Phase 1 study on the safety and efficacy of E6011, antifractalkine antibody, in patients with Crohn's disease

Abstract

Background and Aim: E6011 is a humanized monoclonal antibody targeting fractalkine (FKN), a CX3C chemokine, which regulates leukocyte trafficking during inflammation. We evaluated the safety and pharmacokinetic profile of E6011 in patients with Crohn's disease (CD) and also performed preliminary pharmacodynamic (PD) and efficacy assessments. Methods: This study included a 12-week multiple ascending dose (MAD) phase (2, 5, 10, and 15 mg/kg intravenously every 2 weeks, n = 6, 8, 7, and 7, respectively) and a 40-week Extension phase (n = 12) at the same dose as the MAD phase. Serum E6011, serum total FKN (free soluble FKN and E6011-FKN complex) as a PD marker and CD activity index were evaluated. The primary outcome was safety assessment in the MAD phase. Results: Twenty-seven (96%) of 28 patients had previously been treated with anti-tumor necrosis factor α agents. During the MAD phase, adverse events (AEs) occurred in 18 (64%). The most common AE was nasopharyngitis (five patients, 18%). No severe AEs occurred. Serious AEs occurred in three patients, progression of CD in two, and anemia in one. Serum E6011 concentrations increased dose-dependently after infusion and reached a plateau around 4-6 weeks. Serum total FKN rose simultaneously. Five (18%) patients developed anti-E6011 antibodies during the study. Overall, clinical response and clinical remission were observed at Week 12 in 40% (10/25) and 16% (4/25) of active CD patients, respectively. Conclusion: E6011 was well-tolerated and might be effective in CD patients. These findings need to be clarified in a randomized controlled study.

Landscape of new drugs and targets in inflammatory bowel disease

“…150 Amiselimod, CBP-307, KRP203 and VTX002 are four oral S1P modulators actually under investigation in UC, and in CD for amiselimod. [151][152][153][154] Other mechanisms of action include anti-chemokines (also playing a pivotal role in T cells recruitment in the gut), 155 oral anti-CD3, anti-CD40 IV/SC, anti-CD162 IV, inhibitor of phosphodiesterase 4 (apremilast PO), 156 oral active TNF-α inhibitor (hemay007) 157 but also anti-TL1A IV. [158][159][160][161][162] ABX464 and Vorinostat are drugs that act on epigenetic mechanisms.…”

Proinflammatory cytokines and their receptors as druggable targets to alleviate pathological pain

“…Drugs available E6011 (Quetmolimab), a humanized anti-CX3CL1 mAb, is welltolerated and safe in clinical trials. 219,321,325,327,328 Furthermore, clinical trials using the CX3CR1-blocker KAND567 suggest beneficial safety profiles (ISRCTN18402242, EudraCT: 2020-002322-85). Therefore, the tailored use of anti-CX3CL1 or anti-CX3CR1 in selected pain patient subgroups carries the potential to achieve significant clinical benefit in pain disorders (Table 5).…”

Psychoneurobiology Research and Personalized Treatment of Schizophrenia

“…The administration of E6011 once every two weeks for 24 weeks significantly improved the clinical RA score, which was evaluated using the American College Rheumatology 20% improvement criteria without severe adverse events [145,146]. A clinical trial of E6011 for Crohn's disease has likewise started [147]. Although clinical studies have not been initiated for schizophrenia, modulators of the C3-CR3 and CX3CL1-CX3CR1 pathways could be potential candidates for future medications for the behavioral and cognitive symptoms of schizophrenia mediated by decelerating excessive synaptic pruning.…”