Chemistry:Osivelotor

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Osivelotor (formerly known as GBT021601, GBT601, and PF-07940367) is an investigational drug under development for the treatment of sickle cell disease (SCD).[1] It is a next-generation sickle hemoglobin (HbS) polymerization inhibitor developed originally by Global Blood Therapeutics and now owned by Pfizer following the 2022 acquisition.[1][2]

Mechanism of action

Osivelotor is an orally bioavailable small molecule that binds to the alpha chain of the hemoglobin molecule, forming a reversible covalent bond with the N-terminal valine.[3] The resulting allosteric modification of hemoglobin increases oxygen affinity and thereby decreases the concentration of deoxygenated sickle hemoglobin, which reduces the tendency for hemoglobin polymerization and subsequent red blood cell sickling.[3][4]

Compared to the first-in-class hemoglobin polymerization inhibitor voxelotor (which was withdrawn from the market in September 2024), osivelotor demonstrates improved pharmacokinetic properties in preclinical studies.[4] In murine models of sickle cell disease, osivelotor treatment resulted in increased hemoglobin oxygen affinity, reduced red blood cell sickling, and improved RBC half-life and hemoglobin levels not observed with voxelotor.[5]

Development history

Osivelotor was originally developed by Global Blood Therapeutics as part of their research into hemoglobin polymerization inhibitors for sickle cell disease.[6] Following Pfizer's acquisition of Global Blood Therapeutics in 2022, development of the compound has continued under Pfizer's leadership.[1]

The compound has been assigned the International Nonproprietary Name (INN) osivelotor and has the UNII identifier UK749B4S16.[7]

Clinical development

Phase 1 trials

Multiple Phase 1 studies have been conducted to evaluate the safety and pharmacokinetics of osivelotor:

  • A Pfizer-sponsored Phase 1 trial (NCT04983264) evaluated single and multiple doses of osivelotor in six adults with sickle cell disease.[8] The results demonstrated that the therapy was well tolerated and increased hemoglobin's affinity for oxygen as intended.[8][9]
  • An additional Phase 1 study (NCT06340347) has been registered on ClinicalTrials.gov, though detailed results have not yet been published.[10]

Phase 2/3 trials

Osivelotor is currently being evaluated in a three-part, multicenter Phase 2/3 clinical trial in participants with sickle cell disease.[11] Part A of the study evaluates the safety, tolerability, and efficacy of osivelotor in adult participants with SCD to determine an optimal dose.[11][12][13]

Preliminary results from Part A of the Phase 2/3 trial were presented at the 29th European Hematology Association Annual Congress in June 2024.[14] The data showed that 35 patients had been treated by the cut-off date, with increases in hemoglobin levels from baseline observed and maintained from week 1 to week 12.[14][15]

Saraf et al 2024 reported preliminary findings from the multicenter Phase 2/3 study.[16]

Open-label extension study

An open-label extension study (GBT021601-022) was also conducted to evaluate the long-term safety and efficacy of osivelotor in participants with sickle cell disease.[17][18]

Safety profile

Preliminary data from clinical trials suggest that osivelotor has a favorable safety profile, with most adverse effects reported as mild to moderate in nature.[19] The treatment has been generally well tolerated in clinical studies conducted to date.[19]

A clinical trial to study the effects on vital signs on taste when mixed with food or liquids is planned.[20]

Regulatory status

As of September 2025, osivelotor has investigational status and is not approved for clinical use.[7] The compound is being developed under Pfizer's leadership following their acquisition of the original developer, Global Blood Therapeutics.[21]

See also

References

  1. ↑ 1.0 1.1 1.2 "Osivelotor for sickle cell disease". 29 May 2024. https://sicklecellanemianews.com/osivelotor-for-sickle-cell-disease/. 
  2. ↑ "Osivelotor" (in en). PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/146567655. 
  3. ↑ 3.0 3.1 "Safety, Pharmacokinetics, and Pharmacodynamics of Osivelotor for Sickle Cell Disease: First-in-Human Studies in Healthy Participants and Patients". Clinical Pharmacology & Therapeutics. 2 September 2025. doi:10.1002/cpt.70028. PMID 40891510. 
  4. ↑ 4.0 4.1 "Discovery of Osivelotor (GBT021601): A Potent, Next-Generation Sickle Hemoglobin Polymerization Inhibitor". ACS Medicinal Chemistry Letters 16 (8): 1526–1532. 14 August 2025. doi:10.1021/acsmedchemlett.5c00076. PMID 40832524. 
  5. ↑ "GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model". British Journal of Haematology 202 (1): 173–183. July 2023. doi:10.1111/bjh.18771. PMID 36960712. 
  6. ↑ "Osivelotor - Drug Targets, Indications, Patents". https://synapse.patsnap.com/drug/b5468d15ffb34015ad8127398f581b53. 
  7. ↑ 7.0 7.1 "NCATS Inxight Drugs — Osivelotor". National Center for Advancing Translational Sciences. https://drugs.ncats.io/drug/UK749B4S16. 
  8. ↑ 8.0 8.1 "Osivelotor for sickle cell disease". 29 May 2024. https://sicklecellanemianews.com/osivelotor-for-sickle-cell-disease/. 
  9. ↑ Clinical trial number NCT04983264 for "An Intrapatient Single Dose and Multiple Ascending Dose Study to Evaluate the Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of GBT021601, a Hemoglobin S Polymerization Inhibitor, in Participants With Sickle Cell Disease (SCD)" at ClinicalTrials.gov
  10. ↑ Clinical trial number NCT06340347 for "A Study to Learn How the Body Processes the Study Medicine Called Osivelotor (PF-07940367) in People With Loss of Liver Function" at ClinicalTrials.gov
  11. ↑ 11.0 11.1 "A Phase 2/3 Study in Adult and Pediatric Participants With SCD". https://ctv.veeva.com/study/gbt021601-021-a-study-in-adult-and-pediatric-participants-with-scd. 
  12. ↑ Clinical trial number NCT05431088 for "A Phase 2/3 Study in Adult and Pediatric Participants With SCD" at ClinicalTrials.gov
  13. ↑ "Osivelotor for the treatment of sickle cell disease". Expert Opinion on Pharmacotherapy 26 (7): 801–808. 3 May 2025. doi:10.1080/14656566.2025.2489123. PMID 40179004. 
  14. ↑ 14.0 14.1 "Osivelotor – TIF". 6 April 2025. https://thalassaemia.org.cy/clinical-trial-updates-scd/osivelotor/. 
  15. ↑ "Abstract: S291: Preliminary Results From a Multicenter Phase 2/3 Study of Next-Generation HBS Polymerization Inhibitor Osivelotor (GBT021601) for the Treatment of Patients With Sickle Cell Disease". European Hematology Association. 13 June 2024. https://library.ehaweb.org/eha/2024/eha2024-congress/422395/santosh.saraf.preliminary.results.from.a.multicenter.phase.2.3.study.of.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Asearch%3Ds291. 
  16. ↑ "Preliminary Results from a Multicenter Phase 2/3 Study of Next-Generation Sickle Hemoglobin Polymerization Inhibitor Osivelotor (Gbt021601) for the Treatment of Patients with Sickle Cell Disease". Hematology, Transfusion and Cell Therapy 46: S30. October 2024. doi:10.1016/j.htct.2024.09.051. 
  17. ↑ "GBT021601-022: A Study of GBT021601 in Participants With Sickle Cell Disease (SCD)". https://www.centerwatch.com/clinical-trials/listings/NCT05632354/gbt021601-022-a-study-of-gbt021601-in-participants-with-sickle-cell-disease-scd. 
  18. ↑ Clinical trial number NCT05632354 for "An Open-label Extension Study to Evaluate the Long-term Safety of GBT021601 Administered to Participants With Sickle Cell Disease Who Have Participated in a GBT021601 Clinical Trial" at ClinicalTrials.gov
  19. ↑ 19.0 19.1 "Osivelotor for the treatment of sickle cell disease". Expert Opinion on Pharmacotherapy 26 (7): 801–808. 2025. doi:10.1080/14656566.2025.2489123. PMID 40179004. 
  20. ↑ Clinical trial number NCT06507904 for "A Phase 1, Randomized, Crossover Design Study to Assess Palatability of Osivelotor (PF-07940367) Pediatric Formulations With Dosing Vehicle (Part 1) and Randomized, Single-Dose, Parallel Design Study to Estimate Relative Bioavailability of Osivelotor Pediatric Formulation With Dosing Vehicle and With Water Compared to Clinical Tablet Formulation, and Effect of Food and/or Acid-Reducing Agent On Bioavailability In Healthy Adult Participants (Part 2)" at ClinicalTrials.gov
  21. ↑ "Osivelotor by Pfizer for Sickle Cell Disease: Likelihood of Approval". 23 January 2025. https://www.pharmaceutical-technology.com/data-insights/osivelotor-pfizer-sickle-cell-disease-likelihood-of-approval/. 



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