Development of a clinical hemoglobin modulator

DESCRIPTION provided by applicant The thalassemias and sickle cell disease are serious genetic blood diseases which are WHO designated as a growing global health burden The disorders decrease production or alter structure of the b chain of adult hemoglobin A and are characterized by anemia chronic organ damage and early mortality HbF is another type of normal hemoglobin which is suppressed in infancy Decades of research have shown that any incremental increase in HbF reduces the severity of sickle cell disease and the life threatening anemia of b thalassemia Pharmacologic augmentation of fetal hemoglobin g globin chain production to replace the defective or missing b globin chains is accepted as a therapeutic modality Only one therapeutic hydroxyurea is approved for sickle cell disease and no definitive therapeutic agent is approved for beta thalassemia Additional HbF inducing therapies are needed We utilized a novel high throughput screening program to interrogate a library of drugs which are already EMEA or FDA approved for other medical conditions and identified a panel of previously unrecognized potent HbF inducing drugs HbF inducing activity was validated in a secondary reporter assays in patientsandapos erythroid progenitors and lead therapeutics were evaluated in baboons on our Phase I STTR grant This primate model has been predictive of subsequent human responses for other drugs One therapeutic Benserazide was particularly intriguing in inducing high level fetal globin by fold over baseline with brif treatment in the baboon We found the drug suppresses two components of a major repressor complex of the fetal hemoglobin gene The drug has been used for decades in Europe and Canada as a PK enhancer of levodopa for treatment of Parkinsonandapos s disease and has a benign safety profile Accordingly we propose to repurpose Benserazide for treatment the beta hemoglobinopathies Our Aims include Aim I Determine an optimal dosing regimen of Benserazide for inducing sustained HbF in vivo in anemic nonhuman primates Aim II Produce a formulation suitable for a dose ranging trial in hemoglobinopathy patients Aim III Obtain a US IND to evaluate the EU approved therapeutic in patients with sickle cell disease and beta thalassemiaPUBLIC HEALTH RELEVANCE This proposal will repurpose a therapeutic which is currently approved in Canada and the EU in a combination tablet for another condition for treatment of serious blood diseases sickle cell disease and beta thalassemia a WHO designated global health burden Dose and regimens will be optimized in a nonhuman primate model a clinical protocol will be designed drug formulated and a US IND obtained This work will enable a Canadian and EU approved therapeutic to enter clinical trials in patients with beta hemoglobinopathies