Fingolimod for Relapsing/Remitting Multiple Sclerosis (RRMS)

PICHON RIVIERE, A.; AUGUSTOVSKI, F. A.; GARCIA MARTI, S.; GLUJOVSKY, D.; ALCARAZ, A.; LOPEZ, A.; BARDACH, A.; CIAPPONI, A; VALANZASCA, P

Fingolimod for Relapsing/Remitting Multiple Sclerosis (RRMS)

IECS

Año: 2012 p. 1 - 30

1668-2793

In Argentina, multiple sclerosis (MS) has an estimated prevalence of 18 cases every 100,000 inhabitants, being the second most common cause of neurological disability in young adults. It mainly affects women 30 years old in average. MS is characterized by the presence of repeated episodes of brain nerve tissue and spinal cord inflammation (relapses or bouts) followed by episodes of complete or incomplete recovery (remission). There are three main types of MS: Relapsing/remitting (RRMS), primary progressive (PPMS) and secondary progressive (SPMS). Eighty percent of the patients initially presents RRMS and within 10 to 15 years, approximately 50% develop SPMS. At present, the most commonly used drugs include Interferon β (IFN-β) and Glatiramer Acetate as standard therapy for RRMS. Fingolimod is proposed as alternative therapy for RRMS. Technology Fingolimod is an orally administered modulator of the sphingosine-1-phosphate receptor. It acts by decreasing the action of immune cells that may harm the Central Nervous System (CNS). In our country, it is under active pharmacovigilance because cardiovascular events and cases of death have been reported. Purpose To assess the available evidence on the efficacy, safety and coverage related issues regarding the use of fingolimod in patients with RRMS. Methods A bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems. Results Two Phase III clinical trials and two systematic reviews were found. In addition, data were reported about coverage policies from the health sponsors evaluated. One randomized controlled clinical trial (RCCT) published in 2010, with a 12-month follow-up, enrolled 1,292 patients with RRMS who had a score between 0 and 5.5 in the Expanded Disability Status Scale and who had suffered at least one relapse recently. Relapse was defined as onset of new neurological symptoms, progression or recurrence of the existing ones, at least 30 days after the latest relapse. Patients were randomized to receive fingolimod 0.5 mg/day, 1.25 mg/day or intramuscular IFN β-1a 30 µg once a week. The annual relapse rate was significantly lower in the fingolimod arm (16% for the 0.5 mg dose and 20% for the 1.25 mg dose) than in the IFN (33%) arm. No significant differences were found among the 3 groups regarding the time to disability progression. In the fingolimod 1.25 mg group, two deaths were observed due to disseminated infections. In 2010, another comparative RCCT against placebo was published which enrolled 1,272 patients similar to the previous study and with a 24-month follow-up. They were randomized to oral fingolimod 1.25 mg/day, 0.5 mg/day or placebo. The annual relapse rate was 18% (95% CI 15-22%) with the 0.5 mg, 16% (95% CI 13-19%) with the 1.25 mg and 40% (95% CI 34-47%) with placebo. Fingolimod at 0.5 mg and 1.25 mg significantly decreased the risk of disability progression during the 24-month period (HR 0.70; 95% CI 0.52-0.96 and 0.68; 95% CI 0.50-0.93, respectively). Those cases that were discontinued because of fingolimod occurred in the group receiving 1.25 mg and had common severe adverse effects such as heart conduction disorders and basal cell carcinoma. In 2012, one systematic review was published on the relative effectiveness of the different MS treatments. Three results were evaluated (1) relapse-free patients, (2) patients without disease progression, and (3) patients without imaging progression. Direct and indirect comparisons were made based on the studies found. Natalizumab (300 mg) and fingolimod (0.5 mg) were better than placebo in the 3 outcomes evaluated in the patients with RRSM (direct analysis). The study which compared fingolimod against IFN β-1a was not included since this was not considered a standard therapy. In the indirect analysis (IFN β-1b 250 µg reference treatment), it was observed that fingolimod 0.5mg and 1.25mg as monotherapy was significantly better than the comparator regarding the absence of relapses (OR 1.82 and 1.75, respectively). The rest of the results indirectly analyzed showed no superiority for fingolimod against IFN β-1b. Another systematic review performed in 2012 compared the annual relapse rate of fingolimod against first line therapy usually used in RRMS patients. Comparisons were made based on indirect analyses due to the lack of ?head to head? studies. Studies assessing fingolimod, INF β-1a, INF β-1b or glatiramer acetate were included. The relative annual relapse rate for each treatment compared against fingolimod was higher for the different treatments and at different doses. Most health sponsors recommend fingolimod in patients with RRMS. Due to its high cost, some health sponsors follow up the treated patient to assess response and therefore, treatment continuation. Conclusions There is evidence, although scarce, showing that fingolimod would have slightly better benefits than INF and glatiramer acetate. However, most studies use placebo as comparator and the systematic reviews are based on indirect methods to evaluate the efficacy of fingolimod versus the active treatment. It is worth mentioning that the cost of this treatment is high when compared to the benefits and adverse effects observed, and in some countries its use is not recommended. In other countries, its use in patients with RRMS is limited to the price/discount the manufacturer may give, in addition to monitoring its effectiveness in the patients treated to evaluate continuous treatment. On the other hand, there is concern about its safety due to the cardiovascular events and deaths reported since its long-term safety profile is unknown. Fingolimod is proposed as oral monotherapy and disease modifying drug in patients with highly active RRMS and who are refractory to IFN-β therapy.