Chemistry:Inclacumab

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Inclacumab (also known as LC-1004-002, RO4905417, and PF-07940370) is an investigational monoclonal antibody originally developed by Roche for cardiovascular disease and later acquired by Global Blood Therapeutics (GBT), which was subsequently acquired by Pfizer in 2022 for $5.4 billion.[1] It is a fully human monoclonal antibody against P-selectin being developed primarily for the treatment of sickle cell disease with vaso-occlusive crises.[2][3][4][5][6][7][8][9][10][11]

Mechanism of action

Inclacumab is a recombinant monoclonal antibody against P-selectin, with potential anti-inflammatory, antithrombotic, and antiatherogenic properties.[12] P-selectin works to mediate leukocyte, platelet, and endothelial interactions through the binding of P-selectin to the P-selectin glycoprotein ligand (PSGL)-1 located on the surface of leukocytes.[13]

A crystal structure of inclacumab and P-selectin reveals that inclacumab directly binds to an epitope in the PSGL-1 binding region on P-selectin and thus competitively inhibits P-selectin and its ligand interaction.[14]

Clinical development

Phase I studies

This phase 1, open-label, single-ascending-dose study of inclacumab in healthy participants was conducted at a single clinical facility (Linear Clinical Research, Nedlands, Western Australia) between September 2020 and May 2021.[15] Plasma PK parameters were generally dose-proportional, with a terminal half-life of 13 to 17 days.[15]

Inclacumab displayed a well-tolerated safety profile for up to 29 weeks following a single dose of 20 or 40 mg/kg in healthy subjects.[16]

Cardiovascular studies

The SELECT-ACS (Selective Antagonist of P-selectin for Ischemia Reperfusion) trial was a randomized, double-blind, placebo-controlled study that enrolled 544 patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.[12] The study evaluated two doses of inclacumab (5 mg/kg and 20 mg/kg) compared to placebo. Results showed that inclacumab 20 mg/kg significantly reduced troponin I levels, with placebo-adjusted reductions of 24.4% at 24 hours (p=0.05) and peak troponin I reduced by 23.8% (p=0.05).[17] Benefits were greater when administered within 3 hours before PCI.[18][5]

The SELECT-CABG trial evaluated inclacumab in patients undergoing coronary artery bypass graft surgery but failed to show significant differences in pre-specified secondary efficacy measures, with similar rates of major adverse cardiovascular events between placebo and inclacumab groups (13.9% vs 14.2%, p=0.88).[5]

Sickle cell disease studies

P-selectin-mediated platelet-leukocyte aggregate (PLA) formation has been shown to contribute to vaso-occlusion.[16] The THRIVE clinical program consisted of three Phase 3 studies: THRIVE-131, THRIVE-132, and THRIVE-133 (open-label extension).[19]

THRIVE-131 was the pivotal Phase 3 efficacy study that enrolled participants aged ≥12 years with sickle cell disease experiencing 2-10 vaso-occlusive crises in the previous 12 months. The primary endpoint was the rate of VOCs during the 48-week treatment period with inclacumab administered every 12 weeks.[20] The trial failed to meet its primary endpoint of significant reduction in the rate of vaso-occlusive crises compared to placebo, though the therapy was generally well tolerated.[21]

THRIVE-132 (NCT04927247) was designed to evaluate the proportion of participants with readmission for a VOC within 90 days of randomization but was terminated due to slow patient recruitment.[22]

Safety profile

This selectivity is an essential safety requirement because blockade of P-selectin and E-selectin or of P-selectin and L-selectin results in an immunocompromised phenotype based on evidence from double-selectin knockout mice.[2] Two inclacumab-related treatment-emergent adverse events were reported in 1 participant; no dose-limiting toxicities were observed.[15]

Regulatory status

Inclacumab was granted orphan drug and rare pediatric disease designations by the U.S. Food and Drug Administration (FDA) in 2022.[23] The drug remains investigational and has not received regulatory approval for any indication. Following the failure of the THRIVE-131 Phase 3 trial to meet its primary endpoint, the future regulatory pathway remains uncertain.

References

  1. ↑ "After terminating one of 2 late-stage sickle cell disease trials, Pfizer still expects FDA approval in 2026". 2024-03-27. https://www.fiercebiotech.com/biotech/after-terminating-1-2-late-stage-sickle-cell-disease-trials-pfizer-still-expects-fda. 
  2. ↑ 2.0 2.1 "First-in-Man Study With Inclacumab, a Human Monoclonal Antibody Against P-selectin". Journal of Cardiovascular Pharmacology 65 (6): 611–619. June 2015. doi:10.1016/j.jcin.2014.10.023. PMID 25714598. 
  3. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 106". WHO Drug Information 25 (4). 2011. https://www.who.int/medicines/publications/druginformation/innlists/Final_PL106.pdf. 
  4. ↑ "Error". http://www.ama-assn.org/resources/doc/usan/x-pub/inclacumab.pdf. 
  5. ↑ 5.0 5.1 5.2 "Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention According to Timing of Infusion: Insights From the SELECT-ACS Trial". Journal of the American Heart Association 5 (11). November 2016. doi:10.1161/JAHA.116.004255. PMID 27852589. 
  6. ↑ "Effects of P-Selectin Antagonist Inclacumab in Patients Undergoing Coronary Artery Bypass Graft Surgery: SELECT-CABG Trial". Journal of the American College of Cardiology 67 (3): 344–346. January 2016. doi:10.1016/j.jacc.2015.10.071. PMID 26796402. 
  7. ↑ "Lack of ethnic differences in the pharmacokinetics and pharmacodynamics of inclacumab in healthy Japanese and Caucasian subjects". European Journal of Clinical Pharmacology 71 (11): 1365–1374. November 2015. doi:10.1007/s00228-015-1938-4. PMID 26363899. 
  8. ↑ "Absence of pharmacodynamic interaction between inclacumab and heparin in healthy smokers". Journal of Cardiovascular Pharmacology 65 (4): 386–392. April 2015. doi:10.1097/FJC.0000000000000211. PMID 25602360. 
  9. ↑ "Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial". Journal of the American College of Cardiology 61 (20): 2048–2055. May 2013. doi:10.1016/j.jacc.2013.03.003. PMID 23500230. 
  10. ↑ "Pharmacological control of platelet-leukocyte interactions by the human anti-P-selectin antibody inclacumab--preclinical and clinical studies". Thrombosis Research 131 (5): 401–410. May 2013. doi:10.1016/j.thromres.2013.02.020. PMID 23522853. 
  11. ↑ "Form 8K - Entry into a Material Definitive Agreement Between Global Blood Therapeutics, Inc. and Hoffmann-La Roche Inc.". United States Securities and Exchange Commission. https://www.sec.gov/Archives/edgar/data/1629137/000117184318006225/f8k_082218.htm. 
  12. ↑ 12.0 12.1 "Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial". Journal of the American College of Cardiology 61 (20): 2048–2055. May 2013. doi:10.1016/j.jacc.2013.03.003. PMID 23500230. 
  13. ↑ "Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities". Pharmacology & Therapeutics 186: 73–87. 2018. doi:10.1016/j.pharmthera.2018.01.001. PMID 29330085. 
  14. ↑ "Inclacumab, a Fully Human Anti-P-Selectin Antibody, Directly Binds to PSGL-1 Binding Region and Demonstrates Robust and Durable Inhibition of Cell Adhesion". Blood 136 (Supplement 1): 10. 2020. doi:10.1182/blood-2020-138298. https://ashpublications.org/blood/article/136/Supplement%201/10/471401/Inclacumab-a-Fully-Human-Anti-P-Selectin-Antibody. 
  15. ↑ 15.0 15.1 15.2 "A phase 1 study in healthy participants to characterize the safety and pharmacology of inclacumab, a fully human anti-P-selectin antibody, in development for treatment of sickle cell disease". European Journal of Clinical Pharmacology 79 (9): 1219–1228. September 2023. doi:10.1007/s00228-023-03514-3. PMID 37436495. 
  16. ↑ 16.0 16.1 "Preliminary Results of a Phase 1 Study in Healthy Subjects Administered Inclacumab, a Fully Human IgG4 Anti-P-Selectin Monoclonal Antibody in Development for Treatment of Sickle Cell Disease". Blood 138 (Supplement 1): 977. 2021. doi:10.1182/blood-2021-153058. https://ashpublications.org/blood/article/138/Supplement%201/977/480913/Preliminary-Results-of-a-Phase-1-Study-in-Healthy. 
  17. ↑ "Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial". Journal of the American College of Cardiology 61 (20): 2048–2055. May 2013. doi:10.1016/j.jacc.2013.03.003. PMID 23500230. 
  18. ↑ "Hydrogel versus Bare Platinum Coils in Patients with Large or Recurrent Aneurysms Prone to Recurrence after Endovascular Treatment: A Randomized Controlled Trial". AJNR. American Journal of Neuroradiology 38 (3): 432–441. March 2017. doi:10.1161/JAHA.116.004255. PMID 28082261. 
  19. ↑ "Trials in Progress: The THRIVE Studies Evaluating the Efficacy, Safety, and Long-Term Treatment with Inclacumab, a P-selectin Inhibitor, in Patients with Sickle Cell Disease". Experimental Hematology 126 (Suppl): 23–24. 2023. doi:10.1097/01.HS9.0000928300.84715.89. 
  20. ↑ "Pfizer Provides Update on Phase 3 Inclacumab Study for the Treatment of People with Sickle Cell Disease". https://www.pfizer.com/news/announcements/pfizer-provides-update-phase-3-inclacumab-study-treatment-people-sickle-cell. 
  21. ↑ "THRIVE-131 Trial: Pfizer's Inclacumab Falls Short in SCD". 16 August 2025. https://oncodaily.com/fda-approvals/thrive-131-trial-scd-pfizer-inclacumab. 
  22. ↑ "Pfizer Terminates Phase III Sickle Cell Study Due to Slow Patient Recruitment". 2024-03-27. https://www.biospace.com/pfizer-terminates-phase-iii-sickle-cell-study-due-to-slow-patient-recruitment. 
  23. ↑ "Inclacumab for sickle cell disease". 2024-05-21. https://sicklecellanemianews.com/inclacumab-for-sickle-cell-disease/. 



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