When switching from natalizumab (Tysabri, Biogen Idec) to fingolimod (Gilenya, Novartis) oral therapy in patients with multiple sclerosis (MS), a washout period of 8 weeks or less seems advisable, according to data from 2 new studies presented at last week's 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

One of the reports also suggested that patients can switch from natalizumab to fingolimod without a marked increase in MS relapse rate. In the Australian observational cohort study, which included 350 patients switching from natalizumab to fingolimod, 85% of patients had no MS relapse in the first 6 months of fingolimod therapy.

Presenting the data, Vilija Jokubaitis, PhD, University of Melbourne, Australia, reported that the annual relapse rate increased slightly, from 0.26 on natalizumab to 0.38 with fingolimod (relative risk, 1.84), which she said was consistent with differences in efficacy between the 2 drugs. The greatest predictor of time to first relapse with fingolimod was having had a relapse in the 6 months before starting fingolimod, with a hazard ratio of 1.6 for each previous relapse.

In addition, patients with a washout time of more than 2 months had a greater risk for relapse. Median switch time in this study was 79 days. "Our data support shorter washout periods when switching from natalizumab to fingolimod," Dr. Jokubaitis commented.

Asked why other studies have suggested much higher relapse rates upon switching from natalizumab to fingolimod, Dr. Jokubaitis noted that patients in those studies have stabilized during longer-term follow-up, adding that patients with washout periods of less than 8 weeks have better outcomes.

She suggested that case reports of relapsing upon switching from natalizumab to fingolimod could have represented reporting bias or the inclusion of patients with highly active disease and long washout periods.

In a summary of the meeting highlights, Bernd Kieseier, MD, Heinrich Heine University, Düsseldorf, Germany, used this study as an example of how decisions will be made in the future on use of all the new drugs sequentially.

"The entire therapeutic arena is extremely complex," Dr. Kieseier commented. "We will never have phase 3 studies to tell us what sequence to use these drugs in. So we must collect data in observational studies like this one which will help us understand treatment algorithms in a real-world setting."

TOFINGO Study

In the second study, known as TOFINGO, presented by Davorka Tomic, MD, from Novartis, Basel, Switzerland, shorter washout periods of 8 or 12 weeks upon switching from natalizumab to fingolimod were associated with fewer active lesions and clinical disease recurrence compared with a 16-week washout.

Although the 8- and 12-week washout groups did not differ with regard to the primary outcome — number of active T2 lesions during washout and first 8 weeks of fingolimod — the 8-week washout group had the least amount of activity over 8 weeks of fingolimod therapy and over 24 weeks since last natalizumab dose, and the smallest change in T2 volume from baseline to week 24.

There was no increase in infections or other treatment-related adverse effects compared with other studies.

"After seeing these results I would advise an 8-week washout or maybe even shorter — possibly 4 weeks," Dr. Tomic commented to Medscape Medical News.

Session chair, Vesna Brinar, MD, University Hospital Zagreb, Croatia, said this was "a very important study for clinical practice."

Dr. Tomic noted that natalizumab often has to be discontinued because of the risk for progressive multifocal leukoencephalopathy, and fingolimod is the most common drug to switch to at present.

"It is important to understand the optimum timing for initiating patients on fingolimod following natalizumab discontinuation," she said.

The TOFINGO study involved 142 patients who were stable while receiving natalizumab for at least 6 months and received the last dose within 1 week of randomization. Mean Expanded Disability Status Scale score was 3.6, and most patients were coming off natalizumab because of positive JC virus antibody status. They were randomly assigned to washout periods of 8, 12, or 16 weeks before starting fingolimod treatment.

Table. TOFINGO Results

Endpoint 8-Week Washout 12-Week Washout 16-Week Washout
Mean lesion count during washout and first 8 weeks of fingolimod (n) 2.1 1.7 8.2
Patients with no active lesions (%) 68 69 36
Mean change in T2 lesion volume from baseline to 24 weeks –107 204 1351
Patients free from gadolinium-enhancing lesions at 24 weeks (%) 75 61 47
Annualized clinical relapse rate during fingolimod therapy 0.36 0.33 0.65

 

"Possibility an even shorter washout period would be better," Dr. Tomic commented to Medscape Medical News. She explained that when this study was started in 2011, it was unknown what overlap of treatments would do.

"We had no experience. We know that natalizumab continues to have biological effects for quite some time — up to 3 months — after discontinuation, so for safety reasons we didn't go shorter. Many neurologists have not been happy to switch quickly for safety concerns."

She added: "Patients on natalizumab normally have highly active disease before starting therapy. When stopping the drug, resumption of disease activity is often seen. But when fingolimod is started disease activity is reduced again. It takes about 8 weeks for fingolimod to work."

29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Abstracts #167 and #179. Presented October 4, 2013.

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