Background: Maintaining oxygen delivery during conditions of hypoxia is important, particularly for patients with hemoglobinopathies.Evidence in comparative physiology indicates that high hemoglobin-oxygen (Hb-O2) affinity serves as a beneficial hematological adaptation to chronic hypoxia exposure. The improved hypoxia tolerance is likely due to an increase in arterial oxygen saturation with high Hb-O2 affinity. However, the relationship between high Hb-O2 affinity and hypoxia tolerance in humans is not well understood. Etavopivat is a potent, selective, once-daily, oral activator of the red blood cell (RBC) pyruvate kinase isozyme (PKR), with a half-life of ~13 hours, under investigation for the treatment of sickle cell disease (SCD) and other hematological conditions. Etavopivat has a multimodal mechanism of action in RBCs by decreasing 2,3-diphosphoglycerate (2,3-DPG) levels to increase Hb-O2 affinity and increasing adenosine triphosphate (ATP) levels to improve RBC health. In Phase 1 trials etavopivat increased Hb-O2 affinity in healthy volunteers (HVs; Forsyth et al. Clin Pharmacol Drug Dev 2022) and patients with SCD (Saraf et al. Blood Adv 2024) in room air.

Aim: To investigate arterial oxygenation changes with etavopivat under conditions of moderate and severe hypoxia in HVs.

Methods: HVs visited the laboratory for assessments at baseline and following 7 days of etavopivat exposure (400 mg once daily). Participants completed rhythmic handgrip exercises (rest, 10% and 20% maximum voluntary contraction [MVC]) during graded hypoxic exposure, breathing room air (21% O2), moderate hypoxic gas (15% O2), and severe hypoxic gas (10% O2), resulting in acute duration (~12 minutes) of exposure to each level of hypoxia. Hb-O2 affinity was assessed by partial pressure of oxygen at 50% Hb saturation (P50), measured using dual-wavelength spectrophotometry at a standardized pH (~7.4) and temperature (37 ºC). Arterial catheterization was used to collect samples for fractional oxygen saturation (FO2Hb) and Hb and to measure arterial blood pressure. Blood gases were analyzed after 5 minutes of resting exposure to each inspirate, then ~2.5 minutes after commencing each of the 3-minute handgrip exercises (10% followed by 20% MVC). Liquid chromatography-tandem mass spectrometry was used to evaluate 2,3-DPG and ATP levels in whole blood. Data for FO2Hb and heart rate were analyzed using separate repeated measures 2 (treatment) x 3 (intensity) ANOVA for each inspirate and all other hematological data pre vs post etavopivat were analyzed using paired-sample t-tests. Statistical significance was set at P<0.05. Data presented are mean ± standard deviation.

Results: Sixteen HVs (five women) aged 32 ±8 years were enrolled. After 7 days of oral once-daily 400 mg etavopivat, P50 decreased from 28.6 ±1.6 at baseline to 24.8 ±1.3 mmHg (P<0.001). Hb concentration remained unchanged from baseline (14.6 ±1.1 g/dL), post etavopivat (14.5 ±1.1 g/dL; P>0.05). FO2Hb at rest decreased from 96.0% ±0.6 under normal oxygen conditions to 74.6% ±6.7 during severe hypoxic exposure; however, this decrease in FO2Hb was mitigated post etavopivat exposure (79.7% ±5.2, P<0.001). A similar mitigation of the FO2Hb decrease was observed during the handgrip exercise (20% MVC, P<0.001). Concentrations of 2,3-DPG decreased and RBC ATP increased following etavopivat exposure during both normoxia and moderate hypoxia (P<0.001). Mean arterial pressure was lower post etavopivat exposure under normoxia, but not during moderate or severe hypoxia. Heart rate showed no change post etavopivat exposure during normoxia and hypoxia (P>0.50). Etavopivat was well tolerated with no unexpected adverse events reported.

Conclusions: Etavopivat enhanced FO2Hb during brief hypoxic episodes with an apparent relationship to hypoxia severity for which the greatest improvements were observed at more severe hypoxic exposure. In SCD, high Hb-O2 affinity is beneficial for maintaining Hb ‘R’ state, thereby reducing the risk of polymerization and associated sickling. Increased Hb-O2 affinity, together with maintenance of a high FO2Hb under hypoxic conditions, demonstrates etavopivat's ability to promote oxygen exchange and subsequent delivery. Together with projected improvement of RBC health, also achieved via PKR activation, this indicates a potential clinical benefit with etavopivat for hemoglobinopathies and beyond.

Disclosures

Wiggins:Novo Nordisk: Research Funding. Webb:Novo Nordisk: Research Funding. Gasner:Novo Nordisk: Research Funding. Pruter:Novo Nordisk: Research Funding. Navani:Pfizer: Ended employment in the past 24 months; Novo Nordisk Ltd: Current Employment; Novo Nordisk: Current equity holder in publicly-traded company. Carden:Cogent Biosciences: Current Employment; Novo Nordisk: Ended employment in the past 24 months. Joyner:Novo Nordisk: Research Funding.

Off Label Disclosure:

Etavopivat is under investigation for the treatment of sickle cell disease and other hematologic conditions, and is not currently licensed for these or other diseases.

This content is only available as a PDF.
Sign in via your Institution