FDA Approves First Oral Treatment for Relapsing Forms of MS

A New Disease-Modifying Therapy for MS
Novartis Pharmaceuticals Corporation announced today that the United States Food and Drug Administration (FDA) has approved Gilenya® (fingolimod) as a first-line treatment for relapsing forms of multiple sclerosis (MS). Gilenya is the first oral disease-modifying therapy available for the long-term treatment of MS. The approval of a treatment that may be taken orally (by mouth), versus injection or infusion, is exciting news for members of the MS community.

Seven other disease-modifying therapies (including two identical drugs marketed under different brand names) have been previously approved by the FDA and are presently available by prescription. These are given via self injections at the patient’s home or by infusion at a medical facility.

Gilenya (pronounced as "Jil-EN-ee-ah") presents a new option for individuals with MS. While many members of the MS community presently take one of the previously approved disease-modifying therapies and are doing very well on these therapies, not everyone responds to or is able to tolerate these medications. Particularly for these individuals, and for people who are uncomfortable with injections and/or experience injection-site reactions, the prospect of a new oral medication for MS is very encouraging.

MSAA Chief Medical Officer Dr. Jack Burks explains, "Gilenya represents the first FDA-approved oral drug for MS, which will provide additional opportunities to greatly help many people affected by this disease. The effectiveness data for Gilenya is very impressive. The MS world is excited to add this new class of drug in an oral capsule. However, patients and their doctors must realize that new classes of drugs come with new types of side effects that will require attention. Learning about these adverse events and how to minimize them are an important consideration in deciding if this drug is right for each individual patient."

Administration, Therapeutic Action, Efficacy, and Other Oral Drugs in the Pipeline
This new oral drug will be available by prescription in early October. The dose is a single 0.5 mg capsule taken once daily, with or without food. Since it has been approved as a first-line treatment, doctors may prescribe this medication as a first disease-modifying therapy for MS; in other words, a patient does not need to try other treatments prior to starting on Gilenya.

Formerly known as "FTY720," Gilenya 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. Gilenya blocks potentially damaging T cells from leaving lymph nodes, lowering their number in the blood and tissues. It may also reduce damage to the central nervous system (CNS) and enhance the repair of damaged neurons. Additionally, animal data suggest that this drug may provide neuroprotective effects. If treatment with Gilenya is discontinued, white blood cells are no longer retained in the lymph nodes and they return to circulation in the body.

Gilenya has been shown to reduce relapse rate and delay the progression of disability, as well as reduce brain lesion activity and brain volume loss as seen on magnetic resonance imaging (MRI), when compared to control groups given a placebo. In addition, in a one-year study, Gilenya compared favorably over interferon beta-1a (Avonex®).

Gilenya is one of five oral medications that have been recently under investigation for the treatment of MS. These include oral cladribine, which has been given Fast Track status by the FDA and may be approved later this year or in early 2011, and oral laquinimod, which has been given Fast Track status as well. Additionally, the developers of oral teriflunomide have recently announced positive data from their pivotal trials, while oral BG-12 (dimethyl fumarate) is also in phase III studies with the hopes of filing for FDA approval in the near future.

Clinical Trial Information
The information in this section is an excerpt from the upcoming cover story, "Multiple Sclerosis Research Update." The full cover story will appear in MSAA’s Summer/Fall 2010 issue of The Motivator, due out in late October. The "Multiple Sclerosis Research Update" was written by Diana M. Schneider, Ph.D and reviewed by MSAA’s Chief Medical Officer Jack Burks, MD. The information to follow is an overview of some of the pivotal trial results for Gilenya.

The FREEDOMS Phase III study of low-dose (0.5 mg) and high-dose (1.25 mg) Gilenya (fingolimod) versus placebo is scheduled to end in March 2011. Outcome measures to date show the drug to be safe and well tolerated. Interim data show a 60-percent reduction in annualized relapse rate, a significant reduction in disability progression, a 74 to 82-percent reduction in the burden of disease as measured by MRI, and a reduction in whole-brain atrophy.

An extension study, FREEDOMS II, evaluated long-term safety, tolerability and efficacy; all 1,080 participants received Gilenya. Two deaths resulted from Herpes virus infection in the FREEDOMS trials; both of these individuals had received a higher dose than that submitted to the FDA. No deaths were reported in lower-dose group, which used the same dose as approved by the FDA.

The TRANSFORMS Phase III trial was a 12-month study of the efficacy of two doses of Gilenya (0.5 mg and 1.25 mg) as compared to weekly intramuscular injections of Avonex in individuals with RRMS. Its primary outcome measure was a reduction of relapse rate. Secondary measures include frequency of relapses, inflammatory disease activity as measured on MRI, and time to progression of disability.

In the TRANSFORMS trial, the annualized relapse rate was lower with Gilenya 0.5 mg (0.16) versus Avonex (0.33) at 12 months. The proportion of relapse-free patients was also higher with Gilenya. In summary, Gilenya was more effective in reducing relapse rate and relapse frequency, 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.

Another new clinical trial began in April 2010. It has 1,850 participants, all of whom are receiving Gilenya. This trial is scheduled for completion in April 2011. The primary outcome measure is the safety and tolerability profile in patients with relapsing forms of MS. Secondary measures include the incidence of macular edema (swelling behind the eye) and any changes in heart rate or function as seen on an electrocardiogram. Secondary measures also include patient-reported outcomes based on surveys of health status and treatment satisfaction.

The 36-month INFORMS study in 940 individuals is the only trial now ongoing for PPMS. It will evaluate the effect of Gilenya relative to placebo on delaying the time to sustained disability progression, as well as safety, tolerability, and the effects on MRI parameters.

Side Effects, Adverse Events, and Precautionary Steps to Minimize Risks
These oral medications offer the advantage of not requiring injections or infusions, as with drugs approved prior to September 2010. Oral medications do not cause related side effects such as injection-site reactions and flu-like symptoms. However, these new drugs are not without potential side effects and adverse events, which need to be discussed with one’s healthcare provider prior to making any treatment decisions.

The most commonly reported side effects with Gilenya include headache, flu, diarrhea, back pain, abnormal liver tests and cough. Women are strongly advised to use contraception to avoid pregnancy while taking Gilenya – and to continue contraception for two months following the discontinuation of Gilenya. Although no studies have been conducted to see the effects of pregnancy with humans while taking Gilenya, animal studies suggest that it could cause fetal harm. Researchers also do not know if the drug is passed through breast milk, so the makers of Gilenya also strongly advise against breast feeding.

Adverse events with Gilenya include: a reduction in heart rate (dose-related and transient); infrequent transient AV conduction block of the heart; a mild increase in blood pressure; macular edema (a condition that can affect vision, caused by swelling behind the eye); reversible elevation of liver enzymes; and a slight increase in lung infections (primarily bronchitis). Infections, including herpes infection, are also of concern.

A number of precautionary steps have been put in place to minimize risks and enable doctors to better evaluate and treat any possible adverse events. Within six months prior to starting Gilenya, patients should be given a baseline evaluation for any issues with the heart, lungs, liver, eyes and vision, as well as white-blood-cell count (which may indicate an existing infection). Present medications also need to be considered. Vitals (blood pressure, pulse, etc.) should be taken at baseline and periodically while on treatment.

Since the drug causes a reduction in circulating white blood cells, individuals considering Gilenya also need to indicate if they have had chicken pox or a chicken pox vaccination recently; if so, they may need to wait before starting the medication. Individuals who test negative for the chicken pox virus may need to be vaccinated and delay starting Gilenya. Patients will also need to avoid vaccinations with live viruses.

When beginning the drug, patients must be observed at a medical facility for the first six hours following the first dose. This is necessary as Gilenya may slow the heart rate, with the most significant drop usually occurring within the first six hours. While taking this drug, patients need to contact their doctor immediately if they experience any symptoms such as dizziness, tiredness, slow or irregular heartbeat, breathing difficulties, visual changes, or signs of an infection or liver problem.

If an adverse event occurs, the treating physician may determine the best follow-up treatment. In the case of an infection, in studies, Gilenya was usually discontinued for two weeks. No withdraw issues occurred, however, when restarting the drug, patients need to be observed again for the first six hours following the first return dose. In studies, macular edema occurred in a small number (0.4 percent) of those treated with the approved dose. In such instances, study protocol required patients to discontinue Gilenya and the condition generally improved or resolved afterward in most but not all cases.

A Risk Evaluation and Mitigation Strategy (REMS) has been approved to provide information to patients as well as healthcare professionals on how to use the drug safely, along with possible risks that may occur. Novartis will conduct a five-year observational safety study to further evaluate any adverse events. They have also organized a voluntary registry for women who become pregnant while taking or within two months after discontinuing this drug to document possible effects.

For More Information
Both patients as well as medical professionals are encouraged to visit Gilenya’s website at www.gilenya.com for more detailed information on this new treatment. Individuals may also call Gilenya’s Patient Service Center at (877) 408-4974 for more information. The Patient Service Center can also provide advocacy with insurance claims as well as financial assistance to those who qualify.

For more information on MS and its treatments, please call MSAA’s Helpline at (800) 532-7667.

Written by Susan Wells Courtney, MSAA Senior Writer
Reviewed by Jack Burks, MD, MSAA Chief Medical Officer