Rapid Development of a Lead Aromatic Aldehyde Derivative with both Oxygen Dependent and Novel, Oxygen Independent Anti-Sickling Effects: Building on a Paradigm Shift in Sickle Cell Disease Therapy - Sickle cell disease (SCD), which results from a genetic mutation in hemoglobin (Hb) that causes red blood cells
(RBCs) to become malformed and rigid (‘sickled’), affects approximately 100,000 Americans (and millions
worldwide), with an estimated cost to the US healthcare system of over $1B annually. Red blood cell sickling,
the primary cause of downstream adverse SCD effects, including painful crises, progressive organ damage, and,
eventually premature death, is a consequence of the intracellular polymerization of deoxygenated “Tense” (T-
state) sickle-type Hemoglobin (HbS) (only T-state HbS tends to polymerize and not oxygen (O2)-liganded
“Relaxed” (R-state) HbS). Therefore, RBC sickling typically develops under conditions of hypoxia. The recent
FDA approval of Voxelotor, the first in a new class of potentially disease-modifying drugs, sets the stage for a
paradigm shift in the way SCD is therapeutically managed. Prior to the approval of Voxelotor, there had been no
new therapeutics targeting the underlying cause of the disease in more than two decades. Aromatic aldehyde-
containing compounds, such as Voxelotor, address the primary etiology of SCD by allosterically binding to, and
stabilizing, the high O2 affinity R-state of HbS, which does not polymerize. Using an iterative, structure-based
approach, our team of medicinal chemists has, for over 15 years, been focused on developing aromatic
aldehyde-containing analogs with enhanced therapeutic potential by rationally-modifying natural compounds,
such as vanillin. Guided by insights from X-ray co-crystallography and molecular modeling, vanillin derivatives
with increasing potency and duration of action have been attained by incorporating a tethered pyridine moiety
with diverse substitutions and modifications. Our lead therapeutic candidate, VZHE-039, is unique in that it not
only provides significantly increased Hb allosteric modulation via an O2 dependent mechanism, but also engages
in inter-molecular contacts with the Hb αF-helix, which directly destabilizes polymer formation via an O2
independent mechanism. This novel dual mechanism of action, which is not solely O2 dependent, has the
potential to provide for even more potent anti-sickling effects without inherently limiting tissue O2 unloading.
Based on a significant body of highly encouraging, preliminary in vitro and in vivo data, we have developed a
research strategy that will facilitate a rapid transition to Phase II SBIR studies and, subsequently, an
Investigational New Drug (IND) application. The principle goal of this Phase I proposal is to identify and evaluate
an optimal oral formulation for VZHE-039 to improve gastrointestinal solubility and oral bioavailability. The
optimized formulation will be evaluated in both rats and mice to determine its pharmacokinetic and
pharmacodynamic profile with single oral doses of the drug, as well as multiple repeat dose exposure to steady
state. An agent with improved in vivo oral bioavailability and optimal steady state kinetics will be ready for
definitive efficacy studies in an SCD mouse model, as well as IND-enabling toxicology in higher order mammals.
