SAN DIEGO—Encouraging results from a phase II trial suggest that a novel oral treatment for multiple sclerosis (MS) may outperform other disease-modifying drugs. The new drug, FTY 720, or fingolimod, reduced relapses by more than 50 percent compared with placebo during the first six months of a large phase II trial in patients with relapsing-remitting MS, the most common form of the disease. The reduction in relapse was sustained in a 12-month extension phase of the study, reported Paul O'Connor, MD, here at the AAN Annual Meeting in April. Dr. O'Connor is Associate Professor of Neurology at the University of Toronto.
Dr. O'Connor said that the original placebo patients – from the six-month double-blind, placebo-controlled phase – switched to the drug for the 12-month open-label extension phase and exhibited reductions in relapse rates and in number of active lesions – gadolinium-enhancing (Gd+) lesions – on MRI. Hopes are high among MS experts that phase III studies will confirm these findings.
FIRST ORAL DISEASE-MODIFYING AGENT
If these preliminary results are replicated, fingolimod could become the first oral disease-modifying agent for relapsing-remitting MS, although two other oral agents, including teriflunomide and cladribine, are also in phase III development. Other approved drugs, which include beta-interferon 1-b, beta-interferon 1-a, and glatiramer acetate, are injectable.
Experiments in rodent model show that fingolimod binds to the sphingosine 1-phosphate recetpor-1 (SlPl) on some circulating lymphocytes, reversibly trapping the cells in lymph nodes. This lowers the number of active T-cells circulating to the CNS, and decreases neuroinflammation and myelin damage in the brain and spinal cord.
The phase II trial was conducted at 32 centers in 11 countries in Europe and Canada. The first six-month phase of the study enrolled 281 patients and randomized them in a 1:1 ratio to placebo, oral fingolimod 1.25 mg/day, or oral fingolimod 5 mg/day. After six months, patients could choose to enter the extension phase of the study. Those already on the drug continued on the originally assigned dose, and placebo patients were re-randomized to receive either fingolimod 1.5 mg/day or 5 mg/day. At the end of the extension phase, the 5 mg arm was discontinued and patients switched to the lower dose.
DOSE-BLINDED ACTIVE PHASE
After the first six months of treatment, there was a 43 percent reduction in mean number of Gd+ lesions – a measure of disease activity and inflammation – in the 1.25 mg/day group and 62 percent in the 5 mg/day group compared with placebo. The mean number of Gd+ lesions was 14.8 in the placebo group, 8.4 in the 1.25 mg group, and 5.7 in the 5 mg group. The risk reduction in relapse was 55 percent for those taking 1.25 mg and 53 percent for those taking 5 mg. Relapse was defined as an acute worsening of >0.5 point on the Expanded Disability Status Scale (EDSS) or 1 point in >1 the functional systems scale scores.
[The EDSS assesses disability in eight areas: pyramidal, cerebellar, brainstem, senory, bowel and bladder, visual, cerebral, and other. EDSS scores 1.0 to 4.5 refer to people who are fully ambulatory. EDSS scores 5.0 to 9.5 are defined by the impairment to ambulation.]
Two-hundred and forty-nine patients continued in the extension phase of the study, Dr. O'Connor said, “The typical patient in the extension phase was a woman with relapsing-remitting MS, age 37, fully ambulatory, and symptomatic for eight years.
At 18 months, a dramatic reduction in relapse rates was observed in placebo patients who switched to fingolimod, while treated patients from the original phase of the trial maintained their gains. MRI of patients originally assigned to placebo showed an 87 percent reduction in Gd+ lesions when treated with 1.25 mg/day (p+.001) and an 81 percent reduction in Gd+ lesions when given 5 mg/day (p=.004). The number of Gd+ lesions were also fewer in those originally given the drug, but too few MRI scans were obtained in this group at 18 months to calculate percent reduction, Dr. O'Connor said.
The extension phase showed that serious adverse events were more common with the higher dose, while the incidence of side effects was no different in the two dosing groups.
“No particular pattern of serious adverse events was seen. They were different in each group,” Dr. O'Connor said. Frequently reported events were nasopharyngitis, flu-like reactions, and headache. In placebo-switched patients, transient bradycardia by about 15 beats per minute (after the first dose only and lasting for about six hours) was seen. In addition, there were mild increases in blood pressure of about 5 mmHg and mild bronchospasm that persisted during the extension trial. Dr. O'Connor said that these effects were observed in patients on active treatment.
In a separate interview, Dr. O'Connor said that the drug is well tolerated and popular with patients. “Bradycardia and bronchospasm effects are somewhat like those of a beta blocker. The vast majority of patients have no significant side effects,” he noted.
Dr. O'Connor said that the 5 mg dose has been dropped for the phase III program, because it was no more effective than 1.25 mg/day and had more side effects.
Novartis is in discussion with the US Food & Drug Administration about the planned phase III trial. If that goes ahead in the US, high safety hurdles will be set. A phase III trial for relapsing-remitting MS called FREEDOMS (Fingolimod Research Evaluating Effects of Daily Oral Therapy in MS) has already been initiated in Europe, and the doses of fingolimod being studied in that trial are 0.5 mg/day and 1.5 mg/day. More than 1,000 patients with relapsing-remitting MS between the ages of 18 and 55 will be randomized to placebo, 1.5 mg/day, or 5 mg/day of fingolimod and treated for up to 24 months.
OLD DRUG BUT NEW NEWS
MS experts are enthusiastic about fingolimod, specifically, its effects on relapse-rate reductions never seen before in relapsing-remitting MS. “Fingolimod is a novel compound that had been sitting on the shelf for several years,” said Mark Freedman, MD, Professor of Neurology at the University of Ottawa in Canada. “The phase II studies were powered to evaluate only MRI data,” he told Neurology Today in an interview.
“We were surprised that fingolimod showed a highly significant effect on relapse rate that continued to be strong at six months and 18 months, even though the study was underpowered to show that effect,” he said. “If we can replicate at least a 50 percent reduction in relapse rate in the phase III trial, it will be good news for patients and physicians.”
ARTICLE IN BRIEF
✓ Fingolimod reduced relapses by more than 50 percent compared with placebo during the first six months of a large phase II trial in patients with relapsing-remitting MS. The reduction in relapse was sustained in a 12-month extension phase of the study.