Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: results of a phase IIa randomized placebo-controlled trial.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin disease with significant unmet need. Blockade of the OX40-OX40 ligand (OX40L) costimulation pathway by targeting OX40L on antigen-presenting cells (APCs) with a fully human noncytotoxic, nondepleting anti-OX40L 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 AD in a phase IIa double-blind placebo-controlled study. METHODS: The study was conducted at 19 hospitals in Germany, Poland, Spain and the UK. Eligible patients with moderate-to-severe AD were randomized (1 : 1 : 1) to low-dose intravenous (IV) amlitelimab (200 mg), high-dose IV amlitelimab (500 mg) or placebo, followed by three maintenance doses (50% of loading dose) at 4, 8 and 12 weeks, with safety follow-up to week 36. The co-primary endpoints were the incidence of treatment-emergent adverse events (all patients who received ≥ 1 dose of the study drug) and mean percentage change in Eczema Area and Severity Index (EASI) to week 16 (full analysis set). RESULTS: Between 13 December 2018 and 12 May 2020, 89 patients were randomly assigned to low- (n = 29) or high-dose amlitelimab (n = 30) or placebo (n = 29), of whom 88 proceeded to treatment [37 women (42%), 51 (58%) men; mean (SD) age 33.6 (11.9) years]. Amlitelimab was generally well tolerated with an unremarkable safety profile; no hypersensitivity events were reported. For the primary endpoint, the least square mean percentage change in EASI from baseline to week 16 was -80.12% [95% confidence interval (CI) -95.55 to -64.68; P = 0.009 vs. placebo] and -69.97% (95% CI -85.04 to -54.60; P = 0.07 vs. placebo) for the low- (n = 27) and high-dose (n = 27) amlitelimab groups, respectively, vs. -49.37% (95% CI -66.02 to -32.72) for placebo (n = 24). Numerically greater reductions in EASI were observed for amlitelimab vs. placebo from weeks 2 to 16. CONCLUSIONS: Novel targeting of OX40L-expressing APCs with amlitelimab was well tolerated and resulted in clinically meaningful improvements in AD.

OX40L Inhibition Suppresses KLH-driven Immune Responses in Healthy Volunteers: A Randomized Controlled Trial Demonstrating Proof-of-Pharmacology for KY1005.

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.

Individuals with gluteal tendon repair display similar hip biomechanics to those of a healthy cohort during a sit-to-stand task.

BACKGROUND: Gluteal-tendon repair (GTR) is reported to be effective for relieving pain and improving clinical function in patients with gluteal-tendon tears. The sit-to-stand (STS) task is an important activity of daily living and is often used to assess functional capacity in clinical populations. Understanding if and how STS performance is altered in individuals with gluteal tendon repair may be an effective marker of GTR outcomes as well as a possible therapeutic target for post-operative rehabilitation. RESEARCH QUESTION: Do biomechanical parameters during STS differ between age- and sex-matched participants with and without gluteal-tendon repair? METHODS: 27 participants with a GTR and 29 healthy participants performed the STS task. Data were acquired using the three-dimensional motion capture system and forceplates. Outcomes of interest were task duration, rate of force development, trunk, pelvis, and hip joint angles, moments and powers. Differences were assessed using Generalised linear multivariate models and statistical parametric mapping. RESULTS: GTR patients performed the STS movement significantly slower (1.4+/- 0.40 s) compared to controls (1.1+/ -0.2 s) with a significantly lower rate of force development (35.1+/- 5.7 N/kg/ms vs 30.3+/- 8.5 N/kg/ms). There were no group differences for hip, pelvis, or trunk angle over the movement cycle or for maximal or minimal values. Furthermore, there were no significant differences detected in hip joint kinetics. However, there appeared to be substantial between-subject variability indicating different patient-specific movements patterns. SIGNIFICANCE: Individuals with a GTR performed the STS task about 20 % slower than healthy controls with a lower rate of force development. The individual variations indicate that participants likely employed different movement strategies to achieve STS. While the lack of differences between groups could suggest that GTR helps restore function and corrects the proposed underlying aetiology, it is possible that the STS task was not sufficiently challenging to discriminate between groups.

Sequential assessment of bowel function and anorectal physiology after anterior resection for cancer: a prospective cohort study.

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.

People after gluteal tendon repair have gait characteristics which are similar to those of a healthy cohort.

BACKGROUND: Gluteal-tendon repair is reported to be effective for relieving pain and improving function in patients with gluteal-tendon tears. However, post-operative three-dimensional gait analysis has never been conducted in gluteal-tendon repair patients. Thus, our primary aim was to investigate how biomechanical gait parameters differ between age- and sex-matched participants with and without gluteal-tendon repair. METHODS: Vicon motion analysis technology was used to measure gait characteristics of 25 gluteal-tendon repair participants and 29 matched healthy comparison group participants. A generalised linear multivariate model was used to compare external hip-adduction moment, range of movement in hip adduction and internal rotation, pelvic obliquity, trunk lean, stride length and velocity of both cohorts throughout stance. FINDINGS: There were no differences between the groups in external hip adduction moment, pelvic obliquity and range of movement in hip adduction and internal rotation. Gluteal-tendon repair participants had a shorter stride length (P = 0.031) and reduced walking velocity (P = 0.015). Ipsilateral trunk lean was reduced in gluteal-tendon repair participants at the first-peak external hip-adduction moment (P = 0.016), mid-stance minimum external hip-adduction moment (P = 0.029) and second-peak external hip-adduction moment (P = 0.006). INTERPRETATION: There were no differences between the gluteal-tendon repair and comparison groups for external hip-adduction moment and pelvic obliquity. This suggests that gluteal-tendon repair may restore hip control in stance. Slower walking speed, reduced stride length and decreased ipsilateral trunk lean may reflect persistence of pre-operatively developed gait adaptations. Future studies of gait biomechanics before and after gluteal-tendon repair would be needed to substantiate this theory.