ARTICLE IN BRIEF
The FDA approval of the first oral therapy for MS fingolimod has generated excitement in the field, but the FDA advises clinicians to monitor for certain possible adverse events.
On Sept. 22 the FDA approved fingolimod, the first multiple sclerosis (MS) oral therapy, for use in patients with relapsing forms of MS.
Fingolimod binds to the sphingosine 1-phosphate receptor-1 (SIPI) on some lymphocytes, trapping them in the lymph nodes. It produces a reduction in the number of active T-cells circulating to the CNS, which decreases neuroinflammation and also CNS damage.
“The approval will have a tremendous impact on MS treatment because it offers a new mechanistic approach to the treatment of the disease,” said Bruce A. Cohen, MD, professor of neurology and Director of the MS program at the Feinberg School of Medicine at Northwestern University. “It also provides an acceptable form of treatment for patients who are unwilling to take current therapeutics or have failed other therapies. Many people have injection phobias and this treatment offers an alternative.”
The MS world has long anticipated fingolimod's approval, added John Corboy, MD, professor of neurology at the University of Colorado-Denver and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus. “Once we saw the clinical trial data and the FDA review committee's unanimous recommendation of its approval [in June], it was essentially considered a fait accompli that it would be approved.”
The FDA approved the 0.5 mg dose of fingolimod based on the results of two phase 3 clinical trials: TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in RelapsingRemitting Multiple Sclerosis) and FREEDOMS (FTY720 Oral in Relapsing-Remitting Multiple Sclerosis).
TRANSFORMS investigators randomized 1,292 patients to 0.5 mg or 1.25 mg of fingolimod daily, or interferon beta 1A. Researchers found an annualized relapse rate of 0.16 in the 0.5 mg group and 0.20 in the 1.25 mg cohort (52- and 38-percent relapse reduction rates, respectively).
In FREEDOMS, investigators randomized 1,033 patients to 0.5 mg or 1.25 mg of fingolimod or placebo. An annualized relapse rate of 0.18 was reported in patients taking 0.5 mg of fingolimod compared to 0.16 in patients taking 1.25 mg (54- and 60-percent relapse reduction rates, respectively).
(Read the Feb. 18, 2009 Neurology Today story, “Two Oral Therapies Found Effective for MS” online: http://bit.ly/aqdmCy)
The FDA advised that patients using fingolimod be monitored for bradycardia during the first six hours of being given the drug, according to an FDA news release. In addition, patients should receive an ophthalmologic evaluation prior to starting treatment due to the risk of developing macular edema, which occurred in some patients. (See “Possible Adverse Events”)
“We haven't seen any specifics from the FDA or [fingolimod manufacturer, Novartis] on how to do the monitoring,” said Dr. Corboy. “Can the patient be left alone in the office for six hours, or do they need to be hooked up to telemetry, where they're having a continuous EKG? And does an EKG need to be done on all patients, or only those with a history of heart disease?”
He added that most of these decisions will most likely have to be made according to individualized practices.
Aaron E. Miller, MD, chief medical officer of the National MS Society and director of the MS Center at Mt. Sinai Medical Center in New York City, said he will prescribe fingolimod conservatively as more safety data are gathered during the post-marketing period. However, “if the safety profile looks good, then almost any patient with the relapsing form of MS would be a good candidate” for its use — even patients who are doing well on their injectable forms of disease-modifying therapy, he added.
Dr. Cohen advised that neurologists will have to be cognizant of possible later emerging side effects that weren't identified in the clinical trials and may come to light with more widespread use of the agent.
All the experts who spoke to Neurology Today were encouraged by fingolimod's approval and its subsequent impact on MS treatment.
“The treatments that we presently have aren't as good as we would like them to be: they aren't cures, and they're not tolerated or adequate enough for a variety of patients,” said Dr. Corboy. “I'm happy to have another treatment option available and look forward to learning more about it as it goes into general use. I anticipate it will have a significant role in the armamentarium in treating MS patients.”
FINGOLIMOD: POSSIBLE ADVERSE EVENTS
The following are possible adverse events associated with fingolimod. Dr. Corboy noted that the majority of these side effects were more significant at the higher, 1.25mg dosage, which was not approved by the FDA.
* Heart Block
* Increased blood pressure
* Macular edema
* Restrictive lung disease
* Liver function abnormalities
* Influenza and other infections
Kappos L, Radue EW, Burtin P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362(5):387-401; E-pub 2010 20 Jan.
Cohen JA, Barkhof F, Kappos L, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362(5):402-415;E-pub 2010 20 Jan.