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The Latest Treatment Advances for Lupus

ACR Special Report: Philadelphia, PA, October 18-21, 2009

The Latest Treatment Advances

There has not been a new drug approved for lupus in several decades. However, positive results from a major trial of the investigational compound belimumab (Benlysta™), announced during the ACR meeting, coupled with equally positive results of a second trial announced a week later, represent important milestones in the development of new therapeutic options for people with lupus. Human Genome Sciences, Inc. and its partner GlaxoSmithKline PLS are expected to submit marketing applications for regulatory approval of belimumab in the United States, Europe and other regions in the first half on 2010. If approved, belimumab will be the first in a new class of drugs called BLyS-specific inhibitors.

Belimumab (Btibs a protein necessary for the maturation of B-lymphocytes, cells involved in the autoimmune response that underlies lupus. Two recently announced Phase III trials showed that the drug significantly reduced disease activity and increased time to flare compared with placebo. In the first trial reported, participants also experienced less fatigue and improved quality of life, with no difference in adverse effects between those who received a placebo and those who received belimumab with the exception of infusion site reactions.i

Also reported during the conference were the results from a Phase II belimumab trial evaluating its efficacy and safety over four years in 449 people with lupus. Researchers found that the rate of adverse effects remained the same or declined over the four years, while the frequency of new flares decreased significantly. After four years, for instance, flares defined under the SLE Flare Index declined from 72% at six months to 16% after four years.ii

"Such results," said presenter Michelle Petri, MD, professor of rheumatology at the Johns Hopkins Arthritis Center in Baltimore and a former ALR grantee, "show that belimumab could be "widely used" as background therapy to reduce the use of steroids, improve quality of life and prevent flares. This could be the next generation of Plaquenil," she said.

The ALR supported important basic and translational research on the molecule targeted by belimumab, a B Cell stimulator also known as BLyS. Research conducted by previously ALR-funded investigators William Stohl, MD, at the University of Southern California and Robert Carter, MD, currently the Deputy Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, established this molecule, BLyS, as a potential therapeutic target for people with lupus. Their research helped set the stage for this new clinical development program and trial. The ALR has funded more than five million dollars in B-cell research in the past ten years.

Rituximab (Rituxan®)

There was more disappointing news for rituximab (Rituxan) and its potential role as a lupus therapy, however. Rituximab is a monoclonal antibody that depletes CD-20 B cells. Joan T. Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center in Oklahoma City, presented data from two analyses of an ongoing trial evaluating rituximab in people with moderate-to severe lupus.

  • In the phase II/III EXPLORER trial, participants were taking immunosuppressants and steroids. They received four infusions over six months of either a placebo or rituximab, during which the steroids were gradually stopped. After 78 weeks, the rate of serious and minor adverse events, including infection and infusion reactions, were similar between the two groups, although there was a higher incidence of viral herpes, neutropenia and serum sickness in the rituximab group.iii

  • A study evaluating the subset of participants who showed a response to either placebo or rituximab found that severe and moderate flare rates were similar in both groups during the year they were followed. However, the average flare rate in the rituximab group was significantly lower than in the placebo group, suggesting that rituximab may increase the time to flare compared with placebo.iv

The results of the EXPLORER trial troubled clinicians, many of whom use rituximab for patients with lupus even though the drug has not been approved for that use yet. When asked how the results should be interpreted, Dr. Merrill replied: "while there is no evidence that rituximab works, I'm dissatisfied with the evidence that it doesn't."

And, in fact, other studies of the drug presented during the meeting show differing results.

  • A study in 35 African-American and Hispanic patients who received four weekly infusions and were followed for two years showed a significant drop in disease activity throughout the study in all participants, even those with lupus nephritis.v
  • A study in 86 peopled with lupus treated with rituximab with or without other lupus treatments for an average of 15 months found that an estimated 73% of treated patients showed improvement. Overall, 10 people had severe infections and one died from an infection.vi

What this means for people with lupus? It is quite likely that rituximab works in certain populations of people with lupus. The disappointing results from the large, manufacturer-sponsored clinical trials may be related to the way the trials were designed. The decision to use or not use rituximab is one you should make in conjunction with your doctor.

Lenalidomide (Revlimid®)

Victoria P. Werth, MD, of the University of Pennsylvania School of Medicine presented results from an ACR-funded study showing that lenalidomide (Revlimid), a drug typically used to treat multiple myeloma and rare blood disorders called myelodysplastic syndromes, was also quite effective in treating severe cutaneous lupus in a small, preliminary study. Specifically:

  • Four of the five patients in the study experienced a significant improvement.
  • One of the four had to stop the drug because of new symptoms.
  • The study identified biomarkers that could serve to assess patient response to the drug in future
    studies. vii

What this means for people with lupus? Lenalidomide may be an option for treating cutaneous lupus. However, much larger studies are required to assess its efficacy and safety.


References

i Navarra S, Guzman R, Gallacher A, et al. Belimumab, a BLyS-Specific Inhibitor, Reduced Disease Activity, Flares and Prednisone Use in Patients with Active SLE: Efficacy and Safety Results From the Phase 3 BLISS-52 Study. Presentation Number: LB1. Presented at the American College of Rheumatology Annual Meeting, 2009; Philadelphia, PA.

ii Petri M, Furie R, Merrill J, et al. Four-Year Experience of Belimumab, a BLyS-Specific Inhibitor, in Systemic Lupus Erythematosus (SLE) Patients. Presented at the 73rd Annual Scientific Meeting of the American College of Rheumatology, October 17-21, 2009; Philadelphia, PA.

iii Merrill JT, Wallace DJ, Latinis KM, et al. Treatment of Systemic Lupus Erythematosus (SLE) with Rituximab: 78-Week Safety Data From the Phase II/II EXPLORER Trial. Presented at 73th Annual Scientific Meeting of the American College of Rheumatology, October 21, 2009; Philadelphia, PA.

iv Merrill JT, Buyon JP, Furie R, et al. Flare Assessment in Systemic Lupus Erythematosus (SLE) Patients Treated with Rituximab in the Phase II/III EXPLORER Trial. Presented at 73th Annual Scientific Meeting of the American College of Rheumatology, October 19, 2009; Philadelphia, PA.

v Karpouzas GA, Gogia M, Moran RC, Hahn BH. Rituximab Therapy Induces Durable Remissions in Hispanic and African American Patients with Refractory Systemic Lupus Erythematosus (SLE). Presented at 73th Annual Scientific Meeting of the American College of Rheumatology, October 18, 2009; Philadelphia, PA.

vi Terrier B, Hachulla E, Pallot-Prades B, et al. Tolerance and Efficacy of Rituximab (RTX) in Systemic Lupus Erythematosus (SLE): Data of 104 Patients From the AIR (Auto-immunity and Rituximab) Registry. Presented at 73th Annual Scientific Meeting of the American College of Rheumatology, October 18, 2009; Philadelphia, PA.

vii Braunstein I, Goodman NG, Rosenbach M, et al. Correlates of Clinical Response in the Circulating Leukocyte Profile of Subjects On Lenalidomide for Cutaneous Lupus Erythematosus. Presented at 73th Annual Scientific Meeting of the American College of Rheumatology, October 20, 2009; Philadelphia, PA.

 

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

The 2009 American College of Rheumatology Meeting Special Report was made possible in part by generous support from Biogen Idec, Genentech and Johnson & Johnson.

Genentech Biogen IdecJohnson & Johnson

©2009 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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