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In Vivo Studies of a Novel HDAC Inhibitor for Treating Hemoglobin Disorders

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42HL136068-02
Agency Tracking Number: R42HL136068
Amount: $1,073,855.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NHLBI
Solicitation Number: PA18-575
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-09-04
Award End Date (Contract End Date): 2021-08-31
Small Business Information
Fort Collins, CO 80526-6500
United States
DUNS: 078526138
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (706) 721-6893
Business Contact
Phone: (303) 895-8216
Research Institution
1120 15TH STREET
AUGUSTA, GA 30912-0004
United States

 Nonprofit College or University

The β-hemoglobinopathies are prevalent genetic blood diseases with few treatment options. It is estimate that
7% of the worldandapos;s population carries an abnormal hemoglobin gene with 400,000 infants born annually with a
severe life threatening hemoglobinopathy. Drug mediated induction of normal, but developmentally silenced,
fetal hemoglobin (HbF) expression reduces anemia and ameliorates clinical severity in the β-
hemoglobinopathies. Histone deacetylase (HDAC) 1, 2, and 3, are components of the NURD repressor
complex, which promotes silencing of the fetal γ-globin genes in adult erythroid cells. Prior generation HDAC
inhibitors increase HbF in patients with β-hemoglobinopathies, but had limitations for pharmaceutical
application and/or required titration to reduce anti-proliferative effects. Cetya has generated a library of high
potency HDAC inhibitors, one of which, CT-101, has demonstrated efficacy in inducing HbF expression in β-
thalassemia and sickle cell erythroid progenitors and in the β-YAC mouse model that contains the normal
human β-globin gene locus,without significant anti-proliferative effects. We will test the central hypothesis
that CT-101 has a sufficiently wide margin of activity, without significant inhibition of erythroid cell growth, to be
developed as a new agent for treatment of β-hemoglobinopathies. We propose to conduct studies to evaluate
CT-101 in the β-YAC model to optimize dose and schedule, and then confirm efficacy in the Townes sickle cell
disease mouse model. Cetya will scale the CT-101 manufacturing process and produce sufficient quantities to
support the murine studies and oral formulation development. The goal of this project is to develop the new
high-potency HDAC inhibitor CT-101 for an IND and clinical therapeutics. To test our hypothesis the following
aims will be completed. Aim 1. Test the hypothesis that CT-101 induces HbF expression in the preclinical β-
YAC and Townes sickle cell disease mouse models through epigenetic histone modifications. Aim 2. Scale the
manufacturing processes and produce sufficient quantities of CT-101 to conduct IND-enabling studies required
for a Phase I clinical study. Aim 3. Develop an oral dosage formulation of CT-101 suitable for human
administration. The expected outcome of this Phase 2 project is to develop CT-101 as an oral effective HbF
inducer. Our experimental approach rests on the scientifically validated concept of the inhibition of sickle
hemoglobin polymerization by HbF and red blood cell sickling by reversing a well-known epigenetic γ-globin
gene silencing mechanism. Development of the potent HDAC inhibitor CT-101 will impact the field and
addresses an unmet need for additional disease modifying therapy for β-hemoglobinopathies.PROJECT NARRATIVE
This proposal will build on findings obtained in our Phase I grant, utilizing transgenic mouse models to
determine the optimal dose and schedule for a future clinical study in patients. The manufacturing process for
the compound, CT-101, will be optimized at Cetya, and then manufacturing scaled for animal studies and
formulation for oral dosage in human trials. Upon completion of the proposed activities in this Phase 2 grant,
IND-enabling studies will be performed and CT101 advanced rapidly into clinical trials.

* Information listed above is at the time of submission. *

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