FDA Wants More Data Before Approving Alemtuzumab for MS

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-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 when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting 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.

“The 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.” The FDA 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.”

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

The FDA raised concerns 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 that 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.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that 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 with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
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. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-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 when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting 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.

“The 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.” The FDA 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.”

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

The FDA raised concerns 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 that 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.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that 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 with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
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. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams

The FDA has declined to approve alemtuzumab for the treatment of multiple sclerosis (MS), citing a lack of well-controlled data from clinical studies indicating that the benefits outweigh the risks of treatment—a decision that Genzyme, the manufacturer, plans to appeal.

Genzyme announced in a December 30, 2013, statement that the FDA had sent a Complete Response Letter regarding alemtuzumab, an IV-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 when the FDA decides against approval, with explanations of outstanding issues that need to be resolved.

The proposed indication for alemtuzumab is for treatment of relapsing-remitting 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.

“The 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.” The FDA 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.”

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

The FDA raised concerns 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 that 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.

Study Investigators Comment
In an interview, one of the investigators in the studies, Jonathan L. Carter, MD, Associate Professor of Neurology at the Mayo Clinic in Scottsdale, Arizona, said the decision is disappointing because patients “who have broken through the standard first-line therapies” have an unmet need for treatment.

Another investigator, Lily K. Jung Henson, MD, concurs. “I don’t think the FDA recognizes that there is a need for alternative therapies with mechanisms of action that patients who have failed multiple therapies need.” Dr. Henson is a neurologist at the Swedish Neuroscience Institute in Seattle. “I have—and most of us who have large patient populations have—patients who have failed everything else, including natalizumab [Tysabri], and are holding on, waiting for this drug to be released and now have no options.”

Dr. Carter acknowledged the FDA reviewers’ concerns about the effect of unblinding, although he pointed out that 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 with those on Rebif, supported the drug’s efficacy.

On the issue of blinding, another investigator, Christopher C. LaGanke, MD, added that the phase III alemtuzumab studies were rater blinded. “The Expanded Disability Status Scale scores were done by a blinded rater. The relapses were looked at by an adjudication panel that was blinded to any treatment that the patients may have had. The raters of the neurocognitive test, the MS Functional Composite Score, were blinded, and the MRI raters were blinded. So the main assessors were blinded to what the treatment was.” Due to the side effect profiles of the medications, however, patient blinding would have been extremely difficult. “We would like to have everyone blinded in the study. That’s a goal, but here it was not very feasible,” said Dr. LaGanke, who is a private neurologist at North Central Neurology Associates, as well as Director of the Joanne P. LaGanke Multiple Sclerosis Center, both in Cullman, Alabama.

“If the FDA was going to make this decision a priori given the lack of blinding of the study, then I’m concerned that they ethically allowed my patients to take the risk and the sacrifices that they did to enroll and maintain themselves in this study,” Dr. LaGanke said. “And the results were no surprise from the phase II study; so at the end of the day, this has been the most effective treatment we’ve had for relapsing MS, as far as several outcomes, of any of our approved medications, and there was no novel safety signal. It wasn’t that there were differences in the results that would have created a difference in their opinion. So that really concerns me. I feel badly for my patients who went through all of that for naught because of the trial design, because the trial could have been halted from the get go.”

Dr. Henson echoed Dr. LaGanke’s empathy for her own MS patients. “More than anything else, I feel really badly for my patients who have been waiting for this drug because truly it is now back to the drawing board.”

Dr. Carter notes that there is a segment of the MS population—those who are positive for the JC virus antibody and are considered at increased risk for progressive multifocal leukoencephalopathy (PML) with natalizumab (Tysabri) therapy—for whom the options are slim to none.

“There are a lot of patients for whom alemtuzumab is not the right drug,” said Dr. Henson. “It is not as though I am going to recommend this drug to all my patients.” She notes, however, that she has patients with severe MS who have no other options that they can use at this point. “Where I would use this drug is in patients with aggressive disease who have failed the first-line or second-line therapies. It is most likely going to be a third-line therapy for patients who have failed the injectables, failed the orals, and plus or minus failed natalizumab.”

Available Elsewhere, But Not Here
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. “It is disappointing that we in this country do not have access to this medication,” said Dr. LaGanke.

“The implications of this drug being approved in other countries,” Dr. Henson added, “are that we are going to be forced to try to find some way to get these patients the medication, get it paid for, and then figure out how to monitor these patients. That’s just crazy.”

—Elizabeth Mechcatie & Glenn Williams