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Monday, June 24, 2013 4:07 PM | Tony Miles Volg link

Gilenya (pronounced as "Jil-EN-ee-ah") is the first in a new 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. (White blood cells are produced by the immune system to fight infection and disease.) 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 of Gilenya compared with placebo 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, evaluated safety, tolerability, and efficacy of Gilenya compared 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 weekly intramuscular injections of 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 those that required intervention (steroids or hospitalization), and reduced the number of relapses with no or partial recovery. In the TRANSFORMS trial, Gilenya also consistently reduced the annualized relapse rate in patients with highly active MS as compared to Avonex.

The six-month Phase IV EPOC study also concluded in 2012. 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. These outcomes will be compared to those who continue to receive one of the other approved DMTs (and are not taking Gilenya). The study enrolled approximately 1,000 participants and concluded in Fall 2012. Study results are anticipated in 2013.

Although Gilenya was approved for RRMS in 2010, several large clinical trials of this medication are still ongoing. The 36-month INFORMS study in 951 individuals will evaluate the effect of Gilenya relative to placebo on delaying the time to sustained disability progression in patients with PPMS. It will also evaluate safety, tolerability, and the effects on MRI parameters. As there is presently no medicine FDA-approved for PPMS, this is an important study for the field. The INFORMS trial is fully enrolled, and is expected to be completed in the fall of 2014.

Another ongoing Gilenya clinical trial is a Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone.15 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 run through 2014.