Which iMod

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There are four different S1P receptor modulators available and they include fingolimod, siponimod, ozanimod and ponesimod but how are they used.

In the USA it is simple any of the agents can be used. The labels of the FDA say “

XXXXXX (insert any of the above drugs) “is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease”

This is not surprising because all of the above target sphingosine-one-phosphate one receptor to inhibit lymphocyte migration from bone marrow, lymph glands and across the blood brain barrier. Whilst fingolimod can be used in children because the manufacturer has done the studies.

However, the situation in the European Union are different and it makes no biological sense that things are different. Currently

Fingolimod was approved over a decade ago and now

  • Fingolimod is “indicated as single disease modifying therapy in “highly active” relapsing remitting multiple sclerosis”. This means that the drug is not available for all and one has have more severe disease and is indicatwd for people “with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI”.
  • Alternatively it was indicated for “highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy”. This means that you have to have failed a treatment (first-line) to get access to the drug. i.e. it was second line.

The second line indication was not necessarility based on science, and one may say that the side-effects risks we greater than the first line agents so a cautious approach would limit access to side-effets but it cost a lot compared to cheaper first line drugs and so perhaps suited NICE’s limitation of access to fingolimod.

As can be seen below this makes no biological sense, but when siponimod came along the regulation in the EU seemed even more bonkers. Fingolimod targets S1P1, S1P3, S1P4, and S1P5 receptors compared to S1P1 and S1P5 that is targeted by siponimod yet

  • Siponimod is “indicated for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity”

So siponimod can be used in secondary progressive MS and fingolimod can be used in relapsing MS, but siponimod is not approved for relapsing MS, which seems abit strange especially as siponimod binds to the same S1P1 and SP15 receptors that ozanimoid binds too yet:

  • Ozanimod is “indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease as defined by clinical or imaging features”…..This means if there is evidence of new lesions or relapses (active disease) and you can use it for relapsing MS. This agent target the same receptors as siponimod yet this drug has to be used on a different set of people….notably in Scotland

However it has similar uses to ponesimod that binds mainly to S1P1 receprtors here

  • Ponesimod is “indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features”.

So there is a regulatory nonsense at play in th European Union where biological sense prevails in the USA. If you get a highly active agents first line, you do better than if you have failed an agent before you get the highly-active/effective agents. This is seen here with fingolimod.

Cannizzaro M, Ferré L, Clarelli F, Giordano A, Sangalli F, Colombo B, Comi G, Moiola L, Martinelli V, Filippi M, Esposito F Early use of fingolimod is associated with better clinical outcomes in relapsing-remitting multiple sclerosis patients. .J Neurol. 2022. doi: 10.1007/s00415-022-11227-3.

Background: Multiple sclerosis (MS) is a chronic autoimmune disease with huge heterogeneity in terms of clinical course, disease severity and treatment response. The need for a tailored treatment approach has emerged over the last few years. The present observational study aims to assess fingolimod effectiveness in RRMS patients, stratifying them according to the disease-modifying treatments used before fingolimod, to identify subjects who could benefit more from this treatment.

Results: The proportion of patients who maintained NEDA-3 status was higher in the naïve group despite a higher level of baseline disease activity (naïve versus first-line p = 0.025, naïve versus second-line p < 0.001)….Patients switching to fingolimod from first- and second-line treatments showed a higher (Twice to three times) risk of disease reactivation and a four to eight times, respectively shorter time to first relapse. Conclusion: Naïve patients showed a better response to fingolimod compared to patients switching to fingolimod from other drugs. Our findings support the early use of fingolimod in patients with active MS.

However, fingolimod is nearing the end of its potential patent life and it gives pretty poor COVID-19-related vaccine responses and we will see if this may be worse than other S1P receptor modulators. So which would you choose? In the USA you have choices but thsi may be less of an issue in UK/European Union.

COI: multiple but not considered relevant

Disclaimer: Thes are the views of the author

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MouseDoctor

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  • If all of the S1P’s were available to newly diagnosed / treatment naïve PWMS within the European Union, which one would offer the most benefit ?

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