The last issue of the Lancet Neurology journal, has published the extension phase study of the TRANSFORMS trial. Briefly, the TRANSFORMS trial was a randomized controlled trial comparing i.m. interferon beta 1a versus two different doses of fingolimod (0.5mg and 1.25mg). Its results were published on New England Journal of Medicine on February 2010, together with FREEDOMS, a Fingolimod versus placebo trial and CLARITY, a cladribine versus placebo trial. It showed a better perfomance than interferon in annualized relapse rate, with a concerning profile of side effects and some red flags, such as the risk of developing skin neoplasms or herpetic infections. Despite that, the overall performance in that study led to its approval by the FDA and EMEA but, while its being commercialized already in the US, it’s still on its way to the pharmacy in Europe.
In the controlled phase of the trial relapse rate with fingolimod was about a 50% lower than with interferon, and 80% o f patients remained free of relapse with fingolimod while only 63% of them were free of relapse with interferon in the first year of the study. Those were quite good results. There were also good results in MRI parameters. However there were no differences in disability outcomes, in one hand probably because the EDSS is not that a precise measure and in the other hand because overall relapse rates were pretty low. Significant side effects were present in the fingolimod arm, mostly on the high those arm, being the most concerning ones two deaths of herpes virus infections (one varicella zoster and one herpes simplex encephalitis). Another intriguing fact was the higher incidence of skin neoplasms (basal cell carcinomas and in-situ melanomas) in the fingolimod arms. Also heart conduction blocks and macular oedema were more frequent on patients taking fingolimod.
With this background, an extension phase of the trial was started, switching all patients previoulsy on interferon to one of the two doses of fingolimod. It must be said that, the extension phase of the study was not blinded anymore. This extension phase does not add very much to the initial findings but confirms the good efficacy results shown on the first year and clearly demonstrates a reduction on relapse rate in the group of patients treated with fingolimod compared to their first year on the study, when they were on interferon. The reduction on relapse rate was abut 30% compared to that on the first year when patients were on interferon.
Side effects looked pretty similar to those on the first year, also more frequent on the high dose arm, but probably with a slight decrease in the percentage of patients suffering severe adverse events, including death and skin neoplasms.
The data on this extension study, though not new and probably biased by the unblinded uncontrolled nature of the study, provide additional support for Fingolimod as a strong, more effective and, most importantly, oral alternative to current conventional treatments. However, its safety issues make us wonder if it could be better, and even more tolerable, having a monthly iv treatment far more powerful, specific and, attending to the trials (and not post-commercialization surveillance studies, still lacking in fingolimod) almost as safe, called Natalizumab.