Neuromuscular Disorders

ORLANDO – When individuals with multiple sclerosis who were treated with teriflunomide and were using contraception, but became pregnant and followed the clinical program by stopping treatment and flushing the drug out of their systems, they had healthy babies, according to the drug maker’s analysis of several phase II and III trials.

The authors, who presented their findings as a poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, said that there’s need for more prospective data on pregnancy outcomes, and a registry is planned.

The Food and Drug Administration approved teriflunomide, a once-daily oral medication for treating relapsing forms of multiple sclerosis, last year. The drug is currently classified as "X" and is contraindicated in pregnant women and women of childbearing age. Animal studies have shown that teriflunomide is teratogenic and embryo lethal, the authors wrote, although there has been no evidence that it affected the genes or fertility.

For those who worry about using the drug in women, "This is reassuring that if you follow the guidelines, it’s not going be an issue for mommies and daddies for teratogenicity," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC).

Dr. Lisak, who was not involved in the analysis, but has been a part of one of the trials used in the analysis, said that his concern, as a practicing physician, is that women outside of clinical trials are not monitored as closely.

Women who are using the drug are advised to use contraception. Those who want to become pregnant are advised to discontinue treatment and undergo an elimination procedure with cholestyramine or activated charcoal until the drug’s plasma concentrations are less than 0.02 mcg/mL. Men should also stop treatment and undergo accelerated elimination.

Researchers summarized the results of nine phase II and III clinical trials in the MS clinical development program, which included pregnancy outcomes in female patients and partners of men who were exposed to teriflunomide.

The patients had received 7 mg or 14 mg teriflunomide, interferon-beta, placebo, or a combination of treatments. In all trials, reliable contraception was required, but pregnancies were reported.

From a total of more than 4,000 patients, there were 81 pregnancies, 63 of which occurred in women taking teriflunomide, and 18 in women who were on placebo or interferon-beta.

Of those 63, 20 were live births, 26 were induced abortions, 12 were miscarriages, and 5 pregnancies were ongoing when the data collection stopped on April 2013.

The live births in patients treated with teriflunomide resulted in healthy babies. Most of the women had discontinued the drug a few days to 11 weeks after becoming pregnant and underwent an accelerated elimination procedure after discontinuing treatment. Two refused to undergo the procedure. Seven became pregnant after completing the elimination procedure.

The rate of miscarriage in the teriflunomide group was 19%, which is within the range reported in the non–MS population (Eur. J. Obstet. Gynecol. Reprod. Biol. 2002;102:111-9), the authors wrote.

There were 20 pregnancies in partners of 17 men in the teriflunomide clinical trials. In 16, the father was exposed to the drug. There were 12 live births of healthy babies, 1 induced abortion, 1 miscarriage, and 2 ongoing pregnancies when data collection stopped.

Researchers said that planned teriflunomide pregnancy registries will provide more information, but data so far haven’t shown the teratogenic signal seen in the leflunomide registry.

Teriflunomide is the main active metabolite in rheumatoid arthritis drug leflunomide. Animal studies for leflunomide have shown embryo lethality and teratogenicity. But in small human studies, there was no significant difference in teratogenicity and spontaneous abortion rates, compared with the general population (Arthritis Rheum. 2010;62:1494-503; Arthritis Rheum. 2012;64:2085-94), the authors noted.

Teriflunomide also has been detected in human semen. Although there have been no animal studies, researchers said that the estimated female exposure via semen of men treated with the drug is expected to be 100 times lower than in those who actually take the drug with 14-mg dosing.

"Pregnancy outcomes among women who received teriflunomide, including rates of spontaneous abortion, and gestational age and weight at birth, are consistent with those for non–MS populations," the authors wrote. The treatment "is a therapeutic option for women of childbearing potential and for male patients with female partners of childbearing potential, when using reliable contraception."

Some of the authors were employees of Sanofi or had received research support from the company. The study was supported by Genzyme, a Sanofi company, which is marketed as teriflunomide (Aubagio).

[email protected]

On Twitter @naseemsmiller

ORLANDO – When individuals with multiple sclerosis who were treated with teriflunomide and were using contraception, but became pregnant and followed the clinical program by stopping treatment and flushing the drug out of their systems, they had healthy babies, according to the drug maker’s analysis of several phase II and III trials.

The authors, who presented their findings as a poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, said that there’s need for more prospective data on pregnancy outcomes, and a registry is planned.

The Food and Drug Administration approved teriflunomide, a once-daily oral medication for treating relapsing forms of multiple sclerosis, last year. The drug is currently classified as "X" and is contraindicated in pregnant women and women of childbearing age. Animal studies have shown that teriflunomide is teratogenic and embryo lethal, the authors wrote, although there has been no evidence that it affected the genes or fertility.

For those who worry about using the drug in women, "This is reassuring that if you follow the guidelines, it’s not going be an issue for mommies and daddies for teratogenicity," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC).

Dr. Lisak, who was not involved in the analysis, but has been a part of one of the trials used in the analysis, said that his concern, as a practicing physician, is that women outside of clinical trials are not monitored as closely.

Women who are using the drug are advised to use contraception. Those who want to become pregnant are advised to discontinue treatment and undergo an elimination procedure with cholestyramine or activated charcoal until the drug’s plasma concentrations are less than 0.02 mcg/mL. Men should also stop treatment and undergo accelerated elimination.

Researchers summarized the results of nine phase II and III clinical trials in the MS clinical development program, which included pregnancy outcomes in female patients and partners of men who were exposed to teriflunomide.

The patients had received 7 mg or 14 mg teriflunomide, interferon-beta, placebo, or a combination of treatments. In all trials, reliable contraception was required, but pregnancies were reported.

From a total of more than 4,000 patients, there were 81 pregnancies, 63 of which occurred in women taking teriflunomide, and 18 in women who were on placebo or interferon-beta.

Of those 63, 20 were live births, 26 were induced abortions, 12 were miscarriages, and 5 pregnancies were ongoing when the data collection stopped on April 2013.

The live births in patients treated with teriflunomide resulted in healthy babies. Most of the women had discontinued the drug a few days to 11 weeks after becoming pregnant and underwent an accelerated elimination procedure after discontinuing treatment. Two refused to undergo the procedure. Seven became pregnant after completing the elimination procedure.

The rate of miscarriage in the teriflunomide group was 19%, which is within the range reported in the non–MS population (Eur. J. Obstet. Gynecol. Reprod. Biol. 2002;102:111-9), the authors wrote.

There were 20 pregnancies in partners of 17 men in the teriflunomide clinical trials. In 16, the father was exposed to the drug. There were 12 live births of healthy babies, 1 induced abortion, 1 miscarriage, and 2 ongoing pregnancies when data collection stopped.

Researchers said that planned teriflunomide pregnancy registries will provide more information, but data so far haven’t shown the teratogenic signal seen in the leflunomide registry.

Teriflunomide is the main active metabolite in rheumatoid arthritis drug leflunomide. Animal studies for leflunomide have shown embryo lethality and teratogenicity. But in small human studies, there was no significant difference in teratogenicity and spontaneous abortion rates, compared with the general population (Arthritis Rheum. 2010;62:1494-503; Arthritis Rheum. 2012;64:2085-94), the authors noted.

Teriflunomide also has been detected in human semen. Although there have been no animal studies, researchers said that the estimated female exposure via semen of men treated with the drug is expected to be 100 times lower than in those who actually take the drug with 14-mg dosing.

"Pregnancy outcomes among women who received teriflunomide, including rates of spontaneous abortion, and gestational age and weight at birth, are consistent with those for non–MS populations," the authors wrote. The treatment "is a therapeutic option for women of childbearing potential and for male patients with female partners of childbearing potential, when using reliable contraception."

Some of the authors were employees of Sanofi or had received research support from the company. The study was supported by Genzyme, a Sanofi company, which is marketed as teriflunomide (Aubagio).

[email protected]

On Twitter @naseemsmiller

ORLANDO – When individuals with multiple sclerosis who were treated with teriflunomide and were using contraception, but became pregnant and followed the clinical program by stopping treatment and flushing the drug out of their systems, they had healthy babies, according to the drug maker’s analysis of several phase II and III trials.

The authors, who presented their findings as a poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, said that there’s need for more prospective data on pregnancy outcomes, and a registry is planned.

The Food and Drug Administration approved teriflunomide, a once-daily oral medication for treating relapsing forms of multiple sclerosis, last year. The drug is currently classified as "X" and is contraindicated in pregnant women and women of childbearing age. Animal studies have shown that teriflunomide is teratogenic and embryo lethal, the authors wrote, although there has been no evidence that it affected the genes or fertility.

For those who worry about using the drug in women, "This is reassuring that if you follow the guidelines, it’s not going be an issue for mommies and daddies for teratogenicity," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC).

Dr. Lisak, who was not involved in the analysis, but has been a part of one of the trials used in the analysis, said that his concern, as a practicing physician, is that women outside of clinical trials are not monitored as closely.

Women who are using the drug are advised to use contraception. Those who want to become pregnant are advised to discontinue treatment and undergo an elimination procedure with cholestyramine or activated charcoal until the drug’s plasma concentrations are less than 0.02 mcg/mL. Men should also stop treatment and undergo accelerated elimination.

Researchers summarized the results of nine phase II and III clinical trials in the MS clinical development program, which included pregnancy outcomes in female patients and partners of men who were exposed to teriflunomide.

The patients had received 7 mg or 14 mg teriflunomide, interferon-beta, placebo, or a combination of treatments. In all trials, reliable contraception was required, but pregnancies were reported.

From a total of more than 4,000 patients, there were 81 pregnancies, 63 of which occurred in women taking teriflunomide, and 18 in women who were on placebo or interferon-beta.

Of those 63, 20 were live births, 26 were induced abortions, 12 were miscarriages, and 5 pregnancies were ongoing when the data collection stopped on April 2013.

The live births in patients treated with teriflunomide resulted in healthy babies. Most of the women had discontinued the drug a few days to 11 weeks after becoming pregnant and underwent an accelerated elimination procedure after discontinuing treatment. Two refused to undergo the procedure. Seven became pregnant after completing the elimination procedure.

The rate of miscarriage in the teriflunomide group was 19%, which is within the range reported in the non–MS population (Eur. J. Obstet. Gynecol. Reprod. Biol. 2002;102:111-9), the authors wrote.

There were 20 pregnancies in partners of 17 men in the teriflunomide clinical trials. In 16, the father was exposed to the drug. There were 12 live births of healthy babies, 1 induced abortion, 1 miscarriage, and 2 ongoing pregnancies when data collection stopped.

Researchers said that planned teriflunomide pregnancy registries will provide more information, but data so far haven’t shown the teratogenic signal seen in the leflunomide registry.

Teriflunomide is the main active metabolite in rheumatoid arthritis drug leflunomide. Animal studies for leflunomide have shown embryo lethality and teratogenicity. But in small human studies, there was no significant difference in teratogenicity and spontaneous abortion rates, compared with the general population (Arthritis Rheum. 2010;62:1494-503; Arthritis Rheum. 2012;64:2085-94), the authors noted.

Teriflunomide also has been detected in human semen. Although there have been no animal studies, researchers said that the estimated female exposure via semen of men treated with the drug is expected to be 100 times lower than in those who actually take the drug with 14-mg dosing.

"Pregnancy outcomes among women who received teriflunomide, including rates of spontaneous abortion, and gestational age and weight at birth, are consistent with those for non–MS populations," the authors wrote. The treatment "is a therapeutic option for women of childbearing potential and for male patients with female partners of childbearing potential, when using reliable contraception."

Some of the authors were employees of Sanofi or had received research support from the company. The study was supported by Genzyme, a Sanofi company, which is marketed as teriflunomide (Aubagio).

[email protected]

On Twitter @naseemsmiller

ORLANDO – Effective oral therapy has been at the top of the wish list of many multiple sclerosis patients for a long time – and now, seemingly all of a sudden, three approved oral agents are available to choose from.

For patients, the obvious attractions of oral therapy are ease of administration and that it’s less of a reminder that they have a serious chronic illness. But which agent is the right fit for a given patient?

All three oral drugs – fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera) – are "definitely" suitable as first-line therapy in selected newly diagnosed MS patients, Dr. Mariko Kita asserted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.

Today few neurologists – certainly less than 10% – are using any oral agent as first-line therapy. That’s in part due to cost and reimbursement issues, but to a much greater extent it’s because most physicians don’t yet feel comfortable that the safety profiles of the oral agents are fully known. The drugs are still too new, in the eyes of most practitioners. After all, both natalizumab (Tysabri) – considered the most effective of the injectable agents – and fingolimod – the first oral agent to receive marketing approval, back in October 2010 – had to have revisionary cautions added to their labeling shortly after they were introduced.

But provider experience with the orals is expected to grow quickly. And absent any late bombshells regarding side effects, it’s widely anticipated that the use of oral agents for MS will surge within the next few years, with a corresponding decline in popularity of injectable therapies.

Demand for oral therapy will be high all across the patient spectrum: in newly diagnosed patients, in individuals with a lengthy disease history who have tried all the available disease-modifying therapies with less than satisfactory results and have been awaiting something new, in patients intolerant to or experiencing breakthrough disease on a first-line injectable agent, as well as in patients who are stable on their current injectable disease-modifying therapy but are experiencing injection fatigue or growing more concerned about their parenteral therapy’s long-term risks, Dr. Kita predicted.

Choosing between the oral options appropriately requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and consideration of how the oral drug will fit in to the big picture of a long-term, staged therapy plan, she added.

Here’s her personal clinical rundown on the approved oral drugs:

• Fingolimod: This is a drug best reserved for MS patients who are otherwise relatively healthy, in Dr. Kita’s view. Specifically, it’s a less favorable option for patients with diabetes, smokers, and others with reduced pulmonary function, and in individuals at increased risk of infection, including those with a high Expanded Disability Status Scale score.

Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so they can’t participate in autoimmune activity. The required testing prior to starting the drug, the need for careful observation during the first dose, and the necessary ongoing monitoring as long as the patient is on fingolimod make this a labor-intensive drug.

Bearing those caveats in mind, she continued, fingolimod is "reasonable" to use as a first-line agent, or as a second-line agent in the setting of intolerance to or breakthrough disease while on prior therapy.

"But I would caution those who are reserving these oral agents as second-line that we need to think about what we can reasonably expect from them. If we’re moving to them as second-line because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral will be better than a failed injectable has not yet been proven," Dr. Kita said.

• Teriflunomide: This is the active metabolite of leflunomide, a treatment approved by the Food and Drug Administration for rheumatoid arthritis. It was approved for treating relapsing forms of MS last fall. Teriflunomide nonselectively inhibits rapidly dividing cell populations by curbing pyrimidine synthesis via bonding to the enzyme dihydroorotate dehydrogenase.

Who’s the right fit for teriflunomide? Because the drug is rated category X and has teratogenicity potential in both men and women, it’s a given that the candidate must be on effective contraception. Also, the patient should definitely not have comorbid liver disease. And in Dr. Kita’s view, an appropriate candidate for teriflunomide has mild MS. Otherwise, the physician can get backed into a corner. That’s because the drug is excreted very slowly and is not dialyzable. Indeed, it takes 8-24 months after drug discontinuation for plasma levels to become undetectable.

"Teriflunomide could definitely be used as first-line therapy. It can be used second-line in a patient intolerant to a prior agent. But I think the long half-life complicates its use as second-line therapy in patients who’ve had breakthrough disease on prior agents, because if we need to consider a switch from teriflunomide, that long half-life has to be taken into consideration. You’ll need to consider the elimination protocol," she advised.

Patients find the elimination protocol arduous. It entails swallowing 8 g of oral cholestyramine every 8 hours for 11 days, or 50 g of activated charcoal given orally every 12 hours for 11 days.

• Dimethyl fumarate: This twice-daily oral agent, which was approved last March, activates the nuclear factor transcriptional pathway, thereby defending against oxidative stress–induced neuronal death. Dimethyl fumarate also supports myelin integrity in the central nervous system.

The drug’s side effect profile, consisting mostly of short-term flushing and gastrointestinal complaints, is the most benign of the three oral agents. Thus, it could potentially see broader use both as a first-line drug in newly diagnosed patients and as second-line therapy in patients intolerant to or experiencing disease breakthrough on other agents.

That being said, it’s still unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. A couple of studies of fingolimod showed a high relapse rate in this situation, and there are simply no data as yet on the two newer agents, according to Dr. Kita.

• Upcoming oral agents: The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule that has completed two phase III clinical trials and is now under review by the European Medicines Agency for possible marketing approval. Teva has not yet applied to the Food and Drug Administration for U.S. approval.

Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively and thus pose fewer potential immunocompromise issues than fingolimod. These include siponimod, ponesimod, and ONO-4641.

Dr. Kita reported receiving research support from Biogen Idec (which markets Tecfidera), Novartis (which markets Gilenya and is developing siponimod), Serono, and Acorda, as well as personal compensation from Biogen Idec, Bayer, and Genzyme (which markets Aubagio).

[email protected]

ORLANDO – Effective oral therapy has been at the top of the wish list of many multiple sclerosis patients for a long time – and now, seemingly all of a sudden, three approved oral agents are available to choose from.

For patients, the obvious attractions of oral therapy are ease of administration and that it’s less of a reminder that they have a serious chronic illness. But which agent is the right fit for a given patient?

All three oral drugs – fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera) – are "definitely" suitable as first-line therapy in selected newly diagnosed MS patients, Dr. Mariko Kita asserted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.

Today few neurologists – certainly less than 10% – are using any oral agent as first-line therapy. That’s in part due to cost and reimbursement issues, but to a much greater extent it’s because most physicians don’t yet feel comfortable that the safety profiles of the oral agents are fully known. The drugs are still too new, in the eyes of most practitioners. After all, both natalizumab (Tysabri) – considered the most effective of the injectable agents – and fingolimod – the first oral agent to receive marketing approval, back in October 2010 – had to have revisionary cautions added to their labeling shortly after they were introduced.

But provider experience with the orals is expected to grow quickly. And absent any late bombshells regarding side effects, it’s widely anticipated that the use of oral agents for MS will surge within the next few years, with a corresponding decline in popularity of injectable therapies.

Demand for oral therapy will be high all across the patient spectrum: in newly diagnosed patients, in individuals with a lengthy disease history who have tried all the available disease-modifying therapies with less than satisfactory results and have been awaiting something new, in patients intolerant to or experiencing breakthrough disease on a first-line injectable agent, as well as in patients who are stable on their current injectable disease-modifying therapy but are experiencing injection fatigue or growing more concerned about their parenteral therapy’s long-term risks, Dr. Kita predicted.

Choosing between the oral options appropriately requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and consideration of how the oral drug will fit in to the big picture of a long-term, staged therapy plan, she added.

Here’s her personal clinical rundown on the approved oral drugs:

• Fingolimod: This is a drug best reserved for MS patients who are otherwise relatively healthy, in Dr. Kita’s view. Specifically, it’s a less favorable option for patients with diabetes, smokers, and others with reduced pulmonary function, and in individuals at increased risk of infection, including those with a high Expanded Disability Status Scale score.

Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so they can’t participate in autoimmune activity. The required testing prior to starting the drug, the need for careful observation during the first dose, and the necessary ongoing monitoring as long as the patient is on fingolimod make this a labor-intensive drug.

Bearing those caveats in mind, she continued, fingolimod is "reasonable" to use as a first-line agent, or as a second-line agent in the setting of intolerance to or breakthrough disease while on prior therapy.

"But I would caution those who are reserving these oral agents as second-line that we need to think about what we can reasonably expect from them. If we’re moving to them as second-line because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral will be better than a failed injectable has not yet been proven," Dr. Kita said.

• Teriflunomide: This is the active metabolite of leflunomide, a treatment approved by the Food and Drug Administration for rheumatoid arthritis. It was approved for treating relapsing forms of MS last fall. Teriflunomide nonselectively inhibits rapidly dividing cell populations by curbing pyrimidine synthesis via bonding to the enzyme dihydroorotate dehydrogenase.

Who’s the right fit for teriflunomide? Because the drug is rated category X and has teratogenicity potential in both men and women, it’s a given that the candidate must be on effective contraception. Also, the patient should definitely not have comorbid liver disease. And in Dr. Kita’s view, an appropriate candidate for teriflunomide has mild MS. Otherwise, the physician can get backed into a corner. That’s because the drug is excreted very slowly and is not dialyzable. Indeed, it takes 8-24 months after drug discontinuation for plasma levels to become undetectable.

"Teriflunomide could definitely be used as first-line therapy. It can be used second-line in a patient intolerant to a prior agent. But I think the long half-life complicates its use as second-line therapy in patients who’ve had breakthrough disease on prior agents, because if we need to consider a switch from teriflunomide, that long half-life has to be taken into consideration. You’ll need to consider the elimination protocol," she advised.

Patients find the elimination protocol arduous. It entails swallowing 8 g of oral cholestyramine every 8 hours for 11 days, or 50 g of activated charcoal given orally every 12 hours for 11 days.

• Dimethyl fumarate: This twice-daily oral agent, which was approved last March, activates the nuclear factor transcriptional pathway, thereby defending against oxidative stress–induced neuronal death. Dimethyl fumarate also supports myelin integrity in the central nervous system.

The drug’s side effect profile, consisting mostly of short-term flushing and gastrointestinal complaints, is the most benign of the three oral agents. Thus, it could potentially see broader use both as a first-line drug in newly diagnosed patients and as second-line therapy in patients intolerant to or experiencing disease breakthrough on other agents.

That being said, it’s still unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. A couple of studies of fingolimod showed a high relapse rate in this situation, and there are simply no data as yet on the two newer agents, according to Dr. Kita.

• Upcoming oral agents: The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule that has completed two phase III clinical trials and is now under review by the European Medicines Agency for possible marketing approval. Teva has not yet applied to the Food and Drug Administration for U.S. approval.

Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively and thus pose fewer potential immunocompromise issues than fingolimod. These include siponimod, ponesimod, and ONO-4641.

Dr. Kita reported receiving research support from Biogen Idec (which markets Tecfidera), Novartis (which markets Gilenya and is developing siponimod), Serono, and Acorda, as well as personal compensation from Biogen Idec, Bayer, and Genzyme (which markets Aubagio).

[email protected]

ORLANDO – Effective oral therapy has been at the top of the wish list of many multiple sclerosis patients for a long time – and now, seemingly all of a sudden, three approved oral agents are available to choose from.

For patients, the obvious attractions of oral therapy are ease of administration and that it’s less of a reminder that they have a serious chronic illness. But which agent is the right fit for a given patient?

All three oral drugs – fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera) – are "definitely" suitable as first-line therapy in selected newly diagnosed MS patients, Dr. Mariko Kita asserted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

But the three oral drugs are not interchangeable. Each has a different mechanism of action and its own side effect profile, emphasized Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.

Today few neurologists – certainly less than 10% – are using any oral agent as first-line therapy. That’s in part due to cost and reimbursement issues, but to a much greater extent it’s because most physicians don’t yet feel comfortable that the safety profiles of the oral agents are fully known. The drugs are still too new, in the eyes of most practitioners. After all, both natalizumab (Tysabri) – considered the most effective of the injectable agents – and fingolimod – the first oral agent to receive marketing approval, back in October 2010 – had to have revisionary cautions added to their labeling shortly after they were introduced.

But provider experience with the orals is expected to grow quickly. And absent any late bombshells regarding side effects, it’s widely anticipated that the use of oral agents for MS will surge within the next few years, with a corresponding decline in popularity of injectable therapies.

Demand for oral therapy will be high all across the patient spectrum: in newly diagnosed patients, in individuals with a lengthy disease history who have tried all the available disease-modifying therapies with less than satisfactory results and have been awaiting something new, in patients intolerant to or experiencing breakthrough disease on a first-line injectable agent, as well as in patients who are stable on their current injectable disease-modifying therapy but are experiencing injection fatigue or growing more concerned about their parenteral therapy’s long-term risks, Dr. Kita predicted.

Choosing between the oral options appropriately requires a focus on patient-specific factors, including comorbid conditions, reproductive status, and consideration of how the oral drug will fit in to the big picture of a long-term, staged therapy plan, she added.

Here’s her personal clinical rundown on the approved oral drugs:

• Fingolimod: This is a drug best reserved for MS patients who are otherwise relatively healthy, in Dr. Kita’s view. Specifically, it’s a less favorable option for patients with diabetes, smokers, and others with reduced pulmonary function, and in individuals at increased risk of infection, including those with a high Expanded Disability Status Scale score.

Fingolimod is a sphingosine-1-phosphate agonist. It sequesters lymphocytes in the lymph nodes so they can’t participate in autoimmune activity. The required testing prior to starting the drug, the need for careful observation during the first dose, and the necessary ongoing monitoring as long as the patient is on fingolimod make this a labor-intensive drug.

Bearing those caveats in mind, she continued, fingolimod is "reasonable" to use as a first-line agent, or as a second-line agent in the setting of intolerance to or breakthrough disease while on prior therapy.

"But I would caution those who are reserving these oral agents as second-line that we need to think about what we can reasonably expect from them. If we’re moving to them as second-line because of tolerability issues with first-line agents, yes, I think that’s most reasonable. But if we’re moving because of breakthrough disease, our experience with these agents in cases of failure with standard first-line therapies is very, very limited. Sure, the differing mechanism of action offers a reasonable alternative option, but the expectation that the oral will be better than a failed injectable has not yet been proven," Dr. Kita said.

• Teriflunomide: This is the active metabolite of leflunomide, a treatment approved by the Food and Drug Administration for rheumatoid arthritis. It was approved for treating relapsing forms of MS last fall. Teriflunomide nonselectively inhibits rapidly dividing cell populations by curbing pyrimidine synthesis via bonding to the enzyme dihydroorotate dehydrogenase.

Who’s the right fit for teriflunomide? Because the drug is rated category X and has teratogenicity potential in both men and women, it’s a given that the candidate must be on effective contraception. Also, the patient should definitely not have comorbid liver disease. And in Dr. Kita’s view, an appropriate candidate for teriflunomide has mild MS. Otherwise, the physician can get backed into a corner. That’s because the drug is excreted very slowly and is not dialyzable. Indeed, it takes 8-24 months after drug discontinuation for plasma levels to become undetectable.

"Teriflunomide could definitely be used as first-line therapy. It can be used second-line in a patient intolerant to a prior agent. But I think the long half-life complicates its use as second-line therapy in patients who’ve had breakthrough disease on prior agents, because if we need to consider a switch from teriflunomide, that long half-life has to be taken into consideration. You’ll need to consider the elimination protocol," she advised.

Patients find the elimination protocol arduous. It entails swallowing 8 g of oral cholestyramine every 8 hours for 11 days, or 50 g of activated charcoal given orally every 12 hours for 11 days.

• Dimethyl fumarate: This twice-daily oral agent, which was approved last March, activates the nuclear factor transcriptional pathway, thereby defending against oxidative stress–induced neuronal death. Dimethyl fumarate also supports myelin integrity in the central nervous system.

The drug’s side effect profile, consisting mostly of short-term flushing and gastrointestinal complaints, is the most benign of the three oral agents. Thus, it could potentially see broader use both as a first-line drug in newly diagnosed patients and as second-line therapy in patients intolerant to or experiencing disease breakthrough on other agents.

That being said, it’s still unclear whether any of the available oral agents is the best choice after natalizumab discontinuation. A couple of studies of fingolimod showed a high relapse rate in this situation, and there are simply no data as yet on the two newer agents, according to Dr. Kita.

• Upcoming oral agents: The investigational oral agent furthest along in the developmental pipeline is laquinimod, a quinolone-3-carboxamide small molecule that has completed two phase III clinical trials and is now under review by the European Medicines Agency for possible marketing approval. Teva has not yet applied to the Food and Drug Administration for U.S. approval.

Several second-generation sphingosine-1-phosphate agonists are in development. They are believed to act more selectively and thus pose fewer potential immunocompromise issues than fingolimod. These include siponimod, ponesimod, and ONO-4641.

Dr. Kita reported receiving research support from Biogen Idec (which markets Tecfidera), Novartis (which markets Gilenya and is developing siponimod), Serono, and Acorda, as well as personal compensation from Biogen Idec, Bayer, and Genzyme (which markets Aubagio).

[email protected]

MADRID – Arimoclomol showed promise as a treatment for the most common type of inflammatory myopathy in adults over age 50 in a 1-year, phase IIa, "proof-of-concept" study.

Not only was the novel oral agent "well tolerated," which was the study’s main objective to assess, but it also showed early signs that it could be effective in the treatment of patients with sporadic inclusion body myositis (IBM). Indeed, there was a trend toward slower deterioration in physical function, muscle strength, and right-hand grip muscle strength for arimoclomol when compared against placebo at 8 months’ follow-up.

"IBM is an enigmatic disease," study investigator Dr. Pedro Machado said at the recent annual European Congress of Rheumatology. "IBM muscle tissue displays [both] inflammatory and degenerative features."

Dr. Machado, a senior clinical research associate at the MRC Centre for Neuromuscular Diseases at University College London (UCL), explained that arimoclomol targets the heat shock response, amplifying the expression of heat shock protein. As such, it potentially targets both the degenerative and inflammatory components of the disease. "Previous studies have only involved agents directly purely at the inflammatory component of IBM pathology, and all were ineffective," the researcher observed.

For the double-blind study, teams based at UCL and the University of Kansas, Kansas City, collaborated to recruit 17 men and 7 women (mean age, 67 years) who had had IBM for an average of about 8 years. These patients were randomized in a 2:1 ratio to receive active therapy with arimoclomol 100 mg three times daily or matching placebo for 4 months, with follow-up lasting for 12 months (Ann. Rheum. Dis. 2013;72:164).

The investigators assessed patients for the development of adverse events, physical function using the IBM functional rating scale (IBMFRS), and muscle strength via manual muscle testing and maximum voluntary isometric contraction testing (MVICT) at 4, 8, and 12 months. They also measured the patients’ fat-free mass percentage with dual-energy x-ray absorptiometry at 4 and 12 months, and took muscle biopsies to assess the levels of heat shock protein 70 in muscle tissue before and after 4 months of treatment.

Fourteen of the 16 patients randomized to arimoclomol completed 4 months of treatment; 1 patient returned for final assessment at 12 months’ follow-up. All eight placebo patients completed 12 months of follow-up.

"The drug was very safe and well tolerated. Compliance was, on average, 99%, and we also performed ophthalmological assessment, and there were no ophthalmological problems," Dr. Machado said.

The most common adverse events were gastrointestinal problems, infections, and falls, although there was no difference between the arimoclomol and placebo groups in terms of the frequency, type, or severity of these or other adverse events. "We have to remind ourselves that this is an elderly population," Dr. Machado said, noting that the infections seen all responded to standard antibiotic therapy.

"There was one serious adverse event," he conceded. This was a case of hypertension requiring prolonged hospitalization in a patient given arimoclomol. "There were also two cases of hyponatremia in the arimoclomol group, but this was mild, transient, and asymptomatic, and it resolved without treatment."

At 4, 8, and 12 months after baseline, scores on the IBMFRS in the arimoclomol versus the placebo arm changed by a respective –0.34 vs. –0.88 (P = .239), –0.68 vs. –2.50 (P = .055), and –2.03 vs. –3.50 (P = .538). These data suggest that less deterioration in physical function occurred with arimoclomol than with placebo, Dr. Machado said.

Muscle strength appeared to improve with active treatment, as did right-hand grip strength based on MVICT results at 8 months that approached significance (1.26 vs. –0.54; P = .064).

"A trend towards a slower deterioration was observed in the arimoclomol group for the IBMFRS, for the [muscle] strength score, and for the quantitative muscle assessment only for the right-hand grip assessment at 8 months," Dr. Machado said.

He concluded: "This shows a preliminary signal for potential therapeutic benefit in patients with IBM, and therefore we believe that these data support further research of arimoclomol in inclusion body myositis."

The study was funded by Arthritis Research UK, a University of Kansas Neurology Ziegler Grant, and a University of Kansas General Clinical Research Center CReFF Grant. Dr. Machado had no disclosures.

[email protected]

MADRID – Arimoclomol showed promise as a treatment for the most common type of inflammatory myopathy in adults over age 50 in a 1-year, phase IIa, "proof-of-concept" study.

Not only was the novel oral agent "well tolerated," which was the study’s main objective to assess, but it also showed early signs that it could be effective in the treatment of patients with sporadic inclusion body myositis (IBM). Indeed, there was a trend toward slower deterioration in physical function, muscle strength, and right-hand grip muscle strength for arimoclomol when compared against placebo at 8 months’ follow-up.

"IBM is an enigmatic disease," study investigator Dr. Pedro Machado said at the recent annual European Congress of Rheumatology. "IBM muscle tissue displays [both] inflammatory and degenerative features."

Dr. Machado, a senior clinical research associate at the MRC Centre for Neuromuscular Diseases at University College London (UCL), explained that arimoclomol targets the heat shock response, amplifying the expression of heat shock protein. As such, it potentially targets both the degenerative and inflammatory components of the disease. "Previous studies have only involved agents directly purely at the inflammatory component of IBM pathology, and all were ineffective," the researcher observed.

For the double-blind study, teams based at UCL and the University of Kansas, Kansas City, collaborated to recruit 17 men and 7 women (mean age, 67 years) who had had IBM for an average of about 8 years. These patients were randomized in a 2:1 ratio to receive active therapy with arimoclomol 100 mg three times daily or matching placebo for 4 months, with follow-up lasting for 12 months (Ann. Rheum. Dis. 2013;72:164).

The investigators assessed patients for the development of adverse events, physical function using the IBM functional rating scale (IBMFRS), and muscle strength via manual muscle testing and maximum voluntary isometric contraction testing (MVICT) at 4, 8, and 12 months. They also measured the patients’ fat-free mass percentage with dual-energy x-ray absorptiometry at 4 and 12 months, and took muscle biopsies to assess the levels of heat shock protein 70 in muscle tissue before and after 4 months of treatment.

Fourteen of the 16 patients randomized to arimoclomol completed 4 months of treatment; 1 patient returned for final assessment at 12 months’ follow-up. All eight placebo patients completed 12 months of follow-up.

"The drug was very safe and well tolerated. Compliance was, on average, 99%, and we also performed ophthalmological assessment, and there were no ophthalmological problems," Dr. Machado said.

The most common adverse events were gastrointestinal problems, infections, and falls, although there was no difference between the arimoclomol and placebo groups in terms of the frequency, type, or severity of these or other adverse events. "We have to remind ourselves that this is an elderly population," Dr. Machado said, noting that the infections seen all responded to standard antibiotic therapy.

"There was one serious adverse event," he conceded. This was a case of hypertension requiring prolonged hospitalization in a patient given arimoclomol. "There were also two cases of hyponatremia in the arimoclomol group, but this was mild, transient, and asymptomatic, and it resolved without treatment."

At 4, 8, and 12 months after baseline, scores on the IBMFRS in the arimoclomol versus the placebo arm changed by a respective –0.34 vs. –0.88 (P = .239), –0.68 vs. –2.50 (P = .055), and –2.03 vs. –3.50 (P = .538). These data suggest that less deterioration in physical function occurred with arimoclomol than with placebo, Dr. Machado said.

Muscle strength appeared to improve with active treatment, as did right-hand grip strength based on MVICT results at 8 months that approached significance (1.26 vs. –0.54; P = .064).

"A trend towards a slower deterioration was observed in the arimoclomol group for the IBMFRS, for the [muscle] strength score, and for the quantitative muscle assessment only for the right-hand grip assessment at 8 months," Dr. Machado said.

He concluded: "This shows a preliminary signal for potential therapeutic benefit in patients with IBM, and therefore we believe that these data support further research of arimoclomol in inclusion body myositis."

The study was funded by Arthritis Research UK, a University of Kansas Neurology Ziegler Grant, and a University of Kansas General Clinical Research Center CReFF Grant. Dr. Machado had no disclosures.

[email protected]

MADRID – Arimoclomol showed promise as a treatment for the most common type of inflammatory myopathy in adults over age 50 in a 1-year, phase IIa, "proof-of-concept" study.

Not only was the novel oral agent "well tolerated," which was the study’s main objective to assess, but it also showed early signs that it could be effective in the treatment of patients with sporadic inclusion body myositis (IBM). Indeed, there was a trend toward slower deterioration in physical function, muscle strength, and right-hand grip muscle strength for arimoclomol when compared against placebo at 8 months’ follow-up.

"IBM is an enigmatic disease," study investigator Dr. Pedro Machado said at the recent annual European Congress of Rheumatology. "IBM muscle tissue displays [both] inflammatory and degenerative features."

Dr. Machado, a senior clinical research associate at the MRC Centre for Neuromuscular Diseases at University College London (UCL), explained that arimoclomol targets the heat shock response, amplifying the expression of heat shock protein. As such, it potentially targets both the degenerative and inflammatory components of the disease. "Previous studies have only involved agents directly purely at the inflammatory component of IBM pathology, and all were ineffective," the researcher observed.

For the double-blind study, teams based at UCL and the University of Kansas, Kansas City, collaborated to recruit 17 men and 7 women (mean age, 67 years) who had had IBM for an average of about 8 years. These patients were randomized in a 2:1 ratio to receive active therapy with arimoclomol 100 mg three times daily or matching placebo for 4 months, with follow-up lasting for 12 months (Ann. Rheum. Dis. 2013;72:164).

The investigators assessed patients for the development of adverse events, physical function using the IBM functional rating scale (IBMFRS), and muscle strength via manual muscle testing and maximum voluntary isometric contraction testing (MVICT) at 4, 8, and 12 months. They also measured the patients’ fat-free mass percentage with dual-energy x-ray absorptiometry at 4 and 12 months, and took muscle biopsies to assess the levels of heat shock protein 70 in muscle tissue before and after 4 months of treatment.

Fourteen of the 16 patients randomized to arimoclomol completed 4 months of treatment; 1 patient returned for final assessment at 12 months’ follow-up. All eight placebo patients completed 12 months of follow-up.

"The drug was very safe and well tolerated. Compliance was, on average, 99%, and we also performed ophthalmological assessment, and there were no ophthalmological problems," Dr. Machado said.

The most common adverse events were gastrointestinal problems, infections, and falls, although there was no difference between the arimoclomol and placebo groups in terms of the frequency, type, or severity of these or other adverse events. "We have to remind ourselves that this is an elderly population," Dr. Machado said, noting that the infections seen all responded to standard antibiotic therapy.

"There was one serious adverse event," he conceded. This was a case of hypertension requiring prolonged hospitalization in a patient given arimoclomol. "There were also two cases of hyponatremia in the arimoclomol group, but this was mild, transient, and asymptomatic, and it resolved without treatment."

At 4, 8, and 12 months after baseline, scores on the IBMFRS in the arimoclomol versus the placebo arm changed by a respective –0.34 vs. –0.88 (P = .239), –0.68 vs. –2.50 (P = .055), and –2.03 vs. –3.50 (P = .538). These data suggest that less deterioration in physical function occurred with arimoclomol than with placebo, Dr. Machado said.

Muscle strength appeared to improve with active treatment, as did right-hand grip strength based on MVICT results at 8 months that approached significance (1.26 vs. –0.54; P = .064).

"A trend towards a slower deterioration was observed in the arimoclomol group for the IBMFRS, for the [muscle] strength score, and for the quantitative muscle assessment only for the right-hand grip assessment at 8 months," Dr. Machado said.

He concluded: "This shows a preliminary signal for potential therapeutic benefit in patients with IBM, and therefore we believe that these data support further research of arimoclomol in inclusion body myositis."

The study was funded by Arthritis Research UK, a University of Kansas Neurology Ziegler Grant, and a University of Kansas General Clinical Research Center CReFF Grant. Dr. Machado had no disclosures.

[email protected]

ORLANDO – The randomized trials evidence supporting a positive clinical effect for medical marijuana in relieving symptoms of multiple sclerosis is strongest for improvement of pain, patient-reported spasticity, and sleep disturbances.

That’s the clear message from an analysis of the 19 published, reasonable-quality randomized trials of cannabis use in patients with MS, Dr. Allen C. Bowling reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

"That’s consistent with my personal observation in a state where we’ve had medical marijuana for 12 years and where recreational marijuana was approved in last November’s election. The most consistent effect my patients report is on nocturnal pain and/or spasticity, which is consistent with the results of the clinical trials. The patients typically use a little bit at bedtime," according to Dr. Bowling, medical director of the MS service and director of the complementary and alternative medicine service at the Colorado Neurological Institute, Englewood.

The evidence that medical marijuana is of benefit for the bladder dysfunction associated with MS is weaker: Of 9 clinical trials that included bladder dysfunction as an endpoint, 4 were positive, 5 negative.

Occupying the bottom tier in terms of evidence-based therapy are objectively measured spasticity and tremor. Of 13 clinical trials that incorporated objective, clinician-assessed spasticity as an endpoint, only 2 were positive, with 11 negative. And none of the 5 decent-quality randomized trials that examined medical marijuana for relief of tremor in MS patients was positive.

In contrast, 9 of 11 studies that looked at pain as an endpoint reported a positive effect. Of 13 studies with patient-reported spasticity as an endpoint, 9 were positive, 4 negative. And of 6 randomized trials with sleep quality as an endpoint, 5 were positive, 1 negative, noted Dr. Bowling, who is clinical professor of neurology at the University of Colorado, Denver.

Medical marijuana is now legal in 18 states and the District of Columbia.

The largest and in Dr. Bowling’s view one of the best-conducted randomized trials in the field was the multicenter U.K. CAMS trial. The 15-week study included 630 MS patients who were randomized to oral tetrahydrocannabinol (Marinol); Cannador, an oral capsule containing a standardized amount of whole-plant extract; or placebo. The investigators found no significant difference between the cannabis-based therapies and placebo in improving spasticity as objectively measured using the Ashworth score, which was the primary study endpoint. However, the two active treatment arms did show significant benefit in terms of the secondary endpoints of improvement in pain, self-reported spasticity, and sleep (Lancet 2003;362:1517-26).

Another speaker at the session on prescribing medical marijuana underscored the beneficial effect on sleep disruption.

"In every single population – whether it’s Crohn’s disease, epilepsy, HIV, noncancer pain, cancer pain – improved sleep is always one of the most robust outcomes patients report. This is something that in clinical practice we tend to push to one side. We have some medications for pain management that we sometimes use for sleep, but cannabis use at nighttime seems to be a very powerful agent to improve sleep quality," observed Dr. Mark F. Ware, a family physician and anesthesiologist who is director of clinical research at the Alan Edwards Pain Management Unit of McGill University in Montreal.

Dr. Bowling estimated that roughly 80% of his MS patients have little or no interest in medical marijuana. Those who are using it span a spectrum ranging from patients who were recreational users of pot before their MS diagnosis and who now seek beneficial MS effects or simply a license to use it recreationally, to elderly individuals with no history of marijuana use who have found cannabis is the only thing that effectively relieves some of their symptoms.

The neurologist noted two glaring paradoxes that emerged from his review of the clinical trials literature on medical marijuana for MS. One is that only 2 of the 19 studies utilized smoked marijuana, even though it’s far and away the most readily available form of the agent for U.S. patients. The most widely studied agent nabiximols (Sativex), an extract formulated as an oral spray – is approved as a prescription drug in Canada, the United Kingdom, and other countries, but not in the United States. And while Marinol and oral nabilone (Cesamet) are approved by the Food and Drug Administration, they’re not widely prescribed.

"I find it particularly challenging to apply the medical literature in this area to clinical situations. In our clinical practice, the way it seems to work out best is for patients to experiment on their own with marijuana as a prn add-on to their spasticity and/or pain medications, especially at bedtime or, if symptoms are worse, in the afternoon. But the dose, frequency, formulation, quality control ... it’s a real challenge. It’s like there are parallel universes of care, where we’re prescribing the conventional medications, and then we find out that the patients are also using marijuana," Dr. Bowling said.

The other paradox is the huge disconnect between the generally quite favorable subjective patient self-reports of improvement in spasticity and the largely negative objective results. The explanation may lie in part in the inadequacy of the Ashworth score as an outcome measure. It has come under frequent criticism, since some approved antispasticity medications have shown only modest or no improvement in Ashworth scores. But the limitations of the Ashworth score are probably only part of the story, in Dr. Bowling’s view.

"Patients’ assessments are 24/7; ours is a brief clinical visit at a prespecified time. Also, there is a pain component to spasticity, so for some patients who feel their spasticity is improving with the use of marijuana it may just be the pain aspect of the spasticity, or a euphoric view of the world that’s changing their perception of how severe the spasticity is. But for some patients, maybe it doesn’t matter whether it’s a subjective or objective assessment that’s improving, especially for those who don’t have high physical or cognitive demands during the day," he said.

Dr. Bowling reported having no conflicts of interest. Dr. Ware has received lecture fees from the Canadian Consortium for the Investigation of the Cannabinoids and a research grant and honoraria from Valeant for conducting a randomized trial of nabilone in fibromyalgia patients.

[email protected]

ORLANDO – The randomized trials evidence supporting a positive clinical effect for medical marijuana in relieving symptoms of multiple sclerosis is strongest for improvement of pain, patient-reported spasticity, and sleep disturbances.

That’s the clear message from an analysis of the 19 published, reasonable-quality randomized trials of cannabis use in patients with MS, Dr. Allen C. Bowling reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

"That’s consistent with my personal observation in a state where we’ve had medical marijuana for 12 years and where recreational marijuana was approved in last November’s election. The most consistent effect my patients report is on nocturnal pain and/or spasticity, which is consistent with the results of the clinical trials. The patients typically use a little bit at bedtime," according to Dr. Bowling, medical director of the MS service and director of the complementary and alternative medicine service at the Colorado Neurological Institute, Englewood.

The evidence that medical marijuana is of benefit for the bladder dysfunction associated with MS is weaker: Of 9 clinical trials that included bladder dysfunction as an endpoint, 4 were positive, 5 negative.

Occupying the bottom tier in terms of evidence-based therapy are objectively measured spasticity and tremor. Of 13 clinical trials that incorporated objective, clinician-assessed spasticity as an endpoint, only 2 were positive, with 11 negative. And none of the 5 decent-quality randomized trials that examined medical marijuana for relief of tremor in MS patients was positive.

In contrast, 9 of 11 studies that looked at pain as an endpoint reported a positive effect. Of 13 studies with patient-reported spasticity as an endpoint, 9 were positive, 4 negative. And of 6 randomized trials with sleep quality as an endpoint, 5 were positive, 1 negative, noted Dr. Bowling, who is clinical professor of neurology at the University of Colorado, Denver.

Medical marijuana is now legal in 18 states and the District of Columbia.

The largest and in Dr. Bowling’s view one of the best-conducted randomized trials in the field was the multicenter U.K. CAMS trial. The 15-week study included 630 MS patients who were randomized to oral tetrahydrocannabinol (Marinol); Cannador, an oral capsule containing a standardized amount of whole-plant extract; or placebo. The investigators found no significant difference between the cannabis-based therapies and placebo in improving spasticity as objectively measured using the Ashworth score, which was the primary study endpoint. However, the two active treatment arms did show significant benefit in terms of the secondary endpoints of improvement in pain, self-reported spasticity, and sleep (Lancet 2003;362:1517-26).

Another speaker at the session on prescribing medical marijuana underscored the beneficial effect on sleep disruption.

"In every single population – whether it’s Crohn’s disease, epilepsy, HIV, noncancer pain, cancer pain – improved sleep is always one of the most robust outcomes patients report. This is something that in clinical practice we tend to push to one side. We have some medications for pain management that we sometimes use for sleep, but cannabis use at nighttime seems to be a very powerful agent to improve sleep quality," observed Dr. Mark F. Ware, a family physician and anesthesiologist who is director of clinical research at the Alan Edwards Pain Management Unit of McGill University in Montreal.

Dr. Bowling estimated that roughly 80% of his MS patients have little or no interest in medical marijuana. Those who are using it span a spectrum ranging from patients who were recreational users of pot before their MS diagnosis and who now seek beneficial MS effects or simply a license to use it recreationally, to elderly individuals with no history of marijuana use who have found cannabis is the only thing that effectively relieves some of their symptoms.

The neurologist noted two glaring paradoxes that emerged from his review of the clinical trials literature on medical marijuana for MS. One is that only 2 of the 19 studies utilized smoked marijuana, even though it’s far and away the most readily available form of the agent for U.S. patients. The most widely studied agent nabiximols (Sativex), an extract formulated as an oral spray – is approved as a prescription drug in Canada, the United Kingdom, and other countries, but not in the United States. And while Marinol and oral nabilone (Cesamet) are approved by the Food and Drug Administration, they’re not widely prescribed.

"I find it particularly challenging to apply the medical literature in this area to clinical situations. In our clinical practice, the way it seems to work out best is for patients to experiment on their own with marijuana as a prn add-on to their spasticity and/or pain medications, especially at bedtime or, if symptoms are worse, in the afternoon. But the dose, frequency, formulation, quality control ... it’s a real challenge. It’s like there are parallel universes of care, where we’re prescribing the conventional medications, and then we find out that the patients are also using marijuana," Dr. Bowling said.

The other paradox is the huge disconnect between the generally quite favorable subjective patient self-reports of improvement in spasticity and the largely negative objective results. The explanation may lie in part in the inadequacy of the Ashworth score as an outcome measure. It has come under frequent criticism, since some approved antispasticity medications have shown only modest or no improvement in Ashworth scores. But the limitations of the Ashworth score are probably only part of the story, in Dr. Bowling’s view.

"Patients’ assessments are 24/7; ours is a brief clinical visit at a prespecified time. Also, there is a pain component to spasticity, so for some patients who feel their spasticity is improving with the use of marijuana it may just be the pain aspect of the spasticity, or a euphoric view of the world that’s changing their perception of how severe the spasticity is. But for some patients, maybe it doesn’t matter whether it’s a subjective or objective assessment that’s improving, especially for those who don’t have high physical or cognitive demands during the day," he said.

Dr. Bowling reported having no conflicts of interest. Dr. Ware has received lecture fees from the Canadian Consortium for the Investigation of the Cannabinoids and a research grant and honoraria from Valeant for conducting a randomized trial of nabilone in fibromyalgia patients.

[email protected]

ORLANDO – The randomized trials evidence supporting a positive clinical effect for medical marijuana in relieving symptoms of multiple sclerosis is strongest for improvement of pain, patient-reported spasticity, and sleep disturbances.

That’s the clear message from an analysis of the 19 published, reasonable-quality randomized trials of cannabis use in patients with MS, Dr. Allen C. Bowling reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

"That’s consistent with my personal observation in a state where we’ve had medical marijuana for 12 years and where recreational marijuana was approved in last November’s election. The most consistent effect my patients report is on nocturnal pain and/or spasticity, which is consistent with the results of the clinical trials. The patients typically use a little bit at bedtime," according to Dr. Bowling, medical director of the MS service and director of the complementary and alternative medicine service at the Colorado Neurological Institute, Englewood.

The evidence that medical marijuana is of benefit for the bladder dysfunction associated with MS is weaker: Of 9 clinical trials that included bladder dysfunction as an endpoint, 4 were positive, 5 negative.

Occupying the bottom tier in terms of evidence-based therapy are objectively measured spasticity and tremor. Of 13 clinical trials that incorporated objective, clinician-assessed spasticity as an endpoint, only 2 were positive, with 11 negative. And none of the 5 decent-quality randomized trials that examined medical marijuana for relief of tremor in MS patients was positive.

In contrast, 9 of 11 studies that looked at pain as an endpoint reported a positive effect. Of 13 studies with patient-reported spasticity as an endpoint, 9 were positive, 4 negative. And of 6 randomized trials with sleep quality as an endpoint, 5 were positive, 1 negative, noted Dr. Bowling, who is clinical professor of neurology at the University of Colorado, Denver.

Medical marijuana is now legal in 18 states and the District of Columbia.

The largest and in Dr. Bowling’s view one of the best-conducted randomized trials in the field was the multicenter U.K. CAMS trial. The 15-week study included 630 MS patients who were randomized to oral tetrahydrocannabinol (Marinol); Cannador, an oral capsule containing a standardized amount of whole-plant extract; or placebo. The investigators found no significant difference between the cannabis-based therapies and placebo in improving spasticity as objectively measured using the Ashworth score, which was the primary study endpoint. However, the two active treatment arms did show significant benefit in terms of the secondary endpoints of improvement in pain, self-reported spasticity, and sleep (Lancet 2003;362:1517-26).

Another speaker at the session on prescribing medical marijuana underscored the beneficial effect on sleep disruption.

"In every single population – whether it’s Crohn’s disease, epilepsy, HIV, noncancer pain, cancer pain – improved sleep is always one of the most robust outcomes patients report. This is something that in clinical practice we tend to push to one side. We have some medications for pain management that we sometimes use for sleep, but cannabis use at nighttime seems to be a very powerful agent to improve sleep quality," observed Dr. Mark F. Ware, a family physician and anesthesiologist who is director of clinical research at the Alan Edwards Pain Management Unit of McGill University in Montreal.

Dr. Bowling estimated that roughly 80% of his MS patients have little or no interest in medical marijuana. Those who are using it span a spectrum ranging from patients who were recreational users of pot before their MS diagnosis and who now seek beneficial MS effects or simply a license to use it recreationally, to elderly individuals with no history of marijuana use who have found cannabis is the only thing that effectively relieves some of their symptoms.

The neurologist noted two glaring paradoxes that emerged from his review of the clinical trials literature on medical marijuana for MS. One is that only 2 of the 19 studies utilized smoked marijuana, even though it’s far and away the most readily available form of the agent for U.S. patients. The most widely studied agent nabiximols (Sativex), an extract formulated as an oral spray – is approved as a prescription drug in Canada, the United Kingdom, and other countries, but not in the United States. And while Marinol and oral nabilone (Cesamet) are approved by the Food and Drug Administration, they’re not widely prescribed.

"I find it particularly challenging to apply the medical literature in this area to clinical situations. In our clinical practice, the way it seems to work out best is for patients to experiment on their own with marijuana as a prn add-on to their spasticity and/or pain medications, especially at bedtime or, if symptoms are worse, in the afternoon. But the dose, frequency, formulation, quality control ... it’s a real challenge. It’s like there are parallel universes of care, where we’re prescribing the conventional medications, and then we find out that the patients are also using marijuana," Dr. Bowling said.

The other paradox is the huge disconnect between the generally quite favorable subjective patient self-reports of improvement in spasticity and the largely negative objective results. The explanation may lie in part in the inadequacy of the Ashworth score as an outcome measure. It has come under frequent criticism, since some approved antispasticity medications have shown only modest or no improvement in Ashworth scores. But the limitations of the Ashworth score are probably only part of the story, in Dr. Bowling’s view.

"Patients’ assessments are 24/7; ours is a brief clinical visit at a prespecified time. Also, there is a pain component to spasticity, so for some patients who feel their spasticity is improving with the use of marijuana it may just be the pain aspect of the spasticity, or a euphoric view of the world that’s changing their perception of how severe the spasticity is. But for some patients, maybe it doesn’t matter whether it’s a subjective or objective assessment that’s improving, especially for those who don’t have high physical or cognitive demands during the day," he said.

Dr. Bowling reported having no conflicts of interest. Dr. Ware has received lecture fees from the Canadian Consortium for the Investigation of the Cannabinoids and a research grant and honoraria from Valeant for conducting a randomized trial of nabilone in fibromyalgia patients.

[email protected]

ORLANDO – The burgeoning treatment options for multiple sclerosis are increasingly pushing the disease beyond the comfort zone of general neurologists, according to Dr. Mariko Kita.

"MS has become a very, very active area. We’re diagnosing this condition now earlier than ever before. We are initiating treatments at the earliest sign of this condition. We’re going to be seeing, if we haven’t already, a greater influx of patients into MS centers to try to tease apart which disease-modifying therapy might be best for them. And it’s possible that the general neurologists who aren’t referring patients to us at MS centers are going to limit their discussion. They’re going to stick to their go-to drugs: They’ll say, ‘I’ve got one go-to injectable and one go-to oral, and those are the things I’m going to talk about,’ " predicted Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.

There are currently nine Food and Drug Administration–approved disease-modifying therapies for MS, including three recently approved oral agents. Plenty of additional medications are advancing through the developmental pipeline.

"All of these new treatments have definitely had an impact on our clinical practice. They’ve increased our burden in a number of ways," Dr. Kita said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

For one, patient education regarding treatment options has become quite time consuming.

"The discussion of the educational component of the injectables has already been fairly complicated, and now we’re adding to it agents that have a very wide spectrum of mechanisms of action," the neurologist said. "So the question is, how much detail do you go into? What information do you share? And if you’re not in an MS center, do you have help from a nurse educator or others to do this education?"

And then there is the numbing challenge of securing insurance authorization for treatment. "This is perhaps the single biggest unreimbursed burden on my clinic and clinic staff. This is really a major deal for MS centers," Dr. Kita said.

Requisite patient monitoring is also increasingly elaborate. This may include testing prior to putting a patient on an agent, first-dose monitoring, and ongoing monitoring for treatment adherence and the possible emergence of serious side effects.

Take, for example, fingolimod (Gilenya), approved in September 2010 as the first disease-modifying oral agent for MS, and thus the oral drug with which physicians have the most experience.

"The start-up, let’s face it, is labor intensive," Dr. Kita said.

Her personal practice before placing a patient on fingolimod is to order an electrocardiogram, pulmonary function tests, a retinal optical coherence tomography (OCT) scan, a dermatologic evaluation, and a check of varicella titers, with vaccination if appropriate. Then comes the supervised, 6-hour, first-dose observation period.

"We do that in the clinic. We have the patient bring in a companion. They take up an exam room and are not under continuous surveillance, so if issues should arise, we want a companion on hand to call for help. Plus, a medical assistant goes in every hour. And the prescribing physician checks in before the first dose and at the end of the day," she explained.

If patients are taking a medication that prolongs the QT interval, however, as many do in order to control their chronic pain, they should be hospitalized for the first dose of fingolimod, Dr. Kita added.

Monitoring needs to be done on an ongoing basis, although as yet there are no clear guidelines as to the specifics. She recommended an annual brain MRI, an ECG, pulmonary function tests, a dermatologic evaluation, and an OCT, because cases of macular edema have occurred 2 years into treatment.

"That’s not necessarily everyone’s standard practice, but it’s what we do," she continued.

And then there is the issue of monitoring circulating CD4 cell counts. Fingolimod’s mechanism of action involves sequestration of lymphocytes in lymph nodes so they can’t contribute to autoimmunity. As a result, patients maintained on fingolimod experience abnormally low levels of circulating CD4 cells, the clinical significance of which remains unclear.

"I think the immunocompromise issue hasn’t really been resolved. I know of practitioners who say, ‘I don’t want to check CD4 counts because it makes me nervous,’ and I’m not sure that’s the best practice. Having said that, it’s hard to know what to do with those exceedingly low CD4 counts," Dr. Kita said.

She added that she views the development of shingles in a patient on fingolimod as a potential red flag warranting serious consideration of a switch to another agent.

Dr. Kita reported receiving research support from Biogen Idec, Novartis (which markets Gilenya), Serono, and Acorda, and personal compensation from Biogen Idec, Bayer, and Genzyme.

[email protected]

ORLANDO – The burgeoning treatment options for multiple sclerosis are increasingly pushing the disease beyond the comfort zone of general neurologists, according to Dr. Mariko Kita.

"MS has become a very, very active area. We’re diagnosing this condition now earlier than ever before. We are initiating treatments at the earliest sign of this condition. We’re going to be seeing, if we haven’t already, a greater influx of patients into MS centers to try to tease apart which disease-modifying therapy might be best for them. And it’s possible that the general neurologists who aren’t referring patients to us at MS centers are going to limit their discussion. They’re going to stick to their go-to drugs: They’ll say, ‘I’ve got one go-to injectable and one go-to oral, and those are the things I’m going to talk about,’ " predicted Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.

There are currently nine Food and Drug Administration–approved disease-modifying therapies for MS, including three recently approved oral agents. Plenty of additional medications are advancing through the developmental pipeline.

"All of these new treatments have definitely had an impact on our clinical practice. They’ve increased our burden in a number of ways," Dr. Kita said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

For one, patient education regarding treatment options has become quite time consuming.

"The discussion of the educational component of the injectables has already been fairly complicated, and now we’re adding to it agents that have a very wide spectrum of mechanisms of action," the neurologist said. "So the question is, how much detail do you go into? What information do you share? And if you’re not in an MS center, do you have help from a nurse educator or others to do this education?"

And then there is the numbing challenge of securing insurance authorization for treatment. "This is perhaps the single biggest unreimbursed burden on my clinic and clinic staff. This is really a major deal for MS centers," Dr. Kita said.

Requisite patient monitoring is also increasingly elaborate. This may include testing prior to putting a patient on an agent, first-dose monitoring, and ongoing monitoring for treatment adherence and the possible emergence of serious side effects.

Take, for example, fingolimod (Gilenya), approved in September 2010 as the first disease-modifying oral agent for MS, and thus the oral drug with which physicians have the most experience.

"The start-up, let’s face it, is labor intensive," Dr. Kita said.

Her personal practice before placing a patient on fingolimod is to order an electrocardiogram, pulmonary function tests, a retinal optical coherence tomography (OCT) scan, a dermatologic evaluation, and a check of varicella titers, with vaccination if appropriate. Then comes the supervised, 6-hour, first-dose observation period.

"We do that in the clinic. We have the patient bring in a companion. They take up an exam room and are not under continuous surveillance, so if issues should arise, we want a companion on hand to call for help. Plus, a medical assistant goes in every hour. And the prescribing physician checks in before the first dose and at the end of the day," she explained.

If patients are taking a medication that prolongs the QT interval, however, as many do in order to control their chronic pain, they should be hospitalized for the first dose of fingolimod, Dr. Kita added.

Monitoring needs to be done on an ongoing basis, although as yet there are no clear guidelines as to the specifics. She recommended an annual brain MRI, an ECG, pulmonary function tests, a dermatologic evaluation, and an OCT, because cases of macular edema have occurred 2 years into treatment.

"That’s not necessarily everyone’s standard practice, but it’s what we do," she continued.

And then there is the issue of monitoring circulating CD4 cell counts. Fingolimod’s mechanism of action involves sequestration of lymphocytes in lymph nodes so they can’t contribute to autoimmunity. As a result, patients maintained on fingolimod experience abnormally low levels of circulating CD4 cells, the clinical significance of which remains unclear.

"I think the immunocompromise issue hasn’t really been resolved. I know of practitioners who say, ‘I don’t want to check CD4 counts because it makes me nervous,’ and I’m not sure that’s the best practice. Having said that, it’s hard to know what to do with those exceedingly low CD4 counts," Dr. Kita said.

She added that she views the development of shingles in a patient on fingolimod as a potential red flag warranting serious consideration of a switch to another agent.

Dr. Kita reported receiving research support from Biogen Idec, Novartis (which markets Gilenya), Serono, and Acorda, and personal compensation from Biogen Idec, Bayer, and Genzyme.

[email protected]

ORLANDO – The burgeoning treatment options for multiple sclerosis are increasingly pushing the disease beyond the comfort zone of general neurologists, according to Dr. Mariko Kita.

"MS has become a very, very active area. We’re diagnosing this condition now earlier than ever before. We are initiating treatments at the earliest sign of this condition. We’re going to be seeing, if we haven’t already, a greater influx of patients into MS centers to try to tease apart which disease-modifying therapy might be best for them. And it’s possible that the general neurologists who aren’t referring patients to us at MS centers are going to limit their discussion. They’re going to stick to their go-to drugs: They’ll say, ‘I’ve got one go-to injectable and one go-to oral, and those are the things I’m going to talk about,’ " predicted Dr. Kita, director of the Virginia Mason MS Center, Seattle, and director of the MS clinical trials unit at Virginia Mason’s Benaroya Research Institute.

There are currently nine Food and Drug Administration–approved disease-modifying therapies for MS, including three recently approved oral agents. Plenty of additional medications are advancing through the developmental pipeline.

"All of these new treatments have definitely had an impact on our clinical practice. They’ve increased our burden in a number of ways," Dr. Kita said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

For one, patient education regarding treatment options has become quite time consuming.

"The discussion of the educational component of the injectables has already been fairly complicated, and now we’re adding to it agents that have a very wide spectrum of mechanisms of action," the neurologist said. "So the question is, how much detail do you go into? What information do you share? And if you’re not in an MS center, do you have help from a nurse educator or others to do this education?"

And then there is the numbing challenge of securing insurance authorization for treatment. "This is perhaps the single biggest unreimbursed burden on my clinic and clinic staff. This is really a major deal for MS centers," Dr. Kita said.

Requisite patient monitoring is also increasingly elaborate. This may include testing prior to putting a patient on an agent, first-dose monitoring, and ongoing monitoring for treatment adherence and the possible emergence of serious side effects.

Take, for example, fingolimod (Gilenya), approved in September 2010 as the first disease-modifying oral agent for MS, and thus the oral drug with which physicians have the most experience.

"The start-up, let’s face it, is labor intensive," Dr. Kita said.

Her personal practice before placing a patient on fingolimod is to order an electrocardiogram, pulmonary function tests, a retinal optical coherence tomography (OCT) scan, a dermatologic evaluation, and a check of varicella titers, with vaccination if appropriate. Then comes the supervised, 6-hour, first-dose observation period.

"We do that in the clinic. We have the patient bring in a companion. They take up an exam room and are not under continuous surveillance, so if issues should arise, we want a companion on hand to call for help. Plus, a medical assistant goes in every hour. And the prescribing physician checks in before the first dose and at the end of the day," she explained.

If patients are taking a medication that prolongs the QT interval, however, as many do in order to control their chronic pain, they should be hospitalized for the first dose of fingolimod, Dr. Kita added.

Monitoring needs to be done on an ongoing basis, although as yet there are no clear guidelines as to the specifics. She recommended an annual brain MRI, an ECG, pulmonary function tests, a dermatologic evaluation, and an OCT, because cases of macular edema have occurred 2 years into treatment.

"That’s not necessarily everyone’s standard practice, but it’s what we do," she continued.

And then there is the issue of monitoring circulating CD4 cell counts. Fingolimod’s mechanism of action involves sequestration of lymphocytes in lymph nodes so they can’t contribute to autoimmunity. As a result, patients maintained on fingolimod experience abnormally low levels of circulating CD4 cells, the clinical significance of which remains unclear.

"I think the immunocompromise issue hasn’t really been resolved. I know of practitioners who say, ‘I don’t want to check CD4 counts because it makes me nervous,’ and I’m not sure that’s the best practice. Having said that, it’s hard to know what to do with those exceedingly low CD4 counts," Dr. Kita said.

She added that she views the development of shingles in a patient on fingolimod as a potential red flag warranting serious consideration of a switch to another agent.

Dr. Kita reported receiving research support from Biogen Idec, Novartis (which markets Gilenya), Serono, and Acorda, and personal compensation from Biogen Idec, Bayer, and Genzyme.

[email protected]

ORLANDO – Lower urinary tract symptoms in patients with multiple sclerosis are common, bothersome, and often undiscussed and untreated, according to a national patient survey.

The online survey was completed by a convenience sample of 1,052 MS patients recruited through the National Multiple Sclerosis Society and other patient advocacy organizations. Fully 88% of the respondents indicated they have lower urinary tract symptoms involving bladder dysfunction and urinary incontinence. The source of these common symptoms in patients with MS is increased contractile activity of the bladder’s detrusor muscle.

The most common lower urinary tract symptom reported by survey respondents was terminal dribble upon voiding, which affected 65% of patients. The next most common symptoms were urinary urgency, experienced by 62%, and incomplete emptying, cited by 61%, Kristin M. Khalaf, Pharm.D., reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Fifty-three percent of patients reported having urgency urinary incontinence, and 45% complained of stress urinary incontinence.

The lower urinary tract symptom that patients found most bothersome was urgency; indeed, one-third of the overall study population indicated they were bothered "quite a bit" or "a great deal" by this problem. Twenty-nine percent of respondents stated they were bothered at least quite a bit by urgency incontinence, added Dr. Khalaf of Allergan, Irvine, Calif.

Only one-third of the 922 MS patients with lower urinary tract symptoms had discussed their symptoms with a health care provider during the past year. When they did speak with a professional, 74% of the time it was with their neurologist. Fifty-two percent spoke to their primary care physician about their problem within the last year.

Among the 42% of survey respondents who indicated they were bothered at least quite a bit by urinary incontinence, 46% hadn’t discussed the problem with a health care provider within the past year, and 35% had never received any form of treatment for it.

Among patients who had ever discussed their lower urinary tract symptoms with a physician or other health care professional, 38% reported currently treating their problem via pelvic exercises or bladder training, 23% were using an oral anticholinergic agent, 4% were taking herbal medicines for their symptoms, 3% were receiving botulinum toxin type A (onabotulinumtoxinA) injections, and 2% had a neural stimulation device.

Most patients currently receiving treatment for their lower urinary tract symptoms pronounced themselves very or somewhat satisfied with their therapy.

The survey was funded by Allergan.

[email protected]

ORLANDO – Lower urinary tract symptoms in patients with multiple sclerosis are common, bothersome, and often undiscussed and untreated, according to a national patient survey.

The online survey was completed by a convenience sample of 1,052 MS patients recruited through the National Multiple Sclerosis Society and other patient advocacy organizations. Fully 88% of the respondents indicated they have lower urinary tract symptoms involving bladder dysfunction and urinary incontinence. The source of these common symptoms in patients with MS is increased contractile activity of the bladder’s detrusor muscle.

The most common lower urinary tract symptom reported by survey respondents was terminal dribble upon voiding, which affected 65% of patients. The next most common symptoms were urinary urgency, experienced by 62%, and incomplete emptying, cited by 61%, Kristin M. Khalaf, Pharm.D., reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Fifty-three percent of patients reported having urgency urinary incontinence, and 45% complained of stress urinary incontinence.

The lower urinary tract symptom that patients found most bothersome was urgency; indeed, one-third of the overall study population indicated they were bothered "quite a bit" or "a great deal" by this problem. Twenty-nine percent of respondents stated they were bothered at least quite a bit by urgency incontinence, added Dr. Khalaf of Allergan, Irvine, Calif.

Only one-third of the 922 MS patients with lower urinary tract symptoms had discussed their symptoms with a health care provider during the past year. When they did speak with a professional, 74% of the time it was with their neurologist. Fifty-two percent spoke to their primary care physician about their problem within the last year.

Among the 42% of survey respondents who indicated they were bothered at least quite a bit by urinary incontinence, 46% hadn’t discussed the problem with a health care provider within the past year, and 35% had never received any form of treatment for it.

Among patients who had ever discussed their lower urinary tract symptoms with a physician or other health care professional, 38% reported currently treating their problem via pelvic exercises or bladder training, 23% were using an oral anticholinergic agent, 4% were taking herbal medicines for their symptoms, 3% were receiving botulinum toxin type A (onabotulinumtoxinA) injections, and 2% had a neural stimulation device.

Most patients currently receiving treatment for their lower urinary tract symptoms pronounced themselves very or somewhat satisfied with their therapy.

The survey was funded by Allergan.

[email protected]

ORLANDO – Lower urinary tract symptoms in patients with multiple sclerosis are common, bothersome, and often undiscussed and untreated, according to a national patient survey.

The online survey was completed by a convenience sample of 1,052 MS patients recruited through the National Multiple Sclerosis Society and other patient advocacy organizations. Fully 88% of the respondents indicated they have lower urinary tract symptoms involving bladder dysfunction and urinary incontinence. The source of these common symptoms in patients with MS is increased contractile activity of the bladder’s detrusor muscle.

The most common lower urinary tract symptom reported by survey respondents was terminal dribble upon voiding, which affected 65% of patients. The next most common symptoms were urinary urgency, experienced by 62%, and incomplete emptying, cited by 61%, Kristin M. Khalaf, Pharm.D., reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Fifty-three percent of patients reported having urgency urinary incontinence, and 45% complained of stress urinary incontinence.

The lower urinary tract symptom that patients found most bothersome was urgency; indeed, one-third of the overall study population indicated they were bothered "quite a bit" or "a great deal" by this problem. Twenty-nine percent of respondents stated they were bothered at least quite a bit by urgency incontinence, added Dr. Khalaf of Allergan, Irvine, Calif.

Only one-third of the 922 MS patients with lower urinary tract symptoms had discussed their symptoms with a health care provider during the past year. When they did speak with a professional, 74% of the time it was with their neurologist. Fifty-two percent spoke to their primary care physician about their problem within the last year.

Among the 42% of survey respondents who indicated they were bothered at least quite a bit by urinary incontinence, 46% hadn’t discussed the problem with a health care provider within the past year, and 35% had never received any form of treatment for it.

Among patients who had ever discussed their lower urinary tract symptoms with a physician or other health care professional, 38% reported currently treating their problem via pelvic exercises or bladder training, 23% were using an oral anticholinergic agent, 4% were taking herbal medicines for their symptoms, 3% were receiving botulinum toxin type A (onabotulinumtoxinA) injections, and 2% had a neural stimulation device.

Most patients currently receiving treatment for their lower urinary tract symptoms pronounced themselves very or somewhat satisfied with their therapy.

The survey was funded by Allergan.

[email protected]

ORLANDO – Patients with multiple sclerosis are at significantly reduced risk of being diagnosed with cancer, compared with the general population, but delayed cancer detection – that is, diagnostic neglect – appears to be a contributing factor, a study from British Columbia has shown.

"Diagnostic neglect is unlikely to account for the entire reduced cancer risk that we’re seeing, but I think it could have major implications for the health, well-being, and longevity of people with multiple sclerosis," said Helen Tremlett, Ph.D, a neuroepidemiologist at the University of British Columbia, Vancouver.

In the population-based Malignancy and Multiple Sclerosis (MaMS) study, she and her coinvestigators linked data from the British Columbia MS registry with the provincial cancer registry. The study included 6,820 MS patients who visited a British Columbia MS clinic in 1980-2004. Most had never been exposed to an immunomodulatory therapy. They had a collective 110,666 person-years of follow-up. Their cancer incidence over time was compared with that of the age-, sex-, and calendar year–matched general population of British Columbia.

Bruce Jancin/IMNG Medical Media

The standardized incidence ratio for all cancers in the MS cohort was 0.86, meaning MS patients had a highly significant overall 14% reduction in the risk of being diagnosed with cancer. The risk reduction was particularly striking for colorectal cancer: Patients with MS were 44% less likely than controls to be diagnosed with this malignancy.

The cancer risk reductions were similar in men and women with MS, and in those with relapsing-remitting as compared with primary progressive MS, Dr. Tremlett reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Of note, the cancer risk reduction identified in the MaMS study was consistent with an earlier meta-analysis of five studies by other investigators around the world, who concluded that the risk of being diagnosed with cancer was 8% lower in MS patients than controls, a statistically significant difference (J. Neurol. Neurosurg. Psychiatry 2010;81:1413-4).

Unlike the other researchers, however, Dr. Tremlett and her coworkers also looked at tumor size at the time of diagnosis for the four most common cancers: breast, prostate, lung, and colorectal cancer. They found a consistent pattern: MS patients diagnosed with cancer had a lower-than-expected rate of the smaller T1 and T2 tumors than in the matched general population with cancer, and a greater-than-expected rate of T3 and T4 tumors.

The most likely explanation for the observed larger-than-expected tumor size is that when MS patients report, say, a new sense of fatigue, it may be ascribed to their MS, whereas if a patient from the general population had the same complaint, a battery of tests would be ordered, she said.

The MS patients’ 14% reduction in the risk of being diagnosed with cancer had an impressive P value. In contrast, the association between MS and larger tumor size, while statistically significant, had a less than stellar P value of .04. For this reason, Dr. Tremlett said she doesn’t believe diagnostic neglect is the entire explanation for the MS patients’ reduction in cancer incidence. Other possible contributing factors worthy of further study are that MS patients’ hypervigilant immune system renders them less vulnerable to cancer growth, or that MS and cancer share a common and as-yet-unidentified genetic predisposition, or that upon receiving the diagnosis of MS, affected patients adopt a healthier lifestyle.

Dr. Tremlett stressed the importance of being on the lookout for cancer and other aging-related comorbidities, especially now that patients with MS are living longer. In a recent study of 6,917 MS patients in British Columbia, she and her coinvestigators determined that the median survival age was 78.6 years for women and 74.3 years for men. Those are some of the longest life spans ever reported, but still about 6 years less than expected for the general British Columbia population.

Median survival from disease onset was markedly longer for patients with relapsing-onset MS than primary progressive MS: 49.7 years compared with 32.5 years. However, the two groups lived to about the same age.

Patients with primary progressive MS had a 1.52-fold greater relative mortality risk than did those with relapsing-onset MS. Women with primary progressive MS had a 1.55-fold survival disadvantage compared with men with primary progressive disease (J. Neurol. Neurosurg. Psychiatry 2012;83:61-6).

The MaMS study is sponsored by the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada. Dr. Tremlett reported having no relevant financial disclosures.

[email protected]

ORLANDO – Patients with multiple sclerosis are at significantly reduced risk of being diagnosed with cancer, compared with the general population, but delayed cancer detection – that is, diagnostic neglect – appears to be a contributing factor, a study from British Columbia has shown.

"Diagnostic neglect is unlikely to account for the entire reduced cancer risk that we’re seeing, but I think it could have major implications for the health, well-being, and longevity of people with multiple sclerosis," said Helen Tremlett, Ph.D, a neuroepidemiologist at the University of British Columbia, Vancouver.

In the population-based Malignancy and Multiple Sclerosis (MaMS) study, she and her coinvestigators linked data from the British Columbia MS registry with the provincial cancer registry. The study included 6,820 MS patients who visited a British Columbia MS clinic in 1980-2004. Most had never been exposed to an immunomodulatory therapy. They had a collective 110,666 person-years of follow-up. Their cancer incidence over time was compared with that of the age-, sex-, and calendar year–matched general population of British Columbia.

Bruce Jancin/IMNG Medical Media

The standardized incidence ratio for all cancers in the MS cohort was 0.86, meaning MS patients had a highly significant overall 14% reduction in the risk of being diagnosed with cancer. The risk reduction was particularly striking for colorectal cancer: Patients with MS were 44% less likely than controls to be diagnosed with this malignancy.

The cancer risk reductions were similar in men and women with MS, and in those with relapsing-remitting as compared with primary progressive MS, Dr. Tremlett reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Of note, the cancer risk reduction identified in the MaMS study was consistent with an earlier meta-analysis of five studies by other investigators around the world, who concluded that the risk of being diagnosed with cancer was 8% lower in MS patients than controls, a statistically significant difference (J. Neurol. Neurosurg. Psychiatry 2010;81:1413-4).

Unlike the other researchers, however, Dr. Tremlett and her coworkers also looked at tumor size at the time of diagnosis for the four most common cancers: breast, prostate, lung, and colorectal cancer. They found a consistent pattern: MS patients diagnosed with cancer had a lower-than-expected rate of the smaller T1 and T2 tumors than in the matched general population with cancer, and a greater-than-expected rate of T3 and T4 tumors.

The most likely explanation for the observed larger-than-expected tumor size is that when MS patients report, say, a new sense of fatigue, it may be ascribed to their MS, whereas if a patient from the general population had the same complaint, a battery of tests would be ordered, she said.

The MS patients’ 14% reduction in the risk of being diagnosed with cancer had an impressive P value. In contrast, the association between MS and larger tumor size, while statistically significant, had a less than stellar P value of .04. For this reason, Dr. Tremlett said she doesn’t believe diagnostic neglect is the entire explanation for the MS patients’ reduction in cancer incidence. Other possible contributing factors worthy of further study are that MS patients’ hypervigilant immune system renders them less vulnerable to cancer growth, or that MS and cancer share a common and as-yet-unidentified genetic predisposition, or that upon receiving the diagnosis of MS, affected patients adopt a healthier lifestyle.

Dr. Tremlett stressed the importance of being on the lookout for cancer and other aging-related comorbidities, especially now that patients with MS are living longer. In a recent study of 6,917 MS patients in British Columbia, she and her coinvestigators determined that the median survival age was 78.6 years for women and 74.3 years for men. Those are some of the longest life spans ever reported, but still about 6 years less than expected for the general British Columbia population.

Median survival from disease onset was markedly longer for patients with relapsing-onset MS than primary progressive MS: 49.7 years compared with 32.5 years. However, the two groups lived to about the same age.

Patients with primary progressive MS had a 1.52-fold greater relative mortality risk than did those with relapsing-onset MS. Women with primary progressive MS had a 1.55-fold survival disadvantage compared with men with primary progressive disease (J. Neurol. Neurosurg. Psychiatry 2012;83:61-6).

The MaMS study is sponsored by the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada. Dr. Tremlett reported having no relevant financial disclosures.

[email protected]

ORLANDO – Patients with multiple sclerosis are at significantly reduced risk of being diagnosed with cancer, compared with the general population, but delayed cancer detection – that is, diagnostic neglect – appears to be a contributing factor, a study from British Columbia has shown.

"Diagnostic neglect is unlikely to account for the entire reduced cancer risk that we’re seeing, but I think it could have major implications for the health, well-being, and longevity of people with multiple sclerosis," said Helen Tremlett, Ph.D, a neuroepidemiologist at the University of British Columbia, Vancouver.

In the population-based Malignancy and Multiple Sclerosis (MaMS) study, she and her coinvestigators linked data from the British Columbia MS registry with the provincial cancer registry. The study included 6,820 MS patients who visited a British Columbia MS clinic in 1980-2004. Most had never been exposed to an immunomodulatory therapy. They had a collective 110,666 person-years of follow-up. Their cancer incidence over time was compared with that of the age-, sex-, and calendar year–matched general population of British Columbia.

Bruce Jancin/IMNG Medical Media

The standardized incidence ratio for all cancers in the MS cohort was 0.86, meaning MS patients had a highly significant overall 14% reduction in the risk of being diagnosed with cancer. The risk reduction was particularly striking for colorectal cancer: Patients with MS were 44% less likely than controls to be diagnosed with this malignancy.

The cancer risk reductions were similar in men and women with MS, and in those with relapsing-remitting as compared with primary progressive MS, Dr. Tremlett reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Of note, the cancer risk reduction identified in the MaMS study was consistent with an earlier meta-analysis of five studies by other investigators around the world, who concluded that the risk of being diagnosed with cancer was 8% lower in MS patients than controls, a statistically significant difference (J. Neurol. Neurosurg. Psychiatry 2010;81:1413-4).

Unlike the other researchers, however, Dr. Tremlett and her coworkers also looked at tumor size at the time of diagnosis for the four most common cancers: breast, prostate, lung, and colorectal cancer. They found a consistent pattern: MS patients diagnosed with cancer had a lower-than-expected rate of the smaller T1 and T2 tumors than in the matched general population with cancer, and a greater-than-expected rate of T3 and T4 tumors.

The most likely explanation for the observed larger-than-expected tumor size is that when MS patients report, say, a new sense of fatigue, it may be ascribed to their MS, whereas if a patient from the general population had the same complaint, a battery of tests would be ordered, she said.

The MS patients’ 14% reduction in the risk of being diagnosed with cancer had an impressive P value. In contrast, the association between MS and larger tumor size, while statistically significant, had a less than stellar P value of .04. For this reason, Dr. Tremlett said she doesn’t believe diagnostic neglect is the entire explanation for the MS patients’ reduction in cancer incidence. Other possible contributing factors worthy of further study are that MS patients’ hypervigilant immune system renders them less vulnerable to cancer growth, or that MS and cancer share a common and as-yet-unidentified genetic predisposition, or that upon receiving the diagnosis of MS, affected patients adopt a healthier lifestyle.

Dr. Tremlett stressed the importance of being on the lookout for cancer and other aging-related comorbidities, especially now that patients with MS are living longer. In a recent study of 6,917 MS patients in British Columbia, she and her coinvestigators determined that the median survival age was 78.6 years for women and 74.3 years for men. Those are some of the longest life spans ever reported, but still about 6 years less than expected for the general British Columbia population.

Median survival from disease onset was markedly longer for patients with relapsing-onset MS than primary progressive MS: 49.7 years compared with 32.5 years. However, the two groups lived to about the same age.

Patients with primary progressive MS had a 1.52-fold greater relative mortality risk than did those with relapsing-onset MS. Women with primary progressive MS had a 1.55-fold survival disadvantage compared with men with primary progressive disease (J. Neurol. Neurosurg. Psychiatry 2012;83:61-6).

The MaMS study is sponsored by the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada. Dr. Tremlett reported having no relevant financial disclosures.

[email protected]

ORLANDO – Epstein-Barr virus exposure and vitamin D insufficiency, which are some of the known risk factors for multiple sclerosis in children and adults, appear not to be associated with transverse myelitis, a small study has shown.

"What we found was that MS risk factors are specific for multiple sclerosis, and not necessarily for all autoimmune demyelinating diseases," said Kelley M. Weinfurtner, a third-year medical student at the University of California, San Francisco (UCSF), who presented a poster detailing the study at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Transverse myelitis (TM) has substantial clinical overlap, especially at early stages, with autoimmune diseases such as multiple sclerosis and neuromyelitis optica, according to Ms. Weinfurtner.

Risk factors for TM are not known, and finding what they are "could be helpful in terms of stratifying when patients come in with TM," and deciding whether the patients would be at risk of MS further down the line, she said.

Ms. Weinfurtner and her colleagues collected blood samples from patients with TM (16), neuromyelitis optica (34), and MS (184) at early stages of disease, and from neurologic controls (95) through the Stony Brook Pediatric MS Center and the Accelerated Cure Project for MS Guthy Jackson Biobank.

They measured serum 25-hydroxyvitamin D levels and checked the blood samples for Epstein-Barr virus, cytomegalovirus, herpes simplex virus (HSV), and HLA-DRB1 allele status.

The median ages at disease onset were 12 years for TM, 11 years for neuromyelitis optica, and 14 years for MS; the median ages at sampling were 30, 16, and 16 years, respectively. The median age of healthy controls at the time of sampling was 16 years.

The majority of the patients were female (61%-70%) and white (all TM patients were white).

The results showed that TM patients were less likely to have been exposed to Epstein-Barr virus, compared with MS patients (odds ratio = 0.021; P less than .001), neuromyelitis optica patients (OR = 0.154; P = .054), and controls (P = .001). TM patients were more likely to have been exposed to HSV-1, although the data did not reach statistical significance.

TM patients also had higher levels of 25-hydroxyvitamin D, compared with MS patients (P = .037) and healthy controls (P = .01).

Meanwhile, there were no significant differences in the frequency of the HLA-DRB1*1501 allele or exposure to cytomegalovirus among TM patients, compared with MS and neuromyelitis optica patients and neurologic controls.

TM patients were significantly older and further from disease onset at the time of the blood draw, but the findings were adjusted for age at the time of the draw. The discrepancy in age "could explain the trend toward higher HSV-1 exposure in TM patients, but only strengthens the findings that TM patients have a lower prevalence of [Epstein-Barr virus] exposure than MS patients," she reported in the poster.

The difference in age could also explain the higher levels of 25-hydroxyvitamin D in TM patients, because they may have been on vitamin D supplementation after diagnosis.

The sample size for the study was small, and TM patients were not stratified by etiology or extent of cord involvement, although they all met criteria for TM, Ms. Weinfurtner said. The investigators were not able to adjust for race or ethnicity, because all TM patients were white.

Her study is not published and she said there’s a need for larger studies to confirm the findings.

Her research was supported by a grant from the Dean’s Office Medical Student Research Program at UCSF. The study is an offshoot of a large, multicenter study conducted by the Pediatric MS Network, which is in the third year of its 5-year period.

[email protected]

On Twitter @NaseemSMiller

ORLANDO – Epstein-Barr virus exposure and vitamin D insufficiency, which are some of the known risk factors for multiple sclerosis in children and adults, appear not to be associated with transverse myelitis, a small study has shown.

"What we found was that MS risk factors are specific for multiple sclerosis, and not necessarily for all autoimmune demyelinating diseases," said Kelley M. Weinfurtner, a third-year medical student at the University of California, San Francisco (UCSF), who presented a poster detailing the study at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Transverse myelitis (TM) has substantial clinical overlap, especially at early stages, with autoimmune diseases such as multiple sclerosis and neuromyelitis optica, according to Ms. Weinfurtner.

Risk factors for TM are not known, and finding what they are "could be helpful in terms of stratifying when patients come in with TM," and deciding whether the patients would be at risk of MS further down the line, she said.

Ms. Weinfurtner and her colleagues collected blood samples from patients with TM (16), neuromyelitis optica (34), and MS (184) at early stages of disease, and from neurologic controls (95) through the Stony Brook Pediatric MS Center and the Accelerated Cure Project for MS Guthy Jackson Biobank.

They measured serum 25-hydroxyvitamin D levels and checked the blood samples for Epstein-Barr virus, cytomegalovirus, herpes simplex virus (HSV), and HLA-DRB1 allele status.

The median ages at disease onset were 12 years for TM, 11 years for neuromyelitis optica, and 14 years for MS; the median ages at sampling were 30, 16, and 16 years, respectively. The median age of healthy controls at the time of sampling was 16 years.

The majority of the patients were female (61%-70%) and white (all TM patients were white).

The results showed that TM patients were less likely to have been exposed to Epstein-Barr virus, compared with MS patients (odds ratio = 0.021; P less than .001), neuromyelitis optica patients (OR = 0.154; P = .054), and controls (P = .001). TM patients were more likely to have been exposed to HSV-1, although the data did not reach statistical significance.

TM patients also had higher levels of 25-hydroxyvitamin D, compared with MS patients (P = .037) and healthy controls (P = .01).

Meanwhile, there were no significant differences in the frequency of the HLA-DRB1*1501 allele or exposure to cytomegalovirus among TM patients, compared with MS and neuromyelitis optica patients and neurologic controls.

TM patients were significantly older and further from disease onset at the time of the blood draw, but the findings were adjusted for age at the time of the draw. The discrepancy in age "could explain the trend toward higher HSV-1 exposure in TM patients, but only strengthens the findings that TM patients have a lower prevalence of [Epstein-Barr virus] exposure than MS patients," she reported in the poster.

The difference in age could also explain the higher levels of 25-hydroxyvitamin D in TM patients, because they may have been on vitamin D supplementation after diagnosis.

The sample size for the study was small, and TM patients were not stratified by etiology or extent of cord involvement, although they all met criteria for TM, Ms. Weinfurtner said. The investigators were not able to adjust for race or ethnicity, because all TM patients were white.

Her study is not published and she said there’s a need for larger studies to confirm the findings.

Her research was supported by a grant from the Dean’s Office Medical Student Research Program at UCSF. The study is an offshoot of a large, multicenter study conducted by the Pediatric MS Network, which is in the third year of its 5-year period.

[email protected]

On Twitter @NaseemSMiller

ORLANDO – Epstein-Barr virus exposure and vitamin D insufficiency, which are some of the known risk factors for multiple sclerosis in children and adults, appear not to be associated with transverse myelitis, a small study has shown.

"What we found was that MS risk factors are specific for multiple sclerosis, and not necessarily for all autoimmune demyelinating diseases," said Kelley M. Weinfurtner, a third-year medical student at the University of California, San Francisco (UCSF), who presented a poster detailing the study at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Transverse myelitis (TM) has substantial clinical overlap, especially at early stages, with autoimmune diseases such as multiple sclerosis and neuromyelitis optica, according to Ms. Weinfurtner.

Risk factors for TM are not known, and finding what they are "could be helpful in terms of stratifying when patients come in with TM," and deciding whether the patients would be at risk of MS further down the line, she said.

Ms. Weinfurtner and her colleagues collected blood samples from patients with TM (16), neuromyelitis optica (34), and MS (184) at early stages of disease, and from neurologic controls (95) through the Stony Brook Pediatric MS Center and the Accelerated Cure Project for MS Guthy Jackson Biobank.

They measured serum 25-hydroxyvitamin D levels and checked the blood samples for Epstein-Barr virus, cytomegalovirus, herpes simplex virus (HSV), and HLA-DRB1 allele status.

The median ages at disease onset were 12 years for TM, 11 years for neuromyelitis optica, and 14 years for MS; the median ages at sampling were 30, 16, and 16 years, respectively. The median age of healthy controls at the time of sampling was 16 years.

The majority of the patients were female (61%-70%) and white (all TM patients were white).

The results showed that TM patients were less likely to have been exposed to Epstein-Barr virus, compared with MS patients (odds ratio = 0.021; P less than .001), neuromyelitis optica patients (OR = 0.154; P = .054), and controls (P = .001). TM patients were more likely to have been exposed to HSV-1, although the data did not reach statistical significance.

TM patients also had higher levels of 25-hydroxyvitamin D, compared with MS patients (P = .037) and healthy controls (P = .01).

Meanwhile, there were no significant differences in the frequency of the HLA-DRB1*1501 allele or exposure to cytomegalovirus among TM patients, compared with MS and neuromyelitis optica patients and neurologic controls.

TM patients were significantly older and further from disease onset at the time of the blood draw, but the findings were adjusted for age at the time of the draw. The discrepancy in age "could explain the trend toward higher HSV-1 exposure in TM patients, but only strengthens the findings that TM patients have a lower prevalence of [Epstein-Barr virus] exposure than MS patients," she reported in the poster.

The difference in age could also explain the higher levels of 25-hydroxyvitamin D in TM patients, because they may have been on vitamin D supplementation after diagnosis.

The sample size for the study was small, and TM patients were not stratified by etiology or extent of cord involvement, although they all met criteria for TM, Ms. Weinfurtner said. The investigators were not able to adjust for race or ethnicity, because all TM patients were white.

Her study is not published and she said there’s a need for larger studies to confirm the findings.

Her research was supported by a grant from the Dean’s Office Medical Student Research Program at UCSF. The study is an offshoot of a large, multicenter study conducted by the Pediatric MS Network, which is in the third year of its 5-year period.

[email protected]

On Twitter @NaseemSMiller

ORLANDO – The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis is greatly reduced by aspirin pretreatment, Dr. J. Theodore Phillips said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

In contrast, slowed titration of dimethyl fumarate (Tecfidera) does not diminish the gastrointestinal adverse effects which are the other common side effect encountered during the first month or two of therapy, added Dr. Phillips, a neurologist in the multiple sclerosis research program at the Baylor Institute for Immunology Research, Dallas.

Dr. Phillips was part of an expert consensus panel which presented recommendations for maximizing the tolerability of dimethyl fumarate, approved earlier this year as the third oral agent for treatment of MS.

In an interview, he said the recommendations are largely based upon expert opinion rather than being rigorously evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to poll the investigators who had enrolled at least 10 patients in the trials as to how they managed the flushing and GI upset problems which arose. The flushing and GI side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild-to-moderate in nature. Flushing resulted in study dropout in 2.5% of patients, while another 4.3% discontinued due to GI adverse events.

Thirty of the 84 invited clinical investigators completed the questionnaire. Meanwhile, investigators at Biogen Idec, which markets Tecfidera, conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the expert panel’s recommendations. Participants in the 8-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion over 1 week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1-4, replaced by aspirin placebo in weeks 5-8; dimethyl fumarate plus aspirin placebo during weeks 1-4; dimethyl fumarate slow-titrated over the course of 3 weeks; and double placebo.

Roughly 80% of subjects on dimethyl fumarate without aspirin experienced flushing events, self-assessed as mild-to-moderate. In contrast, while subjects were on both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to participants on double-placebo.

Slow titration of dimethyl fumarate had no impact on GI symptoms or flushing frequency or severity.

Given that slow titration of dimethyl fumarate proved ineffective in reducing GI symptoms in the phase IIIb study, the expert panel’s recommendations for managing nausea/vomiting or abdominal pain were to take the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea/vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.

"Vasocutaneous flushing and GI upset in association with dosing of Tecfidera could for obvious reasons affect a person’s enthusiasm for going on," Dr. Phillips observed. "The main thing is for the physician to set expectations by up-front acknowledging these issues as part of the risk/benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them."

The investigator survey that formed the basis for the expert panel recommendations was funded by Biogen Idec. Dr. Phillips is on the company’s medical advisory board. He has also received honoraria from Avanir, Genzyme, Novartis, and Teva.

[email protected]

ORLANDO – The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis is greatly reduced by aspirin pretreatment, Dr. J. Theodore Phillips said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

In contrast, slowed titration of dimethyl fumarate (Tecfidera) does not diminish the gastrointestinal adverse effects which are the other common side effect encountered during the first month or two of therapy, added Dr. Phillips, a neurologist in the multiple sclerosis research program at the Baylor Institute for Immunology Research, Dallas.

Dr. Phillips was part of an expert consensus panel which presented recommendations for maximizing the tolerability of dimethyl fumarate, approved earlier this year as the third oral agent for treatment of MS.

In an interview, he said the recommendations are largely based upon expert opinion rather than being rigorously evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to poll the investigators who had enrolled at least 10 patients in the trials as to how they managed the flushing and GI upset problems which arose. The flushing and GI side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild-to-moderate in nature. Flushing resulted in study dropout in 2.5% of patients, while another 4.3% discontinued due to GI adverse events.

Thirty of the 84 invited clinical investigators completed the questionnaire. Meanwhile, investigators at Biogen Idec, which markets Tecfidera, conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the expert panel’s recommendations. Participants in the 8-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion over 1 week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1-4, replaced by aspirin placebo in weeks 5-8; dimethyl fumarate plus aspirin placebo during weeks 1-4; dimethyl fumarate slow-titrated over the course of 3 weeks; and double placebo.

Roughly 80% of subjects on dimethyl fumarate without aspirin experienced flushing events, self-assessed as mild-to-moderate. In contrast, while subjects were on both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to participants on double-placebo.

Slow titration of dimethyl fumarate had no impact on GI symptoms or flushing frequency or severity.

Given that slow titration of dimethyl fumarate proved ineffective in reducing GI symptoms in the phase IIIb study, the expert panel’s recommendations for managing nausea/vomiting or abdominal pain were to take the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea/vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.

"Vasocutaneous flushing and GI upset in association with dosing of Tecfidera could for obvious reasons affect a person’s enthusiasm for going on," Dr. Phillips observed. "The main thing is for the physician to set expectations by up-front acknowledging these issues as part of the risk/benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them."

The investigator survey that formed the basis for the expert panel recommendations was funded by Biogen Idec. Dr. Phillips is on the company’s medical advisory board. He has also received honoraria from Avanir, Genzyme, Novartis, and Teva.

[email protected]

ORLANDO – The flushing frequently reported in conjunction with oral dimethyl fumarate therapy for relapsing forms of multiple sclerosis is greatly reduced by aspirin pretreatment, Dr. J. Theodore Phillips said at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

In contrast, slowed titration of dimethyl fumarate (Tecfidera) does not diminish the gastrointestinal adverse effects which are the other common side effect encountered during the first month or two of therapy, added Dr. Phillips, a neurologist in the multiple sclerosis research program at the Baylor Institute for Immunology Research, Dallas.

Dr. Phillips was part of an expert consensus panel which presented recommendations for maximizing the tolerability of dimethyl fumarate, approved earlier this year as the third oral agent for treatment of MS.

In an interview, he said the recommendations are largely based upon expert opinion rather than being rigorously evidence-based guidelines. After the pivotal phase III DEFINE and CONFIRM clinical trials were completed, he and four other study leaders decided to poll the investigators who had enrolled at least 10 patients in the trials as to how they managed the flushing and GI upset problems which arose. The flushing and GI side effects were reported by 36% and 42%, respectively, of study patients randomized to the drug. The incidence decreased after the first month. These side effects were generally rated by investigators as mild-to-moderate in nature. Flushing resulted in study dropout in 2.5% of patients, while another 4.3% discontinued due to GI adverse events.

Thirty of the 84 invited clinical investigators completed the questionnaire. Meanwhile, investigators at Biogen Idec, which markets Tecfidera, conducted their own randomized, double-blind, phase IIIb study in 172 healthy volunteers, the results of which have been incorporated into the expert panel’s recommendations. Participants in the 8-week trial were randomized to one of four treatment arms: dimethyl fumarate titrated in standard fashion over 1 week plus 325 mg of non–enteric-coated aspirin taken 30 minutes beforehand during weeks 1-4, replaced by aspirin placebo in weeks 5-8; dimethyl fumarate plus aspirin placebo during weeks 1-4; dimethyl fumarate slow-titrated over the course of 3 weeks; and double placebo.

Roughly 80% of subjects on dimethyl fumarate without aspirin experienced flushing events, self-assessed as mild-to-moderate. In contrast, while subjects were on both dimethyl fumarate and aspirin, their flushing frequency and severity were similar to participants on double-placebo.

Slow titration of dimethyl fumarate had no impact on GI symptoms or flushing frequency or severity.

Given that slow titration of dimethyl fumarate proved ineffective in reducing GI symptoms in the phase IIIb study, the expert panel’s recommendations for managing nausea/vomiting or abdominal pain were to take the drug with food and consider prescribing a proton pump inhibitor or H2 receptor antagonist. Metoclopramide or domperidone is another recommended option for those with nausea/vomiting. For patients who experience medication-related diarrhea, the panel advised loperamide or other standard antidiarrheal agents.

"Vasocutaneous flushing and GI upset in association with dosing of Tecfidera could for obvious reasons affect a person’s enthusiasm for going on," Dr. Phillips observed. "The main thing is for the physician to set expectations by up-front acknowledging these issues as part of the risk/benefit discussion prior to initiating the drug. Tell the patient that if those side effects were to happen, we’ve got game plans to deal with them."

The investigator survey that formed the basis for the expert panel recommendations was funded by Biogen Idec. Dr. Phillips is on the company’s medical advisory board. He has also received honoraria from Avanir, Genzyme, Novartis, and Teva.

[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.

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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]