Non-active SPMS more is needed


Roos from Australia has looked to see if high efficacy and platform drugs in non-active secondary progressive MS and found no difference. This Real-Life data shows that we need something different for progressive MS…

Roos I, Leray E, Casey R, Horakova D, Havrdova E, Izquierdo G, Madueño SE, Patti F, Edan G, Debouverie M, Pelletier J, Ozakbas S, Amato MP, Clavelou P, Grammond P, Boz C, Buzzard K, Skibina O, Ciron J, Gerlach O, Grand’Maison F, Lechner-Scott J, Malpas MPsych CliNeuro C, Butzkueven H, Vukusic S, Kalincik T; MSBase and OFSEP Study Groups. Effects of High and Low Efficacy Therapy in Secondary Progressive Multiple Sclerosis. Neurology. 2021 Jun 30:10.1212/WNL.0000000000012354. 

Objective: To compare the clinical effectiveness of high- and low-efficacy treatments in patients with recently active and inactive secondary progressive multiple sclerosis (SPMS) after accounting for therapeutic lag.

Methods: Patients treated with high- (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine, fingolimod) or low-efficacy (interferon β, glatiramer acetate, teriflunomide) therapies after SPMS onset were selected from MSBase and OFSEP, two large observational cohorts. Therapeutic lag was estimated for each patient based on their demographic and clinical characteristics. Propensity score was used to match patients treated with high and low-efficacy therapies. Outcomes after disregarding the period of therapeutic lag were compared in paired, pairwise-censored analyses.

Results: 1000 patients were included in the primary analysis. Patients with active SPMS treated with high-efficacy therapy experienced less frequent relapses than those on low-efficacy therapy (hazard ratio [HR] 0.7, p=0.006). In patients with inactive SPMS, there was no evidence for a difference in relapse frequency between groups (HR=0.8,p=0.39). No evidence for a difference in the risk of disability progression was observed.

Conclusion: In treated patients with SPMS, high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active, but not those with inactive, SPMS. However, more potent therapies do not offer an advantage in reducing disability progression in this patient group.

Classification of evidence: This study provides class III evidence that high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active SPMS whilst we did not find a difference in disability progression between patients treated with high- and low-efficacy therapy.

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  • MD,

    Thanks for this. A not unexpected result.

    “we need something different for progressive MS…”. We’ve known this for a while now. Unfortunately Phase 3 trials reporting to date have not had any impact.

    Any thoughts on what the something different might be. Simvastatin and Ibudilast reported effects on brain volume loss in Phase 2 trials, but Phase 3 results don’t always deliver the same. I’m not sure what drugs are being tested in the Octopus trial. I like your work on B plasma cells (Sizomus trial). Always hopeful of a Black Swan eg effective antiviral.

    PS don’t forget to cheer loudly for England. I’ll be in the Punch House from 7pm and will buy you a pint if I see you.

  • Luckily there is a btk inhibitor in a phase 3 trial being tested in SPMS.

    Sanofi is recruiting 1290 participants to test their brain penetrant btk inhibitor named Tolebrutinib in secondary progressive multiple sclerosis as well in primary progressive multiple sclerosis and relapsing forms of ms.

    This is the title for the one involving SPMS : Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES)

    • Didn’t BTK inhibitors only slow progression in progressive MS by about 30-40% in the Phase II trials? And I suspect the results will be mainly driven by the PPMS cohort, much like Ibudilast, given that late SPMS is such an advanced disease stage and so difficult to modify. And Phase III results are invariably worse than Phase II. This class of drug may not end up being much better than anti-CD20.

        • It occurs to me that there might be a very long period of therapeutic lag as was seen with the interferon beta extension study in PPMS (five years if I recall correctly). Perhaps after 5-6 years the effect on progression will grow larger after all the neurodegeneration queued by previous microglial damage burns out.

      • BTK inhibitors have never been tried in progressive ms so far but have a lot of potential for people with spms and ppms . The phase 2 trial was oNLY tested in rrms. Also the trial I put in the link is recruiting oNLY spms. They want 1290 participants of spms for this trial. They have another completely SepErAte trial testing it in ppms and another 2 completely separate trial for rrms.

        Btk inhibitors are interesting because :

        1. They block B cell function in the blood and should whithin the brain

        2. Innate immunity such as microglia and macrophages are in part btk dependent so they will also be affected ( reduced in activity relating to inflammation )

        3. Btk inhibitors are effective against these B cell population that are typically resistant to anti-cd20 especially activated plasma blasts.

        Stephen L. Hauser, MD: Fenebrutinib and BTK Inhibiton in Progressive MS

        • Masitinib has been trialed in progressive MS already (see my comment above). I’m not sure if the others have or not.

      • “Didn’t BTK inhibitors only slow progression in progressive MS by about 30-40% in the Phase II trials?”

        Where’s the data on this? I don’t think progression was measured in any of the BTK phase 2 trails. Well not publicly announced

  • Round and round on the merry-go-round we go, sometimes on the lion, sometimes the mare, sometimes the unicorn, sometimes the bear.

    Most often on the donkey though, and going nowhere.

    Yours frustratedly,

    An acerbic PwPPMS.

  • I read the full article and I noticed that in the active SPMS cohort 79.1% of patients were treated with either natalizumab or fingolimod, with another 16.9% being on mitoxantrone. In the inactive SPMS cohort, 58.3% of patients are on natalizumab/fingolimod plus 37.1% on mitoxantrone. The rest of drugs (Ocrelizumab, Rituximab, Alemtuzumab, Cladribine) only amount to 4% and 4.6% of, respectively, the first and second cohort of patients treated with high efficacy drugs. It looks to me that this study shows that Natalizumab, Fingolimod, and Mitoxantrone have no effect on progression in SPMS, but it can’t say much about the effects of rest of the drugs mentioned. Thoughts on this?



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