{"doi":"10.1111/bjh.19697","title":"Therapeutic potential of the latest oxygen affinity‐modifying agent, <scp>GBT021601</scp> , for treating sickle cell disease is questionable","abstract":"We think it is important that readers of the British Journal of Haematology should be aware of several important aspects of the latest oxygen-modifying drug, GBT021601, for treating sickle cell disease (SCD) published last year in your journal by Dufu et al.1 Treating SCD by modifying oxygen affinity is a complex strategy owing to many subtle aspects of sickle haemoglobin (haemoglobin S [HbS]) biochemistry, physiology and kinetics that must be considered.2 To make our discussion of this subject more easily understandable, we first provide some important background information. Haemoglobin has two arrangements of its four subunits, 2α and 2β, that are in rapidly reversible equilibrium.3 One, called T to represent the tension provided by inter-subunit salt-bridges, has a low affinity for oxygen and has the conformation of fully deoxygenated haemoglobin and the other, called R for relaxed (no inter-subunit salt bridges), has a high affinity for oxygen and has the conformation of fully oxygenated haemoglobin.3 As haemoglobin is deoxygenated in the tissues, the shift in the equilibrium population from R to T gives rise to the characteristic sigmoid shape of the oxygen dissociation curve (ODC) that facilitates binding of oxygen in the lungs and unloading it in the tissues. In the case of HbS, deoxygenation results in the formation of fibres that stiffen and distort (‘sickle’) red blood cells (RBC's), the root cause of vaso-occlusion and its consequent pathology in SCD.4 Experiments showed that only the T conformation polymerizes and that two different tertiary conformations (t and r) within T also play a role.5 These experiments, as well as early studies by Beutler,6 led to the concept that binding a drug to shift the conformational equilibrium towards non-polymerizing R would reduce sickling and therefore be a viable strategy for drug treatment of SCD. This approach resulted in many attempts to develop a drug that binds preferentially to R. Voxelotor (GBT440, oxybryta) is the only one so far approved by the FDA that acts by this mechanism. There was no evidence that voxelotor decreases sickle cell crisis frequency, which is of utmost important to the patient. However, crisis frequency was not an end-point in FDA's consideration, which approved the drug because of the increase in haemoglobin levels. The reason that treatment with voxelotor is controversial is that the reduction in sickling is counteracted by the higher oxygen affinity, which compromises oxygen unloading in the tissues in SCD.2, 7, 8 In our 2021 Blood article,9 we provided a theoretical answer to the question of how much oxygen is delivered when cells from patients with SCD sickle during the in vivo rapid oxygen pressure decrease that occurs in seconds as RBCs pass through the microcirculation. By evaluating the clinically relevant positive and negative effects on oxygen delivery of decreased sickling and a highly left-shifted oxygen binding curve, respectively, we concluded that, in spite of much reduced sickling and an increase in haemoglobin levels, the net effect would be a decrease in oxygen delivery (see also Worth et al.10). This prediction was born out by the extended double-blind studies of Howard et al.11, 12 In Henry et al.'s study,9 we pointed out that voxelotor is bound so tightly to the HbS molecule, shifting the conformational equilibrium towards R to such an extent, that it effectively locks the HbS conformation in R. The same is true for GBT021601, as evidenced by the biphasic ODC (Figure 1A). The oxygen affinity of R is so high that it unloads little or no oxygen at the oxygen pressures of the tissues. Consequently, although the total Hb increases with drug treatment, the functional Hb actually decreases. As an example, consider an SCD patient with an 8 g/dL Hb level that increases with 30% drug occupancy of HbS to 10 g/dL. 30% of the Hb molecules are non-functional, so the functioning level is now about 7 g/dL. Thus, the anaemia is actually worse! ","journal":"British Journal of Haematology","year":2024,"id":469719,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":758967,"name":"Belhu Metaferia","orcid":null,"position":1,"is_corresponding":false},{"id":1242117,"name":"Troy Cellmer","orcid":null,"position":2,"is_corresponding":false},{"id":247166,"name":"Swee Lay Thein","orcid":"0000-0002-9835-6501","position":3,"is_corresponding":false},{"id":1303362,"name":"H. Franklin Bunn","orcid":"0000-0001-8918-2207","position":4,"is_corresponding":false},{"id":328712,"name":"William A. Eaton","orcid":"0000-0002-9244-5407","position":5,"is_corresponding":false},{"id":1303797,"name":"Braydon Alaimo","orcid":null,"position":0,"is_corresponding":true}],"reference_count":14,"raw_metadata":null,"created_at":"2026-07-19T02:05:32.241298Z","pmid":"39503354","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}