WASHINGTON – An analysis of long-term safety data of fingolimod in patients with relapsing multiple sclerosis treated for as long as 7 years has not identified new safety issues or increases in any known adverse events identified in the core studies conducted before approval, Dr. Jeffrey Cohen reported at the annual meeting of the American Academy of Neurology.
The results, based on data from the ongoing LONGTERMS open-label extension study following the safety and tolerability of fingolimod in patients enrolled in phase II and III trials, confirm that the treatment is “suitable” for long-term therapy for patients with relapsing MS, said Dr. Cohen, director of the Mellen Center for MS Treatment and Research at the Cleveland Clinic.
Dr. Jeffrey Cohen
Fingolimod, a sphingosine 1-phosphate receptor modulator marketed as Gilenya, was approved by the Food and Drug Administration in 2010 for relapsing forms of MS at a dose of 0.5 mg taken orally once a day. As of November 2014, more than 114,000 people worldwide have been treated with fingolimod, representing more than 195,000 patient-years of exposure, according to Dr. Cohen, who cited data from Novartis, the manufacturer.
He presented the results of the analysis of adverse events (AEs), serious adverse events (SAEs), and AEs of “special interest,” among 1,655 people with relapsing-remitting MS enrolled in LONGTERMS who were treated with fingolimod (0.5 mg a day) for a mean of 4 years (839 were on treatment for at least 7 years). They included 1,212 people treated with fingolimod in the core studies, as well as people in those studies who were on placebo or a comparator treatment and were rerandomized to treatment with fingolimod. At enrollment in the original study, the mean age was 38 years, and 70% of the patients were females. The patients had had MS for a mean of 5 years, and had a mean score of 2.31 on the Expanded Disability Status Scale (EDSS).
The analysis compared the safety profile in the extension and core studies by calculating the incidence rate (IR) for the events in each database, and calculating the incidence rate ratio (IRR) by dividing the IR for the longterm study cohort by the IR for the core cohort. (The IRs were expressed as the number of AEs “per 100 patient-years of the at-risk population.”) AEs of special interest were infections, hypertension, respiratory conditions, lymphopenia, macular edema, bradyarrhythmia after the first dose, reproductive toxicity, liver transaminase elevation, skin cancer, other malignant neoplasms, and thromboembolic events.
The only SAE with an IRR that exceeded 1 was herpes zoster infections, but the odds ratio was broad and overlapped one, Dr. Cohen said. The results for other SAEs included an IRR of 0.47 for bradyarrhythmia after the first dose, and an IRR of 0.45 for macular edema.
In the analysis of AEs, leucopenia and lymphopenia “seem to be increased” with more time on fingolimod, he noted. In the long-term cohort, the IR for this adverse event was 6.2, compared with 4.6 for the core cohort, for an IRR of 1.36. However, this could have been a result of increased reporting resulting from investigators’ awareness of lymphocyte counts, since it is an open-label study, he said, pointing out that in the core studies, lymphocyte counts were unblinded only if they reached 0.2 x 109/L. There was no evidence of a progressive decline in lymphocyte counts, with no significant differences in trends over time with mean lymphocyte counts between those in the core and extension studies, although “we can’t eliminate” this possibility, he added.
The overall rate of infections did not appear to increase over time, with an IRR of 0.72.
There were more serious infections with longer treatment among patients with sustained low levels of peripheral lymphocyte counts, defined as absolute lymphocyte counts below 0.4 x 109/L for at least 60% of the records during the corresponding time interval. There were 28 cases of serious infection among those on treatment for more than 2 years and 14 cases among those on treatment for 2 years or less. The occurrence rate for the number of serious infections, which could be more than once for an individual patient, was 1.4 among those treated for more than 2 years vs. 1.0 for those treated for 2 years or less, for an occurrence rate ratio of 1.47.
Pointing out that the number of cases was small and the confidence intervals for this finding were wide, Dr. Cohen concluded that the LONGTERMS data do not support “an overall increased risk of infections with long-term exposure or with sustained low peripheral lymphocyte counts.”