Cardiovascular Risks With Oral Fingolimod for Multiple Sclerosis

Allison Gandey

April 21, 2011

April 21, 2011 (Honolulu, Hawaii) — Results from a pooled analyses of phase 3 clinical trials of fingolimod — the first oral agent for multiple sclerosis — show the drug has transient and long-term cardiovascular effects.

Reporting here at the American Academy of Neurology (AAN) 63rd Annual Meeting, investigators showed fingolimod increases the risk for hypertension. At initiation, physicians can also expect to see transient heart rate and atrioventricular conduction slowing.

Prescribing information for the Novartis product marketed as Gilenya already advises that patients be monitored for signs and symptoms of bradycardia for 6 hours after first dose. These new results confirm this recommendation and point to other longer-term risks.

"Transient heart rate reduction and atrioventricular conduction slowing are expected pharmacodynamic effects of fingolimod therapy initiation and were usually asymptomatic," John DiMarco, MD, from the University of Virginia Medical Center in Charlottesville, said at the meeting. "Rates of hypertension-related adverse events were higher with fingolimod than placebo."

Investigators pooled safety data from the original clinical trials. FREEDOMS, also known as FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis, included US Food and Drug Administration (FDA)–mandated safety measures.

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

The pooled analysis included 2552 people. Investigators found an increase in arterial pressure at 1 year and more hypertension-related adverse events in patients taking fingolimod.

Table. Increase in Arterial Pressure at 1 Year in FREEDOMS Patients

Outcome Fingolimod, 0.5 mg Fingolimod, 1.25 mg Placebo
Arterial pressure, mm Hg +1.1 +2.6 –0.5
Hypertension-related adverse events, % 6.1 6.3 3.8
Antihypertensive drug use, % 5.0 5.8 5.5

FREEDOMS = FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis

As anticipated, the researchers found that fingolimod was associated with a dose-dependent decrease in heart rate that reached its nadir 5 hours after dosing. Patients taking low-dose fingolimod had an average decline of 8 beats per minute. Those in the high-dose group had a decline of 11 beats per minute.

The atrioventricular conduction slowing was asymptomatic in most patients; however, 4 people received medication for bradycardia.

Dr. DiMarco said these changes tended to lessen with continued therapy and return to baseline levels by month 1. His team confirmed heart rate and electrocardiogram findings by 24-hour Holter monitoring in a subset of patients from TRANSFORMS (n = 129). Echocardiography, performed on some of these patients, revealed no relevant changes in left ventricular function (n = 33).

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.

Adverse Events

According to the FDA, 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.

At the ANA meeting in September, FREEDOMS investigators reported serious adverse events.

Gordon Francis, MD, head of the clinical science unit at Novartis, showed bradycardia in both low- and high-dose patients, multiple sclerosis relapse, basal cell carcinoma, chest pain, and macular edema. In the high-dose group, there were also 2 cases of epilepsy, headache, and lymphopenia.

When the FREEDOMS trial was first published in January 2010, 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."

Dr. Carroll told Medscape Medical News at the time of publication that 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.

This study was funded by Novartis. Dr. DiMarco received compensation from the company.

American Academy of Neurology (ANA) 63rd Annual Meeting: Abstract S41.007. Presented April 14, 2010.


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