No placebo, too early to conclude imo.
BioMarin Announces Positive Results From Phase 2A Clinical Study of 6R-BH4 in Sickle Cell Disease
biz.yahoo.com
NOVATO, Calif., Oct. 15 /PRNewswire-FirstCall/ -- BioMarin Pharmaceutical Inc. (Nasdaq: BMRN - News) today 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.
Key findings from the study:
-- Endothelial dysfunction, measured using the EndoPAT device to assess
peripheral arterial tonometry (PAT), was common in the sickle cell
disease patient population. At baseline, 56% of the patients in the
trial had endothelial dysfunction (PAT score less than or equal to
1.67), consistent with prior studies using other methods for measuring
endothelial function.
-- Endothelial dysfunction in SCD patients treated with escalating doses
of 6R-BH4 showed improvement at week 8 (5 mg/kg; p=0.042), week 12
(10mg/kg; p=0.003) and week 16 (20 mg/kg; p=0.075).
-- SCD patients with an abnormal PAT scores of less than or equal to
1.67 at baseline demonstrated greater improvement at all dose
levels (2.5, 5, 10 and 20 mg/kg).
-- The mean endothelial function PAT score improved from the abnormal to
the normal range (>1.67) in SCD patients with an abnormal PAT score at
baseline.
-- Improvement in endothelial dysfunction appeared to be dose-dependent.
-- 6R-BH4 was well-tolerated 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, M.D., Ph.D., 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 U.S. 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, M.D., Ph.D., Associate Professor of Pediatric Hematology & 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 hemolysis and the release of hemoglobin from red cells."
Study Design
The Phase 2a multi-center, open-label study enrolled 32 subjects and was conducted at 12 U.S. sites. Among other eligibility criteria, to participate in the study, SCD patients were at least 15 years of age and were not receiving hydroxyurea or hypertransfusion therapy. Study patients received 6R-BH4 at 2.5 mg/kg, 5 mg/kg, 10 mg/kg and 20 mg/kg for four weeks each in a 16-week dose-escalation study. A total of 21 patients completed the baseline and final assessments.
The primary objective in the study was to evaluate the safety of oral 6R-BH4 administered in escalating doses in patients with sickle cell disease. The secondary objective was to evaluate changes in physiological and biochemical markers of endothelial function which underlie some key aspects of SCD. PAT scores were measured at the end of each 4 week dose period and compared to the baseline PAT score for statistical purposes.
Abstract at American Society of Hematology Conference
Abstract: Peripheral Arterial Tonometry Assessment of Endothelial Dysfunction in Sickle Cell Patients |
