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Inclacumab

In today's world, Inclacumab has become a very relevant topic. In both the public and private spheres, Inclacumab has captured the attention of a wide spectrum of individuals and organizations. Its impact has been felt in multiple areas, from politics to technology, culture and society in general. In this article, we will delve into the analysis of Inclacumab, exploring its different facets and examining its influence in various contexts. From its origins to its current situation, Inclacumab has aroused great interest and raises important reflections that deserve to be addressed in depth.

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Inclacumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
Targetselectin P
Clinical data
Other namesLC1004-002
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6452H9930N1730O2024S42
Molar mass145465.02 g·mol−1

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] The study was subsequently discontinued in November 2025.[22]

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.[23]

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.[24] 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". Fierce Biotech. 2024-03-27. Retrieved 2025-09-16.
  2. ^ a b Schmitt C, Abt M, Ciorciaro C, Kling D, Jamois C, Schick E, et al. (June 2015). "First-in-Man Study With Inclacumab, a Human Monoclonal Antibody Against P-selectin". Journal of Cardiovascular Pharmacology. 65 (6): 611–619. doi:10.1016/j.jcin.2014.10.023. PMC 4461388. PMID 25714598.
  3. ^ World Health Organization (2011). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 106" (PDF). WHO Drug Information. 25 (4).
  4. ^ "Error" (PDF). www.ama-assn.org. Archived from the original (PDF) on 2016-04-02. Retrieved 2025-09-16.
  5. ^ a b c Stähli BE, Gebhard C, Duchatelle V, Cournoyer D, Petroni T, Tanguay JF, et al. (November 2016). "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) e004255. doi:10.1161/JAHA.116.004255. PMC 5210344. PMID 27852589.
  6. ^ Stähli BE, Tardif JC, Carrier M, Gallo R, Emery RW, Robb S, et al. (January 2016). "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. doi:10.1016/j.jacc.2015.10.071. PMID 26796402.
  7. ^ Morrison M, Palermo G, Schmitt C (November 2015). "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. doi:10.1007/s00228-015-1938-4. PMID 26363899.
  8. ^ Schmitt C, Mudie N, Ciorciaro C, Gaudreault J (April 2015). "Absence of pharmacodynamic interaction between inclacumab and heparin in healthy smokers". Journal of Cardiovascular Pharmacology. 65 (4): 386–392. doi:10.1097/FJC.0000000000000211. PMID 25602360.
  9. ^ Tardif JC, Tanguay JF, Wright SR, Duchatelle V, Petroni T, Grégoire JC, et al. (May 2013). "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. doi:10.1016/j.jacc.2013.03.003. PMID 23500230.
  10. ^ Kling D, Stucki C, Kronenberg S, Tuerck D, Rhéaume E, Tardif JC, et al. (May 2013). "Pharmacological control of platelet-leukocyte interactions by the human anti-P-selectin antibody inclacumab--preclinical and clinical studies". Thrombosis Research. 131 (5): 401–410. 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.
  12. ^ a b Tardif JC, Tanguay JF, Wright SR, Duchatelle V, Petroni T, Grégoire JC, et al. (May 2013). "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. doi:10.1016/j.jacc.2013.03.003. PMID 23500230.
  13. ^ Ong S, Hernández-Reséndiz S, Crespo-Avilan GE, Mukhametshina RT, Kwek X, Cabrera-Fuentes HA, et al. (2018). "Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities". Pharmacology & Therapeutics. 186: 73–87. doi:10.1016/j.pharmthera.2018.01.001. PMC 5981007. 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 (inactive 16 September 2025).{{cite journal}}: CS1 maint: DOI inactive as of September 2025 (link)
  15. ^ a b c Mayer CL, Koeck K, Hottmann M, Redfern A, Davis M, Barth A, et al. (September 2023). "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. doi:10.1007/s00228-023-03514-3. PMC 10427511. PMID 37436495.
  16. ^ a b Hottmann M, Davis M, Barth A, Mayer CL (2021). "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. doi:10.1182/blood-2021-153058 (inactive 16 September 2025).{{cite journal}}: CS1 maint: DOI inactive as of September 2025 (link)
  17. ^ Tardif JC, Tanguay JF, Wright SR, Duchatelle V, Petroni T, Grégoire JC, et al. (May 2013). "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. doi:10.1016/j.jacc.2013.03.003. PMID 23500230.
  18. ^ Raymond J, Klink R, Chagnon M, Barnwell SL, Evans AJ, Mocco J, et al. (March 2017). "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. doi:10.1161/JAHA.116.004255. PMC 5210344. PMID 28082261.
  19. ^ Andemariam B, Inati A, Colombatti R, Minniti C, Brown C, Hottmann M, et al. (2023). "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. doi:10.1097/01.HS9.0000928300.84715.89. PMC 10112492.
  20. ^ "Pfizer Provides Update on Phase 3 Inclacumab Study for the Treatment of People with Sickle Cell Disease". Pfizer. Retrieved 2025-09-16.
  21. ^ "THRIVE-131 Trial: Pfizer's Inclacumab Falls Short in SCD". OncoDaily. 16 August 2025. Retrieved 2025-09-16.
  22. ^ Masson G (2025-11-04). "Pfizer pulls the plug on 11 programs". www.fiercebiotech.com. Retrieved 2025-11-06.
  23. ^ "Pfizer Terminates Phase III Sickle Cell Study Due to Slow Patient Recruitment". BioSpace. 2024-03-27. Retrieved 2025-09-16.
  24. ^ "Inclacumab for sickle cell disease". Sickle Cell Disease News. 2024-05-21. Retrieved 2025-09-16.
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