Results tagged “SLE” from Pathophilia

Another phase 3 trial of belimumab (Benlysta; Human Genome Sciences/GSK) in patients with systemic lupus erythematosus (SLE) has met its primary endpoint, according to a company press release. These data complement results of a previous phase 3 study, BLISS-52, in which the mAb (when compared with placebo) significantly improved disease activity* at 1 year.

Combined trial data will undoubtedly be used to support a biologics license application (BLA) to the FDA. Neither phase 3 study, however, has been published in a peer-reviewed journal.

In the placebo-controlled BLISS-76, belimumab 10 mg/kg significantly improved the SLE Responder Index** at 52 weeks (43.2% vs 33.8% with placebo; P = .021). However, the 1-mg/kg dose was not associated with statistically significant improvement. Outcomes of several secondary endpoints (eg, Physician's Global Assessment, reduction of corticosteroid dosage, SF-36 Physical Component Summary) also did not reach statistical significance.

Serious or severe infections were observed in 7.2% of patients who received belimumab and 8.0% of patients who received placebo. Rates of serious or severe infusion reactions were 1.1% with belimumab and 0.7% with placebo. Rates of discontinuation due to adverse events were 7.2% with belimumab and 7.6% with placebo. A handful of malignancies and deaths were also reported.

A comparison of the BLISS-52 and BLISS-76 results is provided here:

Outcome	BLISS-52	BLISS-76
Primary endpoint (52 weeks)	√ (1 and 10 mg/kg)	√ (10 mg/kg only)
Belimumab 10 mg/kg, %	57.6	43.2
Belimumab 1 mg/kg, %	51.7	40.6 (NS)
Placebo, %	43.6	33.8
Secondary endpoints
Reduction of SELENA SLEDAI score	√ (1 and 10 mg/kg)	√ (10 mg/kg only)
Belimumab 10 mg/kg, %	58.3	46.9
Belimumab 1 mg/kg, %	53.1	42.8 (NS)
Placebo, %	46.0	35.6
Improvement in PGA	√ (10 mg/kg only)	NS
Reduction of corticosteroid dosage (≥25% to ≤7.5 mg/d)	√ (1 and 10 mg/kg)	NS
SF-36 Physical Component Summary	NS	NS
Adverse events
Serious infections
Belimumab, %	6.1	7.2
Placebo, %	5.9	8.0
Infusion reactions
Belimumab, %	N/A	1.1
Placebo, %	N/A	0.7
Discontinuation
Belimumab, %	N/A	7.2
Placebo, %	N/A	7.6

Per protocol, BLISS-76 will continue for another 24 weeks, and according to the CEO of HGS, a BLA will likely be submitted to the FDA in the first half of next year.

Belimumab is a human mAb that inhibits the activity of B-lymphocyte stimulator (BLyS), which promotes the survival of (auto)antibody-producing B cells. The drug was discovered by HGS, which entered into a codevelopment and comarketing agreement with GSK in 2006. Other anti-B-cell therapies in clinical development for SLE include epratuzumab (Immunomedics) and ocrelizumab (Genentech, Biogen), aka Son of Rituxan.

A recent great hope for SLE, mycophenolate mofetil (CellCept; Roche) died a death of noninferiority after it performed no better than cyclophosphamide in the induction treatment of lupus nephritis. Rituximab (Rituxan) also flopped in a recent phase 3 study of lupus nephritis.

According to the Lupus Foundation of America, roughly 1.5 million Americans and more than 5 million people worldwide have lupus.

mAb = monoclonal antibody; N/A = not available; NS = not significant.

* Measured by using a combination of 4 recognized scales: a reduction of the SELENA SLEDAI score by at least 4 points from baseline; no worsening per the Physician's Global Assessment (PGA); no new BILAG-A organ domain score; and no more than 1 new BILAG-B organ domain score.

** The SLE Responder Index defines patient response as an improvement in the SELENA SLEDAI score by at least 4 points and no clinically significant decline per the BILAG score or PGA.

Pharma biz sources

are buzzing with the PR news that belimumab (Benlysta*; GSK, Human Genome Sciences) improved the disease activity of systemic lupus erythematosus (SLE) in a 1-year, 2-dose, placebo-controlled, phase 3 study (BLISS-52). The mAb also enabled the reduction of the corticosteroid dosage.

The primary endpoint of the study, which was met with belimumab treatment, was a combination of 4 recognized measurements of SLE activity.** The reported patient response rates were 57.6% for belimumab 10 mg/kg; 51.7% for belimumab 1 mg/kg, and 43.6% for placebo (respective P values = .0006 and .011, vs placebo). All patients received "standard of care." Individual secondary measures were also consistent with the statistically significant primary-endpoint results.

The rates of serious infections were 6.1% and 5.9% with belimumab and placebo, respectively, and rates of common adverse advents—headache, arthralgia, URI, UTI, and influenza—were also comparable between the 2 treatments. An important footnote in this relatively short-term study: no observed malignancies.

Results of a longer-term, placebo-controlled, phase 3 study with belimumab in SLE, BLISS-76, are expected in November (although the combined primary endpoint will be assessed at 52 weeks). As in BLISS-52, 2 belimumab dosages, 1 and 10 mg/kg, have been randomly assigned. Positive results will undoubtedly bolster a biologics license application to the FDA.

Belimumab is a human mAb that inhibits the activity of B-lymphocyte stimulator (BLyS), which promotes the survival of (auto)antibody-producing B cells. The drug was discovered by Human Genome Sciences, which entered into a codevelopment and comarketing agreement with GSK 3 years ago. Other anti-B-cell therapies in clinical development for SLE include rituximab (Rituxan; Genentech), epratuzumab (Immunomedics), and ocrelizumab (Genentech, Biogen) aka Son of Rituxan.

The most recent great hope for SLE, mycophenolate mofetil (CellCept; Roche) died a death of noninferiority, after it performed no better than cyclophosphamide for the induction treatment of lupus nephritis.

According to the Lupus Foundation of America, roughly 1.5 million Americans and more than 5 million people in the world have lupus.

mAb = monoclonal antibody; URI = upper respiratory tract infection; UTI = urinary tract infection.

* Formerly LymphStat-B.

** A reduction from baseline in the SELENA SLEDAI score of at least 4 points; no worsening in Physician Global Assessment (PGA); no new BILAG-A organ domain score; and no more than one new BILAG-B organ domain score from baseline.

The monoclonal antibody Rituxan (rituximab) is not clinically effective in patients with systemic lupus erythematosus (SLE) who do not have lupus nephritis, according to data from a 52-week phase 2/3 study. The results were announced today by the drug's US comarketers, Genentech and Biogen Idec. A phase 3 study of Rituxan in lupus nephritis, which affects approximately one third of SLE patients, is currently recruiting subjects.

In today's reported study, 257 patients with moderate-to-severe SLE received 2 infusions (15 days apart) of randomized Rituxan or placebo in a double-blind fashion, in addition to background prednisone therapy. Patients were retreated at 6 months and evaluated every 4 weeks. At 1 year, the proportions of patients who reached the primary endpoint—a major or partial clinical response per the BILAG index score—were not statistically different between the 2 treatment groups. (Percentages were not provided in the companies' press release.) The assessment of 6 secondary endpoints also failed to show statistical treatment differences.

Current long-time therapies for SLE, which may affect more than 1.5 million Americans according to the Lupus Foundation of America, include corticosteroids; the corticosteroid-sparing agents methotrexate, cyclophosphamide, and azathioprine; and the anti-organ-rejection agent mycophenolate mofetil (CellCept; Roche). Given the potential roles of B cells in the pathogenesis of SLE, including antigen presentation and the production of autoantibodies, the investigation of anti-B-cell therapies like Rituxan in SLE is mechanistically founded. Another B-cell targeted therapy, which is entering phase 3 development in SLE, is belimumab (LymphoStat B)—a fully human monoclonal antibody that inhibits the cytokine B-lymphocyte stimulator (BLyS).

BILAG = British Isles Lupus Assessment Group.