Multiple Sclerosis

Pain in multiple sclerosis (MS) is common, occurring in 63% of patients with the disease, researchers reported in the May issue of Pain. Headache and extremity neuropathic pain are the most common pain syndromes in patients with MS.

Peter Foley, MRCP, and colleagues based their findings on a systematic review and meta-analysis of 17 prospective studies (5,319 patients) that explored pain prevalence in definite MS. The percentage of females in the studies ranged from 55% to 96%, mean age ranged from 31 to 54, mean disease duration ranged from 2.5 to 23 years, and between 30% and 100% of subjects had relapsing-remitting MS (RRMS).

The researchers found a pooled overall pain prevalence of 62.8%. They quantified a prevalence of 43% for headache, 26% for extremity neuropathic pain, 20% for back pain, 15% for painful spasms, 16% for painful Lhermitte sign, and 3.8% for trigeminal neuralgia. The prevalence of pain at MS disease milestones—prior to onset, at onset, and at relapse—and during longitudinal follow-up was “poorly described,” according to Dr. Foley, from the Division of Clinical Neurosciences, University of Edinburgh.

Among the studies that were reviewed, one investigated pain prevalence soon after MS diagnosis and found a 73.5% prevalence of any pain, with a mean disease duration at assessment of 30.5 months. A separate study analyzed headache during relapse and found a prevalence of 38.9%. In addition, two studies prospectively examined overall pain evolution with disease progression—one study found a nonsignificant reduction in prevalence of pain over time in early MS, while another found an increasing prevalence of pain over time in later MS, particularly in those with worsening disability.

“Pain seems to affect approximately 63% of people with MS,” Dr. Foley told Neurology Reviews. “People with MS suffer from a complex variety of pain problems, with both neuropathic and nociceptive mechanisms, and we now have a clearer idea of how common these different pain problems are in MS. Looking at pain overall in these studies, although there was significant variability between studies, we didn’t find that patient disability scores, disease duration, gender mix, or mix of people with progressive MS and RRMS in the studies significantly affected the prevalence of pain.

“Because pain is so common, and seems to affect all groups of people with MS, doctors should strongly consider asking their patients about pain,” Dr. Foley concluded. “Future research studies using standardized designs might give us further evidence to identify who is most at risk of pain, and how this might relate to inflammatory, degenerative, or other processes in MS.”

—Colby Stong
Editor

Suggested Reading
Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632-642.

Pain in multiple sclerosis (MS) is common, occurring in 63% of patients with the disease, researchers reported in the May issue of Pain. Headache and extremity neuropathic pain are the most common pain syndromes in patients with MS.

Peter Foley, MRCP, and colleagues based their findings on a systematic review and meta-analysis of 17 prospective studies (5,319 patients) that explored pain prevalence in definite MS. The percentage of females in the studies ranged from 55% to 96%, mean age ranged from 31 to 54, mean disease duration ranged from 2.5 to 23 years, and between 30% and 100% of subjects had relapsing-remitting MS (RRMS).

The researchers found a pooled overall pain prevalence of 62.8%. They quantified a prevalence of 43% for headache, 26% for extremity neuropathic pain, 20% for back pain, 15% for painful spasms, 16% for painful Lhermitte sign, and 3.8% for trigeminal neuralgia. The prevalence of pain at MS disease milestones—prior to onset, at onset, and at relapse—and during longitudinal follow-up was “poorly described,” according to Dr. Foley, from the Division of Clinical Neurosciences, University of Edinburgh.

Among the studies that were reviewed, one investigated pain prevalence soon after MS diagnosis and found a 73.5% prevalence of any pain, with a mean disease duration at assessment of 30.5 months. A separate study analyzed headache during relapse and found a prevalence of 38.9%. In addition, two studies prospectively examined overall pain evolution with disease progression—one study found a nonsignificant reduction in prevalence of pain over time in early MS, while another found an increasing prevalence of pain over time in later MS, particularly in those with worsening disability.

“Pain seems to affect approximately 63% of people with MS,” Dr. Foley told Neurology Reviews. “People with MS suffer from a complex variety of pain problems, with both neuropathic and nociceptive mechanisms, and we now have a clearer idea of how common these different pain problems are in MS. Looking at pain overall in these studies, although there was significant variability between studies, we didn’t find that patient disability scores, disease duration, gender mix, or mix of people with progressive MS and RRMS in the studies significantly affected the prevalence of pain.

“Because pain is so common, and seems to affect all groups of people with MS, doctors should strongly consider asking their patients about pain,” Dr. Foley concluded. “Future research studies using standardized designs might give us further evidence to identify who is most at risk of pain, and how this might relate to inflammatory, degenerative, or other processes in MS.”

—Colby Stong
Editor

Suggested Reading
Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632-642.

Pain in multiple sclerosis (MS) is common, occurring in 63% of patients with the disease, researchers reported in the May issue of Pain. Headache and extremity neuropathic pain are the most common pain syndromes in patients with MS.

Peter Foley, MRCP, and colleagues based their findings on a systematic review and meta-analysis of 17 prospective studies (5,319 patients) that explored pain prevalence in definite MS. The percentage of females in the studies ranged from 55% to 96%, mean age ranged from 31 to 54, mean disease duration ranged from 2.5 to 23 years, and between 30% and 100% of subjects had relapsing-remitting MS (RRMS).

The researchers found a pooled overall pain prevalence of 62.8%. They quantified a prevalence of 43% for headache, 26% for extremity neuropathic pain, 20% for back pain, 15% for painful spasms, 16% for painful Lhermitte sign, and 3.8% for trigeminal neuralgia. The prevalence of pain at MS disease milestones—prior to onset, at onset, and at relapse—and during longitudinal follow-up was “poorly described,” according to Dr. Foley, from the Division of Clinical Neurosciences, University of Edinburgh.

Among the studies that were reviewed, one investigated pain prevalence soon after MS diagnosis and found a 73.5% prevalence of any pain, with a mean disease duration at assessment of 30.5 months. A separate study analyzed headache during relapse and found a prevalence of 38.9%. In addition, two studies prospectively examined overall pain evolution with disease progression—one study found a nonsignificant reduction in prevalence of pain over time in early MS, while another found an increasing prevalence of pain over time in later MS, particularly in those with worsening disability.

“Pain seems to affect approximately 63% of people with MS,” Dr. Foley told Neurology Reviews. “People with MS suffer from a complex variety of pain problems, with both neuropathic and nociceptive mechanisms, and we now have a clearer idea of how common these different pain problems are in MS. Looking at pain overall in these studies, although there was significant variability between studies, we didn’t find that patient disability scores, disease duration, gender mix, or mix of people with progressive MS and RRMS in the studies significantly affected the prevalence of pain.

“Because pain is so common, and seems to affect all groups of people with MS, doctors should strongly consider asking their patients about pain,” Dr. Foley concluded. “Future research studies using standardized designs might give us further evidence to identify who is most at risk of pain, and how this might relate to inflammatory, degenerative, or other processes in MS.”

—Colby Stong
Editor

Suggested Reading
Foley PL, Vesterinen HM, Laird BJ, et al. Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis. Pain. 2013;154(5):632-642.

ORLANDO – The anti-JC virus antibody index appears to be an important new tool in further delineating the risk of developing progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis patients, according to Dr. Patricia K. Coyle.

Indeed, progressive multifocal leukoencephalopathy (PML) risk stratification could very well transform natalizumab (Tysabri) from a second-line agent for relapsing forms of MS to first-line therapy, she predicted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

After all, it’s widely accepted that natalizumab is the most effective of all the Food and Drug Administration–approved treatments for MS. And adherence is a nonissue, since the medication has to be given monthly at an infusion center. Natalizumab is clearly the preferred agent for patients with highly active disease, those with a poor prognosis, and African Americans, because the databases demonstrate they respond so well to it.

"The only thing holding back natalizumab from first-line treatment status is the PML risk. But there’s afoot the possibility of considering natalizumab as a first-line agent by risk-stratifying patients," explained Dr. Coyle, professor of neurology and director of the MS comprehensive care center at Stony Brook (N.Y.) Medical Center.

It’s increasingly clear that an individual’s risk level can be refined on the basis of three factors: anti-JC virus antibody status, natalizumab treatment duration, and a history of prior immunosuppressive therapy.

The JC virus is a ubiquitous DNA polyomavirus shed in the urine of 25% of normal individuals. Up to 70% of the general population is seropositive. It’s ordinarily a benign virus, yet it’s a requirement for developing PML.

An analysis of large clinical trial databases indicates that anti-JC virus antibody–negative MS patients on natalizumab have a reassuringly low risk of developing PML: roughly 1 in 10,000. The good news is that antibody-positive patients with a low antibody index appear to have a similarly low risk.

In an analysis presented at the CMSC/ACTRIMS meeting by Dr. Tatiana Plavina and Dr. Meena Subramanyam of Biogen Idec, Weston, Mass., the investigators estimated the risk of PML in anti-JC virus antibody–positive patients with an antibody index of 0.9 or less at 1 in 10,000 patients during their first 24 months on natalizumab, inching up to 3 per 10,000 with 25-40 months of use, and 4 per 10,000 with 49-72 months of use.

In contrast, the PML risk in anti-JC virus antibody–positive patients with an antibody index above 1.5 was 10 per 10,000 during the first 24 months, 81 per 10,000 with 25-48 months on natalizumab, and 85 per 10,000 with 49-72 months. These risk estimates were based on analysis of close to 6,000 blood samples from 51 natalizumab users who developed PML and 2,242 others who didn’t.

"This needs to be confirmed in other large databases. If this holds up, measuring the antibody index is going to be something we’ll routinely be doing," Dr. Coyle commented.

In fact, she’s already doing it in her own practice. She now checks the anti-JC virus antibody status of her antibody-negative patients on natalizumab every 3 months.

"The goal is to identify PML at an early asymptomatic stage," she noted.

If a patient turns positive, she obtains the antibody index and uses it to guide patient management. The antibody index reflects antibody titers but is a more reliable measure. The antibody index is easily measured using a commercially available kit. Typically, the index appears to persist at the same level – low or high risk – for an extended period.

An important caveat about the anti-JC virus antibody index as a risk stratification tool is that it doesn’t work if a patient has had prior immunosuppressive therapy of any type, even if only for a relatively brief time.

"All bets are off if you have prior immunosuppression. You can’t use the risk figures. This speaks to the importance of carefully staging your therapies," according to the neurologist.

Although the risk of PML appears to rise after about 2 years on natalizumab, in her view there’s nothing magic about that time line. In an anti-JC virus antibody–positive patient with a low antibody index who wants to continue on natalizumab after being fully informed of the risks as understood today, Dr. Coyle is willing to do so. Under those circumstances she suggests backing off from infusions every 4 weeks to a 6- to 8-week schedule, with MRIs every 4 months instead of 6.

"There are no data to show backing off in this way reduces PML risk, but I think it’s rational," she explained.

Natalizumab is such an effective agent that if a patient with MS experiences breakthrough disease activity on the drug, it’s time to check for the possible presence of neutralizing antibodies to natalizumab.

"We have very good data that if somebody has formed persistent neutralizing antibodies, the drug is not working. And there’s no point in putting a patient at any extra risk for a drug that is not working," Dr. Coyle said.

A significant infusion reaction is another indicator that neutralizing antibodies may be present, she added.

What does the future hold for natalizumab?

Dr. Coyle predicted that in the short term the drug will see increasing use as physicians become comfortable with risk stratification as a means of identifying the portion of the MS population at low risk for PML. But she forecast that several years from now this highly effective medication will have fallen by the wayside.

"I think the era of natalizumab is ending," she said. "In my opinion it’s going to be supplanted by anti-CD20 agents in the next couple of years – drugs with equivalent efficacy and greater safety."

She reported having received honoraria from Biogen Idec and eight other pharmaceutical companies.

bjancin@frontlinemedcom.com

ORLANDO – The anti-JC virus antibody index appears to be an important new tool in further delineating the risk of developing progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis patients, according to Dr. Patricia K. Coyle.

Indeed, progressive multifocal leukoencephalopathy (PML) risk stratification could very well transform natalizumab (Tysabri) from a second-line agent for relapsing forms of MS to first-line therapy, she predicted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

After all, it’s widely accepted that natalizumab is the most effective of all the Food and Drug Administration–approved treatments for MS. And adherence is a nonissue, since the medication has to be given monthly at an infusion center. Natalizumab is clearly the preferred agent for patients with highly active disease, those with a poor prognosis, and African Americans, because the databases demonstrate they respond so well to it.

"The only thing holding back natalizumab from first-line treatment status is the PML risk. But there’s afoot the possibility of considering natalizumab as a first-line agent by risk-stratifying patients," explained Dr. Coyle, professor of neurology and director of the MS comprehensive care center at Stony Brook (N.Y.) Medical Center.

It’s increasingly clear that an individual’s risk level can be refined on the basis of three factors: anti-JC virus antibody status, natalizumab treatment duration, and a history of prior immunosuppressive therapy.

The JC virus is a ubiquitous DNA polyomavirus shed in the urine of 25% of normal individuals. Up to 70% of the general population is seropositive. It’s ordinarily a benign virus, yet it’s a requirement for developing PML.

An analysis of large clinical trial databases indicates that anti-JC virus antibody–negative MS patients on natalizumab have a reassuringly low risk of developing PML: roughly 1 in 10,000. The good news is that antibody-positive patients with a low antibody index appear to have a similarly low risk.

In an analysis presented at the CMSC/ACTRIMS meeting by Dr. Tatiana Plavina and Dr. Meena Subramanyam of Biogen Idec, Weston, Mass., the investigators estimated the risk of PML in anti-JC virus antibody–positive patients with an antibody index of 0.9 or less at 1 in 10,000 patients during their first 24 months on natalizumab, inching up to 3 per 10,000 with 25-40 months of use, and 4 per 10,000 with 49-72 months of use.

In contrast, the PML risk in anti-JC virus antibody–positive patients with an antibody index above 1.5 was 10 per 10,000 during the first 24 months, 81 per 10,000 with 25-48 months on natalizumab, and 85 per 10,000 with 49-72 months. These risk estimates were based on analysis of close to 6,000 blood samples from 51 natalizumab users who developed PML and 2,242 others who didn’t.

"This needs to be confirmed in other large databases. If this holds up, measuring the antibody index is going to be something we’ll routinely be doing," Dr. Coyle commented.

In fact, she’s already doing it in her own practice. She now checks the anti-JC virus antibody status of her antibody-negative patients on natalizumab every 3 months.

"The goal is to identify PML at an early asymptomatic stage," she noted.

If a patient turns positive, she obtains the antibody index and uses it to guide patient management. The antibody index reflects antibody titers but is a more reliable measure. The antibody index is easily measured using a commercially available kit. Typically, the index appears to persist at the same level – low or high risk – for an extended period.

An important caveat about the anti-JC virus antibody index as a risk stratification tool is that it doesn’t work if a patient has had prior immunosuppressive therapy of any type, even if only for a relatively brief time.

"All bets are off if you have prior immunosuppression. You can’t use the risk figures. This speaks to the importance of carefully staging your therapies," according to the neurologist.

Although the risk of PML appears to rise after about 2 years on natalizumab, in her view there’s nothing magic about that time line. In an anti-JC virus antibody–positive patient with a low antibody index who wants to continue on natalizumab after being fully informed of the risks as understood today, Dr. Coyle is willing to do so. Under those circumstances she suggests backing off from infusions every 4 weeks to a 6- to 8-week schedule, with MRIs every 4 months instead of 6.

"There are no data to show backing off in this way reduces PML risk, but I think it’s rational," she explained.

Natalizumab is such an effective agent that if a patient with MS experiences breakthrough disease activity on the drug, it’s time to check for the possible presence of neutralizing antibodies to natalizumab.

"We have very good data that if somebody has formed persistent neutralizing antibodies, the drug is not working. And there’s no point in putting a patient at any extra risk for a drug that is not working," Dr. Coyle said.

A significant infusion reaction is another indicator that neutralizing antibodies may be present, she added.

What does the future hold for natalizumab?

Dr. Coyle predicted that in the short term the drug will see increasing use as physicians become comfortable with risk stratification as a means of identifying the portion of the MS population at low risk for PML. But she forecast that several years from now this highly effective medication will have fallen by the wayside.

"I think the era of natalizumab is ending," she said. "In my opinion it’s going to be supplanted by anti-CD20 agents in the next couple of years – drugs with equivalent efficacy and greater safety."

She reported having received honoraria from Biogen Idec and eight other pharmaceutical companies.

bjancin@frontlinemedcom.com

ORLANDO – The anti-JC virus antibody index appears to be an important new tool in further delineating the risk of developing progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis patients, according to Dr. Patricia K. Coyle.

Indeed, progressive multifocal leukoencephalopathy (PML) risk stratification could very well transform natalizumab (Tysabri) from a second-line agent for relapsing forms of MS to first-line therapy, she predicted at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

After all, it’s widely accepted that natalizumab is the most effective of all the Food and Drug Administration–approved treatments for MS. And adherence is a nonissue, since the medication has to be given monthly at an infusion center. Natalizumab is clearly the preferred agent for patients with highly active disease, those with a poor prognosis, and African Americans, because the databases demonstrate they respond so well to it.

"The only thing holding back natalizumab from first-line treatment status is the PML risk. But there’s afoot the possibility of considering natalizumab as a first-line agent by risk-stratifying patients," explained Dr. Coyle, professor of neurology and director of the MS comprehensive care center at Stony Brook (N.Y.) Medical Center.

It’s increasingly clear that an individual’s risk level can be refined on the basis of three factors: anti-JC virus antibody status, natalizumab treatment duration, and a history of prior immunosuppressive therapy.

The JC virus is a ubiquitous DNA polyomavirus shed in the urine of 25% of normal individuals. Up to 70% of the general population is seropositive. It’s ordinarily a benign virus, yet it’s a requirement for developing PML.

An analysis of large clinical trial databases indicates that anti-JC virus antibody–negative MS patients on natalizumab have a reassuringly low risk of developing PML: roughly 1 in 10,000. The good news is that antibody-positive patients with a low antibody index appear to have a similarly low risk.

In an analysis presented at the CMSC/ACTRIMS meeting by Dr. Tatiana Plavina and Dr. Meena Subramanyam of Biogen Idec, Weston, Mass., the investigators estimated the risk of PML in anti-JC virus antibody–positive patients with an antibody index of 0.9 or less at 1 in 10,000 patients during their first 24 months on natalizumab, inching up to 3 per 10,000 with 25-40 months of use, and 4 per 10,000 with 49-72 months of use.

In contrast, the PML risk in anti-JC virus antibody–positive patients with an antibody index above 1.5 was 10 per 10,000 during the first 24 months, 81 per 10,000 with 25-48 months on natalizumab, and 85 per 10,000 with 49-72 months. These risk estimates were based on analysis of close to 6,000 blood samples from 51 natalizumab users who developed PML and 2,242 others who didn’t.

"This needs to be confirmed in other large databases. If this holds up, measuring the antibody index is going to be something we’ll routinely be doing," Dr. Coyle commented.

In fact, she’s already doing it in her own practice. She now checks the anti-JC virus antibody status of her antibody-negative patients on natalizumab every 3 months.

"The goal is to identify PML at an early asymptomatic stage," she noted.

If a patient turns positive, she obtains the antibody index and uses it to guide patient management. The antibody index reflects antibody titers but is a more reliable measure. The antibody index is easily measured using a commercially available kit. Typically, the index appears to persist at the same level – low or high risk – for an extended period.

An important caveat about the anti-JC virus antibody index as a risk stratification tool is that it doesn’t work if a patient has had prior immunosuppressive therapy of any type, even if only for a relatively brief time.

"All bets are off if you have prior immunosuppression. You can’t use the risk figures. This speaks to the importance of carefully staging your therapies," according to the neurologist.

Although the risk of PML appears to rise after about 2 years on natalizumab, in her view there’s nothing magic about that time line. In an anti-JC virus antibody–positive patient with a low antibody index who wants to continue on natalizumab after being fully informed of the risks as understood today, Dr. Coyle is willing to do so. Under those circumstances she suggests backing off from infusions every 4 weeks to a 6- to 8-week schedule, with MRIs every 4 months instead of 6.

"There are no data to show backing off in this way reduces PML risk, but I think it’s rational," she explained.

Natalizumab is such an effective agent that if a patient with MS experiences breakthrough disease activity on the drug, it’s time to check for the possible presence of neutralizing antibodies to natalizumab.

"We have very good data that if somebody has formed persistent neutralizing antibodies, the drug is not working. And there’s no point in putting a patient at any extra risk for a drug that is not working," Dr. Coyle said.

A significant infusion reaction is another indicator that neutralizing antibodies may be present, she added.

What does the future hold for natalizumab?

Dr. Coyle predicted that in the short term the drug will see increasing use as physicians become comfortable with risk stratification as a means of identifying the portion of the MS population at low risk for PML. But she forecast that several years from now this highly effective medication will have fallen by the wayside.

"I think the era of natalizumab is ending," she said. "In my opinion it’s going to be supplanted by anti-CD20 agents in the next couple of years – drugs with equivalent efficacy and greater safety."

She reported having received honoraria from Biogen Idec and eight other pharmaceutical companies.

bjancin@frontlinemedcom.com

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.

bjancin@frontlinemedcom.com

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.

bjancin@frontlinemedcom.com

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.

bjancin@frontlinemedcom.com

ORLANDO—An international group of researchers has begun to study whether mesenchymal stem cells (MSCs) could reduce inflammatory lesions in patients with multiple sclerosis (MS). Pilot clinical trials have demonstrated that MSCs are safe, but their patient populations have been too small to prove the treatment’s efficacy, according to a presentation given at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).

MSCs can be derived from bone marrow or placenta, said Mark Freedman, MD, Professor of Neurology at the University of Ottawa. Various anti-inflammatory models showed that the cells have immunologic properties, and they can release growth factors that might offer neuroprotection, he added. Human MSCs promoted the differentiation of myelin-expressing cells in a mouse model of experimental autoimmune encephalomyelitis.

An International Study of MSCs’ Efficacy
Dr. Freedman and Antonio Uccelli, MD, Associate Professor of Medical Sciences at the University of Genoa, led a group that established a consensus protocol for a clinical trial to test the efficacy of MSCs for patients with relapsing-remitting, secondary progressive, or primary progressive MS who continue to have active relapses or enhancing MRI lesions despite receiving treatment. Research groups in 12 countries will participate in the protocol, which was published in the April 2010 Multiple Sclerosis Journal. The investigators will aspirate bone marrow from each patient and culture MSCs from it. The researchers will create enough cells for the trial and additional cells that can be studied for their immunologic properties.

Patients will be randomized to sham treatment or to a standard IV dose of one to two million MSCs per kilogram. Participants in the treatment arm will receive MSCs cultured from their own bone marrow. The study’s primary outcomes are safety and the reduction in the number and volume of new enhancing lesions over six months. After six months, the investigators will administer MSCs to patients in the sham group. All patients will be followed for one year so that the researchers can examine the crossover effect in the patients who received delayed treatment.

In addition to efficacy, the investigators plan to study the endurance of MSCs’ effect over time and whether MSCs can promote CNS repair. Several exploratory outcome measures, such as effects on reparative signals on MRI, neurophysiology, cognition, or clinical capability “are key to deciding whether these cells are capable of doing the wonderful things that you’ve heard about,” said Dr. Freedman.

Pilot Studies Indicate That MSCs Are Safe
An “intriguing” proof-of-concept study published in the February 2012 Lancet Neurology suggested that MSCs could promote recovery in patients with secondary progressive MS and optic nerve lesions, said Dr. Freedman. The investigators gave 10 patients an IV infusion of approximately two million autologous MSCs per kilogram. The cells had been derived from the patients’ bone marrow and cultured with fetal bovine serum. During the 10-month follow-up, patients’ visual acuity and visual evoked response latency improved. In addition, the diameter of patients’ optic nerves increased. “There were trends on the general MRIs of the brain to having fewer T2 lesions and less atrophy,” added Dr. Freedman.

A recent case study also suggested a potential benefit of MSCs for patients with MS. Researchers in China preconditioned a patient with cyclophosphamide and subsequently administered 10 million MSCs intrathecally and 20 million MSCs IV. On day three, the patient had sensory impairment, but muscle strength increased by day nine. The patient’s neurologic signs improved by day 52, and the patient became mobile. The Expanded Disability Status Scale (EDSS) score decreased to 6.5, and the MRI showed improvement.

Results of other small studies have been less clear. Israeli researchers gave 15 patients with MS intrathecal and IV doses of autologous MSCs. Some of the patients in this study developed headache and fever, which were interpreted as side effects of intrathecal administration. Patients’ EDSS decreased slightly, but not significantly, from a mean of approximately 6.

In a phase 1 study, Iranian researchers gave infusions of MSCs to 10 patients with progressive MS and followed them for various periods of time. EDSS declined from 4.5 to 2.5 for some patients, but other patients got worse. At least six patients had continued attacks that required the administration of steroids. The treatment “certainly didn’t turn off the disease,” said Dr. Freedman.

“We’re all in agreement that these cells are easy to get and easy to culture,” he added. The current, large-scale study will provide more clarity about the therapeutic potential of MSCs.

—Erik Greb
Senior Associate Editor

Suggested Reading

Auletta JJ, Bartholomew AM, Maziarz RT, et al. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis. Immunotherapy. 2012;4(5):529-547.

Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150-156.

Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.

Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells as treatment for MS—progress to date. Mult Scler. 2013;19(5):515-519.

ORLANDO—An international group of researchers has begun to study whether mesenchymal stem cells (MSCs) could reduce inflammatory lesions in patients with multiple sclerosis (MS). Pilot clinical trials have demonstrated that MSCs are safe, but their patient populations have been too small to prove the treatment’s efficacy, according to a presentation given at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).

MSCs can be derived from bone marrow or placenta, said Mark Freedman, MD, Professor of Neurology at the University of Ottawa. Various anti-inflammatory models showed that the cells have immunologic properties, and they can release growth factors that might offer neuroprotection, he added. Human MSCs promoted the differentiation of myelin-expressing cells in a mouse model of experimental autoimmune encephalomyelitis.

An International Study of MSCs’ Efficacy
Dr. Freedman and Antonio Uccelli, MD, Associate Professor of Medical Sciences at the University of Genoa, led a group that established a consensus protocol for a clinical trial to test the efficacy of MSCs for patients with relapsing-remitting, secondary progressive, or primary progressive MS who continue to have active relapses or enhancing MRI lesions despite receiving treatment. Research groups in 12 countries will participate in the protocol, which was published in the April 2010 Multiple Sclerosis Journal. The investigators will aspirate bone marrow from each patient and culture MSCs from it. The researchers will create enough cells for the trial and additional cells that can be studied for their immunologic properties.

Patients will be randomized to sham treatment or to a standard IV dose of one to two million MSCs per kilogram. Participants in the treatment arm will receive MSCs cultured from their own bone marrow. The study’s primary outcomes are safety and the reduction in the number and volume of new enhancing lesions over six months. After six months, the investigators will administer MSCs to patients in the sham group. All patients will be followed for one year so that the researchers can examine the crossover effect in the patients who received delayed treatment.

In addition to efficacy, the investigators plan to study the endurance of MSCs’ effect over time and whether MSCs can promote CNS repair. Several exploratory outcome measures, such as effects on reparative signals on MRI, neurophysiology, cognition, or clinical capability “are key to deciding whether these cells are capable of doing the wonderful things that you’ve heard about,” said Dr. Freedman.

Pilot Studies Indicate That MSCs Are Safe
An “intriguing” proof-of-concept study published in the February 2012 Lancet Neurology suggested that MSCs could promote recovery in patients with secondary progressive MS and optic nerve lesions, said Dr. Freedman. The investigators gave 10 patients an IV infusion of approximately two million autologous MSCs per kilogram. The cells had been derived from the patients’ bone marrow and cultured with fetal bovine serum. During the 10-month follow-up, patients’ visual acuity and visual evoked response latency improved. In addition, the diameter of patients’ optic nerves increased. “There were trends on the general MRIs of the brain to having fewer T2 lesions and less atrophy,” added Dr. Freedman.

A recent case study also suggested a potential benefit of MSCs for patients with MS. Researchers in China preconditioned a patient with cyclophosphamide and subsequently administered 10 million MSCs intrathecally and 20 million MSCs IV. On day three, the patient had sensory impairment, but muscle strength increased by day nine. The patient’s neurologic signs improved by day 52, and the patient became mobile. The Expanded Disability Status Scale (EDSS) score decreased to 6.5, and the MRI showed improvement.

Results of other small studies have been less clear. Israeli researchers gave 15 patients with MS intrathecal and IV doses of autologous MSCs. Some of the patients in this study developed headache and fever, which were interpreted as side effects of intrathecal administration. Patients’ EDSS decreased slightly, but not significantly, from a mean of approximately 6.

In a phase 1 study, Iranian researchers gave infusions of MSCs to 10 patients with progressive MS and followed them for various periods of time. EDSS declined from 4.5 to 2.5 for some patients, but other patients got worse. At least six patients had continued attacks that required the administration of steroids. The treatment “certainly didn’t turn off the disease,” said Dr. Freedman.

“We’re all in agreement that these cells are easy to get and easy to culture,” he added. The current, large-scale study will provide more clarity about the therapeutic potential of MSCs.

—Erik Greb
Senior Associate Editor

Suggested Reading

Auletta JJ, Bartholomew AM, Maziarz RT, et al. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis. Immunotherapy. 2012;4(5):529-547.

Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150-156.

Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.

Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells as treatment for MS—progress to date. Mult Scler. 2013;19(5):515-519.

ORLANDO—An international group of researchers has begun to study whether mesenchymal stem cells (MSCs) could reduce inflammatory lesions in patients with multiple sclerosis (MS). Pilot clinical trials have demonstrated that MSCs are safe, but their patient populations have been too small to prove the treatment’s efficacy, according to a presentation given at the Fifth Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).

MSCs can be derived from bone marrow or placenta, said Mark Freedman, MD, Professor of Neurology at the University of Ottawa. Various anti-inflammatory models showed that the cells have immunologic properties, and they can release growth factors that might offer neuroprotection, he added. Human MSCs promoted the differentiation of myelin-expressing cells in a mouse model of experimental autoimmune encephalomyelitis.

An International Study of MSCs’ Efficacy
Dr. Freedman and Antonio Uccelli, MD, Associate Professor of Medical Sciences at the University of Genoa, led a group that established a consensus protocol for a clinical trial to test the efficacy of MSCs for patients with relapsing-remitting, secondary progressive, or primary progressive MS who continue to have active relapses or enhancing MRI lesions despite receiving treatment. Research groups in 12 countries will participate in the protocol, which was published in the April 2010 Multiple Sclerosis Journal. The investigators will aspirate bone marrow from each patient and culture MSCs from it. The researchers will create enough cells for the trial and additional cells that can be studied for their immunologic properties.

Patients will be randomized to sham treatment or to a standard IV dose of one to two million MSCs per kilogram. Participants in the treatment arm will receive MSCs cultured from their own bone marrow. The study’s primary outcomes are safety and the reduction in the number and volume of new enhancing lesions over six months. After six months, the investigators will administer MSCs to patients in the sham group. All patients will be followed for one year so that the researchers can examine the crossover effect in the patients who received delayed treatment.

In addition to efficacy, the investigators plan to study the endurance of MSCs’ effect over time and whether MSCs can promote CNS repair. Several exploratory outcome measures, such as effects on reparative signals on MRI, neurophysiology, cognition, or clinical capability “are key to deciding whether these cells are capable of doing the wonderful things that you’ve heard about,” said Dr. Freedman.

Pilot Studies Indicate That MSCs Are Safe
An “intriguing” proof-of-concept study published in the February 2012 Lancet Neurology suggested that MSCs could promote recovery in patients with secondary progressive MS and optic nerve lesions, said Dr. Freedman. The investigators gave 10 patients an IV infusion of approximately two million autologous MSCs per kilogram. The cells had been derived from the patients’ bone marrow and cultured with fetal bovine serum. During the 10-month follow-up, patients’ visual acuity and visual evoked response latency improved. In addition, the diameter of patients’ optic nerves increased. “There were trends on the general MRIs of the brain to having fewer T2 lesions and less atrophy,” added Dr. Freedman.

A recent case study also suggested a potential benefit of MSCs for patients with MS. Researchers in China preconditioned a patient with cyclophosphamide and subsequently administered 10 million MSCs intrathecally and 20 million MSCs IV. On day three, the patient had sensory impairment, but muscle strength increased by day nine. The patient’s neurologic signs improved by day 52, and the patient became mobile. The Expanded Disability Status Scale (EDSS) score decreased to 6.5, and the MRI showed improvement.

Results of other small studies have been less clear. Israeli researchers gave 15 patients with MS intrathecal and IV doses of autologous MSCs. Some of the patients in this study developed headache and fever, which were interpreted as side effects of intrathecal administration. Patients’ EDSS decreased slightly, but not significantly, from a mean of approximately 6.

In a phase 1 study, Iranian researchers gave infusions of MSCs to 10 patients with progressive MS and followed them for various periods of time. EDSS declined from 4.5 to 2.5 for some patients, but other patients got worse. At least six patients had continued attacks that required the administration of steroids. The treatment “certainly didn’t turn off the disease,” said Dr. Freedman.

“We’re all in agreement that these cells are easy to get and easy to culture,” he added. The current, large-scale study will provide more clarity about the therapeutic potential of MSCs.

—Erik Greb
Senior Associate Editor

Suggested Reading

Auletta JJ, Bartholomew AM, Maziarz RT, et al. The potential of mesenchymal stromal cells as a novel cellular therapy for multiple sclerosis. Immunotherapy. 2012;4(5):529-547.

Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150-156.

Freedman MS, Bar-Or A, Atkins HL, et al. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503-510.

Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells as treatment for MS—progress to date. Mult Scler. 2013;19(5):515-519.

ORLANDO – Alemtuzumab is far more effective than is high-dose interferon beta-1a in treating patients with highly active relapsing-remitting multiple sclerosis despite prior therapy, according to a new subgroup analysis of the CARE-MS II trial.

Twenty-four percent of alemtuzumab-treated patients in the subgroup with highly-active disease at baseline remained entirely free of demonstrable MS disease activity – both clinically and by MRI – throughout the 2-year randomized trial. In contrast, none of the patients on subcutaneous interferon beta-1a (Rebif) achieved that high standard, Dr. Stephen Krieger 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 an unusual result to see in any of our trials and in any subgroups: zero percent of patients achieving an efficacy goal with one of our approved and highly efficacious agents. I think this demonstrates the high disease activity of these patients, the efficacy gradient between alemtuzumab and interferon, and it also highlights the unmet need for patients with highly-active disease," said Dr. Krieger of Mount Sinai Medical Center, New York.

The CARE-MS II subanalysis also strongly suggests alemtuzumab may provide an important new treatment option for this group of severely affected patients, he added.

Alemtuzumab is a humanized monoclonal antibody to CD52, a protein present on the surface of mature lymphocytes but not on the stem cells from which they originate. Alemtuzumab is approved as Campath for treatment of B-cell chronic lymphocytic leukemia. Genzyme has applied to the Food and Drug Administration and European regulators for a new indication under the trade name Lemtrada for treatment of MS.

CARE-MS II (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) was a 2-year, rater-blinded, multicenter, international, phase III clinical trial in which 667 patients with relapsing-remitting MS who had experienced two or more relapses despite treatment during the 2 years immediately prior to enrollment. Participants were randomized 2:1 to alemtuzumab or interferon beta-1a. Alemtuzumab at 12 mg was administered intravenously on 5 consecutive days at the start of the study and again on 3 consecutive days at the 1-year mark, for a total of just 8 doses in 2 years. In contrast, subcutaneous interferon beta-1a at 44 mcg was given three times weekly throughout the study.

The overall results, now published (Lancet 2012;380:1829-39), showed the alemtuzumab group had reductions of 49% in the risk of relapse and 42% in the risk of sustained accumulation of disability, compared with the interferon group.

Dr. Krieger presented a new analysis restricted to the 145 CARE-MS II participants with the most highly active disease as defined by two or more relapses in the year prior to randomization as well as the presence of at least one gadolinium-enhancing lesion on baseline MRI.

"Basically, we’re taking the most active patients from the trial of the more active patients who had already experienced disease activity despite prior therapy," the neurologist explained.

The annualized relapse rate in these patients with highly active disease was 0.33 events with alemtuzumab and .65 events with interferon, for a 51% reduction in favor of the investigational agent. Sixty-four percent of the alemtuzumab group and 36% on interferon remained relapse free during the 2-year study.

Freedom from clinical disease activity was defined as being relapse free as well as free of sustained accumulation of disability, meaning an absence of at least a 1-point increase over baseline on the Expanded Disability Status Scale lasting for at least 6 months. Clinical disease activity–free status for the full 2 years of follow-up was attained by 61% of the alemtuzumab group, compared with 33% of patients on interferon. The adjusted odds ratio was 3.18, meaning patients with highly active disease were more than three times more likely to remain free of clinical disease activity throughout the study if they were on alemtuzumab rather than interferon.

Turning to the serial MRI results, Dr. Krieger noted that 40% of the alemtuzumab group remained free of disease activity by MRI, meaning no new gadolinium-enhancing lesions and no new or enlarging T2 lesions. Only 7.5% of patients with highly active disease assigned to interferon therapy remained free of MRI evidence of disease activity during the 2-year study. Patients on alemtuzumab were an adjusted ninefold more likely to be free of MRI activity than were those on interferon.

The post hoc composite endpoint of freedom from demonstrable MS disease activity required 2 years of freedom from relapse, freedom from MRI activity, and freedom from sustained accumulation of disability. This was the outcome achieved by 24% of patients on alemtuzumab and 0% of those on interferon.

The safety data in the subgroup with highly active disease reflected the findings in the overall CARE-MS II population. Infections occurred in 84% of highly active patients on alemtuzumab and 64% on interferon. Thyroid disorders occurred in 15.5% on alemtuzumab, compared with 2.4% on interferon. Adverse events leading to study discontinuation were seen in 1% on alemtuzumab, compared with 2.4% on interferon.

CARE-MS II was sponsored by Genzyme. Dr. Krieger is a consultant to Genzyme and half a dozen other pharmaceutical companies.

bjancin@frontlinemedcom.com

ORLANDO – Alemtuzumab is far more effective than is high-dose interferon beta-1a in treating patients with highly active relapsing-remitting multiple sclerosis despite prior therapy, according to a new subgroup analysis of the CARE-MS II trial.

Twenty-four percent of alemtuzumab-treated patients in the subgroup with highly-active disease at baseline remained entirely free of demonstrable MS disease activity – both clinically and by MRI – throughout the 2-year randomized trial. In contrast, none of the patients on subcutaneous interferon beta-1a (Rebif) achieved that high standard, Dr. Stephen Krieger 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 an unusual result to see in any of our trials and in any subgroups: zero percent of patients achieving an efficacy goal with one of our approved and highly efficacious agents. I think this demonstrates the high disease activity of these patients, the efficacy gradient between alemtuzumab and interferon, and it also highlights the unmet need for patients with highly-active disease," said Dr. Krieger of Mount Sinai Medical Center, New York.

The CARE-MS II subanalysis also strongly suggests alemtuzumab may provide an important new treatment option for this group of severely affected patients, he added.

Alemtuzumab is a humanized monoclonal antibody to CD52, a protein present on the surface of mature lymphocytes but not on the stem cells from which they originate. Alemtuzumab is approved as Campath for treatment of B-cell chronic lymphocytic leukemia. Genzyme has applied to the Food and Drug Administration and European regulators for a new indication under the trade name Lemtrada for treatment of MS.

CARE-MS II (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) was a 2-year, rater-blinded, multicenter, international, phase III clinical trial in which 667 patients with relapsing-remitting MS who had experienced two or more relapses despite treatment during the 2 years immediately prior to enrollment. Participants were randomized 2:1 to alemtuzumab or interferon beta-1a. Alemtuzumab at 12 mg was administered intravenously on 5 consecutive days at the start of the study and again on 3 consecutive days at the 1-year mark, for a total of just 8 doses in 2 years. In contrast, subcutaneous interferon beta-1a at 44 mcg was given three times weekly throughout the study.

The overall results, now published (Lancet 2012;380:1829-39), showed the alemtuzumab group had reductions of 49% in the risk of relapse and 42% in the risk of sustained accumulation of disability, compared with the interferon group.

Dr. Krieger presented a new analysis restricted to the 145 CARE-MS II participants with the most highly active disease as defined by two or more relapses in the year prior to randomization as well as the presence of at least one gadolinium-enhancing lesion on baseline MRI.

"Basically, we’re taking the most active patients from the trial of the more active patients who had already experienced disease activity despite prior therapy," the neurologist explained.

The annualized relapse rate in these patients with highly active disease was 0.33 events with alemtuzumab and .65 events with interferon, for a 51% reduction in favor of the investigational agent. Sixty-four percent of the alemtuzumab group and 36% on interferon remained relapse free during the 2-year study.

Freedom from clinical disease activity was defined as being relapse free as well as free of sustained accumulation of disability, meaning an absence of at least a 1-point increase over baseline on the Expanded Disability Status Scale lasting for at least 6 months. Clinical disease activity–free status for the full 2 years of follow-up was attained by 61% of the alemtuzumab group, compared with 33% of patients on interferon. The adjusted odds ratio was 3.18, meaning patients with highly active disease were more than three times more likely to remain free of clinical disease activity throughout the study if they were on alemtuzumab rather than interferon.

Turning to the serial MRI results, Dr. Krieger noted that 40% of the alemtuzumab group remained free of disease activity by MRI, meaning no new gadolinium-enhancing lesions and no new or enlarging T2 lesions. Only 7.5% of patients with highly active disease assigned to interferon therapy remained free of MRI evidence of disease activity during the 2-year study. Patients on alemtuzumab were an adjusted ninefold more likely to be free of MRI activity than were those on interferon.

The post hoc composite endpoint of freedom from demonstrable MS disease activity required 2 years of freedom from relapse, freedom from MRI activity, and freedom from sustained accumulation of disability. This was the outcome achieved by 24% of patients on alemtuzumab and 0% of those on interferon.

The safety data in the subgroup with highly active disease reflected the findings in the overall CARE-MS II population. Infections occurred in 84% of highly active patients on alemtuzumab and 64% on interferon. Thyroid disorders occurred in 15.5% on alemtuzumab, compared with 2.4% on interferon. Adverse events leading to study discontinuation were seen in 1% on alemtuzumab, compared with 2.4% on interferon.

CARE-MS II was sponsored by Genzyme. Dr. Krieger is a consultant to Genzyme and half a dozen other pharmaceutical companies.

bjancin@frontlinemedcom.com

ORLANDO – Alemtuzumab is far more effective than is high-dose interferon beta-1a in treating patients with highly active relapsing-remitting multiple sclerosis despite prior therapy, according to a new subgroup analysis of the CARE-MS II trial.

Twenty-four percent of alemtuzumab-treated patients in the subgroup with highly-active disease at baseline remained entirely free of demonstrable MS disease activity – both clinically and by MRI – throughout the 2-year randomized trial. In contrast, none of the patients on subcutaneous interferon beta-1a (Rebif) achieved that high standard, Dr. Stephen Krieger 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 an unusual result to see in any of our trials and in any subgroups: zero percent of patients achieving an efficacy goal with one of our approved and highly efficacious agents. I think this demonstrates the high disease activity of these patients, the efficacy gradient between alemtuzumab and interferon, and it also highlights the unmet need for patients with highly-active disease," said Dr. Krieger of Mount Sinai Medical Center, New York.

The CARE-MS II subanalysis also strongly suggests alemtuzumab may provide an important new treatment option for this group of severely affected patients, he added.

Alemtuzumab is a humanized monoclonal antibody to CD52, a protein present on the surface of mature lymphocytes but not on the stem cells from which they originate. Alemtuzumab is approved as Campath for treatment of B-cell chronic lymphocytic leukemia. Genzyme has applied to the Food and Drug Administration and European regulators for a new indication under the trade name Lemtrada for treatment of MS.

CARE-MS II (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) was a 2-year, rater-blinded, multicenter, international, phase III clinical trial in which 667 patients with relapsing-remitting MS who had experienced two or more relapses despite treatment during the 2 years immediately prior to enrollment. Participants were randomized 2:1 to alemtuzumab or interferon beta-1a. Alemtuzumab at 12 mg was administered intravenously on 5 consecutive days at the start of the study and again on 3 consecutive days at the 1-year mark, for a total of just 8 doses in 2 years. In contrast, subcutaneous interferon beta-1a at 44 mcg was given three times weekly throughout the study.

The overall results, now published (Lancet 2012;380:1829-39), showed the alemtuzumab group had reductions of 49% in the risk of relapse and 42% in the risk of sustained accumulation of disability, compared with the interferon group.

Dr. Krieger presented a new analysis restricted to the 145 CARE-MS II participants with the most highly active disease as defined by two or more relapses in the year prior to randomization as well as the presence of at least one gadolinium-enhancing lesion on baseline MRI.

"Basically, we’re taking the most active patients from the trial of the more active patients who had already experienced disease activity despite prior therapy," the neurologist explained.

The annualized relapse rate in these patients with highly active disease was 0.33 events with alemtuzumab and .65 events with interferon, for a 51% reduction in favor of the investigational agent. Sixty-four percent of the alemtuzumab group and 36% on interferon remained relapse free during the 2-year study.

Freedom from clinical disease activity was defined as being relapse free as well as free of sustained accumulation of disability, meaning an absence of at least a 1-point increase over baseline on the Expanded Disability Status Scale lasting for at least 6 months. Clinical disease activity–free status for the full 2 years of follow-up was attained by 61% of the alemtuzumab group, compared with 33% of patients on interferon. The adjusted odds ratio was 3.18, meaning patients with highly active disease were more than three times more likely to remain free of clinical disease activity throughout the study if they were on alemtuzumab rather than interferon.

Turning to the serial MRI results, Dr. Krieger noted that 40% of the alemtuzumab group remained free of disease activity by MRI, meaning no new gadolinium-enhancing lesions and no new or enlarging T2 lesions. Only 7.5% of patients with highly active disease assigned to interferon therapy remained free of MRI evidence of disease activity during the 2-year study. Patients on alemtuzumab were an adjusted ninefold more likely to be free of MRI activity than were those on interferon.

The post hoc composite endpoint of freedom from demonstrable MS disease activity required 2 years of freedom from relapse, freedom from MRI activity, and freedom from sustained accumulation of disability. This was the outcome achieved by 24% of patients on alemtuzumab and 0% of those on interferon.

The safety data in the subgroup with highly active disease reflected the findings in the overall CARE-MS II population. Infections occurred in 84% of highly active patients on alemtuzumab and 64% on interferon. Thyroid disorders occurred in 15.5% on alemtuzumab, compared with 2.4% on interferon. Adverse events leading to study discontinuation were seen in 1% on alemtuzumab, compared with 2.4% on interferon.

CARE-MS II was sponsored by Genzyme. Dr. Krieger is a consultant to Genzyme and half a dozen other pharmaceutical companies.

bjancin@frontlinemedcom.com

ORLANDO – Patients who had multiple sclerosis for a long time or frequently used the Internet were not as accepting of a pilot telecare program as were newer MS patients who didn’t use computers often, according to a small study.

The difference is partly due to the greater body of knowledge that patients with a longer history of MS have gained over the years, sometimes through going online frequently, said Eunme Cha, an epidemiologist at Johns Hopkins University, Baltimore. She presented her poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Naseem S. Miller/IMNG Medical Media

Participants reported that the program had benefits, such as helping them to keep a daily diary of their symptoms and to communicate with their physicians and nurses.

Ms. Cha and her colleagues at the Washington DC VA Medical Center recruited 20 veterans in Washington to use the Home Automated Telemanagement (HAT) system, an online tool they could access via their home computers.

"I wouldn’t say that this is going to replace the entire doctor visit," Ms. Cha said. "But they come pretty far to see the doctor. Traffic is pretty bad in D.C. Some patients travel an entire day to get to their doctor appointment, so they really liked the fact that they could get things done at home."

Mult. Scler.2012;18:472-80A few studies have shown that telemedicine programs can be helpful in the care management of patients with MS. For instance, a 2012 study of 40 patients found that "telecare is a powerful tool for monitoring MS patients at home, carries the potential to improve health care while reducing costs, and should be considered for implementation as part of the management of chronic neurological diseases" (Mult. Scler. 2012;18:472-80).

"I think telemedicine is going to grow in every field of neurology and in every field of medicine that you don’t have to have a hands-on procedure," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC). He was not involved in the study.

But there are challenges to overcome. For example, physicians need to be licensed in every state where they are going to be using telemedicine, Dr. Lisak said in an interview. "But if the politics and the economics can be solved, this is very helpful for people and hospitals that are underserved by subspecialists, and even specialists."

For the pilot study, the research staff visited the patients’ homes, provided them with a link to the MS HAT program, and trained them on the system. 

"We asked the patients to log in every day and enter "my diary" so that they can report their symptoms on a daily basis," said Ms. Cha. "And then physicians and nurses can log in to the clinician site and see what the patient has put in. Also, patients can put in questions to doctors and nurses. So we try to facilitate communication between patients and physicians."

The 20 veterans (mean age, 54 years) included 14 men and 12 African Americans. They had MS for a mean of 15 years. Sixteen patients said they used a computer at home, and the same number reported using the Internet daily. The patients had a mean Expanded Disability Scale Score (EDSS) of 5.3. Their MS subtypes included secondary progressive (11 patients), relapsing-remitting (6), and primary progressive (3). 

A linear regression analysis showed that the length of time patients had MS, how often patients used a computer at home, and English proficiency were all significant predictors of how well the patients accepted the MS HAT program. Meanwhile, race, age, and years of education had no significant relationship with acceptance of the telecare program.

Patients also reported back the benefits of the program, their concerns, and their suggestions. Some said that they liked the ability to report their symptoms right away, keep track of their symptoms, and refresh their memory. They reported concerns with the length of the daily questionnaire and sometimes the redundancy of the content. 

Ms. Cha and her colleagues said that "tailoring this technology to patient needs and preferences may improve its acceptance by veterans in MS."

The team is now looking into conducting a clinical trial, comparing a traditional patient group with those who use the telemedicine program, to see if there are any differences in clinical outcomes and patients’ disease management. 

Ms. Cha had no disclosures. Dr. Lisak has received research grants from and has been an advisor for several companies, including Avanir, Bayer, Novartis, Questcor, and Teva.

nmiller@frontlinemedcom.com
On Twitter @NaseemSMiller

ORLANDO – Patients who had multiple sclerosis for a long time or frequently used the Internet were not as accepting of a pilot telecare program as were newer MS patients who didn’t use computers often, according to a small study.

The difference is partly due to the greater body of knowledge that patients with a longer history of MS have gained over the years, sometimes through going online frequently, said Eunme Cha, an epidemiologist at Johns Hopkins University, Baltimore. She presented her poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Naseem S. Miller/IMNG Medical Media

Participants reported that the program had benefits, such as helping them to keep a daily diary of their symptoms and to communicate with their physicians and nurses.

Ms. Cha and her colleagues at the Washington DC VA Medical Center recruited 20 veterans in Washington to use the Home Automated Telemanagement (HAT) system, an online tool they could access via their home computers.

"I wouldn’t say that this is going to replace the entire doctor visit," Ms. Cha said. "But they come pretty far to see the doctor. Traffic is pretty bad in D.C. Some patients travel an entire day to get to their doctor appointment, so they really liked the fact that they could get things done at home."

Mult. Scler.2012;18:472-80A few studies have shown that telemedicine programs can be helpful in the care management of patients with MS. For instance, a 2012 study of 40 patients found that "telecare is a powerful tool for monitoring MS patients at home, carries the potential to improve health care while reducing costs, and should be considered for implementation as part of the management of chronic neurological diseases" (Mult. Scler. 2012;18:472-80).

"I think telemedicine is going to grow in every field of neurology and in every field of medicine that you don’t have to have a hands-on procedure," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC). He was not involved in the study.

But there are challenges to overcome. For example, physicians need to be licensed in every state where they are going to be using telemedicine, Dr. Lisak said in an interview. "But if the politics and the economics can be solved, this is very helpful for people and hospitals that are underserved by subspecialists, and even specialists."

For the pilot study, the research staff visited the patients’ homes, provided them with a link to the MS HAT program, and trained them on the system. 

"We asked the patients to log in every day and enter "my diary" so that they can report their symptoms on a daily basis," said Ms. Cha. "And then physicians and nurses can log in to the clinician site and see what the patient has put in. Also, patients can put in questions to doctors and nurses. So we try to facilitate communication between patients and physicians."

The 20 veterans (mean age, 54 years) included 14 men and 12 African Americans. They had MS for a mean of 15 years. Sixteen patients said they used a computer at home, and the same number reported using the Internet daily. The patients had a mean Expanded Disability Scale Score (EDSS) of 5.3. Their MS subtypes included secondary progressive (11 patients), relapsing-remitting (6), and primary progressive (3). 

A linear regression analysis showed that the length of time patients had MS, how often patients used a computer at home, and English proficiency were all significant predictors of how well the patients accepted the MS HAT program. Meanwhile, race, age, and years of education had no significant relationship with acceptance of the telecare program.

Patients also reported back the benefits of the program, their concerns, and their suggestions. Some said that they liked the ability to report their symptoms right away, keep track of their symptoms, and refresh their memory. They reported concerns with the length of the daily questionnaire and sometimes the redundancy of the content. 

Ms. Cha and her colleagues said that "tailoring this technology to patient needs and preferences may improve its acceptance by veterans in MS."

The team is now looking into conducting a clinical trial, comparing a traditional patient group with those who use the telemedicine program, to see if there are any differences in clinical outcomes and patients’ disease management. 

Ms. Cha had no disclosures. Dr. Lisak has received research grants from and has been an advisor for several companies, including Avanir, Bayer, Novartis, Questcor, and Teva.

nmiller@frontlinemedcom.com
On Twitter @NaseemSMiller

ORLANDO – Patients who had multiple sclerosis for a long time or frequently used the Internet were not as accepting of a pilot telecare program as were newer MS patients who didn’t use computers often, according to a small study.

The difference is partly due to the greater body of knowledge that patients with a longer history of MS have gained over the years, sometimes through going online frequently, said Eunme Cha, an epidemiologist at Johns Hopkins University, Baltimore. She presented her poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Naseem S. Miller/IMNG Medical Media

Participants reported that the program had benefits, such as helping them to keep a daily diary of their symptoms and to communicate with their physicians and nurses.

Ms. Cha and her colleagues at the Washington DC VA Medical Center recruited 20 veterans in Washington to use the Home Automated Telemanagement (HAT) system, an online tool they could access via their home computers.

"I wouldn’t say that this is going to replace the entire doctor visit," Ms. Cha said. "But they come pretty far to see the doctor. Traffic is pretty bad in D.C. Some patients travel an entire day to get to their doctor appointment, so they really liked the fact that they could get things done at home."

Mult. Scler.2012;18:472-80A few studies have shown that telemedicine programs can be helpful in the care management of patients with MS. For instance, a 2012 study of 40 patients found that "telecare is a powerful tool for monitoring MS patients at home, carries the potential to improve health care while reducing costs, and should be considered for implementation as part of the management of chronic neurological diseases" (Mult. Scler. 2012;18:472-80).

"I think telemedicine is going to grow in every field of neurology and in every field of medicine that you don’t have to have a hands-on procedure," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC). He was not involved in the study.

But there are challenges to overcome. For example, physicians need to be licensed in every state where they are going to be using telemedicine, Dr. Lisak said in an interview. "But if the politics and the economics can be solved, this is very helpful for people and hospitals that are underserved by subspecialists, and even specialists."

For the pilot study, the research staff visited the patients’ homes, provided them with a link to the MS HAT program, and trained them on the system. 

"We asked the patients to log in every day and enter "my diary" so that they can report their symptoms on a daily basis," said Ms. Cha. "And then physicians and nurses can log in to the clinician site and see what the patient has put in. Also, patients can put in questions to doctors and nurses. So we try to facilitate communication between patients and physicians."

The 20 veterans (mean age, 54 years) included 14 men and 12 African Americans. They had MS for a mean of 15 years. Sixteen patients said they used a computer at home, and the same number reported using the Internet daily. The patients had a mean Expanded Disability Scale Score (EDSS) of 5.3. Their MS subtypes included secondary progressive (11 patients), relapsing-remitting (6), and primary progressive (3). 

A linear regression analysis showed that the length of time patients had MS, how often patients used a computer at home, and English proficiency were all significant predictors of how well the patients accepted the MS HAT program. Meanwhile, race, age, and years of education had no significant relationship with acceptance of the telecare program.

Patients also reported back the benefits of the program, their concerns, and their suggestions. Some said that they liked the ability to report their symptoms right away, keep track of their symptoms, and refresh their memory. They reported concerns with the length of the daily questionnaire and sometimes the redundancy of the content. 

Ms. Cha and her colleagues said that "tailoring this technology to patient needs and preferences may improve its acceptance by veterans in MS."

The team is now looking into conducting a clinical trial, comparing a traditional patient group with those who use the telemedicine program, to see if there are any differences in clinical outcomes and patients’ disease management. 

Ms. Cha had no disclosures. Dr. Lisak has received research grants from and has been an advisor for several companies, including Avanir, Bayer, Novartis, Questcor, and Teva.

nmiller@frontlinemedcom.com
On Twitter @NaseemSMiller

ORLANDO – An investigational pegylated formulation of subcutaneous interferon beta-1a appears to offer the efficacy and safety of currently available interferon therapy for relapsing-remitting multiple sclerosis with the advantage of less frequent injections, a study has shown.

In the phase III, double-blind ADVANCE trial, peginterferon beta-1a at 125 mcg self-administered subcutaneously every 2 weeks for 1 year consistently provided statistically significant advantages over placebo for all clinical and radiologic outcomes, Dr. Peter A. Calabresi reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Peginterferon beta-1a dosed every 4 weeks was less effective than every 2 weeks. It bested placebo on some but not all endpoints, added Dr. Calabresi, professor of neurology and director of the multiple sclerosis center at Johns Hopkins University, Baltimore.

Bruce Jancin/IMNG Medical Media

The ADVANCE trial involved 1,516 randomized patients with relapsing-remitting MS, 86% of whom had a baseline Expanded Disability Status Scale (EDSS) score of less than 4.

The primary endpoint was the annualized relapse rate at 1 year: 0.397 with placebo; 0.2888 with peginterferon beta-1a every 4 weeks, for a 27.5% reduction compared with placebo; and 0.256 with biweekly therapy, for a 35.6% reduction. The 1-year incidence of relapse was reduced by 26% with monthly dosing and by 39% with biweekly dosing of peginterferon beta-1a, compared with placebo.

A key secondary outcome measure, disability progression during year 1 as defined by at least a 1-point increase in the EDSS sustained for 12 weeks or more, was reduced by 38% in both peginterferon beta-1a arms, compared with placebo.

In terms of MRI outcomes reflecting disease activity, the mean number of new or enlarging T2 lesions at 1 year was 10.9 with placebo, 7.9 with peginterferon every 4 weeks, and 3.6 – a 67% reduction compared with placebo – with biweekly therapy. The mean number of gadolinium-enhancing MRI lesions was 1.4 with placebo, 0.9 with peginterferon every 4 weeks, and 0.2 with biweekly peginterferon, an 86% reduction compared with placebo.

The incidence of interferon-neutralizing antibodies believed capable of interfering with the effect of the drug was reassuringly low at less than 1% in all three study arms at 1 year.

The adverse events profile of peginterferon beta-1a would be familiar to physicians who prescribe other interferons: injection site reactions, flulike illness, and headaches, for example – all typically rated mild and lasting less than 48 hours, Dr. Calabresi continued.

One audience member, noting that peginterferon beta-1a every 2 weeks was clearly more effective than every 4 weeks, asked why once-weekly injections weren’t studied. Dr. Calabresi replied that the every-2-week regimen appears to provide a reduction in the relapse rate that’s roughly equivalent to that achieved with standard nonpegylated interferon beta-1a given more frequently. For patients who’ve done well on interferon therapy for years, the idea of switching from Avonex given intramuscularly once weekly or Rebif given subcutaneously three times per week to an every 2-week dosing regimen that provides the efficacy and safety they’re accustomed to is likely to be very attractive, he added.

Pegylation is a strategy for increasing the half-life and pharmacodynamic effects of a drug. Less frequent dosing means greater convenience for patients and possibly improved adherence as well. Ninety-one percent of the placebo group completed year 1 of ADVANCE, as did 88% on peginterferon beta-1a given every 4 weeks and 86% on biweekly dosing.

The ADVANCE study is now in its second and final year, during which patients continue on the same peginterferon dosing schedule they had in year 1, while patients formerly on placebo are randomized to a year on one of the two peginterferon dosing regimens. After the 2 years of ADVANCE are completed, there will be a 2-year extension study called ATTAIN.

The ADVANCE trial is sponsored by Biogen Idec. Dr. Calabresi reported receiving grant support from that company and serving as a consultant to Vaccinex, Abbott, and Vertex.

bjancin@frontlinemedcom.com

ORLANDO – An investigational pegylated formulation of subcutaneous interferon beta-1a appears to offer the efficacy and safety of currently available interferon therapy for relapsing-remitting multiple sclerosis with the advantage of less frequent injections, a study has shown.

In the phase III, double-blind ADVANCE trial, peginterferon beta-1a at 125 mcg self-administered subcutaneously every 2 weeks for 1 year consistently provided statistically significant advantages over placebo for all clinical and radiologic outcomes, Dr. Peter A. Calabresi reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Peginterferon beta-1a dosed every 4 weeks was less effective than every 2 weeks. It bested placebo on some but not all endpoints, added Dr. Calabresi, professor of neurology and director of the multiple sclerosis center at Johns Hopkins University, Baltimore.

Bruce Jancin/IMNG Medical Media

The ADVANCE trial involved 1,516 randomized patients with relapsing-remitting MS, 86% of whom had a baseline Expanded Disability Status Scale (EDSS) score of less than 4.

The primary endpoint was the annualized relapse rate at 1 year: 0.397 with placebo; 0.2888 with peginterferon beta-1a every 4 weeks, for a 27.5% reduction compared with placebo; and 0.256 with biweekly therapy, for a 35.6% reduction. The 1-year incidence of relapse was reduced by 26% with monthly dosing and by 39% with biweekly dosing of peginterferon beta-1a, compared with placebo.

A key secondary outcome measure, disability progression during year 1 as defined by at least a 1-point increase in the EDSS sustained for 12 weeks or more, was reduced by 38% in both peginterferon beta-1a arms, compared with placebo.

In terms of MRI outcomes reflecting disease activity, the mean number of new or enlarging T2 lesions at 1 year was 10.9 with placebo, 7.9 with peginterferon every 4 weeks, and 3.6 – a 67% reduction compared with placebo – with biweekly therapy. The mean number of gadolinium-enhancing MRI lesions was 1.4 with placebo, 0.9 with peginterferon every 4 weeks, and 0.2 with biweekly peginterferon, an 86% reduction compared with placebo.

The incidence of interferon-neutralizing antibodies believed capable of interfering with the effect of the drug was reassuringly low at less than 1% in all three study arms at 1 year.

The adverse events profile of peginterferon beta-1a would be familiar to physicians who prescribe other interferons: injection site reactions, flulike illness, and headaches, for example – all typically rated mild and lasting less than 48 hours, Dr. Calabresi continued.

One audience member, noting that peginterferon beta-1a every 2 weeks was clearly more effective than every 4 weeks, asked why once-weekly injections weren’t studied. Dr. Calabresi replied that the every-2-week regimen appears to provide a reduction in the relapse rate that’s roughly equivalent to that achieved with standard nonpegylated interferon beta-1a given more frequently. For patients who’ve done well on interferon therapy for years, the idea of switching from Avonex given intramuscularly once weekly or Rebif given subcutaneously three times per week to an every 2-week dosing regimen that provides the efficacy and safety they’re accustomed to is likely to be very attractive, he added.

Pegylation is a strategy for increasing the half-life and pharmacodynamic effects of a drug. Less frequent dosing means greater convenience for patients and possibly improved adherence as well. Ninety-one percent of the placebo group completed year 1 of ADVANCE, as did 88% on peginterferon beta-1a given every 4 weeks and 86% on biweekly dosing.

The ADVANCE study is now in its second and final year, during which patients continue on the same peginterferon dosing schedule they had in year 1, while patients formerly on placebo are randomized to a year on one of the two peginterferon dosing regimens. After the 2 years of ADVANCE are completed, there will be a 2-year extension study called ATTAIN.

The ADVANCE trial is sponsored by Biogen Idec. Dr. Calabresi reported receiving grant support from that company and serving as a consultant to Vaccinex, Abbott, and Vertex.

bjancin@frontlinemedcom.com

ORLANDO – An investigational pegylated formulation of subcutaneous interferon beta-1a appears to offer the efficacy and safety of currently available interferon therapy for relapsing-remitting multiple sclerosis with the advantage of less frequent injections, a study has shown.

In the phase III, double-blind ADVANCE trial, peginterferon beta-1a at 125 mcg self-administered subcutaneously every 2 weeks for 1 year consistently provided statistically significant advantages over placebo for all clinical and radiologic outcomes, Dr. Peter A. Calabresi reported at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Peginterferon beta-1a dosed every 4 weeks was less effective than every 2 weeks. It bested placebo on some but not all endpoints, added Dr. Calabresi, professor of neurology and director of the multiple sclerosis center at Johns Hopkins University, Baltimore.

Bruce Jancin/IMNG Medical Media

The ADVANCE trial involved 1,516 randomized patients with relapsing-remitting MS, 86% of whom had a baseline Expanded Disability Status Scale (EDSS) score of less than 4.

The primary endpoint was the annualized relapse rate at 1 year: 0.397 with placebo; 0.2888 with peginterferon beta-1a every 4 weeks, for a 27.5% reduction compared with placebo; and 0.256 with biweekly therapy, for a 35.6% reduction. The 1-year incidence of relapse was reduced by 26% with monthly dosing and by 39% with biweekly dosing of peginterferon beta-1a, compared with placebo.

A key secondary outcome measure, disability progression during year 1 as defined by at least a 1-point increase in the EDSS sustained for 12 weeks or more, was reduced by 38% in both peginterferon beta-1a arms, compared with placebo.

In terms of MRI outcomes reflecting disease activity, the mean number of new or enlarging T2 lesions at 1 year was 10.9 with placebo, 7.9 with peginterferon every 4 weeks, and 3.6 – a 67% reduction compared with placebo – with biweekly therapy. The mean number of gadolinium-enhancing MRI lesions was 1.4 with placebo, 0.9 with peginterferon every 4 weeks, and 0.2 with biweekly peginterferon, an 86% reduction compared with placebo.

The incidence of interferon-neutralizing antibodies believed capable of interfering with the effect of the drug was reassuringly low at less than 1% in all three study arms at 1 year.

The adverse events profile of peginterferon beta-1a would be familiar to physicians who prescribe other interferons: injection site reactions, flulike illness, and headaches, for example – all typically rated mild and lasting less than 48 hours, Dr. Calabresi continued.

One audience member, noting that peginterferon beta-1a every 2 weeks was clearly more effective than every 4 weeks, asked why once-weekly injections weren’t studied. Dr. Calabresi replied that the every-2-week regimen appears to provide a reduction in the relapse rate that’s roughly equivalent to that achieved with standard nonpegylated interferon beta-1a given more frequently. For patients who’ve done well on interferon therapy for years, the idea of switching from Avonex given intramuscularly once weekly or Rebif given subcutaneously three times per week to an every 2-week dosing regimen that provides the efficacy and safety they’re accustomed to is likely to be very attractive, he added.

Pegylation is a strategy for increasing the half-life and pharmacodynamic effects of a drug. Less frequent dosing means greater convenience for patients and possibly improved adherence as well. Ninety-one percent of the placebo group completed year 1 of ADVANCE, as did 88% on peginterferon beta-1a given every 4 weeks and 86% on biweekly dosing.

The ADVANCE study is now in its second and final year, during which patients continue on the same peginterferon dosing schedule they had in year 1, while patients formerly on placebo are randomized to a year on one of the two peginterferon dosing regimens. After the 2 years of ADVANCE are completed, there will be a 2-year extension study called ATTAIN.

The ADVANCE trial is sponsored by Biogen Idec. Dr. Calabresi reported receiving grant support from that company and serving as a consultant to Vaccinex, Abbott, and Vertex.

bjancin@frontlinemedcom.com

SAN DIEGO—A drug formulation made of polyethylene glycol chains attached to interferon beta-1a (PEGylated interferon beta-1a) may reduce annualized relapse rate significantly for patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 65th Annual Meeting of the American Academy of Neurology. The drug may also prolong the time to first relapse and reduce the accumulation of disability.

In a phase III pivotal clinical trial, annualized relapse rate was 27.5% lower for patients with MS who received PEGylated interferon beta-1a once every four weeks, compared with patients who received placebo, said Peter Calabresi, MD, Professor of Neurology at the Johns Hopkins Multiple Sclerosis Center in Baltimore. Annualized relapse rate was 35.6% lower among patients receiving the drug every two weeks, compared with patients receiving placebo.

The hazard ratio of a prolonged time to first relapse was 0.61 for patients who received the drug every two weeks and 0.74 for patients who received the drug every four weeks. At one year, disability accumulation was significantly reduced among active patients, compared with controls. The hazard ratio for reduced disability accumulation was 0.62 for all treated patients.

Comparing Two Dosing Frequencies With Placebo

Dr. Calabresi and colleagues enrolled approximately 1,500 patients with relapsing-remitting MS in a two-year, multicenter, randomized, double-blind study. Eligible patients were younger than 65 and had an Expanded Disability Status Scale (EDSS) score of 5 or lower. The trial’s primary end point was annualized relapse rate at one year. Secondary end points included the proportions of patients who relapsed during one year, the proportions of patients with disability progression over one year, and new and newly enlarging T2 hyperintense lesions. The trial was conducted at sites located in India, North America, Western and Eastern Europe, and other countries.

Equal numbers of patients were randomized to receive placebo, 125 µg of PEGylated interferon beta-1a subcutaneously once every four weeks, or 125 µg of PEGylated interferon beta-1a subcutaneously once every two weeks. The treatment groups were well balanced in terms of age, gender, and race. Most patients had an EDSS score lower than 4, and MRI activity was well distributed.

PEGylated Interferon Beta-1a Reduced MRI Activity

At one year, patients receiving PEG­ylated interferon beta-1a every four weeks had a 28% reduction in new and newly enlarging T2 lesions, compared with controls. Patients receiving the drug every two weeks had a 67% reduction in T2 lesions, compared with controls.

Participants who received PEGylated interferon beta-1a every four weeks had a 36% reduction in gadolinium-enhancing lesions, compared with participants receiving placebo. This result was not statistically significant, but was “a strong trend,” said Dr. Calabresi. Participants who received PEGylated interferon beta-1a every two weeks had an 86% reduction in gadolinium-enhancing lesions, compared with controls, and this result was highly significant.

Researchers observed neutralizing antibodies in less than 1% of patients in both treatment arms. Adverse events were similar in both treatment groups, and the majority of adverse events were mild or moderate. Common adverse events included injection-site reactions, influenza-like illness, and pyrexia. Slightly more active patients than controls dropped out of the trial because of adverse events.

“At year one of the placebo-controlled component of the trial, which was [the time of our] preplanned primary analysis, PEGylated interferon had an effect on the clinical and radiologic measures and seemed to offer the safety profile of presently available interferon beta-1a molecules,” concluded Dr. Calabresi.

—Erik Greb
Senior Associate Editor

Suggested Reading

Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52(6):798-808.

Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.

Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308(3):247-256.

SAN DIEGO—A drug formulation made of polyethylene glycol chains attached to interferon beta-1a (PEGylated interferon beta-1a) may reduce annualized relapse rate significantly for patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 65th Annual Meeting of the American Academy of Neurology. The drug may also prolong the time to first relapse and reduce the accumulation of disability.

In a phase III pivotal clinical trial, annualized relapse rate was 27.5% lower for patients with MS who received PEGylated interferon beta-1a once every four weeks, compared with patients who received placebo, said Peter Calabresi, MD, Professor of Neurology at the Johns Hopkins Multiple Sclerosis Center in Baltimore. Annualized relapse rate was 35.6% lower among patients receiving the drug every two weeks, compared with patients receiving placebo.

The hazard ratio of a prolonged time to first relapse was 0.61 for patients who received the drug every two weeks and 0.74 for patients who received the drug every four weeks. At one year, disability accumulation was significantly reduced among active patients, compared with controls. The hazard ratio for reduced disability accumulation was 0.62 for all treated patients.

Comparing Two Dosing Frequencies With Placebo

Dr. Calabresi and colleagues enrolled approximately 1,500 patients with relapsing-remitting MS in a two-year, multicenter, randomized, double-blind study. Eligible patients were younger than 65 and had an Expanded Disability Status Scale (EDSS) score of 5 or lower. The trial’s primary end point was annualized relapse rate at one year. Secondary end points included the proportions of patients who relapsed during one year, the proportions of patients with disability progression over one year, and new and newly enlarging T2 hyperintense lesions. The trial was conducted at sites located in India, North America, Western and Eastern Europe, and other countries.

Equal numbers of patients were randomized to receive placebo, 125 µg of PEGylated interferon beta-1a subcutaneously once every four weeks, or 125 µg of PEGylated interferon beta-1a subcutaneously once every two weeks. The treatment groups were well balanced in terms of age, gender, and race. Most patients had an EDSS score lower than 4, and MRI activity was well distributed.

PEGylated Interferon Beta-1a Reduced MRI Activity

At one year, patients receiving PEG­ylated interferon beta-1a every four weeks had a 28% reduction in new and newly enlarging T2 lesions, compared with controls. Patients receiving the drug every two weeks had a 67% reduction in T2 lesions, compared with controls.

Participants who received PEGylated interferon beta-1a every four weeks had a 36% reduction in gadolinium-enhancing lesions, compared with participants receiving placebo. This result was not statistically significant, but was “a strong trend,” said Dr. Calabresi. Participants who received PEGylated interferon beta-1a every two weeks had an 86% reduction in gadolinium-enhancing lesions, compared with controls, and this result was highly significant.

Researchers observed neutralizing antibodies in less than 1% of patients in both treatment arms. Adverse events were similar in both treatment groups, and the majority of adverse events were mild or moderate. Common adverse events included injection-site reactions, influenza-like illness, and pyrexia. Slightly more active patients than controls dropped out of the trial because of adverse events.

“At year one of the placebo-controlled component of the trial, which was [the time of our] preplanned primary analysis, PEGylated interferon had an effect on the clinical and radiologic measures and seemed to offer the safety profile of presently available interferon beta-1a molecules,” concluded Dr. Calabresi.

—Erik Greb
Senior Associate Editor

Suggested Reading

Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52(6):798-808.

Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.

Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308(3):247-256.

SAN DIEGO—A drug formulation made of polyethylene glycol chains attached to interferon beta-1a (PEGylated interferon beta-1a) may reduce annualized relapse rate significantly for patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 65th Annual Meeting of the American Academy of Neurology. The drug may also prolong the time to first relapse and reduce the accumulation of disability.

In a phase III pivotal clinical trial, annualized relapse rate was 27.5% lower for patients with MS who received PEGylated interferon beta-1a once every four weeks, compared with patients who received placebo, said Peter Calabresi, MD, Professor of Neurology at the Johns Hopkins Multiple Sclerosis Center in Baltimore. Annualized relapse rate was 35.6% lower among patients receiving the drug every two weeks, compared with patients receiving placebo.

The hazard ratio of a prolonged time to first relapse was 0.61 for patients who received the drug every two weeks and 0.74 for patients who received the drug every four weeks. At one year, disability accumulation was significantly reduced among active patients, compared with controls. The hazard ratio for reduced disability accumulation was 0.62 for all treated patients.

Comparing Two Dosing Frequencies With Placebo

Dr. Calabresi and colleagues enrolled approximately 1,500 patients with relapsing-remitting MS in a two-year, multicenter, randomized, double-blind study. Eligible patients were younger than 65 and had an Expanded Disability Status Scale (EDSS) score of 5 or lower. The trial’s primary end point was annualized relapse rate at one year. Secondary end points included the proportions of patients who relapsed during one year, the proportions of patients with disability progression over one year, and new and newly enlarging T2 hyperintense lesions. The trial was conducted at sites located in India, North America, Western and Eastern Europe, and other countries.

Equal numbers of patients were randomized to receive placebo, 125 µg of PEGylated interferon beta-1a subcutaneously once every four weeks, or 125 µg of PEGylated interferon beta-1a subcutaneously once every two weeks. The treatment groups were well balanced in terms of age, gender, and race. Most patients had an EDSS score lower than 4, and MRI activity was well distributed.

PEGylated Interferon Beta-1a Reduced MRI Activity

At one year, patients receiving PEG­ylated interferon beta-1a every four weeks had a 28% reduction in new and newly enlarging T2 lesions, compared with controls. Patients receiving the drug every two weeks had a 67% reduction in T2 lesions, compared with controls.

Participants who received PEGylated interferon beta-1a every four weeks had a 36% reduction in gadolinium-enhancing lesions, compared with participants receiving placebo. This result was not statistically significant, but was “a strong trend,” said Dr. Calabresi. Participants who received PEGylated interferon beta-1a every two weeks had an 86% reduction in gadolinium-enhancing lesions, compared with controls, and this result was highly significant.

Researchers observed neutralizing antibodies in less than 1% of patients in both treatment arms. Adverse events were similar in both treatment groups, and the majority of adverse events were mild or moderate. Common adverse events included injection-site reactions, influenza-like illness, and pyrexia. Slightly more active patients than controls dropped out of the trial because of adverse events.

“At year one of the placebo-controlled component of the trial, which was [the time of our] preplanned primary analysis, PEGylated interferon had an effect on the clinical and radiologic measures and seemed to offer the safety profile of presently available interferon beta-1a molecules,” concluded Dr. Calabresi.

—Erik Greb
Senior Associate Editor

Suggested Reading

Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52(6):798-808.

Kieseier BC, Calabresi PA. PEGylation of interferon-b-1a: a promising strategy in multiple sclerosis. CNS Drugs. 2012;26(3):205-214.

Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308(3):247-256.

ORLANDO – In patients with secondary-progressive multiple sclerosis, rituximab could potentially stabilize or reverse the rate of disease progression, according to a small, retrospective, single-center study.

Given the findings, rituximab, a B-cell depletion therapy, is a reasonable option for patients with secondary-progressive multiple sclerosis (SPMS) who no longer respond to primary and secondary lines of treatment, said Christopher M. Perrone, a fourth-year medical student at the University of Massachusetts, Worcester.

Mr. Perrone presented his poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Patients with SPMS have few treatment options. The only FDA-approved therapy for SPMS is mitoxantrone, which, because of severe side effects, is used only after patients stop responding to first and second-line treatments.

Phase I and II studies have shown rituximab’s safety in relapsing-remitting MS. The National Institute of Neurological Disorders and Stroke is recruiting patients for a double-blind, placebo-controlled, single center, phase I/II study on the safety and efficacy of combined systemic and intrathecal rituximab in patients with SPMS.

Mr. Perrone’s review of 25 patients at the University of Massachusetts Multiple Sclerosis Center showed that the disability score for patients with SPMS treated with rituximab for 2 years either stabilized or improved in 84% of the patients.

Four patients (16%) did not respond to rituximab and their disease continued to progress.

Mr. Perrone and his colleagues evaluated the Expanded Disability Status Scale (EDSS), 25-foot walk, and nine-hole peg test scores for 30 patients who were on rituximab therapy for 2 years.

Inclusion criteria were diagnosis of SPMS, at least two cycles of rituximab therapy (each treatment cycle included 1g rituximab IV, 2 weeks apart), and records of the three primary outcomes analyzed in the study.

There were 13 men and 17 women, mean age 56 years, with an average disease duration of 12 years. Five patients were later excluded.

Researchers obtained patient scores 2 years before rituximab therapy to establish rate of progression, and they obtained scores 1 year before treatment to establish baseline. The study had no control groups.

Results showed that 2 years before rituximab therapy, there were statistically significant increases in EDSS scores (0.5 points per year; P = .02), Mr. Perrone and his colleagues reported. However, after the therapy began, there were no significant differences, when compared with baseline values in the majority of the patients (less than 0.1-point increase between first and second treatment cycle, and 0.05-point increase between second and third treatment cycle), "suggesting that patients were at least stabilized on therapy," the authors reported. The treatment cycles were 6 months apart.

Authors then stratified the patients based on EDSS scores. At 2 years, 12 patients (48%) were stable and showed no change in EDSS score, 9 patients (36%) showed significant improvement in EDSS scores, and, in 4 patients (16%), the disease continued to progress.

The researchers noted that it was interesting to find that patients with higher initial EDSS scores were more likely to stabilize after treatment, while patients with lower initial EDSS scores were more likely to exhibit a significant change in EDSS.

There were no changes in MRI activity throughout the course of treatment, except for a nonenhancing lesion in one patient. The reported adverse events, including UTI, rash, fatigue, headache, and serum sickness disease, were not severe.

Mr. Perrone said that given the limited options available, rituximab should be considered an option for patients who have failed primary and secondary therapy, and that the study’s findings were encouraging.

His study has not been published and he said that larger studies are needed to confirm the findings.

Mr. Perrone had no disclosures. The study was funded by a grant from the Foundation of the Consortium of Multiple Sclerosis Centers’ MS Workforce of the Future program.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller

ORLANDO – In patients with secondary-progressive multiple sclerosis, rituximab could potentially stabilize or reverse the rate of disease progression, according to a small, retrospective, single-center study.

Given the findings, rituximab, a B-cell depletion therapy, is a reasonable option for patients with secondary-progressive multiple sclerosis (SPMS) who no longer respond to primary and secondary lines of treatment, said Christopher M. Perrone, a fourth-year medical student at the University of Massachusetts, Worcester.

Mr. Perrone presented his poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Patients with SPMS have few treatment options. The only FDA-approved therapy for SPMS is mitoxantrone, which, because of severe side effects, is used only after patients stop responding to first and second-line treatments.

Phase I and II studies have shown rituximab’s safety in relapsing-remitting MS. The National Institute of Neurological Disorders and Stroke is recruiting patients for a double-blind, placebo-controlled, single center, phase I/II study on the safety and efficacy of combined systemic and intrathecal rituximab in patients with SPMS.

Mr. Perrone’s review of 25 patients at the University of Massachusetts Multiple Sclerosis Center showed that the disability score for patients with SPMS treated with rituximab for 2 years either stabilized or improved in 84% of the patients.

Four patients (16%) did not respond to rituximab and their disease continued to progress.

Mr. Perrone and his colleagues evaluated the Expanded Disability Status Scale (EDSS), 25-foot walk, and nine-hole peg test scores for 30 patients who were on rituximab therapy for 2 years.

Inclusion criteria were diagnosis of SPMS, at least two cycles of rituximab therapy (each treatment cycle included 1g rituximab IV, 2 weeks apart), and records of the three primary outcomes analyzed in the study.

There were 13 men and 17 women, mean age 56 years, with an average disease duration of 12 years. Five patients were later excluded.

Researchers obtained patient scores 2 years before rituximab therapy to establish rate of progression, and they obtained scores 1 year before treatment to establish baseline. The study had no control groups.

Results showed that 2 years before rituximab therapy, there were statistically significant increases in EDSS scores (0.5 points per year; P = .02), Mr. Perrone and his colleagues reported. However, after the therapy began, there were no significant differences, when compared with baseline values in the majority of the patients (less than 0.1-point increase between first and second treatment cycle, and 0.05-point increase between second and third treatment cycle), "suggesting that patients were at least stabilized on therapy," the authors reported. The treatment cycles were 6 months apart.

Authors then stratified the patients based on EDSS scores. At 2 years, 12 patients (48%) were stable and showed no change in EDSS score, 9 patients (36%) showed significant improvement in EDSS scores, and, in 4 patients (16%), the disease continued to progress.

The researchers noted that it was interesting to find that patients with higher initial EDSS scores were more likely to stabilize after treatment, while patients with lower initial EDSS scores were more likely to exhibit a significant change in EDSS.

There were no changes in MRI activity throughout the course of treatment, except for a nonenhancing lesion in one patient. The reported adverse events, including UTI, rash, fatigue, headache, and serum sickness disease, were not severe.

Mr. Perrone said that given the limited options available, rituximab should be considered an option for patients who have failed primary and secondary therapy, and that the study’s findings were encouraging.

His study has not been published and he said that larger studies are needed to confirm the findings.

Mr. Perrone had no disclosures. The study was funded by a grant from the Foundation of the Consortium of Multiple Sclerosis Centers’ MS Workforce of the Future program.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller

ORLANDO – In patients with secondary-progressive multiple sclerosis, rituximab could potentially stabilize or reverse the rate of disease progression, according to a small, retrospective, single-center study.

Given the findings, rituximab, a B-cell depletion therapy, is a reasonable option for patients with secondary-progressive multiple sclerosis (SPMS) who no longer respond to primary and secondary lines of treatment, said Christopher M. Perrone, a fourth-year medical student at the University of Massachusetts, Worcester.

Mr. Perrone presented his poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

Patients with SPMS have few treatment options. The only FDA-approved therapy for SPMS is mitoxantrone, which, because of severe side effects, is used only after patients stop responding to first and second-line treatments.

Phase I and II studies have shown rituximab’s safety in relapsing-remitting MS. The National Institute of Neurological Disorders and Stroke is recruiting patients for a double-blind, placebo-controlled, single center, phase I/II study on the safety and efficacy of combined systemic and intrathecal rituximab in patients with SPMS.

Mr. Perrone’s review of 25 patients at the University of Massachusetts Multiple Sclerosis Center showed that the disability score for patients with SPMS treated with rituximab for 2 years either stabilized or improved in 84% of the patients.

Four patients (16%) did not respond to rituximab and their disease continued to progress.

Mr. Perrone and his colleagues evaluated the Expanded Disability Status Scale (EDSS), 25-foot walk, and nine-hole peg test scores for 30 patients who were on rituximab therapy for 2 years.

Inclusion criteria were diagnosis of SPMS, at least two cycles of rituximab therapy (each treatment cycle included 1g rituximab IV, 2 weeks apart), and records of the three primary outcomes analyzed in the study.

There were 13 men and 17 women, mean age 56 years, with an average disease duration of 12 years. Five patients were later excluded.

Researchers obtained patient scores 2 years before rituximab therapy to establish rate of progression, and they obtained scores 1 year before treatment to establish baseline. The study had no control groups.

Results showed that 2 years before rituximab therapy, there were statistically significant increases in EDSS scores (0.5 points per year; P = .02), Mr. Perrone and his colleagues reported. However, after the therapy began, there were no significant differences, when compared with baseline values in the majority of the patients (less than 0.1-point increase between first and second treatment cycle, and 0.05-point increase between second and third treatment cycle), "suggesting that patients were at least stabilized on therapy," the authors reported. The treatment cycles were 6 months apart.

Authors then stratified the patients based on EDSS scores. At 2 years, 12 patients (48%) were stable and showed no change in EDSS score, 9 patients (36%) showed significant improvement in EDSS scores, and, in 4 patients (16%), the disease continued to progress.

The researchers noted that it was interesting to find that patients with higher initial EDSS scores were more likely to stabilize after treatment, while patients with lower initial EDSS scores were more likely to exhibit a significant change in EDSS.

There were no changes in MRI activity throughout the course of treatment, except for a nonenhancing lesion in one patient. The reported adverse events, including UTI, rash, fatigue, headache, and serum sickness disease, were not severe.

Mr. Perrone said that given the limited options available, rituximab should be considered an option for patients who have failed primary and secondary therapy, and that the study’s findings were encouraging.

His study has not been published and he said that larger studies are needed to confirm the findings.

Mr. Perrone had no disclosures. The study was funded by a grant from the Foundation of the Consortium of Multiple Sclerosis Centers’ MS Workforce of the Future program.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller