FDA wants more data before approving alemtuzumab for MS

The Food and Drug Administration has declined to approve alemtuzumab for the treatment of multiple sclerosis, citing a lack of well-controlled data from clinical studies indicating the benefits outweigh the risks of treatment – a decision that Genzyme, the manufacturer, plans to appeal.

The company announced in a Dec. 30 statement that the agency had sent a "Complete Response Letter" regarding alemtuzumab, an intravenously infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent to manufacturers when the FDA decides against approval, with explanations of outstanding issues that need to be resolved. The FDA does not publicly announce when these letters are issued, but manufacturers often do so.

The proposed indication for alemtuzumab is for treatment of relapsing forms of MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

"FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects," according to the Genzyme statement. "The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients," and the FDA has also said that one or more "additional active comparator clinical trials of different design and execution" are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it "strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision." No other details about the appeal were provided by the company, which is owned by Sanofi.

FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November of 2013, and in documents provided before the meeting.

The FDA raised issues about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed the unblinded studies were likely biased, the majority voted 12-6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

In an interview, one of the investigators in the studies, Dr. Jonathan Carter, a consultant in the department of neurology at the Mayo Clinic in Scottsdale, Ariz., said he understood the FDA’s concerns about toxicity, and if it had been approved, alemtuzumab would probably have been designated a second- or third-line therapy. However, the decision is disappointing, since there is an unmet need for treatment in patients "who have broken through the standard first-line therapies," who do not have many options, particularly those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri), he said.

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared to those on Rebif, supported efficacy.

Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia.

Dr. Carter said he had no disclosures, other than being an investigator in the study.

[email protected]

The Food and Drug Administration has declined to approve alemtuzumab for the treatment of multiple sclerosis, citing a lack of well-controlled data from clinical studies indicating the benefits outweigh the risks of treatment – a decision that Genzyme, the manufacturer, plans to appeal.

The company announced in a Dec. 30 statement that the agency had sent a "Complete Response Letter" regarding alemtuzumab, an intravenously infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent to manufacturers when the FDA decides against approval, with explanations of outstanding issues that need to be resolved. The FDA does not publicly announce when these letters are issued, but manufacturers often do so.

The proposed indication for alemtuzumab is for treatment of relapsing forms of MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

"FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects," according to the Genzyme statement. "The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients," and the FDA has also said that one or more "additional active comparator clinical trials of different design and execution" are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it "strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision." No other details about the appeal were provided by the company, which is owned by Sanofi.

FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November of 2013, and in documents provided before the meeting.

The FDA raised issues about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed the unblinded studies were likely biased, the majority voted 12-6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

In an interview, one of the investigators in the studies, Dr. Jonathan Carter, a consultant in the department of neurology at the Mayo Clinic in Scottsdale, Ariz., said he understood the FDA’s concerns about toxicity, and if it had been approved, alemtuzumab would probably have been designated a second- or third-line therapy. However, the decision is disappointing, since there is an unmet need for treatment in patients "who have broken through the standard first-line therapies," who do not have many options, particularly those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri), he said.

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared to those on Rebif, supported efficacy.

Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia.

Dr. Carter said he had no disclosures, other than being an investigator in the study.

[email protected]

The Food and Drug Administration has declined to approve alemtuzumab for the treatment of multiple sclerosis, citing a lack of well-controlled data from clinical studies indicating the benefits outweigh the risks of treatment – a decision that Genzyme, the manufacturer, plans to appeal.

The company announced in a Dec. 30 statement that the agency had sent a "Complete Response Letter" regarding alemtuzumab, an intravenously infused monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Complete response letters are sent to manufacturers when the FDA decides against approval, with explanations of outstanding issues that need to be resolved. The FDA does not publicly announce when these letters are issued, but manufacturers often do so.

The proposed indication for alemtuzumab is for treatment of relapsing forms of MS, with a risk evaluation and mitigation strategy (REMS) that addresses the drug’s serious risks, which include immune thrombocytopenia and thyroid-related adverse events. The company’s proposed trade name for the MS indication for alemtuzumab is Lemtrada.

"FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects," according to the Genzyme statement. "The conclusion is related to the design of the completed [phase III] active comparator studies of Lemtrada in relapsing-remitting MS patients," and the FDA has also said that one or more "additional active comparator clinical trials of different design and execution" are needed before alemtuzumab is approved for MS, the statement said.

In the statement, Genzyme said that it "strongly disagrees with the FDA’s conclusions and plans to appeal the agency’s decision." No other details about the appeal were provided by the company, which is owned by Sanofi.

FDA reviewers made their concerns about alemtuzumab clear at a meeting of the FDA’s Peripheral and Central Nervous System advisory committee in November of 2013, and in documents provided before the meeting.

The FDA raised issues about the elevated rates of serious adverse events in patients treated with alemtuzumab and the open-label design of the clinical trials, questioning whether bias had an impact on the efficacy results. Patients and clinicians were not blinded to the treatment in those studies, which compared alemtuzumab to subcutaneous interferon beta-1a (Rebif) in about 1,400 patients and found significant reductions in the relapse rates among those treated with alemtuzumab (49% and 55%), compared with those on Rebif.

The advisory panel did not vote specifically on whether to recommend approval for MS. But while panelists agreed the unblinded studies were likely biased, the majority voted 12-6 that the manufacturer had provided substantial evidence that the drug was effective for the proposed indication. Several panelists said they would recommend the drug only for patients with severe MS, as a second- or third-line treatment.

In an interview, one of the investigators in the studies, Dr. Jonathan Carter, a consultant in the department of neurology at the Mayo Clinic in Scottsdale, Ariz., said he understood the FDA’s concerns about toxicity, and if it had been approved, alemtuzumab would probably have been designated a second- or third-line therapy. However, the decision is disappointing, since there is an unmet need for treatment in patients "who have broken through the standard first-line therapies," who do not have many options, particularly those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri), he said.

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out it can be difficult to maintain blinding of patients and clinicians in studies of products with marked side effects, such as infusion reactions. Despite the potential effects of unblinding on clinical outcome measures, however, he noted that MRI data showing less enhancing lesion activity in alemtuzumab-treated patients, compared to those on Rebif, supported efficacy.

Alemtuzumab was approved by the FDA in 2001 and marketed as Campath for B-cell chronic lymphocytic leukemia in the United States. But in September 2012, the company took Campath off the market and is providing it free of charge to leukemia patients in a distribution program. Alemtuzumab has been approved for MS in the European Union, Canada, and Australia.

Dr. Carter said he had no disclosures, other than being an investigator in the study.

[email protected]