Safety of extended treatment with sapropterin dihydrochloride in patients with phenylketonuria: Results of a phase 3b study Barbara K. Burton a, ⁎, Maria Nowacka b , Julia B. Hennermann c , Mark Lipson d , Dorothy K. Grange e , Anupam Chakrapani f , Friedrich Trefz g , Alex Dorenbaum h , Michael Imperiale i , Sun Sook Kim i , Paul M. Fernhoff j,1 a Children's Memorial Hospital, Chicago, IL, USA b Instytut Matki I Dziecka, Warszawa, Poland c Charité University Medical Center, Berlin, Germany d Kaiser Permanente Medical Center, Sacramento, CA, USA e Washington University School of Medicine, St. Louis, MO, USA f Birmingham Children's Hospital, Birmingham, UK g Klinik für Kinder-und Jugendmedizin Reutlingen, Reutlingen, Germany h Previously BioMarin Pharmaceutical, Inc., Novato, CA, USA; Now Genentech, Inc., South San Francisco, CA, USA i BioMarin Pharmaceutical, Inc., Novato, CA, USA j Emory University School of Medicine, Decatur, GA, USA abstract article info Article history: Received 2 February 2011 Received in revised form 24 March 2011 Accepted 24 March 2011 Available online 31 March 2011 Keywords: 6R-BH 4 Clinical trial Phenylalanine Phenylketonuria Sapropterin Tetrahydrobiopterin Background: Phenylketonuria (PKU) results from impaired breakdown of phenylalanine (Phe) due to deficient phenylalanine hydroxylase (PAH) activity. Sapropterin dihydrochloride (sapropterin, Kuvan®) is the only US- and EU-approved pharmaceutical version of naturally occurring 6R-BH 4 , the cofactor required for PAH activity. Sapropterin enhances residual PAH activity in sapropterin-responsive PKU patients and, in conjunction with dietary management, helps reduce blood Phe concentrations for optimal control. Approval was based on the positive safety and efficacy results of four international clinical studies, the longest of which was 22 weeks in duration. Objective: To evaluate the safety of long-term treatment with sapropterin in PKU subjects who participated in previous Phase 3 sapropterin trials. Methods: PKU-008 was designed as a Phase 3b, multicenter, multinational, open-label, 3-year extension trial to evaluate the long-term safety of sapropterin in patients with PKU who were classified as sapropterin responders and participated in prior Phase 3 sapropterin studies: 111 subjects aged 4–50 years completed prior studies and were subsequently enrolled in study PKU-008. Routine safety monitoring was performed at 3-month intervals and included adverse event reporting, blood Phe monitoring, clinical laboratory evaluations, physical examinations and vital sign measurements. Results: Average exposure during PKU-008 was 658.7 ± 221.3 days (range, 56–953; median, 595). The average total duration of participation in multiple studies (PKU-001, PKU-003, PKU-004, and PKU-008; or PKU-006 and PKU-008) was 799.0 ± 237.5 days (range, 135-1151). The mean sapropterin dose was 16.2 ± 4.7 mg/kg/day. Most adverse events were considered unrelated to treatment, were mild or moderate in severity, and were consistent with prior studies of sapropterin. No age-specific differences were observed in adverse event reporting. Three subjects discontinued treatment due to adverse events that were considered possibly or probably related to study treatment (one each of difficulty concentrating, decreased platelet count, and intermittent diarrhea). No deaths were reported. Of seven reported serious adverse events, one was considered possibly related to study treatment (gastroesophageal reflux). There were no laboratory or physical examination abnormalities requiring medical interventions. For most subjects, blood Phe concentrations were consistently within target range, confirming the durability of response in subjects undergoing extended treatment with sapropterin. Conclusion: Sapropterin treatment was found to be safe and well tolerated at doses of 5 to 20 mg/kg/day for an average exposure of 659 days. This study supports the safety and tolerability of sapropterin as long-term treatment for patients with PKU. © 2011 Elsevier Inc. All rights reserved. Molecular Genetics and Metabolism 103 (2011) 315–322 Abbreviations: 6R-BH 4 , 6R-tetrahydrobiopterin; AE, adverse event; PKU, phenylketonuria; PAH, phenylalanine hydroxylase; Phe, phenylalanine; SAE, serious adverse event; ULN, upper limit of normal. ⁎ Corresponding author at: Division of Genetics, Birth Defects, and Metabolism, Children's Memorial Hospital, 2300 North Childrens Plaza, Chicago, IL 60614, USA. Fax: + 1 773 929 9565. E-mail address: bburton@childrensmemorial.org (B.K. Burton). 1 For the Sapropterin Research Group. 1096-7192/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2011.03.020 Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme