SLE: Belimumab Safety, Efficacy Sustained Over 6 Years

LONDON – Belimumab therapy in patients with active systemic lupus erythematosus was well tolerated and associated with sustained disease improvement over 6 years, judging from the findings of a continuation study of a phase II randomized controlled trial.

Hyped regularly as the first new drug approved for the treatment of systemic lupus erythematosus (SLE) in 50 years, belimumab has been shown to reduce disease activity and flares in serologically active patients when combined with standard therapy versus placebo, Dr. Michelle A. Petri reported at the annual European Congress of Rheumatology. Belimumab inhibits B-lymphocyte stimulator. Among the "unanswered questions" about the recently approved monoclonal antibody, however, are the durability of the disease improvement and the drug’s safety over time, said Dr. Petri, director of the lupus center at Johns Hopkins University, Baltimore.

To examine long-term safety and efficacy of the drug, Dr. Petri and her colleagues conducted a follow-up study of patients who participated in a 1-year phase II randomized controlled trial (Arthritis Rheum. 2009;61:1168-78) and who continued treatment for up to 6 years. After the randomized phase of the trial, all of the patients entered the open-label extension phase of the trial during which they were continued on one of three belimumab (Benlysta) doses – 1 mg/kg, 4 mg/kg, or 10 mg/kg. At study week 80, a total of 296 of the patients entered the continuation phase during which they all received 10 mg/kg doses of the drug, Dr. Petri explained. As of July 2010, a total of 200 patients remained in the study, she said.

Focusing specifically on the subset of seropositive SLE patients (positive for antineutrophil antibody or positive for anti–double-stranded DNA ) in whom the B-cell–directed therapy is considered to be most effective, the investigators measured disease activity using the SLE Flare Index (SFI), the British Isles Lupus Assessment Group(BILAG) 1A/2B flares, the SLE responder Index (SRI), and biomarkers (complement and autoantibodies), and assessed adverse events at each study visit, Dr. Petri said. "Over 6 years, patient response rates improved, the frequency of new flares decreased significantly, and the rate of adverse events remained stable or declined, compared to year 1," she said.

Specifically, the SRI rate increased from 46% at year 1 to 55%-61% through year 6; the frequency of 1 new BILAG A or 2 new B flares decreased from 35% at 1 year to 11% at year 6; and the frequency of SFI flares decreased from 76% at 1 year to 42% at year 6, Dr. Petri said. Additionally, the rate of severe flares, which was 17% at year 1, decreased to 5% at year 6. "Patients had to be really sick to get into this study in the first place, so to see the severe flares disappear to that degree is really clinically important," she explained.

The proportion of patients with increased complement 3 or 4 and decreased anti-Sm, anti–double-stranded DNA, and anticardiolipin antibodies increased over time, suggesting a sustained or improved therapeutic response, Dr. Petri said. Additionally, concomitant corticosteroid use decreased by a mean of 34% from baseline, with an absolute reduction of 4.7 mg/day at year 6, compared with baseline.

Belimumab is not indicated as a stand-alone, first-line therapy but rather as an adjunct therapy in patients who have not responded to the standard of care, "especially in whom there is evidence that B-cells are driving disease activity, such as anti-DNA or low complement," Dr. Petri said.

The findings of this study are limited by the potential for self-selection bias, in that patients not responding positively to the belimumab may have dropped out during the course of the study, while those benefiting from the drug would be more likely to continue treatment, Dr. Petri said. Even so, the safety and tolerability data suggest that, in "the appropriately targeted SLE population, belimumab has the potential to be a widely used, steroid-sparing background therapy."

Yet to be addressed "meaningfully" in clinical trials are the safety and efficacy of belimumab in black patients, as well as the drug’s effects on patients with lupus nephritis or central nervous system involvement – both of which were excluded from this and the pivotal trials that led to FDA approval of the drug – as well as pediatric and pregnant patients, Dr. Petri said in an interview.

Dr. Petri disclosed receiving research support and consultancy fees for Human Genome Sciences/GlaxoSmithKline.

LONDON – Belimumab therapy in patients with active systemic lupus erythematosus was well tolerated and associated with sustained disease improvement over 6 years, judging from the findings of a continuation study of a phase II randomized controlled trial.

Hyped regularly as the first new drug approved for the treatment of systemic lupus erythematosus (SLE) in 50 years, belimumab has been shown to reduce disease activity and flares in serologically active patients when combined with standard therapy versus placebo, Dr. Michelle A. Petri reported at the annual European Congress of Rheumatology. Belimumab inhibits B-lymphocyte stimulator. Among the "unanswered questions" about the recently approved monoclonal antibody, however, are the durability of the disease improvement and the drug’s safety over time, said Dr. Petri, director of the lupus center at Johns Hopkins University, Baltimore.

To examine long-term safety and efficacy of the drug, Dr. Petri and her colleagues conducted a follow-up study of patients who participated in a 1-year phase II randomized controlled trial (Arthritis Rheum. 2009;61:1168-78) and who continued treatment for up to 6 years. After the randomized phase of the trial, all of the patients entered the open-label extension phase of the trial during which they were continued on one of three belimumab (Benlysta) doses – 1 mg/kg, 4 mg/kg, or 10 mg/kg. At study week 80, a total of 296 of the patients entered the continuation phase during which they all received 10 mg/kg doses of the drug, Dr. Petri explained. As of July 2010, a total of 200 patients remained in the study, she said.

Focusing specifically on the subset of seropositive SLE patients (positive for antineutrophil antibody or positive for anti–double-stranded DNA ) in whom the B-cell–directed therapy is considered to be most effective, the investigators measured disease activity using the SLE Flare Index (SFI), the British Isles Lupus Assessment Group(BILAG) 1A/2B flares, the SLE responder Index (SRI), and biomarkers (complement and autoantibodies), and assessed adverse events at each study visit, Dr. Petri said. "Over 6 years, patient response rates improved, the frequency of new flares decreased significantly, and the rate of adverse events remained stable or declined, compared to year 1," she said.

Specifically, the SRI rate increased from 46% at year 1 to 55%-61% through year 6; the frequency of 1 new BILAG A or 2 new B flares decreased from 35% at 1 year to 11% at year 6; and the frequency of SFI flares decreased from 76% at 1 year to 42% at year 6, Dr. Petri said. Additionally, the rate of severe flares, which was 17% at year 1, decreased to 5% at year 6. "Patients had to be really sick to get into this study in the first place, so to see the severe flares disappear to that degree is really clinically important," she explained.

The proportion of patients with increased complement 3 or 4 and decreased anti-Sm, anti–double-stranded DNA, and anticardiolipin antibodies increased over time, suggesting a sustained or improved therapeutic response, Dr. Petri said. Additionally, concomitant corticosteroid use decreased by a mean of 34% from baseline, with an absolute reduction of 4.7 mg/day at year 6, compared with baseline.

Belimumab is not indicated as a stand-alone, first-line therapy but rather as an adjunct therapy in patients who have not responded to the standard of care, "especially in whom there is evidence that B-cells are driving disease activity, such as anti-DNA or low complement," Dr. Petri said.

The findings of this study are limited by the potential for self-selection bias, in that patients not responding positively to the belimumab may have dropped out during the course of the study, while those benefiting from the drug would be more likely to continue treatment, Dr. Petri said. Even so, the safety and tolerability data suggest that, in "the appropriately targeted SLE population, belimumab has the potential to be a widely used, steroid-sparing background therapy."

Yet to be addressed "meaningfully" in clinical trials are the safety and efficacy of belimumab in black patients, as well as the drug’s effects on patients with lupus nephritis or central nervous system involvement – both of which were excluded from this and the pivotal trials that led to FDA approval of the drug – as well as pediatric and pregnant patients, Dr. Petri said in an interview.

Dr. Petri disclosed receiving research support and consultancy fees for Human Genome Sciences/GlaxoSmithKline.

LONDON – Belimumab therapy in patients with active systemic lupus erythematosus was well tolerated and associated with sustained disease improvement over 6 years, judging from the findings of a continuation study of a phase II randomized controlled trial.

Hyped regularly as the first new drug approved for the treatment of systemic lupus erythematosus (SLE) in 50 years, belimumab has been shown to reduce disease activity and flares in serologically active patients when combined with standard therapy versus placebo, Dr. Michelle A. Petri reported at the annual European Congress of Rheumatology. Belimumab inhibits B-lymphocyte stimulator. Among the "unanswered questions" about the recently approved monoclonal antibody, however, are the durability of the disease improvement and the drug’s safety over time, said Dr. Petri, director of the lupus center at Johns Hopkins University, Baltimore.

To examine long-term safety and efficacy of the drug, Dr. Petri and her colleagues conducted a follow-up study of patients who participated in a 1-year phase II randomized controlled trial (Arthritis Rheum. 2009;61:1168-78) and who continued treatment for up to 6 years. After the randomized phase of the trial, all of the patients entered the open-label extension phase of the trial during which they were continued on one of three belimumab (Benlysta) doses – 1 mg/kg, 4 mg/kg, or 10 mg/kg. At study week 80, a total of 296 of the patients entered the continuation phase during which they all received 10 mg/kg doses of the drug, Dr. Petri explained. As of July 2010, a total of 200 patients remained in the study, she said.

Focusing specifically on the subset of seropositive SLE patients (positive for antineutrophil antibody or positive for anti–double-stranded DNA ) in whom the B-cell–directed therapy is considered to be most effective, the investigators measured disease activity using the SLE Flare Index (SFI), the British Isles Lupus Assessment Group(BILAG) 1A/2B flares, the SLE responder Index (SRI), and biomarkers (complement and autoantibodies), and assessed adverse events at each study visit, Dr. Petri said. "Over 6 years, patient response rates improved, the frequency of new flares decreased significantly, and the rate of adverse events remained stable or declined, compared to year 1," she said.

Specifically, the SRI rate increased from 46% at year 1 to 55%-61% through year 6; the frequency of 1 new BILAG A or 2 new B flares decreased from 35% at 1 year to 11% at year 6; and the frequency of SFI flares decreased from 76% at 1 year to 42% at year 6, Dr. Petri said. Additionally, the rate of severe flares, which was 17% at year 1, decreased to 5% at year 6. "Patients had to be really sick to get into this study in the first place, so to see the severe flares disappear to that degree is really clinically important," she explained.

The proportion of patients with increased complement 3 or 4 and decreased anti-Sm, anti–double-stranded DNA, and anticardiolipin antibodies increased over time, suggesting a sustained or improved therapeutic response, Dr. Petri said. Additionally, concomitant corticosteroid use decreased by a mean of 34% from baseline, with an absolute reduction of 4.7 mg/day at year 6, compared with baseline.

Belimumab is not indicated as a stand-alone, first-line therapy but rather as an adjunct therapy in patients who have not responded to the standard of care, "especially in whom there is evidence that B-cells are driving disease activity, such as anti-DNA or low complement," Dr. Petri said.

The findings of this study are limited by the potential for self-selection bias, in that patients not responding positively to the belimumab may have dropped out during the course of the study, while those benefiting from the drug would be more likely to continue treatment, Dr. Petri said. Even so, the safety and tolerability data suggest that, in "the appropriately targeted SLE population, belimumab has the potential to be a widely used, steroid-sparing background therapy."

Yet to be addressed "meaningfully" in clinical trials are the safety and efficacy of belimumab in black patients, as well as the drug’s effects on patients with lupus nephritis or central nervous system involvement – both of which were excluded from this and the pivotal trials that led to FDA approval of the drug – as well as pediatric and pregnant patients, Dr. Petri said in an interview.

Dr. Petri disclosed receiving research support and consultancy fees for Human Genome Sciences/GlaxoSmithKline.