Fingolimod 3-Year Results Show Continued Low Relapse and Disease Activity in MS

Susan Jeffrey

April 25, 2008

April 25, 2008 (Chicago) — Results from the 3-year extension of an earlier randomized trial of FTY720, or fingolimod (Novartis), a still-investigational oral treatment in patients with relapsing-remitting multiple sclerosis (RRMS), show continued low rates of relapse and disease activity on magnetic resonance imaging (MRI), researchers report.

Results of the extension study, funded by Novartis Pharma AG, were presented here at the American Academy of Neurology 60th Annual Meeting.

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"In conclusion, here we have a drug that is an oral drug, and this is a very important point to underline" for patients, Giancarlo Comi, MD, from Vita-Salute San Raffaele University, in Milan, Italy, told a press conference here. "The drug, based on the data that we have, seems to be active even for the extended 3-year period tested in this type of clinical trial, and it seems that the safety profile, at least as far as we know today, is not presenting any major problems."

An Oral Alternative

Currently approved treatments for MS are the immune-modulating agents beta interferon and glatiramer acetate, which reduce relapse rates by about 30%, the authors note. However, both types of drugs are given either intramuscularly or subcutaneously, and interferons are associated with systemic reactions in some 60% of patients, with implications for adherence to treatment.

Fingolimod is a still-investigational drug that, given orally, acts as a superagonist to sphingosine-1-phosphate (S1P) receptors on the surface of thymocytes and lymphocytes, causing them to be sequestered in secondary lymph organs. This reduces the overall number of circulating lymphocytes available to mount an autoimmune reaction to the myelin sheath surrounding axons in MS. The phase 2 study was a double-blind, placebo-controlled proof-of-concept study that randomized 281 patients with relapsing MS to 1 of 3 treatment groups — 1.25-mg oral fingolimod, 5.0-mg oral fingolimod, or placebo — for 6 months (the core study). The primary end point was the total cumulative number of gadolinium-enhancing lesions on 6 postbaseline MRI scans. Other MRI parameters and clinical parameters were also evaluated. Of 281 randomized patients, 255 completed the 6-month core study. The most common reasons for premature discontinuation were adverse events and withdrawal of consent, the authors note. In their report of the primary results, published in 2006 in the New England Journal of Medicine, the authors showed that the median number of enhancing lesions on MRI — indicative of active disease — was significantly reduced with fingolimod treatment compared with placebo. Although the study was not powered to detect a treatment effect on clinical relapse-related end points, the authors pointed out that there were significant improvements in the annualized relapse rate with both fingolimod doses (reduced by 53% in the 5.0-mg group and 55% in the 1.25-mg group) compared with placebo (Kappos L et al. N Engl J Med. 2006;355:1124-1140). They then carried out a long-term extension study, where patients who had received placebo in the core study were randomized again to 1 of the 2 fingolimod doses. Of the 255 patients who completed the core study, 250 entered the extension. Investigators and patients remained blinded during this phase to their original treatment assignment.

Results of the first 6 months of that extension study with oral fingolimod in patients with RRMS, published in the original report, continued to show low levels of disease activity on MRI as well as low relapse rates in patients who received the drug continuously through 12 months. The group of patients who had been receiving placebo during in the core study and were switched to active drug in the extension showed marked reduction in disease activity on MRI and clinical relapses after 6 months on fingolimod compared with the 6 months on placebo.

At the meeting here, Dr. Comi and colleagues reported on the results of the analysis at 36 months (30 months of the extension to the original 6-month core trial). A total of 173 of the 250 patients who entered the extension study completed month 36.

Between month 18 and month 24, all patients who had been on the 5-mg dose were converted to 1.25 mg, since both doses were equally effective, but the lower dose was seen to be better tolerated. At the month-36 analysis, patients originally on the 5-mg dose had been receiving 1.25 mg for at least 12 months.

At 36 months, the mean number of enhancing lesions remained very low in the overall cohort, Dr. Comi said. Almost 90% of patients were free of gadolinium-enhancing lesions, and annualized relapse rates were low in all groups. In addition, between 70% and 78% of patients treated for up to 36 months, depending on the group, were free of new T2 lesions on MRI since month 24.

Mean Number of Gadolinium-Enhancing Lesions with Fingolimod at 24 and 36 months

Gadolinium-Enhanced Lesions on MRI, Mean n Placebo-Fingolimod Continuous Fingolimod, 1.25 mg Continuous Fingolimod, 5 mg/1.25 mg
24 mo 0.2 0.7 0.2
36 mo 0.1 0.2 0.3



Percent of Patients Free of Gadolinium-Enhancing Lesions with Fingolimod at 36 months

End Point Placebo-Fingolimod Continuous Fingolimod, 1.25 mg Continuous Fingolimod, 5 mg/1.25 mg

% Free of Gadolinium-Enhanced Lesions on MRI

89.3 87.5 89.1



Annualized Relapse Rate in Core Study vs 24- and 36-Month Extension Study of Fingolimod in Relapsing MS

Annualized Relapse Rate

Placebo-Fingolimod

Continuous Fingolimod, 1.25 mg

Continuous Fingolimod, 5 mg/1.25 mg

Months 0 – 6

0.77

0.35

0.36

Months 0 – 24

0.28 – 0.38*

0.20

0.22

Months 0 – 36

0.31

0.20

0.21

*0.28 for the group switched from placebo to 1.5 mg, 0.38 for group switched from placebo to 5.0 mg

The most frequent adverse events were nasopharyngitis, influenza, headache, and fatigue. Most of the adverse events frequently reported in the first 6 months of the core study appeared todecline over the period of follow-up, Dr. Comi said.

Interestingly, given the benefits of a potential oral agent, only 73% of patients completed the 3 years. Many of the dropouts occurred in the early part of the extension, he noted. The most common reason for discontinuation was adverse events (occurring in 5 of 16 patients who withdrew between months 24 and 36) and withdrawal of consent (frequently a decision by women to become pregnant).

Macular edema had been seen with fingolimod in previous transplantation trials, and there were 4 cases of suspected macular edema in this trial (1 since the month-24 analysis). However, the diagnosis was not confirmed by external review of retinal specialists. There was some elevation of hepatic enzymes, but as had been seen with other adverse events, the frequency declined over time, Dr. Comi noted.

"All of these data taken together continue to suggest that the drug is active; second, the frequency of adverse effects tends to decrease with continuation of the treatment, and there was no evidence of any new adverse effects except some reports of skin malignancies," he said.

Seven cases of skin malignancies were observed during the extension trial: 3 basal-cell carcinomas, 2 squamous-cell carcinomas, and 2 melanomas. All were in situ, and all have been treated without other complications, he said.

 

This potential effect will be monitored closely in phase 3 trials that are now under way. In more than 3000 patients enrolled in those trials to date, all of whom are being evaluated by dermatologists, 8 skin malignancies have been reported (with the treatment code still masked), again all in situ and all treated, Dr. Comi said. The safety monitoring board reviewing the safety data from all ongoing fingolimod studies has not indicated at this time that there is an imbalance between placebo and active-treatment groups.

"The real problem is that . . . we started a program of surveillance . . . that resulted in [an] immediate early diagnosis, so we are still [asking] whether it is because we are paying attention to the problem that we are seeing cases or whether it because there is a real excess. We don't underestimate the problem, but we need to understand," he said.

Two of the phase 3 trials are comparing fingolimod with placebo, and 1 is using an active comparator, interferon beta-1a (Avonex, Biogen). "It will be fundamental to see whether these phase 3 trials will confirm the quite good profile of the drug seen in this extension of the original trial," he told Medscape Neurology & Neurosurgery.

Continual and Prolonged Effect

Asked for comment on these results by Medscape Neurology & Neurosurgery, B. Mark Keegan, MD, a neurologist at the Mayo Clinic in Rochester, Minnesota, said, "This is an important study in the ongoing search for safe and effective oral medications for MS patients. Given MS is a long-term chronic disease, it is essential that the effects on reducing relapses and new MRI activity be continual and prolonged, and this is what the study suggests."

The study was supported by Novartis Pharma AG. Dr. Comi reports that he has received personal compensation for activities with Teva Neuroscience, Schering-Plough, and EMD Serono. Disclosures for coauthors appear in the abstract. Dr. Keegan reports no disclosures relevant to this study.

American Academy of Neurology 60th Annual Meeting: Abstract S12.005. Presented April 15, 2008.

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