Advances in oral immunomodulating therapies in relapsing multiple sclerosis

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. These distinct mechanisms of action allow better adaption of treatments according to individual comorbidities and offer different mechanisms of treatment such as inhibition of immune cell trafficking versus immune cell depletion, thereby substantially expanding the available treatment options. 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. 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 and evobrutinib, respectively. Minocycline reduced conversion to multiple sclerosis in patients with a clinically isolated syndrome. Evobrutinib reduced MRI activity 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. 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. 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. S