Human Genome Sciences and GlaxoSmithKline Announce Topline 76-Week Results of Phase 3 Trial of BENLYSTA in Systemic Lupus Erythematosus
It is difficult to imagine a drug with such weak results to be a multibillion dollar drug. Someone help us. It appears that the primary endpoint of this trial was the composite of 3 endpoints that we have known all along. What I see from this data is the this Selena Sledai score is the endpoint that seemed to change most significantly. The problem is that I think that is the least clinically meaningful endpoint. Can someone confirm or deny that statement? I am curious
Companies:Human Genome Sciences Inc.
Press Release Source: Human Genome Sciences, Inc. On Tuesday April 20, 2010, 7:00 am EDT
ROCKVILLE, Md. & LONDON--(BUSINESS WIRE)--Human Genome Sciences, Inc. (Nasdaq: HGSI - News) and GlaxoSmithKline PLC (GSK) today announced topline secondary endpoints from BLISS-76, the second of two pivotal Phase 3 trials of BENLYSTA™ (belimumab) in seropositive patients with systemic lupus erythematosus (SLE). BENLYSTA 10 mg/kg already met its primary efficacy endpoint at Week 52 in both BLISS-52 and BLISS-76, as announced in July and November 2009.
At Week 76 in the BLISS-76 study, belimumab plus standard of care showed higher response rates compared with placebo plus standard of care as measured by the SLE Responder Index; however, this secondary endpoint did not reach statistical significance. Study results also showed that belimumab continued to be generally well tolerated, as demonstrated by a similar rate of discontinuations due to adverse events across treatment groups, with overall adverse event rates comparable between belimumab and placebo treatment groups.
“A positive overall picture has emerged from our pivotal Phase 3 studies of BENLYSTA, including its achievement of statistical significance on the primary efficacy endpoint at Week 52 with a favorable safety profile in both BLISS-52 and BLISS-76,” said H. Thomas Watkins, President and Chief Executive Officer, HGS. “We view the results of these studies as strongly supportive of our view that BENLYSTA has the potential to become the first new approved drug in more than 50 years for people living with systemic lupus.”
Carlo Russo, M.D., Senior Vice President, Biopharm Development, GSK, said, “Based on the totality of data in BLISS-52 and BLISS-76, we believe that belimumab could deliver a significant therapeutic option for patients with lupus, a chronic condition which has a devastating effect on the lives of patients living with the disease.”
The data from the BLISS-76 study were previously analyzed after 52 weeks in accord with the study protocol, in support of a potential Biologics License Application in the United States and Marketing Authorization Applications in Europe and other regions. The primary efficacy endpoints in both pivotal Phase 3 studies of belimumab, BLISS-52 and BLISS-76, were the patient response rates at Week 52 as measured by the SLE Responder Index. BLISS-76 then continued for an additional 24 weeks. Belimumab is an investigational drug and the first in a new class of drugs called BLyS-specific inhibitors. Belimumab is being developed by HGS and GSK under a co-development and commercialization agreement entered into in 2006.
Key Findings from BLISS-76
“These new data from BLISS-76 provide additional evidence of the beneficial effect of belimumab despite not reaching statistical significance on the secondary endpoint. The results of our Phase 3 trials support a potentially important role for belimumab added to standard of care for the treatment of seropositive patients with systemic lupus,” said David C. Stump, M.D., Executive Vice President, Research and Development, HGS. “We and GSK are working together to complete and submit regulatory applications for belimumab in the United States and Europe in the second quarter of this year. We look forward to the full presentation of BLISS-76 52-week and 76-week results at appropriate scientific meetings later this year.”
Based on an intention-to-treat (ITT) analysis, patient response rates for belimumab plus standard of care versus placebo plus standard of care, as measured by the SLE Responder Index (SRI) at Week 76, were: 38.5% for 10 mg/kg belimumab, 39.1% for 1 mg/kg belimumab, and 32.4% for placebo (p=0.13 and p=0.11 for 10 mg/kg and 1 mg/kg belimumab, respectively vs. placebo). The SRI defines patient response as an improvement in SELENA SLEDAI score of 4 points or greater, with no clinically significant BILAG worsening and no clinically significant worsening in Physician’s Global Assessment.
Topline Week 76 results currently available for secondary endpoints include:
The proportion of patients with a reduction in SELENA SLEDAI score of at least 4 points was 41.4% for belimumab 10 mg/kg, 42.1% for belimumab 1 mg/kg, and 33.8% for placebo (p=0.066 and p=0.049 for belimumab 10 mg/kg and 1 mg/kg, respectively vs. placebo). Who cares about reduction in Selena Sledai score
Mean improvement from baseline in Physician’s Global Assessment (PGA) was 0.51 for belimumab 10 mg/kg, 0.53 for belimumab 1 mg/kg, and 0.49 for placebo (p=0.21 for both belimumab 10 mg/kg and for 1 mg/kg, vs. placebo). this is the important score
At entry into the BLISS-76 study, approximately 46% of patients were receiving steroids at a prednisone-equivalent dose of at least 7.5 mg per day. Among these patients, the percentage of patients who had their average steroid dose reduced by at least 25% from baseline to 7.5 mg per day or less during the last 12 weeks of the study (Week 64 through Week 76) was 24.2% for belimumab 10 mg/kg, 26.9% for belimumab 1 mg/kg, and 17.5%% for placebo (p=0.27 and p=0.07 for belimumab 10 mg/kg and 1 mg/kg, respectively, vs. placebo. Whoopdi do
In BLISS-76 at Week 76, the mean percent reduction in SELENA SLEDAI score was 37.0% for belimumab 10 mg/kg, 36.1% for belimumab 1 mg/kg, and 27.8% for placebo (p=0.01 and p=0.03 for 10mg/kg belimumab and 1 mg/kg belimumab, respectively vs. placebo). At Week 52, the reduction in SELENA SLEDAI was 36.0% for belimumab 10 mg/kg, 33.9% for belimumab 1 mg/kg, and 26% for the placebo (p<0.01 and p=0.04 for 10 mg/kg and 1 mg/kg belimumab, respectively vs. placebo).
Biomarker responses have been studied throughout the program and belimumab consistently demonstrated a beneficial effect on anti double-stranded DNA and complement with both doses.
Additional analyses are ongoing, including post-hoc analyses, to further understand these data.
In BLISS-76 through 76 weeks, belimumab was generally well tolerated, with rates of overall adverse events, serious and/or severe adverse events, all infections, serious and/or severe infections, and discontinuations due to adverse events comparable between treatment groups receiving belimumab plus standard of care and the treatment group receiving placebo plus standard of care. Serious and/or severe adverse events were reported in 29.0% of patients on belimumab and 26.2% of patients on placebo. Infections were reported in 74.3% of patients on belimumab and 69.1% of patients on placebo. Serious and/or severe infections were reported in 4.2% of patients on belimumab and 3.6% of patients on placebo. Serious and/or severe infusion reactions were reported in 1.1% of patients on belimumab and 0.7% of patients on placebo. Discontinuations due to adverse events were 7.5% in the belimumab treatment groups and 8.4% in the placebo treatment group. One new malignancy was reported since the Week 52 data were announced, with a total 2, 4, and 1 subjects in the belimumab 10 mg/kg, belimumab 1 mg/kg and placebo groups, respectively. No additional deaths were reported since the Week 52 data were announced, with a total of three deaths in the study: 1, 2, and 0 reported in the belimumab 10 mg/kg, belimumab 1 mg/kg and placebo groups, respectively. Malignancies and deaths are nothing to sneeze at when you have such a weak effect. I do not get it.About the Belimumab Phase 3 Development Program
The Phase 3 development program for belimumab included two double-blind, placebo-controlled, multi-center Phase 3 superiority trials – BLISS-52 and BLISS-76 – to evaluate the efficacy and safety of belimumab plus standard of care, versus placebo plus standard of care, in seropositive (HEp-2 ANA = 1:80 and/or anti-dsDNA = 30 IU/mL) patients with SLE. Both BLISS-52 and BLISS-76 have now been completed. This is the largest clinical trial program ever conducted in lupus patients. BLISS-52 randomized and treated 865 patients at 90 clinical sites in 13 countries, primarily in Asia, South America and Eastern Europe. BLISS-76 randomized and treated 819 patients at 136 clinical sites in 19 countries, primarily in North America and Europe. The design of the two trials was similar, but the duration of therapy in the two studies was different – 52 weeks for BLISS-52 and 76 weeks for BLISS-76. Data from BLISS-76 were analyzed after 52 weeks in support of a potential Biologics License Application in the United States and Marketing Authorization Applications in Europe and other regions. HGS designed the Phase 3 program for belimumab in collaboration with GSK and leading international SLE experts, and the program is being conducted under a Special Protocol Assessment agreement with FDA.
The primary efficacy endpoint of BLISS-52 and BLISS-76 was the patient response rate at Week 52 as measured by the SLE Responder Index, which is defined by: (1) a reduction from baseline of at least 4 points on the SELENA SLEDAI disease activity scale (which indicates a clinically important reduction in SLE disease activity); (2) no worsening of disease as measured by the Physician’s Global Assessment (worsening defined as an increase of 0.30 points or more from baseline); (3) no new BILAG A organ domain score (which indicates a severe flare of lupus disease activity) and no more than one new BILAG B organ domain score (which indicates a moderate flare of disease activity). Analysis for the primary endpoint is based on intention-to-treat and adjusted for baseline stratification factors, including SELENA SLEDAI score, proteinuria and race. The patient response rate at Week 76 as measured by the SLE Responder Index was a protocol-specified major secondary endpoint of the BLISS-76 study.
In each of the two Phase 3 trials, patients were randomized to one of three treatment groups: 10 mg/kg belimumab (BLISS-52, n=290; BLISS-76, n=273), 1 mg/kg belimumab (BLISS-52, n=288; BLISS-76, n=271), or placebo (BLISS-52, n=287; BLISS-76, n=275). Patients were dosed intravenously on Days 0, 14 and 28, then every 28 days thereafter for the duration of the study. All patients received standard of care therapy in addition to the study medication. Safety was reviewed by an independent Data Monitoring Committee throughout both studies.
