User login
ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.
Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.
“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.
Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.
Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.
Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.
Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.
Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.
Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.
Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.
Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.
Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.
Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.
Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.
—Bruce Jancin
IMNG Medical News
Suggested Reading
Deiß A, Brecht I, Haarmann A, Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013;13(3):313-335.
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.
Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.
Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.
“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.
Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.
Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.
Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.
Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.
Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.
Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.
Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.
Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.
Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.
Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.
Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.
—Bruce Jancin
IMNG Medical News
ORLANDO—In the expanding array of disease-modifying therapies for multiple sclerosis (MS), some “old companions” among the parenteral agents likely will fall by the wayside, said Patricia K. Coyle, MD, at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). Dr. Coyle discussed parenteral agents now in development and described the likely future of the current parenteral drugs.
Interferon Beta and Glatiramer Acetate
Since receiving approval from the FDA for relapsing forms of MS and clinically isolated syndrome, interferon beta and glatiramer acetate have become old standbys. The drugs are fairly well tolerated, and their safety profiles have been thoroughly established during the past two decades. These agents’ big disadvantage, however, is that they must be injected with a needle, said Dr. Coyle, Professor of Clinical Neurology at Stony Brook Medical Center in New York.
“I don’t think the market for interferon beta and glatiramer acetate is going to disappear, but I think it’s going to slowly shrink because now we have oral options,” predicted Dr. Coyle. “The biggest impact is going to be on treatment-naïve, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable. “It’s beginning to become a crowded market among the interferon betas. It’s likely you’re going to see one interferon beta emerge as the dominant option in a shrinking market,” she added.
Natalizumab
Although it is highly effective, natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML). Nonetheless, natalizumab use could increase during the coming years because of emerging risk-stratification methods that identify a subset of MS patients at low risk of PML. But once the novel anti-CD20 monoclonal antibodies reach the marketplace, natalizumab use will decline, predicted Dr. Coyle.
Mitoxantrone
A true induction agent with sustained efficacy that lasts after the cessation of treatment, mitoxantrone has FDA approval for all forms of MS except primary progressive MS. The drug’s associated risks of cardiotoxicity and leukemia require lifetime monitoring for the patient, however, and the therapy can only be administered 10 or 11 times. “As far as I can tell, mitoxantrone is not being used for MS at all in the United States any longer,” according to Dr. Coyle.
Rituximab
Rituximab, an IgG1-anti-CD20 chimeric monoclonal antibody, rapidly depletes B cells for four to 12 months. Eventually, naïve B cells return pre-ferentially over memory B cells. Rituximab is marketed for non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. Its manufacturer does not intend to seek an indication for MS, but highly promising phase II studies have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting MS.
Some neurologists use rituximab off label for MS. A common regimen includes 1,000 mg of IV rituximab followed 15 days later by 500 mg, with dosing repeated every six months, said Dr. Coyle.
Parenteral Agents in Development
Of the parenteral agents in development, alemtuzumab is likely to be the first to be marketed, said Dr. Coyle. This agent, which knocks out T cells, is now under FDA review for possible marketing approval based on impressive phase III results. Alemtuzumab, a true induction agent, is administered on eight days over the course of two years. The effects appear to last for several years after the last dose, but the drug does not cure MS, Dr. Coyle emphasized.
Pegylated interferon beta-1a is being evaluated in an ongoing, two-year, phase III trial. The first-year results indicated that self-administered subcutaneous dosing every two weeks may be more effective than dosing every four weeks. It is too early to tell whether pegylated interferon beta-1a will become the dominant interferon-beta in the marketplace, said Dr. Coyle. Generic interferon-beta may become available in the US. A 40-mg dose of glatiramer acetate can be administered subcutaneously three times per week, rather than daily, as with the familiar 20-mg formulation. In the Glatiramer Acetate Low Frequency Administration Study, a 40-mg dose of glatiramer acetate was associated with an annualized relapse rate 34% lower than that of placebo and a 34% reduction in new or relapsing T2 lesions on brain MRI.
Novel Anti-CD20 Agents
Ocrelizumab is the furthest along in development of the novel anti-CD20 agents. The humanized monoclonal antibody is in three phase III clinical trials: two for relapsing MS and one for primary progressive MS. In a phase II study, various doses of ocrelizumab reduced relapses by 73% to 80% and suppressed MRI contrast lesions by 89% to 96%. “The data with ocrelizumab look great. I think it could potentially replace natalizumab, depending on the safety,” said Dr. Coyle. Development of ocrelizumab as a treatment for rheumatoid arthritis and lupus was discontinued because of concerns about an increase in opportunistic infections. “We’ve not really seen that [effect] in the MS cohort. So far, ocrelizumab seems pretty safe,” said Dr. Coyle.
Daclizumab, a humanized IgG1 monoclonal antibody against CD25, is a subcutaneously administered agent on the market for the prevention of transplanted organ rejection. Investigators are comparing the drug with intramuscular interferon beta-1a as a treatment for MS in an ongoing phase III clinical trial. Previous studies raised concerns regarding daclizumab’s safety and tolerability.
Neurologists have long sought biomarkers of efficacy for MS therapies. Daclizumab appears to provide such a biomarker in the form of an increase in CD56 bright natural killer cells.
Other anti-CD20 monoclonal antibodies in development include ofatumumab, which is now marketed for the treatment of refractory chronic lymphocytic leukemia. A second, secukinumab, is an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study. In addition, an anti-LINGO-1 monoclonal antibody in development is intended to stimulate myelin repair.
Dr. Coyle predicted that more efficacy biomarkers will emerge and that neuroprotection and CNS restoration will be fertile areas for drug development. “A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue,” she concluded.
—Bruce Jancin
IMNG Medical News
Suggested Reading
Deiß A, Brecht I, Haarmann A, Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013;13(3):313-335.
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.
Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
Suggested Reading
Deiß A, Brecht I, Haarmann A, Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013;13(3):313-335.
Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.
Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471.
Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.
