Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus

Abstract

We aimed to evaluate the pharmacodynamics, efficacy, safety and tolerability of the JAK1 inhibitor GSK2586184 in adults with systemic lupus erythematosus (SLE). In this adaptive, randomized, double-blind, placebo-controlled study, patients received oral GSK2586184 50-400 mg, or placebo twice daily for 12 weeks. Primary endpoints included interferon-mediated messenger RNA transcription over time, changes in Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index score, and number/severity of adverse events. A pre-specified interim analysis was performed when ≥ 5 patients per group completed 2 weeks of treatment. In total, 84-92% of patients were high baseline expressors of the interferon transcriptional biomarkers evaluated. At interim analysis, GSK2586184 showed no significant effect on mean interferon transcriptional biomarker expression (all panels). The study was declared futile and recruitment was halted at 50 patients. Shortly thereafter, significant safety data were identified, including elevated liver enzymes in six patients (one confirmed and one suspected case of Drug Reaction with Eosinophilia and Systemic Symptoms), leading to immediate dosing cessation. Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index scores were not analysed due to the small number of patients completing the study. The study futility and safety data described for GSK2586184 do not support further evaluation in patients with SLE. Study identifiers: GSK Study JAK115919; ClinicalTrials.gov identifier: NCT01777256.

Evaluation of a Janus kinase 1 inhibitor, PF‐04965842, in healthy subjects: A phase 1, randomized, placebo‐controlled, dose‐escalation study

“…There were no incidences of anaemia or thrombocytopenia during this study and the incidence of infections was low. Changes in lipid parameters were observed in this study, as has been reported in some studies with other JAK inhibitors . The most dramatic effects on HDL and LDL cholesterol were observed in subjects receiving PF‐04965842 BID.…”

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases

“…Another Phase II study in SLE of solcitinib was nonetheless terminated due to its toxicity (Thanou & Merrill, 2018). Two patients in this study exhibited a drug reaction and also a reversible elevation in the liver function test was observed in six other cases (Kahl et al, 2016; van Vollenhoven et al, 2015). Thus, this data does not support further clinical improvement for SLE therapy.…”

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

“…Currently, a phase II clinical trial investigates the efficacy of orally administered JAK1 inhibitor filgotinib in female patients with active CLE (NCT03134222). In SLE patients, JAK1 inhibitor GSK2586184 had no significant effect on IFN transcriptional biomarker expression compared to placebo in a phase II clinical study, most probably due to limitations by low numbers of patients (47). A clinical study with JAK1/2 inhibitor baricitinib, however, revealed significantly improved SLE symptoms, supporting a critical role of JAK/STAT signaling in the pathogenesis of SLE (48).…”