Expert Outlines Drug-Development Obstacles in Lupus

DESTIN, FLA. — “The problem with drug development in lupus is lupus,” Dr. Joan T. Merrill said at the Congress of Clinical Rheumatology.

“Lupus is an incredibly heterogeneous disease. We know from the results of clinical trials that no one drug can be expected to work for more than 60% of patients with lupus. But we can't yet pick out in advance the subgroup of patients who will respond to a given drug,” she said.

The heterogeneity of the disease across patients and the absence of scientific evidence to explain the biological mechanisms underlying the variations have been impediments to fruitful clinical experimentation, and have led to a series of disappointing clinical trial outcomes, said Dr. Merrill, of the University of Oklahoma in Oklahoma City.

“Targeted therapies can only work if you know what you're targeting, in whom, and why,” she noted. “We have the technology to be able to identify those subsets of patients that we ought to be targeting with each treatment, but we don't have the will.

Additional complications include the inconsistent clinical course of the disease, which is characterized by flares and remissions that make it difficult to assess the impact of investigational therapies and also complicate the selection of meaningful clinical end points, and the need (according to the Food and Drug Administration) to show clinical superiority of the investigational agents over standard treatment, said Dr. Merrill. “The irony, of course, is that the standard of care in lupus is off-label therapy, because there hasn't been a new drug approved for the disease in more than 50 years,” she said.

Because the standard treatments are off label, their therapeutic effect has not been established in clinical trials. “Many clinical trials in lupus have to be carried out for a whole year, and they can't really be performed unless patients are on these background medications, but we don't know what these background medications are doing biologically to patients, or how they are interfering with our assessment of a study agent,” Dr. Merrill said.

Arguably, the potentially promising agents that have failed to achieve intended levels of improvement in patient outcomes in lupus trials—including mycophenolate mofetil (CellCept), abatacept (Orencia), prasterone (Prestara), abetimus sodium (Riquent), and rituximab (Rituxan)—might have demonstrated treatment effects if patient selection had been optimized based on patient-specific biology, if investigators had a better understanding of the impact that background medications have on patient response and adverse events, and if more specific responder indices were available to assess treatment effect, according to Dr. Merrill.

In fact, it is the attention paid to some of these factors that likely contributed to the recent success of two separate phase III trials of belimumab (Benlysta), the monoclonal antibody that targets B-lymphocyte stimulator (BLyS), she said.

In the initial phase II, double-blind, placebo-controlled trial of belimumab in patients with active lupus, the drug failed to improve disease activity as measured by the SLEDAI (Systemic Lupus Erythematosus Disease Activity Index), and did not decrease time to first SLE flare (Arthritis Rheum. 2009;61:1168–78).

In a post hoc exploratory analysis of the data, however, the investigators “noticed that if they looked just at the subset of patients who had been either ANA [antinuclear antibody] positive or [anti–double-stranded DNA] positive at study entry, they actually could see more patients with a 4-point reduction in the SLEDAI over time at each visit” than in the placebo group, said Dr. Merrill.

Based on this observation, the investigators used the phase II trial data to develop a new SLE Responder Index (SRI) that incorporated components of the SLEDAI, the BILAG (British Isles Lupus Assessment Group) disease activity instrument, and the PGA (Physician Global Assessment).

They used the new instrument as the primary efficacy end point at week 52 in the BLISS-52 (Belimumab in Subjects With Systemic Lupus Erythematosus–52) and BLISS-76 phase III trials, said Dr. Merrill.

In both BLISS trials, belimumab met the efficacy end point, which was defined as a reduction from baseline of at least 4 points on the SLEDAI disease activity scale, no worsening of disease as measured by the PGA, no new BILAG grade A organ domain score, and no more than one new BILAG grade B organ domain score, Dr. Merrill noted.

The differences between the treatment and control groups that were observed in both trials were small but statistically significant, and they were historically meaningful because they put the drug on the pathway for FDA approval, she said.

“This is a major development, not because [belimumab] is expected to be a cure-all or the best treatment for every lupus patient, because it is not,” said Dr. Merrill. Rather, FDA approval of belimumab, if it happens, will break ground for other studies to follow and, after 50 years, “there will finally be an approved therapy that we can hold other [experimental] therapies up against.”

Disclosures: Dr. Merrill has served as a consultant and clinical trialist for Genentech/Roche, Bristol-Myers Squibb Co., MedImmune Inc., and Human Genome Sciences; she has been a consultant for Amgen Inc., UCB Pharma Inc., and Serono Inc.; and she has received grants from Aspreva/Vifor and Wyeth/Pfizer for investigator-initiated studies.

In lupus, 'targeted therapies can only work if you know what you're targeting, in whom, and why.'

Source DR. MERRILL

DESTIN, FLA. — “The problem with drug development in lupus is lupus,” Dr. Joan T. Merrill said at the Congress of Clinical Rheumatology.

“Lupus is an incredibly heterogeneous disease. We know from the results of clinical trials that no one drug can be expected to work for more than 60% of patients with lupus. But we can't yet pick out in advance the subgroup of patients who will respond to a given drug,” she said.

The heterogeneity of the disease across patients and the absence of scientific evidence to explain the biological mechanisms underlying the variations have been impediments to fruitful clinical experimentation, and have led to a series of disappointing clinical trial outcomes, said Dr. Merrill, of the University of Oklahoma in Oklahoma City.

“Targeted therapies can only work if you know what you're targeting, in whom, and why,” she noted. “We have the technology to be able to identify those subsets of patients that we ought to be targeting with each treatment, but we don't have the will.

Additional complications include the inconsistent clinical course of the disease, which is characterized by flares and remissions that make it difficult to assess the impact of investigational therapies and also complicate the selection of meaningful clinical end points, and the need (according to the Food and Drug Administration) to show clinical superiority of the investigational agents over standard treatment, said Dr. Merrill. “The irony, of course, is that the standard of care in lupus is off-label therapy, because there hasn't been a new drug approved for the disease in more than 50 years,” she said.

Because the standard treatments are off label, their therapeutic effect has not been established in clinical trials. “Many clinical trials in lupus have to be carried out for a whole year, and they can't really be performed unless patients are on these background medications, but we don't know what these background medications are doing biologically to patients, or how they are interfering with our assessment of a study agent,” Dr. Merrill said.

Arguably, the potentially promising agents that have failed to achieve intended levels of improvement in patient outcomes in lupus trials—including mycophenolate mofetil (CellCept), abatacept (Orencia), prasterone (Prestara), abetimus sodium (Riquent), and rituximab (Rituxan)—might have demonstrated treatment effects if patient selection had been optimized based on patient-specific biology, if investigators had a better understanding of the impact that background medications have on patient response and adverse events, and if more specific responder indices were available to assess treatment effect, according to Dr. Merrill.

In fact, it is the attention paid to some of these factors that likely contributed to the recent success of two separate phase III trials of belimumab (Benlysta), the monoclonal antibody that targets B-lymphocyte stimulator (BLyS), she said.

In the initial phase II, double-blind, placebo-controlled trial of belimumab in patients with active lupus, the drug failed to improve disease activity as measured by the SLEDAI (Systemic Lupus Erythematosus Disease Activity Index), and did not decrease time to first SLE flare (Arthritis Rheum. 2009;61:1168–78).

In a post hoc exploratory analysis of the data, however, the investigators “noticed that if they looked just at the subset of patients who had been either ANA [antinuclear antibody] positive or [anti–double-stranded DNA] positive at study entry, they actually could see more patients with a 4-point reduction in the SLEDAI over time at each visit” than in the placebo group, said Dr. Merrill.

Based on this observation, the investigators used the phase II trial data to develop a new SLE Responder Index (SRI) that incorporated components of the SLEDAI, the BILAG (British Isles Lupus Assessment Group) disease activity instrument, and the PGA (Physician Global Assessment).

They used the new instrument as the primary efficacy end point at week 52 in the BLISS-52 (Belimumab in Subjects With Systemic Lupus Erythematosus–52) and BLISS-76 phase III trials, said Dr. Merrill.

In both BLISS trials, belimumab met the efficacy end point, which was defined as a reduction from baseline of at least 4 points on the SLEDAI disease activity scale, no worsening of disease as measured by the PGA, no new BILAG grade A organ domain score, and no more than one new BILAG grade B organ domain score, Dr. Merrill noted.

The differences between the treatment and control groups that were observed in both trials were small but statistically significant, and they were historically meaningful because they put the drug on the pathway for FDA approval, she said.

“This is a major development, not because [belimumab] is expected to be a cure-all or the best treatment for every lupus patient, because it is not,” said Dr. Merrill. Rather, FDA approval of belimumab, if it happens, will break ground for other studies to follow and, after 50 years, “there will finally be an approved therapy that we can hold other [experimental] therapies up against.”

Disclosures: Dr. Merrill has served as a consultant and clinical trialist for Genentech/Roche, Bristol-Myers Squibb Co., MedImmune Inc., and Human Genome Sciences; she has been a consultant for Amgen Inc., UCB Pharma Inc., and Serono Inc.; and she has received grants from Aspreva/Vifor and Wyeth/Pfizer for investigator-initiated studies.

In lupus, 'targeted therapies can only work if you know what you're targeting, in whom, and why.'

Source DR. MERRILL

DESTIN, FLA. — “The problem with drug development in lupus is lupus,” Dr. Joan T. Merrill said at the Congress of Clinical Rheumatology.

“Lupus is an incredibly heterogeneous disease. We know from the results of clinical trials that no one drug can be expected to work for more than 60% of patients with lupus. But we can't yet pick out in advance the subgroup of patients who will respond to a given drug,” she said.

The heterogeneity of the disease across patients and the absence of scientific evidence to explain the biological mechanisms underlying the variations have been impediments to fruitful clinical experimentation, and have led to a series of disappointing clinical trial outcomes, said Dr. Merrill, of the University of Oklahoma in Oklahoma City.

“Targeted therapies can only work if you know what you're targeting, in whom, and why,” she noted. “We have the technology to be able to identify those subsets of patients that we ought to be targeting with each treatment, but we don't have the will.

Additional complications include the inconsistent clinical course of the disease, which is characterized by flares and remissions that make it difficult to assess the impact of investigational therapies and also complicate the selection of meaningful clinical end points, and the need (according to the Food and Drug Administration) to show clinical superiority of the investigational agents over standard treatment, said Dr. Merrill. “The irony, of course, is that the standard of care in lupus is off-label therapy, because there hasn't been a new drug approved for the disease in more than 50 years,” she said.

Because the standard treatments are off label, their therapeutic effect has not been established in clinical trials. “Many clinical trials in lupus have to be carried out for a whole year, and they can't really be performed unless patients are on these background medications, but we don't know what these background medications are doing biologically to patients, or how they are interfering with our assessment of a study agent,” Dr. Merrill said.

Arguably, the potentially promising agents that have failed to achieve intended levels of improvement in patient outcomes in lupus trials—including mycophenolate mofetil (CellCept), abatacept (Orencia), prasterone (Prestara), abetimus sodium (Riquent), and rituximab (Rituxan)—might have demonstrated treatment effects if patient selection had been optimized based on patient-specific biology, if investigators had a better understanding of the impact that background medications have on patient response and adverse events, and if more specific responder indices were available to assess treatment effect, according to Dr. Merrill.

In fact, it is the attention paid to some of these factors that likely contributed to the recent success of two separate phase III trials of belimumab (Benlysta), the monoclonal antibody that targets B-lymphocyte stimulator (BLyS), she said.

In the initial phase II, double-blind, placebo-controlled trial of belimumab in patients with active lupus, the drug failed to improve disease activity as measured by the SLEDAI (Systemic Lupus Erythematosus Disease Activity Index), and did not decrease time to first SLE flare (Arthritis Rheum. 2009;61:1168–78).

In a post hoc exploratory analysis of the data, however, the investigators “noticed that if they looked just at the subset of patients who had been either ANA [antinuclear antibody] positive or [anti–double-stranded DNA] positive at study entry, they actually could see more patients with a 4-point reduction in the SLEDAI over time at each visit” than in the placebo group, said Dr. Merrill.

Based on this observation, the investigators used the phase II trial data to develop a new SLE Responder Index (SRI) that incorporated components of the SLEDAI, the BILAG (British Isles Lupus Assessment Group) disease activity instrument, and the PGA (Physician Global Assessment).

They used the new instrument as the primary efficacy end point at week 52 in the BLISS-52 (Belimumab in Subjects With Systemic Lupus Erythematosus–52) and BLISS-76 phase III trials, said Dr. Merrill.

In both BLISS trials, belimumab met the efficacy end point, which was defined as a reduction from baseline of at least 4 points on the SLEDAI disease activity scale, no worsening of disease as measured by the PGA, no new BILAG grade A organ domain score, and no more than one new BILAG grade B organ domain score, Dr. Merrill noted.

The differences between the treatment and control groups that were observed in both trials were small but statistically significant, and they were historically meaningful because they put the drug on the pathway for FDA approval, she said.

“This is a major development, not because [belimumab] is expected to be a cure-all or the best treatment for every lupus patient, because it is not,” said Dr. Merrill. Rather, FDA approval of belimumab, if it happens, will break ground for other studies to follow and, after 50 years, “there will finally be an approved therapy that we can hold other [experimental] therapies up against.”

Disclosures: Dr. Merrill has served as a consultant and clinical trialist for Genentech/Roche, Bristol-Myers Squibb Co., MedImmune Inc., and Human Genome Sciences; she has been a consultant for Amgen Inc., UCB Pharma Inc., and Serono Inc.; and she has received grants from Aspreva/Vifor and Wyeth/Pfizer for investigator-initiated studies.

In lupus, 'targeted therapies can only work if you know what you're targeting, in whom, and why.'

Source DR. MERRILL