Systemic lupus erythematosus is a heterogeneous disease that requires a customized approach to its management. Therapies range from nonsteroidal anti-inflammatory drugs to one of any number of immunomodulators or biologics. However, the clinical community has yet to arrive at a perfect therapy or even a perfect combination of therapies.
“Every patient with lupus is different,” Ziv Paz, MD, MPH, MSc, of the Division of Rheumatology & Lupus Center at Beth Israel Deaconess Medical Center and Harvard Medical School, said in an interview with Healio Rheumatology. “All of the lupus patients are grouped together, but there are multiple subgroups depending on whether the skin, kidney, heart, brain or other systems are impacted. We do not yet fully understand what is driving lupus, or how one patient is different from the other. This makes it difficult to find targeted therapies.”
Researchers have spent decades chasing a cure to systemic lupus erythematosus (SLE), according to Paz.
“Almost every branch of the immune system is involved in the pathophysiology of SLE, including B cells and T cells. We try to block different cytokines, receptors and signal transduction pathways. We keep trying the obvious,” he said.
Despite the obstacles, there is reason for optimism in the SLE pipeline, according to H. Michael Belmont, MD, professor in the Department of Medicine, associate director of clinical affairs in the Division of Rheumatology and medical director of the Hospital for Joint Diseases at NYU Langone Medical Center.
“We are understanding the biology of the disease better,” he said. “We are nailing down our understanding of the autoreactive processes that contribute to SLE,” he said.
Paz agreed, but with qualifications.
“We know more about this disease every year, which leads to the development of new lines of treatment,” Paz said. “But it is an uphill battle. The problem with lupus as a disease is that we still do not know exactly what is going on in terms of pathogenesis and how to explain the versatility of the disease.”
This unsteady journey toward understanding the disease has fueled the pipeline. Strides have been made, but at great cost and during a long period of time. An example is the FDA approval of belimumab, an inhibitor of the B lymphocyte stimulator (BLyS) protein. In 2011, it became the first SLE therapy approved in 50 years. Other treatments targeting the same pathway — namely blisibimod and atacicept — are in development.
“Some therapies have shown great success in animal models, but no activity in humans,” Paz said. “Most of these trials are stopping between phase 1 and phase 2.”
Similar things could be said for other drugs and targets in the pipeline right now, including those that target interferon-gamma (IFN-gamma) or interferon-alpha (IFN-alpha); Toll-like receptors (TLRs); B-cell activating factor (BAFF) antagonists; CD20 inhibitors; and approaches ranging from statins to tetrahydrocannabinol (THC) metabolites.
In this Cover Story,Healio Rheumatology takes a look at some of the drugs in the SLE pipeline.
Elusive Target: A Rundown of the Drug Pipeline for Systemic Lupus Erythematosus
Richard Alan Furie, MD, chief of the Division of Rheumatology at Northwell Health, an investigator at The Feinstein Institute for Medical Research and professor of Medicine at Hofstra Northwell School of Medicine, and colleagues, conducted a phase 2 study with anifrolumab, an anti-IFN-alpha receptor monoclonal antibody, in a cohort of 305 patients with moderate to severe SLE. Findings from the randomized, double-blind, placebo-controlled study were presented at last year’s American College of Rheumatology Annual Meeting.
Eligible participants received the study drug (300 mg or 1000 mg) intravenously or placebo every 4 weeks for 48 weeks. Composite SLE responder index (SRI) response at day 169 with sustained reduction of oral corticosteroid use (,10 mg/day and , day-1 dose maintained between days 85 and 169) served as the primary outcome measure. The two secondary endpoints, which were assessed at day 365, included a composite of SRI at day 365 with a reduction of oral corticosteroid use between days 281 and 365 and a reduction of corticosteroids to less than or equal to 7.5 mg/day by day 365 among patients treated with greater than or equal to 10 mg/day at baseline.
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