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) affects ~100,000 individuals in the US and millions more worldwide. The disease
causes a range of adverse pathophysiological effects resulting in painful crises, organ failure, and eventually,
premature death. Our scientists spearheaded the development of a novel class of oral anti-sickling drugs based
on natural aromatic aldehydes, like vanillin from vanilla extract. This groundbreaking work demonstrated the
potential of aromatic aldehydes as allosteric effectors to stabilize the high O2-affinity state of hemoglobin S (HbS)
and reduce its tendency to polymerize, thereby inhibiting RBC sickling. This scientific foundation eventually led
to FDA approval of the first aromatic aldehyde drug Voxelotor. While the discovery of Voxelotor was monumental
for patients with this devastating condition, there are key limitations to its clinical efficacy, in particular the lack
of a definitive reduction in vaso-occlusions and other disease sequalae. There is still a major opportunity for next
generation oral drugs to push the limits of this therapeutic paradigm and transform SCD into a manageable
chronic condition. Over the past 15 years, our team has evaluated hundreds of aromatic aldehyde compounds
to identify best-in-class anti-sickling drug candidates. Novel insights from our structure-activity screening have
led to the discovery of aromatic aldehyde compounds with unique polymer-destabilizing properties. More
specifically, we discovered that certain aromatic aldehydes retain high anti-sickling potency even in total anoxia,
whereas Voxelotor completely loses efficacy in anoxia. Unlike Voxelotor, which relies solely on increasing
O2-affinity, our polymer-destabilizing compounds directly disrupt key polymer-forming contacts of HbS on the
αF-helix, thus inhibiting polymer formation. Induction of fetal Hb expression in RBCs is also known to destabilize
polymer formation by similarly disrupting key lateral contacts. A polymer destabilizing drug that can interrupt
polymer formation pancellularly across all RBCs may be the holy grail for the SCD treatment if it can overcome
key limitations to achieve unprecedented disease-modifying benefits with significantly less residual disease
sequalae. Based on highly encouraging preliminary data, we have plans to advance two bona fide lead drug
candidates to undergo pre-IND studies. VZHE-059 and IEX-021 are the most potent polymer destabilizing
compounds discovered to date, and have other favorable lead-like properties that would suggest these
candidates can become promising human drugs. VZHE-059 has already shown a clean toxicology profile. We
propose a robust panel of in vivo studies in the Townes homozygous HbSS mouse model to definitively
demonstrate the potential efficacy of VZHE-059 and IEX-021 for treating SCD to support advancing a lead drug
into a human trial. The proposed work includes formulation of each of the study drugs followed by trials of
voluntary oral administration to mice either in food chow or drinking water. Subsequently, definitive studies will
evaluate the efficacy of our lead compounds in terms of reversal of chronic hemolysis and recovery of anemia,
improvements in RBC half-life and deformability, and prevention of vaso-occlusion with hypoxia-reoxygenation.
