Lupus community panel proposals for optimising clinical trials: 2018

Abstract

Formidable impediments stand in the way of treatment development for lupus. These include the unwieldy size of current trials, international competition for scarce patients, complex outcome measures and a poor understanding of these outcomes in the world at large. The heterogeneity of the disease itself coupled to superimposition of variegated background polypharmacy has created enough immunological noise to virtually ensure the failure of lupus treatment trials, leaving an understandable suspicion that at least some of the results in testing failed drugs over the years may not have been negative, but merely uninterpretable. The authors have consulted with many clinical trial investigators, biopharmaceutical developers and stakeholders from government and voluntary sectors. This paper examines the available evidence that supports workable trial designs and proposes approaches to improve the odds of completing interpretable treatment development programs for lupus.

Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study

“…Three decades of failed clinical trials and limited evidence to guide the selection of standard of care treatments hinder optimal care for individual SLE patients [1]. Key roadblocks in the development of new lupus treatments include incomplete understanding of the underlying molecular mechanisms of disease, the heterogeneity of disease across poorly defined clusters of patients, high placebo response rates, the cacophony of background therapies, and other factors [2,3]. This study set forth to address the heterogeneity of lupus by applying machine learning approaches to extensive gene expression, soluble mediator, autoantibody, and clinical information in a large cohort of carefully clinically-characterized patients.…”

“…These trials have almost universally failed to meet their pre-specified primary outcomes. Although multiple factors contribute to the failure of lupus trials [2,3], many treatments have shown efficacy in secondary endpoints or exploratory analyses [1]. Moreover, an exploratory analysis revealed differential effects of standard of care medications on the expression of genes that represent the targets for treatments currently under development.…”

Antibody against envelope protein from human endogenous retrovirus activates neutrophils in systemic lupus erythematosus

“…Hallmarks of disease include autoreactive T and B cells, immune complex deposition in tissues, and systemic activation of type I interferon (IFN) signaling and cytokines (Tsokos et al, 2016). Billions of dollars have been spent on research and development and clinical trials over the past few decades, yet belimumab (anti-BAFF monoclonal antibody) is the only FDAapproved targeted therapy for SLE, and it is only effective for roughly half of treated patients (Merrill et al, 2018). Therefore, there is a great need to develop new effective therapies.…”

A double‐blind, randomized, placebo‐controlled, phase II trial of baricitinib for systemic lupus erythematosus: how to optimize lupus trials to examine effects on cutaneous lupus erythematosus

“…At a recent international CLE meeting, based on the numerous validation studies and successful discrimination of skin improvement in clinical trials, it was unanimously agreed that the CLASI should be used as the skin outcome for lupus trials examining responsiveness in the skin . After extensive consultation with the key leaders in the lupus community there was a similar recommendation for use of the CLASI for measuring lupus skin disease . However, the CLASI, like any other outcome measure for lupus, needs to be used in a manner that is optimal for the conditions of the trial design.…”

“…We know that 25% of patients with moderate‐to‐severe discoid lupus erythematosus do not meet criteria for SLE, but would benefit from new therapies. This recommendation was agreed upon in the white paper co‐authored by many prominent experts within the lupus community . Automatic disenfranchisement of these patients from treatments approved only for SLE underscores the importance of determining whether or not treatments efficacious for ‘rash or arthritis’ are actually working for CLE.…”