Sequencing MS therapies: 2 studies


Report from the 1st Congress of the European Academy of Neurology, Berlin, Germany, June 20-23, 2015 – Few studies have examined the feasibility of switching MS patients from one higher-efficacy therapy to another. In the TOFINGO and ENIGM (Enquête Nationale sur l’Introduction du Fingolimod en Relais au Natalizumab) prospective studies, disease reactivation was generally well controlled after switching from natalizumab to fingolimod, most notably when the washout period did not exceed 12 weeks (Kappos et al. Neurology 2015; epublished May 29, 2015; Cohen et al. JAMA Neurol 2014;71:436-441).

The MSBase study group has recommended a maximum 8-week washout period (Jokubaitis et al. Neurology 2014;82:1204-1211).

Preliminary data are now available for two other switches: alemtuzumab to fingolimod; and natalizumab to rituximab.

In the CARE-MS studies, patients received two annual courses of alemtuzumab, and re-treatment was permitted, as needed, during the extensions. For example, in the CARE-MS II trial of previously-treated patients, 68% of patients did not require retreatment and 24% received a third course (Havrdova et al. AAN 2015; abstract P7.276). Alternatively, patients could switch to another agent, and safety data are now available for 13 patients in the alemtuzumab extension studies who switched to fingolimod (Selmaj et al. EAN 2015; abstract F3151).

Most patients (11 of 13) received two or three courses of alemtuzumab; one patient received one course and one patient received four courses. The mean time from last alemtuzumab dose to fingolimod initiation was two years. The mean follow-up was 1.4 years. As expected, T and B cell counts increased following the last dose of alemtuzumab, then decreased after fingolimod initiation. There was no consistent trend to adverse effects following the switch. Two serious adverse events (syncope in one patient, subacute pericarditis, basal cell carcinoma and papillary thyroid cancer in a second patient) occurred during treatment with fingolimod. Efficacy data were not available.

A second study examined the efficacy of rituximab in 10 natalizumab-treated patients who switched due to a high risk of PML (median 42 infusions) (Malucchi et al. EAN 2015; abstract P1252). The median washout period was 3.3 months. Rituximab dosing (375 mg/mq IV every week for four weeks) differed from that used in MS trials. During the follow-up, 9 of 10 patients showed clinical and radiological stability during the washout; one patient who started rituximab after an 8-month washout experienced disease reactivation. Radiological stability was maintained in all patients at 6 months, and in 5 of 5 patients on treatment for 12 months, suggesting that rituximab may provide adequate disease control after natalizumab discontinuation, however, the risk of PML with this drug sequence would need to be determined.

Dr. Daniel Selchen:
The size of the above-noted data sets is an illustration of the problems we face in terms of trying to develop safe and effective strategies for switching treatments in aggressive disease. This is an area where properly designed phase IV trials could be very helpful, at least in terms of efficacy data. Safety – particularly with regard to PML risk – is going to take years of observation and careful reporting.

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