Repurposing an EU Therapeutic for Hemoglobinopathies

National Center For Advancing Translational Sciences

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Abstract

The oxygen-carrying hemoglobin protein (Hemoglobin A or HbA) is a tetrameric molecule, comprising two paired alpha-chain/beta-chain protein dimers. Beta-thalassemia is caused by mutations that result in insufficient production of the beta-globin protein, whereas sickle cell disease is caused by a point mutation in the beta-globin protein that causes the hemoglobin tetramers to form rigid polymers that deform the red blood cell, causing early cell death, abnormal adhesion to blood vessels and resulting widespread organ damage. HbA is the adult form of hemoglobin, produced mostly after birth. At earlier developmental stages, fetal forms of hemoglobin (HbF) are expressed. Importantly, these fetal globin proteins can replace the abnormal adult beta-globin proteins found in sickle cell disease and compensate for the absence of adult beta-globin proteins in beta-thalassemia. Although fetal globin expression stops shortly after birth, the drug PB-04 can reactivate expression of the fetal-stage beta-globin gene. This activation may lead to production of sufficient levels of HbF to mitigate the beta-hemoglobinopathies. The goal of this project is to repurpose this drug, currently in use in the European Union and Canada for another indication, for treatment of the hemoglobin disorders beta-thalassemia and sickle cell disease. The TRND team completed pharmacology and efficacy studies to recapitulate key data generated by the collaborator. The team received recommendations from the Food and Drug Administration (FDA) regarding the proposed studies required to support the filing of an Investigational New Drug (IND) application via pre-IND interactions. Pharmacokinetic, bioanalytical, ADME (absorption, distribution, metabolism, excretion) and IND-enabling toxicology studies were completed, as were formulation and manufacturing of the drug product. These data and materials enabled the collaborator to file regulatory applications, which were cleared by both the US FDA and Health Canada, to begin clinical trials for beta thalassemia intermedia. The TRND team continued to support) manufacturing of the drug product, and clinical pharmacology efforts. An additional batch of GMP drug product was manufactured, and clinical pharmacology support to address clinical sample analyses for the ongoing Phase 1b/2a clinical trial which is near completion.