The Latest Treatment Advances for Lupus
The painstaking basic and animal research of the past 15 years to unravel the molecular pathways involved in lupus are finally showing tangible rewards. In late 2010, an FDA committee recommended approval of the first new drug for lupus in 50 years--belimumab (Benylsta). The full FDA is expected to deliver its decision this spring. The drug, developed by Human Genome Sciences, is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-Lymphocyte stimulator (BLyS), also known as B cell activation factor of the TNF family (BAFF). Not surprisingly, there were several presentations of data from late-stage trials on belimumab. Among them:
- Long-term safety and efficacy. Most clinical trials last a few weeks, a year or two at the most. But many adverse effects from immune-suppressing drugs like the new biologics under investigation might take years to appear. That’s what makes the presentation of safety data from patients receiving belimumab for 5 years so important. The data came from patients who participated in the original Phase 3 trials, but who continued on the drug (or started on it if they’d been in the placebo arm) when the trial ended.
Overall, 296 patients enrolled in the trial, with about 3% to 9% dropping out each year. Adverse events either remained the same or declined over the 5 years. The frequency of one new BILAG A or 2 BILAG B flares decreased from 30% over the first 6 months of treatment to 11% in the final 6 months of the 5-year follow up. Meanwhile, the frequency of SS Flare Index (SFI) flares declined from 72% (13% severe) in the first 6 months to 22% at the final 6 months (1% severe). Autoantibody levels also declined.iii
Lead investigator Joan Merrill, MD, who directs the Clinical Pharmacology Research Program at Oklahoma Medical Research Institute in Oklahoma City, noted that the positive effects couldbe related to the patients who dropped out if they had more flares . But what’s really important, she said, is that after 5 years, 45% of patients were still returning for treatment, meaning they felt the benefits of the drug outweighed any negatives.
- Less steroid medication required with belimumab. Significantly more participants in the Phase 3 belimumab trials BLISS-52 and BLISS-76 who received the medication were able to taper off their corticosteroid medication as their condition improved more than those receiving placebo.iv
Key point: Long-term use of corticosteroids increases the risk of severe side effects, including osteoporosis, diabetes, and cataracts. Reducing steroid dosages could provide significant benefits.
- Pooled analysis shows benefits. A pooled analysis of data from both Phase 3 clinical trials found that participants receiving the drug demonstrated statistically significant improvements in several disease markers. The pooled group included 1,684 people (94% women) with SLE. Those receiving the higher dose of belimumab (10 mg/kg) had lower rates of disease activity, longer time to new flares, longer response, and reduced prednisone use compared to patients receiving placebo.v
- Benefits of immunization continue. A pooled analysis from both Phase 3 trials showed that vaccine protection against pneumonia, tetanus, and influenza in patients with lupus remained after belimumab treatment.vi
Key point: Vaccines stimulate B cells to create antibodies against certain pathogens so if you get infected with those viruses, your immune system can spring to action quickly, eliminating the threat before you get sick. Although belimumab works by reducing certain B -cell activity, it did not cause a significant reduction in pre-existing antibodies to the pneumococcal and tetanus vaccines, and had no effect on antibodies to the influenza vaccine. In other words, major parts of the immune system remain functional during belimumab treatment.
- Belimumab and disease biomarkers. In addition to the clinical benefits of belimumab in patients with lupus, the drug also showed significant effects on biomarkers of the disease, including B and T cells. Significantly more patients receiving belimumab during the drug’s Phase 3 trials converted from positive levels of key autoantibodies (anti-dsDNA, anti-Sm, anti-ribosomal P, and aCL-IgG), than those receiving placebo.vii They also had far higher levels of complement 3 and 4, a sign of immune health.
Key point: Belimumab appears to attack the underlying immune pathology of the disease, providing actual disease-specific benefit, not just symptom relief.
Positive Results in Phase 2 Epratuzumab Trial
Epratuzumab is a humanized monoclonal antibody under investigation by Immunomedics and UCB. The compound targets CD22 proteins expressed on mature B cells.
Researchers presented two studies during the meeting, both from the Phase 2 EMBLEM™ study. In an oral presentation, principal investigator Daniel J. Wallace, MD, a rheumatologist in private practice in Los Angeles, California, described the results seen in 227 people with moderate/severe lupus. Patients received 1 of 6 intravenous regimens for 12 weeks: 5 with different doses of epratuzumab; one with placebo. All continued on their regular medication.
After 8 weeks, scores in indexes used to measure disease activity were better in all patients who received the drug. They were significantly better in those that received the 600 mg dose every week for 4 weeks, and the group that received the 1200-mg dose every other week (37.8% s 35.1% vs 21.1%). Improvements continued over the final 4 weeks, with 45.9% of patients in the 600-mg group and 40.5% of those in the 1200-mg group demonstrating significant improvement compared to 21.1% in the placebo group. In addition, by week 12, 37.9% in the 600-mg group and 35.3% of patients in the 1200-mg demonstrated improvement of all body systems compared to 22.2% in the placebo group.viii
None of the patients in the treatment groups required additional medication and the rate of serious side effects and reactions to the infusion were similar in the treatment and placebo groups.
A poster presentation reported on an evaluation of disease status in 112 patients receiving the 600- or 1,200-mg doses. The analysis focused on the BILAG index, which assesses disease activity in various organs in the body. It found rates of response in those receiving the drug were twice those of the placebo group, with particular improvement in the cardiorespiratory and neuropsychiatric systems.ix
Next step: The positive results from the Phase 2 trial means that epratuzumab is moving into Phase 3 clinical trials, with the first patient enrolled in the trial in December. The FDA has put the drug on a fast track approval process designed to facilitate its development and expedite its review once the application is submitted.
Looking Down the Road: A Look at New Therapies Under Investigation for Lupus
What’s next in lupus therapies? Here’s a look at two compounds that are still in the very early stages of investigation as lupus treatments. These reports are based on the Phase 1 trials, the first phase of clinical testing, in which the safety, tolerability, dosing, and actions in the body, or pharmacodynamics, of a drug are evaluated.
AMG 557. This compound is being developed by Amgen, in Thousand Oaks, Calif. This fully humanized monoclonal antibody binds to a B7-related protein that stimulates T cell responses.x In a study presented at the ACR meeting, researchers described a new blood test the company developed that should help them determine the most appropriate dosing in future clinical trials.
What’s next: A Phase 1 trial continues in humans.
SBI-087. This compound is a humanized SMIP™ (Small Modular ImmunoPharmaceutical) biologic being developed by Pfizer. The compound is directed against the CD20 antigen located on B cells.xi Although its target is similar to that of rituximab (Rituxan®), which has shown disappointing results in clinical trials in lupus, SBI-087 is structurally different from rituximab. It is also being developed for subcutaneous administration (i.e., a shot under the skin), which would avoid the need for intravenous (IV) infusions and premedication with IV corticosteroids that is required with rituximab.
Researchers presented the results of a phase 1 study in 24 healthy individuals, 23 of them women. The results showed B cell depletion in patients who received the drug both intravenously and subcutaneously with few adverse events. One person experienced flu-like side effects; two had chills; and two had some flushing on the day of the injection.
What’s next: The company is recruiting participants for a phase 2 trial, with results expected in 2011. You can learn more about the trial at www.clinicaltrials.gov, or ask your doctor if you might be eligible for inclusion.
More information about lupus and treatment advances can be found by visiting www.lupusresearch.org.
The 2010 American College of Rheumatology Meeting Special Report was made possible in part by generous support from Biogen Idec, Genentech and Johnson & Johnson.
©2010 Alliance for Lupus Research. All Rights Reserved.
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i Bingham CO, et al. Citrullination and Peptidylarginine Deiminase (PAD) Expression Is Detected in the Oral Mucosa and Periodontium in the Absence of Rheumatoid Arthritis.
ii Scher JU, et al. Characteristic Oral and Intestinal Microbiota in Rheumatoid Arthritis (RA): A Trigger for Autoimmunity?
iii Merrill JT, et al. Five-Year Experience with Belimumab, a BLyS-Specific Inhibitor, in Patients with Systemic Lupus Erythematosus (SLE).
iv Vollenhoven RF, et al. Belimumab, a BLyS-Specific Inhibitor, Reduced Corticosteroid Use in Patients with Active SLE: Results from the Phase 3 BLISS-52 and -76 Studies.
v Petri MA, et al. Belimumab, a BLyS-Specific Inhibitor, Reduced Disease Activity, Flares, and Prednisone Use in Patients with Seropositive SLE: Combined Efficacy Results from the Phase 3 BLISS-52 and -76 Studies.
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vii Stohl W. Belimumab, a BLyS-Specific Inhibitor, Significantly Reduced Autoantibodies, Normalized Low Complement, and Reduced Selected B-Cell Populations in Patients with Seropositive Systemic Lupus Erythematosus (SLE): The Phase 3 BLISS Studies.
viii Wallace DJ, et al. Epratuzumab Demonstrates Clinically Meaningful Improvements in Patients with Moderate to Severe Systemic Lupus Erythematosus (SLE): Results from EMBLEM™, a Phase IIb Study.
ix Kalunian KC, et al. BILAG-Measured Improvement in Moderately and Severely Affected Body Systems in Patients with Systemic Lupus Erythematosus (SLE) by Epratuzumab: Results from EMBLEM™, a Phase IIb Study.
x Sullivan BA, et al. A Flow Cytometric Receptor Occupancy Assay Demonstrates Dose-Dependent Blockade of B7RP-1 by AMG 557 on Circulating B Cells from SLE Subjects.
xi Fleischmann RM. Evidence of Peripheral B Cell Depletion in Subjects with Controlled Systemic Lupus Erythematosus (SLE) Following Subcutaneous Administration of SBI-087.
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xvi Izmirly PM, et al. Hydroxychloroquine and Prevention of Anti-SSA/Ro Associated Cardiac Disease in Mothers with a Previous Child with Neonatal Lupus