bims-sicedi 2025-08-24 papers

ACS Med Chem Lett. 2025 Aug 14. 16(8): 1526-1532

Discovery of Osivelotor (GBT021601): A Potent, Next-Generation Sickle Hemoglobin Polymerization Inhibitor.

Zhe Li, Carsten Alt, Kobina Dufu, Athiwat Hutchaleelaha, Qing Xu, Xinchun Zhang, Chien-Ming Li, Peter Rademacher, Caroline Bosmajian, Mira Patel Pochron, James R Partridge, Donna Oksenberg, Brian E Cathers.

This report details the discovery path of GBT021601 (osivelotor) (16), a novel, small molecule, sickle hemoglobin (HbS) polymerization inhibitor. Following a streamlined testing funnel with cassette dosing in rat pharmacokinetic (PK) studies, we identified this next-generation HbS polymerization inhibitor, which had improved PK properties compared with the first-in-class drug, voxelotor (1). GBT021601 has ∼4.8-fold greater exposure and a ∼3.5-fold longer half-life in rats compared with voxelotor. In a murine model of sickle cell disease (SCD), GBT021601 treatment resulted in an increase in hemoglobin oxygen affinity, a reduction in sickling of red blood cells (RBCs), and an increase in both RBC half-life and hemoglobin levels not seen with voxelotor preclinically. The improved half-life and exposure appear to translate to similar levels of HbS occupancy at lower doses than voxelotor, thus reducing treatment burden. GBT021601 is being investigated in a phase 2/3 clinical trial for the treatment of patients with SCD (NCT05431088).

Keywords: Schiff-base formation; covalent sickle hemoglobin modulator; hemoglobin oxygen affinity; osivelotor; red blood cell partitioning; sickle cell disease

DOI: https://doi.org/10.1021/acsmedchemlett.5c00076

Blood Adv. 2025 Aug 19. pii: bloodadvances.2025017204. [Epub ahead of print]

KDIGO-Defined Kidney Dysfunction Predicts Long-Term Outcomes in a Multi-Center Cohort of Adults with Sickle Cell Disease.

Xu Zhang, Michael R DeBaun, Kristin Wuichet, Rima Zahr, Zalaya K Ivy, Mitchell J Weiss, Alexander G Bick, Victor R Gordeuk, Santosh L Saraf.

Approximately 15% of deaths in adults with sickle cell disease (SCD) are attributed to kidney failure. Although urine albumin-to-creatinine ratio (UACR) is recommended to screen for kidney damage, its utility to predict long-term complications in SCD remains unclear. We investigated whether "Kidney Disease: Improving Global Outcomes (KDIGO)" algorithms used to assess kidney disease in the general population predicted chronic kidney disease (CKD) progression and mortality in a longitudinal cohort of 379 SCD adults from two academic institutions. KIDGO criteria include UACR detected in two consecutive measurements ≥3 months apart and a heat map integrating UACR with estimated glomerular filtration rate. KDIGO-defined CKD was present in 39.8% of individuals in our SCD cohort. Over a median follow up of 3.3 years, incremental KDIGO-defined UACR category independently predicted a 2-fold greater risk of CKD progression and 1.8-fold greater risk of mortality (P≤0.05). KDIGO-defined CKD heat map strengthened the ability to predict CKD progression and mortality risk (P≤0.0087). Our data provides clinical support for the screening utility of UACR based on repeated abnormal values ≥3 months apart. The KDIGO-heat map further refines risk of long-term outcomes in adults with SCD and should be applied to guide future studies for monitoring and intervention strategies.

DOI: https://doi.org/10.1182/bloodadvances.2025017204

J Pediatr Pharmacol Ther. 2025 Aug;30(4): 464-470

Impact of a Procalcitonin Guided Antibiotic Management Strategy in Pediatric Sickle Cell Patients With Fever.

Hannah Robinson, Andrew B Gainey, Robert Daniels, Shannon DeRienzo, Deborah Hurley, Angie Brown, Carla Roberts, Anna-Kathryn Burch.

OBJECTIVE: This study assessed the relationship between antibiotic durations and the use of procalcitonin (PCT) in febrile pediatric patients with sickle cell disease (SCD), including those diagnosed with acute chest syndrome (ACS) and/or vaso-occlusive crisis (VOC).
METHODS: This multicenter, retrospective cohort study compared antibiotic durations in febrile pediatric SCD patients between 2 cohorts, 1 utilizing PCT (PCT cohort) and 1 not utilizing PCT (no-PCT cohort). Secondary endpoints compared the impact of PCT on antibiotic durations in those also diagnosed with ACS and/or VOC.
RESULTS: A total of 258 patient encounters were included. The overall mean antibiotic duration in the PCT cohort was 4.2 days (SD 2.6) vs 4.7 days (SD 3.6) (p = 0.991). For those diagnosed with ACS (n = 17), the mean antibiotic duration was 6 days (SD 2.2) in the PCT cohort vs 9.7 days (SD 3.5) (p = 0.037; n = 7). Those diagnosed with both VOC and ACS (n = 40) averaged 5.6 days (SD 1.9) in the PCT cohort vs 9.3 days (SD 3.2) (p = 0.002; n = 9). Regression analyses revealed an increased odds of longer antibiotic duration in the no-PCT cohort for those with ACS (OR 1.51, 95% CI 1.07-2.13, p = 0.019), and for those with both VOC and ACS (OR 1.72, 95% CI 1.22-2.42, p = 0.002).
CONCLUSIONS: There was not a significant difference in overall antibiotic durations between cohorts. However, in the PCT cohort there was a significant reduction of antibiotic durations seen in patients diagnosed with ACS or VOC and ACS, averaging 3.7 fewer days of antibiotics.

Keywords: acute chest syndrome; antibiotics; infection; pediatrics; procalcitonin; sickle cell disease; vaso-occlusive crisis

DOI: https://doi.org/10.5863/JPPT-24-00085

Cureus. 2025 Jul;17(7): e88234

Pulmonary Hypertension Among Individuals Living With Hemoglobinopathies: A Systematic Review.

Collins C Okeke, Angela Ojo, Madeleine O Okere, Onyinye E Ebiliekwe, Ifunanya R Ekeocha, Kris N Idion, Onyeka Egemonye, Omosimisola O Alli, Euodia A Ugo-Ihanetu, Sylvahelen Okorienta, Afamefuna O Onyeogulu, Elo Agidah, Amarachi Nduji, Emmanuel I Akinteye, Olaoluwa E Ebiekuraju, Joseph O Egbunike.

Hemoglobinopathy has a diverse clinical presentation and complications, and is severe among individuals with the homozygous form. It is the most common cause of chronic anemia among affected individuals. Hemoglobinopathy is an inherited blood disorder arising from mutations in globin genes and is broadly categorized into those involving structural changes that produce abnormal hemoglobin variants or defects in globin chain production. This review aims to evaluate the risk factors and outcomes of pulmonary hypertension among individuals with hemoglobinopathies. A search was conducted on PubMed and Google Scholar databases from inception to April 30, 2025. In total, 1,825 articles were synthesized, of which 13 were included in the final qualitative analysis and data extraction. We included English-language original articles published in peer-reviewed journals that reported the risk factors and outcomes of pulmonary hypertension in patients of any age and gender diagnosed with any type of hemoglobinopathy. This review synthesized 13 articles from 10 countries. A total of 2,873 individuals were diagnosed with hemoglobinopathy (1,031 (36%) with sickle cell disease and 1,842 (64%) with β-thalassemia), and 472 were diagnosed with pulmonary hypertension. Among those with pulmonary hypertension, 289 (61%) had sickle cell disease, while 183 (39%) had β-thalassemia. Older age (>40 years), a history of splenectomy, a hemoglobin level of <8 g/dL, frequent blood transfusions, frequent hospitalization for vaso-occlusive crisis, and β-thalassemia were associated with pulmonary hypertension. Some laboratory parameters (serum creatinine, reticulocyte, albumin, nucleated red blood cells, globulin, cell-free hemoglobin, N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, soluble vascular cell adhesion molecule, platelet, lactate dehydrogenase) were associated with pulmonary hypertension. Overall, the mortality rate was 27 (10%), with respiratory failure, sudden death, and cor pulmonale as the common causes of mortality. Early recognition and risk stratification for pulmonary hypertension must become integral components of hemoglobinopathy care, particularly in adult patients and those with high-risk profiles. Establishment of a standardized treatment guideline and optimizing the use of disease-modifying therapies, such as hydroxyurea and iron chelators, and exploring novel pharmacologic strategies (endothelin receptor antagonist, phosphodiesterase type 5 inhibitors), may hold promise for altering the trajectory of pulmonary hypertension in this vulnerable group. Our findings confirm that pulmonary hypertension is not only a prevalent complication but also a serious prognostic marker associated with increased morbidity and mortality in this population.

Keywords: hemoglobinopathy; outcome; pulmonary hypertension; risk factor; sickle cell disease (scd); thalassemia

DOI: https://doi.org/10.7759/cureus.88234

Pediatrics. 2025 Aug 19. pii: e2024070158. [Epub ahead of print]

Fever In Sickle Cell Disease: Thinking Beyond Bacteremia.

Sweta Dubey, Shubhangi Tuli, Sana Usmani, Matthew Gesner, Diana Weaver, Ratna Basak.

Sickle cell disease (SCD) is a complex pathophysiology with a wide range of symptoms. More than one-third of pediatric SCD emergency department encounters are due to fever. Patients with SCD are immunocompromised because of hyposplenism. Therefore, infection is a serious concern in any febrile patient with SCD. Although bacteremia is seen in only 1.1% of febrile patients with SCD, it remains the leading cause of death globally. However, several noninfectious causes of fever can be seen in SCD, which should be considered in appropriate settings. We present a case of an adolescent female patient with SCD who had an unusually prolonged fever and a complicated disease course that was initially attributed to infection but failed to resolve by appropriate antibiotics. Further investigations identified noninfectious etiologies of fever in the patient.

DOI: https://doi.org/10.1542/peds.2024-070158