Long-term efficacy and safety of fingolimod in Japanese patients with relapsing multiple sclerosis: 3-year results of the phase 2 extension study

Abstract

Background: The low level of disease activity and manageable safety profile seen with fingolimod versus placebo in a 6-month, phase 2, randomized controlled trial in Japanese patients with relapsing multiple sclerosis (MS; ClinicalTrials.gov Identifier NCT00537082) were maintained in the initial 6-month observational study extension. Here, we report long-term safety and efficacy results of the 3-year follow-up to the phase 2 study extension.

Methods: The 6-month core study was completed by 147 patients, of whom 143 entered the extension and took at least one dose of fingolimod. Those originally randomized to placebo were re-randomized to fingolimod 1.25 mg (n = 23) or 0.5 mg (n = 27). During the extension, the patients taking fingolimod 1.25 mg (n = 46) were switched to open-label fingolimod 0.5 mg, and those originally randomized to fingolimod 0.5 mg (n = 47) continued with open-label fingolimod 0.5 mg.

Results: Continuous fingolimod treatment was associated with a sustained low level of MRI and relapse activity for the duration of the extension phase; 75-100% (range across all assessment time points up to end of study) of patients remained free of Gd-enhanced T1 lesions, 88-100% remained free of new/newly enlarged T2 lesions, and 45-62% remained relapse-free. In patients who switched to the active treatment, a 79.5% decrease in annualized relapse rate (ARR; from 1.131 before switch to 0.232 6-months after switch) was observed in the first 6 months of the extension phase and thereafter remained low until the end of study (0.16-0.31 across all assessment time points after switch up to end of study). The mean number of Gd-enhanced T1 and new/newly enlarged T2 lesions decreased up to month 9 and thereafter remained low until the end of study (0.0-0.1 and 0.0-0.3, respectively, across all assessment time points after switch up to end of study). Fingolimod was generally well-tolerated and the safety profile was consistent with the core and 6-month extension. Serious adverse events were reported in 13.3% of patients during the extension study, with the range in the continuous fingolimod and placebo-fingolimod switch groups (3.7-21.7%) being similar to that reported in the core study for the placebo and fingolimod groups (5.3-20.4%).

Conclusion: Continuous fingolimod treatment over 36 months was associated with maintained efficacy and a manageable safety profile with no new safety signals. These results indicate that fingolimod provides long-term treatment benefit for Japanese patients with relapsing MS.

Trial registration: ClinicalTrials.gov NCT00670449 (April 28, 2008).

Keywords: Aquaporin 4; Fingolimod; Multiple sclerosis; Phase 2 study extension; Relapse.

Figures

Fig. 1

Enrollment and follow-up of patients who completed the core 6-month study and entered the long-term extension. A patient was defined as having completed the extension study if he/she was taking part in the study at the time of fingolimod launch in Japan

Fig. 2

a Number of (i) Gd + lesions and (ii) new T2 lesions, and b proportion of patients free of (i) Gd + T1 and (ii) new T2 lesions in the core and extension study

Fig. 3

Relapse outcomes presented as a aggregate annualized relapse rate up to end of study by time period and treatment, and b Kaplan-Meier plot of time to first confirmed relapse

Fig. 4

Change in mean lymphocyte count during the core and extension study (extension safety population). EoS (end of study): in this instance is the last non-missing value up to 2 days after the last dose date and is summarized as last assessment on study drug. Data at 0.5 months (day 15) for fingolimod 0.5 mg (n = 54) and 1.25 mg (n = 56) represent values obtained during the core study (safety population)