Are We Close to Understanding the Role of Fingolimod in the Treatment of MS?
Abstract & Commentary
By Susan Gauthier, DO, MS, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Gauthier reports no financial relationships relevant to this field of study.
Synopsis: Patients originally on interferon beta-1a in the TRANSFORMS study were re-randomized to either 0.5 or 1.25 mg of fingolimod. There was a reduction in relapse rate and MRI activity in patients that switched to fingolimod without an increase in severe adverse events.
Source: Khatri B, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: A randomized extension of the TRANSFORMS study. Lancet Neurol 2011;10:520-529.
Fingolimod recently was approved by the FDA at the 0.5 mg dose for the treatment of relapsing forms of multiple sclerosis (MS). As a sphingosine 1-phosphate receptor agonist, the adverse event profile differs significantly from current first-line immunomodulatory agents (IMA) used to treat MS, and it still has yet to be determined where this agent will fall within our treatment algorithm. To advance our understanding of fingolimod, patients within the TRANSFORMS core study were enrolled into an extension study for which the clinical benefit and safety of switching to fingolimod from interferon beta-1a (IFN b-1a) was studied.
In the original 12-month study, patients were randomized to receive either IFN b-1a, fingolimod 0.5 mg, or fingolimod 1.25 mg where a significant benefit of both doses of fingolimod compared to IFN b-1a was found by both clinical (relapse rate) and MRI outcomes. In the TRANSFORMS extension study reported here, the patients originally assigned IFN b-1a were re-randomized to receive either 0.5 mg or 1.25 mg of fingolimod, and those patients assigned to fingolimod during the core study remained at the same dose. After an additional 12 months of treatment (months 13-24), the groups were compared by clinical, MRI, and safety measures. There was a 30% and 36% reduction in annualized relapse rate (ARR) in months 13-24 in patients that switched to 0.5 mg and 1.25 mg of fingolimod, respectively. The ARR for months 13-24 in both switched groups was still higher than those patients that remained on fingolimod; therefore, the 24-month (core + extension) ARR for the continuous fingolimod groups remained less than those that switched. Likewise, there was an improvement in new T2 and contrast-enhancing lesions in the switched groups during months 13-24. There was also a reduction in brain atrophy rate in months 13-24 months in patients that switched to fingolimod. However, this rate was lower than the rate found in the patients continuously treated with fingolimod; consequently, the 24-month atrophy rate was similar across groups. There was no difference in disability in the core or extension phases. The adverse event profile in the patients that switched from IFN b-1a to fingolimod was lymphopenia, abnormal hepatic enzyme levels, first dose bradycardia, and three cases of macular edema, all of which were expected. Importantly, the rate of infectious adverse events did not increase with a switch to fingolimod. Adverse events in months 13-24 in the continuously fingolimod-treated patients remained stable.
The current study demonstrates the clinical and MRI benefits of switching to fingolimod from IFN b-1a without a significant compromise on safety. Given the beneficial treatment affect of fingolimod over IFN b-1a in the core study (0-12 months), it isn't surprising to see a benefit after switching, although the design of this switch study is much preferred to observational studies given that patients are matched and randomly assigned to treatment. However, both phases of the TRANSFORMS study are extremely short; thus we can only state that fingolimod has short-term superiority over IFN b-1a. The lower relapse rate in patients continuously treated with fingolimod compared to those that switched in months 13-24 might indicate that a delay of fingolimod treatment is detrimental, but long-term disability data is required to make that determination. Of note, the immunomodulatory agents have established long-term safety profiles, and we have no long-term safety data on fingolimod or information regarding the effects of chronic lymphopenia induced by this drug. In addition, the long-term infectious and malignancy risks remain to be seen. Thus, as it now stands, the role of fingolimod for the treatment of MS is less likely to be as a first-line treatment, but reserved as an option when patients fail their initial IMA.