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An Observational Study Finds Two Oral MS Drugs Are More Alike Than Different

Article In Brief

An observational study found that teriflunomide and dimethyl-fumarate showed similar clinical effectiveness with risks of relapse after two years of treatment. But patients taking dimethyl-fumarate were less likely to develop new lesions on MRI.

A large observational study of two popular oral medications for multiple sclerosis (MS) found that teriflunomide and dimethyl-fumarate showed similar clinical effectiveness in terms of risk of relapse after two years of treatment, but patients taking dimethyl-fumarate were less likely to develop new lesions on MRI.

The results, reported in the July 12 online edition of Neurology, come from an analysis of 1,770 people with relapsing-remitting MS in the French Multiple Sclerosis Registry. The study's lead author, David-Axel Laplaud, MD, PhD, professor of neurology at Nantes University Hospital in France, said his team decided to examine the effectiveness of teriflunomide versus dimethyl-fumarate because they are the most common MS drugs in France.

In France, “they have replaced interferons and glatiramer acetate in terms of prescriptions during the last years, so they are very important to compare and to know whether one of these drugs is better than the other one in efficacy and tolerance,” Dr. Laplaud said in an email to Neurology Today.

The two drugs are part of a growing lineup of disease-modifying therapies (DMTs) for MS, for which there is a lack of head-to-head drug comparisons. Oral teriflunomide was approved by the FDA in 2012 and dimethyl fumarate in 2013, and both are generally considered in the mid-range of potency for MS drugs, Dr. Laplaud said.

The study authors noted that both medications “have demonstrated their efficacy in relapsing-remitting MS to reduce annualized relapse-rate, disability accumulation and T2 lesion accrual at two years compared with placebo,” though some recent observational studies have yielded inconsistent results as to their efficacy.

While a randomized controlled trial would be the ideal way to compare two drugs, the researchers said an observational study “had the advantage of being more representative of real-life practices and effects, even if the patients are often non-comparable directly due to indication biases.”

Study Design

The French MS registry draws on a network of neurologists, mainly from 34 MS centers around France. Data are collected prospectively at each visit or hospitalization on a standardized form, including information on clinical exams, MRI and other tests, as well as key episodes in the patient's MS course, such as dates of relapses, date of secondary progression and dates, and levels of disability progression. When a drug is discontinued, doctors fill in a short questionnaire about reason for discontinuation, whether it be for patient intolerance (local, general, and/or biological), ineffectiveness, pregnancy or desire to become pregnant.

Figure

A summary of the odds ratios for comparing dimethyl fumarate (DMF) and teriflunomide (TRF) on clinical outcomes—relapses, EDSS, MRI outcomes (T2 lesions), no evidence of disease activity (NEDA), treatment withdrawal for lack of effectiveness, and treatment withdrawal for adverse events after 2 years.

Figure

Confounder-adjusted survival curves of time to first relapse show the difference between TRF and DMF was not statistically significant.

The study cohort included RRMS patients ages 18 to 65 who initiated treatment with teriflunomide or dimethyl-fumarate between May 2014 and January 2016, either as their first DMT or following treatment with injectable interferon or glatiramer acetate. The patients included in the analysis also had an available MRI scan and Expanded Disability Status Scale (EDSS) assessment within six months of treatment initiation and had to have an EDSS score ranging from 0 to 5.5 at treatment initiation. Patients with prior second-line MS treatment were not included.

Because the analysis was based on real-life data, MRI and EDSS assessments were not scheduled at a set time. The researchers defined two periods for their analysis: Data collected between six months pre-initiation of treatment and three months-post initiation were considered as baseline MRI and EDSS; data collected between nine and 18 months post-initiation were considered as one-year MRI or EDSS. The primary one-year outcome was relapse.

Of the 1,770 patients included in the analysis, 713 were on teriflunomide and 1,057 were on dimethyl-fumarate. After the researchers did a statistical adjustment for differences between the two groups at baseline (called a confounder adjustment), 21 percent of the teriflunomide group had a relapse by one year compared to 20.2 percent of the dimethyl fumarate group. By two years, after the numbers were statistically adjusted, 30.4 percent of the teriflunomide group had at least one relapse as did 29.5 percent of the dimethyl-fumarate group. The differences were not statistically significant, the researchers wrote, nor were there significant differences in EDSS scores between the two groups.

Follow-up MRIs were not available on all patients in the study, but among the 835 who had them, 46.9 percent of the teriflunomide group had new T2 lesions at one year compared with 42.9 percent of the dimethyl-fumarate group. At two years, those numbers were 72.2 percent versus 60.8 percent, “showing a significant effect of DMF [dimethyl-fumarate] reducing the risk of new T2 lesions,” the researchers reported. New lesions can be indicative of disease activity even in the absence of clinical symptoms.

Those on teriflunomide were also more likely to stop their treatment due to ineffectiveness than were those on dimethyl-fumarate (14.5 percent versus 8.5 percent at two years, after statistical adjustment). There were more reports of intolerance and side effects in the dimethyl-fumarate group as well.

“Our cohort-based study found no significant differences between TRF and DMT in terms of clinical activity of the disease, but a better control of MRI activity while on DMF after two years,” the researchers reported. “This result must be interpreted with caution, as the possible higher effectiveness of DMF must be counterbalanced with the higher rate of treatment withdrawal due to intolerance.”

The research had limitations including the fact that the study was observational rather than a randomized, controlled trial. There could have been provider bias in which patients were given which treatment and which got a follow-up MRI. One of the study's strength is its large size.

Dr. Laplaud said he hopes to use the French MS Registry to do other drug comparisons, including a comparison of fingolimod, anti-CD20 antibodies, and natalizumab.

Expert Commentary

Mary Alice Willis, MD, medical director of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, said the French study was a welcome addition to the literature, but it was impossible to say based on the findings “which types of patients are better for one medicine or another.”

She said it was striking that “most patients in this study had breakthrough disease within two years.” According to the statistically adjusted numbers in the study, 90.2 percent of patients in the teriflunomide group and 85.6 percent of those getting dimethyl-fumarate had signs of active disease at two years. (To meet the criteria of No Evidence of Disease Activity, NEDA-3, patients had to have no new T2 lesions, no increase in their EDSS score and no relapses.)

Dr. Willis said she hoped the study would serve as a reminder to doctors that getting regular MRI scans is critical to understanding how patients are faring with treatment and their disease overall. A patient could be doing well clinically, she said, while their disease is getting worse.

“Not all MRI lesions are immediately symptomatic, but over time the accumulation of these lesions increases the possibility of brain atrophy and disability in the future,” Dr. Willis said. “We don't have any way of undoing these lesions once they develop.”

“Relapses are the tip of the iceberg,” she said. “There is much more to MS inflammation than relapses.”

Paul Giacomini, MD, associate professor of neurology and neurosurgery at McGill University, said his key takeaway from the French study was that teriflunomide and dimethyl-fumarate “are probably more similar than dissimilar in their effectiveness,” which he says affirms his own clinical perspective. But he said it was hard for him to draw more conclusions beyond that. “To say that one drug is superior to another you'd have to have a randomized controlled study.”

Dr. Giacomini, associate director of the Multiple Sclerosis Clinic at Montreal Neurological Institute, noted that the time period of the trial, 2014 to 2016, while only a few years ago, seems like a rather long time ago given the ever-expanding options in MS treatment.

“The landscape is constantly changing,” he said, with the new infused drugs generally considered more efficacious than drugs such as teriflunomide and dimethyl-fumarate, which he considers both as first-line therapies and is unlikely to switch from one to another.

Dr. Giacomini said having more options is great for patients, but said the decision still comes down to an individual's needs and goals.

“I spend a lot of time getting to know my patients to understand what their objectives are and what their risk tolerance is,” he said. He added that while the trend in MS care is to use more potent drugs from the first signs of disease, not every patient may be “willing to go with a very powerful agent right out of the gate, with its greater potential risks and greater uncertainty than with older drugs.”

Shiv Saidha, MD, associate professor of neurology at Johns Hopkins Hospital, agreed that the French study, while “highly informative,” needs to be “interpreted with caution.”

“Both of these drugs continue to be used extensively in the treatment of MS,” he said. “At the same time, however, it is a study of two drugs that have been available for several years, and since their original release, numerous additional treatments have become available.” He said he considers neither teriflunomide nor dimethyl-fumarate, which have different mechanisms of action, to be “high-potency treatments,” but that doesn't mean they aren't right for many patients.

Dr. Saidha said that while head-to-head comparisons of drugs are useful, a separate question that needs to be addressed in a methodical way is “what is the impact of using high-efficacy versus low-efficacy treatments early on in the disease course,” in terms of disease activity benefits weighed against potential risks.

He said some answers may emerge from clinical trials such as the one being led by Johns Hopkins investigators (Ellen Mowry and Scott Newsome) called TREAT-MS, which will randomize MS patients to treatment with either an early aggressive therapy (natalizumab, alemtuzumab, ocrelizumab, or rituximab) or a traditional and less aggressive therapy (teriflunomide and dimethyl-fumarate are included in that group).

“These questions are important to ask so we can improve long-term outcomes in our patients,” Dr. Saidha said.

Disclosures

Dr. Willis has received compensation for participation on the speaker's bureau and advisory board for Genzyme and Biogen. Dr. Saidha has served on scientific advisory boards for Biogen, Genzyme, Genentech Corporation, EMD Serono, Celgene & Novartis. He is the principal investigator of investigator-initiated studies funded by Genentech Corporation and Biogen. He has received equity compensation for consulting from JuneBrain LLC, a retinal imaging device developer. He is also the site investigator of a trial sponsored by MedDay Pharmaceuticals.

Link Up for More Information

• Laplaud DA, Casey R, Barbin L, et al; for the SFSEP and OFSEP Groups. Comparative effectiveness of teriflunomide vs dimethyl fumarate in multiple sclerosis https://n.neurology.org/content/early/2019/07/12/WNL.0000000000007938. Neurology 2019; Epub 2019 July 12.