Lessons learned from the failure of several recent trials with biologic treatment in systemic lupus erythematosus

ABSTRACT

Introduction: Treatment of systemic lupus erythematosus (SLE) represents a challenge due to variable disease manifestations, clinical course, and outcome. Long-term outcome in SLE remain unsatisfactory and a search for new therapeutic options is definitely warranted. Despite expectations, most clinical trials performed in SLE and lupus nephritis in the last decade did not reach primary outcome, and the only drug that has been licensed is belimumab.

Areas covered: Results of negative trials testing monoclonal antibodies and other biologic agents in SLE are briefly summarized. Reasons for the failure of the trials are listed and discussed.

Expert opinion: Future studies should recruit patients with similar organ involvement, better defined disease manifestations, higher activity, and similar severity. In addition to testing higher efficacy if given as add-on treatment to standard-of-care, the trials should be aimed at reducing dosing, or completely eliminating some parts of the current standard treatment, especially corticosteroids. Median follow-up of the patients should be longer. Moreover, specific biomarkers are needed to help to identify eligible patients and to better define response to treatment. An urgent unmet need is testing these new drugs in patients with severe SLE (including those refractory to current treatment).

KEYWORDS:

• SLE
• biologic treatment
• clinical trial
• monoclonal antibodies
• treatment

Article highlights

• Treatment of SLE should result in preventing organ damage, reducing morbidity, improving patient survival and health-related quality of life.

• Despite expectations, most clinical trials performed in SLE and lupus nephritis in the last decade did not reach primary outcome, and the only biologic drug that has been licensed is belimumab.

• Reasons for failure of the trials include: design of the trials, sample size, entry criteria, definition of endpoints, outcome measures, heterogeneity of the disease, geographical and ethnic differences, strong ‘background’ medication, or too short follow-up.

• Future studies should recruit patients with similar organ involvement, well-defined disease activity, and similar severity.

• New drugs should be tested not only as ‘add-on’ treatment, but also as a way to reduce (or completely avoid) the (potentially toxic) background therapy.

• New drugs should be also tested in the settings of severe SLE (namely lupus nephritis and CNS involvement) where the greatest unmet need is present.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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 relationships or otherwise to disclose.

Additional information

Funding

RVO VFN64165 of the Ministry of Health, Czech Republic.