On Feb. 16, 12:00PM PST, I’ll be hosting Dr. Mira Pochon, Staff Scientist and Head of Translational Biology at Global Blood Therapeutics, for a PBSS/CLSA webinar on one of my favorite 2019 drug approvals, voxelotor (GBT440).  Mira has been with GBT since it’s early days in 2011, and will be able to tell the whole story.  GBT’s chemistry team was led by their CSO Dr. Brian Metcalf, former head of drug discovery at Incyte and SVP at SmithKline Beecham, where he was a co-inventor of the approved covalent drug vigabatrin, which also has a fascinating mechanism.  Since most of our international audience won’t be able to make it, here’s a short primer on the voxelotor and why I think it’s cool.

Voxelotor is a reversible covalent aldehyde drug for sickle cell anemia that’s dosed orally 1.5g QD.  That’s a very high dose for a covalent drug, and gets to why this drug is so interesting.  Part of the magic is that it has a blood to plasma partition ratio of 15:1(!) in humans, meaning nearly all of it resides in red blood cells, where it’s supposed to work.  The relatively low free concentration of the drug in plasma, combined with its reversibility and selectivity, allows it to be well-tolerated in a chronic indication.  The partitioning of the drug to red blood cells is partly due to its target being hemoglobin (~5 mM concentration in RBCs).

Sickle cell disease is most often caused by mutations in hemoglobin (Hb).  Normal hemoglobin is a tetramer of four globin subunits (2 α, 2 β) which each carry one molecule of oxygen.  A mutation like Glu6 to Val6 in both copies of the β-globin subunit (Hbβ) can create a lipophilic surface on Hbβ, allowing hemoglobin to polymerize pathogenically.  Voxelotor works by binding to and stabilizing the oxygenated form of hemoglobin, which is less prone to polymerization, resulting in less cell sickling.

voxelotor mechanism of action on hemoglobin for sickle cell anemia

The idea to stabilize hemoglobin in this way had been tried with aldehydes clinically before, as with tucaresol.  Since the N-terminal Val1 of hemoglobin is uniquely acidic with a pKaof only 6.9, it is significantly more reactive with aldehydes at physiological pH than other amines.  Unfortunately, this feature alone wasn’t enough to drive selectivity, and compounds like tucaresol were not developed further due to significant adverse reactions.

tucaresol voxelotor mechanism of action

The GBT team thought it might be possible to improve upon the aldehyde concept and improve tolerability with good medicinal chemistry.  To do this they needed a robust framework of assays to evaluate compounds.  Interestingly, their initial leads like compound 6 were found to bind in a 2:1 drug-to-tetramer stoichiometry in a binding pocket created by two globin subunits, as also seen recently with Pfizer’s non-covalent HbS modifiers.

voxelotor mechanism of action

Further optimization for whole blood anti-sickling activity and in vivo stability led to the identification of voxelotor.  Surprisingly, the GBT team found that compounds like voxelotor actually bind in a 1:1 drug-to-tetramer stoichiometry. The pyrazole fills a portion of the site formerly occupied by a second molecule and forms a hydrogen bond to Ser131.

voxelotor mechanism of action

Voxelotor entered clinical development in 2014, and was granted Accelerated Approval in 2019 based on the results of the Ph. III HOPE trial with only 274 patients, based on a significant increase in hemoglobin response rate in the drug group.  While the approval was based only on a biomarker endpoint, in a case series with 7 patients voxelotor treatment does appear to reduce transfusions needed and hospitalizations for pain.  Studies are on-going to determine the long-term effects of voxelotor treatment.  Assuming it continues to prove safe and effective, analysts project it will achieve blockbuster status within the decade.

Chemists seem bent on making aldehydes great again, making waves with recent drugs like voxelotor and candidates like one of 2020’s Small Molecules of the Year, roblitinib.  I personally feel like I’m making a full circle in my own attitude towards aldehydes.  As an undergraduate, there seemed to be nothing wrong with consuming grams of aldehydes like glucose (though to be fair Fisher projections seemed reasonable back then too).  Dealing with reactive, smelly aldehyde intermediates in the lab for some time, my attitude turned staunchly negative, and I forgot that aldehydes are quite common in biology.  Today, as my colleagues recently wrote about, aldehydes seem perfectly reasonable again – there are certainly crazier things to find in drugs.

Hope this was helpful, and check out Mira’s seminar on the 16th for much more detail.  Explore drughunter.com for more.