New data on Novartis' investigational oral multiple sclerosis therapy Gilenia (fingolimod), which was presented at the American Academy of Neurology meeting on April 13, strengthened the efficacy profile of the low dose 0.5 mg version of the drug and highlighted potential benefits of switching from Biogen Idec's Avonex (interferon beta-1a).

The data holds great significance for Novartis, which is hoping that Gilenia will be the first oral drug on the market for the treatment of MS; the medication is the only one currently pending at FDA, with a June 21 user fee date, although others like Merck Serono and Biogen Idec are also in the race to develop oral drugs. Merck ran into a snag with its oral candidate, cladribine, after it submitted an NDA in September 2009, but FDA refused to file the application

"The data demonstrate the effectiveness of Gilenia irrespective of treatment history, and further support both the sustained efficacy of Gilenia over two years and the potential benefits of switching from interferon beta-1a," Novartis Global Head of Development Trevor Mundel said in a statement.

The continued positive efficacy data for the low-dose version is important since Novartis opted to submit the 0.5 mg dose - rather than a higher 1.25 mg dose - to regulators in the U.S. and EU to mitigate the risks seen in clinical trials ([A#1409093003]). Among the potential safety signals seen in clinical trials for the drug is a risk of cancer.

The company presented additional data from the two completed Phase III studies supporting Gilenia: the two-year FREEDOMS trial comparing Gilenia to placebo and TRANFORMS, a one-year study with a one-year extension phase comparing Gilenia to Avonex. The full results of the two Phase III trials were published in The New England Journal of Medicine in January.

Among the data presented at AAN was the first from an extension study of the TRANSFORMS trial - which enrolled 1,027 patients (about 89 percent of those who participated in the original trial). Patients in the extension study who received Gilenia in the original study remained on their original dose (either 0.5 mg or 1.25 mg once daily), while patients who received Avonex were randomized to receive Gilenia 0.5 mg or 1.25 mg once daily.

The extension portion of the trial demonstrated several key findings, lead investigator Jeffrey Cohen, MD, (Cleveland Clinic) said in an interview. In patients that continued on treatment, efficacy was maintained for two years; no sign of significant efficacy difference was seen between the 0.5 mg dose and the 1.25 mg dose; an improved efficacy in relapse rate and MRI brain lesions was seen in patients who switched to Gilenia from Avonex; and no new safety concerns emerged, he said.

The efficacy findings in the extension phase of the study were largely in line with those of the core TRANSFORMS study, demonstrating Gilenia 0.5 mg significantly reduced annualized relapse rates by 52 percent versus Avonex.

How Gilenia could ultimately stack up in the treatment paradigm for MS remains to be seen. "In terms of efficacy, it is going to require more experience with the drug after it hopefully gets approved," Cohen said.

Whether or not Gilenia gets approved on the first go around could depend largely on how the FDA views the safety profile of the drug, a potential first-in-class sphingosine 1-phosphate receptor modulator that has been associated with several safety signals, including a potential cancer risk.

Gilenia and Novartis' proposed risk minimization plan for the drug are scheduled to be reviewed by FDA's Peripheral and Central Nervous System Drugs Advisory Committee June 10 (Also see "Novartis Talking About Fingolimod Safety With FDA; Will Talk To Advisory Panel In June" - Pink Sheet, 5 April, 2010.).

Malignancies were reported more frequently in patients treated with Gilenia than the control arm in the TRANSFORMS study, but the opposite pattern was seen in the two-year FREEDOMS trial. In the extension phase of TRANSFORMS, Cohen said a "small number" of additional cancers were seen, but that they were evenly distributed between the 0.5 mg and 1.25 mg dose arms of Gilenia and the Avonex arm.

"Cancer is still a concern, but it is becoming less worrisome," Cohen maintained.

-Jessica Merrill (j.merrill@elsevier.com)

Novartis' Gilenia Extension Trial Data Support Efficacy Of Low-Dose Version

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