BioMarin Pharmaceutical Inc announced results from its phase-2a multi-center, open-label, dose-escalation clinical study of 6R-BH4 in patients with sickle cell disease (SCD) designed to evaluate whether 6R-BH4 can improve the endothelial dysfunction observed in SCD patients. Oral administration of 6R-BH4 was associated with an improvement in endothelial dysfunction in sickle cell disease patients.

Pending feedback from the FDA at a pre-IND meeting in November, future development plans could include a cross-sectional study in sickle cell disease patients to assess the relationship between endothelial dysfunction and the frequency and severity of sickle cell crises, and a three month double-blind, placebo-controlled dose finding study with a primary endpoint of improvement in endothelial function.

Emil Kakkis, chief medical officer of BioMarin stated, "We are very encouraged by the study results as it suggests that the known severe endothelial dysfunction present in sickle cell disease patients is due to an acquired BH4 deficiency and is responsive to 6R-BH4 replacement therapy. Endothelial dysfunction in SCD is now believed to play a greater role in the pathophysiology of sickle cell vasoocclusive crises than had previously been realized. The ability to reverse this dysfunction with oral 6R-BH4 therapy represents a new opportunity to treat SCD."

Dr Kakkis continued, "The EndoPAT device is a new reproducible method to measure the effect of endothelial dysfunction on small vessel function and has been adopted by the ongoing Framingham study of cardiovascular risks and outcomes as recently published. The PAT score has been shown to correlate with other cardiovascular risk factors and endothelial dysfunction in general has been shown to predict adverse cardiovascular events in at least 10 prospective studies. With this current SCD study, we have an indication that 6R-BH4 is active in improving endothelial function, and we hope to establish a clear relationship between the degree of endothelial dysfunction and the frequency and severity of sickle cell crises using a survey of SCD patients with the EndoPAT test."

"Sickle cell disease is a chronic, lifelong disease that affects a significantly large population of approximately 100,000 people in the US. These patients suffer periods of intense pain, poor blood flow, organ damage and other serious medical complications. To date, however, there are very limited treatment options for this debilitating disease and average life expectancy is only in the forties," said Lewis Hsu, associate Professor of Paediatric Haematology & interim director of Marian Anderson Comprehensive Sickle Cell Center, St Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA. "These study findings are significant and support the concept of using BH4 to treat sickle cell disease, a somewhat novel but plausible approach. Recent reviews of the pathophysiology in sickle cell disease have shifted the focus away from the physical sickling of red blood cells and more toward the deteriorating health of the blood vessels resulting from haemolysis and the release of haemoglobin from red cells."

The 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).

BioMarin develops and commercializes innovative biopharmaceuticals for serious diseases and medical conditions.