Oxbryta (voxelotor) / Pfizer - LARVOL DELTA

Anti-sickling efficacy and safety of Sailin-HbS, an indigenous Ayurvedic formulation. (PubMed, Blood Cells Mol Dis) - "We compared the anti-sickling effect of Sailin-HbS with known anti-sickling agents, Niprisan, SCD 101, AES-103/5-HMF and GBT440/Voxelotor, and found it to be equally and/or more effective. Sub-acute and chronic toxicity assessments in rats reveal no adverse effects on organ function or body weight, biochemical parameters, or complete blood counts, demonstrating its safety profile with established threshold levels. Thus, Sailin-HbS exhibits considerable anti-sickling efficacy without inducing toxicity, suggesting its translational potential in SCD."

Journal • Gene Therapies • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease

Canine Mdr1 Knockout MDCK Cells Reliably Estimate Human Small Intestinal Permeability (Peff) and Fraction Absorbed (fa). (PubMed, Mol Pharm) - "The correlations were subsequently used to estimate Peff and fa for six test APIs: acetaminophen, voriconazole, fedratinib, voxelotor, lemborexant, and istradefylline. The projected Peff and fa values for the test APIs aligned well with literature permeabilities derived using other methods and clinical pharmacokinetic studies, respectively. This work highlights the usefulness of cMdr1 KO MDCK cells in permeability classification, especially for highly permeable APIs, and supports its broader use in both research and regulatory contexts."

Journal • ABCB1

Discovery of Osivelotor (GBT021601): A Potent, Next-Generation Sickle Hemoglobin Polymerization Inhibitor. (PubMed, ACS Med Chem Lett) - P2/3 | "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)."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Assessing Physical Function in Sickle Cell Patients Taking Voxelotor (clinicaltrials.gov) - P2 | N=6 | Active, not recruiting | Sponsor: Inova Health Care Services | Trial completion date: Jul 2025 ➔ Dec 2025 | Trial primary completion date: Jun 2025 ➔ Oct 2025

Trial completion date • Trial primary completion date • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Spleen Tyrosine Kinase Inhibition Mitigates Hemin-Induced Thromboinflammation in an Organ-Specific Manner in Sickle Cell Mice. (PubMed, Arterioscler Thromb Vasc Biol) - "The recent withdrawal of promising therapies, such as the anti-P-selectin antibody Crizanlizumab and the hemoglobin polymerization inhibitor Voxelotor, highlights the urgent need for innovative approaches to alleviate VOC and thromboinflammation. On the contrary, increasing the dose exacerbated hemin-induced bleeding in the lungs due to the complete abolishment of platelet adhesion in the pulmonary microcirculation. These findings underscore the critical role of Syk in vascular thrombo-inflammation and hypoperfusion in SCD, suggesting that Syk inhibition is a promising strategy to reduce VOC, improve renal and pulmonary perfusion, and reduce organ damage."

Journal • Preclinical • Cardiovascular • Genetic Disorders • Hematological Disorders • Inflammation • Pulmonary Embolism • Sickle Cell Disease • SYK

Reversible Diffusion-Restricting White Matter Lesions in Sickle Cell Disease During Pain Crises: A Case Report. (PubMed, Neurohospitalist) - "Remarkably, the patient experienced near-complete neurological recovery with aggressive disease-targeted therapy, including hydroxyurea, voxelotor, and serial exchange transfusions. Clinicians should maintain a high index of suspicion for reversible white matter injury when evaluating patients with sickle cell disease presenting with acute neurological symptoms. Incorporating serial neuroimaging and a multidisciplinary treatment approach is essential for timely diagnosis and optimizing neurological recovery in this vulnerable population."

Journal • Cerebral Hemorrhage • CNS Disorders • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease

Grandchildren of GRNDaD: Shifts in disease-modifying therapy at the adolescent transition in sickle cell disease. (PubMed, Br J Haematol) - "Of the 3169 active patients in GRNDaD, about 65% of subjects were on hydroxyurea (hydroxycarbamide; HU), and 2130 had SCA. For novel therapeutics, we examined use prior to voxelotor's removal from the market and prior to publication of the negative phase III trial of crizanlizumab. Voxelotor utilization in this cohort was three times that reported by claims data while crizanlizumab usage was nearly double, suggesting high-quality comprehensive sickle cell care could increase utilization of novel therapies."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Updated Review of Current Therapeutic Approaches for the Management of Sickle Cell Disease. (PubMed, Cardiovasc Hematol Disord Drug Targets) - "There are six Food and Drug Administration (FDA)-approved drugs, hydroxyurea, L-glutamine, crizanlizumab- TMCA, voxelotor, Casgevy, and Lyfgenia, that are used for the prophylaxis and treatment of serious complications of sickle cell disease. Ongoing research seeks to enhance treatment options and develop potential cures for SCD. This review attempts to present a comprehensive overview of the current therapeutic approaches and newly developed innovative medicines to combat and potentially eradicate SCD with an emphasis on their mechanisms, efficacy, and clinical implications."

Journal • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Infectious Disease • Pain • Sickle Cell Disease • Transplantation

Rapid withdrawal of voxelotor can precipitate sickle cell disease related crisis. (PubMed, Ann Hematol) - "Also, one patient (9.1%) developed acute chest syndrome, whereas five (45.5%) patients needed blood transfusions. Our data confirms that rapid withdrawal of voxelotor could precipitate severe SCD-related crisis."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

PEOPLE WITH SICKLE CELL DISEASE EXPERIENCE SUBSTANTIAL SYMPTOM IMPACT DESPITE TREATMENT: FINDINGS FROM THE GLOBAL LISTEN SURVEY (EHA 2025) - "Data for impact of symptoms are reported as the proportion of PwSCD who responded that symptoms have a substantial effect on daily life (responses of "very much" or "a lot") and as a subanalysis by self-reported current SCD treatments: hydroxyurea (HU) only or other treatments (l-glutamine, voxelotor, or crizanlizumab) with or without HU.Overall, 1,145 PwSCD (58% female) with a median age of 30 years completed the LISTEN Survey. Despite the use of HU and other treatments, clinical features of SCD such as fatigue, depressive symptoms, and pain disrupt the lives of PwSCD, and VOCs continue to be experienced regularly. Therefore, more effective treatments are needed to address the unmet needs in managing the impact of SCD."

Clinical • Anemia • CNS Disorders • Fatigue • Genetic Disorders • Hematological Disorders • Mood Disorders • Pain • Psychiatry • Sickle Cell Disease

Overcoming the Hydrolytic Susceptibility of Thiol-Reactive Reversible Warheads through the Development of Substituted Phenyl Cyanoacrylamides. (PubMed, J Am Chem Soc) - "During these studies, we unexpectedly discovered that an α-cyanoacrylamide-functionalized derivative of the sickle cell inhibitor, voxelotor, was exceptionally stable toward hydrolysis...Extensive quantum chemistry calculations provide an electronic and structural understanding of this selective reactivity. The utility of the DiMe warhead was demonstrated in the context of small molecule BTK inhibition and should find broad use as a hydrolytically stable yet thiol-reactive reversible warhead in other applications."

Journal

AWARENESS AND MANAGEMENT OF PRIAPISM IN SICKLE CELL DISEASE - TERTIARY-CENTRE EXPERIENCE AND REGIONAL MODEL OF CARE (EHA 2025) - "64% (16/25) were on disease modifying therapy for SCD: hydroxycarbamide 48% (12/25), red cell transfusion programme 32% (8/25) and voxelotor 4% (1/25). Priapism is a potentially irreversible contributor to infertility in patients with SCD. Fertility preservation is an important part of comprehensive SCD care, particularly in the era of transformative cellular therapies. A history of priapism was documented in males as young as 9 years, emphasising the importance of early and frequent healthcare provider-led discussion of this complication to facilitate early and definitive management."

Beta-Thalassemia • Erectile Dysfunction • Genetic Disorders • Hematological Disorders • Infertility • Pain • Sexual Disorders • Sickle Cell Disease

IMPROVEMENT IN CEREBRAL OXYGEN SATURATIONS AND VASOREACTIVITY AFTER 12 MONTHS OF VOXELOTOR MEASURED BY NEAR-INFRARED SPECTROSCOPY (NIRS) IN SICKLE CELL DISEASE PATIENTS (EHA 2025) - P2 | "A stable dose for at least 3 months was required for patients treated with hydroxyurea (HU) or angiotensin-converting enzyme inhibitors HU. An improvement in TSI and vasoreactivity was observed in both hemispheres after 1 months of treatment with Voxelotor. This work shows the value of studies such as HEMOPROVE in understanding and making better use of new next-generation compounds such as GBT0 1601 a next-generation HbS polymerization inhibitor for treatment of sickle cell disease."

Clinical • Cardiovascular • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Vascular Neurology

NEUROPATHIC CHRONIC PAIN IN SICKLE CELL DISEASE IS ASSOCIATED WITH WORSE QUALITY OF LIFE, HEMOLYSIS, AND TNF INFLAMMATION (EHA 2025) - "(Table 1)For TNF cytokines, neuropathic pain was significantly associated with TNFRFS9 (R2 = 0.5, p=0.03) and TWEAK (R2 = 0.4, p=0.03) after adjusting for gender, age, genotype, hydroxyurea, and voxelotor use. SCD individuals living with neuropathic chronic pain experience worse pain quality compared to those with chronic non-neuropathic pain. A distinct laboratory profile emerged for those with the neuropathic chronic pain phenotype with significantly higher hemolysis (elevated LDH and hemolysis index) and inflammation (elevated VCAM and TNF cytokines). This would suggest that, in comparison to other forms of chronic pain, neuropathic pain may be driven by hemolysis and TNF inflammatory pathways."

HEOR • Genetic Disorders • Hematological Disorders • Inflammation • Neuralgia • Pain • Renal Disease • Sickle Cell Disease • TGFA • TNFSF12 • TNFSF14

OXIDATIVE METABOLISM IMPROVEMENT DURING EXERCISE IN SICKLE CELL DISEASE PATIENTS TREATED 12 MONTHS WITH VOXELOTOR. ANALYSIS OF HEMOPROVE TRIAL. (EHA 2025) - P2 | ">1 month from a vaso-occlusive crisis (VOC), >3 months from blood transfusion with a stable dose of hydroxyurea). After 12 months of Voxelotor, SCD patients showed improved blood oxygenation and oxidative metabolism during standardized exercise testified by the shift of the exercise blood lactate curve. Hence, despite the increased O2 affinity for Hb under treatment, peripheral oxygen delivery tended to be improved. These data suggest that the [Hb] rise along with hemolysis reduction RBC deformability improvement and peripheral saturation enhancement can counterbalance the higher affinity for O2, favoring O2 delivery, extraction and utilization."

Clinical • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

PRELIMINARY VALIDATION OF THE DYNAMIC SICKLING ASSAY (DSA) AS A DIAGNOSTIC TOOL FOR ASSESSING SICKLE CELL DISEASE SEVERITY AND MONITORING THERAPY EFFICACY (EHA 2025) - "For dose-response treatment of voxelotor, blood was adjusted to 20% hematocrit and treated in vitro at 37°C for 1 hour under continuous agitation with increasing Hb modification doses (0%, 25%, 50%, and 100%)... Parameters derived from DSA kinetic profiles demonstrate superior or comparable performance to existing technologies, positioning the DSA as a precise and comprehensive tool for evaluating the fundamental sickling pathology of SCD and pharmacodynamic efficacy of Hb-modifying therapies. Further development of our standalone DSA device holds significant potential to address the critical need for advanced diagnostics and therapeutic monitoring in both clinical and research settings."

Clinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Resolution of Sickle Cell Leg Ulcers with Voxelotor (RESOLVE) (clinicaltrialsregister.eu) - P3 | N=80 | Sponsor: Pfizer Inc.

New P3 trial • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Voxelotor (Oxbryta) Binds Multiple Hemoglobin Sites and Influences Protein Structure. (PubMed, bioRxiv) - "The properties of Hb with Voxelotor bound at secondary sites have not been explored but should be considered at high doses. Heterogeneous binding should be assessed in other drugs of this class including GBT(021)601 currently in clinical trial."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Impact of Voxelotor on Red Blood Cell Exchange Therapeutic Procedures: Evaluation of Multi-Institutional Procedure Data. (PubMed, J Clin Apher) - "If the HbS total is not used to calculate RBCX replacement volumes in patients taking voxelotor, there is a significantly lower amount of RBC that would be ordered, which would lead to higher HbS after RBCX. Additional studies regarding the role of transfusion in such patients are necessary."

Journal

Prescribing Trends of Disease-Modifying Medications in Texas Medicaid Enrollees with Sickle Cell Disease (ISPOR 2025) - "Hydroxyurea remains the dominant DMT prescribed. The number of monthly users of L-glutamine, voxelotor, and crizanlizumab increased gradually; however, that number remains low."

Medicaid • Reimbursement • US reimbursement • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Characteristics of Patients Enrolled in a Pharmacist Managed Rare Disease Program: Highlighting National Diversity and Representation (ISPOR 2025) - " Among the 7,633 patients enrolled in the Ph-RDP, 55% were diagnosed with sleep disorders, primarily treated with pitolisant, while 34% had sickle cell disease, with voxelotor being the most common medication. The findings highlight the program’s broad reach, including substantial patient enrollment from rural and urban areas and high vulnerability areas as a proxy for providing accessible care to underserved populations. Patient participation and high engagement levels, evidenced by the number of assessments and duration of enrollment, emphasize the program’s potential impact in improving care and health outcomes."

Clinical • CNS Disorders • Genetic Disorders • Hematological Disorders • Rare Diseases • Sickle Cell Disease • Sleep Disorder

Patient Characteristics Associated with the Use of Newly Approved Disease-Modifying Therapy (DMT) for Sickle Cell Disease in Texas Medicaid (ISPOR 2025) - "OBJECTIVES: This study aimed to identify patient characteristics associated with the utilization of new DMTs, including L-glutamine, crizanlizumab-tmca, and voxelotor. Age and greater healthcare utilization (i.e., more outpatient visits, more VOC events, and previous use of hydroxyurea) indicating severe conditions were associated with use of newly approved DMTs."

Clinical • Medicaid • Reimbursement • US reimbursement • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Voxelotor Withdrawal From the Sickle Cell World: A Single Institution Experience (ASPHO 2025) - "We observed more VOE's in individuals that abruptly discontinued Voxelotor as compared to patients who followed a wean schedule. This was supported by evidence of hemolysis on serial labs in the group that abruptly discontinued the medication. This study highlights the importance of the timely guidance received from National Alliance of Sickle Cell Centers (NASCC) for weaning the Voxelotor."

Clinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Treatment Course for Prolonged Renal Papillary Necrosis in an Adolescent With Sickle Cell Disease (ASPHO 2025) - "He received 48 hours of ceftriaxone and three days of oral Vitamin K for a mildly prolonged prothrombin time (PT)...Hydroxyurea was increased to 2000mg daily...Over a year later, he continues to be in remission from RPN but has frequent vaso-occlusive pain episodes and transitioned off Voxelotor to chronic exchange transfusions, and is preparing for a sibling-matched hematopoietic stem cell transplant. RPN is rare but can be seen in patients with SCD, without many published cases to determine a specific treatment course. This case demonstrates the utility of supportive care and disease modifying treatments for RPN in SCD."

Bone Marrow Transplantation • Cardiovascular • Genetic Disorders • Hematological Disorders • Nephrology • Pain • Renal Disease • Sickle Cell Disease • Thrombosis

Screen of the ReFRAME Compound Library for Therapeutic Agents to Prevent Red Blood Cell Sickling Using an Improved High Throughput Sickling Assay. (PubMed, ACS Omega) - "We were able to increase the number of blood samples that were adequate for identifying anti-sickling compounds in the improved sickling assay and identified voxelotor and SNS-314 as compounds that successfully prevented sickling. The improved sickling assay will increase access to valuable blood samples from SCD volunteers, providing more opportunities to develop anti-sickling compounds for treating SCD."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease