A Phase 3 study of the efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH₄) in reducing phe levels in subjects with phenylketonuria. H. Levy¹, A. Milanowski², A. Chakrapani³, M. Cleary⁴, F. Trefz⁵, C. Whitley⁶, F. Feillet⁷, A. Feigenbaum⁸, J. Bebchuk⁹, H. Christ-Schmidt⁹, A. Dorenbaum¹⁰. 1) Dept Medicine, Children's Hosp, Boston, Boston, MA; 2) Instytut Matki i Dziecka, Warszawa, Poland; 3) Birmingham Childrens Hospital, Birmingham, UK; 4) Great Ormond Street Hospital, London, UK; 5) Klinik fur Kinder und Jugendmedizin Reutlingen, Reutlingen, Germany; 6) University of Minnesota, Minneapolis, MN; 7) Hopital dEnfants - CHU Brabois, Vandoeuvre les Nancy, France; 8) Hospital for Sick Children, Toronto, Ontario, Canada; 9) Statistics Collaborative, Inc, Washington, DC; 10) BioMarin Pharmaceutical,Inc. Novato, CA.
   Strict dietary management of Phenylketonuria (PKU) is the only option to prevent mental retardation. Major challenges remain to achieve optimal outcomes. We studied Sapropterin, a synthetic form of BH₄, as a new treatment for PKU that could potentially improve long-term care. Patients previously screened for BH₄ response enrolled in a Phase 3, multicenter, randomized, double-blind, placebo controlled trial. Safety and efficacy in reducing blood phenylalanine (Phe) were compared in PKU patients treated with oral sapropterin 10 mg/kg, or placebo, once daily for 6 weeks. Of the 89 subjects enrolled, 87 completed treatment. Age ranged from 8 to 49 years (mean 209.7). At baseline, mean (SE) blood Phe was 843 (47) M and 888 (47) M in the sapropterin and placebo groups, respectively. After 6 weeks of treatment, sapropterin-treated patients achieved a mean blood Phe decrease of 236 (40) M (-29%) compared with a 3 (35) M (+3%) increase in the placebo group (p0.0001). At week 6, the percentages of subjects with blood Phe levels 600 M were 54% and 23% for the sapropterin and placebo groups, respectively (versus 17% and 19% at baseline). There was a consistent reduction over time in the average mean change in weekly blood Phe levels in the sapropterin group compared to the placebo group (p0.001). The type and incidence of adverse events were similar in the two study arms. Sapropterin was well tolerated and effective in significantly reducing blood Phe levels in PKU patients previously screened for BH4 responsiveness.