REPORT FROM THE 67TH AMERICAN ACADEMY OF NEUROLOGY (AAN) ANNUAL MEETING – WASHINGTON DC, APRIL 18-25, 2015 – A number of new studies at AAN 2015 presented longer-term data on the use of second-generation disease-modifying therapies for MS. The following is a summary of key studies:
Fingolimod: LONGTERMS is the extension of phase II and III studies of fingolimod to assess safety and tolerability (Cohen et al. AAN 2015; abstract S4.006). Median duration of fingolimod exposure was 3.9 years. The overall incidence rate ratio for adverse events or serious adverse events was 0.75. Adverse events of interest (e.g. infections, hypertension, respiratory conditions, macular edema, etc.) occurred less frequently during long-term treatment compared to during the core phase of the phase III trials. The sole exception was lymphopenia, which was less frequent in clinical trials; this was attributed to blinding of lymphocyte counts above 200 cells/mm3.
PANGAEA is an ongoing non-interventional study of patients receiving fingolimod in real-world practice (Ziemssen et al. AAN 2015; abstract P3.251). The dataset currently exceeds 147,000 patient-years of fingolimod exposure. In an analysis of patients receiving fingolimod for up to three years, two-thirds were relapse-free both in year 1 and year 2 of treatment. The average EDSS score was stable. The discontinuation rate was 12.7%; the most common reason for discontinuation was adverse effects (4.5%). At 24 months, 98% of clinicians and patients rated treatment tolerability as very good/good.
Teriflunomide: The long-term safety of teriflunomide was analysed with 12-year extension data from the phase II study (cumulative exposure 990 patient-years) (Kremenchutzky et al. AAN 2015; abstract P7.223). The proportion of patients remaining relapse-free was higher in the 14-mg group compared to the 7-mg group (51.5% vs. 39.5%). EDSS changes were minimal at 528 weeks of therapy. Drug tolerability during long-term therapy was comparable to that seen in clinical trials. No new safety issues have emerged.
Dimethyl fumarate: In ENDORSE, the extension of the two phase III trials of DMF, the annualized relapse rates (ARR) remained low over a 5-year treatment period (Bar-Or et al. AAN 2015; abstract P7.234). For those in the DMF 240 mg BID group, ARR was 0.202 and 0.163 during the first two years of the double-blind phase, then 0.139, 0.143 and 0.138 during the three-year extension. For the entire observation period, ARR was 0.123 in patients who had not received prior DMTs, and 0.195 in those receiving one or more prior DMTs (Bar-Or et al. AAN 2015; abstract P7.229). However, the analyses were based on a low proportion of patients from the original trials, and the authors noted that results should be interpreted with caution since sample sizes were small.
In the ENDORSE safety analysis (4980 patient-years), the overall incidence of serious adverse events with DMF 240 mg BID was 22%, or comparable to what was seen with placebo (Pozzilli et al. AAN 2015; abstract P7.235). The incidence of adverse events leading to discontinuation was 6-7% for those continuing on treatment, and 14-26% for the placebo patients who switched to DMF. The incidence of serious infections was less than 5%.
Alemtuzumab: The efficacy of alemtuzumab appears to be sustained for up to four years, according to the extension results of the CARE-MS trials. For de novo patients in CARE-MS I, 73% of patients did not require a third course of treatment (Compston et al. AAN 2015; abstract S4.007). The ARR in years 3 and 4 was 0.19 and 0.14. Overall, 83% of patients did not experience 6-month sustained accumulation of disability; EDSS scores improved in about one-third of patients. The incidence of thyroid-related adverse events peaked in year 3 and declined thereafter.
In the two-year follow-up to the CARE-MS II trial of previously-treated patients, 68% of patients did not require a third course of treatment (Havrdova et al. AAN 2015; abstract P7.276). ARR remained low in year 3 (0.22) and year 4 (0.23). Two-thirds of patients had stable or improved EDSS scores from baseline to the end of year 4. Overall, 76% had no 6-month sustained accumulation of disability, and 41% had a sustained reduction in disability. A separate analysis found that the incidence of infections decreased over time, from 59.9% in year 1 to 46.0% in year 4 (Henson et al. AAN 2015; abstract P7.265). Infections were generally mild to moderate and were not associated with study withdrawal. The most common infections were nasopharyngitis, urinary tract infection and upper respiratory tract infection.
Guest Reviewer: Dr. Daniel Selchen, Head of Neurology, St. Michael’s Hospital, Toronto, Canada