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