In a phase 2 trial, higher doses of an orally active, alpha4beta-integrin antagonist therapy — firategrast — achieved its primary endpoint — a reduction in the number of lesions on MRI in patients with the relapsing remitting form of multiple sclerosis (MS), investigators reported in the February Lancet Neurology.
The researchers had hoped that the oral drug with its shorter half-life would prove a safer and effective alternative to other monoclonal therapies — notably, natalizumab, another alpha4beta-integrin antagonist, which has been associated with the development of progressive multifocal leukoencephalopathy (PML). Firategrast has a half-life of about 2.5 to 4.5 hours, which could offer “faster washout and hence faster reversal of pharmacodynamic effects when concerns about safety and tolerability arise,” the study authors said. By comparison, the half-life of natalizumab is 11 days.
But MS experts not involved with the study told Neurology Today that although the results of the phase 2 trial showed some promise for the drug, they were not overly impressed with the findings.
It is always challenging to compare the results from different trials, said John Corboy, MD, professor of neurology at the University of Colorado School of Medicine, who also serves on the editorial advisory board for Neurology Today. But, he added, the results in this study were not nearly as impressive as those previously reported in a phase 2 trial for natalizumab, which showed a much greater reduction in new MRI lesions. “This study was also way too small and way too brief to see is there is a risk of PML or other conditions related to long-term use,” he said. [See http://bit.ly/xUmBQk for the Neurology Today article on the phase 2 natalizumab trial reported in 2003 in the New England Journal of Medicine.]
Led by David H. Miller, MD, professor in the department of neuroinflammation at the UCL Institute of Neurology in London, the study included 343 patients with relapsing-remitting MS from 78 centers in Australia, Austria, Canada, France, Germany, Italy, Netherlands, New Zealand, Norway, Poland, Russia, Spain, and the United Kingdom. Patients were randomized to take a placebo or firategrast twice daily at different doses — 150 mg, 600 mg, 900 mg (women) or 1200 mg (men) for 24 weeks. They were monitored for an additional 12 weeks, and continued in an extended follow-up phase for up to 12 months after receiving their last dose of the experimental drug.
The primary outcome measure was the cumulative number of gadolinium-enhancing lesions on monthly MRI scans during the treatment phase.
Among findings, the investigators reported a 49 percent reduction in the cumulative number of new gadolinium-enhancing lesions in those taking 900 mg or 1200 mg of firategrast (2.69 lesions on average) — 95% CI 21.6-67.6; p=0.0026 — versus the placebo group (5.31 lesions on average). At lower doses, the findings were not statistically significant.
Indeed, at the lowest dose, 150 mg, the drug seemed to have the opposite effect. There was a 79 percent increase in new lesions (9.51 lesions on average) compared with placebo. The researchers said that further study was needed to understand why that occurred.
“This study shows efficacy on imaging endpoints for firategrast at the highest doses tested, and suggests that further investigation of short-acting α4β integrin blockade therapies is warranted,” the study authors concluded.
Side effects were similar across all treatment groups, except for an increase in the rate of urinary tract infections in the high-dose group.
“No cases of PML were reported during treatment and follow-up, although the risk of this complication with natalizumab is related to treatment duration and is increased after at least 2 years of treatment,” the report said. “Nonetheless, the short half-life of firategrast might confer advantages if PML is detected because cessation of treatment should allow rapid return of normal lymphocyte trafficking into the CNS, which might help to prevent progression of PML.”
In an accompanying editorial, Alexandre Prat, MD, PhD, associate professor of neurology at the University of Montreal Center of Excellence in Neuromics and MS Clinic, and Olaf Stuve, MD, PhD, associate professor of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center noted that the increase in urinary track infections in patients at the upper doses was concerning because it could suggest interference with immune surveillance by this agent. “For instance, firategrast could interfere with the ability of innate immune cells to migrate to secondary lymphoid organs to present foreign antigens, or it could have a negative effect on T-cell stimulation,” they wrote.
MORE RESEARCH NEEDED
Jeffrey A. Cohen, MD, professor of medicine (neurology) at the Cleveland Clinic Lerner College of Medicine, said more research was needed to understand why “the potency of firategrast didn't seem to be as great as that for natalizumab,” especially since they target the same molecule.
“The field is really evolving right now,” he said. Safety questions have recently been raised about one of the MS drugs already on the market, fingolimod because of reports of cardiac concerns and the death of a patient after initiation of the treatment.”
Jerry Wolinsky MD, professor of neurology at University of Texas Health Science Center at Houston, said it was noteworthy that firategrast only seemed to be effective at the upper range of tolerability. He said that while having a drug in pill form, rather than as an injection, seems desirable, it does not necessarily lead to better patient compliance. Firategrast is taken in two doses each day.
“It's an interesting article,” he said, but he said more research would be needed to determine whether patients taking firategrast experienced fewer relapses and lessening of the severity of symptoms. He noted that the question of the risk of PML also remains unclear.
Does firategrast have substantial advantages over natalizumab in regard to PML? the editorialists asked. “Miller and colleagues do not provide conclusive answers to this question,” they wrote. “We are therefore left to wonder whether firategrast is natalizumab in pill form, and whether firategrast possesses clinically and biologically relevant advantages.”
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