Researchers Review Safety of Oral Fingolimod in Multiple Sclerosis

Allison Gandey

September 16, 2010

September 16, 2010 (San Francisco, California) — Excitement is building that a new oral agent will soon be available for patients with multiple sclerosis in the United States, but experts warn that enthusiasm about fingolimod should be tempered with vigilance about the potential risks of the new immunomodulator.

Treatment will require close monitoring, say investigators.

Presenting here at the American Neurological Association 135th Annual Meeting, Peter Calabresi, MD, a FREEDOMS trial investigator, acknowledged the strong efficacy numbers for fingolimod, but also its safety signals.

Dr. Calabresi at Johns Hopkins in Baltimore, Maryland, is principal investigator of the original phase 3 trial, also known as FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis, which has US Food and Drug Administration (FDA)-mandated safety measures. The new postmarketing phase 4 study is anticipated to include about 6000 patients.

"My personal feeling is that physicians should have access to this drug, but patients will have to be closely monitored," he said during an interview. "I am concerned about the dermatological effects, malignancies, and infections."

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

In another recent trial of fingolimod, 2 patients died of herpetic infections. The Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis, or TRANSFORMS, showed a benefit with fingolimod against interferon beta and against placebo, but the adverse events were significant. One patient died with disseminated primary varicella zoster, and another with herpes simplex encephalitis.

One problem, Dr. Calabresi said, is that neurologists may not feel entirely equipped to closely monitor the entire body to assess complications of the skin, cancers, and infections. Still, he says, "If you prescribe it, you're responsible for it." And he calls on clinicians to remain vigilant.

If you prescribe it, you're responsible for it.

Gordon Francis, MD, head of the clinical science unit at Novartis, is in negotiations with the FDA for approval of fingolimod and told Medscape Medical News that he is expecting to hear from regulators before the end of the month.

After receiving a unanimous vote in favor of approval from an FDA advisory committee, many are speculating the drug will be given the green light to market. Novartis plans to promote fingolimod as Gilena.

Dr. Gordon Francis

In a poster presentation here at the meeting, Dr. Francis reviewed safety data in FREEDOMS that have since been analyzed more closely. A great number of questions have been put forward by physicians, he told Medscape Medical News, and the company took this opportunity to field some of them.

The 2-year FREEDOMS trial involved 1272 patients with relapsing-remitting multiple sclerosis. Patients were randomly assigned to receive placebo or fingolimod 0.5 mg or 1.25 mg.

Investigators found that the annualized relapse rate was significantly reduced with both doses of fingolimod vs placebo. The relapse rate was 0.18 with the lower dose and 0.16 with the higher dose compared with 0.40 with placebo (P < .001; N Engl J Med. 2010;362:387-401).

The risk for disability progression was reduced with fingolimod in both doses, with hazard ratios of 0.70 for the low dose and 0.68 for the high dose (P = .02) The cumulative probability of disability progression confirmed at 3 months was 17.7% for those receiving the lower dose, 16.6% with the higher dose, and 24.1% with placebo.

However, adverse effects were in some cases serious. Dr. Francis also acknowledges that close monitoring will be necessary for patients receiving treatment.

Table. Serious Adverse Events in FREEDOMS I Trial

Event Placebo (n = 418) Fingolimod 0.5 mg (n = 425) Fingolimod 1.25 mg (n = 429)
Bradycardia 1 4 3
Multiple sclerosis relapse 1 4 3
Basal cell carcinoma 3 4 1
Chest pain 2 4 0
Macular edema 0 0 3
Breast cancer 3 0 1
Abnormal liver function 1 0 2
Depression 1 0 2
Back pain 1 2 0
Urinary tract infection 0 2 0
Epilepsy 0 0 2
Lymphopenia 0 0 2
Headache 0 0 2

When the FREEDOMS trial was first published in January, William Carroll, MD, from Sir Charles Gairdner Hospital in Perth, Australia, wrote an accompanying editorial. "Clinicians and patients will need to evaluate the risks and benefits," he noted. "Given the recent studies documenting the development of progressive multifocal leukoencephalopathy among patients receiving natalizumab...close postmarketing surveillance will be important to detect any increase in these or other unexpected adverse effects."

In an interview at the time of publication, Dr. Carroll said that when these drugs become available, it is likely that neurologists will be under a lot of pressure from the "needle-phobic" patient to move to an oral drug. Still, he said, the adverse effect profiles appear to be more serious than those of currently available drugs and are simply not completely known as yet.

Timothy West, MD, from the University of California–San Francisco, who gave a presentation at the meeting on the challenges with natalizumab, agreed there will be challenges as well with fingolimod.

"I believe the new drug should be used second line, similar to natalizumab," he said. "The safety is not entirely certain, and it will take a long time to determine. For patients who are doing well on injections, they should stay on them because we know they're relatively safe."

Asked by Medscape Medical News to comment, William Sheremata, MD, from the University of Miami in Florida, said that physician and patient education will be necessary if fingolimod is approved. "I'm very concerned about its safety profile," he said.

Can clinicians expect another TOUCH program similar to the one designed for natalizumab? "I don't think so," Dr. Calabresi said. "But we'll have to see what the FDA decides."

The FREEDOMS Trial and subsequent analyses were supported by Novartis Pharmaceuticals. Dr. Peter Calabresi has received financial support from the company, and Dr. Gordon Francis is an employee of Novartis.

American Neurological Association 135th Annual Meeting: Posters T-70 and T-75. Presented September 14, 2010.

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