The non-profit issued this recommendation after reviewing adverse events that were reported to the FDA during the second quarter of 2011, shortly after the drug was approved. "Problems of widespread toxicity that were already evident in clinical testing of (Gilenya) are now producing strong signals in the postmarket adverse event data," ISMP writes in its latest Quarter Watch report on drug safety.
Among 286 reports were 60 cases of retinal injuries and other adverse effects on vision. There were 68 reports of infections at various sites including the eye, skin, urinary and upper respiratory tracts. And there were complications of its vascular adverse effects: 16 cases of blackouts or syncope, 27 cases of reduced blood pressure, slow heart rate or bradycardia, and 10 cases of peripheral edema.
While acknowledging that Gilenya offers advantages because the drug is the first pill for multiple sclerosis and has a novel mechanism of action, the non-profit argues that clinical testing prior to FDA approval "revealed a troubling safety profile that might have halted the development of drugs for many other disorders with a less serious long-term prognosis."
Specifically, ISMP points to a decision by Novartis to discontinue a 1.25 mg dose because of serious adverse events that included two deaths from opportunistic herpes infections, a highly unusual and fatal MS deterioration and six vascular events. As a result, the 1.25 mg dose arms of several ongoing trials were terminated for safety reasons and Novartis sought approval only of a 0.5 mg dose.
Nonetheless, the FDA agreed to a so-called 'fast track' approval schedule. Yet, ISMP notes, the documentation provided the FDA to support approval disclosed numerous serious side effects, including birth defects in standard animal screening studies; herpes infections; lower respiratory tract infections, along with unusual infections of the ear, sinus, and eye. There were also two deaths.
There were other issues: 8 percent of patients taking the recommended dose had laboratory evidence of liver damage, but routine liver testing is not currently recommended. And while trials prior to approval included three cancer deaths in which the FDA could not rule out the possibility that Gilenya played a role, pre-approval testing was not sufficient to assess any cancer risk.
ISMP contends an unnecessarily high dose may have been approved by the FDA. Gilenya was tested at doses of 5 mg, 2.5 mg, 1.25 mg and 0.5 mg, although all of the doses higher than 0.5 mg proved toxic for humans, ISMP notes. An FDA advisory committee voted 20-to-5 for a study at a lower dose, but none of the panelists voted to delay approval until after studies had been conducted. The FDA did require a study of a 0.25 mg dose by 2015, along with nine other studies to address safety questions.
But ISMP contends this was too little, too late. "The unfolding safety profile of Gilenya shows that getting faster access to innovative new drugs can also involve substantial risks to the public. The fact is a powerful new drug might help you and it might harm you, and only time-consuming testing separates the help from the harm," Thomas Moore, a senior scientist at ISMP, writes us.
We have asked Novartis, the FDA and the National Multiple Sclerosis Society for a reply and will update you accordingly.
[UPDATE: Timothy Coetzee, chief research officer at the National Multiple Sclerosis Society, has this to say: "The FDA has already announced that it is reviewing the safety profile of Gilenya. We are following the matter closely and waiting to see the results of their investigation. Therefore, we feel that it would be a somewhat premature to comment in advance of the release of the FDA findings, which we anticipate will be forthcoming soon.”]
[ANOTHER UPDATE: A Novartis spokesman sends us this: "Novartis believes that Gilenya provides a benefit for patients with relapsing remitting multiple sclerosis and remains committed to engaging with the FDA and EMA, other health authorities and the MS community with the goal of ensuring that appropriate patients will have access to Gilenya. There is increasing experience of (Gilenya's) long-term effectiveness and safety profile, with approximately 30,000 patients having been treated in clinical trials and in a post-marketing setting. Currently, there is more than 25,000 patient years of exposure....
["In clinical trials, the most common side effects were headache, liver enzyme elevations, influenza, diarrhea, back pain, and cough. Other Gilenya-related side effects included transient, generally asymptomatic, heart rate reduction and atrioventricular block upon treatment initiation, mild blood pressure increase, macular edema, and mild bronchoconstriction. The rates of infections overall, including serious infections, were comparable among treatment groups, although a slight increase in lower respiratory tract infections (primarily bronchitis) was seen in patients treated with Gilenya. The number of malignancies reported across the clinical trial program was small, with comparable rates between the Gilenya and control groups.”]