An emerging and very important differentiator in the MS space is rebound activity that occurs when stopping a therapy. The MHRA have now made this a reportable, or yellow-card, event. It is good to see the regulators taking such a keen interest in such an important issue. Maybe they are begging to flex their muscles before the EMA departs after Brexit.
MHRA: Multiple sclerosis therapies: signal of rebound effect after stopping or switching therapy. April 2017.
Healthcare professionals should report any suspected adverse effects relating to fingolimod (Gilenya▼) or other treatments for multiple sclerosis, including suspected adverse effects occurring after discontinuation, via the Yellow Card Scheme.
We are aware of two recently published articles1 2 describing a suspected rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected for that patient prior to discontinuation or treatment change) in patients with multiple sclerosis after treatment with fingolimod (Gilenya▼) was stopped, some of whom were switched to other treatments.
In conjunction with other European national regulatory authorities and the European Medicines Agency, we are evaluating all available evidence on this safety signal. Further information on the outcome of the review and any relevant new guidance will be issued as soon as it is available.
Healthcare professionals are reminded to be vigilant for such events and report any suspected adverse effects relating to fingolimod or other treatments for multiple sclerosis via the Yellow Card Scheme.
For any reports of suspected rebound effect, please provide as much detail as possible. This could include any clinical, imaging and other test details; along with a description of disease activity prior to and during therapy.
Article citation: Drug Safety Update volume 10, issue 9, April 2017: 3.
Hatcher SE et al. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol 2016; 73: 790–94.
Willis M et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2017; 4: e320.
"The MHRA is aware of two recent articles about rebound post fingolimod"Get ready for another one. We have one that will be reporting soon.What defines a rebound over natural history and attacks, given that no disease modifying treatment is 100% effective attacks on or off any drug will have a chance of occuring.However anti-migration drugs may not stop the disease process and keep cells in the periphery "under starters orders" to race into the CNS. So once the drugs are removed BAM an attack can occur. So will we have to yellow card pregnancy :-)?However a carefully constructed mechanism of action has been constructed that says that fingolimod traps white blood cells in the lymph glands. It is a nice simple argument that we have all bought into, but now it will bite them in the bum as it is yellow card in the making.Do we get do we get buster gonad…of lymph nodes reaady to explode because they are full of cells…MD2 looked…and the answer was no. When looking into this when asked about B cells, it is evident that the cells that circulate into lymph glands are lacking in the blood, but the population in the blood would contain the cells where I would assume the pathogenic cells are. However, when you look at absolute numbers there less cells so it is depleting cells and maybe a reason why fingolimod rebounds are still uncommon. However there is an oppertunity to see what cells reappear with the rebound as it may tell us what the causal cell type is. However when we look for this we will see that some people do not repopulate very well…good news may be that they will not rebound, back news could be that they are immunosuppressed.However, surely it does that mean one has to have a strategy for switching drug in place before you start any new treatment and it has to a question you have to ask!Would it be fair that a drug accumulates lots of yellow cards because the neurologists have not made a plan and washed the drug out leaving disease to return, without having a plan to stop what is probably going to occur.The responsibility will be put on the company to give neurologists that switch plan ASAP.Therefore the decision tree perhaps becomes harder because not only do you have to chosse your drug and balance side effects and efficicacy but you have to consider the switch and how your previous history impacts on the effects likely to be seen on the future. However if all MS drugs work because of depleting memory B cells, which the may not, this would now become alot easier.
Begging…or beginning..?