Sunday, 21 February 2016

Ocrelizumab Trial Results

The results  of the Ocrelizumab Trial are online (CLICK for RRMS and PPMS posters)

Here are the Trial Results from the phase III RRMS trials



The results compare the effect of ocrelizumab to beta interferon. The results of the two trials are comparable and show superiority to beta interferon and the results are comparable to that found with alemtuzumab. However, there were no reported cases of secondary autoimmunity andno reported cases (yet)  of PML. There very impressive in terms of efficacy and seemingly safer than other highly effective DMT. 

The annualized relapse rate was abount 0.15 and NEDA-3 was 47% which is comparable to that reported with oral cladribine. Also similar  to or should I say seemingly worse than cladribine was the occurance of malignancies in the PPMS trial

Here are the Ocrelizumab in PPMS  trial


Actrims 2016 oratorio poster montalban_p023 (1) from BartsMSBlog

So if we look at the malignacies it was 11 with ocrelizumab verses 2 in Placebo group and one can argue that the basal cell cancinomas aren't malignancies moving it to 8 to 1. Now there are more people taking ocrelizumab (double) than placebo, but if we remember that oral cladribine was rejected by the regulators with comparable number of people on drug on what turned out to be only 3 malignacies on cladrinine verses 0 on placebo. 8 to 1 is somewhat more. In fact it in the placebo group it was adeno carcinoma in situ which is not a malignancy and so it 8 to 0. There was only one trial with movectro and the mud stuck, but serves to show how one trial can skew the view. Will the same mud be thrown? or will the additional trials pacify the nay sayers?

This is because when we look at the RRMS studies there were only 4 malignacies in the ocrelizumab group n =>800 and 2 in the control group (n=>800). Suggesting that the PPMS results were a fluke. However 6 breast cancers  (Ocrelizumab in 1100-1200 verses 0 in the control arms (n=1000) may raise some eyebrows.

However it is clear that PPMS is not immovable and it is the beginning.

36 comments:

  1. Will we have one more off-label drug?

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  2. Although very favorable points conspiring in favor of Ocrelizumab I will continue thinking be Cladribine Injectable a fully effective and viable treatment for MS ...

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  3. Breast cancer is a bit unexpected - we have used rituximab (which basically does the same thing) for a long time now and I do not remember anybody raising any red flags about breast cancer.

    But there will be some PML, as rituximab was not free from that when used in patients with haematological diseases and off label in lupus. It's just the numbers game (enough patients using it for long enough and neurologists aware enough of the possibility - testing for it in suspicious cases).

    But it is absolutely an interesting proposition, I am now considering switch from fingolimod to ocrelizumab when it becomes available.

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    1. You are correct but and may be a chance event.

      However the point I was making is that cladribine was assessed at the EMA by a cancer specialist and they got hung up with that and cladribine got rejected and they ignored the years and years of cladribine use in hairy cell leukaemia. So the past use of rituximab is not going to factor into it I suspect. It is a different drug entity.

      As to PML I suspect you are right it will be a matter of time.

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  4. "However it is clear that PPMS is not immovable and it is the beginning"

    Yes; speaking personally, I'm not that excited. Only the beginning of what will need to be a long, winding and boulder-strewn road?

    Perhaps I'm a perfectionist idealist who prefers to dwell in a dreamland with a black swan. Was the Swan of Tuonela a black swan? A beautiful Sibelius composition, nonetheless.

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  5. Were there just breast cancer cases or other cancers also occurred?

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    1. No there are others like melanoma, they are all detailed in the posters

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  6. what will happen if someone stops taking ocrelizumab? probably you people know the answer already since rituximab has been around for years, is there a rebound similar to natalizumab?

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    1. It depends if it is an induction therapy, if not disease will return

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    2. The last I heard this was being trialed as an every-six-months-for-life dose. What are the odds it would be approved as induction therapy if it's not being trialed that way?

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    3. You are correct it is trialled as every six month dosing for life.
      This doesnt mean it could not be am induction treatment buy that needs to tested

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    4. They'll never let another alemtuzumab happen - I'm convinced the only reason the FDA approved it is because they think it's another mitoxantrone and the side effect profile will eventually kill it.

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    5. the side effect profile proabaly kill it but it was approved because it works

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    6. what will they do with HSCT in a couple of years when the trial finishes

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    7. I don't think the FDA is involved with new procedures. Just drugs. Since alemtuzumab and rituximab are already approved for MS I guess you could get it done here if you could afford it? You just gotta find the doctors and $$...

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  7. Thinking about cancers and PML, and parallels with alemtuzumab...ocrelizumab is an ongoing therapy you're expected to take every 6 months for life, right? It's not like alemtuzumab because you're rebooting your B cells all the time? Or do I misunderstand?

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    1. yes at the moment ocrelizumab is evry 6 months it remains to be seen if data withh arrive that shows it to be an induction therapy that only needs a few doses

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  8. I think the images you uploaded may be too low resolution even when I view them full screen. I'm not sure if they were supposed to be higher resolution or pdf or something, but they are unreadable on my computer. If I'm doing it wrong, let me know. Thanks!

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    1. The posters are online on the ACTRIMS website
      click on the links and then you can download the pdf

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  9. In placebo group it is adeno carinoma in situ and it is argued that this is not a malignancy and therefore in the PPMS it was 8 to 0. In the movectro trial it was 3 to 0 and it got rejected.

    So if Ocreluzimab gets approved for PPMS on the basis of one trial could on cry foul play or does it get approved and thenthis issue should be a non issue for movectro especially as there is extra data.

    Likewise the occurence of lymphopaenia brought up by the regulators should be a non-issue when they have approved alemtuzumab where there is marked lymphopaenia

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  10. Both in lupus and in RA Ocrelizumab were halted due to serious infections, some of them deadly. I am aware of that Ocrelizumab was combined with another riummunosupressive drig int hese trials, but nevertheless, both studies were stoped due to severe infections.

    And as previous "anonymous stated above at 12:03:00 pm above, there bound to be some incidence of PML sooner or later, as rituximab was not free from PML events.

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    1. yes ocrelizumab is being developed in MS verses rituximab. It is all about patent life

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  11. These are he Box Warnings that came up Rituximab CD-20 in Non-Hodgkins lymfom (NHL)

    http://www.rituxan.com/hem/hcp (*Scroll down a bit on the page*)

    The safety experince was made, to my best understanding, when it was given as a single agent in NHL and the doses used, to my understanding, are lower than those used in the phase III with

    Now Roche would say, that would differ Rituximab CD-20 antagonist from Ocrelizumab antagonist (... everyone talks for their sick mother as we say in my country) in that Rituximab is a chimeric antibody and Ocrelizumab is humanised antibody.

    But I would buy any sutch argument that Ocrelizumab should not earn the same Box Warnings as Rituximab, unless hardcore proof will show rational for this.

    And these 8 to 0 malignancy events that MD elaborate about in the PPMS Ocrelizumab trial does not make the picture any better.

    Furthermore, Genentech/Roche have all the reason in the world to alienate themselves from Rituximab, since it would pose a threat for the company´s profit ambitions with Ocrelizumab ...

    My point:
    These pharma giants never tell the dark side of the story plus they always will guide you in the directions where they could make the biggest profits. But what else is new ...

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    1. yes. Rituximab is a chimeric antibody and so people will make an anti-globulin response to it, but it is not being developed because it has no patent life and so ocrelizumab is being investigated

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  12. Thanks MD for publish my comment about the clear similarities between Rituximab and Ocrelizumab.

    But due to my problems with uper limbs (PPMS +10 years), my comment had a lot of errors with regard to Spelling (nothing else), so I give it a go again - this time hopefully without errors in Spelling etc.

    OK here we go:

    These are he Box Warnings that came up Rituximab CD-20 in Non-Hodgkins lymfom (NHL)

    http://www.rituxan.com/hem/hcp (*Scroll down a bit on the page*)

    The safety experince was made, to my best understanding, when it was given as a single agent in NHL and the doses used, to my understanding, are lower than those used in the phase III with Ocrelizumab ...


    Now Roche would say, that would differ Rituximab CD-20 antagonist from Ocrelizumab antagonist (... everyone talks for their sick mother as we say in my country) in that Rituximab is a chimeric antibody and Ocrelizumab is humanised antibody. But hold on. I don´t Think anyone with some sense would buy such a "statement". No the similarities between the 2 CD-20 anatagonist are apparent. Of course Roche /Genentech wiull try to talk their way out of it, with a lot of bla bla statement, aired without a solid rational. To much Money is involved for this to be happen.


    So, an argument from Roche side, that Ocrelizumab should not earn the same Box Warnings as its sister Rituximab one can neglect totally, unless hardcore proof will show solid rational for that Ocrelizumab will not carry the same safety risks as its "sister" Rituximab. And it is Roche which has the burden of proof for this.


    Furthermore, these 8 to 0 malignancy events (read: metastatic cancer events) that MD elaborate about in the PPMS Ocrelizumab trial, does not make the picture any better with regard to safety.


    So, Genentech/Roche have all the reason in the world to alienate themselves from Rituximab, since it would pose a threat for the company´s profit ambitions with Ocrelizumab ...


    My point:
    These pharma giants never tell the dark side of the story plus they always will guide you in the directions where they could make the biggest profits. But what else is new ...

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  13. Questions to MD (or Prof G)


    Estimated median terminal half-life of rituximab was 32 Days.

    I would assume that Ocrelizumab would be in the same range. If so, then if something goes wrong with safety, you will have the drug in your system for a long time ...

    But maybe MD could shed some light over this issue with regard to Ocrelizumab half Life and if safety issues will arise ...

    And put into that context of the (presumably) long half Life for CD-20 antagonist Ocrelizumab, this would worsen or escalate the problem with Lymphopenia compare to shorter half Life.


    I would be glad if MD or Prof G could elaborate about these issues.

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    1. of you have a therapeutic antibody then it will indeed hang around for a while. If things go wrong you either ride out the storm or you could do a plasma exchange to rid the unwanted immune response.

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  14. A question to MD or Professor Gavin in relation to why the PPMS study ORATORIO study was (intentionally) statistical "underpowered" as regard to gain statistical significant results on the 2 subgroups, GD+ and GD- at baseline:

    So the ORATORIO Ocrelizumab study in PPMS showed 24% risk redcution on CDP with regard to the overall Group - compricing patients with and without enhancing lesions (GD+ and GD-) at baseline. Fine enough.

    But for me it is VERY PUZZLING, the fact, that why did not Genentech/Roche enroll enough patients into each subgroup, so that each subgroup would be challanged to deliver statistical significant result on CDP - not only when they are combined together (?)


    You can rest for sure, that Genentech have done the maths on this back and forward, up and down, that each subgroup were most likely to small ("underpowered") to deliver statistical significance for both of these 2 subgroups

    Keep in mind, that ca 27% had GD+ lesions at baseline and 73% were without GD+ lesions at baseline.

    MY Point:
    Given what I said above, why in the heavens name would Genentech go ahead with a trial that was underpowered in this aspect? Wouldn’t logic guide that they design the trial to settle this vital issue in a statistically definitive manner once and for all? Especially since ca 85% of PPMSs patients do not have enhancing lesions (!)

    So, what does MD or Prof G Think about this issue - don´t hesitate being honest (cynical) what you think about this issue.

    I have a bad feeling, that Genentech did this intentionally. So MD and Prof G, what are your honest thoughts on the matter ?

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    1. ProfG is conflicted and so may not want to or be able to say anything, but is it not genious. We all know in our heads that the effect is because the drug affects active MS and so should link with gadolinium enhancement but if you only link it to one point in time you miss all the other gadolinium positive peple put into the gadolinium negative group, but the way the data is collected/analysed does not allow you to make this distinction so they get licenced for all of PPMS...Genious-or cynical because it means you treat every one and some may nioot benefit as much as others.

      It could bite them in the arse/ass if the regulators ask for another trial because thats another 5 years away, so they hope that you will push for licencing.

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    2. Anonymous, Prof G was involved in designing the study so cannot explain for political reasons why it was intentionally under-powered.

      I think MD hinted at some of the reasons.

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  15. Which is more efficient lemtrada or ocrevus?

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    1. I think efficacy wise they are roughly the same but ocrevus may have a better safety profile, depending on how it is used with continuous use of ocrevus then the risks of infections will increase

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  16. How does ocrelizumab efficacy compare to tysabri? I have been stable on tysabri for 6 years but am JCV + with a risk scoring of 1.9. My neurologist has suggested ocrelizumab but I am worried if it doesn't provide stability will I be able to resume tysabri 3 months post ocrelizumab?

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    1. In terms of efficacy they are in a similar league please talk to your neurologist about your options. Ocrelizumab is not yet licenced

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