It’s been a while since i wrote last post, but NeuroImmunology has been busy with several other projects. It’s been a while too since i decided to write a monographic post about the different oral treatments that are already available or are about to arrive but i postponed it until i had enough time to do it carefully. I will try to clarify the different pros and cons of the oral treatments in general and of each one in particular. It’s also an attempt to organize my ideas about the subject. Until very recently the only disease-modifying treatments available for MS were injected therapies (I say disease-modifying because steroids are only used for relapses and do not modify the course of the disease in the long-term). Interferon and glatiramer acetate (subcutaneous or intramuscular), mitoxantrone (intravenous) and, more recently, natalizumab (intravenous) were the only available options for MS. In some countries people used intravenous immunoglobulins (IVIg), azathioprine (oral) and cyclophosphamide (oral or intravenous) but the evidence for their use in MS is very weak and they were not considered standard treatments for MS. Several major claims and complaints of patients with MS related to the treatment route of administration. Needles, need for portable fridges, problems in the airports and customs, an injection every two days, subcutaneous nodules, risk of infections… So, research on oral therapies was one of the main targets of researchers and companies and one of the things patients are more interested and askabout more often. And oral therapies finally arrived. At this moment there is only one treatment fully available in Europe, fingolimod (Gilenya), four more laquinimod, BG-12 (dimethyl fumarate) teriflunomide and cladribine have completed phase III trials and another one, firategrast, is still on phase II trials but shows promising results. The first and most obvious advantage
A few days ago we had access to this alert in Medscape. An MS patient, that had completed the 6-hour vigilance period after the first dose of fingolimod, died unexpectedly the next day. We don’t know much about it and we should wait until this case is resolved and an official report released. We only know that the patient was already taking beta-blockers and calcium channel antagonists, with bradycardia among their side effects. However, it re-inforces my view that Fingolimod safety has to be carefully followed-up. Anyway, one important message is that an oral treatment, a pill, does not necessarily have to be safer than a biological treatment. It may be easier to take for patients but not necessarily innocuous.
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.
First, the good news, a week ago the EMEA informed positively for Gilenya (Fingolimod) approval. This will expand the spectrum of therapeutic options for patients with multiple sclerosis and will fulfill the long desired availability of oral drugs for that chronic disease. The bad news are that only selected patients will have access to this new drug and will not need to inject anything. Candidate pantients will be those that do not respond to a complete “a full and adequate” course of Interferon beta or those with high activity at the begining of the disease. This indication copies that of the Tysabri and restricts quite a bit the number of candidate patients. It is quite surprising that EMEA had not reserved a third indication for those that have cutaneous or systemic side effects wih current treatments, mostly when the great advantages that fingolimod pills add are comfort in administration and tolerance, and not efficacy that only slightly overtakes that of interferons. On one hand we may have an alternative for those patients with increased activity in which we think natalizumab may be too much but in the other hand this can delay natalizumab start in those patients who really deserve it. Anyway, Gilenya approval is good news for the Neuroimmunology community and hope we can have it available the sooner to treat MS. For details, find attached the EMEA report.