Results of two pivotal Phase III clinical trials with oral FTY720 published

Results of the TRANSFORMS and FREEDOMS studies, the two pivotal Phase III clinical trials with oral FTY720 (fingolimod), have been published in The New England Journal of Medicine, providing comprehensive evidence to support the efficacy and safety profile of this first-in-class therapy for multiple sclerosis (MS).

The data, from one of the largest Phase III programs conducted in MS, were included in the applications for regulatory approval submitted to the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) in December 2009. In both studies, two doses of FTY720 were examined (0.5 mg and 1.25 mg). Approval is sought for the lower 0.5 mg dose as the results from the studies indicate that this dose has the most positive benefit-risk profile.

"Innovative science leading to new medicines for MS patients is badly needed," said John Richert, MD, Executive Vice President of Research and Clinical Programs for the US National Multiple Sclerosis Society. "The positive results published in The New England Journal of Medicine showing benefit of fingolimod on the clinical and MRI outcomes assessed is very encouraging for MS patients, their families and their physicians."

The one-year TRANSFORMS study involving 1,292 patients showed that oral FTY720 0.5 mg reduced relapses by 52% compared to interferon beta-1a (Avonex(R)) given by intramuscular injection, while the reduction with FTY720 1.25 mg was 38% (both p(less than)0.001). The two-year FREEDOMS study, involving 1,272 patients, showed that FTY720 reduced the relapse rate by 54% for the 0.5 mg dose and 60% for the 1.25 mg dose compared to placebo (both p(less than)0.001). Patients on FTY720 0.5 mg also had a 30% lower risk of disability progression, three month confirmed>

In both studies, treatment with FTY720 also resulted in statistically significant reductions in brain lesion activity and reduced loss of brain volume as measured by magnetic resonance imaging (MRI).

"The TRANSFORMS data demonstrate the efficacy of fingolimod compared to a current standard of care. These findings may represent a real step forward in the fight against MS," said Jeffrey Cohen, MD, TRANSFORMS study lead investigator and staff physician at the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research in Cleveland, Ohio, USA. "Current disease-modifying therapies for relapsing-remitting MS are administered by injection or infusion, which may negatively affect tolerability, convenience, and compliance for patients on these therapies."

Professor Ludwig Kappos, MD, principal investigator for the FREEDOMS clinical trial and Chair of Neurology and Research Group Leader in the Department of Biomedicine at the University Hospital in Basel, Switzerland, said: "FTY720 demonstrated clear clinical superiority over placebo in terms of reducing relapse rates and disability progression. The positive findings of TRANSFORMS and FREEDOMS give an increasingly complete understanding of the efficacy and safety of FTY720."

Up to 2.5 million people worldwide are affected by MS, an inflammatory and neurodegenerative condition that often begins when patients are in the prime of their lives.

FTY720 has the potential to be the first approved therapy in a new class of drugs called sphingosine 1-phosphate (S1P) receptor modulators. These medicines reduce inflammation and may also have a direct beneficial effect on cells in the central nervous system (CNS). FTY720 acts selectively by retaining certain lymphocytes (a sub-group of white blood cells) in the lymph nodes, reducing the number of lymphocytes that reach the brain where they can cause inflammatory destruction. This lymphocyte retention is reversible, allowing circulating lymphocytes to regain normal levels if treatment is stopped.

"These data demonstrate that oral FTY720 has the potential to offer an important new treatment option for patients with MS," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "We have a long-term commitment to the MS community, and trust that FTY720, once approved, will prove to be a valuable treatment option for many people who live with this disease."

In both TRANSFORMS and FREEDOMS, adherence to therapy was best for the FTY720 0.5 mg and control groups compared to the 1.25 mg group. The most commonly reported adverse events for both FTY720 and control groups were nasopharyngitis, headache and fatigue. FTY720-related adverse events included dose-related, transient, generally asymptomatic heart rate reduction, infrequent transient AV conduction block, mild (1-3 mm Hg) blood pressure increase, macular edema (more common with 1.25 mg than the 0.5 mg target dose), and asymptomatic, reversible elevation of liver enzymes.

The rates of infections overall, including serious infections, were comparable between treatment groups, although a slight increase in lung infections (primarily bronchitis) was seen in patients treated with FTY720. The number of malignancies reported in the two studies was small with comparable rates between the FTY720 and control groups; malignancies were reported more frequently with FTY720 than the control group in the one-year TRANSFORMS study but the opposite pattern was seen in the two-year FREEDOMS study.

Serious adverse events were comparable between treatment groups, though generally slightly higher with the 1.25 mg than 0.5 mg dose. Overall rates of drug-related adverse events, particularly those related to the mechanism of action, as well as discontinuations due to adverse events, were more common with 1.25 mg than 0.5 mg.

The completed MS FTY720 studies and their extensions include more than 2,300 patients with approximately 4,000 patient-years of exposure, including some patients now in their sixth year of treatment. Safety is also being monitored in approximately 1,000 additional patients in ongoing MS studies.

The publication in The New England Journal of Medicine marks the first presentation of full results from the two studies. Top line results of FREEDOMS and TRANSFORMS have been disclosed in Novartis press releases, and the TRANSFORMS study has also been presented at scientific congresses.