A Phase 2 Study of the Effects of Sapropterin Dihydrochloride on Symptomatic Peripheral Arterial Disease

Inclusion Criteria: * At least 40 years and no more than 80 years old * A 6-month (or longer) history of walking limitation because of IC, severity of which has not changed in the past 3 months * Diagnosis of PAD secondary to atherosclerosis, with PAD documented at Screening by one of the following criteria: 1. Resting ankle-brachial index (ABI) \< 0.9 in at least one leg 2. If resting ABI is 0.9-1.0, minimum post-exercise drop in ABI of at least 25% in at least one leg 3. If resting ABI is \> 1.3 (indicating non-compressible vessels), vascular etiology documented by toe-brachial index (TBI) \< 0.7 in at least one leg * On Gardner graded treadmill protocol, peak walking time (PWT) of at least 1 minute, but no more than 12 minutes * Variation in PWT between two consecutive screening treadmill tests less than or equal to 25% * If currently receiving treatment with or taking any of the following, willing and able to discontinue for 30 days before Screening and throughout the entire study (including the follow-up period): phosphodiesterase (PDE) 5 inhibitor (eg, Viagra®, Cialis®, Levitra®, or Revatio™), any PDE 3 inhibitor (eg, cilostazol, milrinone, or vesnarinone), pentoxifylline (Trental®), nitrates, L-arginine, ginkgo biloba, or Heart Bar * For the approximately 50% of subjects enrolled to receive vitamin C with study drug or placebo, subjects must be willing to discontinue taking vitamin C supplements or a multivitamin containing vitamin C during study. * Antihypertensive therapy, cholesterol-lowering therapy (eg, statins), and diabetic therapy (if applicable) has been stable for 30 days prior to Screening. * Has not changed smoking or exercise habits in 30 days prior to randomization and is unlikely to do so during the study period * Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any research-related procedures * Willing and able to comply with all study-related 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 Exclusion Criteria: * Critical leg ischemia, manifested by pain at rest, ulceration, gangrene, or leg amputation * Surgical intervention to alleviate symptoms of claudication (eg, vascular reconstruction, sympathectomy) within 6 months or any endovascular interventions or cardiovascular surgery within 3 months * Walking limited by reasons other than claudication (eg, arthritis, lung disease, exercise-limiting cardiac disease, or skin or foot lesions that limit walking) * Clinically significant ECG change during or after exercise treadmill test at Screening or Baseline visit(s) * Myocardial infarction, deep vein thrombosis, or cerebrovascular infarct within 3 months of Screening * Body mass index \> 40 (gross obesity) * Hypertension at Screening, defined as seated mean resting BP value of \> 160 mmHg systolic, \> 110 mmHg diastolic, or both * Hypotension at Screening, defined as seated mean resting BP values of \< 100 mmHg systolic or \< 55 mmHg diastolic, or as clinically significant symptomatic (orthostatic) hypotension * Non-atherosclerotic vascular disease (eg, Buerger's disease or popliteal entrapment syndrome) * Previous treatment with any formulation of BH4 * Known allergy or hypersensitivity to any excipient of 6R-BH4 * Concurrent disease or condition that would interfere with study participation or safety such as bleeding disorders, history of severe gastrointestinal reflux disease, arrhythmia, organ transplant, organ failure, current neoplasm, type 1 diabetes mellitus, or serious neurological disorders (including seizures) * Previous treatment with gene therapy or other vascular endothelial growth factor (VEGF)-related treatment * Any severe co-morbid condition that would limit life expectancy to less than 6 months * Serum creatinine \> 2.0 mg/dL or hepatic enzyme levels more than 2 times the upper limit of normal * Concomitant treatment with levodopa * Requirement for concomitant treatment with any drug known to inhibit folate metabolism (eg, methotrexate) * Use of any investigational product or device 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 (subject or partner) at any time during the study