EULAR: BLISS-76 Yields Positive Data on Belimumab in SLE

The complete set of data from the BLISS-76 study of belimumab in seropositive patients with systemic lupus erythematosus supports the efficacy of the B-lymphocyte stimulator inhibitor as a treatment for SLE, and provides encouraging safety data, according to Dr. Ronald van Vollenhoven, speaking to a standing-room-only session at the European Congress of Rheumatology on June 16.

In what was the first full presentation of the BLISS-76 (Belimumab in Subjects With Systemic Lupus Erythematosus–76) data at a scientific meeting, Dr. van Vollenhoven, a rheumatologist at the Karolinska Institute in Stockholm, discussed how belimumab plus standard therapy was effective in reducing disease activity and severe flares, as well as achieving a higher response rate, compared with standard care alone. The treatment and placebo groups had similar adverse events.

Two doses were studied: 1 mg/kg and 10 mg/kg administered intravenously once every 4 weeks. Efficacy according to the trial’s primary outcome was seen with the higher dose. Most of the trial’s secondary end points either achieved significance for at least one of the dosages vs. placebo, or showed trends in the right direction, he added.

Based on these data as well as those from the previously reported BLISS-52 trial with the same drug, “the clear conclusion is that belimumab is efficacious,” Dr. van Vollenhoven said in an interview. Although the magnitude of the differences in response rates between active drug and placebo could have been larger, BLISS-76 was a successful study, he noted.

Among the unanswered questions that may need to be explored further is whether doses between 1 mg/kg and 10 mg/kg might also be efficacious, he added. Additional analyses are ongoing to determine if any group of patients is more likely to benefit from the drug.

Human Genome Sciences Inc. (HGS) and GlaxoSmithKline (GSK) are developing belimumab, which inhibits the biological activity of B-lymphocyte stimulator (BLyS), as a treatment for SLE. HGS has filed for approval for the 10-mg/kg dose in the United States.

BLISS-76, a 76-week, double-blind, international study that compared the two belimumab doses vs. placebo in 819 seropositive patients with SLE, is one of the two pivotal studies to evaluate the safety and efficacy of belimumab in this population. Patients in the study had to have an antinuclear antibody ratio of at least 1:80 and/or anti–double-stranded DNA of at least 30 IU/mL, with a SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus–National Assessment SLE Disease Activity Index) score of at least 6 on stable therapy.

Patients had had the disease for a mean of 7.5 years, 63% used antimalarials, 76% used steroids, and 56% used immunosuppressants. Patients received standard-of-care treatment and were randomized to receive either IV belimumab at days 0, 14, 28, and then every 28 days for 72 weeks, or placebo.

Some of the top-line BLISS-76 results were reported in November 2009 by HGS and GSK. At that time, the developers announced that the study had met its primary end point, which was the patient response rate as measured by the SLE Responder Index (SRI) at 52 weeks. In all, 43% of those on the higher dose and 41% of those on the lower dose met this end point, compared with 34% of those on placebo. The difference between the higher dose and placebo was statistically significant.

According to the SRI, which was developed in collaboration with the Food and Drug Administration, a patient response is defined as an improvement in the SELENA-SLEDAI score of 4 points or greater, with no clinically significant worsening on the either the BILAG (British Isles Lupus Assessment Group) index or the Physician’s Global Assessment (PGA).

Secondary end points included components of the primary end point. In all, 47% of those on the higher dose and 43% of those on the lower dose had at least a 4-point reduction in the SELENA-SLEDAI score at 52 weeks, compared with 36% among placebo. The difference between the higher dose and placebo was significant.

The proportion of patients who did not have a worsening in the PGA score greater than 0.3 points was 69% and 73% in the 10-mg/kg and 1-mg/kg groups, respectively, compared with 63% in the placebo group. The difference between the 1-mg/kg dose and placebo was significant. There were no statistically significant improvements in PGA or in steroid dose reductions among the two belimumab-treated groups, compared with placebo, according to Dr. van Vollenhoven.

In addition, 69% of those on the 10-mg/kg dose, 75% of those on the 1-mg/kg dose, and 65% of those on placebo had no new BILAG grade A or B scores. The difference between the 1-mg/kg dose and placebo was significant.

There were no significant differences between the three groups in the risk of having a flare, or in the median time to the first flare, based on the SELENA Flare Index (SFI). But the proportion of patients who had a severe SFI flare was lower in the two treatment groups (18% of those on the higher dose and 16% of those on the lower dose, compared with 24% of those on placebo), he said, noting that the difference was significant between the 1-mg/kg and placebo groups.

Other secondary end points included the mean in SF-36 Physical Component Summary (PCS) scores from baseline to week 52, which increased by a mean of 3.4, 4.4 and 2.9, in the 10-mg/kg, 1-mg/kg and placebo groups, respectively. The difference was significant only between placebo and the 1-mg/kg dose. The change in the FACIT-F (Functional Assessment of Chronic Illness Therapy–Fatigue) score from baseline at 52 weeks increased by a mean of 4.6, 5.7, and 2.9 respectively, with the difference being significant between the 1-mg/kg dose and placebo, Dr. van Vollenhoven said. “These data are important in that they reflect patient-reported aspects of the disease, namely physical function and fatigue, which are of major importance in terms of quality of life,” Dr. van Vollenhoven said in the interview. “In fact, fatigue has been identified by lupus patients in our unit as their most important symptom.”

He added, “All these instruments are blunt, however. It’s like having an old radio with a lot of background noise.”

In the study, treatment was well tolerated, with similar rates of deaths, adverse events, serious adverse events, infections, and laboratory abnormalities in the three groups. There was a modest increase in serious or severe infusion reactions among those on belimumab, compared with those on placebo, he noted. The overall infusion reaction rate was 13%-15% in the two belimumab groups, compared with 10% in the placebo group; the rate of severe infusion reactions was 1.1% in the 10-mg/kg group and 0.4% in the 1-mg/kg and placebo groups. Thus, the clinical response to the 10-mg dose appeared to be more robust. However, we need to learn more in the future about refining doses.”

There were six malignancies in the study, one in a patient on placebo, and five in the belimumab-treated patients. The infection rate was 72% in the two belimumab groups, compared with 67% in the placebo group; the serious infection rate was 7% in the 10-mg group, 6% in the 1-mg/kg group, and 5% in the placebo group, Dr. van Vollenhoven said.

Dr. van Vollenhoven was an investigator in the BLISS-76 study and is a consultant to HGS and GSK; he also served on the BLISS-52 and BLISS-76 steering committees. Some of the investigators on this trial are HGS employees.

The complete set of data from the BLISS-76 study of belimumab in seropositive patients with systemic lupus erythematosus supports the efficacy of the B-lymphocyte stimulator inhibitor as a treatment for SLE, and provides encouraging safety data, according to Dr. Ronald van Vollenhoven, speaking to a standing-room-only session at the European Congress of Rheumatology on June 16.

In what was the first full presentation of the BLISS-76 (Belimumab in Subjects With Systemic Lupus Erythematosus–76) data at a scientific meeting, Dr. van Vollenhoven, a rheumatologist at the Karolinska Institute in Stockholm, discussed how belimumab plus standard therapy was effective in reducing disease activity and severe flares, as well as achieving a higher response rate, compared with standard care alone. The treatment and placebo groups had similar adverse events.

Two doses were studied: 1 mg/kg and 10 mg/kg administered intravenously once every 4 weeks. Efficacy according to the trial’s primary outcome was seen with the higher dose. Most of the trial’s secondary end points either achieved significance for at least one of the dosages vs. placebo, or showed trends in the right direction, he added.

Based on these data as well as those from the previously reported BLISS-52 trial with the same drug, “the clear conclusion is that belimumab is efficacious,” Dr. van Vollenhoven said in an interview. Although the magnitude of the differences in response rates between active drug and placebo could have been larger, BLISS-76 was a successful study, he noted.

Among the unanswered questions that may need to be explored further is whether doses between 1 mg/kg and 10 mg/kg might also be efficacious, he added. Additional analyses are ongoing to determine if any group of patients is more likely to benefit from the drug.

Human Genome Sciences Inc. (HGS) and GlaxoSmithKline (GSK) are developing belimumab, which inhibits the biological activity of B-lymphocyte stimulator (BLyS), as a treatment for SLE. HGS has filed for approval for the 10-mg/kg dose in the United States.

BLISS-76, a 76-week, double-blind, international study that compared the two belimumab doses vs. placebo in 819 seropositive patients with SLE, is one of the two pivotal studies to evaluate the safety and efficacy of belimumab in this population. Patients in the study had to have an antinuclear antibody ratio of at least 1:80 and/or anti–double-stranded DNA of at least 30 IU/mL, with a SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus–National Assessment SLE Disease Activity Index) score of at least 6 on stable therapy.

Patients had had the disease for a mean of 7.5 years, 63% used antimalarials, 76% used steroids, and 56% used immunosuppressants. Patients received standard-of-care treatment and were randomized to receive either IV belimumab at days 0, 14, 28, and then every 28 days for 72 weeks, or placebo.

Some of the top-line BLISS-76 results were reported in November 2009 by HGS and GSK. At that time, the developers announced that the study had met its primary end point, which was the patient response rate as measured by the SLE Responder Index (SRI) at 52 weeks. In all, 43% of those on the higher dose and 41% of those on the lower dose met this end point, compared with 34% of those on placebo. The difference between the higher dose and placebo was statistically significant.

According to the SRI, which was developed in collaboration with the Food and Drug Administration, a patient response is defined as an improvement in the SELENA-SLEDAI score of 4 points or greater, with no clinically significant worsening on the either the BILAG (British Isles Lupus Assessment Group) index or the Physician’s Global Assessment (PGA).

Secondary end points included components of the primary end point. In all, 47% of those on the higher dose and 43% of those on the lower dose had at least a 4-point reduction in the SELENA-SLEDAI score at 52 weeks, compared with 36% among placebo. The difference between the higher dose and placebo was significant.

The proportion of patients who did not have a worsening in the PGA score greater than 0.3 points was 69% and 73% in the 10-mg/kg and 1-mg/kg groups, respectively, compared with 63% in the placebo group. The difference between the 1-mg/kg dose and placebo was significant. There were no statistically significant improvements in PGA or in steroid dose reductions among the two belimumab-treated groups, compared with placebo, according to Dr. van Vollenhoven.

In addition, 69% of those on the 10-mg/kg dose, 75% of those on the 1-mg/kg dose, and 65% of those on placebo had no new BILAG grade A or B scores. The difference between the 1-mg/kg dose and placebo was significant.

There were no significant differences between the three groups in the risk of having a flare, or in the median time to the first flare, based on the SELENA Flare Index (SFI). But the proportion of patients who had a severe SFI flare was lower in the two treatment groups (18% of those on the higher dose and 16% of those on the lower dose, compared with 24% of those on placebo), he said, noting that the difference was significant between the 1-mg/kg and placebo groups.

Other secondary end points included the mean in SF-36 Physical Component Summary (PCS) scores from baseline to week 52, which increased by a mean of 3.4, 4.4 and 2.9, in the 10-mg/kg, 1-mg/kg and placebo groups, respectively. The difference was significant only between placebo and the 1-mg/kg dose. The change in the FACIT-F (Functional Assessment of Chronic Illness Therapy–Fatigue) score from baseline at 52 weeks increased by a mean of 4.6, 5.7, and 2.9 respectively, with the difference being significant between the 1-mg/kg dose and placebo, Dr. van Vollenhoven said. “These data are important in that they reflect patient-reported aspects of the disease, namely physical function and fatigue, which are of major importance in terms of quality of life,” Dr. van Vollenhoven said in the interview. “In fact, fatigue has been identified by lupus patients in our unit as their most important symptom.”

He added, “All these instruments are blunt, however. It’s like having an old radio with a lot of background noise.”

In the study, treatment was well tolerated, with similar rates of deaths, adverse events, serious adverse events, infections, and laboratory abnormalities in the three groups. There was a modest increase in serious or severe infusion reactions among those on belimumab, compared with those on placebo, he noted. The overall infusion reaction rate was 13%-15% in the two belimumab groups, compared with 10% in the placebo group; the rate of severe infusion reactions was 1.1% in the 10-mg/kg group and 0.4% in the 1-mg/kg and placebo groups. Thus, the clinical response to the 10-mg dose appeared to be more robust. However, we need to learn more in the future about refining doses.”

There were six malignancies in the study, one in a patient on placebo, and five in the belimumab-treated patients. The infection rate was 72% in the two belimumab groups, compared with 67% in the placebo group; the serious infection rate was 7% in the 10-mg group, 6% in the 1-mg/kg group, and 5% in the placebo group, Dr. van Vollenhoven said.

Dr. van Vollenhoven was an investigator in the BLISS-76 study and is a consultant to HGS and GSK; he also served on the BLISS-52 and BLISS-76 steering committees. Some of the investigators on this trial are HGS employees.

The complete set of data from the BLISS-76 study of belimumab in seropositive patients with systemic lupus erythematosus supports the efficacy of the B-lymphocyte stimulator inhibitor as a treatment for SLE, and provides encouraging safety data, according to Dr. Ronald van Vollenhoven, speaking to a standing-room-only session at the European Congress of Rheumatology on June 16.

In what was the first full presentation of the BLISS-76 (Belimumab in Subjects With Systemic Lupus Erythematosus–76) data at a scientific meeting, Dr. van Vollenhoven, a rheumatologist at the Karolinska Institute in Stockholm, discussed how belimumab plus standard therapy was effective in reducing disease activity and severe flares, as well as achieving a higher response rate, compared with standard care alone. The treatment and placebo groups had similar adverse events.

Two doses were studied: 1 mg/kg and 10 mg/kg administered intravenously once every 4 weeks. Efficacy according to the trial’s primary outcome was seen with the higher dose. Most of the trial’s secondary end points either achieved significance for at least one of the dosages vs. placebo, or showed trends in the right direction, he added.

Based on these data as well as those from the previously reported BLISS-52 trial with the same drug, “the clear conclusion is that belimumab is efficacious,” Dr. van Vollenhoven said in an interview. Although the magnitude of the differences in response rates between active drug and placebo could have been larger, BLISS-76 was a successful study, he noted.

Among the unanswered questions that may need to be explored further is whether doses between 1 mg/kg and 10 mg/kg might also be efficacious, he added. Additional analyses are ongoing to determine if any group of patients is more likely to benefit from the drug.

Human Genome Sciences Inc. (HGS) and GlaxoSmithKline (GSK) are developing belimumab, which inhibits the biological activity of B-lymphocyte stimulator (BLyS), as a treatment for SLE. HGS has filed for approval for the 10-mg/kg dose in the United States.

BLISS-76, a 76-week, double-blind, international study that compared the two belimumab doses vs. placebo in 819 seropositive patients with SLE, is one of the two pivotal studies to evaluate the safety and efficacy of belimumab in this population. Patients in the study had to have an antinuclear antibody ratio of at least 1:80 and/or anti–double-stranded DNA of at least 30 IU/mL, with a SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus–National Assessment SLE Disease Activity Index) score of at least 6 on stable therapy.

Patients had had the disease for a mean of 7.5 years, 63% used antimalarials, 76% used steroids, and 56% used immunosuppressants. Patients received standard-of-care treatment and were randomized to receive either IV belimumab at days 0, 14, 28, and then every 28 days for 72 weeks, or placebo.

Some of the top-line BLISS-76 results were reported in November 2009 by HGS and GSK. At that time, the developers announced that the study had met its primary end point, which was the patient response rate as measured by the SLE Responder Index (SRI) at 52 weeks. In all, 43% of those on the higher dose and 41% of those on the lower dose met this end point, compared with 34% of those on placebo. The difference between the higher dose and placebo was statistically significant.

According to the SRI, which was developed in collaboration with the Food and Drug Administration, a patient response is defined as an improvement in the SELENA-SLEDAI score of 4 points or greater, with no clinically significant worsening on the either the BILAG (British Isles Lupus Assessment Group) index or the Physician’s Global Assessment (PGA).

Secondary end points included components of the primary end point. In all, 47% of those on the higher dose and 43% of those on the lower dose had at least a 4-point reduction in the SELENA-SLEDAI score at 52 weeks, compared with 36% among placebo. The difference between the higher dose and placebo was significant.

The proportion of patients who did not have a worsening in the PGA score greater than 0.3 points was 69% and 73% in the 10-mg/kg and 1-mg/kg groups, respectively, compared with 63% in the placebo group. The difference between the 1-mg/kg dose and placebo was significant. There were no statistically significant improvements in PGA or in steroid dose reductions among the two belimumab-treated groups, compared with placebo, according to Dr. van Vollenhoven.

In addition, 69% of those on the 10-mg/kg dose, 75% of those on the 1-mg/kg dose, and 65% of those on placebo had no new BILAG grade A or B scores. The difference between the 1-mg/kg dose and placebo was significant.

There were no significant differences between the three groups in the risk of having a flare, or in the median time to the first flare, based on the SELENA Flare Index (SFI). But the proportion of patients who had a severe SFI flare was lower in the two treatment groups (18% of those on the higher dose and 16% of those on the lower dose, compared with 24% of those on placebo), he said, noting that the difference was significant between the 1-mg/kg and placebo groups.

Other secondary end points included the mean in SF-36 Physical Component Summary (PCS) scores from baseline to week 52, which increased by a mean of 3.4, 4.4 and 2.9, in the 10-mg/kg, 1-mg/kg and placebo groups, respectively. The difference was significant only between placebo and the 1-mg/kg dose. The change in the FACIT-F (Functional Assessment of Chronic Illness Therapy–Fatigue) score from baseline at 52 weeks increased by a mean of 4.6, 5.7, and 2.9 respectively, with the difference being significant between the 1-mg/kg dose and placebo, Dr. van Vollenhoven said. “These data are important in that they reflect patient-reported aspects of the disease, namely physical function and fatigue, which are of major importance in terms of quality of life,” Dr. van Vollenhoven said in the interview. “In fact, fatigue has been identified by lupus patients in our unit as their most important symptom.”

He added, “All these instruments are blunt, however. It’s like having an old radio with a lot of background noise.”

In the study, treatment was well tolerated, with similar rates of deaths, adverse events, serious adverse events, infections, and laboratory abnormalities in the three groups. There was a modest increase in serious or severe infusion reactions among those on belimumab, compared with those on placebo, he noted. The overall infusion reaction rate was 13%-15% in the two belimumab groups, compared with 10% in the placebo group; the rate of severe infusion reactions was 1.1% in the 10-mg/kg group and 0.4% in the 1-mg/kg and placebo groups. Thus, the clinical response to the 10-mg dose appeared to be more robust. However, we need to learn more in the future about refining doses.”

There were six malignancies in the study, one in a patient on placebo, and five in the belimumab-treated patients. The infection rate was 72% in the two belimumab groups, compared with 67% in the placebo group; the serious infection rate was 7% in the 10-mg group, 6% in the 1-mg/kg group, and 5% in the placebo group, Dr. van Vollenhoven said.

Dr. van Vollenhoven was an investigator in the BLISS-76 study and is a consultant to HGS and GSK; he also served on the BLISS-52 and BLISS-76 steering committees. Some of the investigators on this trial are HGS employees.