A Novel Non Cytotoxic Epigenetic Therapeutic for Sickle Cell Disease

ABSTRACT The goal of this Fast Track proposal is to develop a novel non cytotoxic epigenetic therapeutic for life long disease modification of sickle cell disease SCD SCD is a morbid life shortening condition caused by mutated hemoglobin sickle hemoglobin HbS The pathophysiology triggered by sickle hemoglobin is interrupted by another hemoglobin that the body usually produces in utero fetal hemoglobin HbF The epigenetic protein DNA methyltransferase DNMT is known to directly silence HbF DNMT is depleted by the generic drug decitabine Dec Moreover because of its chemistry Dec can deplete DNMT without cytotoxicity Early phase clinical trials that repositioned Dec for non cytotoxic DNMT depletion in HU refractory SCD have demonstrated notable efficacy Unfortunately marketed Dec has severe pharmacologic limitations undermining viability for life long disease modification i it is rapidly destroyed within minutes by the enzyme cytidine deaminase CDA This is a significant problem because DNMT depletion by Dec is S phase dependent in other words exposure time dependent ii Very high CDA levels in the intestines and liver are a barrier to oral bioavailability undermining feasibility for life long disease modification To solve these related problems we combined oral Dec with an inhibitor of CDA tetrahydrouridine THU A Phase I clinical trial has demonstrated that THU Dec solves the fundamental pharmacologic limitations of Dec alone However the Phase I trial was conducted `powder in bottleandapos patients attended the clinic for API reconstituted in the pharmacy then drunk orally Also THU a new chemical entity is synthesized by a batched poor yield very expensive synthesis scheme $ kg We will address these two major but technically tractable hurdles to clinical adoption via the following aims Phase Aim Complete process optimization of THU synthesis Instead of combining hydrogenation and reduction of uridine in a step process we pursue a step reaction scheme that separately optimizes hydrogenation and reduction reactions to produce higher scalable stereo selective THU yields at substantially lower costs We have very promising preliminary data Phase Aim Formulate oral THU and oral Dec into a combination drug product that releases THU immediately and Dec about minutes later We will pursue a combination THU Dec `tablet in tabletandapos strategy such that THU is released immediately in the stomach but the Dec component coated with a pH sensitive polymer is released in the small intestine neutral pH In vivo studies in a baboon model will be used to confirm that the product recapitulates or improves over `powder in bottleandapos PK Phase Aim Conduct a Phase IIa clinical study to confirm the dose of the combination drug product to be used in subsequent studies The body of scientific safety and efficacy data already generated for THU and Dec has de risked this endeavour to an extent very unusual for most early stage drug development efforts completion of this project promises rapid movement through pivotal clinical trials to NDA and to patients in need NARRATIVE Sickle cell disease SCD continues to exact a terrible toll of morbidity and mortality in the USA and worldwide underscoring the need for scientifically rational cost effective oral therapy for disease modification We have already generated clinical proof of principle of a novel non cytotoxic epigenetic therapy approach oral tetrahydrouridine decitabine THU Dec that has the potential to meet this need however there are fundamental technical barriers related to the synthesis and formulation of the new chemical entity THU that need to be overcome if commercialization and clinical adoption are to be feasible In this Fast Track project we have assembled the team of experts that can overcome these hurdles through hypothesis driven process optimization and formulation development culminating with a Phase IIa clinical trial thereby positioning this novel non cytotoxic epigenetic therapeutic for rapid movement through pivotal clinical trials to NDA and to patients in need