Aneuryst Inc

Enzyme Phenotyping of Hydroxyfasudil - Abstract a Subarachnoid Hemorrhage (SAH) Is a Devastating Neurocritical Emergency Characterized by the Extravasation of Blood Into the Subarachnoid Space Surrounding the Brain. Aside From Sah Caused by Trauma, Most Cases of Sah (85%) Are Caused by a Spontaneous Rupture of an Aneurysm Located on a Cerebral Artery. Approximately 10-15% of Individuals Who Experience an Sah Will Not Survive to Reach Hospital. at the Hospital, the Rupture Is Secured Either Surgically or Endovascularly. However, 2-3 Days After the Rupture, the Spilt Blood in the Subarachnoid Space Degrades Into Inflammatory By-products That Cause Cerebral Arteries to Constrict. This Constriction Is Called “cerebral Vasospasm,” and Is a Leading Cause of Death and Disability After Sah. the Only Treatment Ever Approved in the Us and Europe for Cerebral Vasospasm Is Nimodipine, a Calcium- Channel Blocker. However, Even With Nimodipine, Sah Has a Cumulative Death Rate of 18% Within the First 48 Hours; 22% by the First Week; 33% by the First Month; and 43% by the First Year; With Permanent Deficits in 75% of the Remaining Survivors in Contrast, Japan Has Never Approved Nimodipine. for Almost Three Decades, the Japanese Treatment for Vasospasm Has Been a Combination of Fasudil (a Rho-kinase (“rock”) Inhibitor) and Ozagrel (a Thromboxane A2 Synthesis Inhibitor). Neither Fasudil nor Ozagrel Ever Have Been Studied or Approved for Sah in the Us or Eu. a 2022 Observational Study From China Demonstrated That Patients Who Received Fasudil in Combination With Nimodipine Demonstrated Statistically Significant Improvements of 120% and 145% Respectively Over Nimodipine Alone on Well-established Measures of Cognition (montreal Cognitive Assessment Score) and Functional Independence (barthel Index). However, to Establish a Causal Relationship Between the Addition of Fasudil With the Observed Improvements, a Randomized Trial Will Be Required. Before Such a Randomized Trial Can Begin, Both the Fda and Ema Require Us to Identify All Metabolizing Enzymes Responsible for ≥25% of the Elimination of Both Fasudil and Any Fasudil Metabolite Expected to Account for ≥50% of the Parent Drug’s in Vivo Pharmacological Effect. the Metabolizing Enzyme for Fasudil Already Is Known, But the Metabolizing Enzymes for Fasudil’s Active Metabolite (hydroxyfasudil (“HF”)) Remain Unidentified. in This Phase I Sbir, Our Specific Aims Will Generate the in Vitro Enzyme-phenotyping Data on HF Required by the Fda and Ema. Specific Aim 1 Quantifies HF’S Metabolism From All Metabolizing Enzymes; Specific Aim 2 Characterizes the Contribution of Phase I Cyp Enzymes to HF’S Total Metabolism; and Specific Aim 3 Then Characterizes the Contribution of Phase Ii Ugt Enzymes to HF’S Metabolism. Successful Conclusion of This Program Will Satisfy the Enzyme-phenotyping Requirements to Begin Controlled Trials.