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BUENOS AIRES – Despite some early letdowns in clinical trials, biologic therapies targeting nearly every point in the pathway of the known pathogenesis of systemic lupus erythematosus are currently in the pipeline.
At the International Congress on Systemic Lupus Erythematosus, investigators presented promising new data on several experimental biologics. And in the shadow of some costly failures, they also discussed ways to refine endpoints, inclusion criteria, and the use of background medicines to make trial results for these agents clearer.
Biomarker-driven response to rontalizumab
Rontalizumab, a humanized antibody against anti-interferon-alpha, was shown in a phase II randomized controlled trial of 159 patients with moderate to severe SLE to improve signs and symptoms, flare rates, and need for steroids at 24 weeks in the subset of patients who had low interferon signature gene expression metric (ISM), an emerging biomarker in SLE, at baseline.
Although whether patients are classified as ISM high or low makes little difference in terms of measurable disease activity, it does appear to affect how treatments work. "No matter what drug you look at, the impact differs depending on whether the patients are ISM high or low," said Dr. Joan T. Merrill, one of the coauthors of the rontalizumab study, which was presented at the meeting by Dr. William Kennedy, senior medical director of Genentech.
Rontalizumab was associated with improvement in the ISM-low subgroup in the trial, which compared both intravenous and subcutaneous forms of rontalizumab with placebo. In ISM-low patients, a quarter of the total enrolled, IV rontalizumab vs. placebo SLE Responder Index (SRI) response rates were 75% vs. 18%. Treatment groups saw a nearly 40% reduced risk of disease flare based on SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index) flare rates, compared with placebo (hazard ratio 0.61 [90% confidence interval 0.46-0.81; P = .0040]), driven by ISM-low patients. Also, 91% of ISM-low patients in the treatment groups achieved prednisone reduction (10 mg/day) by week 24, compared with 67% of placebo subjects (Lupus 2013;22[Suppl.]:O22).
Limiting background medications in trials
Background immunosuppressants were not used in the rontalizumab study, and steroids were limited. Dr. Merrill, of the University of Oklahoma Health Sciences Center, Oklahoma City, discussed some of the thinking behind this. Limiting background medications "can lead to more interpretable results," she said. While many investigators have argued that only the sickest and most refractory patients should be enrolled in SLE clinical trials as a way to discern a clearer differences between treatment and placebo, Dr. Merrill instead championed recruiting less-sick patients for whom it is safer to withdraw or minimize background medicines.
Patients without severe disease will still die early and accumulate increasing damage over time, Dr. Merrill said. "They represent a huge unmet need. So if we could do trials with these patients and limit the background noise caused by their medications, perhaps we could also see a difference between treatment and placebo. Trials would be easier to recruit, we would see fewer infections, and most importantly, there would be a bigger market for pharma companies to pursue."
Targeting CD22 antigen on B cells
Two randomized, placebo-controlled trials of epratuzumab, a monoclonal antibody targeting CD22 antigen on B cells, had to be terminated when drug supply was interrupted. However, the early findings had shown clinically meaningful improvements in disease activity and corticosteroid sparing. Final results from an open-label extension study for SLE patients previously enrolled in these trials (n = 429), sponsored by UCB Pharma, showed that continued administration of epratuzumab resulted in sustained improvements after a mean four years of treatment, with no new safety signals (Lupus 2013;22[Suppl.]:O25).
Phase II data on blisibimod
Blisibimod, a biologic injected subcutaneously that inhibits B-cell activating factor, or BAFF, was investigated in a phase IIb manufacturer-sponsored trial of 547 patients with anti-dsDNA or anti-nuclear antibodies and SELENA-SLEDAI score of 6 or higher at baseline. Dr. Morton Scheinberg of Rheumatology Hospital Abreu Sodre Pesquisa Clínica, São Paulo, Brazil, led the trial, sponsored by Anthera Pharmaceuticals, in which patients were randomized to one of three doses or placebo. The composite primary endpoint, SRI-5 (defined as a 5-point improvement in SELENA-SLEDAI, no new BILAG A or 2B organ domain scores, and no worsening in Physician’s Global Assessment) was not met because efficacy was not shown in the lower doses. However, more subjects who received the highest dose (200 mg once weekly) met the response criteria starting in week 16 (8%, P = .14), through week 24 (8.2%, P = .15), reaching statistical significance at week 20 (Lupus 2013;22[Suppl.]:O21).
Improving on past trial missteps
One of the coinvestigators on the blisibimod trial, Dr. Richard A. Furie, discussed missteps in the design of earlier studies. "Trials of new biologic therapies have taught us to be humble and logical, and to persevere – we’ve made a lot of mistakes over last 20 years," he told the conference, pointing to a handful of trials in which subjects did not have serologic evidence of disease at baseline. "In my book, if someone is clinically active they should have autoantibodies," he said. "So the rules for entry were changed for all trials."
Dr. Furie, chief of the division of rheumatology and allergy-clinical immunology in the North Shore–LIJ Health System and professor of medicine at Hofstra University, Hempstead, N.Y., said that while inclusion criteria had improved, investigators of biologic agents still had far to go in refining SLE trial endpoints. "No two endpoints are the same – we’ve customized the endpoints and are struggling with extrarenal trials whether it should be a single or composite endpoint, whether it should be based on SLEDAI or BILAG alone or should we use SRI – there is no consensus." Echoing Dr. Merrill, he stressed that background medications were another area in need of increased scrutiny and consensus. "Each trial has handled steroids and immunosuppressants differently," he said.
Dr. Merrill has received support from Genentech. Dr. Furie has received support from Anthera, Genentech, and UCB Pharma. Both rheumatologists have received support from many other companies involved in lupus research and therapy.
BUENOS AIRES – Despite some early letdowns in clinical trials, biologic therapies targeting nearly every point in the pathway of the known pathogenesis of systemic lupus erythematosus are currently in the pipeline.
At the International Congress on Systemic Lupus Erythematosus, investigators presented promising new data on several experimental biologics. And in the shadow of some costly failures, they also discussed ways to refine endpoints, inclusion criteria, and the use of background medicines to make trial results for these agents clearer.
Biomarker-driven response to rontalizumab
Rontalizumab, a humanized antibody against anti-interferon-alpha, was shown in a phase II randomized controlled trial of 159 patients with moderate to severe SLE to improve signs and symptoms, flare rates, and need for steroids at 24 weeks in the subset of patients who had low interferon signature gene expression metric (ISM), an emerging biomarker in SLE, at baseline.
Although whether patients are classified as ISM high or low makes little difference in terms of measurable disease activity, it does appear to affect how treatments work. "No matter what drug you look at, the impact differs depending on whether the patients are ISM high or low," said Dr. Joan T. Merrill, one of the coauthors of the rontalizumab study, which was presented at the meeting by Dr. William Kennedy, senior medical director of Genentech.
Rontalizumab was associated with improvement in the ISM-low subgroup in the trial, which compared both intravenous and subcutaneous forms of rontalizumab with placebo. In ISM-low patients, a quarter of the total enrolled, IV rontalizumab vs. placebo SLE Responder Index (SRI) response rates were 75% vs. 18%. Treatment groups saw a nearly 40% reduced risk of disease flare based on SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index) flare rates, compared with placebo (hazard ratio 0.61 [90% confidence interval 0.46-0.81; P = .0040]), driven by ISM-low patients. Also, 91% of ISM-low patients in the treatment groups achieved prednisone reduction (10 mg/day) by week 24, compared with 67% of placebo subjects (Lupus 2013;22[Suppl.]:O22).
Limiting background medications in trials
Background immunosuppressants were not used in the rontalizumab study, and steroids were limited. Dr. Merrill, of the University of Oklahoma Health Sciences Center, Oklahoma City, discussed some of the thinking behind this. Limiting background medications "can lead to more interpretable results," she said. While many investigators have argued that only the sickest and most refractory patients should be enrolled in SLE clinical trials as a way to discern a clearer differences between treatment and placebo, Dr. Merrill instead championed recruiting less-sick patients for whom it is safer to withdraw or minimize background medicines.
Patients without severe disease will still die early and accumulate increasing damage over time, Dr. Merrill said. "They represent a huge unmet need. So if we could do trials with these patients and limit the background noise caused by their medications, perhaps we could also see a difference between treatment and placebo. Trials would be easier to recruit, we would see fewer infections, and most importantly, there would be a bigger market for pharma companies to pursue."
Targeting CD22 antigen on B cells
Two randomized, placebo-controlled trials of epratuzumab, a monoclonal antibody targeting CD22 antigen on B cells, had to be terminated when drug supply was interrupted. However, the early findings had shown clinically meaningful improvements in disease activity and corticosteroid sparing. Final results from an open-label extension study for SLE patients previously enrolled in these trials (n = 429), sponsored by UCB Pharma, showed that continued administration of epratuzumab resulted in sustained improvements after a mean four years of treatment, with no new safety signals (Lupus 2013;22[Suppl.]:O25).
Phase II data on blisibimod
Blisibimod, a biologic injected subcutaneously that inhibits B-cell activating factor, or BAFF, was investigated in a phase IIb manufacturer-sponsored trial of 547 patients with anti-dsDNA or anti-nuclear antibodies and SELENA-SLEDAI score of 6 or higher at baseline. Dr. Morton Scheinberg of Rheumatology Hospital Abreu Sodre Pesquisa Clínica, São Paulo, Brazil, led the trial, sponsored by Anthera Pharmaceuticals, in which patients were randomized to one of three doses or placebo. The composite primary endpoint, SRI-5 (defined as a 5-point improvement in SELENA-SLEDAI, no new BILAG A or 2B organ domain scores, and no worsening in Physician’s Global Assessment) was not met because efficacy was not shown in the lower doses. However, more subjects who received the highest dose (200 mg once weekly) met the response criteria starting in week 16 (8%, P = .14), through week 24 (8.2%, P = .15), reaching statistical significance at week 20 (Lupus 2013;22[Suppl.]:O21).
Improving on past trial missteps
One of the coinvestigators on the blisibimod trial, Dr. Richard A. Furie, discussed missteps in the design of earlier studies. "Trials of new biologic therapies have taught us to be humble and logical, and to persevere – we’ve made a lot of mistakes over last 20 years," he told the conference, pointing to a handful of trials in which subjects did not have serologic evidence of disease at baseline. "In my book, if someone is clinically active they should have autoantibodies," he said. "So the rules for entry were changed for all trials."
Dr. Furie, chief of the division of rheumatology and allergy-clinical immunology in the North Shore–LIJ Health System and professor of medicine at Hofstra University, Hempstead, N.Y., said that while inclusion criteria had improved, investigators of biologic agents still had far to go in refining SLE trial endpoints. "No two endpoints are the same – we’ve customized the endpoints and are struggling with extrarenal trials whether it should be a single or composite endpoint, whether it should be based on SLEDAI or BILAG alone or should we use SRI – there is no consensus." Echoing Dr. Merrill, he stressed that background medications were another area in need of increased scrutiny and consensus. "Each trial has handled steroids and immunosuppressants differently," he said.
Dr. Merrill has received support from Genentech. Dr. Furie has received support from Anthera, Genentech, and UCB Pharma. Both rheumatologists have received support from many other companies involved in lupus research and therapy.
BUENOS AIRES – Despite some early letdowns in clinical trials, biologic therapies targeting nearly every point in the pathway of the known pathogenesis of systemic lupus erythematosus are currently in the pipeline.
At the International Congress on Systemic Lupus Erythematosus, investigators presented promising new data on several experimental biologics. And in the shadow of some costly failures, they also discussed ways to refine endpoints, inclusion criteria, and the use of background medicines to make trial results for these agents clearer.
Biomarker-driven response to rontalizumab
Rontalizumab, a humanized antibody against anti-interferon-alpha, was shown in a phase II randomized controlled trial of 159 patients with moderate to severe SLE to improve signs and symptoms, flare rates, and need for steroids at 24 weeks in the subset of patients who had low interferon signature gene expression metric (ISM), an emerging biomarker in SLE, at baseline.
Although whether patients are classified as ISM high or low makes little difference in terms of measurable disease activity, it does appear to affect how treatments work. "No matter what drug you look at, the impact differs depending on whether the patients are ISM high or low," said Dr. Joan T. Merrill, one of the coauthors of the rontalizumab study, which was presented at the meeting by Dr. William Kennedy, senior medical director of Genentech.
Rontalizumab was associated with improvement in the ISM-low subgroup in the trial, which compared both intravenous and subcutaneous forms of rontalizumab with placebo. In ISM-low patients, a quarter of the total enrolled, IV rontalizumab vs. placebo SLE Responder Index (SRI) response rates were 75% vs. 18%. Treatment groups saw a nearly 40% reduced risk of disease flare based on SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index) flare rates, compared with placebo (hazard ratio 0.61 [90% confidence interval 0.46-0.81; P = .0040]), driven by ISM-low patients. Also, 91% of ISM-low patients in the treatment groups achieved prednisone reduction (10 mg/day) by week 24, compared with 67% of placebo subjects (Lupus 2013;22[Suppl.]:O22).
Limiting background medications in trials
Background immunosuppressants were not used in the rontalizumab study, and steroids were limited. Dr. Merrill, of the University of Oklahoma Health Sciences Center, Oklahoma City, discussed some of the thinking behind this. Limiting background medications "can lead to more interpretable results," she said. While many investigators have argued that only the sickest and most refractory patients should be enrolled in SLE clinical trials as a way to discern a clearer differences between treatment and placebo, Dr. Merrill instead championed recruiting less-sick patients for whom it is safer to withdraw or minimize background medicines.
Patients without severe disease will still die early and accumulate increasing damage over time, Dr. Merrill said. "They represent a huge unmet need. So if we could do trials with these patients and limit the background noise caused by their medications, perhaps we could also see a difference between treatment and placebo. Trials would be easier to recruit, we would see fewer infections, and most importantly, there would be a bigger market for pharma companies to pursue."
Targeting CD22 antigen on B cells
Two randomized, placebo-controlled trials of epratuzumab, a monoclonal antibody targeting CD22 antigen on B cells, had to be terminated when drug supply was interrupted. However, the early findings had shown clinically meaningful improvements in disease activity and corticosteroid sparing. Final results from an open-label extension study for SLE patients previously enrolled in these trials (n = 429), sponsored by UCB Pharma, showed that continued administration of epratuzumab resulted in sustained improvements after a mean four years of treatment, with no new safety signals (Lupus 2013;22[Suppl.]:O25).
Phase II data on blisibimod
Blisibimod, a biologic injected subcutaneously that inhibits B-cell activating factor, or BAFF, was investigated in a phase IIb manufacturer-sponsored trial of 547 patients with anti-dsDNA or anti-nuclear antibodies and SELENA-SLEDAI score of 6 or higher at baseline. Dr. Morton Scheinberg of Rheumatology Hospital Abreu Sodre Pesquisa Clínica, São Paulo, Brazil, led the trial, sponsored by Anthera Pharmaceuticals, in which patients were randomized to one of three doses or placebo. The composite primary endpoint, SRI-5 (defined as a 5-point improvement in SELENA-SLEDAI, no new BILAG A or 2B organ domain scores, and no worsening in Physician’s Global Assessment) was not met because efficacy was not shown in the lower doses. However, more subjects who received the highest dose (200 mg once weekly) met the response criteria starting in week 16 (8%, P = .14), through week 24 (8.2%, P = .15), reaching statistical significance at week 20 (Lupus 2013;22[Suppl.]:O21).
Improving on past trial missteps
One of the coinvestigators on the blisibimod trial, Dr. Richard A. Furie, discussed missteps in the design of earlier studies. "Trials of new biologic therapies have taught us to be humble and logical, and to persevere – we’ve made a lot of mistakes over last 20 years," he told the conference, pointing to a handful of trials in which subjects did not have serologic evidence of disease at baseline. "In my book, if someone is clinically active they should have autoantibodies," he said. "So the rules for entry were changed for all trials."
Dr. Furie, chief of the division of rheumatology and allergy-clinical immunology in the North Shore–LIJ Health System and professor of medicine at Hofstra University, Hempstead, N.Y., said that while inclusion criteria had improved, investigators of biologic agents still had far to go in refining SLE trial endpoints. "No two endpoints are the same – we’ve customized the endpoints and are struggling with extrarenal trials whether it should be a single or composite endpoint, whether it should be based on SLEDAI or BILAG alone or should we use SRI – there is no consensus." Echoing Dr. Merrill, he stressed that background medications were another area in need of increased scrutiny and consensus. "Each trial has handled steroids and immunosuppressants differently," he said.
Dr. Merrill has received support from Genentech. Dr. Furie has received support from Anthera, Genentech, and UCB Pharma. Both rheumatologists have received support from many other companies involved in lupus research and therapy.
AT THE INTERNATIONAL CONGRESS ON SLE
