Fingolimod

Comparative studies

In a multicenter phase IIa study, fingolimod (n = 167) was compared with mycophenolate mofetil (n = 41), in combination with ciclosporin and glucocorticoids [ ]. The incidences of biopsy-confirmed acute rejection rates at month 3 were 23%, 35%, 18%, and 9.8% with doses of 0.25, 0.5, 1.0, and 2.5 mg/day versus 17% with mycophenolate mofetil. The incidence for the composite endpoint, defined as biopsy-confirmed acute rejection, graft loss, or death, was lowest with fingolimod in a dose of 2.5 mg/day at month 3 (15%) compared with fingolimod in doses of 0.25 mg/day (26%), 0.5 mg/day (35%), and 1.0 mg/day (18%), and mycophenolate mofetil (20%). Fingolimod 2.5 mg/day was as effective as mycophenolate mofetil in combination with ciclosporin for the prevention of acute rejection after kidney transplantation.

In a 24-month, double-blind, randomized study in 1033 adults with relapsing-remitting multiple sclerosis, oral fingolimod 0.5 and 1.25 mg/day both reduced the risk of disability progression [ ]. Rates of serious adverse events did not differ, although adverse events that led to drug withdrawal were more common at a dose of 1.25 mg/day (14%) compared with 0.5 mg/day (7.5%) and placebo (7.7%). The overall incidence of infections was similar; only lower respiratory tract infections were more common with fingolimod than with placebo; they occurred in 41 patients (9.6%) taking 0.5 mg/day, 49 patients (11%) taking 1.25 mg/day, and 25 patients (6.0%) taking placebo. Transient bradycardia 5 hours after the first dose was reported in nine patients taking 0.5 mg/day, 14 taking 1.25 mg/day, and three taking placebo. Electrocardiography showed first-degree atrioventricular block in 20 patients taking 0.5 mg/day, 37 taking 1.25 mg/day, and six taking placebo. At month 24, the mean systolic and diastolic blood pressures had increased by 1.9 and 0.7 mmHg respectively with 0.5 mg/day and by 3.6 and 2.1 mmHg with 1.25 mg/day, and had fallen by 0.4 and 0.5 mmHg with placebo. Macular edema was diagnosed in seven patients, all of whom were taking 1.25 mg/day; five of these occurred within 3 months of therapy. As expected on the basis of its mechanism of action, peripheral blood lymphocytes were reduced at 1 month by an average of 73% by 0.5 mg/day and 76% by 1.25 mg/day, and remained stable thereafter. There were transient increases in alanine aminotransferase activity in 8.5% of those taking 0.5 mg/day, 12.5% of those taking 1.25 mg/day, and 1.7% of those taking placebo.

In a 12-month, double-blind, randomized study in 1153 patients with relapsing-remitting multiple sclerosis, who were randomly assigned to either oral fingolimod 1.25 or 0.5 mg/day or intramuscular interferon beta-1a, the annualized relapse rate was significantly lower in those who took fingolimod [ ]. Bradycardia and atrioventricular block (observed after the first administration of fingolimod), increased blood pressure, reduced peripheral lymphocyte count, and transiently raised alanine aminotransferase activity were more common in those who took fingolimod [ ]. There were herpesvirus infections in 23 patients (5.5%) taking 1.25 mg/day, in nine (2.1%) of those taking 0.5 mg/day, and in 12 (2.8%) who took interferon. Two deaths were reported during the trial, both in those who were taking 1.25 mg/day; one was caused by disseminated primary varicella infection in a patient who was exposed to a child with chicken-pox during a course of high-dose glucocorticoids for a relapse of multiple sclerosis and the other was caused by herpes simplex encephalitis, which developed after 339 days of fingolimod therapy. Two other patients who took fingolimod 1.25 mg/day died after the study ended; one stopped taking fingolimod after 11 months because of neurological deterioration, and progressive multifocal leukoencephalopathy was ruled out; the other died from metastatic breast cancer 10 months after discontinuing fingolimod. Ten localized skin cancers were reported: five basal cell carcinomas in those who took fingolimod and one in the interferon group, three superficial melanomas in those who took fingolimod 0.5 mg/day and one squamous cell carcinoma in the interferon group. Breast cancer was reported in two patients in each of the fingolimod groups; three cases were diagnosed within 4 months after the start of treatment and one was diagnosed 11 months after enrolment.