Type I interferon antagonists in clinical development for lupus

ABSTRACT

Introduction

Systemic lupus erythematosus (SLE) is a severe chronic and incurable autoimmune disease. Treatment includes glucocorticoids and immunosuppressants which typically result in partial responses, and hence there is a great need for new therapies. The type I interferon (IFN) pathway is activated in more than 50% of SLE patients, and it is strongly implicated as a pathogenic factor in SLE.

Areas covered

We searched the literature using ‘SLE and interferon antagonists’ as search terms. This identified a number of therapeutics that have entered clinical development targeting type I IFN in SLE. These include monoclonal antibodies against type I IFN cytokines and a kinoid vaccination strategy to induce anti-IFN antibodies.

Expert opinion

Type I IFN antagonists have had some success, but many molecules have not progressed to phase III. These varied results are likely attributed to the multiple concurrent cytokine abnormalities present in SLE, the imprecise nature of the IFN signature as a readout for type I IFN and difficulties with clinical trials such as background medication use and diffuse composite disease activity measures. Despite these challenges, it seems likely that a type I IFN antagonist will come to clinical utility for SLE given the large unmet need and the recent phase III success with anifrolumab.

KEYWORDS:

• Lupus
• interferon
• clinical trials
• autoimmune disease
• systemic lupus erythematosus
• type I interferon pathway
• IFN pathway
• type I IFN antagonists

Article highlights

• Type I IFN is a primary pathogenic factor in SLE that is associated with high disease activity.

• Overexpression of IFN-induced genes in circulating blood cells known as the IFN signature is used as a metric to evaluate therapeutic effectiveness.

• Type I IFN antagonist therapy has shown efficacy and safety, and is a promising strategy in SLE

• Although development of rontalizamub and sifalimumab was discontinued; IFN-kinoid will be further assessed in a phase III clinical trial

• Results from phase III trials of anifrolumab showed that many metrics improved, including IFN gene signature, arthritis, and rash, but only one of the two-phase III trials met its primary endpoint.

• Conducting trials in SLE continues to be difficult due to disease heterogeneity, the need for background therapy, and the use of composite outcome measures.

This box summarizes key points contained in the article.

Declaration of interest

TB Niewold has received research grants from EMD Serono and Janssen, Inc., and has consulted for Thermo Fisher and Inova, all unrelated to the current manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work of the authors is funded by the National Institutes of Health (AR065964, DK107984), Lupus Research Foundation, and the Colton Center for Autoimmunity