New Lupus Drugs Remain Elusive After 50 Years

FORT LAUDERDALE, FLA. — The saga of mycophenolate mofetil for lupus exemplifies the difficulties in developing new drugs for the condition, for which there has not been a new approval in half a century.

“An important question is whether the newer drugs don't work, or whether we're not testing them and measuring response correctly,” said Dr. Susan Manzi, director of the Lupus Center of Excellence at the University of Pittsburgh.

Only corticosteroids, hydroxychloroquine, and aspirin have FDA approval for systemic lupus erythematosus (SLE). And although current off-label therapy often also includes nonsteroidal anti-inflammatory drugs, cyclophosphamide, azathioprine, and cyclosporine, newer immunosuppressants and biologic agents have had disappointing results in lupus, according to Dr. Manzi.

Mycophenylate mofetil (MMF) is an example, having been compared with cyclophosphamide in three randomized trials. Cyclophosphamide is generally considered effective—if toxic—although randomized data are lacking and the drug is not FDA approved for SLE.

“We all got very excited about MMF when the first study came out in 2000,” she said. That study included 42 patients with diffuse proliferative lupus nephritis who were randomized to receive either oral MMF plus prednisolone for 12 months or oral cyclophosphamide plus prednisolone for 6 months, followed by azathioprine plus prednisolone for an additional 6 months. The investigators found that MMF was as effective as cyclophosphamide but less toxic, with 17 (81%) and 16 (76%) of the MMF and cyclophosphamide patients, respectively, achieving complete remission (N. Engl. J. Med. 2000;343:1156–62).

This was followed in 2005 by an open-label noninferiority trial that compared MMF in doses up to 3,000 mg/day with monthly intravenous cyclophosphamide (0.5–1.0 g/m

In this trial, too, MMF was more effective than cyclophosphamide, with 23% of MMF patients and 6% of cyclophosphamide patients achieving complete remission. The safety profile also was better with MMF, with no cases of amenorrhea, compared with three cases in the cyclophosphamide group (N. Engl. J. Med. 2005;353:2219–28).

“I think most people said MMF might be a good drug for patients without rapidly progressive disease,” Dr. Manzi said at a meeting sponsored by RHEUMATOLOGY NEWS and the Skin Disease Education Foundation.

But then came the Aspreva Lupus Management Study, a large industry-sponsored randomized trial, presented as a late-breaking abstract at the 2007 American College of Rheumatology (ACR) meeting. This superiority study randomized 370 patients with class III-V lupus nephritis to 24 weeks of MMF in target doses of 3 g/day or intravenous cyclophosphamide at 0.5–1.0 g/m

With 56% of MMF patients and 53% of cyclophosphamide patients responding, the study did not meet its primary efficacy end point of showing superiority for MMF. Moreover, there was no difference between the groups in terms of adverse events.

“Even though MMF performed the same as cyclophosphamide in this trial, the FDA's view is: That is not good enough. Because cyclophosphamide is not approved, it is considered the same as placebo, and you have to do better than placebo,” she said. “So even though three randomized trials have shown that efficacy and safety are equal to or better than cyclophosphamide in lupus nephritis, MMF is not approved.”

Other agents also are being tested, with mixed results. In a phase II study, belimumab did not meet the primary outcome measure, but a post hoc analysis found that many patients in the trial were not serologically positive. A phase III trial is underway.

At the 2008 ACR annual meeting, results for trials of rituximab and abatacept were presented as late-breaking abstracts. In a phase II/III study that included 257 patients with moderate to severe extrarenal lupus, there were no differences between patients who received rituximab and those who got placebo on any clinical end points.

In an exploratory phase II trial, 175 patients whose primary disease manifestations were discoid rash, polyarthritis, or serositis were randomized to receive prednisone plus abatacept, 10 mg/kg, or placebo by intravenous infusion on days 1, 15, and 29 and then every 4 weeks for 1 year. This again was negative, with 79% and 82% of patients in the abatacept and placebo groups flaring when the steroids were tapered.

“So lupus is still a complex disease, and measuring response remains incredibly challenging,” said Dr. Manzi.

Dr. Manzi receives grant research support and is on the speakers bureau for multiple companies including Aspreva Pharmaceuticals Corp., maker of MMF.

Both the SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

'Lupus is still a complex disease, and measuring response remains incredibly challenging.' DR. MANZI

FORT LAUDERDALE, FLA. — The saga of mycophenolate mofetil for lupus exemplifies the difficulties in developing new drugs for the condition, for which there has not been a new approval in half a century.

“An important question is whether the newer drugs don't work, or whether we're not testing them and measuring response correctly,” said Dr. Susan Manzi, director of the Lupus Center of Excellence at the University of Pittsburgh.

Only corticosteroids, hydroxychloroquine, and aspirin have FDA approval for systemic lupus erythematosus (SLE). And although current off-label therapy often also includes nonsteroidal anti-inflammatory drugs, cyclophosphamide, azathioprine, and cyclosporine, newer immunosuppressants and biologic agents have had disappointing results in lupus, according to Dr. Manzi.

Mycophenylate mofetil (MMF) is an example, having been compared with cyclophosphamide in three randomized trials. Cyclophosphamide is generally considered effective—if toxic—although randomized data are lacking and the drug is not FDA approved for SLE.

“We all got very excited about MMF when the first study came out in 2000,” she said. That study included 42 patients with diffuse proliferative lupus nephritis who were randomized to receive either oral MMF plus prednisolone for 12 months or oral cyclophosphamide plus prednisolone for 6 months, followed by azathioprine plus prednisolone for an additional 6 months. The investigators found that MMF was as effective as cyclophosphamide but less toxic, with 17 (81%) and 16 (76%) of the MMF and cyclophosphamide patients, respectively, achieving complete remission (N. Engl. J. Med. 2000;343:1156–62).

This was followed in 2005 by an open-label noninferiority trial that compared MMF in doses up to 3,000 mg/day with monthly intravenous cyclophosphamide (0.5–1.0 g/m

In this trial, too, MMF was more effective than cyclophosphamide, with 23% of MMF patients and 6% of cyclophosphamide patients achieving complete remission. The safety profile also was better with MMF, with no cases of amenorrhea, compared with three cases in the cyclophosphamide group (N. Engl. J. Med. 2005;353:2219–28).

“I think most people said MMF might be a good drug for patients without rapidly progressive disease,” Dr. Manzi said at a meeting sponsored by RHEUMATOLOGY NEWS and the Skin Disease Education Foundation.

But then came the Aspreva Lupus Management Study, a large industry-sponsored randomized trial, presented as a late-breaking abstract at the 2007 American College of Rheumatology (ACR) meeting. This superiority study randomized 370 patients with class III-V lupus nephritis to 24 weeks of MMF in target doses of 3 g/day or intravenous cyclophosphamide at 0.5–1.0 g/m

With 56% of MMF patients and 53% of cyclophosphamide patients responding, the study did not meet its primary efficacy end point of showing superiority for MMF. Moreover, there was no difference between the groups in terms of adverse events.

“Even though MMF performed the same as cyclophosphamide in this trial, the FDA's view is: That is not good enough. Because cyclophosphamide is not approved, it is considered the same as placebo, and you have to do better than placebo,” she said. “So even though three randomized trials have shown that efficacy and safety are equal to or better than cyclophosphamide in lupus nephritis, MMF is not approved.”

Other agents also are being tested, with mixed results. In a phase II study, belimumab did not meet the primary outcome measure, but a post hoc analysis found that many patients in the trial were not serologically positive. A phase III trial is underway.

At the 2008 ACR annual meeting, results for trials of rituximab and abatacept were presented as late-breaking abstracts. In a phase II/III study that included 257 patients with moderate to severe extrarenal lupus, there were no differences between patients who received rituximab and those who got placebo on any clinical end points.

In an exploratory phase II trial, 175 patients whose primary disease manifestations were discoid rash, polyarthritis, or serositis were randomized to receive prednisone plus abatacept, 10 mg/kg, or placebo by intravenous infusion on days 1, 15, and 29 and then every 4 weeks for 1 year. This again was negative, with 79% and 82% of patients in the abatacept and placebo groups flaring when the steroids were tapered.

“So lupus is still a complex disease, and measuring response remains incredibly challenging,” said Dr. Manzi.

Dr. Manzi receives grant research support and is on the speakers bureau for multiple companies including Aspreva Pharmaceuticals Corp., maker of MMF.

Both the SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

'Lupus is still a complex disease, and measuring response remains incredibly challenging.' DR. MANZI

FORT LAUDERDALE, FLA. — The saga of mycophenolate mofetil for lupus exemplifies the difficulties in developing new drugs for the condition, for which there has not been a new approval in half a century.

“An important question is whether the newer drugs don't work, or whether we're not testing them and measuring response correctly,” said Dr. Susan Manzi, director of the Lupus Center of Excellence at the University of Pittsburgh.

Only corticosteroids, hydroxychloroquine, and aspirin have FDA approval for systemic lupus erythematosus (SLE). And although current off-label therapy often also includes nonsteroidal anti-inflammatory drugs, cyclophosphamide, azathioprine, and cyclosporine, newer immunosuppressants and biologic agents have had disappointing results in lupus, according to Dr. Manzi.

Mycophenylate mofetil (MMF) is an example, having been compared with cyclophosphamide in three randomized trials. Cyclophosphamide is generally considered effective—if toxic—although randomized data are lacking and the drug is not FDA approved for SLE.

“We all got very excited about MMF when the first study came out in 2000,” she said. That study included 42 patients with diffuse proliferative lupus nephritis who were randomized to receive either oral MMF plus prednisolone for 12 months or oral cyclophosphamide plus prednisolone for 6 months, followed by azathioprine plus prednisolone for an additional 6 months. The investigators found that MMF was as effective as cyclophosphamide but less toxic, with 17 (81%) and 16 (76%) of the MMF and cyclophosphamide patients, respectively, achieving complete remission (N. Engl. J. Med. 2000;343:1156–62).

This was followed in 2005 by an open-label noninferiority trial that compared MMF in doses up to 3,000 mg/day with monthly intravenous cyclophosphamide (0.5–1.0 g/m

In this trial, too, MMF was more effective than cyclophosphamide, with 23% of MMF patients and 6% of cyclophosphamide patients achieving complete remission. The safety profile also was better with MMF, with no cases of amenorrhea, compared with three cases in the cyclophosphamide group (N. Engl. J. Med. 2005;353:2219–28).

“I think most people said MMF might be a good drug for patients without rapidly progressive disease,” Dr. Manzi said at a meeting sponsored by RHEUMATOLOGY NEWS and the Skin Disease Education Foundation.

But then came the Aspreva Lupus Management Study, a large industry-sponsored randomized trial, presented as a late-breaking abstract at the 2007 American College of Rheumatology (ACR) meeting. This superiority study randomized 370 patients with class III-V lupus nephritis to 24 weeks of MMF in target doses of 3 g/day or intravenous cyclophosphamide at 0.5–1.0 g/m

With 56% of MMF patients and 53% of cyclophosphamide patients responding, the study did not meet its primary efficacy end point of showing superiority for MMF. Moreover, there was no difference between the groups in terms of adverse events.

“Even though MMF performed the same as cyclophosphamide in this trial, the FDA's view is: That is not good enough. Because cyclophosphamide is not approved, it is considered the same as placebo, and you have to do better than placebo,” she said. “So even though three randomized trials have shown that efficacy and safety are equal to or better than cyclophosphamide in lupus nephritis, MMF is not approved.”

Other agents also are being tested, with mixed results. In a phase II study, belimumab did not meet the primary outcome measure, but a post hoc analysis found that many patients in the trial were not serologically positive. A phase III trial is underway.

At the 2008 ACR annual meeting, results for trials of rituximab and abatacept were presented as late-breaking abstracts. In a phase II/III study that included 257 patients with moderate to severe extrarenal lupus, there were no differences between patients who received rituximab and those who got placebo on any clinical end points.

In an exploratory phase II trial, 175 patients whose primary disease manifestations were discoid rash, polyarthritis, or serositis were randomized to receive prednisone plus abatacept, 10 mg/kg, or placebo by intravenous infusion on days 1, 15, and 29 and then every 4 weeks for 1 year. This again was negative, with 79% and 82% of patients in the abatacept and placebo groups flaring when the steroids were tapered.

“So lupus is still a complex disease, and measuring response remains incredibly challenging,” said Dr. Manzi.

Dr. Manzi receives grant research support and is on the speakers bureau for multiple companies including Aspreva Pharmaceuticals Corp., maker of MMF.

Both the SDEF and RHEUMATOLOGY NEWS are owned by Elsevier.

'Lupus is still a complex disease, and measuring response remains incredibly challenging.' DR. MANZI