Teriflunomide Approved in UK for MS; TOWER Published

January 30, 2014

The new oral multiple sclerosis (MS) drug teriflunomide (Aubagio, Genzyme/Sanofi), has been accepted for use in the United Kingdom (UK) National Health Service by the National Institute for Health and Care Excellence (NICE) for the treatment of patients with relapsing-remitting MS. This does not include patients with highly active or rapidly evolving severe relapsing-remitting MS.

The development comes as the second phase 3 study of teriflunomide, called Teriflunomide Oral in people With relapsing-remitting MultiplE ScleRosis (TOWER), is published online January 23 in Lancet Neurology. The results were first presented, and reported by Medscape Medical News, at the 2012 European Committee for Treatment and Research In Multiple Sclerosis (ECTRIMS) meeting.

The 14-mg dose of teriflunomide was approved by the European Medicines Agency in August 2013. The drug is also approved in the United States, where the 7-mg dose is also available, as well as in Australia, Argentina, Canada, Chile, Mexico, New Zealand, South Korea, and Switzerland.

In the UK, teriflunomide has been priced at £1037.84 per 28-tablet pack, with the annual cost estimated at £13,529 per patient per year. Additionally, Genzyme has agreed to a patient access scheme with the Department of Health regarding a discount, the level of which is confidential.

TEMSO and TOWER

Teriflunomide has been tested in 2 phase 3 placebo-controlled studies: the TEriflunomide MS Oral (TEMSO) trial and TOWER. TEMSO showed a relative risk reduction in annualized relapse rate of 31% for both the 7-mg and 14-mg doses vs placebo and a relative risk reduction for confirmed progression of disability of 23.7% for the 7-mg dose and 29.8% for the 14-mg dose.

The second study, TOWER, showed relative reductions in the annualized relapse rate of 22% for the 7-mg dose and 36% for the 14-mg dose vs placebo, and reductions of sustained accumulation of disability of 4.5% and 31%, respectively.

Commenting for Medscape Medical News, Ben Turner, MD, consultant neurologist at Barts Health NHS Trust, London, UK, said teriflunomide was the first oral agent for MS to be made available in the UK as a first-line agent.

The other oral agent, fingolimod (Gilenya, Novartis), is restricted to second-line use in the UK. He sees teriflunomide as a good first-line option as an alternative to the β-interferons or glatiramer acetate (Copaxone, Teva Pharmaceuticals).

"I would say the efficacy of teriflunomide looks similar to β-interferons/Copaxone in terms of relapse rate, and the disability results are more consistent," Dr. Turner said. "As all these agents have relatively mild adverse effect profiles, I would think it will be up to patient preference which drug they start on, and many patients are likely to choose the oral agent first."

"The simplicity of taking a tablet once a day over having to give yourself an injection will be a major priority for many people. This will allow patients to lead as normal a life as possible, which is what most people want, especially if they have mild disease."

But he also noted that some patients may prefer to go with the long-proven experience with these standard injectables over a new drug.

Another factor to be taken into account is the teratogenicity of teriflunomide. Dr. Turner agreed that some patients may be put off by this, but the need to avoid pregnancy when taking the drug would be stressed, and it can be eliminated easily if pregnancy is planned.

On the exclusion of patients with highly active or rapidly evolving severe relapsing-remitting MS from the UK indication for teriflunomide, Dr. Turner explained that a rapidly evolving form of relapsing-remitting MS is now recognized, and it is accepted that these patients need a stronger treatment.

"In these cases we would go straight in with natalizumab [Tysabri, Biogen Idec), and possibly in the future alemtuzumab (Lemtrada, Genzyme/Sanofi) if NICE approves it, so teriflunomide would not be appropriate for this group."

Alemtuzumab is approved for use in Europe, Canada, and Australia, but recently was declined approval by the US Food and Drug Administration.

TOWER Publication

In a Comment accompanying the current TOWER publication, Bernd C. Kieseier, MD, Heinrich-Heine University, Düsseldorf, Germany, and Heinz Wiendl, MD, Westfälische-Wilhelms-University, Münster, Germany, write: "TOWER largely confirms the findings of TEMSO by showing significant efficacy of the 14 mg dose in the reduction of relapse activity and disability progression. Additionally, TOWER reveals a dose effect, supporting the view that the higher dose of teriflunomide is more efficacious than the lower dose."

Dr. Kieseier and Dr. Wiendl point out that 30% of patients discontinued study treatment in TOWER, which they say is "surprising" given the convenience of the oral administration. But they say this is line with TEMSO and other studies investigating oral drugs in MS, such as fingolimod.

"Therefore, although oral treatment might seem more convenient, physicians should address adherence to therapy once an oral immunotherapy has been chosen," they say.

In terms of safety, Dr. Kieseier and Dr. Wiendl note that TOWER showed results similar to those of other studies with teriflunomide — ie, it lowers peripheral leukocytes, can raise liver enzymes, and is associated with reversible hair thinning and diarrhea.

They conclude: "Despite some limitations in the trial design, TOWER corroborates findings that teriflunomide is a simple once-daily therapy for relapsing multiple sclerosis," adding that teriflunomide has the potential to become one of the most appropriate drugs for patients with mild to moderate disease activity.

Dr. Turner has received travel and research grants from Genzyme/Sanofi. Dr. Kieseier has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Genzyme/Sanofi, and Dr. Wiendl has received honoraria and consultation fees from Genzyme/Sanofi.

Lancet Neurol. Published online January 23, 2014. Abstract Comment

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