osivelotor (PF-07940367) / Pfizer - LARVOL DELTA

Quantify sickling kinetics in sickle cell disease through microfluidics combined AI-driven analysis tool | Poster Board #1197 (ACS-Fall 2026) - "Although curative treatments such as gene therapy and hematopoietic stem cell transplantation exist, their high cost, limited donor availability, and uncertain long-term risks highlight the need for effective pharmacological interventions, including anti-sickling agents such as osivelotor, currently in Phase II/III clinical trials...To overcome these challenges, we developed a dual-layer microfluidic assay integrated with an AI-driven image analysis pipeline to quantify sickling kinetics at the single-cell level. This combined platform enables high-throughput phenotyping of diverse RBC subpopulations, offering deeper insights into cell classification and the biophysical heterogeneity of SCD, and supporting the development and evaluation of more effective therapeutic strategies in other cellular diseases (Figure)."

Bone Marrow Transplantation • Cardiovascular • Gene Therapies • Genetic Disorders • Hematological Disorders • 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

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

OSIVELOTOR IMPROVES BIOMARKERS OF HEMOLYSIS, OXIDATIVE STRESS, AND INFLAMMATION IN PATIENTS WITH SICKLE CELL DISEASE IN A MULTICENTER PHASE 2/3 TRIAL (EHA 2026) - P2/3 | "Heme oxygenase-1 levels are presented as normalized protein expression (NPX), a relative quantification unit on a log-2 scale; negative mean values are expected when measurements correspond to values below 1 on the linear scale. NPX, normalized protein expression; SD, standard deviation."

Biomarker • Clinical • Oxidative stress • P2/3 data • Genetic Disorders • Hematological Disorders • Inflammation • Sickle Cell Disease • HMOX1 • HP • HPX • VCAM1

A Phase 1 Microtracer Study Evaluating the Mass Balance, Excretion, and Pharmacokinetics of Osivelotor in Healthy Participants. (PubMed, Clin Transl Sci) - P1 | "The results of this unique study design provide insights into the absorption, metabolism, and excretion (ADME) of osivelotor and support its continued development for SCD. Trial Registration: ClinicalTrials.gov NCT05718687."

Journal • P1 data • PK/PD data • Genetic Disorders • Hematological Disorders • 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

A Study to Learn How Different Preparations of Osivelotor Taste and Enter the Blood With Food or Liquids or With an Antacid in Healthy Adults (clinicaltrials.gov) - P1 | N=52 | Not yet recruiting | Sponsor: Pfizer | Trial completion date: Oct 2026 ➔ May 2027 | Trial primary completion date: Oct 2026 ➔ Feb 2027

Trial completion date • Trial primary completion date • Pediatrics

GBT021601-021: A Phase 2/3 Study in Adult and Adolescent Participants With SCD (clinicaltrials.gov) - P2/3 | N=389 | Recruiting | Sponsor: Pfizer | Active, not recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

High-throughput oxygen dissociation assay enables rapid screening of hemoglobin oxygen affinity modifying therapies (ASH 2025) - "The distinct and reproducible shifts in ODCs observed with mitapivat, voxelotor, and GBT021601 emphasize RHODA's potential as a powerful tool for evaluating therapeutic efficacy and optimizing dosage strategies for novel Hb-O₂ affinity-modifying drugs. By enabling routine ODC assessment in a microplate format, RHODA stands to accelerate drug development, facilitate genome-editing-based therapies, support blood bank quality control, and inform personalized management of hemoglobinopathies such as SCD."

Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Efficacy and safety of osivelotor in participants with sickle cell disease in a 12-week phase 2, multicenter, open-label, dose-finding trial and extension study (ASH 2025) - P2/3 | "Overall, median age was 24 (range 18–59) years, 30/54 (55.6%) participants were female,52/54 (96%) had HbSS and 2 (4%) had HbSβ0 genotype, and 20/54 (37%) were receiving hydroxyurea atscreening. In adults with SCD, osivelotor was generally well tolerated in both the 12-week phase 2study and OLE study. With osivelotor treatment, substantial and clinically meaningful increases in Hbwere observed, and Hb improvements were sustained in the OLE. No SAEs or fatal events wereconsidered treatment-related, and no increase in VOC events was observed with osivelotor over thephase 2 study and OLE."

Clinical • P2 data • Cardiovascular • Genetic Disorders • Hematological Disorders • Infectious Disease • Malaria • Sickle Cell Disease

Development of whole blood viscosity measurements under hypoxia for use in sickle cell disease (ASH 2025) - "Hypoxia significantly increases the WBV compared to normoxic conditions for HbSS samples (median 6.3vs 3.23, p <0.0001), while there was no statistically significant difference between WBV under hypoxiaand normoxia for HbAA samples (median 3.02 vs 2.01, p= 0.06). The change in WBV with hypoxiacompared to normoxia was significantly more in HbSS compared to HbAA (median 3.3 vs 1.02, p= 0.0009).The change in WBV with hypoxia was significantly less when HbSS samples were pre-treated withosivelotor compared to HbSS samples not pre-treated with osivelotor (1.94 vs 2.41, p=0.0016). We alsoobserved minimal WBV change with hypoxia for the post GT sample (1.05), comparable to HbAA (median1.11) and lower than HbSS (median 3.35)."

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

Optimization of stem cell fitness and mobilization using moderate transfusion and an oral anti-sickling agent in the sickle mouse model. (ASH 2025) - "HbSS mice weretreated with 0.4% osivelotor chow for 8-weeks and mobilized with plerixafor. A weakness of our study is the lack of comparison to standard CTT goal of<30%. Less aggressive transfusion goals and an oral non-myelosuppressive disease modifying agent arepotential alternatives to traditional CTT to optimize ex-vivo GT for SCD."

Preclinical • Anemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Inflammation • Sickle Cell Disease • KIT • PTPRC

Targeting hemolysis and raas: Osivelotor and losartan ameliorate sickle cell renal pathology (ASH 2025) - "Osivelotor (GBT021601), a second-generation inhibitor of sickle hemoglobin (Hb)polymerization, shares a mechanism with voxelotor, but has improved pharmacokinetics. The combination treatment led tothe greatest improvement across functional, molecular and structural indicators of kidney damage. Thesefindings suggest that co-targeting hemolytic and RAAS pathways addresses the multifactorial nature ofSCD nephropathy, offering a potentially synergistic therapeutic strategy."

Cardiovascular • Fibrosis • Genetic Disorders • Hematological Disorders • Hypertension • Immunology • Nephrology • Renal Disease • Sickle Cell Disease • CST3 • KIM1

Evaluating Osivelotor in Sickle Cell Disease: Pivotal Trial Updates (ASH 2025) - "Supported By Pfizer For in-person participants only"

Genetic Disorders • Hematological Disorders • Sickle Cell Disease

In Silico Post-screening of Anti-polymerization Agents to Treat Sickle Cell Disease. (PubMed, bioRxiv) - "We first demonstrate the effectiveness of our integrated platform by showcasing the therapeutic efficacy of two FDA-approved drugs, Hydroxyurea (HU) and voxelotor. Next, we evaluate the therapeutic efficacy of two potential anti-sickling agents under clinical trial, namely Bitopertin and osivelotor...We further quantify the relationship between drug dosage and the duration of noncompliance that leads to loss of therapeutic efficacy for voxelotor and osivelotor, providing guidance for optimizing dosage strategies to reduce the risk associated with noncompliance. In summary, our in silico platform serves as a valuable tool for post-screening analysis of potential anti-sickling agents by considering their PK and anti-sickling efficacy under patient-specific hemoglobin level and organ-specific oxygen level, thereby gaining insights into their potential therapeutic efficacy alone or in combination before clinical trials."

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

Predictive Biomarker Analysis from the GBT021601 Survival Study in Townes Sickle Mice (ASH 2023) - "Longer-term GBT021601 treatment as part of chow was well tolerated by Townes SS mice, and compound exposure was comparable with studies of a shorter duration of treatment. Early compound exposure was predictive of a long-term survival benefit in Townes SS mice. Early reductions in % reticulocytes were more likely in Townes SS mice with a high GBT021601 exposure and were predictive of a long-term survival benefit."

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

Methods to Assess the Impact of Combined Pharmacologic and Transfusion Therapies on Red Cell Deformability (ASH 2024) - "GBT021601-modified red cells had similar MIRCA deformability values to healthy controls; we expect to see a similar benefit in patients on dual transfusion and drug therapy. Future work will involve the use of MIRCA to assess the longitudinal variability of RBC deformability in individuals on chronic transfusion therapy alone and in combination with anti-sickling agents, to determine if transfusions can be reduced in frequency and volume without sacrificing RBC quality."

Cardiovascular • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Long-Term Therapy with GBT021601 and Moderate Chronic Transfusion Therapy Prevent the Development of Hyperalgesia (ASH 2024) - "More importantly, an oral agent 601 equally reduces development of chronic pain as early as 4 weeks of therapy in the sickle mouse model. Pain phenotypes should be further investigated with 601 in the prevention of chronic pain in clinical studies."

Cardiovascular • Genetic Disorders • Hematological Disorders • Musculoskeletal Pain • Pain • Sickle Cell Disease

Preliminary Results from a Multicenter Phase 2/3 Study of Next-Generation HbS Polymerization Inhibitor GBT021601 for the Treatment of Patients with Sickle Cell Disease (ASH 2023) - P2/3 | "GBT021601 has the potential for higher Hb occupancies at lower doses than voxelotor and could potentially reduce treatment burden and improve clinical outcomes...The 100-mg group consisted of 17/35 patients (48.6%), with a mean (range) age of 29.1 (18-49) years; 7/17 patients (41.2%) were on hydroxyurea (HU)... Loading and daily doses of GBT021601 for 12 weeks were well tolerated in adult participants with SCD. Despite large increases in mean Hb levels, pain episodes did not increase and there was a reduction of adherent cells in a flow adhesion assay with VCAM-1, a potential biomarker for VOC risk. Data from Part A of this phase 2/3 study support the ongoing clinical development of GBT021601 as a potential treatment for individuals with SCD."

Clinical • P2/3 data • Anemia • CNS Disorders • Dermatology • Epilepsy • Genetic Disorders • Hematological Disorders • Immunology • Infectious Disease • Pediatrics • Septic Shock • Sickle Cell Disease • Urticaria • VCAM1

Evaluation of GBT021601 As a Therapeutic Agent to Restore Bone Marrow Health and Effective Erythropoiesis in a Sickle Mouse Model (ASH 2023) - "Treatment with GBT021601 was effective at reducing extramedullary hematopoiesis as determined by the reduction in spleen size compared with control mice. VCAM-1 and ANG-1 are increased in HbSS compared with HbAA mice; treatment with GBT021601 reduced factors that contribute to pathogenic angiogenesis. Treatment with GBT021601 did not change ANG-2 and VEGF-A expression; notably, VEGF-A levels are similar between HbSS and HbAA mice."

Preclinical • Gene Therapies • Genetic Disorders • Hematological Disorders • Retinal Disorders • Sickle Cell Disease • Vascular Neurology • ANGPT1 • ANXA5 • KIT • VCAM1

Preliminary Pharmacodynamic Results from a Multicenter Phase 2/3 Study of Next-Generation HbS Polymerization Inhibitor GBT021601 for the Treatment of Patients with Sickle Cell Disease (ASH 2023) - P2/3 | "Voxelotor is a first-in-class HbS polymerization inhibitor approved in the US for the treatment of SCD in patients aged ≥4 years and in Europe for the treatment of hemolytic anemia due to SCD in patients aged ≥12 years as monotherapy or with hydroxyurea. In patients with SCD, GBT021601 maintenance doses of 100 mg and 150 mg led to increased Hb, increased Hct, and improvements in RBC deformability by 6 weeks, which were maintained through to Week 12. Analyses of PD data show promising evidence of efficacy with near normalization of Hb and oxygenscan parameters consistent with the improved mechanism of the drug. PD data from Part A of this phase 2/3 study demonstrated blood parameters approaching normal ranges and support for the ongoing clinical development of GBT021601 as a potential treatment for individuals with SCD."

Clinical • P2/3 data • PK/PD data • Anemia • Genetic Disorders • Hematological Disorders • Pediatrics • Sickle Cell Disease

Evaluating anti-sickling therapies for sickle cell disease: a microfluidic assay for red blood cell-mediated microvascular occlusion under hypoxia. (PubMed, Lab Chip) - "Additionally, the HOI assay effectively assessed the efficacy of therapeutic agents, including hemoglobin-oxygen affinity modifiers (GBT021601, GBT440) and protein kinase R (PKR) activators (PKR-3, FT4202), which significantly reduced OI in SCD RBCs. Notably, combination therapies showed enhanced effectiveness, highlighting the assay's potential for optimizing treatment regimens. This study establishes the chemically induced hypoxia OcclusionChip assay as a reliable and clinically useful tool for evaluating RBC deformability in SCD, with significant potential to improve personalized treatment strategies and thus patient outcomes."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Safety, Pharmacokinetics, and Pharmacodynamics of Osivelotor for Sickle Cell Disease: First-in-Human Studies in Healthy Participants and Patients. (PubMed, Clin Pharmacol Ther) - "Furthermore, Hb-oxygen affinity and RBC deformability improved, whereas dense RBCs and circulating sickled cells decreased. In conclusion, once-daily osivelotor was generally well tolerated at exposures associated with meaningful PD activity, supporting the ongoing clinical investigation."

Journal • P1 data • PK/PD data • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

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