GBT, its lead drug voxelotor and the possible accelerated approval of the drug for SCD have been covered very well by Clover Biotech Research (https://seekingalpha.com/article/4236122-global-blood-therapeutics-investment-update-new-data-via-passionate-use), who has written extensively on GBT, and more recently by Bret Jensen (https://seekingalpha.com/article/4239451-global-blood-therapeutics-crucial-year-ahead). Suffice to say that I share the excitement and the optimistic view they have of voxelotor’s activity and potential.
Based on animal studies, voxelotor was studied in health volunteers and patients with idiopathic pulmonary fibrosis. The results did not show clinically meaningful benefit and the development of voxelotor for this indication was discontinued (Press Release | Investors | Global Blood Therapeutics).
GBT1118 is a structural analog of voxelotor, and is one of several compounds described in a patent (US20160083343A1 - Compounds and uses thereof for the modulation of hemoglobin - Google Patents) that is different from the original GBT440 patent (US9447071B2 - Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde - Google Patents).
It has the same hemoglobin-modifying properties that voxelotor has (https://www.gbt.com/file.cfm/82/docs/150103718-09%20GBT1118_vaso-occlusion.pdf). From the poster: “The allosteric Hb modulator GBT1118, an analog of voxelotor, improved vascular patency in a mouse model of SCD both before and after challenge with hypoxia/reoxygenation, possibly by delaying hypoxia-triggered HbS polymerization sufficiently for RBCs to transit the microcirculation without sickling or adhering to the vessel wall. These results support the potential for hemoglobin modifiers to improve sickling, vaso-occlusion and microvascular blood flow in patients with SCD, thus modifying both the acute and chronic complications of the disease.”
GBT1118 in lung injury
A team of GBT scientists evaluated GBT1118 in a mouse model of bleomycin‐induced lung fibrosis (https://physoc.onlinelibrary.wiley.com/doi/full/10.14814/phy2.12965).
Bleomycin is a chemotherapy drug that can cause lung fibrosis as a major complication, and this particular mouse model is regularly used to explore utility of interventions in lung fibrosis. Giving GBT1118 for 8 days after induction of lung injury resulted in the following beneficial effects: improved arterial oxygen saturation, and reduction of lung fibrosis, collagen deposition (a marker of scarring), and loss of weight.
GBT1118 in hypoxia
Another team of GBT scientists studied GBT1118 in a mouse model of hypoxia (GBT1118, a potent allosteric modifier of hemoglobin O2 affinity, increases tolerance to severe hypoxia in mice | American Journal of Physiology-Heart and Circulatory Physiology).
As expected, GBT1118 increased the oxygen affinity of hemoglobin and decreased the PO2 (pressure of oxygen in the blood) at which 50% of hemoglobin was saturated with oxygen. There was also a reduction in hypoxia-induced hypotension (low BP). Hypotension can compromise blood flow in this situation. Microvascular blood flow was higher during hypoxia in GBT1118-treated groups. This is important to reduce the risk of tissue damage from lack of oxygen. The authors concluded that “increased Hb O2 affinity enhanced physiological tolerance to hypoxia, as evidenced by improved hemodynamics and tissue oxygenation. Therefore, pharmacologically induced increases in Hb O2 affinity become (sic) a potential therapeutic approach to improve tissue oxygenation in pulmonary diseases characterized by severe hypoxemia.”
Another group of GBT scientists studied GBT1118 in another mouse model of acute lung injury (https://www.physiology.org/doi/full/10.1152/japplphysiol.00079.2017).
They found that low-dose GBT1118 reduced mortality to less than half that of controls and high-dose GBT1118 to less than one-third, and also reduced severity of illness. Treatment with GBT1118 apparently did not alter alveolar-capillary permeability, inflammatory cell numbers in the lungs, or the amount of inflammatory cytokines – possibly indicating that the beneficial effect came from its inherent property of increasing oxygen affinity of hemoglobin. High-dose GBT1118 did not affect histological lung injury but decreased tissue hypoxia measured in the liver and kidneys. These are the two major organs that can fail because of hypoxia. They concluded that “increasing the oxygen affinity of hemoglobin using GBT1118 may be a novel therapy for treating hypoxemia associated with acute lung injury.” I am puzzled by lack of changes in inflammatory markers, because that would be expected for local improvement to be seen (as shown in the bleomycin experiments). It is possible that differences in study design could account for this.
Does GBT1118 have another property that can contribute to lung effects?
Coming across this exciting article prompted this post. Unlike the articles described above, I have not had access to the complete article here - but only the abstract.
Prepublication citation/description (The effect of the anti-sickling compound GBT1118 on the permeability of red blood cells from patients with sickle cell anaemia) of a study from UK showed that GBT1118 increased red cell hydration; decreasing shrinkage and fragility. I am not sure that this has been shown with voxelotor. That may suggest that GBT1118 could be a better drug than voxelotor for SCD. Decreased red cell fragility may prevent hemolysis in the microcirculation – possibly explaining the beneficial effects in mice with lung injury. By implication, it may also be beneficial in clinical studies of lung injury where voxelotor failed – and clinical trials should be done in this setting.
I do not think GBT is a one-trick pony (although if you have a trick that’s as good as voxelotor, it’s not a bad thing!).
If GBT1118 turns out to have beneficial lung effects in clinical trials, it would be wonderful for patients in tough medical situations. It could also enhance the value of GBT dramatically because voxelotor could continue being used in SCD, and GBT1118 could be used in appropriate ICU patients for short durations at a very different price point (improvement in ARDS could easily be worth $20-50,000) and long durations in patients with pulmonary fibrosis.
Disclosure: I am/we are long GBT.
Additional disclosure: Also long BLUE and CRSP (both working in the SCD space), CELG (collaborating with BLUE), and BMY (acquiring CELG).