NEW TREATMENT FOR LUPUS

October 26, 2009 (Philadelphia, Pennsylvania) — Positive 1-year results from the BLISS-52 study show that belimumab (Benlysta) achieved clinically meaningful improvements and was safe in patients with systemic lupus erythematosus (SLE). "Belimumab represents the first new treatment for SLE in decades," said Sandra Navarra, MD, from the University of Santo Tomas Hospital in Manila, Philippines, who presented results here at a late-breaking session of American College of Rheumatology (ACR) 2009.

It has been more than 50 years since the US Food and Drug Administration (FDA) has approved a new medication for lupus. Belimumab inhibits the B-lymphocyte stimulator and presumably reduces autoantibody levels in SLE.

Belimumab significantly reduced disease activity, disease flares, and use of steroids, and improved fatigue and quality of life, compared with placebo. BLISS-52 is the first of 2 pivotal phase 3 trials in SLE. If results of the second phase 3 trial (BLISS-76) are positive when released in November 2009, the drug will be submitted for FDA approval in the first half of 2010.

The double-blind placebo-controlled BLISS-52 study involved 865 patients with active SLE who were randomized to 1 of 3 groups: placebo (n = 286), belimumab 1 mg/kg (n = 288), or belimumab 10/mg/kg (n = 290). Patients in all 3 groups also received standard of care, including prednisone (96%) and immunosuppressants (42%). Baseline demographic and disease characteristics were similar in the 3 groups. Average age was about 35 years, 95% of the study population was female, and Asians comprised 36% of the population.

At week 52, belimumab achieved a clinically and statistically significant improvement in the primary composite end point, called the SLE Responder Index (SRI) (a 4-point improvement on the SELENA SLE Disease Activity Index [SLEDAI], plus no new British Isles Lupus Assessment Group [BILAG] 1A or 2B flares, plus no worsening on Physician Global Assessment [PGA]).

Both doses of belimumab achieved a significant improvement on SRI, compared with placebo; response rates were 57.6% for belimumab 10 mg/kg plus standard of care; 51.4% for belimumab 1 mg/kg plus standard of care; and 43.6% for placebo plus standard of care (P = .0006 and P = .013 for the 10 and 1 mg/kg doses, respectively).

Improvement was sustained for both doses of belimumab from week 24 and week 28, respectively, through week 52 (P < .05 for both treatment groups compared with placebo). The improvement was consistent across subgroups and ethnicities, Dr. Navarra said. A dose-response trend was seen, with more responses in the higher-dose group.

Time to severe flares and moderate flares was delayed with belimumab. Median time to first SLE flare was 119 days for belimumab 10 mg/kg, 126 days for belimumab 1 mg/kg, and 84 days for placebo (P = .0036 and P = .0026 for the 2 doses, respectively, vs placebo). The risk of having a severe flare was reduced by 43% and 24% in the 2 groups, respectively (P = .0055 and P = .01342, respectively, vs placebo). The risk of experiencing a severe flare (BILAG A) or more than 1 moderate flare (BILAG B) was reduced by 42% and 13% in the 2 treatment groups, respectively (P = .0016 and P = .3722, respectively, vs placebo).

Belimumab 10 mg/kg significantly improved PGA at week 52 (P = .0003), and both doses improved quality of life results as reflected by the SF-36 Physical Component Summary (P = .02 and P = .025 for the 1 and 10 mg/kg doses, respectively, vs placebo).

Belimumab was also prednisone-sparing, with a higher percentage of patients who reduced their steroid drugs by at least 50% at week 52 (27.7% for the 10 mg/kg group, 23% for the 1 mg/kg group, and 17.7% for the placebo group).

Fatigue and quality of life were also better in the 10 mg/kg group than in the placebo group within 4 to 8 weeks of study initiation and, by week 52, both belimumab groups achieved significant improvement in health-related quality of life on the FACIT-Fatigue Scale (P < .05 for both doses vs placebo).

Belimumab was generally well tolerated, with comparable rates of adverse events, serious adverse events, infections, and deaths for all 3 groups. Serious infections occurred in 6.1% of the belimumab-treated patients and 5.9% of the placebo-treated patients. The most common adverse events included headache, arthralgia, upper respiratory tract infections, urinary tract infections, and influenza, and these were comparable between groups. No malignancies were reported.

Results Called a Major Achievement

Zahi Touma, MD, from the University of Toronto in Ontario, called this trial a major achievement. "Other trials of biologic agents for treatment of lupus have failed. Finally, we have a study that shows a drug that works, with positive results in lupus patients. This is very important. Nothing has been approved by the FDA since cyclophosphamide," he said.

Dr. Touma believes that the explanation for the failure of other drug trials is the lack of a good primary outcome measure to assess disease activity in SLE. "The BLISS-52 investigators generated a novel outcome measure — the SLE Responder Index, which is a composite measure of SLEDAI, BILAG, and quality-of-life measures. It's too early to validate this measure, but the composite end point allowed the investigators to demonstrate improvement," he said.

Dr. Touma is developing an instrument called the SRI-50, which shows at least a 50% improvement in SLE, similar to the ACR50 for rheumatoid arthritis.

The BLISS-52 study was funded by Human Genome Sciences and GlaxoSmithKline. Dr. Navarra reports financial ties with Pfizer, Merck, Roche, Wyeth, Human Genome Sciences, and Schering-Plough. Dr. Touma has disclosed no relevant financial relationships.

American College of Rheumatology (ACR) 2009: Late-Breaking Abstract 1. Presented October 20, 2009.