Fingolimod Receives FDA Approval as First Oral MS Treatment

September 22, 2010 — The US Food and Drug Administration (FDA) today announced approval of fingolimod (Gilenya, Novartis), the first of the long-anticipated oral treatments for multiple sclerosis (MS). Fingolimod is approved to reduce relapses and delay disability progression in patients with relapsing forms of MS, an FDA release notes.

"Gilenya is the first oral drug that can slow the progression of disability and reduce the frequency and severity of symptoms in MS, offering patients an alternative to the currently available injectable therapies," Russell Katz, MD, director of the Division of Neurology Products at the Center for Drug Evaluation and Research, said in the FDA statement.

Patients should be monitored for bradycardia when starting fingolimod therapy, and treatment is also associated with an increased risk for infection, the release adds. Macular edema has also occurred, and ophthalmologic evaluation is recommended for those taking the drug.

A release from Novartis adds that fingolimod has been approved with a Risk Evaluation and Mitigation Strategy (REMS) to "inform patients and healthcare providers on the safe use and serious risks of Gilenya in treating relapsing forms of MS. The approved REMS includes a medication guide for patients and a letter and safety information guide for healthcare providers."

The company has also initiated a 5-year, worldwide postauthorization safety study to monitor particular safety outcomes and a voluntary pregnancy registry to provide more data on use of fingolimod in women with MS who are pregnant or may become pregnant.

The approval was largely expected after fingolimod received a unanimous endorsement from the FDA's Peripheral and Central Nervous System Drugs Advisory Committee in June.

Given orally, fingolimod acts as a superagonist to sphingosine-1-phosphate receptors on the surface of thymocytes and lymphocytes, reducing the overall number of circulating lymphocytes available to mount an autoimmune reaction to the myelin sheath surrounding axons in MS.

The most frequent adverse reactions reported by patients taking fingolimod in clinical trials include headache, influenza, diarrhea, back pain, elevation of liver enzyme levels, and cough, the FDA statement notes.

Fingolimod was approved in the 0.5-mg dose, the lower of 2 doses investigated in phase 3 trials. The FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial and the TRial Assessing injectable interferoN vS FTY720 Oral in RrMS (TRANSFORMS) showed benefit with fingolimod against placebo and against interferon beta, respectively, in reducing relapse rates and new or enlarging lesions on magnetic resonance imaging.

In FREEDOMS, with 24 months of follow-up, there was also less risk of progression of disability with fingolimod vs placebo. The trials were both published in the January 20, 2010, issue of the New England Journal of Medicine.

Two deaths were seen during the TRANSFORMS study, both in the higher-dose group; 1 death was attributed to disseminated primary varicella zoster and the other to herpes simplex encephalitis. Other adverse events with fingolimod in that study included nonfatal herpes virus infections, skin cancer, and elevated liver enzymes.

In FREEDOMS, causes of study discontinuation included bradycardia and atrioventricular conduction block with fingolimod on drug initiation, macular edema, elevated liver enzymes, and mild hypertension. No increase was seen in cancer risk, although the researcher cautioned that longer follow-up is necessary because the risk for cancer is potentially increased by any immunomodulatory agent.

A "Significant Step"

A statement from the National MS Society (NMSS) "applauds" the approval.

"The FDA's approval of the first oral disease-modifying therapy is a significant step for people with MS and helps address the unmet need for additional therapies," said NMSS Chief Medical Officer Aaron Miller, MD, professor of neurology and medical director of the MS Center at Mount Sinai Medical Center in New York City.

The release cautions though that the long-term safety of the drug is unknown. "Other phase 3 clinical trials of fingolimod, including one involving people with primary progressive MS, are still under way, as are extension studies involving those who've completed fingolimod trials," the NMSS release notes. "These and other postmarketing studies should provide additional data on the safety and efficacy of fingolimod."

Loren Rolak, MD, at the Marshfield Multiple Sclerosis Center, part of the Marshfield Clinic in Wisconsin, who was not involved in the fingolimod trials and has no relevant conflicts of interest, commented on the approval for the NMSS.

In discussing with his neurologist colleagues how the drug will be used in practice, Dr. Rolak says, "I've found a pretty wide range of opinion frankly." Some plan to approach use of fingolimod conservatively, since side effects in these trials, although fairly rare, were still serious, even fatal, which will give many pause. Others appear to be taking a more liberal view, he said, particularly since it has been shown to be not only as good as but better than standard therapy in TRANSFORMS.

The advantage of an oral formulation is obvious; for a start, it will mean being able to offer effective therapy to the patient who for whatever reason will not consider current treatments. "That has been a real barrier to treating MS," he said. Having an oral alternative is "going to be a real asset." But the decision will basically be up to neurologists and MS patients. "The FDA-approved fingolimod in a very open way — that is, there are no restrictions on doctors as far as who you can prescribe it for," Dr. Rolak told Medscape Medical News. "You don't have to have failed other treatments, for example, or be at a certain stage in your illness or anything like that, so there will be newly diagnosed, otherwise healthy patients doing well who will immediately go on fingolimod, and it will therefore supplant the current treatments that we have now," he said.

A lot of experts, though, will probably stick with well-known standard therapies to begin with. "They're shots unfortunately, but they're safe and effective and maybe reserve the fingolimod for people who are more advanced and having more problems or failing conventional therapy."

Lily Jung Henson, MD, director of the neurology clinic at the Swedish Neuroscience Institute/Swedish Physicians Division, Seattle, Washington, and member of the American Academy of Neurology, is one of those who leans conservatively.

"It's exciting to have the first oral agent," she told Medscape Medical News in an emailed comment. "Obviously it is important to figure out who is the right patient for this drug. If someone is stable on their current meds, it would not be advisable to make a change," she added. "We also have to figure out the logistics of how to monitor patients, particularly monitoring heart rate with first dose for 6 hours."

Other Oral Agents on the Way

Cladribine (Merck) was also in the race for first oral agent for the treatment of MS in the United States. Although the drug was previously granted fast-track status by the FDA in 2006, the agency refused to file the company's new drug application in November 2009 amid speculation about "tabulation errors" and potential safety concerns. In August 2010, however, the FDA accepted the company's application and granted it priority review.

Cladribine was recently approved in Russia and Australia and is under review by the European Commission and other regulatory agencies.

Other oral MS treatments in development include laquinimod (Teva), teriflunomide (Sanofi-Aventis), and BG-12 (Biogen