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Neurology Today:
doi: 10.1097/01.NT.0000407902.56530.e3
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A New Oral Drug for MS: How Does it Compare?

Valeo, Tom

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ARTICLE IN BRIEF

Investigators reported that teriflunomide increased the time to a first relapse, and enabled more multiple sclerosis (MS) patients to remain free of relapse than a placebo. But independent experts said the data, while welcome, is not a game-changer for MS treatmet.

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Anew oral medication, teriflunomide, may not be the game-changer neurologists have been awaiting, but it appears to restrain the progression of multiple sclerosis (MS) as well as drugs already approved by the FDA — without producing significantly more side effects.

“It's not really a new drug,” said Timothy L. Vollmer, MD, professor of neurology at the University of Colorado Health Sciences Center, and medical director of the Rocky Mountain MS Center at Anschutz Medical Center. “Teriflunomide is in the same class as azathioprine, an oral chemotherapy drug, so it's a new formulation of something used for many years in cancer and autoimmunity.”

Teriflunomide is a drug metabolite of leflunomide, approved to treat rheumatoid arthritis, “and the major issue with leflunomide has been liver toxicity,” Dr. Vollmer said. “The good thing is that the liver toxicity of teriflunomide does not seem to be significantly different from fingolimod and the interferons. It's just one of those safety issues we'll have to monitor. As physicians we're fairly comfortable with teriflunomide because we've used similar drugs for years.”

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NEW STUDY DATA

According to the results of the Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, reported in the Oct. 6 New England Journal of Medicine (NEJM), teriflunomide increased the time to a first relapse, and enabled more patients to remain free of relapse than a placebo.

TEMSO, a randomized, double-blind, placebo-controlled, parallel-group phase 3 trial supported by Sanofi-aventis, which is developing teriflunomide, involved 1,088 MS patients aged 18 to 55 who scored 5.5 or lower on the Expanded Disability Status Scale, and who had at least one relapse in the previous year, or two relapses in the previous two years.

The patients were divided into three groups, receiving either 7 mg or 14 mg of teriflunomide, or a placebo for 108 weeks.

“Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging,” according to the study authors. Also, the increase in lesion volume from baseline was significantly lower in the 7 mg and 14 mg groups than in the placebo group (p = .03 and p < .001, respectively). Patients taking teriflunomide showed less progression of disability, although there was only a slight difference between the 7- and 14-mg dose groups (21.7 percent and 20.2 percent respectively, vs. 27.3 percent on placebo).

“Teriflunomide is effective clinically and radiologically,” said Paul O'Connor, MD, lead author of the study. “It's safe, and it's oral, and it's easier to use than fingolimod. There's no need for first-dose monitoring, no macular edema, and unlike fingolimod, teriflunomide can be washed out of the patient within days — for example, if the patient becomes pregnant.” Fingolimod (Gilenya), in contrast takes 45 days to wash out of the system.

Teriflunomide reduced relapses by 31 percent — about the same as interferon and glatiramer acetate, although head-to-head data are not available yet, said

Dr. O'Connor, professor of neurology at the University of Toronto, and director of the Multiple Sclerosis Clinic and MS Research, and the Evoked Potentials Laboratory at St. Michael's Hospital in Toronto.

“It also reduced the risk of disability progression by 30 percent — the same as fingolimod, interferon, and glatiramer acetate,” he added. “It reduced the increase in T2 lesion volume by 67 percent, new lesions by 70 percent, and gadolinium-enhanced lesions by 80 percent — very respectable compared to glatiramer acetate, interferon-beta, and fingolimod, although head-to-head studies would need to be performed to properly compare these drugs. Teriflunomide also produced no deaths or opportunistic infections, and showed no significant effect on heart or lung function. Serious adverse events were no more common in treated patients than in those who received a placebo.”

The most common side effects, including diarrhea, nausea, elevations of the liver enzyme alanine aminotransferase (ALT), and hair thinning, most likely result from teriflunomide's ability to inhibit dihydroorotate dehydrogenase, a mitochondrial enzyme involved in DNA replication. This inhibition disrupts DNA synthesis in rapidly dividing cells, such as hair follicle cells, but it also reduces the proliferation of T cells and B cells in response to autoantigens. However, the authors maintain that teriflunomide preserves the replication and function of slowly dividing cells such as memory T cells by exploiting the so-called salvage pathway.

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EXPERTS COMMENT

DR. TIMOTHY VOLLMER ...
DR. TIMOTHY VOLLMER ...
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DR. PAUL OCONNOR Ter...
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While teriflunomide appears to be modestly effective and relatively safe, its most exciting quality may turn out to be the additional choice it offers MS patients, said Bruce A. Cohen, MD, professor of neurology and director of the Comprehensive Multiple Sclerosis Program at Northwestern University's Feinberg School of Medicine. Dr. Cohen was not involved with the trial.

“From my perspective, multiple options are attractive when trying to match an individual patient with a drug,” Dr. Cohen said. “There may be people who, due to their genetic makeup or to certain characteristics of their disease, respond better to one agent than another. We're not able to predict at this point which agent would be best for each patient, but having agents with different mechanisms may allow us to find better matches. Having more choices is better.”

One impressive aspect of the study is that it lasted for more than two years — long enough to spot the development of opportunistic infections that sometimes develop in people taking other drugs of this type, observed Robyn S. Klein, MD, PhD, associate professor in the departments of internal medicine, neurobiology, and immunology at Washington University School of Medicine. The first trial on natalizumab, another immunosuppressive agent, lasted only six months, but the drug went on to cause progressive multifocal leukoencephalopathy, an extremely rare and usually fatal viral infection, in a few patients.

“Teriflunomide is a drug that inhibits T cell activity,” Dr. Klein said. “It doesn't look like there were many infections, but that doesn't mean there won't be some later. We don't entirely understand how T cell immune surveillance prevents opportunistic infections in immunocompetent patients.”

But if an infection were to develop, she added, teriflunomide can be washed out of the system relatively quickly, thereby allowing the immune system to recover and fight the infection.

The drug itself, in Dr. Klein's opinion, doesn't prevent disease progression, it just slows it down. “It's just another drug that doesn't cure MS,” she said.

While the results reported in the NEJM put teriflunomide on track to win FDA approval, neurologists themselves seem underwhelmed by the drug's effectiveness.

“I think we've come to expect what we've seen with other agents that have come out recently — relapse rate reductions of 50 percent and better,” Dr. Cohen said.

Fingolimod, for example, reduces relapses by 54 percent compared to placebo. BG-12 (dimethyl fumarate), currently undergoing a phase 3 clinical trial as a monotherapy for relapsing-remitting MS and rheumatoid arthritis, has reduced MS relapses by 53 percent. “Teriflunomide is a lot less than that,” Dr. Cohen said.

Dr. Vollmer agrees, and doubts that teriflunomide will have much of an impact on MS treatment. “We're not looking for another drug with only a 30 percent treatment effect,” he said. “We're looking for drugs that achieve a 70 or 80 or even 90 percent treatment effect in terms of disability and relapse reduction.”

DR. BRUCE A. COHEN F...
DR. BRUCE A. COHEN F...
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Also, even though teriflunomide appears to be relatively safe, it is still a low-intensity chemotherapeutic drug that suppresses the immune system, which means it has the potential to affect many tissues and allow opportunistic infections to take hold. “So I think the safety profile of teriflunomide will make it not so attractive as a monotherapy,” Dr. Vollmer added. “However, because there were no major differences in effectiveness between the 7- and 14-mg doses we can improve the safety profile simply by using a lower dose.”

Despite its modest effects and potential side-effects, teriflunomide will still be a welcome addition to the armamentarium neurologists can draw on to treat MS, according to Dr. Cohen.

“I think once we've seen all the data from teriflunomide, fingolimod, laquinimod, and BG-12 we'll have a better picture of the relative merits of each,” he said. “In the next two or three years we may be seeing a widely expanded list of options for treating MS, and that can only be good.”

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REFERENCE:

MS DRUG DATA COMPARI...
MS DRUG DATA COMPARI...
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O'Connor P, Wolinsky JS, Freedman MS, et al, for the TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293–1303.

Cruz-Orengo L, Holman DW, Klein RS, et al. CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. J Exper Med 2011;208(2):327–339.

Kappos L, Radue EW, Burtin P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362:387–401.

Cohen JA, Barkhof F, Kappos L, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362:402–415.

Comi G, Abramsky O, Filippi M, et al, for the LAQ/5063 Study Group. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study. Mult Scler 2010;16(11):1360–1366.

©2011 American Academy of Neurology

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