FDA has approved the oral multiple sclerosis therapy Gilenya (fingolimod) with a Risk Evaluation and Mitigation Strategy more stringent than the sponsor Novartis had proposed, but in line with the prescribing requirements an advisory panel wanted to see.

FDA's Peripheral and Central Nervous System Drugs Advisory Committee voted June 10 to recommend approval of the drug on condition that prescribing physicians do a number of pre-therapy tests and monitor the patients carefully after they take their first dose (Also see "Gilenia's Risk Management Should Key On Initial Doctor Visit, Cmte. Says" - Pink Sheet, 14 June, 2010.). These testing and monitoring provisions were not in the version of the REMS Novartis had proposed (Also see "Gilenia Advisory Committee: Is REMS + Phase IV > FDA Safety Concerns?" - Pink Sheet, 8 June, 2010.).

The spelling of the drug's brand name was changed from "Gilenia" to "Gilenya" after FDA rejected the first version, the company said. The new spelling was in use when the drug was approved in Russia on Sept. 10. The European Medicines Agency is still considering approval.

While the company had proposed to do a post-marketing safety study in 5,000 patients, the advisory committee did not feel that this was sufficient to address safety issues observed in the clinical trials, and voted 20-5 that the drug should be studied at a dose lower than the 0.5 mg that FDA ended up approving, which was a tenfold reduction from the original 5 mg dose used when the drug was first tested for preventing kidney transplant rejection (Also see "How Low Can Gilenia Go? Panel Wants Reduced-Dose Phase IV Trial" - Pink Sheet, 14 June, 2010.).

Gilenya presents a daunting range of safety concerns, among them slow heart rate (bradycardia or bradyarrhythmia), infections, macular edema, breathing and liver problems. The cardiac question led the advisory panel to recommend that the drug be given for the first time in a setting where the patient can be monitored. "I would just hate to give this drug to somebody and then they walk out and crumple by the elevator and you have to call a [cardiac] arrest," Judith Feinberg, University of Cincinnati College of Medicine, said.

Novartis noted that if patients' heart rate slows down, this usually happens at the latest about six hours after the first dose, and that therefore "a doctor will watch patients for the first six hours after they take the first dose to see if they have any serious side effects." This side effect usually fades, with the heart rate returning to normal within about one month after the patient starts taking Gilenya.

Other recommended medical tests accompanying a new Gilenya prescription are:

# Since the drug lowers the number of white blood cells (lymphocytes) in the blood, leaving the patient more vulnerable to infections, prescribing physicians "may" perform a blood test before the patient starts taking Gilenya;

# To be prepared for the possibility of macular edema, "a doctor should test a patient's vision before they start taking Gilenya and three to four months after they start taking Gilenya, or any time they notice vision changes during treatment"; and

# Since the drug may cause liver problems, a doctor "should do blood tests to check a patient's liver before they start taking Gilenya."

In addition, women who can become pregnant should use effective birth control while on Gilenya and for at least two months after stopping, and women who take Gilenya should not breastfeed, as it is not known if Gilenya passes into breast milk. The most common side effects with Gilenya were headache, flu, diarrhea, back pain, abnormal liver tests and cough.

Advisory committee members had noted during their discussion that the neurologists who will be prescribing Gilenya will need advice in many other areas outside their normal field of expertise due to the range of adverse events recorded in the clinical trials.

Gilenya is the first in a new class of drugs called sphingosine 1-phosphate receptors. While the drug's exact mechanism of action is unknown, it is thought to work by reducing the immune system's attack on the central nervous system by retaining certain white blood cells (lymphocytes) in the lymph nodes.

Getting a Jump on the Competition

BMO Capital Markets said in a note to investors that "the broad Gilenya label ... includes first-line treatment and lack[s] 'black box' warnings." However, the details of the labeling are probably less significant than the details of the REMS.

According to Novartis, these include a medication guide for patients, a letter and safety information guide for healthcare providers and "a five-year, worldwide post-authorization safety study to monitor selected safety-related outcomes and a voluntary pregnancy registry, the findings from which will be used to give healthcare providers important information for treating and counseling patients with MS that are pregnant or may become pregnant."

Probably more significant from the standpoint of investors is BMO's speculation that "most physicians likely will initially use Gilenya in the second-line setting following failure with ABCRs [Biogen Idec's Avonex (interferon beta-1a), Bayer's Betaseron (interferon beta-1b), Teva's Copaxone (glatiramer) and EMD Serono and Pfizer's Rebif (interferon beta-1a)] until they have more experience with the drug."

"Therefore, Gilenya should initially compete with [Biogen Idec's] Tysabri [natalizumab], and our forecasts already take this effect into account starting primarily in 1Q11," BMO added. "The patients that are most likely to start Gilenya are those that:

1) "Fail/do not tolerate ABCRs and are worried about starting Tysabri based on PML concerns, or

2) "Strongly prefer an oral agent as opposed to injectable ABCRs, or

3) "Are already on Tysabri and approaching their twenty-fourth infusion, where the risk of PML increases considerably" (Also see "Biogen Idec Reports Strong Earnings Thanks to Robust Sales Of Flagship Products" - Pink Sheet, 20 July, 2010.).

"Gilenya is expected to be a blockbuster for Novartis, and analysts predict it will be a major player in the $10 billion MS market, and many have estimated peak sales for the drug to be just under $2 billion," Novartis said.

Biogen Idec was worried enough about the competition and the possible effect on its share price - which had dropped almost 6 percent just before the market close the day Gilenya's approval was announced - to release a statement of its own to mark the Gilenya approval, pointing out that it has "three late-stage clinical candidates that target multiple pathways thought to be critical in treating MS." For example, BG-12 is in Phase III testing, with results expected in 2011.

The next oral MS drug up for FDA is Merck KGaA's cladribine; the application was granted priority review and a decision by the FDA is expected by the end of the year (Also see "Merck KGaA And Novartis Back In Horse Race For First Oral MS Drug To Market" - Pink Sheet, 28 July, 2010.). In BMO's view, that drug has a 50-50 chance of approval in late 2010 or early 2011.

-Martin Berman-Gorvine ( m.berman-gorvine@elsevier.com )

Novartis Gilenya Approved With Advisory Panel-Enhanced REMS

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