osivelotor (PF-07940367) / Pfizer - LARVOL DELTA

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

PHASE 1 STUDY OF RENAL IMPAIRMENT EFFECTS ON THE PHARMACOKINETICS OF OSIVELOTOR, A SMALL MOLECULE IN DEVELOPMENT FOR SICKLE CELL DISEASE (EHA 2025) - P1 | "Using a popPK/PD-informed approach, this study demonstrated severe RI did not have clinically meaningful effects on osivelotor exposure, and whole blood exposure was generally within the PK variability observed in patients with SCD. Additionally, differences in plasma exposure in severe RI compared with a simulated healthy population were marginal. A single 400 mg dose in participants with severe RI but without SCD was generally well tolerated, with no treatment-related TEAEs."

P1 data • PK/PD data • Chronic Kidney Disease • Genetic Disorders • Hematological Disorders • Infectious Disease • Musculoskeletal Pain • Renal Disease • Respiratory Diseases • Sickle Cell Disease

PRELIMINARY PHARMACODYNAMIC BIOMARKER RESULTS IN PATIENTS WITH SICKLE CELL DISEASE FOLLOWING TREATMENT WITH OSIVELOTOR IN A MULTICENTER PHASE 2/3 TRIAL (EHA 2025) - P2/3 | "These preliminary PD results from patients with SCD suggest promising evidence of improved RBC health and blood flow following osivelotor treatment. Overall, the findings support ongoing clinical development of osivelotor as a potential treatment for individuals with SCD."

Biomarker • Clinical • P2/3 data • PK/PD data • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • VCAM1

GBT021601-021: A Phase 2/3 Study in Adult and Pediatric Participants With SCD (clinicaltrials.gov) - P2/3 | N=429 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Oct 2028 ➔ Dec 2032 | Trial primary completion date: Oct 2028 ➔ Dec 2030

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

Impact of novel mobilizers and disease modifying agents in the sickle mouse (ASGCT 2025) - "The novel mobilizing agent EMU116 increases stem cells with long term potential (LSKLin-) and primitive HSCs able to rapidly reconstitute (%Flt3-CD34-) in the PB of HbSS and HbAA mice significantly more than plerixafor. CFU are also higher with mobilization indicating stem cells able to proliferate and differentiate, although not statistically significant likely due to sample size. SCD modification with anti-sickling drug osivelotor increased plerixafor mobilization of %Flt3-CD34- HSCs."

Preclinical • Gene Therapies • Genetic Disorders • Hematological Disorders • Inflammation • Sickle Cell Disease • CD34 • CXCR4 • FLT3

Use of the Microfluidic Impedance Red Cell Assay (MIRCA) in Sickle Cell Disease. (PubMed, Blood Adv) - "In vitro addition of voxelotor or osivelotor to samples from individuals on CTF improved the deformability of these endogenous RBC. Longitudinally collected NOI and HOI values in HbSS individuals were stable, with a median percent point change of 13.3% and 15.7%, respectively. MIRCA can be used in combination with clinical laboratory tests to monitor RBC deformability as a biomarker of clinical status at routine clinic visits and included in clinical trials of disease modifying agents."

Journal • Cardiovascular • Genetic Disorders • Hematological Disorders • Inflammation • Pain • Pediatrics • Sickle Cell Disease

GBT021601-022: A Study of GBT021601 in Participants With Sickle Cell Disease (SCD) (clinicaltrials.gov) - P2/3 | N=47 | Terminated | Sponsor: Pfizer | Active, not recruiting ➔ Terminated; Study terminated as data obtained from this non-placebo-controlled trial may not be informative for the interpretation of the benefits and risks of osivelotor

Trial termination • 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 2025 ➔ Oct 2026 | Initiation date: Mar 2025 ➔ Apr 2026 | Trial primary completion date: Oct 2025 ➔ Oct 2026

Trial completion date • Trial initiation date • Trial primary completion date • Pediatrics

Osivelotor for the treatment of sickle cell disease. (PubMed, Expert Opin Pharmacother) - "However, osivelotor shares the same mechanism of action as voxelotor, and therefore similar limitations regarding its efficacy for which the improvement in Hb level appears misleading. Several issues remain to be resolved before considering any drug approval."

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

A Study to Learn How the Body Processes the Study Medicine Called Osivelotor (PF-07940367) in People With Loss of Liver Function (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Pfizer | Recruiting ➔ Completed | N=16 ➔ 8 | Trial completion date: Jun 2025 ➔ Sep 2024 | Trial primary completion date: Jun 2025 ➔ Sep 2024

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Hepatology