Design flaws hamper lupus nephritis biologic trials

NEW YORK – Evidence for the use of biologics such as rituximab and abatacept to treat refractory lupus nephritis has been hampered by varying definitions of the condition and design differences in clinical trials, according to Dr. Brad H. Rovin.

Evidence of the benefit to using rituximab 1 g every 2 weeks for refractory lupus nephritis, as suggested by the American College of Rheumatology’s guidelines (Arthritis Care Res. 2012;64:797-808), is hard to confirm with the available data, Dr. Rovin said at a meeting sponsored by New York University.

"The rituximab studies are very difficult to interpret due to small sample size, aggressive concomitant therapies, variable dosing regimens, and nonuniform definitions of refractory," said Dr. Rovin, professor of nephrology and pathology and director of the division of nephrology at Ohio State University in Columbus. "Nonetheless, this collection of data has prompted the idea that rituximab is effective for refractory lupus nephritis."

Although pooled data suggest that rituximab might be helpful in refractory lupus nephritis (Autoimmun. Rev. 2012:11:357-64), only a true randomized controlled trial with sufficient power that is designed to overcome these criticisms will settle the issue, he noted. The European RING (Rituximab for Lupus Nephritis With Remission as a Goal) trial, which started in November 2012, will initially ask whether rituximab can be a useful salvage therapy once a patient still has active disease after 6 months of standard-of-care treatment. However, in Dr. Rovin’s opinion, the patients being recruited for the trial are not truly refractory because the failure of two inductiontype regimens before beginning rituximab is not required.

Examining the LUNAR trial failure

The randomized, double-blind, placebo-controlled phase III LUNAR (Lupus Nephritis Assessment With Rituximab) trial – one of the most anticipated clinical trials of lupus nephritis treatment – failed to reach its primary endpoint (Arthritis Rheum. 2012;64:1215-26), said Dr. Rovin, who was the lead author of the report. In fact, in the last few years, none of the trials of novel therapeutics for lupus nephritis have achieved their primary endpoints.

The primary endpoint of renal response (complete and partial) at week 52 was similar in patients who received rituximab or placebo (56.0% vs. 45.8%, respectively), although improvements were seen with rituximab in serum C3 and C4 and anti–double-stranded DNA antibodies. The trial involved 144 patients with class III or IV lupus nephritis treated with rituximab (1,000 mg) or placebo added on to mycophenolate mofetil and corticosteroids. Patients received rituximab or placebo on days 1, 15, 168, and 182.

Did LUNAR fail because it was added on to an already effective therapy? Dr. Rovin asked. He pointed to data from studies of other current therapies, including intravenous cyclophosphamide, which showed relatively high partial responses (63%) but low complete responses (12%-31%). "Current therapies are only modestly effective, and there is plenty of room for improvement. Evaluating add-on therapies to the standard of care is an acceptable trial design for what we can accomplish now," Dr. Rovin said.

The LUNAR trial was powered to detect complete renal remissions, and its failure to detect a difference between treatment groups does not mean that the trial should have been powered to favor partial remissions, Dr. Rovin said. In a study in which he participated that was presented last year at the American Society of Nephrology, Dr. Rovin and his colleagues found that over a period of 4.5 years, patients who have acute kidney injury as evidenced by renal flares were at heightened risk of developing new chronic kidney disease (CKD) or progression of established kidney disease. Patients with new CKD had a significantly greater frequency of new renal flares than did those without CKD (0.72 per year vs. 0.14 per year; P = .001) as well as a greater duration of time spent in flare (20 months vs. 0 months; P = .0003). These results show that "we should not be satisfied with partial remissions as an endpoint, because unresolved kidney inflammation and injury predispose these patients to CKD," he said.

The issue has also been raised as to whether LUNAR failed because its endpoint of 1 year was too short. There may have been better separation between rituximab and placebo with a 2-year endpoint, but Dr. Rovin’s own findings with repeat biopsies following good clinical responses after the first 6 months of conventional therapy (mycophenolate mofetil or intravenous cyclophosphamide for 6 months) have shown evidence of progressive renal scarring despite significant reductions in creatinine and proteinuria. These data suggest that the goal of therapy should be to decrease the time to response as much as possible and thereby perhaps decrease kidney scarring because scarring and damage to the kidney tubulointerstitium are what determine the renal prognosis. "We should not be satisfied with taking a year or more to achieve remissions," he said.

Failure of abatacept lupus nephritis trial

The failure of another recent trial to show any benefit of abatacept in treating refractory lupus nephritis could also be related to the problem of inconsistent trial endpoints making it difficult to compare therapies (Arthritis Rheum. 2012;64:3660-5). For instance, urine protein-creatinine ratios (UPCRs) are subject to individual variability but the criteria for UPCRs have varied from 0.2 to 0.5 in different lupus nephritis trials, including this abatacept trial, the LUNAR trial, the Aspreva Lupus Management Study (ALMS), and the Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS) trial, as well as in the ACR’s recommendations for lupus nephritis.

Estimated glomerular filtration rate (eGFR) criteria also are inconsistent, and endpoints that refer to "normal" eGFRs are hard to interpret, Dr. Rovin said, because it is unclear what is normal for creatine "unless the patient’s true serum creatinine before SLE is known."

"We need uniform, reasonable and consistent response criteria for lupus nephritis clinical trials, and these responses should be associated with long-term outcomes," said Dr. Rovin, who noted that he is involved in preparing a white paper on clinical trial design for lupus nephritis.

Dr. Rovin has served as a consultant to Bristol-Myers Squibb, which markets abatacept, as well as Biogen Idec and Genentech, which comarket rituximab in the United States. He has also received honoraria from Biogen Idec and Genentech and research funding from Roche, Genentech’s parent company.

NEW YORK – Evidence for the use of biologics such as rituximab and abatacept to treat refractory lupus nephritis has been hampered by varying definitions of the condition and design differences in clinical trials, according to Dr. Brad H. Rovin.

Evidence of the benefit to using rituximab 1 g every 2 weeks for refractory lupus nephritis, as suggested by the American College of Rheumatology’s guidelines (Arthritis Care Res. 2012;64:797-808), is hard to confirm with the available data, Dr. Rovin said at a meeting sponsored by New York University.

"The rituximab studies are very difficult to interpret due to small sample size, aggressive concomitant therapies, variable dosing regimens, and nonuniform definitions of refractory," said Dr. Rovin, professor of nephrology and pathology and director of the division of nephrology at Ohio State University in Columbus. "Nonetheless, this collection of data has prompted the idea that rituximab is effective for refractory lupus nephritis."

Although pooled data suggest that rituximab might be helpful in refractory lupus nephritis (Autoimmun. Rev. 2012:11:357-64), only a true randomized controlled trial with sufficient power that is designed to overcome these criticisms will settle the issue, he noted. The European RING (Rituximab for Lupus Nephritis With Remission as a Goal) trial, which started in November 2012, will initially ask whether rituximab can be a useful salvage therapy once a patient still has active disease after 6 months of standard-of-care treatment. However, in Dr. Rovin’s opinion, the patients being recruited for the trial are not truly refractory because the failure of two inductiontype regimens before beginning rituximab is not required.

Examining the LUNAR trial failure

The randomized, double-blind, placebo-controlled phase III LUNAR (Lupus Nephritis Assessment With Rituximab) trial – one of the most anticipated clinical trials of lupus nephritis treatment – failed to reach its primary endpoint (Arthritis Rheum. 2012;64:1215-26), said Dr. Rovin, who was the lead author of the report. In fact, in the last few years, none of the trials of novel therapeutics for lupus nephritis have achieved their primary endpoints.

The primary endpoint of renal response (complete and partial) at week 52 was similar in patients who received rituximab or placebo (56.0% vs. 45.8%, respectively), although improvements were seen with rituximab in serum C3 and C4 and anti–double-stranded DNA antibodies. The trial involved 144 patients with class III or IV lupus nephritis treated with rituximab (1,000 mg) or placebo added on to mycophenolate mofetil and corticosteroids. Patients received rituximab or placebo on days 1, 15, 168, and 182.

Did LUNAR fail because it was added on to an already effective therapy? Dr. Rovin asked. He pointed to data from studies of other current therapies, including intravenous cyclophosphamide, which showed relatively high partial responses (63%) but low complete responses (12%-31%). "Current therapies are only modestly effective, and there is plenty of room for improvement. Evaluating add-on therapies to the standard of care is an acceptable trial design for what we can accomplish now," Dr. Rovin said.

The LUNAR trial was powered to detect complete renal remissions, and its failure to detect a difference between treatment groups does not mean that the trial should have been powered to favor partial remissions, Dr. Rovin said. In a study in which he participated that was presented last year at the American Society of Nephrology, Dr. Rovin and his colleagues found that over a period of 4.5 years, patients who have acute kidney injury as evidenced by renal flares were at heightened risk of developing new chronic kidney disease (CKD) or progression of established kidney disease. Patients with new CKD had a significantly greater frequency of new renal flares than did those without CKD (0.72 per year vs. 0.14 per year; P = .001) as well as a greater duration of time spent in flare (20 months vs. 0 months; P = .0003). These results show that "we should not be satisfied with partial remissions as an endpoint, because unresolved kidney inflammation and injury predispose these patients to CKD," he said.

The issue has also been raised as to whether LUNAR failed because its endpoint of 1 year was too short. There may have been better separation between rituximab and placebo with a 2-year endpoint, but Dr. Rovin’s own findings with repeat biopsies following good clinical responses after the first 6 months of conventional therapy (mycophenolate mofetil or intravenous cyclophosphamide for 6 months) have shown evidence of progressive renal scarring despite significant reductions in creatinine and proteinuria. These data suggest that the goal of therapy should be to decrease the time to response as much as possible and thereby perhaps decrease kidney scarring because scarring and damage to the kidney tubulointerstitium are what determine the renal prognosis. "We should not be satisfied with taking a year or more to achieve remissions," he said.

Failure of abatacept lupus nephritis trial

The failure of another recent trial to show any benefit of abatacept in treating refractory lupus nephritis could also be related to the problem of inconsistent trial endpoints making it difficult to compare therapies (Arthritis Rheum. 2012;64:3660-5). For instance, urine protein-creatinine ratios (UPCRs) are subject to individual variability but the criteria for UPCRs have varied from 0.2 to 0.5 in different lupus nephritis trials, including this abatacept trial, the LUNAR trial, the Aspreva Lupus Management Study (ALMS), and the Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS) trial, as well as in the ACR’s recommendations for lupus nephritis.

Estimated glomerular filtration rate (eGFR) criteria also are inconsistent, and endpoints that refer to "normal" eGFRs are hard to interpret, Dr. Rovin said, because it is unclear what is normal for creatine "unless the patient’s true serum creatinine before SLE is known."

"We need uniform, reasonable and consistent response criteria for lupus nephritis clinical trials, and these responses should be associated with long-term outcomes," said Dr. Rovin, who noted that he is involved in preparing a white paper on clinical trial design for lupus nephritis.

Dr. Rovin has served as a consultant to Bristol-Myers Squibb, which markets abatacept, as well as Biogen Idec and Genentech, which comarket rituximab in the United States. He has also received honoraria from Biogen Idec and Genentech and research funding from Roche, Genentech’s parent company.

NEW YORK – Evidence for the use of biologics such as rituximab and abatacept to treat refractory lupus nephritis has been hampered by varying definitions of the condition and design differences in clinical trials, according to Dr. Brad H. Rovin.

Evidence of the benefit to using rituximab 1 g every 2 weeks for refractory lupus nephritis, as suggested by the American College of Rheumatology’s guidelines (Arthritis Care Res. 2012;64:797-808), is hard to confirm with the available data, Dr. Rovin said at a meeting sponsored by New York University.

"The rituximab studies are very difficult to interpret due to small sample size, aggressive concomitant therapies, variable dosing regimens, and nonuniform definitions of refractory," said Dr. Rovin, professor of nephrology and pathology and director of the division of nephrology at Ohio State University in Columbus. "Nonetheless, this collection of data has prompted the idea that rituximab is effective for refractory lupus nephritis."

Although pooled data suggest that rituximab might be helpful in refractory lupus nephritis (Autoimmun. Rev. 2012:11:357-64), only a true randomized controlled trial with sufficient power that is designed to overcome these criticisms will settle the issue, he noted. The European RING (Rituximab for Lupus Nephritis With Remission as a Goal) trial, which started in November 2012, will initially ask whether rituximab can be a useful salvage therapy once a patient still has active disease after 6 months of standard-of-care treatment. However, in Dr. Rovin’s opinion, the patients being recruited for the trial are not truly refractory because the failure of two inductiontype regimens before beginning rituximab is not required.

Examining the LUNAR trial failure

The randomized, double-blind, placebo-controlled phase III LUNAR (Lupus Nephritis Assessment With Rituximab) trial – one of the most anticipated clinical trials of lupus nephritis treatment – failed to reach its primary endpoint (Arthritis Rheum. 2012;64:1215-26), said Dr. Rovin, who was the lead author of the report. In fact, in the last few years, none of the trials of novel therapeutics for lupus nephritis have achieved their primary endpoints.

The primary endpoint of renal response (complete and partial) at week 52 was similar in patients who received rituximab or placebo (56.0% vs. 45.8%, respectively), although improvements were seen with rituximab in serum C3 and C4 and anti–double-stranded DNA antibodies. The trial involved 144 patients with class III or IV lupus nephritis treated with rituximab (1,000 mg) or placebo added on to mycophenolate mofetil and corticosteroids. Patients received rituximab or placebo on days 1, 15, 168, and 182.

Did LUNAR fail because it was added on to an already effective therapy? Dr. Rovin asked. He pointed to data from studies of other current therapies, including intravenous cyclophosphamide, which showed relatively high partial responses (63%) but low complete responses (12%-31%). "Current therapies are only modestly effective, and there is plenty of room for improvement. Evaluating add-on therapies to the standard of care is an acceptable trial design for what we can accomplish now," Dr. Rovin said.

The LUNAR trial was powered to detect complete renal remissions, and its failure to detect a difference between treatment groups does not mean that the trial should have been powered to favor partial remissions, Dr. Rovin said. In a study in which he participated that was presented last year at the American Society of Nephrology, Dr. Rovin and his colleagues found that over a period of 4.5 years, patients who have acute kidney injury as evidenced by renal flares were at heightened risk of developing new chronic kidney disease (CKD) or progression of established kidney disease. Patients with new CKD had a significantly greater frequency of new renal flares than did those without CKD (0.72 per year vs. 0.14 per year; P = .001) as well as a greater duration of time spent in flare (20 months vs. 0 months; P = .0003). These results show that "we should not be satisfied with partial remissions as an endpoint, because unresolved kidney inflammation and injury predispose these patients to CKD," he said.

The issue has also been raised as to whether LUNAR failed because its endpoint of 1 year was too short. There may have been better separation between rituximab and placebo with a 2-year endpoint, but Dr. Rovin’s own findings with repeat biopsies following good clinical responses after the first 6 months of conventional therapy (mycophenolate mofetil or intravenous cyclophosphamide for 6 months) have shown evidence of progressive renal scarring despite significant reductions in creatinine and proteinuria. These data suggest that the goal of therapy should be to decrease the time to response as much as possible and thereby perhaps decrease kidney scarring because scarring and damage to the kidney tubulointerstitium are what determine the renal prognosis. "We should not be satisfied with taking a year or more to achieve remissions," he said.

Failure of abatacept lupus nephritis trial

The failure of another recent trial to show any benefit of abatacept in treating refractory lupus nephritis could also be related to the problem of inconsistent trial endpoints making it difficult to compare therapies (Arthritis Rheum. 2012;64:3660-5). For instance, urine protein-creatinine ratios (UPCRs) are subject to individual variability but the criteria for UPCRs have varied from 0.2 to 0.5 in different lupus nephritis trials, including this abatacept trial, the LUNAR trial, the Aspreva Lupus Management Study (ALMS), and the Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS) trial, as well as in the ACR’s recommendations for lupus nephritis.

Estimated glomerular filtration rate (eGFR) criteria also are inconsistent, and endpoints that refer to "normal" eGFRs are hard to interpret, Dr. Rovin said, because it is unclear what is normal for creatine "unless the patient’s true serum creatinine before SLE is known."

"We need uniform, reasonable and consistent response criteria for lupus nephritis clinical trials, and these responses should be associated with long-term outcomes," said Dr. Rovin, who noted that he is involved in preparing a white paper on clinical trial design for lupus nephritis.

Dr. Rovin has served as a consultant to Bristol-Myers Squibb, which markets abatacept, as well as Biogen Idec and Genentech, which comarket rituximab in the United States. He has also received honoraria from Biogen Idec and Genentech and research funding from Roche, Genentech’s parent company.