The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti‐OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty‐four healthy male subjects (26.5 ± 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure‐response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (Tmax) ~ 4 hours, geometric mean terminal half‐life (t½) ~ 24 days). Cutaneous blood perfusion (estimated difference (ED) −13.4 arbitrary unit (AU), 95% confidence interval (CI) −23.0 AU to −3.8 AU) and erythema quantified as average redness (ED −0.23 AU, 95% CI −0.35 AU to −0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure‐response analysis displayed a statistically significant treatment effect on anti‐KLH antibody titers (IgG maximum effect (Emax) −0.58 AU, 95% CI −1.10 AU to −0.06 AU) and skin response (erythema Emax −0.20 AU, 95% CI −0.29 AU to −0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune‐mediated disorders.

Background Atopic dermatitis is an inflammatory skin disease with significant unmet need. Blockade of the OX40/OX40Ligand co-stimulation pathway by targeting OX40Ligand on antigen-presenting cells with a fully human, non-cytotoxic, non-depleting anti-OX40Ligand monoclonal antibody (amlitelimab; SAR445229; KY1005) is a novel way to modulate persistent inflammation. Objectives To assess the safety and efficacy of amlitelimab over 16 weeks in adults with atopic dermatitis in a phase IIa, double-blind, placebo-controlled study. Methods The study was conducted at 19 hospitals in Germany, Poland, Spain and the United Kingdom. Eligible patients with moderate-to-severe atopic dermatitis were randomised (1:1:1) to intravenous amlitelimab low dose (200 mg), high dose (500 mg) or placebo, followed by 3 maintenance doses (50% of loading dose) at 4, 8 and 12 weeks with safety follow-up to week 36. The co-primary endpoints were incidence of treatment-emergent adverse events (all patients who received ≥1 dose of study drug) and mean percentage change in Eczema Area and Severity Index (EASI) to week 16 (full analysis set). Results Between 13 Dec, 2018, and 12 May, 2020, 89 patients (37 [42%] women, 51 [58%] men; mean age 33.6 years [SD 11.95]) were randomly assigned to amlitelimab low or high dose or placebo (N=29, 30 and 29, respectively). Amlitelimab was generally well tolerated with an unremarkable safety profile and no hypersensitivity events were reported. For the primary endpoint, the least square mean percentage change in EASI (95% confidence interval) from baseline to week 16 was -80.12% (-95.55 to -64.68; P=0.009 versus placebo) and -69.97% (-85.04 to -54.60; P=0.072 versus placebo) for low- (N=27) and high-dose (N=27) amlitelimab groups, respectively, compared with -49.37% (-66.02 to -32.72) for placebo (N=24). Numerically greater reductions in EASI were observed for amlitelimab compared with placebo from weeks 2 to 16. Conclusions Novel targeting of OX40Ligand-expressing antigen-presenting cells with amlitelimab was well tolerated and resulted in clinically meaningful improvements in atopic dermatitis. The study is registered with ClinicalTrials.gov, NCT03754309.

OX40Ligand (OX40L) upregulation on antigen-presenting cells (APCs) following antigen presentation contributes to the survival and functional activation of T helper (Th) 2 and Th1/17/22 cells, which are central to the inflammation and pathological outcomes in atopic dermatitis (AD). In a Phase 2a trial (NCT03754309), amlitelimab, a fully human, non-depleting, non-cytotoxic anti-OX40L monoclonal antibody, was effective in treating patients with moderate-to-severe AD. To assess the effects of amlitelimab on interleukin (IL)-22, an important Th22-associated disease mediator of AD. 89 patients with moderate-to-severe AD were enrolled in a Phase 2a randomized, double-blind, placebo-controlled, multicentre trial and randomized 1 : 1 : 1 to intravenous amlitelimab low dose (200 mg loading/100 mg maintenance every 4 weeks [Q4W]; n = 29), high dose (500 mg/250 mg Q4W; n = 30) or placebo (Q4W; n = 29) until week 12. The primary efficacy endpoint was the percentage change in Eczema Area and Severity Index (EASI) from baseline to week 16. Other disease severity measurements included SCORing of Atopic Dermatitis (SCORAD) and validated Investigator Global Assessment (vIGA). Serum was collected at baseline, week 4 and week 16, and further collected at week 24 and week 36 in responders, defined as patients who reached vIGA 0/1 at week 16. IL-22 levels were determined by ultrasensitive single-molecule immunoassay (Simoa). Of 88 subjects who received study treatment, 59 were evaluable at week 16. Amlitelimab was well tolerated with an unremarkable safety profile. The mean percentage change in EASI from baseline at week 16 was −80.12% for amlitelimab low dose and −69.97% for amlitelimab high dose vs. −49.37% for placebo (nominal P-values: 0.009 [amlitelimab low dose vs. placebo] and 0.072 [amlitelimab high dose vs. placebo]). Amlitelimab-treated patients who achieved vIGA 0/1 at week 16 had sustained clinical responses up to week 36. No difference in IL-22 serum levels was found between groups at baseline. IL-22 levels correlated with disease severity at baseline, as measured by EASI and SCORAD (r = 0.53, P < 0.0001; and r = 0.36, P = 0.001; respectively). A significant reduction in IL-22 levels was observed at week 16 in amlitelimab-treated patients (low dose P < 0.0001; high dose P = 0.001), but not in the placebo group (P = 0.381). The amlitelimab-induced decrease in IL-22 levels was maintained until week 36 in those defined as vIGA 0/1 responders at week 16. OX40L blockade on APCs represents a promising novel approach in the treatment of AD by effectively targeting underlying T-cell immune dysregulation. Amlitelimab monotherapy not only provided a sustained and clinically meaningful improvement in disease activity compared with placebo in patients with moderate-to-severe AD, but also significantly decreased serum levels of IL-22, a Th22 cell-associated cytokine involved in the underlying immunopathogenesis of AD.

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Aim The aim of this study was to investigate changes in bowel function and anorectal physiology (ARP) after anterior resection for colorectal cancer. Method Patients were recruited from November 2006 to September 2008. Cleveland Clinic Incontinence (CCI) scores and stool frequency were determined by patient questionnaires before surgery (t0) and at three (t3), six (t6), nine (t9) and 12 (t12) months after restoration of intestinal continuity. ARP measurements were recorded at T0, T3 and T12. Endoanal ultrasound was performed at T0 and T12. Results Eighty‐nine patients were included. CCI score increased postoperatively then normalized, whereas stool frequency did not change. Patients who had neoadjuvant radiotherapy or a lower anastomosis had increased incontinence and stool frequency in the postoperative period, whereas those with defunctioning stomas or open surgery had increased stool frequency alone. Maximum resting pressure, volume at first urge and maximum rectal tolerance were reduced throughout the postoperative period. Radiotherapy, lower anastomosis and defunctioning stoma (but not operative approach) altered manometric parameters postoperatively. Maximum rectal tolerance correlated with incontinence and first urge with stool frequency. The length of the anterior internal anal sphincter decreased postoperatively. Conclusions Incontinence recovers in the first year after anterior resection. Radiotherapy, lower anastomosis, defunctioning stoma and open surgery have a negative influence on bowel function. ARP may be useful if bowel dysfunction persists beyond 12 months.