BioMarin Pharmaceutical Inc. announced that the first patient has initiated treatment in the phase 2 clinical study of 6R-BH4 for the treatment of poorly controlled hypertension. The company expects to announce data from this study in early 2007.
"6R-BH4, commonly known as tetrahydrobiopterin, is an essential enzyme cofactor that plays a key role in the production of nitric oxide, a molecule that regulates vascular tone. A secondary deficiency of 6R-BH4 disrupts NO production, resulting in loss of vasodilation control and increased blood pressure," stated Emil Kakkis, M.D., Ph.D., chief medical officer of BioMarin. "Our goal is to confirm results seen earlier in pilot clinical studies that demonstrated that oral administration of 6R-BH4 can reduce blood pressure in individuals who remain hypertensive despite treatment with other medications."
The phase 2, multicenter, double-blind, placebo-controlled, parallel group study is designed to evaluate the safety and efficacy of 6R-BH4 on blood pressure in patients with poorly controlled systemic hypertension. The study will be conducted at up to 25 sites in the United States and will enrol approximately 84 patients, with the intention that approximately half of the patients will have type 2 diabetes.
Among other eligibility criteria, to participate in the study, patients must have elevated blood pressure while on at least two different medications for hypertension. Study patients will receive oral doses of 5 mg/kg of 6R-BH4 or a placebo twice daily for an eight-week period. The primary endpoint variable of the study is the change in systolic blood pressure (SBP) from baseline to Week 8.
The primary endpoint analysis will compare the mean change in SBP between the 6R-BH4 and placebo groups. A secondary endpoint analysis will compare the mean change in diastolic blood pressure (DBP) between the 6R-BH4 and placebo groups.
6R-BH4, commonly known as BH4 or tetrahydrobiopterin, is a naturally occurring enzyme cofactor that is required for numerous biochemical and physiologic processes, including the synthesis of nitric oxide (NO). NO has been shown to play a key protective role throughout the cardiovascular system and produces multiple positive effects, such as relaxing smooth muscle, reducing blood pressure, controlling inflammation and reducing platelet aggregation.
Researchers have demonstrated that a deficiency of BH4 can disrupt NO synthesis, resulting in a loss of normal endothelial NO production. This loss of endothelial NO production, commonly referred to as endothelial dysfunction, has been associated with many cardiovascular diseases, including hypertension, diabetic vascular disease, peripheral arterial disease, coronary arterial disease and pulmonary hypertension, and has been shown to be a strong predictor of cardiovascular adverse events in a number of clinical studies.
6R-BH4 is the same enzyme cofactor currently being evaluated in BioMarin's Phenoptin (sapropterin dihydrochloride) for phenylketonuria (PKU). In March 2006, BioMarin and Serono, BioMarin's corporate partner for the Phenoptin and 6R-BH4 programs, announced positive results from the Phase 3 clinical study of Phenoptin for PKU. All primary and secondary endpoints of the study were met. The type and incidence of adverse events was similar in the Phenoptin and placebo groups. Phenoptin was well tolerated and investigators reported that no serious adverse event occurred.