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ACR 2012 Special Report 3

ACR Special Report: Chicago, IL 2011

The Latest Treatment Advances for Lupus

IFNa-Kinoid: A Vaccine for Lupus?

What if there was a vaccine that could harness the strength of your own immune system to block the activity of a key protein involved in the underlying disease processes of lupus? It’s not as far-fetched as it sounds. Researchers from the Université Catholique de Louvain, in Brussels, Belgium, presented intriguing data from a small study in 28 patients with mild-to-moderate lupus, 21 of whom received a novel immunotherapy treatment called IFN-a-kinoid, 7 of whom received a placebo.i The injectable treatment, from Paris-based pharmaceutical company NeoVacs, blocks production of interferon alpha (IFNa) inflammatory cytokines. These cytokines stimulate the autoantibody response that forms the hallmark of lupus pathology.

Participants received increasingly higher doses of the study drug, with the initial, lowest dose injected at the trial’s start; a slightly higher dose a week later; another, higher dose at 1 month; and the final, highest dose, given to half the participants at day 84. All participants were followed for 3 to 15 months.

Other than some mild irritation at the injection site, there were no significant side effects. All patients produced antibodies against IFNa, demonstrating that the vaccine had the desired immunological effect. Participants whose blood was positive for the IFNa signature demonstrated a significant reduction in IFNa activity compared to those receiving a placebo (about two-thirds of those with lupus have the IFNa signature). In addition, there was a statistically significant improvement in complement C3, a biomarker for disease activity; a reduction of the IFNa gene signature; and lower levels of dsDNA antibodies, all of which suggest a reduction in disease activity. The results were so encouraging, researchers said, that they plan to begin Phase II trials in 2012 to assess the ability of the vaccine to prevent lupus flares.

Key point: Another possible treatment for lupus is moving forward to the next phase of clinical trials.

Belimumab (Benlysta) for Renal Nephritis

In 2011, belimumab (Benlysta) became the first new drug approved to treat lupus in more than 50 years. Now researchers are investigating its potential for lupus nephritis. In a study presented at ACR, researchers evaluated various kidney-related biomarkers from patients who participated in the large, phase III trials that led to the drug’s approval. None had severe active lupus nephritis, nor were the studies designed to evaluate the effect of belimumab on kidney function. Nonetheless, in this secondary analysis researchers found that individuals who received belimumab for 1 year had lower rates of renal flares, higher rates of lupus nephritis remission, and shorter time to first renal remission than those who received standard therapy (the control group). They also showed greater improvement in proteinuria (a marker of kidney dysfunction) and improvement on 2 assessments used to measure renal function, the SELENA-SLEDAI and BILAG.

Key point: Belimumab may have some benefits for people with lupus nephritis. Human Genome Sciences, which developed belimumab, is considering whether to begin clinical trials focused on patients with lupus nephritis.

Update on Belimumab (Benlysta)

Several posters presented during the ACR meeting highlighted long-term safety and efficacy outcomes from the pivotal clinical trials that led to belimumab’s (Benlysta) approval. In one study, researchers combined data from 3 clinical trials involving 2,133 patients who received belimumab for 76 weeks. Researchers found similar rates of adverse events overall between the group that received a placebo and the group that received belimumab; as well as similar numbers of participants in each group who dropped out of the trial because of adverse events. Participants receiving belimumab did have higher rates of depression, infection, and reactions at the infusion site than the placebo group.ii

Key point: The safety data seen in individual belimumab trials remained relevant even when all the trials were combined.

A second study assessed safety and efficacy data in individuals who had been receiving belimumab for 6 years.iii Researchers reported on 296 patients with lupus who participated in the original clinical trials for the drug. After 6 years, 208 remained on the drug. Rates of adverse events remained stable or actually declined over the time period. Participant scores on the SLE Responder Index (SRI), which measures disease activity, continued to improve, while the number of patients experiencing new flares fell. After the first year on the drug, 38% of patients receiving belimumab experienced at least one BILAG A or 2 new B flares compared to 44% of those receiving a placebo; but by year 6, that figure had dropped to 11%. In addition, while after 1 year on belimumab 84% of participants had experienced an SRI flare (17% severe) compared to 85% (19% severe) on placebo, after 6 years that had dropped to 42% (5% severe). Long-term participants also demonstrated increases in complement C3 or C4 and declining autoantibody levels over the time period. In addition, patients required about a third fewer corticosteroids after 6 years than when they first joined the trial.

Key point: Belimumab appears safe over time, with continued increases in efficacy.

In a third study, researchers evaluated various biomarkers in clinical trial participants who received belimumab for 1 year.iv They found that individuals with higher baseline disease activity (a SELENA-SLEDAI score of 10 or higher); positive anti-dsDNA levels; and low complement (C3/C4) all responded better to belimumab than those with lower disease activity. In other words, the sicker the patients, the greater their response. Patients with positive anti-dsDNA and low complement had response rates of 51.5% with the 10 mg/kg dose compared to response rates of 31.7% with placebo. That compares to overall response rates of all participants receiving belimumab of 50.6% and 38.8% for placebo.

Key point: Patients with greater disease activity are more likely to respond to belimumab therapy than those with mild-to-moderate disease activity.

In a fourth study, researchers evaluated the effects of lupus on health-related quality of life, a measure that addresses numerous areas in which the disease impacts the quality of life.v Other studies find that the impact of lupus is as significant as that of AIDS, rheumatoid arthritis, diabetes, and congestive heart failure. In the clinical trials that led to the approval of belimumab, participants’ quality of life was assessed at the beginning of the trial and again at the end. When researchers evaluated that data, they found that those who benefitted the most from the drug also saw their quality of life improve the greatest. For instance, in response to the question: “Compared with 1 year ago, how are you today?” 76% of responders said they were “somewhat/much better” and 34% responded that they were “much better” compared to just 33.5% and 14.6% of nonresponders, respectively. Responders also experienced significant improvements in fatigue.

Key point: People who respond to belimumab experience not just disease improvement, but improvement in their overall quality of life, including less fatigue.

Abatacept (Orencia) for Lupus Nephritis

One reason it has been so difficult to find effective treatments for lupus and lupus nephritis is related not to the potential efficacy of the medication itself, but to the design of clinical trials developed to assess these investigational compounds. That became quite clear during two presentations this year.

Efficacy and Safety of Abatacept Over 12 Months in Patients with Lupus Nephritis: Results From a Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II/III Study

In the first, researcher Richard Furie, MD, of the North Shore-Long Island Jewish Health System in Lake Success, NY, presented the result of a 12-month study of abatacept in 228 patients with lupus nephritis who also received mycophenolate mofetil (MMF).vi The study found no significant improvement compared to participants who did not receive the study drug. One bright spot is that the 122 patients with nephrotic lupus nephritis, a more serious form of the disease, experienced a greater improvement in their urinary protein-to-creatinine ratio in the second 6 months than those in the placebo group, suggesting that more study should be done in this subset of patients. There were no significant safety issues related to abatacept.

Abatacept for Lupus Nephritis: Alternative Outcome Measures Support Opposing Interpretations of Data From a Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II/III Study

In the second presentation, researcher David Wofsy of the VA Medical Center in San Francisco showed that the results would have been far different if different endpoints, or outcomes, were used.vii In the original study, patients had to achieve a complete response on two successive visits, defined as an eGFR (a test used to measure kidney status) within 10% of the pre-treatment value; a urine protein-to-creatinine ratio less than 30 mg/mmoL; and normal urine sediment. This requirement, said Dr. Wofsy, “is a very high bar to meet,” with few, if any, other studies in lupus nephritis requiring such stringent values or requiring that they be met on two successive visits.

Dr. Wofsy’s analysis used a less stringent but still clinically relevant definition of complete response (which is currently being used in another lupus nephritis trial). It required a blood creatinine level that was either normal or less than or equal to 125% of the baseline ratio; a urine protein/creatinine ratio less than 0.5 mg/mg; and a prednisone dose less than or equal to 10 mg/day at the end of the study.

When this criteria was used, he reported, there were significant improvements between those patients who received the study drug and those who did not, particularly among patients with the most severe nephritis when the study began.

“We are locked into a language that is not ours,” Dr. Wofsy said after presenting the data. Phrases like “complete” and “partial” response come from the oncology world, he noted. “We need to get away from this language that doesn’t describe our disease.”

Key point: Abatacept may have some benefit for patients with lupus nephritis; but, more importantly, clinical trial endpoints significantly impact trial results.

Looking Down the Road: New Therapies Under Investigation for Lupus

What’s next in lupus therapies? Here’s a look at one compound still in the very early stages of investigation as a lupus treatment. The results of this trial were presented at the 2011 ACR meeting.

Sirukumab

This human monoclonal IgG1 kappa antibody is being developed by Centocor Research & Development, a division of Johnson & Johnson Pharmaceutical. It targets and inhibits interleukin-6, which plays a role in autoimmune diseases like lupus. The study presented at ACR was designed to evaluate the safety and pharmacokinetics of various dosages of sirukumab in 33 patients with cutaneous lupus or 15 patients with systemic lupus erythematosus (SLE). The study showed that the drug was generally safe in both groups, with all patients exhibiting decreases in complement C3 and C4. None had any flares, nor did any participants develop antibodies to the drug itself.viii Sirukumab is also being investigated in a Phase II trial for lupus nephritis.

Key point: This study highlights the potential of another drug to treat lupus.


More information about lupus and treatment advances can be found by visiting www.lupusresearch.org.

The Alliance for Lupus Research Special Report on the 2011 American College of Rheumatology Meeting was made possible in part by generous support from Genentech.

©2011 Alliance for Lupus Research. All Rights Reserved.

Contents herein may not be reproduced, republished or distributed without the prior written permission of the Alliance for Lupus Research. To request permission to reproduce, republish or distribute any part of this report, contact us at 212-218-2840 or email info@lupusresearch.org.



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