BioMarin starts phase 2a study of 6R-BH4 in sickle cell disease

May 4 2007

BioMarin Pharmaceutical has announced that the first patient has initiated treatment in the Phase 2a clinical study of 6R-BH4 (sapropterin dihydrochloride) for the treatment of sickle cell disease (SCD).

The company expects to announce data from this study in the first half of 2008.

"The sickle cell disease indication fits well strategically with our focus on rare, undertreated genetic diseases. SCD is an orphan disease with 70,000 to 100,000 patients in the United States, according to the CDC. It is well- diagnosed at birth, but there is only one approved drug treatment option currently available which is used by a minority of patients due to toxicity problems," said Jean-Jacques Bienaime, Chief Executive Officer of BioMarin. "6R-BH4 is an essential enzyme cofactor that is involved in the production of nitric oxide, a molecule that has been shown to play a role in the regulation of endothelial function. Studies of SCD patients suggest that endothelial dysfunction may play a role in sickle cell disease, and studies in an animal model of SCD suggest the potential utility of 6R-BH4 in the treatment of the vascular problems found in this disease."

The Phase 2a multi-center, open-label study is designed to assess the safety and biologic activity of escalating doses of 6R-BH4 in patients with SCD. The study will be conducted at approximately six U.S. sites and will enroll approximately 40 subjects. Among other eligibility criteria, to participate in the study, SCD patients must be at least 15 years of age and not receiving hydroxyurea therapy. Study patients will initially receive a low, once daily oral administration of 6R-BH4 (2.5 mg/kg) and will gradually escalate every four weeks to a final dose of 20 mg/kg/day during a 16-week dose-escalation phase. Patients will be monitored for physiological and biochemical markers of endothelial function. After 16 weeks, patients who show improvement in physiological or biochemical markers of endothelial function and/or derive clinical benefit from 6R-BH4 will have the option to continue drug treatment for up to two years. During this long-term treatment period, patients will also be monitored for sickle cell crises and other vasoocclusive events which are the key problems facing SCD patients.

The primary objective of this study is to evaluate the safety of oral 6R- BH4 administered in escalating doses in patients with sickle cell disease. The secondary objective is to evaluate changes in physiological and biochemical markers of endothelial function which underlie some key aspects of SCD.

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 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 Kuvan(TM) (sapropterin dihydrochloride) for phenylketonuria (PKU). In March 2006, BioMarin and Merck Serono (a division of Merck KGaA, Darmstadt, Germany), BioMarin's corporate partner for the Kuvan and 6R-BH4 programs, announced positive results from the Phase 3 clinical study of Kuvan for PKU. All primary and secondary endpoints of the study were met. The type and incidence of adverse events was similar in the Kuvan and placebo groups. Kuvan was well tolerated and investigators reported that no serious adverse event occurred.