FDA panel has mixed votes on alemtuzumab for multiple sclerosis

SILVER SPRING, MD. – A Food and Drug Administration advisory panel agreed that phase III clinical trials of alemtuzumab for multiple sclerosis were unblinded and likely biased but still voted 12-6 that the manufacturer had provided substantial evidence that the immunomodulating drug was effective as a treatment for patients with relapsing forms of multiple sclerosis.

At a Nov. 13 meeting of the FDA’s Peripheral and Central Nervous System Advisory committee, the six panelists who voted no on this question did so because the studies were not well controlled. But the panelists who voted yes said that the drug clearly had some activity against multiple sclerosis (MS), had not been shown to be worse than the active comparator, and in treated patients had beneficial effects that were seen on MRIs, a more objective measure.

Despite an increased risk of serious side effects of treatment that included immune thrombocytopenia, the panel voted 17-0, with 1 abstention, that safety concerns did not preclude approval of the drug, when the potential benefits of the drug were considered. To address the serious risks of alemtuzumab, the manufacturer Genzyme has proposed a risk evaluation and mitigation strategy (REMS) that includes restricted distribution of the drug to physicians trained and certified in prescribing the drug, administration only in certified infusion centers, and close monitoring of patients for adverse events.

The panel was not asked specifically to recommend approval of the drug, which Genzyme has proposed be approved for treatment of patients with relapsing forms of multiple sclerosis. But panelists indicated in their comments that the drug could benefit some patients with MS – although not as a first-line treatment at this point.

Like other panelists who voted that the safety issues did not preclude approval, the panel chair, Dr. Nathan Fountain, professor of neurology at the University of Virginia, Charlottesville, said he would not want to deny the drug to patients severely affected by MS, who are well informed about the risks, with a stringent risk-management program in place. But, he added, "I don’t think this is appropriate at all for drug-naive, simple, uncomplicated relapsing-remitting patients after their first exacerbation."

Alemtuzumab is a monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Its exact mechanism on disease activity in patients with MS is not entirely clear, but is thought to be related to the depletion and repopulation of lymphocytes that occur after the drug is administered, according to Genzyme. The proposed dose is 12 mg/day in an intravenous infusion for 5 consecutive days, followed by the same dose for 3 consecutive days 1 year later.

In 2001, alemtuzumab was approved for treating B-cell chronic lymphocytic leukemia in the United States; it was approved in September 2013 for MS in the European Union. It is marketed as Campath in the United States, but if approved for MS, it will be marketed as Lemtrada.

In two phase III studies of patients with MS, who were treatment-naive or had failed a previous treatment, alemtuzumab (12 mg/day) administered in a series of IV infusions a year apart was compared with treatment with a subcutaneous injection of 44 mcg of interferon beta-1a (Rebif), approved in 2002 for treatment of relapsing forms of MS.

The rate of relapse (new neurologic symptoms or worsening of previous neurologic symptoms) over 2 years and sustained accumulation of disability over 6 months were the primary efficacy endpoints.

In the study of 581 recently diagnosed, untreated patients, the relapse rate over 2 years was 18% among those treated with alemtuzumab, compared with 39% among those on interferon beta-1a – a 55% reduction in the relapse rate that was statistically significant, according to the manufacturer. At the end of 2 years, 8% of those treated with alemtuzumab had experienced sustained disability, compared with 11% of those on interferon beta-1a, which was not statistically significant.

In the study of 840 MS patients who had experienced disease activity on another treatment, the relapse rate over 2 years was 26% among those on alemtuzumab, compared with 52% of those on interferon beta-1a, a 49% reduction in the relapse rate that was statistically significant. The risk of sustained disability over 2 years was almost 13% among those on alemtuzumab, compared with 21% among those on interferon beta-1a, a 42% reduction in risk that was statistically significant, according to Genzyme.

Major concerns raised by the FDA were elevated rates of serious adverse events in about 1,200 patients treated with alemtuzumab, which include serious thyroid-related adverse events (2.1%), immune thrombocytopenia (1.6%), autoimmune hemolytic anemia (0.2%), nephropathies (0.5%), acquired hemophilia A (0.1%), type 1 diabetes (0.2%), pneumonitis (0.5%), thyroid cancer (0.4%), melanoma (0.2%), and serious infusion reactions (2.6%). These adverse events cannot be prevented with close monitoring of patients or with preventive measures and can also occur years after the last dose is administered, the FDA reviewers pointed out.

Besides safety, the other major issue at the meeting was the disagreement between the FDA and Genzyme over the design of the clinical trials, which were open label, with clinicians and patients unblinded to the treatment. Dr. Billy Dunn, acting deputy director of the FDA’s division of neurology products, said that the FDA reviewers believed that bias was "pervasive" in these studies but that the impact the bias had on efficacy results was unclear.

There was a large difference in dropout rates between the treatment groups after randomization before the initiation of treatment between the two groups – almost 13% among those assigned to interferon beta-1a vs. 2% among those assigned to alemtuzumab in one of the studies. This could be explained by patients assigned to interferon beta-1a wanting the newer drug and was among the evidence FDA reviewers said illustrated the bias that was introduced into the studies because of unblinding.

In other questions posed by the FDA, most of the panel voted that the company had not provided substantial evidence that alemtuzumab had a beneficial on disability (14-2 with 2 abstentions) and that the two phase III studies were not adequate and well controlled (11-6 with 1 abstention).

Genzyme, a Sanofi company, is conducting an extension study of alemtuzumab in about 1,300 patients (including those in the three studies) that is evaluating safety and efficacy for up to 5 years, which includes patients now being treated in Europe.

A decision on approval is expected in December. The FDA usually follows the recommendations of its advisory panels. Members have been cleared of potential conflicts; occasionally, a panelist is given a waiver for a potential conflict, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel agreed that phase III clinical trials of alemtuzumab for multiple sclerosis were unblinded and likely biased but still voted 12-6 that the manufacturer had provided substantial evidence that the immunomodulating drug was effective as a treatment for patients with relapsing forms of multiple sclerosis.

At a Nov. 13 meeting of the FDA’s Peripheral and Central Nervous System Advisory committee, the six panelists who voted no on this question did so because the studies were not well controlled. But the panelists who voted yes said that the drug clearly had some activity against multiple sclerosis (MS), had not been shown to be worse than the active comparator, and in treated patients had beneficial effects that were seen on MRIs, a more objective measure.

Despite an increased risk of serious side effects of treatment that included immune thrombocytopenia, the panel voted 17-0, with 1 abstention, that safety concerns did not preclude approval of the drug, when the potential benefits of the drug were considered. To address the serious risks of alemtuzumab, the manufacturer Genzyme has proposed a risk evaluation and mitigation strategy (REMS) that includes restricted distribution of the drug to physicians trained and certified in prescribing the drug, administration only in certified infusion centers, and close monitoring of patients for adverse events.

The panel was not asked specifically to recommend approval of the drug, which Genzyme has proposed be approved for treatment of patients with relapsing forms of multiple sclerosis. But panelists indicated in their comments that the drug could benefit some patients with MS – although not as a first-line treatment at this point.

Like other panelists who voted that the safety issues did not preclude approval, the panel chair, Dr. Nathan Fountain, professor of neurology at the University of Virginia, Charlottesville, said he would not want to deny the drug to patients severely affected by MS, who are well informed about the risks, with a stringent risk-management program in place. But, he added, "I don’t think this is appropriate at all for drug-naive, simple, uncomplicated relapsing-remitting patients after their first exacerbation."

Alemtuzumab is a monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Its exact mechanism on disease activity in patients with MS is not entirely clear, but is thought to be related to the depletion and repopulation of lymphocytes that occur after the drug is administered, according to Genzyme. The proposed dose is 12 mg/day in an intravenous infusion for 5 consecutive days, followed by the same dose for 3 consecutive days 1 year later.

In 2001, alemtuzumab was approved for treating B-cell chronic lymphocytic leukemia in the United States; it was approved in September 2013 for MS in the European Union. It is marketed as Campath in the United States, but if approved for MS, it will be marketed as Lemtrada.

In two phase III studies of patients with MS, who were treatment-naive or had failed a previous treatment, alemtuzumab (12 mg/day) administered in a series of IV infusions a year apart was compared with treatment with a subcutaneous injection of 44 mcg of interferon beta-1a (Rebif), approved in 2002 for treatment of relapsing forms of MS.

The rate of relapse (new neurologic symptoms or worsening of previous neurologic symptoms) over 2 years and sustained accumulation of disability over 6 months were the primary efficacy endpoints.

In the study of 581 recently diagnosed, untreated patients, the relapse rate over 2 years was 18% among those treated with alemtuzumab, compared with 39% among those on interferon beta-1a – a 55% reduction in the relapse rate that was statistically significant, according to the manufacturer. At the end of 2 years, 8% of those treated with alemtuzumab had experienced sustained disability, compared with 11% of those on interferon beta-1a, which was not statistically significant.

In the study of 840 MS patients who had experienced disease activity on another treatment, the relapse rate over 2 years was 26% among those on alemtuzumab, compared with 52% of those on interferon beta-1a, a 49% reduction in the relapse rate that was statistically significant. The risk of sustained disability over 2 years was almost 13% among those on alemtuzumab, compared with 21% among those on interferon beta-1a, a 42% reduction in risk that was statistically significant, according to Genzyme.

Major concerns raised by the FDA were elevated rates of serious adverse events in about 1,200 patients treated with alemtuzumab, which include serious thyroid-related adverse events (2.1%), immune thrombocytopenia (1.6%), autoimmune hemolytic anemia (0.2%), nephropathies (0.5%), acquired hemophilia A (0.1%), type 1 diabetes (0.2%), pneumonitis (0.5%), thyroid cancer (0.4%), melanoma (0.2%), and serious infusion reactions (2.6%). These adverse events cannot be prevented with close monitoring of patients or with preventive measures and can also occur years after the last dose is administered, the FDA reviewers pointed out.

Besides safety, the other major issue at the meeting was the disagreement between the FDA and Genzyme over the design of the clinical trials, which were open label, with clinicians and patients unblinded to the treatment. Dr. Billy Dunn, acting deputy director of the FDA’s division of neurology products, said that the FDA reviewers believed that bias was "pervasive" in these studies but that the impact the bias had on efficacy results was unclear.

There was a large difference in dropout rates between the treatment groups after randomization before the initiation of treatment between the two groups – almost 13% among those assigned to interferon beta-1a vs. 2% among those assigned to alemtuzumab in one of the studies. This could be explained by patients assigned to interferon beta-1a wanting the newer drug and was among the evidence FDA reviewers said illustrated the bias that was introduced into the studies because of unblinding.

In other questions posed by the FDA, most of the panel voted that the company had not provided substantial evidence that alemtuzumab had a beneficial on disability (14-2 with 2 abstentions) and that the two phase III studies were not adequate and well controlled (11-6 with 1 abstention).

Genzyme, a Sanofi company, is conducting an extension study of alemtuzumab in about 1,300 patients (including those in the three studies) that is evaluating safety and efficacy for up to 5 years, which includes patients now being treated in Europe.

A decision on approval is expected in December. The FDA usually follows the recommendations of its advisory panels. Members have been cleared of potential conflicts; occasionally, a panelist is given a waiver for a potential conflict, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel agreed that phase III clinical trials of alemtuzumab for multiple sclerosis were unblinded and likely biased but still voted 12-6 that the manufacturer had provided substantial evidence that the immunomodulating drug was effective as a treatment for patients with relapsing forms of multiple sclerosis.

At a Nov. 13 meeting of the FDA’s Peripheral and Central Nervous System Advisory committee, the six panelists who voted no on this question did so because the studies were not well controlled. But the panelists who voted yes said that the drug clearly had some activity against multiple sclerosis (MS), had not been shown to be worse than the active comparator, and in treated patients had beneficial effects that were seen on MRIs, a more objective measure.

Despite an increased risk of serious side effects of treatment that included immune thrombocytopenia, the panel voted 17-0, with 1 abstention, that safety concerns did not preclude approval of the drug, when the potential benefits of the drug were considered. To address the serious risks of alemtuzumab, the manufacturer Genzyme has proposed a risk evaluation and mitigation strategy (REMS) that includes restricted distribution of the drug to physicians trained and certified in prescribing the drug, administration only in certified infusion centers, and close monitoring of patients for adverse events.

The panel was not asked specifically to recommend approval of the drug, which Genzyme has proposed be approved for treatment of patients with relapsing forms of multiple sclerosis. But panelists indicated in their comments that the drug could benefit some patients with MS – although not as a first-line treatment at this point.

Like other panelists who voted that the safety issues did not preclude approval, the panel chair, Dr. Nathan Fountain, professor of neurology at the University of Virginia, Charlottesville, said he would not want to deny the drug to patients severely affected by MS, who are well informed about the risks, with a stringent risk-management program in place. But, he added, "I don’t think this is appropriate at all for drug-naive, simple, uncomplicated relapsing-remitting patients after their first exacerbation."

Alemtuzumab is a monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Its exact mechanism on disease activity in patients with MS is not entirely clear, but is thought to be related to the depletion and repopulation of lymphocytes that occur after the drug is administered, according to Genzyme. The proposed dose is 12 mg/day in an intravenous infusion for 5 consecutive days, followed by the same dose for 3 consecutive days 1 year later.

In 2001, alemtuzumab was approved for treating B-cell chronic lymphocytic leukemia in the United States; it was approved in September 2013 for MS in the European Union. It is marketed as Campath in the United States, but if approved for MS, it will be marketed as Lemtrada.

In two phase III studies of patients with MS, who were treatment-naive or had failed a previous treatment, alemtuzumab (12 mg/day) administered in a series of IV infusions a year apart was compared with treatment with a subcutaneous injection of 44 mcg of interferon beta-1a (Rebif), approved in 2002 for treatment of relapsing forms of MS.

The rate of relapse (new neurologic symptoms or worsening of previous neurologic symptoms) over 2 years and sustained accumulation of disability over 6 months were the primary efficacy endpoints.

In the study of 581 recently diagnosed, untreated patients, the relapse rate over 2 years was 18% among those treated with alemtuzumab, compared with 39% among those on interferon beta-1a – a 55% reduction in the relapse rate that was statistically significant, according to the manufacturer. At the end of 2 years, 8% of those treated with alemtuzumab had experienced sustained disability, compared with 11% of those on interferon beta-1a, which was not statistically significant.

In the study of 840 MS patients who had experienced disease activity on another treatment, the relapse rate over 2 years was 26% among those on alemtuzumab, compared with 52% of those on interferon beta-1a, a 49% reduction in the relapse rate that was statistically significant. The risk of sustained disability over 2 years was almost 13% among those on alemtuzumab, compared with 21% among those on interferon beta-1a, a 42% reduction in risk that was statistically significant, according to Genzyme.

Major concerns raised by the FDA were elevated rates of serious adverse events in about 1,200 patients treated with alemtuzumab, which include serious thyroid-related adverse events (2.1%), immune thrombocytopenia (1.6%), autoimmune hemolytic anemia (0.2%), nephropathies (0.5%), acquired hemophilia A (0.1%), type 1 diabetes (0.2%), pneumonitis (0.5%), thyroid cancer (0.4%), melanoma (0.2%), and serious infusion reactions (2.6%). These adverse events cannot be prevented with close monitoring of patients or with preventive measures and can also occur years after the last dose is administered, the FDA reviewers pointed out.

Besides safety, the other major issue at the meeting was the disagreement between the FDA and Genzyme over the design of the clinical trials, which were open label, with clinicians and patients unblinded to the treatment. Dr. Billy Dunn, acting deputy director of the FDA’s division of neurology products, said that the FDA reviewers believed that bias was "pervasive" in these studies but that the impact the bias had on efficacy results was unclear.

There was a large difference in dropout rates between the treatment groups after randomization before the initiation of treatment between the two groups – almost 13% among those assigned to interferon beta-1a vs. 2% among those assigned to alemtuzumab in one of the studies. This could be explained by patients assigned to interferon beta-1a wanting the newer drug and was among the evidence FDA reviewers said illustrated the bias that was introduced into the studies because of unblinding.

In other questions posed by the FDA, most of the panel voted that the company had not provided substantial evidence that alemtuzumab had a beneficial on disability (14-2 with 2 abstentions) and that the two phase III studies were not adequate and well controlled (11-6 with 1 abstention).

Genzyme, a Sanofi company, is conducting an extension study of alemtuzumab in about 1,300 patients (including those in the three studies) that is evaluating safety and efficacy for up to 5 years, which includes patients now being treated in Europe.

A decision on approval is expected in December. The FDA usually follows the recommendations of its advisory panels. Members have been cleared of potential conflicts; occasionally, a panelist is given a waiver for a potential conflict, but not at this meeting.

[email protected]