Inclacumab

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]}

Inclacumab

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	selectin P
Clinical data
Other names	LC1004-002
ATC code	none
Identifiers
CAS Number	1256258-86-2
ChemSpider	none
UNII	A6734I702L
KEGG	D10356
Chemical and physical data
Formula	C6452H9930N1730O2024S42
Molar mass	145465.02 g·mol−1

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.