Oxbryta (voxelotor) / Pfizer - LARVOL DELTA

Announcement of Awards: Roland B. Scott-Charles Drew Excellence in Equity Award and Wallace H. Coulter Award for Lifetime Achievement in Hematology (ASH 2026) - "Among these accomplishments, he demonstrated progressive neurocognitive decline in asymptomatic individuals living with sickle cell disease; played a leading role in the development of disease-modifying therapies, including L-glutamine and voxelotor for sickle cell disease and pyruvate kinase activators for alpha thalassemia; and developed prenatal and fetal therapeutic approaches to alpha thalassemia major...Vichinsky has been a fierce advocate for patients with hemoglobin disorders and health equity, as well as a dedicated mentor to the next generation of hematologists. He remains actively engaged in research, including studies of long-term outcomes associated with sickle cell trait, iron overload and chelation therapy in alpha thalassemia major, and novel approaches to improve bone health in sickle cell disease."

Beta-Thalassemia • Developmental Disorders • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Lymphoma • Multiple Myeloma • Sickle Cell Disease

Endothelin Receptor Antagonism in Sickle Cell Disease: Is the Time Now? (PubMed, Can J Physiol Pharmacol) - "Although hydroxyurea remains the most established disease-modifying therapy and that newer approaches such as L-glutamine, voxelotor, crizanlizumab, and gene therapy have expanded the therapeutic landscape, important limitations remain. In parallel, selective ETA antagonists have rapidly advanced owing to multiple FDA approvals for proteinuric kidney diseases outside the context of SCD, in addition to approvals as antihypertensives. Here, we highlight emerging evidence supporting endothelin pathway blockade as a potential targeted therapy for complications such as sickle cell nephropathy, vasculopathy, and pain, while discussing key considerations for future trials."

Journal • Gene Therapies • Genetic Disorders • Hematological Disorders • Nephrology • Pain • Renal Disease • Sickle Cell Disease • EDN1

Assessing Physical Function in Sickle Cell Patients Taking Voxelotor (clinicaltrials.gov) - P2 | N=6 | Completed | Sponsor: Inova Health Care Services | Active, not recruiting ➔ Completed | Trial completion date: Jun 2026 ➔ Mar 2026

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

HOPE Kids 2: Phase 3, Randomized Trial of Voxelotor in Children With SCD and Conditional Cerebral Blood Flow Velocities. (PubMed, Am J Hematol) - P3 | "Overall, voxelotor showed CBFV reduction in children with SCD and conditional CBFV, suggesting HbS polymerization inhibition has a potential therapeutic role for this group; nevertheless, additional studies evaluating potential regional risks for sickle cell anemia with crisis or mortality are warranted. Trial Registration: ClinicalTrials.gov identifier: NCT04218084."

Journal • P3 data • Cardiovascular • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Benefit-Risk of Voxelotor, Crizanlizumab, and L-Glutamine in Sickle Cell Disease: A Systematic Review. (PubMed, Am J Med Sci) - "The evidence supports therapy-specific benefit signals rather than a pooled class-level conclusion. Benefit-risk interpretation should distinguish vaso-occlusive morbidity from hemoglobin-centered outcomes and account for replication, durability, and safety completeness."

Benefit-risk assessment • Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Dalcetrapib decreases red blood cell sickling propensity in sickle cell disease. (PubMed, Clin Hemorheol Microcirc) - "The combination of both voxelotor and dalcetrapib led to greater RBC rheological improvement. Our findings suggest that dalcetrapib could inhibit RBC sickling during deoxygenation."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Real-world US Experience with Voxelotor for Sickle Cell Disease: A Plain Language Summary of the RETRO and PROSPECT studies. (PubMed, Ther Adv Hematol) - "However, it is always important to study a medicine in real-world medical practice as well. In RETRO and PROSPECT, the effects of voxelotor were like the effects seen in the clinical trials, and researchers did not see any unexpected symptoms related to SCD or unexpected side effects related to the study drug."

Journal • Real-world evidence • Review • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease

GBT-1118 Rescued Impaired Bone Formation but Failed to Rescue Material Properties in Humanized Sickle-Cell-Disease Murine Model. (PubMed, Cells) - "Mechanical testing showed decreases in ultimate stress and Young's modulus in female SCD femurs, with no significant differences in males nor rescue by GBT1118. Thus, while GBT1118 improved hematological parameters, it failed to restore the impaired bone material properties observed in SCD mice, highlighting the need for additional therapeutic strategies to address bone fragility in sickle cell disease."

Journal • Preclinical • Genetic Disorders • Hematological Disorders • Orthopedics • Osteoporosis • Rheumatology • Sickle Cell Disease

An optimized "hypoxia in a pill" regimen reverses neurodegenerative disease phenotypes in multiple preclinical models. (PubMed, bioRxiv) - "We previously introduced a small molecule, "hypoxia-in-a-pill" regimen that combines the hemoglobin affinity enhancer (GBT440) -- which limits oxygen delivery to tissues -- with a HIF-2α inhibitor (PT2399) to prevent compensatory erythropoiesis that can be detrimental. Importantly, body weight was stable with the combination and it did not induce any signs of pulmonary hypertension, likely due to attenuation of HIF-2α. Our findings motivate additional pre-clinical and even clinical studies to evaluate the safety and efficacy of the GBT601/PT2399 combination."

Journal • Preclinical • Ataxia • Cardiovascular • CNS Disorders • Friedreich ataxia • Hypertension • Metabolic Disorders • Movement Disorders • Parkinson's Disease • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • EPAS1

Association between comorbid depression, antidepressant adherence, and disease-modifying therapy adherence among Texas Medicaid patients with sickle cell disease. (PubMed, J Manag Care Spec Pharm) - "Mean PDC for each SCD DMT was 38.7 ± 26.7% (hydroxyurea), 37.5 ± 29.5% (L-glutamine), 33.9 ± 30.4% (crizanlizumab), and 60.9 ± 34.1% (voxelotor). Providers should regularly screen for depression and initiate and encourage antidepressant adherence, as this may potentially improve adherence to SCD DMTs. Given the known association between medication adherence and health outcomes, improving adherence to SCD DMTs may improve the health outcomes in this population."

Journal • Reimbursement • Retrospective data • US reimbursement • CNS Disorders • Depression • Genetic Disorders • Hematological Disorders • Mood Disorders • Psychiatry • Sickle Cell Disease

EFFICACY AND SAFETY OF PYRUVATE KINASE-R ACTIVATORS IN SICKLE CELL DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2026) - "Three agents approved 2017–2019 briefly widened options, but crizanlizumab lost European approval in August 2023 (STAND trial: no VOC benefit), and voxelotor was withdrawn globally in September 2024 due to a fatal events imbalance the effectively resetting the field...Mitapivat (RISE UP) and etavopivat (HIBISCUS) have both completed Phase 2 RCTs in SCD, but their evidence has never been pooled...Baseline Hb was 8.4–8.8 g/dL across both trials, with 65–81% of participants receiving concomitant hydroxyurea...Abbreviations: CI, confidence interval; DL RE, DerSimonian-Laird random-effects model; Hb, haemoglobin; PP, per-protocol; PKR, pyruvate kinase-R; RR, risk ratio; SAE, serious adverse event; SCD, sickle cell disease; VOC, vaso-occlusive crisis; WMD, weighted mean difference; Wk, week. Panel A (Hb response) pooled estimate is exploratory given cross-trial heterogeneity in response definitions and timepoints; Panel C VOC rate ratio reflects HIBISCUS per-protocol..."

Retrospective data • Review • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

TRIAL IN PROGRESS: DREAM – A PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY EVALUATING OSIVELOTOR IN SICKLE CELL DISEASE (EHA 2026) - P2/3 | "Stable hydroxyurea and/or L-glutamine are permitted...Based on the findings of increased deaths and VOCs in 2 post-marketing trials conducted largely in sub-Saharan Africa with voxelotor, participants in or having recently relocated from these regions will be excluded per agreement with the US Food and Drug Administration...‡For analyses, VOC is defined as an acute episode of pain that has no medically determined cause other than a vaso-occlusive event, results in a visit to a medical facility (hospitalization, emergency department, urgent care center, outpatient clinic, or infusion center), and requires parenteral narcotic agents, parenteral NSAIDs, or an increase in oral narcotics. LD, loading dose; MD, maintenance dose; NSAID, nonsteroidal anti-inflammatory drug; PROMIS, Patient- Reported Outcomes Measurement Information System; SF, Short Form; USA, United States of America; VOC, vaso-occlusive crisis."

Clinical • P3 data • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

EFFECT OF THE ANTI-SICKLING DRUG VOXELOTOR ON INFLAMMATORY AND ANGIOGENIC PATHWAYS IN ADULT PATIENTS WITH SICKLE CELL DISEASE (EHA 2026) - "Although voxelotor was withdrawn from global markets in September 2024 due to emerging safety concerns, next-generation HbS polymerization inhibitors such as osivelotor remain in clinical development. Black lines show geometric mean after log2 transformation and back transformation with 95% CI. Red trajectories indicate significant biomarker changes after false discovery rate (FDR) correction with blue lines showing the geometric mean with 95% CI."

Clinical • Cardiovascular • Genetic Disorders • Hematological Disorders • Inflammation • Reperfusion Injury • Sickle Cell Disease • EGLN1

EFFICACY AND SAFETY OF ORAL TETRAHYDROURIDINE-DECITABINE (NDEC) IN ADULTS WITH SICKLE CELL DISEASE: RESULTS FROM THE PHASE 2, GLOBAL, RANDOMIZED, PARALLEL-GROUP ASCENT1 TRIAL (EHA 2026) - P2 | "Chronic transfusion therapy, hematopoietic growth factors, recent voxelotor, crizanlizumab, or L-glutamine use were prohibited. Mean changes in total Hb, %HbF, and %F-cells were estimated from a mixed model for repeated measurements with treatment, number of vaso-occlusive crises in the previous year, region and sex nested within visit as fixed factors and baseline level of the parameter as a covariate. BL, baseline; CI, confidence interval; ETD, estimated treatment difference; F-cells, HbF-enriched red blood cells; Hb, hemoglobin; HbF, fetal hemoglobin; HU, hydroxyurea; PBO, placebo; QW, once-weekly; SD, standard deviation; W2CD, weekly on two consecutive days; wk, week."

Clinical • P2 data • Genetic Disorders • Hematological Disorders • Neutropenia • Sickle Cell Disease • Thrombocytosis • DNMT1

Impact of voxelotor discontinuation on patients with sickle cell disease. (PubMed, Br J Haematol) - No abstract available

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

GBT1118 voxelotor analog improves skeletal muscle function, phenotype and significantly reduced serum myopathy biomarker GDF15 in sickle cell disease mice. (PubMed, Biochem Biophys Res Commun) - "We made the novel observation that Growth and Differentiation Factor 15 (GDF15) a serum biomarker of muscle pathology that was significantly increased in serum of SCD mice of both sexes was significantly reduced by GBT1118. We conclude that GBT1118 might has the potential to enhance certain parameters of skeletal muscle dysfunction in older SCD mice."

Journal • Preclinical • Fibrosis • Genetic Disorders • Hematological Disorders • Immunology • Myositis • Sickle Cell Disease • GDF15

In vitro effects of voxelotor on red blood cell senescence and rheological behavior in sickle cell anemia. (PubMed, Blood Cells Mol Dis) - "The extent of RBC deformability increase with voxelotor was negatively correlated with fetal hemoglobin levels. While voxelotor demonstrated beneficial effects on RBC deformability and sickling propensity, its impact on RBC aggregation properties and ROS generation requires further investigation to better understand its different mechanisms of action."

Journal • Preclinical • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

INCIDENT COMPLICATIONS AND TREATMENT USE IN SICKLE CELL DISEASE IN US COMMERCIAL AND MEDICARE-INSURED PATIENTS (ISPOR 2026) - "Incident medication use during follow-up was: antibiotics 19.9%, opioids 19.0%, prescription NSAIDs 18.8%; disease-modifying therapy use was limited (blood transfusion 7.1%, hydroxyurea 5.3%, L-glutamine 0.6%), and uptake of newer therapies (crizanlizumab, voxelotor) was <1%. Incident complications varied by age, with more febrile/infectious events in children and more chronic organ complications in older adults, consistent with a shift in clinical burden across the lifespan. Incident complications varied by age, with more febrile/infectious events in children and more chronic organ complications in older adults, consistent with a shift in clinical burden across the lifespan. No substantial change in complication incidence was observed after availability of newer therapies. Treatment remained predominantly symptomatic with low uptake of disease-modifying newer agents."

Clinical • Medicare • Reimbursement • US reimbursement • Cardiovascular • Genetic Disorders • Hematological Disorders • Infectious Disease • Renal Disease • Sickle Cell Disease

Prevalence and Determinants of Low Bone Mineral Density in Pediatric Sickle Cell Disease (ASPHO 2026) - "On univariate analysis, lower spine BMD was significantly associated with higher disease severity (p = 0.0046), lower hemoglobin (p = 0.0027), older age (p = 0.0002), lower BMI (p = 0.021), chronic transfusion therapy (p = 0.0099), voxelotor use (p < 0.0001) while HbSC genotype was protective (p = 0.030).In multivariate analysis, older age at DEXA remained independently associated with low BMD (OR = -0.126, p < 0.0001)... We present a large cohort of pediatric patients with SCD with a high prevalence of low BMD. We identified older age as a risk factor for lower BMD, while higher BMI and certain genotypes appeared protective. The association with clinical severity was inconsistent after adjustment, highlighting the multifactorial etiology of bone disease in SCD and supporting the need for early screening to prevent long-term disabilities."

Clinical • Genetic Disorders • Hematological Disorders • Musculoskeletal Diseases • Obesity • Orthopedics • Pediatrics • Reperfusion Injury • Sickle Cell Disease

Discontinued therapies for sickle cell disease: status and future directions. (PubMed, Expert Opin Investig Drugs) - "Over the past decade, the therapeutic landscape for sickle cell disease (SCD) has expanded beyond hydroxyurea to targeted small molecules, monoclonal antibodies, and transformative cellular and gene therapies...Recent advances in sickle cell therapies bring real promise alongside setbacks. Failures are part of progress, but better trial design, transparency, patient partnership, and shared data can reduce harm, strengthen trust, and ensure innovation translates into meaningful, durable patient benefit."

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

Advancing Sickle Cell Disease Treatment in Sub-Saharan Africa: Challenges and Opportunities for Disease Modifying Therapies. (PubMed, Am J Hematol) - "Despite established safety and efficacy of hydroxyurea, its use is limited across the region due to inconsistent healthcare infrastructure, high medication and laboratory costs, inadequate clinician training, and persistent disease stigma...Newly approved medications, such as L-glutamine and crizanlizumab, may provide additional benefits to select patients, but are expensive and unavailable. The increased mortality observed in people on voxelotor in Africa highlights the need to ensure the safety of any new medication in varied settings through high-quality research conducted on the continent...SCD management in Africa can be transformed by addressing systemic barriers and leveraging collaborative partnerships, leading to reduced mortality and alleviation of the individual and economic burdens of the disease. It is a moral and economic imperative to prioritize access to SCD treatment in Africa, the region with the greatest disease burden globally."

Journal • Review • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Rethinking Sickle Cell Disease as a Systemic Vasculopathy. (PubMed, Cells) - "While current standard of care treatments, including hydroxyurea and chronic red blood cell transfusions, have been proven to be disease-modifying, newer therapies like crizanlizumab and voxelotor have only proven to manage symptoms. There is still a significant need to understand how we optimize and personalize therapies to improve outcomes for patients. This review highlights the importance of recognizing SCD as a vascular disease to understand its multi-organ complications and heterogeneity of effects."

Journal • Review • Cardiovascular • Gene Therapies • Genetic Disorders • Hematological Disorders • Inflammation • Sickle Cell Disease

Safety and effectiveness of voxelotor in individuals with sickle cell disease in the RETRO and PROSPECT US registries. (PubMed, Blood Adv) - "No new safety findings were identified. Despite inherent limitations of registry studies, voxelotor treatment increased hemoglobin and decreased hemolysis markers in US clinical practice, with no evidence of an increased frequency of APC."

Journal • Genetic Disorders • Hematological Disorders • Pain • 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: Dec 2025 ➔ Jun 2026

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

Hemoglobin as a Molecular Glue: Toward Potent Inhibition of HbS Polymerization in Sickle Cell Disease. (PubMed, Adv Healthc Mater) - "Current therapies, such as hydroxyurea and voxelotor, provide only partial symptomatic relief, underscoring the urgent need for transformative strategies. These molecular glues, generated through gene editing or synthetic biology, offer a cell-intrinsic, high-concentration mechanism to counteract HbS polymerization, potentially overcoming the limitations of current therapies. We examine the key challenges in translating this paradigm, including precise structural characterization of polymerization intermediates, efficient intracellular delivery to erythrocytes, temporal regulation under hypoxic conditions, and the mitigation of immunogenicity."

Journal • Review • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Targeted Protein Degradation