How to manage RRMS – induction followed by maintenance

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I’ve been harping on about this strategy for the better half of the past two years, and lo and behold someone has actually done it, and it actually works. The drugs utilized in this study are in fact irrelevant, the importance is the strategy itself.

What strategy you ask?

Rodo’s Thinker!

I’m glad you asked. The one where you go in with all guns blazing and then follow it up with diplomacy. In the world of MS immunotherapy, this a highly active induction treatment taken at intervals to achieve immunodepletion, followed by regular maintenance treatment that happens to be less efficacious.

ABSTRACT

Honce et al. Rituximab vs placebo induction prior to glatiramer acetate monotherapy in multiple sclerosis. Neurology. 2019 Jan 11. pii: 10.1212/WNL.0000000000006916.


OBJECTIVE: To examine whether rituximab induction followed by glatiramer acetate (GA) monotherapy is more effective than GA alone for the treatment of relapsing multiple sclerosis with active disease.
METHODS: This was a single-center, double-blind, placebo-controlled study. Fifty-five participants were randomly assigned (1:1 ratio) to either rituximab (R-GA) or placebo (P-GA) induction, followed by GA therapy initiated in all participants. Participants were followed up to 3 years. The primary endpoint was the number of participants with no evidence of disease activity (NEDA): those without relapse, new MRI lesions, and sustained change in disability.
RESULTS: Twenty-eight and 27 participants received rituximab and placebo induction, respectively, with one participant in each arm withdrawing before 6-month MRI. There were no significant differences in baseline characteristics. At end of study, 44.44% of R-GA participants demonstrated NEDA vs 19.23% of P-GA participants (p = 0.049). Treatment failed for a smaller proportion of R-GA participants (37.04% R-GA vs 69.23% P-GA, p = 0.019), and time to treatment failure was longer (23.32 months R-GA vs 11.29 months P-GA, p = 0.027). Fewer participants in the R-GA arm had new lesions (25.93% R-GA vs 61.54% P-GA, p = 0.009), and there were fewer new T2 lesions (0.48 R-GA vs 1.96 P-GA, p = 0.027). Probability of demonstrating NEDA in the R-GA arm returned to baseline within the study period. There were no differences in adverse events.
CONCLUSIONS: Induction therapy with rituximab followed by GA may provide superior efficacy in the short term than GA alone in relapsing multiple sclerosis, but this benefit appears to wane within the study period. Larger studies are needed to assess sustainability of results.
CLINICALTRIALSGOV IDENTIFIER: NCT01569451.

Roughly 44% had no evidence of disease activity (NEDA) on rituximab induction treatment followed by glatiramer acetate (Copaxone) maintenance treatment, whilst only 19% on placebo (or dummy) induction followed by glatiramer actetate achieved NEDA. In another words the induction-maintenance strategy is better than the old maintenance strategy alone.

Great you say, I would agree with you on that one. NEDA, which includes not only no relapses, but no MRI activity or disease progression based on worsening disability is a hard target to achieve. But, the authors are somewhat missing the point. The main reason for utilizing this strategy is not to improve the effectiveness of a lesser treatment (in this case glatiramer acetate) by going first with a more highly active treatment, but in fact, de-risking MS treatments all together. Since, all aficionados in this field have been discussing is how we seem to have more choice than ever before for treating MS, but they’re all scary possibilities; because of the PML risk. This then is exactly the type of strategy to use in treating RRMS when you want to avoid PML and other nasty infections, cancers etc.

Am I miffed that someone has already done it before us? No, not at all. This is the strategy for the future, and it’s about time we moved it along.

What about if you break-though in disease activity in the maintenance phase, you ask? Well, simply go all the way back for another induction phase. And hey presto, RRMS is sorted!

About the author

Neuro Doc Gnanapavan

24 comments

  • Have you considered the possibility that the GA did nothing at all?
    Instead of R-GA vs P-GA , R-P vs R-GA would have been a more useful test

    Another possible explanation of these results:
    – the 19% NEDA in the second group is because of milder disease
    – the benefit wanes because rituximab does need to be repeated

    This study is just trying to show that GA has a role

    • So your design is a different concept all together and tests a pure induction strategy against a combi strategy if that makes sense. It would not be possible to tease out the rituximab effect on this as there maybe a combined effect of using rituximab and glatiramer together.

  • Have you considered the possibility that the GA did nothing at all?
    Instead of R-GA vs P-GA , R-P vs R-GA would have been a more useful test
    It would have shown whether the GA is useful

    Another possible explanation of these results:
    – the 19% NEDA in the second group is because of milder disease
    – the benefit wanes because rituximab does need to be repeated

  • I’m not convinced, but just for this particular use case, not about the general principle. To be sure, we would have to compare not R-GA and P-GA, but R and R-GA. How do you know that the effect is not mainly because of Rituximab and GA’s effect is negligible at best? Yes, in principle this all makes sense, but as you said many times on this blog, we need evidence to be sure. GA has A LOT of problems with adherence, maybe it would be better to use some of the oral DMTs (yes GA doesn’t have PML problems, but if people doesn’t take it because of the AEs, it is pointless to start in the first place – unless you work/have shares for Teva).

    • One way to look at this study design is to realise that the treatment under question is not glatiramer but rituximab! Glatiramer is already licensed for MS, if we want to keep using rituximab off label then efficacy data is important…

  • I’m not convinced, but just for this particular use case, not about the general principle. To be sure, we would have to compare not R-GA and P-GA, but R and R-GA. How do you know that the effect is not mainly because of Rituximab and GA’s effect is negligible at best? Yes, in principle this all makes sense, but as you said many times on this blog, we need evidence to be sure. GA has A LOT of problems with adherence, maybe it would be better to use some of the oral DMTs (yes GA doesn’t have PML problems, but if people doesn’t take it because of the AEs, it is pointless to start in the first place – unless you work/have shares for Teva).

  • “What about if you break-though in disease activity in the maintenance phase, you ask? Well, simply go all the way back for another induction phase. And hey presto, RRMS is sorted!”

    This is exactly the problem of MS management: Neuros pretending the illussionists with RRMS while neglecting the most important aspect of MS which is neurodegeneration. Any benefit RTX can have to progressive MS is of no importance when is limited to a small window in therapy. Good as a test, bad as a medical example.

    • I understand your comment, but a lot needs to be considered when using highly active drugs as induction treatments more frequently than currently used in MS. Of course as you learn not only about the mono therapy effect but about the combination effect, you can then time when the next induction course is given. But the steps still need to be done. Also, breakthrough activity is not necessarily clinical activity but an extra lesion on a scan or raised neurofilament level. The better the NEDA status the good the treatment plan.

      • Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis

        In this cohort study involving 1555 patients with relapsing-remitting MS, initial treatment with fingolimod, natalizumab, or alemtuzumab was associated with a lower risk of conversion to secondary progressive MS compared with interferon beta or glatiramer acetate (hazard ratio, 0.66).

        https://jamanetwork.com/journals/jama/article-abstract/2720726

  • 18 months post HSCT for PPMS here. Prior to HSCT my rate of progression was the same for 15 years…very slow. I tolerated HSCT well until around four months post HSCT when my walking began to deteriorate. I have not returned to pre-HSCT walking level despite consistent PT. Both HSCT doc and neurologist suggest trying Ocrevus but if HSCT made me worse, how could Ocrevus help me? And could it make me worse as well? And yes, my HSCT doc confirmed that it is possible for HSCT to make one worse. He also said that at 18 months post it is highly unlikely that worsening is only from recovery roller-coaster. 🙁 I would prefer to try Rituximab as I had 1,000 mg of Rituximab as final part of HSCT and tolerated it well, but my insurance will not pay and I can’t find anyone who will infuse even if the drug company gives me the drug free of charge. Are there certain blood tests or other measures I should take before trying Ocrevus? I have long suspected a viral implication (Herpes) that set my MS in motion as I began to have symptoms shortly after contracting this virus. And I was originally diagnosed with single demylenating episode, and the doctor said he suspected it was caused by a virus. Should I do some type of test to determine viral load prior to Ocrevus? If so, what test? Many thanks for any info.

  • I’m waiting for an article and study that will describe post HSCT maintenance therapy.
    How about HSCT – Rituximab?

    • How about HSCT-Rituximab?….I think this is called HSCT Mexican style:-), isn’t this the treatment that Caroline Wyatt recieved

          • I’d be happy to top up with cladribine in a while. The thing is, I don’t want any more disease breakthrough. So if there was a med which could lower this risk in a safe way, I’d be happy to take it of course.

      • She’s not thst famous outside UK but this is what I have found:
        ‘The final infusion was a dose of Rituximab, a monoclonal antibody that targets a protein called CD20 that is found on the surface of white blood cells called B-lymphocytes or B-cells.’
        I would say it was part of her HSCT therapy, not the maintenance therapy after transplant. I’m already aware of ‘ Russian style ‘ maintenance – prescribing few doses of RTX when patient has relapsed. Similarly it should work with Ocrelizumab, wouldn’t it?

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