Morbidity and mortality still high in SLE, Drug Discovery Underway

October 2, 2015

Article

New methodologies for clinical trials in lupus are in development. If successful, the next decade could see the development of new targeted therapies for lupus.

Despite the introduction of novel antibiotics, hypertensive drugs, renal replacement therapy, immunosuppressive agents and biologic drugs to treat systemic lupus erythematous (SLE), morbidity and mortality rates remain high for these patients, according to a new review of drug discovery in SLE.[[{"type":"media","view_mode":"media_crop","fid":"42012","attributes":{"alt":"Â©SUWITNGAOKAEW/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_3447455798741","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4508","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":" ","typeof":"foaf:Image"}}]] In the past 30 years, SLE treatment has seen the intro¬duction of guidelines, disease definitions, candidate surrogate markers or biomarkers, metrics and composite indices. “Despite these developments, many study drugs have not met their primary or secondary endpoints - a situation that has led to a re-examination of SLE trial design,” wrote Daniel Wallace, MD, of the Division of Rheumatology at Cedars–Sinai Medical Center in Los Angeles, in a perspectives article published in the October issue of Nature Reviews Rheumatology.

Lupus Biologics Studied Since 2005

Drugs no longer in development for SLE: Abetimus, ocrelizumab, rontiluzumab, tabalumab, sirukumab
Drugs currently under study from a registrational standpoint: Atacicept, epratuzumab, lupuzor, sifilumumab, edratide, abatacept, blisbimod, several iterations of anti-ILâ6 agents
Drugs currently under study from a nonregistrational standpoint: Etanercept, infliximab, rituximab

_{Source: Nature Reviews Rheumatology} Only one agent, belimumab, has been approved by the FDA for use in SLE since 1959. Other widely used off-label agents for SLE, including rituximab, tacrolimus, aza¬thioprine, methotrexate, cyclophosphamide and mycophenolate mofetil, may not receive insurance coverage, Wallace noted.

Key messages about SLE drug development:

SLE is difficult to study in clinical trials. It involves multiple organ systems to varying degrees at different times. Inflammation is difficult to measure. Efforts to improve the metrics of clinical trials are in progress.
âThe best way to evaluate SLE is to use a composite response measure and other instruments that take into account disease activity, organ damage, health-related quality of life and patient-reported outcomes. Other considerations include adverse events, pharmacoeconomics, organ-specific measures, and biomarkers/surrogate markers of activity.
Clinical trials currently underway include registration studies, repurposing studies, and studies investigating existing agents for specific aspects of SLE.
Clinical trial initiatives are moving beyond FDA guidelines established in 2010. These initiatives include improved trial designs and recruitment strategies, new composite measures based on data from completed trials, and enrichment protocols that enable enrollment of fewer patients and shorter study duration, he stated.
For the first time, clinical trials will in the next few years address disease prevention, flare mitigation, interventions in early disease to induce remission and limit subsequent flares. They will also evaluate organ-specific disease as well as outcome measures.

“The lupus community is working together to create new methodologies for use in the design of clini-cal trials with more-efficient and mission-relevant approaches compared with past and current trials,” Wallace stated. “If these efforts are successful, the next decade could witness the approval of a new group of targeted therapies for SLE that will hopefully not only decrease inflammation and prevent damage, but also improve outcomes and quality of life.”

Related coverage in Rheumatology Network

References:

Daniel J. Wallace.

"The evolution of drug discovery in systemic lupus erythematosus,"

Nature Reviews Rheumatology

. 2015 Oct;11(10):616-20. doi: 10.1038/nrrheum.2015.86. Epub 2015 Jun 30.