LYON, FRANCE—Emerging oral therapies for multiple sclerosis (MS) may be more effective than established drugs such as interferon beta and glatiramer acetate, according to research presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS).
Based on various clinical trials, investigators expect the drugs—fingolimod, dimethyl fumarate, teriflunomide, and laquinimod—to suppress inflammation, reduce relapse activity, and provide neuroprotection. “If all these oral drugs appear and deliver what they are promising to do based on the controlled studies, then the future for the ABCR drugs [Avonex, Betaseron, Copaxone, and Rebif] may be a little bit darker,” said Ludwig Kappos, MD, Chair of Neurology at University Hospital in Basel, Switzerland.
Fingolimod Reduces MS-Related Brain Volume Reduction
Fingolimod, a chemical derivative of myriocin, interacts with four of the five S1P receptors that are distributed throughout the body. In three large, prospective, phase III studies (FREEDOMS 1 and 2 and TRANSFORMS), fingolimod reduced annual relapse rate by approximately 50%. The drug was associated with a longer time to relapse and a higher number of relapse-free patients than placebo. In all three studies, fingolimod improved MS Functional Composite (MSFC) score by a statistically significant 5%. The drug also had a greater effect on inflammatory outcomes than once-weekly interferon. “The most intriguing finding” was that fingolimod decreased MS-related brain volume reduction by approximately one-third, said Dr. Kappos. The finding was consistent and statistically significant, appeared after the first six months of treatment, and persisted over time, he added. Fingolimod was associated with bradycardia that developed within one to three days of the initial dose. “If the receptor is saturated with fingolimod …, then the effect cannot be elicited again, and there is no persisting bradyarrhythmic effect after the first dose,” said Dr. Kappos.
Dimethyl Fumarate Reduces Gadolinium-Enhancing Lesions
Dimethyl fumarate is an immunomodulator that induces “a cascade of cytoprotective effects that may be important for the way it acts in MS,” said Dr. Kappos. In the phase III CONFIRM study, which compared the drug with placebo and glatiramer acetate, dimethyl fumarate had an anti-inflammatory effect on gadolinium-enhancing lesions similar to that of fingolimod. The drug’s effect on disability progression, as measured by MSFC score, was statistically insignificant, however. Dimethyl fumarate’s effect on brain atrophy also failed to reach statistical significance. In contrast to fingolimod, dimethyl fumarate was not associated with bradyarrhythmia. The drug was not associated with macular edema, but it was linked to gastrointestinal side effects that “may present an obstacle for compliance,” said Dr. Kappos.
Teriflunomide Reduces Relapse Rate
Teriflunomide “seems to have a mild immunosuppressive and immunomodulating aspect” and “could be a good oral alternative to interferons and glatiramer acetate,” said Dr. Kappos. By reversibly inhibiting dihydroorotate dehydrogenase, teriflunomide inhibits pathologic immune response. In the TEMSO and TOWER studies, 7- and 14-mg doses of teriflunomide reduced relapse rate by 30%. The 14-mg dose of teriflunomide reduced disability progression by 30%, but the 7-mg dose did not have a significant effect on this outcome. In both studies, teriflunomide and placebo were associated with a similar number of adverse events. Although serious adverse events such as hair thinning occurred somewhat more frequently with teriflunomide than with placebo, “this compound will have a place in our therapeutic armamentarium,” said Dr. Kappos.
Laquinimod Has Weak Anti-Inflammatory Effects
Laquinimod, a quinoline-3-carboxamide, appears to provide neuroprotection by reducing astrocyte activation. The drug is notable for the dissociation between its neuroprotective effect and its “rather weak anti-inflammatory effect,” said Dr. Kappos. In the ALLEGRO study, laquinimod reduced relapse rate by a “disappointing” 21%, said Dr. Kappos. The drug reduced inflammatory outcomes by 30%, which is “rather modest” compared with other compounds, he added. At six months, however, laquinimod reduced disability progression by more than 34%. In two phase III studies, the drug also decreased brain volume reduction by 30%—a rate similar to that of fingolimod. Because laquinimod did not raise safety concerns, researchers may investigate whether the dose could be increased and what effect the new dose would have on relapses. But as of now, “laquinimod is perhaps the most remote from [clinical] practice” of all the emerging oral therapies, Dr. Kappos concluded.
—Erik Greb
Senior Associate Editor