This Phase 2a, multicenter, open-label, dose-escalation study is designed to assess the safety and biologic activity of daily oral administration of 4 escalating doses of sapropterin dihydrochloride over 16 weeks in subjects with sickle cell disease. During an optional extension phase, the study will assess the safety, tolerability, and efficacy of extended treatment with sapropterin dihydrochloride, for a total of up to 2 years; The extension phase of this study was terminated.

This Phase 2a, multicenter, open-label, dose-escalation study was designed to assess the safety and biological activity of once-daily (or twice-daily [BID], only for the highest dose level) oral administration of 4 escalating doses of sapropterin dihydrochloride to subjects with Sickle Cell Disease (SCD); 32 subjects were enrolled in the dose-escalation phase of this study. Subjects received oral, once daily (for 2.5, 5, and 10 mg/kg/day) or BID (for 20 mg/kg/day) doses of sapropterin dihydrochloride during a 16-week, dose-escalation period, with dose levels increasing within subjects every 4 weeks, as follows: 2.5, 5, 10, and 20 mg/kg/day. At the highest dose level (20 mg/kg/day), the total dose of sapropterin dihydrochloride was divided, half of the tablets taken in the morning within 1 hour after a meal, and half approximately 12 hours later (or BID) within 1 hour after a meal. The extension phase of this study was terminated.

Inclusion Criteria:

• Diagnosis of SCD, as confirmed by hemoglobin electrophoresis.
• At least 15 years of age.
• Dosage of medication(s) used to treat cardiac disease, hypertension (eg, calcium-channel blockers), elevated cholesterol, iron overload (eg, desferoxamine) and type 2 diabetes must be unchanged for at least 30 days prior to Screening.
• Willing and able to provide written, signed informed consent, or in the case of subjects under the age of 18 years, provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures.
• Willing and able to comply with all study procedures.
• Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study.
• Females of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have been menopausal for at least 2 years, or had a tubal ligation at least 1 year prior to Screening, or who have had a total hysterectomy.

Exclusion Criteria:

• Requires chronic hypertransfusion therapy.
• Sickle cell crisis during the 30 days prior to Screening.
• Myocardial infarction, cerebral vascular accident, or pulmonary embolism during the 6 months prior to Screening.
• History of bone marrow or hematopoietic stem cell transplantation.
• Hepatic dysfunction (alanine aminotransferase [ALT][SGPT] > 2 times the upper limit of normal [ULN]).
• Renal dysfunction with serum creatinine > 1.5 mg/dL.
• On outpatient oxygen therapy, or continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) therapy.
• Uncontrolled hypertension (defined as blood pressure > 135/85 mm Hg) at Screening.
• History of chronic symptomatic hypotension.
• Concurrent disease or condition that would interfere with study participation or safety, including, but not limited to: bleeding disorders, history of syncope or vertigo, severe gastroesophageal reflux disease (GERD), arrhythmia, organ transplant, organ failure, type 1 diabetes mellitus (subjects with type 2 diabetes are allowed), or serious neurological disorders (including seizures).
• Hydroxyurea therapy during the 3 months prior to Screening or anticipated need for hydroxyurea during the course of the study.
• Treatment with any phosphodiesterase (PDE) 5 inhibitor (Viagra®, Cialis®, Levitra® or Revatio™), any PDE 3 inhibitor (eg, cilostazol, milrinone, or vesnarinone), pentoxifylline (Trental®), nitrate/nitrite-based vasodilators, bosentan (Tracleer®), L-arginine, levodopa, or dietary supplements containing L-arginine or gingko biloba within 30 days prior to Screening, or anticipated need for treatment with any of these agents during the course of the study.
• Requirement for concomitant treatment with any drug known to inhibit folate metabolism (eg, methotrexate).
• Previous treatment with vascular endothelial growth factor (VEGF) or VEGF inhibitors.
• Has known hypersensitivity to sapropterin dihydrochloride or its excipients.
• Use of any investigational product, device, or any formulation of BH4 within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
• Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study.
• Any condition that, in the view of the Investigator, places the subject at high risk of poor treatment compliance or of not completing the study.