First‐in‐human study of deucravacitinib: A selective, potent, allosteric small‐molecule inhibitor of tyrosine kinase 2

Abstract This randomized, double‐blind, single‐ and multiple‐ascending dose study assessed the pharmacokinetics (PKs), pharmacodynamics, and safety of deucravacitinib (Sotyktu™), a selective and potent small‐molecule inhibitor of tyrosine kinase 2, in 100 (75 active, 25 placebo) healthy volunteers (NCT02534636). Deucravacitinib was rapidly absorbed, with a half‐life of 8–15 h, and 1.4–1.9‐fold accumulation after multiple dosing. Deucravacitinib inhibited interleukin (IL)‐12/IL‐18‐induced interferon (IFN)γ production ex vivo in a dose‐ and concentration‐dependent manner. Following in vivo challenge with IFNα‐2a, deucravacitinib demonstrated dose‐dependent inhibition of lymphocyte count decreases and expression of 53 IFN‐regulated genes. There were no serious adverse events (AEs); the overall frequency of AEs was similar in the deucravacitinib (64%) and placebo (68%) groups. In this first‐in‐human study, deucravacitinib inhibited IL‐12/IL‐23 and type I IFN pathways in healthy volunteers, with favorable PK and safety profiles. Deucravacitinib is a promising therapeutic option for immune‐mediated diseases, including Crohn's disease, psoriasis, psoriatic arthritis, and systemic lupus erythematosus

Effect of hemodialysis on the signal-averaged electrocardiogram

The presence of late potentials (LPs) on signal-averaged electrocardiography (SAECG) is predictive of ventricular tachycardia. The effect of hemodialysis (HD) on SAECG has not been well studied. SAECG was evaluated in 28 patients with chronic renal failure immediately before and after HD. In each SAECG, QRS duration, low-amplitude signal duration (LASd), and root-mean-square voltage of the terminal 40 milliseconds of the QRS (RMS40) were measured. To evaluate the effect of fluid removal on SAECG, the last 12 patients were studied during two different HD sessions, one with and one without fluid removal. Two-dimensional echocardiography was performed before and after HD on these 12 patients. At baseline, four patients met the criteria for LPs on SAECG. Only one patient met the criteria for LPs on SAECG after HD. After HD, the mean LASd decreased (28.3 ± 12.9 to 24.9 ± 10.1 milliseconds; P = 0.041) and RMS40 increased (63.0 ± 56.9 to 79.0 ± 59.2 μV; P = 0.006). Among the 12 patients who underwent HD with and without fluid removal, left ventricular end-diastolic dimension decreased with (5.4 ± 0.6 to 5.1 ± 0.6 cm; P = 0.024) but not without fluid removal (5.2 ± 0.3 to 5.1 ± 0.4 cm; P = not significant [NS]). RMS40 improved with (43.8 ± 23.1 to 53.2 ± 22.6 μV; P = 0.03) but not without fluid removal (51.0 ± 26.5 to 51.5 ± 24.2 μV; P = NS). A significant negative correlation was found between change in body weight and change in RMS40 parameter ( r = 0.456; P = 0.0381). SAECG parameters are abnormal in a significant proportion of patients with chronic renal failure and improve with HD despite electrolyte and other proarrhythmic changes. Decreased left ventricular dimension because of fluid removal during HD is one possible explanation for this improvement

Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab

PurposeSepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis.MethodsRandomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters.ResultsTwelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase.ConclusionsIn this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any 'cytokine storm'. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT02960854