin 5 mg/kg/day (each dose administered for 2 weeks), indicating a dose dependent effect. During 12 weeks of treatment with the sapropterin dosage individualized to the patient according to the earlier response to sapropterin 5, 10 or 20 mg/kg/day, reductions in plasma phenylalanine were observed in all dosage groups.

In a randomized, double-blind trial in children aged 4–12 years with tetrahydrobiopterin-responsive PKU, patients treated with sapropterin 20 mg/kg/day had reduced blood phenylalanine levels after 3 weeks of treatment. Over the full 10-week trial, sapropterin and placebo recipients experienced a significantly increased tolerance to dietary phenylalanine (20.9 mg/kg/day in sapropterin and 2.9mg/kg/day in placebo recipients).


Sapropterin was well tolerated in patients with PKU. In clinical trials in patients with PKU, the following adverse events were identified: headache, rhinorrhoea (both at a frequency of ≥10%), pharyngolaryngeal pain, nasal congestion, cough, diarrhoea, vomiting, abdominal pain and hypophenylalaninaemia (all at a frequency of ≥1% to <10%). There were no serious adverse events that were thought to be related to sapropterin treatment.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Scriver CR, Levy H, Donlon J. Chapter 77. Hyperphenyla-laninaemia: phenylalanine hydroxylase deficiency. In: Metabolic and molecular bases of inherited disease [on-line]. Available from URL.http://www.ommbid.com/OMMBID/the_online_metabolic_bases_of_inherited_disease/b/fulltoc [Accessed 2009 Jan 12]
  2. 2.
    Blau N, Thöny B, Cotton RGH et al. Chapter 78. Disorders of tetrahydrobiopterin and related biogenic amines. In: Metabolic and molecular bases of inherited disease [online]. Available from URL. http://www.ommbid.com/OMMBID/the_online_metabolic_bases_of_inherited_disease/b/fulltoc [Accessed 2009 Jan 12]
  3. 3.
    Michals-Matalon K. Sapropterin dihydrochloride, 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin, in the treatment of phenylketonuria. Expert Opin Investig Drugs 2008 Feb; 17(2): 245–51PubMedCrossRefGoogle Scholar
  4. 4.
    Gramer G, Burgard P, Garbade SF. Effects and clinical significance of tetrahydrobiopterin supplementation in phenylalanine hydroxylase-deficient hyperphenylalaninaemia. J Inherit Metab Dis 2007 Aug; 30(4): 556–62PubMedCrossRefGoogle Scholar
  5. 5.
    Longo N. Chapter 352. Inherited disorders of amino acid metabolism and storage. in Braunwald E, editor. Harrison's principles of internal medicine (15th edition). New York: McGraw-Hill, 2001: 2301–5Google Scholar
  6. 6.
    Guldberg P, Rey F, Zschocke J, et al. A European multicentre study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. American J Hum Genet 1998 Jul; 63(1): 71–9CrossRefGoogle Scholar
  7. 7.
    Surtees R, Blau N. The neurochemistry of phenylketonuria. Eur J Pediatr 2000; 159 Suppl. 2: S109–13PubMedCrossRefGoogle Scholar
  8. 8.
    de Baulny HO, Abadie V, Feillet F, et al. Management of phenylketonuria and hyperphenylalaninemia. J Nutr 2007 Jun; 137 (6 Suppl. 1): 1561–3SGoogle Scholar
  9. 9.
    Weglage J, Pietsch M, Feldmann R, et al. Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia. Pediatr Res 2001 Apr; 49(4): 532–6PubMedCrossRefGoogle Scholar
  10. 10.
    Kure S, Hou DC, Ohura T, et al. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 1999 Sep; 135(3): 375–8PubMedCrossRefGoogle Scholar
  11. 11.
    Muntau AC, Röschinger W, Habich M, et al. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 2002 Dec 26; 347(26): 2122–32PubMedCrossRefGoogle Scholar
  12. 12.
    Pey AL, Martinez A. Tetrahydrobiopterin for patients with phenylketonuria. Lancet 2007; 370(9586): 462–3PubMedCrossRefGoogle Scholar
  13. 13.
    US FDA. Sapropterin dihydrochloride: prescribing information [online]. Available from URL: http://www.fda.gov/cder/foi/label/2007/022181lbl.pdf [Accessed 2008 Aug 5]
  14. 14.
    Asubio Pharma Co Ltd. Asubio Pharma's inherited metabolic disease agent Biopten® receives approval for additional indication, 2008 Jul 16 [online media release]. Available from URL: http://www.daiichisankyo.com/4less/cgi-bin/cs4view_obj.php/b_newsrelease_n1_eng/554/080716_001v1-e.pdf [Accessed 2009 Mar 13]
  15. 15.
    European Medicines Agency. Kuvan®: summary of product characteristics [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/kuvan/H-943-PI-en.pdf [Accessed 2009 Jan 18]
  16. 16.
    Matalon R, Koch R, Michals-Matalon K, et al. Biopterin responsive phenylalanine hydroxylase deficiency. Genet Med 2004 Jan–Feb; 6(1): 27–32PubMedCrossRefGoogle Scholar
  17. 17.
    Erlandsen H, Stevens RC. A structural hypothesis for BH4 responsiveness in patients with mild forms of hyperpheny-lalaninemia and phenylketonuria. J Inherit Metab Dis 2001 Apr; 24(2): 213–30PubMedCrossRefGoogle Scholar
  18. 18.
    Erlandsen H, Pey AL, Gámez A, et al. Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc Natl Acad Sci U S A 2004; 101(48): 16903–8PubMedCrossRefGoogle Scholar
  19. 19.
    Ormazabal A, Vilaseca MA, Pérez-Dueñas B, et al. Platelet serotonin concentrations in PKU patients under dietary control and tetrahydrobiopterin treatment. J Inherit Metab Dis 2005; 28(6): 863–70PubMedCrossRefGoogle Scholar
  20. 20.
    Feillet F, Clarke L, Meli C, et al. Pharmacokinetics of sapropterin in patients with phenylketonuria. Clin Pharmacokinet 2008; 47(12): 817–25PubMedCrossRefGoogle Scholar
  21. 21.
    US FDA Centre for Drug Evaluation and Research. Sapropterin dihydrochloride review [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2007/022181s000_MedR_P1.pdf [Accessed 2008 Aug 1]
  22. 22.
    Burton BK, Grange DK, Milanowski A, et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J Inherit Metab Dis 2007 Oct; 30(5): 700–7PubMedCrossRefGoogle Scholar
  23. 23.
    Levy HL, Milanowski A, Chakrapani A, et al. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 2007 Aug 11; 370(9586): 504–10PubMedCrossRefGoogle Scholar
  24. 24.
    Lee P, Treacy EP, Crombez E, et al. Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Am J Med Genet Part A 2008 Nov 15; 146A: 2851–9PubMedCrossRefGoogle Scholar
  25. 25.
    Trefz FK, Burton BK, Longo N, et al. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr. Epub 2009 Mar 2Google Scholar
  26. 26.
    US National Institutes of Health. Phenylketonuria: screening and management (National Institutes of Health Consensus Development Conference Statement October 16–18, 2000) [online]. Available from URL: http://consensus.nih.gov/2000/2000Phenylketonuria113html.htm [Accessed 2008 Oct 28]
  27. 27.
    Waisbren SE, Noel K, Fahrbach K, et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab 2007 Sep–Oct; 92(1–2): 63–70PubMedCrossRefGoogle Scholar
  28. 28.
    European Medicines Agency. Committee for Medicinal Products for Human Use assessment report for Kuvan [online]. Available from URL: http://www.emea.eu/humandocs/PDFs/EPAR/kuvan/H-943-en6.pdf [Accessed 2009 Feb 25]
  29. 29.
    Blau N. Defining tetrahydrobiopterin (BH4) responsiveness in PKU. J Inherit Metab Dis 2008 Feb; 31(1): 2–3PubMedCrossRefGoogle Scholar
  30. 30.
    Doggrell SA. Is sapropterin treatment suitable for all subjects with phenylketonuria? Expert Opin Pharmacother 2008 Jan; 9(1): 145–7PubMedCrossRefGoogle Scholar
  31. 31.
    BioMarin Pharmaceutical. Study of phenoptin in subjects with phenylketonuria who have participated in protocols PKU-004 or PKU-006 [ClinicalTrials.gov identifier NCT00332189]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2009 Mar 5]
  32. 32.
    Shintaku H, Kure S, Ohura T, et al. Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene. Pediatr Res 2004 Mar; 55(3): 425–30PubMedCrossRefGoogle Scholar
  33. 33.
    Lambruschini N, Pérez-Dueñas B, Vilaseca MA, et al. Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Mol Genet Metab 2005 Dec; 86 Suppl. 1: S54–60PubMedCrossRefGoogle Scholar
  34. 34.
    Hennermann JB, Bührer C, Blau N, et al. Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab 2005 Dec; 86 Suppl. 1: S86–90PubMedCrossRefGoogle Scholar
  35. 35.
    Koch R, Hanley W, Levy H, et al. The Maternal Phenylketonuria International Study: 1984-2002. Pediatrics 2003 Dec; 112 (6 Suppl. 1): 1523–9PubMedGoogle Scholar
  36. 36.
    Trefz FK, Blau N. Potential role of tetrahydrobiopterin in the treatment of maternal phenylketonuria. Pediatrics 2003 Dec; 112 (6 Suppl. II): 1566–9PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  1. 1.Wolters Kluwer Health ¦ AdisMairangi Bay, North Shore, AucklandNew Zealand
  2. 2.Wolters Kluwer HealthPhiladelphiaUSA

Personalised recommendations