Awaiting FDA Review: MS Patient with PML on Gilenya after Tysabri

April 17, 2012

Novartis released a safety information update on April 13, 2012 stating that an individual with MS who was taking Gilenya® (fingolimod) was diagnosed with progressive multifocal leukoencephalopathy (PML). This infection of the brain has been associated with another treatment for MS, Tysabri® (natalizumab). Depending on the risk factors discussed below, a small number of MS patients may develop PML either while taking Tysabri or up to three months after discontinuing this drug.

According to Novartis, the individual had been given Tysabri for three-and-a-half years prior to starting Gilenya in December 2011, with a six-week break between the two treatments. The patient has been hospitalized since February 2012 and the diagnosis of PML was confirmed in April 2012.

The three main risk factors for PML for individuals taking Tysabri are:

• The presence of anti-JCV antibodies, which identifies a previous exposure to the JC virus
• Longer duration of Tysabri treatment, especially after two years
• Prior treatment with an immunosuppressant medication, such as mitoxantrone (Novantrone®), azathioprine (Imuran®), methotrexate, cyclophosphamide (Cytoxan®), or mycophenolate.

Novartis has informed MSAA that the individual who was taking Gilenya had two of these three Tysabri-related risk factors: testing positive for anti-JCV antibodies (which shows that the patient has been exposed to the JC virus) and taking Tysabri for more than two years. However, the individual had not been given other immunosuppressant medication prior to taking Tysabri.

In the safety update from Novartis, the company notes, "This is the first reported PML case in approximately 36,000 fingolimod-treated patients, of whom approximately 2,400 were treated for more than two years and approximately 500 were treated for more than four years. There is currently no confirmed case of PML reported to Novartis in a fingolimod-treated patient without previous natalizumab treatment... Details on the case are being submitted to health authorities according to regulations as they become available."

About PML
PML is a potentially fatal brain infection, caused by the activation of the JC virus (JCV), which is present in approximately 55 percent of individuals with MS. The JCV remains dormant in most individuals, but may become active in people with weakened immune systems - such as those taking a strong immunosuppressant. An individual who is anti-JCV antibody positive is at risk of developing PML, although a person who is negative could be exposed to the virus at any time.

Other Gilenya News
The risks and benefits of Gilenya, the first approved oral treatment for MS, are presently being re-evaluated by both the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), following the death of a patient within 24 hours of taking Gilenya (in December 2011). The cause of death has not yet been determined and physicians cannot confirm at this time whether or not Gilenya played any role in this individual's death.

Additionally, on April 5, 2012, the Institute for Safe Medication Practices (ISMP) included adverse events relating to Gilenya in its QuarterWatch™ publication. ISMP reviewed 286 adverse events that were reported to the FDA and included in the FDA's MedWatch Report (for the second quarter of 2011).

According to ISMP, of the 286 adverse events reported to the FDA, most notable are 60 cases of damage to the retina (inner membrane of the eye) and other adverse effects on vision. Additionally, 68 cases of infection were reported, including infections of the eye, skin, urinary tract, and upper respiratory tract. Potential vascular complications included 16 cases of blackouts or syncope (fainting), reduced blood pressure, 27 cases of slow heart rate or bradycardia, and 10 cases of peripheral edema (swelling of the legs, ankles, and feet).

The ISMP concludes, "The FDA and manufacturer should consider substantial restrictions on its [Gilenya's] use and enhanced monitoring, as is required for natalizumab (Tysabri). Insufficient data were available for this report to assess whether the risks and benefits of this drug are in balance."

Expert Commentary
MSAA Chief Medical Officer Dr. Jack Burks points out, "Speculations on adverse events with Gilenya (and other MS treatments) are widespread. Unfortunately, not enough data are available to the public to reach any definitive conclusions. The FDA and EMA have access to the true circumstances and data. I await their reports and recommendations before reaching any opinions. In the meantime, treatment discussions are best left to the patient and his or her doctor."

For More Information
Anyone with questions may contact Novartis at (888) NOW-NOVA (888-669-6682) or call MSAA's Helpline at (800) 532-7667.

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