GBT1118 / Pfizer - LARVOL DELTA

Concurrent GBT1118 & Losartan Treatment Improves Sickle Cell Nephropathy (ASH 2024) - "Adding GBT1118 to losartan provided additional protection to the kidney, based upon further improvements in urine TBARS, KIM-1, albumin and protein concentrations, while improving the hemoglobin concentration and maintaining stable serum cystatin C and BUN levels. Our results provide support for developing multimodal strategies, such as the combination of voxelotor + losartan, to treat SCA-related CKD in humans."

Anemia • Chronic Kidney Disease • Genetic Disorders • Hematological Disorders • Nephrology • Renal Disease • Sickle Cell Disease • CST3 • KIM1

GBT1118, a Voxelotor Analog, Ameliorates Hepatopathy in Sickle Cell Disease. (PubMed, Medicina (Kaunas)) - "GBT1118 treatment significantly increased expressions of these genes. Our results suggest GBT1118 treatment in SCD confers the amelioration of sickle hepatopathy by reducing inflammation, fibrosis, apoptosis, iron overload and ferroptosis."

Journal • Cardiovascular • Fibrosis • Genetic Disorders • Hematological Disorders • Hepatology • Immunology • Inflammation • Liver Failure • Reperfusion Injury • Sickle Cell Disease • HMOX1 • PACERR • PTGS2 • SLC7A11

Effects of GBT1118, a voxelotor analog, on bone disease in sickle cell disease mice. (PubMed, Sci Rep) - "Significant alteration in bone and hypoxia related genes of SCD mice of both sexes were differentially modulated by GBT1118. We conclude that "a sickle hemoglobin polymerization inhibitor" might be efficacious in improving some parameters of SCD bone loss."

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

Effect of voxelotor on murine bone marrow and peripheral blood with hematopoietic progenitor cell mobilization for gene therapy of sickle cell disease. (PubMed, Blood Cells Mol Dis) - "We found that 3 weeks of treatment with GBT1118 increased the percentage of bone marrow hematopoietic stem cells and upon plerixafor mobilization, the percentage of peripheral blood hematopoietic stem cells. Our data suggest that voxelotor should be further explored for its potential safety and utility as preparation for hematopoietic stem cell mobilization and collection."

Gene therapy • Journal • Preclinical • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Effects of GBT1118, a voxelotor analog, on intestinal pathophysiology in sickle cell disease. (PubMed, Br J Haematol) - "The improved small intestinal barrier function was associated with higher expression of genes encoding enterocyte E-cadherin, JAM-A, ZO-1, MUC-2 and occludin while the lower intestinal microbial density associated with higher expression of genes encoding the antimicrobial peptides defensin-α 1 and defensin-α 4. Our findings provide the evidence to support the beneficial effects of GBT1118 in SCD-related intestinal pathophysiology."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CDH1 • MUC2 • OCLN • TJP1

GBT021601 Increases Hemoglobin and Improves Red Blood Cell Deformability without Rebound Hyperviscosity upon Drug Clearance in a Sickle Mouse Model (ASH 2022) - "Compared with previous studies with the voxelotor analog GBT1118, Hb dropped off more slowly with GBT021601 treatment; this allowed for the ideal assessment of whole-blood viscosity and HVR when the drug had cleared, and HbS was no longer modified, despite elevated Hb levels. In response to GBT021601, sickle cell mice showed a robust increase in Hb, comparable to that of a HbAS mouse, as well as a marked improvement in PoS and RBC deformability. When normalized to HVR, there was no significant difference in blood viscosity during treatment and after cessation of treatment. This finding suggests that oxygen-carrying capacity is not impaired and provides no indication for rebound hyperviscosity with drug clearance."

Preclinical • Genetic Disorders • Hematological Disorders • Retinal Disorders • Sickle Cell Disease

Improvement of Hemolytic Anemia with GBT1118 is Reno-protective in Transgenic Sickle Mice. (PubMed, Blood Adv) - "Voxelotor is a small molecule allosteric hemoglobin modulator that reduces hemolysis in SCA. This study provides mechanistic insights into potential reno-protective effects of strategies which mitigate hemolysis in SCA. Studies in humans are needed to confirm our findings."

Journal • Preclinical • Anemia • Genetic Disorders • Hematological Disorders • Nephrology • Renal Disease • Sickle Cell Disease • KIM1 • POU4F2 • RGS2

Altered Oxyhemoglobin Affinity And Hypoxia: Effects On Physiology And Performance In Sprague-Dawley Rats (ACSM 2022) - "Prior to all exposures, the rats were administered GBT-1118 (GBT, 100mg/kg) or normal saline... Collectively, the data show that impairments in cerebrovascular function, cerebral oxygenation, and cognitive function resulting from exposure to severe hypoxia can be mitigated through GBT administration to increase O-H binding and, subsequently, increase blood oxygenation."

Preclinical

GBT1118, a voxelotor analog, protects red blood cells from damage during severe hypoxia. (PubMed, Am J Transl Res) - "However, following GBT1118 treatment, cell stability showed significantly less degradation, as evidenced by a significantly smaller RBC MF increase after three cycles of hypoxia-reoxygenation. These findings indicate that GBT1118 prevents hypoxia-induced membrane damage in sickled RBC, in part by alternative mechanisms not associated with induced changes in hemoglobin-oxygen affinity."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Improved Hemolytic Anemia with GBT1118 Is Reno-Protective in Transgenic Sickle Mice (ASH 2021) - "Voxelotor is a small molecule allosteric modulator that binds and maintains sickle hemoglobin in the oxygenated state, thereby preventing hemoglobin S polymerization and red blood cell sickling. Our findings highlight the clinical importance of hemolytic anemia in the pathophysiology of sickle cell nephropathy. Our results also provide support for developing strategies to mitigate hemolysis in sickle cell anemia in order to provide a targeted approach to improve kidney disease, a devastating complication associated with high morbidity and mortality, in sickle cell anemia."

Preclinical • Anemia • Genetic Disorders • Hematological Disorders • Nephrology • Renal Disease • Sickle Cell Disease • HP • HPX • KIM1

Rheological Impact of GBT1118 Cessation in a Sickle Mouse Model. (PubMed, Front Physiol) - "In sickle cell disease (SCD), higher whole blood viscosity is a risk factor for vaso-occlusive crisis, avascular necrosis, and proliferative retinopathy. RBC deformability did not return to baseline, suggesting some residual rheological improvement. These data suggest that concerns regarding viscosity rise above pre-treatment levels upon sudden cessation of voxelotor are not warranted."

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

INCREASED HEMOGLOBIN AFFINITY FOR OXYGEN WITH GBT1118 IMPROVES HYPOXIA TOLERANCE IN SICKLE CELL MICE. (PubMed, Am J Physiol Heart Circ Physiol) - "Voxelotor (also known as GBT440) is a hemoglobin S polymerization inhibitor that increases the hemoglobin (Hb) affinity for oxygen (O) in blood and has been approved for the treatment of sickle cell disease (SCD). Chronic treatment with GBT1118 significantly improved hematological, hemodynamic, and oxygenation parameters during hypoxia, preserved cortical oxygenation during normoxia and improved cortical oxygenation during hypoxia, and increased tolerance to severe hypoxia. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for O in preventing the complete deoxygenation of blood and consequent RBC sickling during hypoxia in SCD."

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

[VIRTUAL] GBT1118, A VOXELOTOR ANALOG PROTECTS RED CELLS FROM POLYMERIZATION-INDUCED DAMAGE DURING SEVERE HYPOXIA (EHA 2021) - "However, when present during hypoxia, GBT1118 significantly reduced membrane damage as shown by reduced RBC propensity to lyse. That highlights the potential of GBT1118, a voxelotor (Oxbryta) analog, to prevent sub-lethal RBC membrane damage likely leading in increased RBC survival in circulation"

Anemia • Complement-mediated Rare Disorders • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

[VIRTUAL] Rheological Impact of GBT1118 Cessation in a Sickle Mouse Model (ASH 2020) - "Background: In sickle cell disease (SCD), elevated blood viscosity is a risk factor for vaso-occlusive crisis (VOC). This may be due to retained improvement in red cell rheology after voxelotor is stopped combined with rapid return to baseline Hb levels. Further study in patients treated with voxelotor may be needed to determine if voxelotor produces additional benefits, such as reduction in oxidative stress, that outlive its presence in the red cell."

Preclinical • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

The effect of the antisickling compound GBT1118 on the permeability of red blood cells from patients with sickle cell anemia. (PubMed, Physiol Rep) - "One of these, voxelotor (GBT440), is currently in advanced clinical trials. Further to its direct effects on O affinity, GBT1118 was therefore found to reduce RBC shrinkage and fragility. Findings reveal important effects of GBT1118 on protecting sickle cells and suggest that this is approach may represent a useful therapy for amelioration of the clinical complications of SCA."

Clinical • Journal

Pharmacological Increase of Hb-O2 Affinity with a Voxelotor Analog Does Not Decrease Brain Tissue pO2 or Limit O2 Extraction in Brain Tissues of Sickle Cell Mice (ASH 2019) - "Sickle Cell Disease (SCD) is characterized by hemolytic anemia, vaso-occlusion, and progressive end-organ damage. Collectively across all brain tissues, the GBT1118-induced increase in Hb-O2 affinity reduced tissue hypoxia in SCD mice under hypoxia as measured by pimonidazole staining (Figure C). Together, these results indicate that a pharmacological increase of Hb-O2 affinity does not decrease cortical tissue pO2 in SCD mice and may reduce brain hypoxia under hypoxic conditions."

Preclinical

GBT1118, a compound that increases the oxygen affinity of hemoglobin, improves survival in murine hypoxic acute lung injury. (PubMed, J Appl Physiol (1985)) - "Increasing the oxygen affinity of hemoglobin using GBT1118 may be a novel therapy for treating hypoxemia associated with acute lung injury."

Journal