In mourning and licking my wounds…but the CRAB drugs are amazing and all made out of stardust:-)

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Yesterday I was involved in a debate “Anti-CD20 therapies should be used as Immune Reconstitution Therapies rather than maintenance therapies“. I feel that I got a preverbial ass-kicking and the audience favoured keeping the status Quo and treating with anti-CD20….forever.

My take was that the biology and preliminary data is reasonably clear but we need a trial to address the safety and efficacy of this approach…….Will it ever happen? ProfG has his DoDO (Double Dose) trial giving more and more ocrelizumab, so hardly any time to do an ADIOS (Adaptive dosing) study to give less and less.

However, stopping was portrayed as having a fear factor……which is strange given that it is well-known that stopping rituximab and ocrelizumab is not associated with rebound-type disease, associated with stopping migration inhibitors (natalizumab/fingolimod).

First we had a mouse study that is a dogs-breakfast of a paper on so many levels and suggested that repopulating B cells were activated. There was a follow up study in humans which one could also ask questions about the interpretations and how it sits with current knowledge. However, that is too nuianced and people accept the headlines. Anecdote is no antidote for evidence. Maybe I am interptreting data wrong. For example the CRAB drugs are amazing and all made out of stardust

Bovis F, Kalincik T, Lublin F, Cutter G, Malpas C, Horakova D, Havrdova EK, Trojano M, Prat A, Girard M, Duquette P, Onofrj M, Lugaresi A, Izquierdo G, Eichau S, Patti F, Terzi M, Grammond P, Bergamaschi R, Sola P, Ferraro D, Ozakbas S, Iuliano G, Boz C, Hupperts R, Grand’Maison F, Oreja-Guevara C, van Pesch V, Cartechini E, Petersen T, Altintas A, Soysal A, Ramo-Tello C, McCombe P, Turkoglu R, Butzkueven H, Wolinsky JS, Solaro C, Sormani MP. Treatment response score to glatiramer acetate or interferon beta-1a. Neurology. 2020 Oct 6:10.1212/WNL.0000000000010991. doi: 10.1212/WNL.0000000000010991. Epub ahead of print.

Objective: To compare the effectiveness of glatiramer acetate (GA) vs intra-muscular Interferon beta-1a (IFNbeta-1a)), we applied a previously published statistical method, aimed at identifying patients’ profiles associated with efficacy of treatments.

Methods: Data from 2 independent multiple sclerosis datasets, a randomized study (the CombiRx trial, evaluating GA vs IFNbeta-1a and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors.

Results: The overall ARR ratio of GA vs IFNbeta-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration and EDSS) detected differential response of GA vs IFNbeta-1a: in the trial, patients with the largest benefit from GA vs IFNbeta-1a (lower score quartile) had an ARR ratio of 0.40 (95%confidence interval [CI] = 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI = 0.61-1.34) and those in the upper quartile of 1.14 (95%CI = 0.59-2.18) (heterogeneity p = 0.012); this result was validated on MSbase, with the corresponding ARR ratios of 0.58 (95% CI = 0.46-0.72), 0.92 (95% CI = 0.77-1.09) and 1.29 (95% CI = 0.97-1.71); heterogeneity p < 0.0001).

Conclusions: We demonstrate the possibility of a criterion, based on patients’ characteristics, to choose whether to treat with GA or IFNbeta-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice.

So a relapse rate of 0.72, so in my mind seven times of what I think should be reasonable….but I wonder if the great and the Good disagree…I am sure they say….GA and beta intererfon are amazing and it is all made out of stardust,

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MouseDoctor

16 comments

  • My Daily Generic Copaxone (Glatopa) shot is sitting out to warm up.
    I was in the CombiRx Study from diagnosed 2007-2014. Randomized to only Copaxone.
    I have been stable for 13 years. Per Neurologist testing. Stopped working about 5 years ago.
    I keep reading about new and improved drugs. Feeling so Old School 🤦‍♀️
    Waiting for you to write about gadolinium retention which I feel might be a bigger problem.
    Meanwhile will stay on daily shots. Never offered new and improved drugs. I’m ok with my current path.

  • They are overdosing with these new drugs adding insult to injury. Was on Gilenya, had to come off because it was not a good option with T1d. Then Tysabri & my jcv levels shot right up, doubling & then tripling. I chose to get off of that one, I don’t need PML on top of my myriad of health issues. Next Ocrevus. My blood levels were drawn same day as my 6 month follow-up treatment. Going by my blood levels, I did NOT need the follow-up infusion they had just given. 6 months later I asked for blood work prior to infusion. Again, not even close to needing it. I made the choice to forego the med as it’s side effects were not worth it. I’m still progressing by EDSS but no new major lesions. I don’t see the point of continuously pouring poison into my body if its not working & not helping & making me actually feel worse, especially when my blood work shows there’s no need for it. It’s been 9 months since last infusion. If in fact I can try anything else i.e. Mavenclad, it’ll be a long time before my blood work will allow that. I’m still at an all time low! I think these drugs killed those cells completely dead forever & here I am still progressing.

    • Based on available data the range of repletion is 27 -175 weeks that is 7 months to three and a bit years with the middle value being 15-18months. This is level in the bllod progression I believe results from action in the brain and this is not effectively targeted.

  • I admire your patient first approach giving only.doses needed to stop ms. But do you really think pharma is going to cut their own knoses to spite their faces? Have constant stream of money and Only have a 2-4 years of revenue for their most lucrative drug? Why do you think prof g is baiting them let’s see what happens with double doses to research budget and if we can further reduce brain inflammation from 99% to 99.999999%. Wow. and people wonder why there’s so much cynicism in this world. But you get my vote MD

    • But do you really think pharma is going to cut their own knoses to spite their faces? ….No
      However their noses may then bite them in the bum as someone does that with another agent, Then it is too late to do the study. e.g. if you had de-risked secondary autoimmunity with alemtuzumab before ocrelizumab came along, the picture could be different now…but once ocrelizumab came along most people said who cares about using alemtuzumab, I will just use ocrelizumab.

      However it needs academics to do the study so their is the evidence…most won’t challenge the status quo but if safety issue raises its head at least the evidence is there to do someting about it.

      The double dose study is going ahead…the insurance companies will pay for it if it works?

      • Thanks MD. You make perfect sense as usual. Too bad the insurance companies won’t pay for you study. But in scale of economies pharma know whats in the pipeline and because they’ve engineered the process to take 10 to 15 years. They calculate as follows. 15 x yearly revenue vs 4 x yearly revenue. That would still give them 4 decades of revenue if they used correct dose. By then who knows a mvarick scientist with some balls and integrity that makes him/her selfless enough to afind cure. Here’s hoping for new Barry marshals or MDs of this world.

        • If Genzyme and Merck can formulate profitability from alemtuzumab and cladribine this can be done with other agents… however it is a matter of a little time that the patents run out then generics come along and the expensive drug is the neuroprotective on top and a cheap DMT on bottom

    • Pharma would be all over a cure. You take all the market and price it higher than current therapies to boot. Dream scenario really.

      • I really don’t know about that. If patients were really cured, they wouldn’t need to take (sometimes) $100k+ a year in other medications for the rest of their lives. In the long run, they’d be losing money. It really seems like a patent expires they just get a new patent on a slightly reformulated version of the same thing.

        • Which people then may or may not pay similar money for.

          Besides,
          1) no guarantee that the next 100k goes to the same pharma company
          2) little money to be made from patients converting to SPMS for lack of truly convincing drugs
          3) large upfront revenues helps managements’ stock options tremendously
          so big incentive to grab money up front.

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