Gilenya® (fingolimod, FTY720)

FDA-Approved Medications: Administered Orally

Company: Novartis Pharmaceuticals Corp.

  • Oral medication; 0.5 mg capsule taken once daily
  • Approved for relapsing forms of MS

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Gilenya is the first in a class of immunomodulatory drugs, called “S1P-receptor modulators.” It is similar in structure to a naturally occurring component of cell-surface receptors on white blood cells. Gilenya blocks potentially damaging T cells from leaving lymph nodes, lowering their number in the blood and tissues. It may reduce damage to the central nervous system (CNS) and enhance the repair of damaged nerves within the brain and spinal cord. Study data suggest that Gilenya may have neuro-protective effects.

Some adverse events with Gilenya include: an initial reduction in heart rate; infrequent changes in the conduction of electricity in the heart (atrioventricular [AV] block); macular edema (a condition that can affect vision, caused by swelling behind the eye); and infections, including reactivation of herpes infections. Following the death of a patient within 24 hours after taking a first dose of Gilenya in November 2011, the FDA conducted an investigation, and in April 2012, updated the prescribing guidelines for Gilenya.

Other deaths from cardiac causes have been reported from among the many thousands of people in several countries who have been treated with this medication. Contraindications now include a history or presence of cardiac conditions (such as myocardial infarction or stroke in the previous six months, second-and third-degree atrioventricular block, or other serious cardiac rhythm disturbances) or in patients treated with certain antiarrhythmic drugs.

The updated prescribing information recommends that all patients starting treatment should undergo electrocardiography immediately before the first dose and at the end of the initial six-hour observation period, along with hourly measurement of blood pressure and heart rate. Continuous cardiac monitoring must be performed in some cases. This “First Dose Observation” is part of a set of monitoring requirements that need to be completed when Gilenya is prescribed.

Study Information

The FREEDOMS Phase III study compared Gilenya with placebo and showed the drug to be safe and well tolerated. Gilenya reduced the risk of confirmed disability progression by 30 to 32 percent versus placebo, and significantly increased the proportion of patients who were disease-free over two years. It also resulted in a 30-percent reduction of brain-volume loss as compared with placebo at one and two years, suggesting a possible direct neuroprotective effect. A second Phase III study, FREEDOMS II, compared Gilenya with placebo, and reported similar results.

Two deaths from herpes virus infections occurred in the FREEDOMS trials; both of these individuals received a higher dose of fingolimod that is not FDA-approved or prescribed. No deaths from infections were reported in those individuals treated with the FDA-approved lower dose, which is the only dose available for MS patients.

The TRANSFORMS Phase III trial was a 12-month study of the efficacy of Gilenya as compared to Avonex in individuals with RRMS. In summary, Gilenya was more effective in reducing the annual relapse rate, resulted in less deterioration in the ability to independently perform daily activities, was associated with a lower rate of brain atrophy, and showed a greater effect on reducing MRI measures of lesion activity. No difference in progression of disability was demonstrated in this 12-month study.

In both the FREEDOMS and TRANSFORMS studies, Gilenya significantly reduced the frequency of severe relapses and the number of individuals who required intervention (steroids or hospitalization), along with reducing the number of relapses with no or only partial recovery. In the TRANSFORMS trial, Gilenya also consistently reduced the annualized relapse rate in patients with highly active MS as compared to Avonex.

Interim data were presented in 2013 from LONGTERMS,34 a single-arm, open-label extension study that began in June 2010 and will continue through June 2016. Clinical disease activity remained low for up to five years in patients treated with Gilenya, an interim data analysis indicates. Most patients remained relapse-free and disability remained stable for up to five years. Approximately 70 percent of patients continuing on Gilenya were relapse-free. As with many extension trials, individuals dropping out may have caused a “selection bias” favoring long-term use.

Several analyses35 of Gilenya’s clinical trials have demonstrated that Gilenya has significant effects on slowing brain atrophy in MS. In the TRANSFORMS trial, Gilenya significantly reduced brain volume loss over one year compared with Avonex, and in the FREEDOMS trials, Gilenya reduced brain volume loss over two years compared with placebo.

Intriguingly, in new research presented in 2013,36 patients on Gilenya who remained disease-free over 48 months were shown to have less brain-volume loss over the four-year study than those who were not disease-free. In addition, reduced brain-volume loss was associated with better clinical outcomes at month 48. These data suggest that the effect of Gilenya on slowing brain atrophy may have a clinical impact on preventing disability.

An Italian study37 confirms that the first dose of Gilenya is generally safe and well- tolerated; these results are consistent with results from previous trials. Data were collected from 812 Italian patients who were undergoing the required six-hour First-Dose Observation period following administration of Gilenya. Most patients (95.2 percent) did not have any adverse events during the six hours. Cardiovascular adverse events occurring in 18 patients were all self-limiting, and did not require intervention.

The six-month Phase IV EPOC38 study also presented data in 2013. This study was designed to evaluate: patient-reported outcomes; physician assessment of a change; as well as safety and tolerability in patients with relapsing MS, who had also been previously treated with other DMTs and are now receiving Gilenya. This study found that, based on the Treatment Satisfaction Questionnaire for Medication (TSQM), people with relapsing multiple sclerosis (MS) reported greater treatment satisfaction after starting the oral treatment Gilenya versus switching to, or staying on, one of the injectable DMTs (one of the interferons or Copaxone).

Although Gilenya was approved for RRMS in 2010, clinical trials have continued to evaluate its role in MS. The 36-month INFORMS trial evaluated the effect of Gilenya relative to placebo on delaying the time to sustained disability progression in patients with PPMS. As there is presently no FDA-approved medication for PPMS, this is an important study for the field.

The enrollment of 969 PPMS patients into the INFORMS trial was completed in 2011, and the trial’s data analysis was completed in 2014. Novartis announced by press release in December 201439 that unfortunately, the primary outcome of the study was not met: Gilenya did not show a significant difference from placebo on a combination of disability measures. Detailed data will be presented at the 2015 American Academy of Neurology meeting, and it is hoped that these data will yield further insight into the pathogenesis of PPMS.

Another ongoing Gilenya clinical trial is a Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone.40 This 12-month trial will compare the marketed dose of Gilenya with one-half this dose, using Copaxone as a comparison, on annual MS relapses and several MRI measures of disease. The goal of this study, which was required by the FDA, is to assess if a lower dose of this medication may be equally effective at preventing relapses. This study is expected to report data in 2015.

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