How Low Can Gilenia Go? Panel Wants Reduced-Dose Phase IV Trial

FDA should approve Novartis' Gilenia (fingolimod), an oral tablet intended to treat relapsing remitting multiple sclerosis, but should require the company to test a lower dose of the medication in a post-market clinical trial due to the product's many risks, a mostly united advisory panel said June 10.

The committee voted unanimously and with very little discussion that Novartis has demonstrated that Gilenia is efficacious for reducing the frequency of clinical exacerbations in relapsing remitting MS, and with only one dissent that it is efficacious at delaying the accumulation of physical disability in these patients. If approved, Gilenia will be the first oral MS medication.

"My only concern is that you can see a lot more information with longer studies to clarify that point," Jacqueline Friedman, director of the Department of Veterans Affairs New York Region Multiple Sclerosis Center, said in explaining why she cast the only no vote on the second question.

The focus of discussion was not efficacy but safety, as FDA had indicated it would be in briefing materials prepared before the meeting (¹ (Also see "Gilenia Advisory Committee: Is REMS + Phase IV > FDA Safety Concerns?" - Pink Sheet, 8 Jun, 2010.)).

The many concerns in this area led the panel to vote 20-5 that the drug should be studied at a dose lower than the 0.5 mg that is up for approval, and which is itself a tenfold reduction from the original 5 mg dose when the drug was first tested for preventing kidney transplant rejection. FDA indicated that a dose of 0.25 mg is likely to be a target of such a study.

However, the committee then cast two separate, unanimous votes that the agency should not force Novartis to do this study before it approves the drug, and that "current safety data at 0.5 mg justify approval."

The panel also voted on the following:

The drug can be used as a first-line treatment, rather than being limited to a second-line setting: 21-3, with 1 abstention;

Patients should be required to receive their first dose in a monitored setting to test for bradycardia and heart conduction abnormalities: a unanimous 25-0 vote;

Routine ophthalmic examination is not sufficient to monitor patients for macular edema: 20-4, with one abstention; and

Routine pharmacovigilance will not be sufficient to mitigate the risks associated with fingolimod's pulmonary toxicity: 17-7 with one abstention. FDA's position on the risk to patients in this area has softened somewhat since it prepared the briefing materials, according to Russell Katz, director of the Division of Neurology Products. "Our current view is that there is definitely a decrement in pulmonary function, but it seems to be stable."

"Absolutely Not Sufficient"

The committee also felt that the post-marketing safety study Novartis proposed to do in 5,000 patients would not be sufficient to address safety issues observed in this database.

FDA did not require a vote on this question, but Judith Feinberg, University of Cincinnati College of Medicine, who said she is an MS patient herself, seemed to speak for the panel when she said, "The proposed study is absolutely not sufficient ... A prospective study of a combination of disease-modifying therapies is going to be crucial to sort out appropriate management. It's valuable to do post-market [surveillance] stuff, but that's pretty passive. If you don't collect data on a routine basis, you don't get it."

However, the dosing study "sounds like a massive trial," Michael Domanski of NIH's National Heart, Lung, and Blood Institute said. Large numbers of patients might have to be enrolled, he and other committee members warned.

"I'm not sure how they're going to do it. It depends what questions they want to answer," Fred Lublin of the Mount Sinai School of Medicine, who delivered one of the presentations for Novartis, said in an interview after the meeting. Options might include a "short proof-of-principle study" examining patients' gadolinium enhancing lesions, a duplicate of the study Novartis already sponsored comparing Gilenia with Biogen Idec's Avonex (interferon beta-1a), or a placebo-controlled trial, although the latter would be hard to do, Lublin said.

The dosing question was critical, because many of the side effects seem to be dose dependent. "As a clinician, I see a two-tiered approach," Eluen Yeh, State University of New York at Buffalo, said. "If we were to have the lowest possible dose, I would be comfortable offering it from the beginning, because it's so effective."

However, the 0.5 mg dose is not necessarily the lowest possible dose, and so, Yeh said, "because of the side effects, which include death, I would now have to offer it in a two-tiered system, as a rescue medication. It should be studied at a lower dose."

Committee members seemed determined not to hold up approval for any of the safety issues raised, although most need further study in a more robust way than Novartis had proposed. For example, Domanski said, "I think cardiac safety has been demonstrated. It would be very interesting to study it at a lower dose, but I would not hold their feet to the fire on that as a condition of approval."

Another major area that needs further study is populations that were excluded from the fingolimod trials, but are likely to be prescribed the drug anyway, such as patients with relapsing remitting MS who are also diabetic.

"If this drug is approved, there will be requirements to study some of these excluded populations," Robert Temple, director of FDA's Office of Drug Evaluation I, assured the committee.

In response, the committee chair, Britt Anderson, University of Waterloo, Canada, said, "It takes some of the nail-biting suspense out of these questions to know what you're going to do anyways!" The room erupted in laughter.

"All the safety questions will be about equal," Lublin said. "Patients will have to do several different things before they get started [on Gilenia], but none of them individually are that onerous ... Monitoring is prudent. In time, all of these questions will be better defined, and we'll learn which are necessary to study and which aren't necessary at all."

- Martin Berman-Gorvine (² [email protected])