Advances in oral immunomodulating therapies in relapsing multiple sclerosis. Derfuss T, Mehling M, Papadopoulou A, Bar-Or A, Cohen JA, Kappos L.Lancet Neurol. 2020 . pii: S1474-4422(19)30391-6.
BACKGROUND: Oral treatment options for disease-modifying therapy in relapsing multiple sclerosis have substantially increased over the past decade with four approved oral compounds now available: fingolimod, dimethyl fumarate, teriflunomide, and cladribine. Although these immunomodulating therapies are all orally administered, and thus convenient for patients, they have different modes of action (Treatment is complex). These distinct mechanisms of action allow better adaption of treatments according to individual comorbidities (The side-effects are different due to their different mechanismsof action) and offer different mechanisms of treatment such as inhibition of immune cell trafficking versus immune cell depletion, thereby substantially expanding the available treatment options (However, if we said they work the same way, with some better than others and some more convenient and safer than others. Then choices could be easier)
RECENT DEVELOPMENTS: New sphingosine-1-phosphate receptor (S1PR) modulators with more specific S1PR target profiles and potentially better safety profiles compared with fingolimod were tested in patients with relapsing multiple sclerosis (There is a glut of new imods coming and many work the same way and some more specific than others). For example, siponimod, which targets S1PR1 and S1PR5, was approved in March, 2019, by the US Food and Drug Administration for the treatment of relapsing multiple sclerosis including active secondary progressive multiple sclerosis. Ozanimod, another S1P receptor modulator in the approval stage that also targets S1PR1 and S1PR5, reduced relapse rates and MRI activity in two phase 3 trials of patients with relapsing multiple sclerosis. Blocking of matrix metalloproteinases or tyrosine kinases are novel modes of action in the treatment of relapsing multiple sclerosis, which are exhibited by minocycline (this drug is never going to be devleoped as a commercial entity as it is too old) and evobrutinib, respectively. Minocycline reduced conversion to multiple sclerosis in patients with a clinically isolated syndrome (This is funny as it was suggested that minocycline is a blocker of microglial activity). Evobrutinib reduced MRI activity (but not in the same league as other agents) in a phase 2 trial, and a phase 3 trial is underway, in patients with relapsing multiple sclerosis. Diroximel fumarate is metabolised to monomethyl fumarate, the active metabolite of dimethyl fumarate, reduces circulating lymphocytes and modifies the activation profile of monocytes, and is being tested in this disease with the aim to improve gastrointestinal tolerability (but it still has to be taken twice a day) . The oral immunomodulator laquinimod did not reach the primary endpoint of reduction in confirmed disability progression in a phase 3 trial of patients with relapsing multiple sclerosis (It is dead and buried and not worth talking about) . In a phase 2 trial of patients with primary progressive multiple sclerosis, laquinimod also did not reach the primary endpoint of a reduction in brain volume loss, as a consequence the development of this drug will probably not be continued in multiple sclerosis (I think we can say it will not be continued). WHERE NEXT?: Several new oral compounds are in late-stage clinical development (Loads more of the same thing..a few imods and some fumarates). With new modes of action (Is this really true) introduced to the treatment of multiple sclerosis, the question of how to select and sequence different treatments in individual patients arises (Should we start with drugs that are most efficacious first and if they all work the same way the choices are easier). Balancing risks with the expected efficacy of disease-modifying therapies will still be key for treatment selection . However, risks as well as efficacy can change when moving from the controlled clinical trial setting to clinical practice. Because some oral treatments, such as cladribine, have long-lasting effects on the immune system, the cumulative effects of sequential monotherapies can resemble the effects of a concurrent combination therapy. This treatment scheme might lead to higher efficacy but also to new safety concerns . These sequential treatments were largely excluded in phase 2 and 3 trials; therefore, monitoring both short-term and long-term effects of sequential disease-modifying therapies in phase 4 studies, cohort studies, and registries will be necessary.