Friday, 3 February 2017

Ocrelizumab looks like an Induction Therapy. The Trial that needs to be Done

#Clinicspeak. Ocrelizumab as an Induction therapy a trial that needs to be done?

So the paper (above) CLICK HERE suggests that B memory cells are a major target for therapy and suggests that ocrelizumab may work like alemtuzumab and so this suggests that CD20-B cell depletion may have induction therapy potential.

Highlights: 

  • Ocrelizumab has induction-therapy-like characteristics
  • 6 monthly dosing could be too often for some people

This is supported by Data that Pharma hold and this is the shocking revelation of the current paper.

Why shocking? This is because many/most neurologists will not be aware of this data and its implications.

I have asked a few and indeed they didn't know about this! 

Did you!

The data was presented as a poster at ECTRIMS in 2012 and again at the ANN 2013 (see below) 


It is shocking, that many senior authors have helped pharma, dump the information in meetings abstracts. Never to surface in the Science literature.

Indeed, it has been over 4 years since the data was presented and so there has been ample time for a paper to surface, had the company wanted it, and had the presenting authors done the right thing.

(Yes ProfG is guilty of the above as he is on many pharma posters that have yet to surface in the literature. Two wrongs do not make a right)

A few weeks ago someone, from the blog sent details (thanks for that) of  the original poster. Here is the QR code
The inference is clear, very clear and this is that.... ocrelizumab is an induction therapy or PIRT, or at least a therapy with long-term efficacy, which may not need to be dosed every six months.

Here is the data presented (Figure 4)



On a population level many people were still doing very well 18 months after the last dose. 

This type of response has also been seen with Rituximab in other studies. Maybe the Neuros in Sweden can trawl through their registry to see if they can come up with any data as they have alot of people taking rituximab.

Therefore, it suggests that 6 monthly dosing may be too often, at least for some people?

This is important because Ocrelizumab, use is not risk free.

Development of ocrelizumab in arthritis and lupus was terminated because of very serious infections and this caused a number of deaths.

By persistently depleting your B cells (and some T cells) you have a persistent risk of infections. These will occur once ocreliziumab becomes licensed. Therefore, it is important that use of ocrelizumab should be de-risked if possible.

The dosing regime is based on a 6 months dosing period because CD19+ B cells are depleted for 6 months. This keeps all CD20+  B cells under control.

However, if you accept that memory B cells are important targets, they are depleted in some studies for over 24 months in some people. So 6 monthly dosing could be too much?

Can you use memory B cell numbers as a way to determine retreatment? They have in other diseases.

Given the risks of ocrelizumab, surely a trial should be performed to determine whether ocrelizimab is indeed a (PIRT) Induction Therapy to make it safer for pwMS.

Maybe there is a good reason for frequent dosing in MS.

CoI None. 

20 comments:

  1. Very likely they did not published because of possible impact on the price. If PIRT therapy, Ocrelizumab price will be compared to Alemtuzumab in negotiations. And Alemtuzumab price is "low" compared to other MS drugs, as previously registered and priced for another indication. I believe they are aiming a premium price, something like current highest price + 10%...
    Eventually EMA will challenge their risk/benefit or limit them to second line, then a reduced dosage could be a good alternative. I am sure they have calculated all scenarios and have a strategy for getting the most financial benefits.
    There is almost no chance Roche will published or fund a reduced dosage study, unless they are forced to. Hopefully there are Swedish neuros reading your post !

    ReplyDelete
    Replies
    1. From our experience (rheumatology), rituximab is not an induction therapy in RA, most patients flare at 9-12 months after treatment. Initially we used the dosage of 2 x 1000 mg i.v. 14 days apart repeated every 6 months. Then there was "wait until the patient begins to flare", then repeat treatment. Then there was : check the B cell counts and get some guidance as to when to retreat.
      Current practice is: 2 x 1000mg i.v. start dose, then 1 infusion 1000 mg every 6 months. This seems to work fine.
      https://www.ncbi.nlm.nih.gov/pubmed/23723317

      RA has the advantage of things showing up clinically - you can see and feel arthritis. MS is not that straightforward, most MRI lesions are clinically silent, so I totally understand that regular dosing regimen is the recommended option.

      Delete
    2. I do not know if Swedish neurologists are reading, but here is the summary of their data:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109942/
      Most MS patients were getting 1000 mg rituximab, some got the initial dose of 1000 mg x 2.

      Delete
    3. Anon 5:39 Thanks for this.
      Checking B cells is this CD19?
      or more focused such as CD19+, CD27+

      What is the arthritis experience of alemtuzumab?
      I see in some studies the duration of treatment effect was short

      Delete
    4. In the swedish cohort

      A total of 59 relapses occurred on rituximab treatment, which corresponded to the following ARRs: 0.044 for RRMS, 0.038 for SPMS, and 0.015 for PPMS. The relapses occurred at a median of 4.7 (0.16–23.9) months after the most recent infusion.

      So some people relapsed after short time after infusion but some people 2 years after infusion. So the question is can we predict why

      Delete
    5. I first saw that alemtuzumab has been used for RA in that paper on 20-years follow-up of the lymphocyte changes post alemtuzumab (first attempts in Cambridge). I have NEVER seen it used in the clinic for the treatment of RA. ( I guess antiTNFs were more efficient and safer?).

      Delete
    6. As for the lymphocytes ... CD19. But our lab does not do it so it was a bit of trouble sending it and it did not give that much info. If arthritis shows up you have to do something anyway.
      It is more difficult with MS because you cannot do MRI every month and the patient may be blissfully unaware of the fact that trouble is brewing.

      Delete
    7. There are interesting papers were treatment was to CD19, CD27 and that allowed reduction of rituximab for $7,000 to $2,000.

      CD27 was not on our routine screening panel at the hospital so there is some negotiating going on about havig it in the panel of test.

      Thank you for your insight.

      Delete
    8. "So some people relapsed after short time after infusion but some people 2 years after infusion. So the question is can we predict why"

      you asked if there is a biomarker on the hsct blog post... is this a similar question?

      are you doing a post on whether b cell (or b memory cell) counts post treatment are related to efficacy? or are the mystery biomarker questions related to australian Kynurenine findings?

      us laymen get easily confused :)

      Delete
    9. yes its a similar question the inference from other papers is that the B cell level may have some predicitve value.

      Will this be the answer in MS, I dont know but worth a look. T

      he problem to my plans was that after acceptence,, the paper was online in 1 .5 days and so not enought time to build up the story I was going to and was planning to do.

      I will have a look at the Kynurenine

      Delete
    10. If you look at the figures in todays and yesterdays post on the same subject one can see a hierarch of the response and it is not that dissimilar to the efficacy of the drugs

      Delete
    11. "MouseDoctorSaturday, February 04, 2017 4:54:00 pm
      yes its a similar question the inference from other papers is that the B cell level may have some predicitve value."

      Thank you. My partner's neuro keeps asking her if she wants rituximab infusions. she is some 12 months post nm hsct. he hasn't recommended rituximab infusions but he keeps asking. i must admit i haven't kept track of her subset levels, though i have some of her blood results in a folder at work. she has bounced back post hsct remarkably.

      the posts over the last few days/week have made our (interrogative) job much easier (i mean more informative) :) i'm looking forward to speaking with him. dear god, i have never said that about a neuro before lol.

      Delete
    12. ProfG told me that after HSCT people in Mexico go on rituximab for 2 years...if correct maybe they are getting an extra induction treatment post HSCT a further induction or atleast 3 years of memory B cell depletion.

      Maybe Caroline Wyatt (BBC reporter undergoing HSCT in Mexico) can answer that, if she is reading, her blog posts have gone quiet

      TAnyway back to your post the B cells are often lumped as CD19 (total B) but I believe once depleted,the blood space is filled with immature B cells, that later mature and may mask rock bottom memeory B. However they will recover. Should I do a post on this?

      Delete
    13. Yeah re Mexico... according to my partner's haemo, the chemo dose in Mexico is administered over a longer period making it slightly less immunoablative or whatever the word is... and that is part of the reason mexico recommends follow up infusions (at i think a slightly low dose) every 2 months for a year post hsct in mexico.

      this is why I'm wondering why my partner's neuro keeps asking her if she would like rituximab... is he working on some kind of theory/belief that is related to my partner's bloods or has he had patients bugging him for rituximab post Mexico and he's just now offering it randomly to all HSCT patients lol.

      My partner didn't have HSCT in Mexico. She's doing remarkably well and is all for being proactive, but is not particularly eager to be overdosed (taking rituximab, even at low dose, 'in case'). At the same time, waiting for a new irreversible lesion to appear to show if the treatment is not or is no longer working.....

      That biomarker would be so useful :D

      At diagnosis in 2014, she fit most criteria for a poor prognostic lol

      Ps. I think my partner's neuro reads this blog from time to time. Poor man.



      Delete
    14. "Her blog posts have gone quiet"

      P.S. Hope everything is OK as things were not sound hunky dory last post I read.

      Delete
  2. Can Memory B-Cell levels be tested easily?

    Is this different from CD19 levels?

    ReplyDelete
    Replies
    1. As easily as checking for CD19, it is an extra marker such as CD27, so you check for CD19 and see how many of them are also CD27, but has to be a double stain as CD27 is also a T cell marker

      Ease it depends on if this routine in the service

      Delete
    2. basic b-cell questionFriday, February 03, 2017 5:13:00 pm
      Can Memory B-Cell levels be tested easily?

      we are in aus, and my partner's haemo has kept trek of all her subset levels for over a year now. i have found that, if you can manage to get a gp to actually understand what you are after, they too can order such tests (though it costs out of pocket when gps have ordered it).

      Delete
    3. Because of the T cell lobby we know alot more of the T cell subsets, whereas as the B cells have been lumped under the CD19 umberella, so good on yer haemo if they have tracked the B cell subsets.

      As Anon says these types of tests are well within the range of any haematology unit.

      For us it can be done , but there is an extra cost to do it.

      The inference that tracking these cells maybe useful is there in the literature, but I am sorry to say I would like to seee the evidence in MS and not base the idea from other conditions.

      So first thing we want is access to clinical trial data to determine whether there is any associated between memory B cells and disease activity.

      We have asked and have had the right noises from some pharma as they have the data to address this.

      If it success game on, but if it fails it should not be the end of the question as the idea may still be abit simple because the memory B cell subset is also more than one type of cell and so we may be able to home in on the subset to look at because the problem cells are always ongoing to be a small subset.

      As we shall see this week the population may not be static so this may influence interpretation

      Delete

    4. "Anyway back to your post the B cells are often lumped as CD19 (total B) but I believe once depleted,the blood space is filled with immature B cells, that later mature and may mask rock bottom memeory B. However they will recover. Should I do a post on this?"

      yes please.

      and looking forward to this - As we shall see this week the population may not be static so this may influence interpretation

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.