A Phase 2, Pharmacokinetic (PK) Study of 6R-BH4 Alone or 6R-BH4 With Vitamin C in Subjects With Endothelial Dysfunction

This was a Phase 2, randomized, open-label, 2-treatment, 2-sequence, 2-period crossover, pharmacokinetic (PK) study designed to compare the plasma concentrations of BH4 in subjects with endothelial dysfunction following 14 days of treatment by each of 2 regimens: sapropterin dihydrochloride with vitamin C and sapropterin dihydrochloride alone. Each subject received each regimen; the 2 treatment groups varied only in the sequence of the 2 regimens. The washout period between treatment regimens comprised the 1 day period between the last dose of study drug under the first regimen and the first dose of study drug under the second regimen (Day 14 morning to Day 15 morning).

Inclusion criteria

• 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.
• Age is ≥ 18 years and ≤ 75 years.
• Willing and able to comply with all study procedures.
• If currently receiving treatment with or taking any of the following supplements, be willing and able to discontinue taking them throughout the treatment period:

• Vit C supplements
• Multivitamins containing vit C
• Any other dietary supplements, nutraceuticals, or other over- the-counter products containing vit C
• Vitamin E-containing supplements
• History of cardiovascular disease or cardiovascular risk factors, eg, stable and well-controlled Type 2 diabetes, peripheral arterial disease, obesity, smoking, hypercholesterolemia
• Endothelial dysfunction, documented at screening by an abnormal peripheral arterial tonometry (PAT) of ≤ 1.70.
• 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 in menopause at least 2 years, or had tubal ligation at least 1 year prior to screening, or who have had total hysterectomy.

Exclusion criteria

• Hypertension secondary to other medical conditions (e.g., renal failure or steroid usage).
• Concurrent disease or condition that would interfere with study participation or safety, such as bleeding disorders; history of syncope or vertigo; severe gastroesophageal reflux disease (GERD); heart failure; symptomatic coronary disease; arrhythmia; serious neurologic disorders, including seizures; organ transplant; or organ failure.
• Type 2 diabetics that are uncontrolled, unstable, newly diagnosed, or have changed therapy in the last three months and all Type 1 diabetics.
• Any severe comorbid condition that would limit life expectancy to < 6 months.
• Serum creatinine > 2.0 mg/dL, or hepatic enzyme concentrations > 2 times the upper limit of normal
• HIV infection, hepatic cirrhosis, other preexisting liver disease, or positive HIV, Hepatitis B or C test at screening.
• Concomitant treatment with:

• Drugs known to inhibit folate metabolism (e.g., methotrexate)
• Levodopa
• A phosphodiesterase (PDE) 5 inhibitor (e.g., Viagra®, Cialis®, Levitra®, or Revatio®)
• A PDE 3 inhibitor (e.g., cilostazol, milrinone, or vesnarinone)
• Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.
• Myocardial infarction, stroke, or surgery within the last 60 days prior to screening.
• History of alcohol and/or drug abuse or a positive alcohol or drug test at screening.
• Previous treatment with any formulation of BH4.
• Has known hypersensitivity to 6R-BH4 or its excipients.
• 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 PI, places the subject at high risk of poor treatment compliance or of not completing the study.