Parenteral drugs for MS: What's ahead

ORLANDO – In the expanding matrix of disease-modifying therapeutic options for multiple sclerosis, some "old companions" among the parenteral agents are likely headed by the wayside, Dr. Patricia K. Coyle predicted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Her plenary address, which highlighted parenteral agents now in the developmental pipeline, also touched on what’s likely to become of the current parenterals.

Here’s her expert analysis:

Interferon-betas and glatiramer acetate: These old standbys are Food and Drug Administration–approved for relapsing forms of MS and for clinically isolated syndrome. Their advantages: they’re fairly well tolerated and their safety profile, thoroughly established over the past 2 decades, holds absolutely no surprises. The big downside is that they are needle-injectable agents.

"I don’t think the market for interferon-betas and glatiramer acetate (Copaxone) is going to disappear, but I think it’s going to slowly shrink because now we have oral options. The biggest impact is going to be on treatment-naive, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable," predicted Dr. Coyle, professor of neurology, vice chair for clinical affairs, and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) Medical Center.

"Also, it’s beginning to become a very 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 continued.

Natalizumab (Tysabri): This highly effective agent has been dogged by its associated risk of progressive multifocal leukoencephalopathy (PML), but could actually see increased use over the next several years as a consequence of emerging risk-stratification methods that identify a subset of MS patients at low PML risk on natalizumab. But once the novel anti-CD20 monoclonal antibodies reach the marketplace (see ocrelizumab and daclizumab, below), the natalizumab era will be over, in Dr. Coyle’s view.

Mitoxantrone: A true induction agent with sustained efficacy lasting after treatment is stopped. This drug is FDA-approved for all forms of MS except for primary progressive MS. But the associated cardiotoxicity and leukemia risks dictate lifetime monitoring for a drug that can only be given 10 or 11 times. That’s a deal breaker.

"As far as I can tell, mitoxantrone is not being used for MS at all in the U.S. any longer," according to the neurologist.

Rituximab (Rituxan): This IgG1-anti-CD20 chimeric monoclonal antibody rapidly depletes B cells for 4-12 months. Eventually, naive B cells return preferentially over memory B cells. Rituximab is already marketed for non-Hodgkin lymphoma and refractory rheumatoid arthritis. Its manufacturer doesn’t intend to seek an indication for MS; however, earlier highly promising phase II MS studies (N. Engl. J. Med. 2008;358:676-88; Ann. Neurol. 2009;66:460-71) have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting this disease.

Off label, some neurologists are using 1,000 mg of rituximab intravenously followed 15 days later by 500 mg, with dosing repeated every 6 months, she said.

Turning to the parenteral agents of the future, Dr. Coyle said the first up is likely to be:

Alemtuzumab: This agent, which knocks out T cells, is now under FDA review for possible marketing approval based upon impressive phase III results.

Alemtuzumab is a true induction agent. It is given on 8 days over the course of 2 years, and never again. The effects appear to last for several years after the last dose. It is not, however, a cure for MS, Dr. Coyle stressed.

Pegylated interferon beta-1a: The first-year results of the ongoing 2-year phase III ADVANCE trial showed self-administered subcutaneous dosing every 2 weeks to be more effective than every 4 weeks. Will this become the dominant interferon-beta in the marketplace? Way too early to tell, in Dr. Coyle’s view. She also noted the possibility that generic interferon-betas may become available in the United States.

Glatiramer acetate 40 mg: This drug is given subcutaneously three times per week, rather than daily as with the familiar 20-mg formulation. In the GALA (Glatiramer Acetate Low Frequency Administration Study) trial, glatiramer acetate 40 mg had an annualized relapse rate 34% lower than placebo, as well as a 34% reduction in new or relapsing T2 lesions on brain MRI.

Ocrelizumab: The furthest along in development of the novel anti-CD20 agents, this humanized monoclonal antibody is currently in three phase III clinical trials: two for relapsing MS and another for primary progressive MS.

In a phase II study, various doses of ocrelizumab showed 73%-80% reductions in relapses and 89%-96% suppression of MRI contrast lesions.

"The data with ocrelizumab looks great. I think, personally, it could potentially replace natalizumab, depending upon the safety," Dr. Coyle said.

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 in the MS cohort so far. It’s a slight background concern. So far, ocrelizumab seems pretty safe," according to the neurologist.

Daclizumab (Zenapax): This subcutaneously administered agent is a humanized IgG1 monoclonal antibody against CD25 and is already on the market for the prevention of organ transplant rejection. It is in the ongoing DECIDE study, a phase III MS clinical trial with intramuscular interferon beta-1a as the comparator. Earlier studies raised some concerns regarding safety and tolerability.

A particularly interesting feature of daclizumab is that it appears to have a biomarker predictive of efficacy: an increase in CD56 bright natural killer cells. Biomarkers of efficacy are desperately needed for MS therapies.

Miscellaneous parenterals: These include other anti-CD20 monoclonal antibodies, among them ofatumumab (Arzerra), already marketed for treatment of refractory chronic lymphocytic leukemia; secukinumab, an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study; an anti-LINGO-1 monoclonal antibody aimed at stimulating myelin repair; and stem cell therapies that are early in development.

Dr. Coyle predicted more efficacy biomarkers are coming, and noted that neuroprotection and CNS restoration are areas wide open for drug development. Her final prediction regarding parenteral therapies for MS: "A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue."

She reported having received honoraria from Acorda, Accordant, Bayer, Biogen Idec, EMD Serono, Genzyme/Sanofi Aventis, Novartis, Roche, and Tera.

[email protected]

ORLANDO – In the expanding matrix of disease-modifying therapeutic options for multiple sclerosis, some "old companions" among the parenteral agents are likely headed by the wayside, Dr. Patricia K. Coyle predicted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Her plenary address, which highlighted parenteral agents now in the developmental pipeline, also touched on what’s likely to become of the current parenterals.

Here’s her expert analysis:

Interferon-betas and glatiramer acetate: These old standbys are Food and Drug Administration–approved for relapsing forms of MS and for clinically isolated syndrome. Their advantages: they’re fairly well tolerated and their safety profile, thoroughly established over the past 2 decades, holds absolutely no surprises. The big downside is that they are needle-injectable agents.

"I don’t think the market for interferon-betas and glatiramer acetate (Copaxone) is going to disappear, but I think it’s going to slowly shrink because now we have oral options. The biggest impact is going to be on treatment-naive, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable," predicted Dr. Coyle, professor of neurology, vice chair for clinical affairs, and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) Medical Center.

"Also, it’s beginning to become a very 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 continued.

Natalizumab (Tysabri): This highly effective agent has been dogged by its associated risk of progressive multifocal leukoencephalopathy (PML), but could actually see increased use over the next several years as a consequence of emerging risk-stratification methods that identify a subset of MS patients at low PML risk on natalizumab. But once the novel anti-CD20 monoclonal antibodies reach the marketplace (see ocrelizumab and daclizumab, below), the natalizumab era will be over, in Dr. Coyle’s view.

Mitoxantrone: A true induction agent with sustained efficacy lasting after treatment is stopped. This drug is FDA-approved for all forms of MS except for primary progressive MS. But the associated cardiotoxicity and leukemia risks dictate lifetime monitoring for a drug that can only be given 10 or 11 times. That’s a deal breaker.

"As far as I can tell, mitoxantrone is not being used for MS at all in the U.S. any longer," according to the neurologist.

Rituximab (Rituxan): This IgG1-anti-CD20 chimeric monoclonal antibody rapidly depletes B cells for 4-12 months. Eventually, naive B cells return preferentially over memory B cells. Rituximab is already marketed for non-Hodgkin lymphoma and refractory rheumatoid arthritis. Its manufacturer doesn’t intend to seek an indication for MS; however, earlier highly promising phase II MS studies (N. Engl. J. Med. 2008;358:676-88; Ann. Neurol. 2009;66:460-71) have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting this disease.

Off label, some neurologists are using 1,000 mg of rituximab intravenously followed 15 days later by 500 mg, with dosing repeated every 6 months, she said.

Turning to the parenteral agents of the future, Dr. Coyle said the first up is likely to be:

Alemtuzumab: This agent, which knocks out T cells, is now under FDA review for possible marketing approval based upon impressive phase III results.

Alemtuzumab is a true induction agent. It is given on 8 days over the course of 2 years, and never again. The effects appear to last for several years after the last dose. It is not, however, a cure for MS, Dr. Coyle stressed.

Pegylated interferon beta-1a: The first-year results of the ongoing 2-year phase III ADVANCE trial showed self-administered subcutaneous dosing every 2 weeks to be more effective than every 4 weeks. Will this become the dominant interferon-beta in the marketplace? Way too early to tell, in Dr. Coyle’s view. She also noted the possibility that generic interferon-betas may become available in the United States.

Glatiramer acetate 40 mg: This drug is given subcutaneously three times per week, rather than daily as with the familiar 20-mg formulation. In the GALA (Glatiramer Acetate Low Frequency Administration Study) trial, glatiramer acetate 40 mg had an annualized relapse rate 34% lower than placebo, as well as a 34% reduction in new or relapsing T2 lesions on brain MRI.

Ocrelizumab: The furthest along in development of the novel anti-CD20 agents, this humanized monoclonal antibody is currently in three phase III clinical trials: two for relapsing MS and another for primary progressive MS.

In a phase II study, various doses of ocrelizumab showed 73%-80% reductions in relapses and 89%-96% suppression of MRI contrast lesions.

"The data with ocrelizumab looks great. I think, personally, it could potentially replace natalizumab, depending upon the safety," Dr. Coyle said.

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 in the MS cohort so far. It’s a slight background concern. So far, ocrelizumab seems pretty safe," according to the neurologist.

Daclizumab (Zenapax): This subcutaneously administered agent is a humanized IgG1 monoclonal antibody against CD25 and is already on the market for the prevention of organ transplant rejection. It is in the ongoing DECIDE study, a phase III MS clinical trial with intramuscular interferon beta-1a as the comparator. Earlier studies raised some concerns regarding safety and tolerability.

A particularly interesting feature of daclizumab is that it appears to have a biomarker predictive of efficacy: an increase in CD56 bright natural killer cells. Biomarkers of efficacy are desperately needed for MS therapies.

Miscellaneous parenterals: These include other anti-CD20 monoclonal antibodies, among them ofatumumab (Arzerra), already marketed for treatment of refractory chronic lymphocytic leukemia; secukinumab, an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study; an anti-LINGO-1 monoclonal antibody aimed at stimulating myelin repair; and stem cell therapies that are early in development.

Dr. Coyle predicted more efficacy biomarkers are coming, and noted that neuroprotection and CNS restoration are areas wide open for drug development. Her final prediction regarding parenteral therapies for MS: "A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue."

She reported having received honoraria from Acorda, Accordant, Bayer, Biogen Idec, EMD Serono, Genzyme/Sanofi Aventis, Novartis, Roche, and Tera.

[email protected]

ORLANDO – In the expanding matrix of disease-modifying therapeutic options for multiple sclerosis, some "old companions" among the parenteral agents are likely headed by the wayside, Dr. Patricia K. Coyle predicted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Her plenary address, which highlighted parenteral agents now in the developmental pipeline, also touched on what’s likely to become of the current parenterals.

Here’s her expert analysis:

Interferon-betas and glatiramer acetate: These old standbys are Food and Drug Administration–approved for relapsing forms of MS and for clinically isolated syndrome. Their advantages: they’re fairly well tolerated and their safety profile, thoroughly established over the past 2 decades, holds absolutely no surprises. The big downside is that they are needle-injectable agents.

"I don’t think the market for interferon-betas and glatiramer acetate (Copaxone) is going to disappear, but I think it’s going to slowly shrink because now we have oral options. The biggest impact is going to be on treatment-naive, newly diagnosed patients. People are going to opt for an oral agent rather than an injectable," predicted Dr. Coyle, professor of neurology, vice chair for clinical affairs, and director of the MS Comprehensive Care Center at Stony Brook (N.Y.) Medical Center.

"Also, it’s beginning to become a very 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 continued.

Natalizumab (Tysabri): This highly effective agent has been dogged by its associated risk of progressive multifocal leukoencephalopathy (PML), but could actually see increased use over the next several years as a consequence of emerging risk-stratification methods that identify a subset of MS patients at low PML risk on natalizumab. But once the novel anti-CD20 monoclonal antibodies reach the marketplace (see ocrelizumab and daclizumab, below), the natalizumab era will be over, in Dr. Coyle’s view.

Mitoxantrone: A true induction agent with sustained efficacy lasting after treatment is stopped. This drug is FDA-approved for all forms of MS except for primary progressive MS. But the associated cardiotoxicity and leukemia risks dictate lifetime monitoring for a drug that can only be given 10 or 11 times. That’s a deal breaker.

"As far as I can tell, mitoxantrone is not being used for MS at all in the U.S. any longer," according to the neurologist.

Rituximab (Rituxan): This IgG1-anti-CD20 chimeric monoclonal antibody rapidly depletes B cells for 4-12 months. Eventually, naive B cells return preferentially over memory B cells. Rituximab is already marketed for non-Hodgkin lymphoma and refractory rheumatoid arthritis. Its manufacturer doesn’t intend to seek an indication for MS; however, earlier highly promising phase II MS studies (N. Engl. J. Med. 2008;358:676-88; Ann. Neurol. 2009;66:460-71) have spurred intensive development of novel anti-CD20 monoclonal antibodies targeting this disease.

Off label, some neurologists are using 1,000 mg of rituximab intravenously followed 15 days later by 500 mg, with dosing repeated every 6 months, she said.

Turning to the parenteral agents of the future, Dr. Coyle said the first up is likely to be:

Alemtuzumab: This agent, which knocks out T cells, is now under FDA review for possible marketing approval based upon impressive phase III results.

Alemtuzumab is a true induction agent. It is given on 8 days over the course of 2 years, and never again. The effects appear to last for several years after the last dose. It is not, however, a cure for MS, Dr. Coyle stressed.

Pegylated interferon beta-1a: The first-year results of the ongoing 2-year phase III ADVANCE trial showed self-administered subcutaneous dosing every 2 weeks to be more effective than every 4 weeks. Will this become the dominant interferon-beta in the marketplace? Way too early to tell, in Dr. Coyle’s view. She also noted the possibility that generic interferon-betas may become available in the United States.

Glatiramer acetate 40 mg: This drug is given subcutaneously three times per week, rather than daily as with the familiar 20-mg formulation. In the GALA (Glatiramer Acetate Low Frequency Administration Study) trial, glatiramer acetate 40 mg had an annualized relapse rate 34% lower than placebo, as well as a 34% reduction in new or relapsing T2 lesions on brain MRI.

Ocrelizumab: The furthest along in development of the novel anti-CD20 agents, this humanized monoclonal antibody is currently in three phase III clinical trials: two for relapsing MS and another for primary progressive MS.

In a phase II study, various doses of ocrelizumab showed 73%-80% reductions in relapses and 89%-96% suppression of MRI contrast lesions.

"The data with ocrelizumab looks great. I think, personally, it could potentially replace natalizumab, depending upon the safety," Dr. Coyle said.

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 in the MS cohort so far. It’s a slight background concern. So far, ocrelizumab seems pretty safe," according to the neurologist.

Daclizumab (Zenapax): This subcutaneously administered agent is a humanized IgG1 monoclonal antibody against CD25 and is already on the market for the prevention of organ transplant rejection. It is in the ongoing DECIDE study, a phase III MS clinical trial with intramuscular interferon beta-1a as the comparator. Earlier studies raised some concerns regarding safety and tolerability.

A particularly interesting feature of daclizumab is that it appears to have a biomarker predictive of efficacy: an increase in CD56 bright natural killer cells. Biomarkers of efficacy are desperately needed for MS therapies.

Miscellaneous parenterals: These include other anti-CD20 monoclonal antibodies, among them ofatumumab (Arzerra), already marketed for treatment of refractory chronic lymphocytic leukemia; secukinumab, an anti-interleukin-17 monoclonal antibody that showed efficacy in terms of MRI lesions in a small study; an anti-LINGO-1 monoclonal antibody aimed at stimulating myelin repair; and stem cell therapies that are early in development.

Dr. Coyle predicted more efficacy biomarkers are coming, and noted that neuroprotection and CNS restoration are areas wide open for drug development. Her final prediction regarding parenteral therapies for MS: "A high-efficacy monoclonal antibody, if it’s safe and convenient, could seize the market. The safety will be the critical issue."

She reported having received honoraria from Acorda, Accordant, Bayer, Biogen Idec, EMD Serono, Genzyme/Sanofi Aventis, Novartis, Roche, and Tera.

[email protected]