Saturday, 20 February 2016

Results from the PPMS Trial

The presentations of Prof Wolinsky at Atrims 2016 are online



Here's the Poster
Actrims 2016 oratorio lb poster wolinsky_lb148 from BartsMSBlog

There was a difference in atrophy rate between placebo and ocrelizumab, when only  you look at gadolinium at baseline verses no gadolinium the results were not difference but the groups were too small to show a difference however people had more MRI than just at baseline and why it was not gadolium positive at any time verses non gadolinium makes me wonder.

So as presented you can not say it only works in  people with active disease

CoI ProfG was a Co-author

14 comments:

  1. Can you please, please do a post on what you perceive the future of PPMSers may be now as a result of this reporting.

    Will these drugs be a sea change, for example? Will only newly diagnosed PPMSers benefit or will all of us get access? Is there any benefit for old PPMSers being given this drug? Is there a degree of smoke and mirrors at play in Roche's reporting?

    Ultimately, are you convinced by what you're hearing?

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  2. At baseline, only 25-27% of patients had gadolinium-enhancing lesions, so the patient selection was not such that the deck was stacked with people with inflammatory disease.

    As they found no difference between the results of active vs. Non active disease at baseline, this seems like good news for all PPMSers.

    I would be interested to know what the percentage of PPMSers had MRI activity in the failed Rituximab trial?

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    1. The way Team G (or should I say MD) was speculating, 100% of patients would have had Gd+ lesions at baseline. 25% is a far cry from this so it is hopeful this has an effect on progression.

      As far as the other trials for progressive disease (Fingolomod and Copaxone) that either failed or were stopped early, the GD+ at baseline was only 15%, but the number of patients was too low to detect any effect.

      This was proven by looking at the male subgroup in the Copaxone trial which showed a statistically significant effect in this population. This is no doubt because males progress faster than females which is why an effect could be detected:

      http://www.ncbi.nlm.nih.gov/pubmed/19426995

      Mouse Doctor shrugs these findings off. I guess he wants a PPMS trial with zero Gd+ at baseline.

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  3. The standard error (the tails on the bar chart) on the placebo arm tightens up in Gd- population (not surprised there); this goes for walking times and T2 lesions. My interpretation therefore is that any disease activity is bad news. Beyond this, haven't a clue what they were looking for, it makes no sense.

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    1. Looking forward to something sensible as the data on T1 black holes...

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    2. Actually, the error bars get tighter for the GD- data because there is substantialy more patients in this subgroup than in the Gd+ subgroup, thus the uncertainty goes down. It's not due to enhancment status.

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    3. thanks for the commentary, it identifies my confusion

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    4. Good pick up, skipped over that slide on the power. Maybe what I want is the standard deviation rather than the error.

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  4. FOR ME THE SUN DOESN´T SHINE THE WAY IT DOES IN ROCHE´s SALES DEPARTMENT

    First of all, I think this ORATORIO with Ocrezilumab is influenced by some biasis.

    To my best understanding, 15% of the patients have gadolinium acitivity at baseline. Now in this study, around 25% (24.7 % placebo and 27.5% in active arm) had Active +GD lesions at start. Thus, not representative for PPMS population, which have been aired about Before in this blog.

    The effect in EDSS/CDP in negative GD lesions patients is very small (HR 0.84 in 3 months CDP and HR 0.81 in 6 months CDP), even if we would imagine that the result would be statistical significant. And these patients represents the vast mayority of PPMS patients: ca 85%.

    BIASIS
    Furthermore, the GD lesions in active arm was 11% higher than in placebo arm (27.5/24.7). Maybe not so much to talk about, but still should be added to the list of biasis.

    But what is more of a worry, it the number of active GD + lesions in active arm were twice (!) as high in active arm as in placebo, 1.2 GD + lesions in active arm vs 0.6 GD + lesions in the placebo arm, thus elevating the ability/probability to perform in CDP/EDSS . Again creating an unbalanced advantage for the Ocrezilumab vs placebo.

    It is clear that the study is super optimized to show a positive result; "to clever" design some would say ...

    SAFETY:
    With reagrd to reported malignancy, there were 11 (2.3%) cases of malignancy in the Ocrelizumab arm compare 2 (0.8%) in the placebo arm.

    2.3% malignancy in Ocrelizumab arm could not be viewed as a normal rate for malignancy. Rather the placebo malignancy rate, 0.8%, I would imagine would be more of a normal incidence rate for malignancy. But perhaps professor Gavin or MD could give a comment on this (?)

    Lastly, for people who is diagnosed when they are relatively young, as in this study, and have active GD+ lesions and will come to treatment short after diagnos, maybe Ocrezilumab could be an option - íf they are willing to take the risk with regard to, as it seems, rather high rate of malignancy. I Always reason with myself: what are the risks and the benifiths ...

    But for me, diagnosed with PPMS 15 years ago and with no active GD lesions ... and with the, in my opinion rather high malignancy rate ....no I doubt it. But we all must reason with ourselves with regard to our preferences.

    But for me:
    Still waiting for a drug that could really work on me and other with PPMS - not just fitted into the + FD lesions subgroup. A PPMS Product with good safety, depending how effective this agent would be.

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  5. So I get that this drug depletes B-cells and they then repopulate. However, is there any real data about whether these B-cells will be auto-reactive as is the case with Lemtrada? Is it too early to know? Also - will the B-cells repopulate to pre-treatment levels? Or will your immune system be permanently depressed as is the case with Cladribine?

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    1. Even in two years autoimmunity develops in alemtuzumab. However work depletes some b cells only transiently and you end up with 150% the normal B cells add to this T cell regulation knocked out of sight and autoimmunity occurs. This does not happen with ocrelizumab or cladribine

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    2. Will ocrelizumab be an induction treatment we have to wait until extension studies are published

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  6. My question is more in respect to those with RRMS where in at least the clinical trial of Ocrelizumab was deemed a game changer. Question being in relation to SPMS which apparently is an unknown.

    Several med folks we've chattered with have stated pretty much all the new therapies and exist from RRMS to SPMS is just an unknown. Dr. Ebers has stated that with the Interferons, basically no difference between those with active RRMS .vs. not taking interferons (aka: not benign MS) still enter into SPMS around the same timeframes, lesions, disabilities or not as I understood it?

    I've tried find data on Copaxone towards this and found nothing. Other meds in the time window of RRMS to SPMS transition really have none short of perhaps Tysabri in that time window.

    Given Ocrelizumab is similar from what I have read to Rituximab is there any indicators towards SPMS? Why would Roche/Genetech trial against PPMS .vs. SPMS or all three?

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    Replies
    1. Trial against RRMS is logical choice.
      Next logical choice is PPMS because of rituximab data. I suspect that they will target some once they get a licence.

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