Novartis’ Gilenya still deemed safe despite EMA-initiated review of deaths

Novartis’ (NYSE:NVS) multiple sclerosis (MS) drug Gilenya is still backed by clinicians in the US, despite the European Medicines Agency’s (EMA) recent initiation of a review of its risk/benefit profile, according to neurologists interviewed by BioPharm Insight.

The review follows concerns over the effects of the drug on the heart after the first dose and the death of a US-based patient less than 24 hours after receiving the first dose of Gilenya, for which the cause remains undetermined, according to EMA issued statements.

The agenda of the Committee for Medicinal Products for Human Use (CHMP) meeting is confidential, said an EMA spokesperson. The CHMP committed to finalize the review by March and any outcome will be communicated after the end of the meeting either on 15 or 16 March, she said.

An FDA spokesperson said the agency has been in touch with EMA, and is still evaluating all data relevant to this issue. “We have not made any determinations about what regulatory actions, if any, are necessary, and have not yet determined whether any new monitoring recommendations are necessary,” an FDA spokesperson responded via e-mail.

“We will notify the public once our review is complete to communicate any recommendations or possible label changes. There is no set timeline at this point,” the FDA spokesperson added.

In the United States, Gilenya is approved for relapsing forms of MS. In the European Union, Gilenya is approved for people with highly active relapsing-remitting MS despite treatment with beta interferon, or in patients with rapidly evolving severe relapsing-remitting MS, according to a Novartis spokesperson.

Gilenya has been available in the EU since March. As the review is underway, clinicians have been advised to increase monitoring of patients after the first dose by way of electrocardiogram (ECG) before treatment and for the first six hours after the first dose, along with measurement of blood pressure and heart rate every hour. After six hours, patients with bradycardia or atrioventricular block must be managed and monitored until improvements are seen. This level of monitoring is already included on the drug’s label as an advisory precaution.

However, Dr Samuel Hunter, a neurologist at the Advanced Neurosciences Institute in Tennessee, who said Gilenya has a lot of patient data, added this decision is likely an overreaction to recent deaths. Novartis has conducted extensive cardiac trials, he said. Most of the recent deaths were in sicker patients, and therefore not unexpected as these are patients who were largely excluded from clinical trials, he noted.

Dr Daniel Kantor, a neurologist based in Florida, said the FDA is taking a better stance, and the EU is “gut reacting.”

In addition to the US death, six other unexplained deaths, including three cases of sudden death, have also been reported. Other reports include three deaths due to heart attack and one due to disruption of the heart rhythm. Currently, it is not clear if these were caused by Gilenya or not, according to EMA documents. Hunter noted that this rate is not out of range for a deadly disease such as MS. Mortality in women with MS is generally three-times greater than healthy individuals, he added.

Gilenya is not currently used as a first-line therapy, noted Dr William Chow, neurologist, Cedars-Sinai Medical Center, Los Angeles, who said newly diagnosed patients are directed toward platform therapies. Gilenya is recommended for needle-phobic patients, who represent less than 10% of patients, he estimated.

According to one neurologist, Novartis has stated that the deaths occurred in patients with more advanced disease. The neurologist said patients were ambulatory, so death was likely attributable to a heart condition, with one patient dying in hospice and should not have been treated with this agent to begin with.

Gilenya is approved for the treatment of relapsing-remitting MS in patients whose disease has failed to respond to a beta-interferon or is severe and worsening.

Patients deemed candidates for Gilenya generally go through the pre-screening process without difficulty, Chow said.”I would still caution patients who are currently doing well on the immune modulators or who are newly diagnosed not to seek the new drugs based on better tolerance,” he said.

According to a National MS Society spokesperson, patients are advised by the organization to follow the label with care. It is difficult to predict whether the deaths were drug-related as the investigation is still ongoing, said the spokesperson.

These cases are within the range expected in the general population but require further analysis, said Dr Aaron Miller, chief medical officer, National Multiple Sclerosis Society and a professor of neurology at Mount Sinai School of Medicine in New York. Miller said he is making patients aware of the situation, but added the current information does not warrant a recommendation to terminate therapy. The medical community is awaiting the FDA review as well as further information regarding cardiac monitoring and statistical analyses from Novartis, he said.

“My view is the EMA recommendation is perhaps premature. I’m not sure that it really necessarily addresses the problem because we don’t really know whether any of these deaths would have been prevented by monitoring,” Miller said, explaining that only one of these deaths occurred near the first dose of administration.

One industry source claimed that some neurologists have not been drug’s label instructions exactly, resulting in complications.

Novartis did a “wonderful job” that was way beyond what neurologists thought was necessary with cardiac monitoring, said Hunter. There was continuous ECG monitoring during the trials, he noted. The drug is appropriately labeled, and there are rare risks of heart blockage, Hunter said. It is not inconceivable that someone with CV risk could be at increased risk for death on this drug, he said.

However, this was not seen in a very carefully done, controlled setting, which included thousands of patients in research trials, Hunter said. More than 30,000 patients have received Gilenya worldwide, according to the EMA.

Some clinicians have been reluctant to use Gilenya due to these reports, said Dr Daniel Ontaneda, a neurologist at the Cleveland Clinic. Still, he said in his experience, more than 500 patients have been treated at the Cleveland Clinic without any reports of cardiac adverse events. Data will be presented at AAN showing that in about 400 patients, there were no significant cardiac adverse events, he said, adding that in his experience, Gilenya is well tolerated in the first-dose observation in the first 24 hours.

The discontinuation rate is around 10% at three months, which is slightly higher than what would be expected for an oral therapy, Ontaneda said.

Adverse events observed during first dose observation, which includes the first six hours after initial treatment, were low in frequency, he said. He said this three month discontinuation rate was mostly due to side effects and not reimbursement issues or relapses. The most frequent side effects in their cohort included headache, nausea, hypertension, and macular edema, he said.

Patients treated with beta-blockers, calcium channel inhibitors and those with structural heart defects were included in the Cleveland Clinic experience. The data will also be submitted for publication, he said.

The 11 deaths are concerning and a useful number to provide to patients when comparing Gilenya to Tysabri, Ontaneda said. The issue must continue to be monitored as more details are needed, he said, noting he suspects they were cardiac related.

The biggest side effect associated with Gilenya is complications with vision, Hunter said. The visual problems, which are known and will occur regularly, are usually transient and affect less than 1% of the patients, he added.

There is clear evidence that Gilenya causes macular edema, said Dr Kiran Turaka, ophthalmologist, Associated Retina Consultants in Arizona, who recently published a case report (J Neurol. 2012 Feb;259(2):386-8). In her experience, a patient with relapsing remitting MS who had been treated with Gilenya for three months presented with clinical cystoid macular edema. When evaluated for all possible causes of macular edema, the only possibility was related to Gilenya, she said, noting the occurrence in Phase I and II studies with the drug. When therapy was terminated and the patient was treated with corticosteroids, there was complete resolution of the macular edema as confirmed by optical coherence tomography, she said.

According to Turaka, the incidence of macular edema associated with Gilenya is very rare and was seen in 0.4% of the population in previous studies but there is clear evidence that the drug does cause macular edema.

In clinical trials, macular edema occurred in 0.4% of patients who received Gilenya 0.5 mg, predominantly within the first three to four months, according to a Safety Information Guide reviewed and approved by the FDA.

If there are some drug-related side effects that caused these deaths, then there will be more stringent scrutiny around administration of Gilenya, Chow added. With new drugs, clinicians have a lot more to do in terms of saf guarding patients and also a greater responsibility to get patients on the right therapy, he added.

When asked whether patients and neurologists will opt to wait until BG-12, an oral MS pill in development that is not as immunosuppressive reaches the market, instead of starting new patients on Gilenya, Miller said doctors have had varying views on Gilenya. “It depends on the doctors, rather than on the patient. Many doctors are more conservative on Gilenya when there are other options for patients. They are waiting for more safety data. I think we still need further clarification,” he said.

He said he remained unsure whether conservative physicians are going to change their views on Gilenya much by the recent deaths. On the other hand, physicians who were potentially prescribing Gilenya as a first line drug, or for the patients who requested to be switched off injectables to Gilenya because its an oral pill – they may take a more conservative view.

Original Article