Friday, 17 March 2017

Monitoring Memory B cell Number to keep Efficacy and Increase Safety

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In this issue, I have predicted that this will be the year of the B cell, as I expect ocrelizumab to get a licence for the treatment of relapsing MS, or perhaps even active (relapsing & progressive) MS.

We have got the year off to a flying B cell start with our recent paper, which shifts the focus from the T cell onto the B cell and notably the memory B cell subsets.
We have made an argument that active treatments act via depletion of memory B cell subsets.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine;16:41-50. 


Not read it….Read it! (CLICK HERE)

We know disease activity does not correlate with blood T cell subsets or even CD19 B cell numbers, based on data with alemtuzumab, but does disease activity relate to memory B cell activity?

Will Pharma come to the table and supply us with the information that we know they have?

We wait to see if disease activity relates to B memory cell activity. 
That is a prediction/hypothesis.

If it does....then maybe bye, bye T cell

If it does not....we may need to drill down to be more specific because the driving force for relapses and active disease is immune activity coming from the blood into the CNS and it will be a small fraction of any immune subset we care to look at.

We also know from studies in arthritis that relapse can occur in the apparent relative absence of B cell activity in the blood so it will not be absolute, suggesting you do not need many of the wrong cells to trigger relapse.

We also know that constant B cell depletion increases your risk of infection

So can we use this information to personalise the medical approach to reduce the risk: benefit?

This has been done in other diseases where CD20-specific antibody is active. 

Can it work in MS?

There are studies that report that disease activity can correlate with peripheral blood memory B cell numbers and that they can be used as a biomarker of when to retreat, as it is clear some people deplete for a few months others for a few years. 


Systemic Lupus Erythematosis               
  • Vital et al.  Arthritis Rheum 2011 63: 14
Neuromyelitis Optica (NMO)                             
  • Kim SH,et al. Arch Neurol 2011 68:1412
  • Kim SH, et al. JAMA Neurol 2015: 72: 994
  • Rosenthal M et al.Neurol Sci. 2017;373:335
Rheumatoid Arthritis                              
  • Leandro et al. 2006 Arthritis Rheum 54:613
  • Iwata et al. J Rhheumatl 2011, 38:633
  • Trouvin et al. 2015 , Clin Exp Immunol 180:11
Ideopathic Nephrotic Syndrome            
  • Colucci et al.  J Am Soc 2016; 27:1811
Myasthenia Gravis                                 
  • Lebrun et al. 2016, J Neuroimmunol 298:79

Using this approach in myasthenia gravis (an antibody-mediated autoimmune disease), where the acetyl choline receptor is blocked stopping muscle function) the mean number of infusions of anti-CD20 could be reduced from 4/year down to 1.3/year by monitoring re-emerging CD27+ memory B cells.

However there is new study looking at NMO, which used to be known by Devics MS. Is this the future way of using rituximab?

We know that NMO is associated with an antibody against astrocytes and some of the treatments promoting wellness in MS, make NMO worse. Likewise we know that some of the issues important in the diseases above are also a problem of antibodies). Therefore, it may be different in MS, but may be it won’t be.

This study treats people with MS, but rather than religiously giving people rituximab treatment every 6 months, they look at the CD19, CD27+ B cell numbers to provide an indication when to retreat as their number seems to increase within about 4 months from the next attack. 

Don’t believe me that there is efficacy?

Look at the figure of before and after from Kim SH, Jeong IH, Hyun JW, Joung A, Jo HJ, Hwang SH, Yun S, Joo J, Kim HJ. Treatment Outcomes With Rituximab in 100 Patients With Neuromyelitis Optica: Influence of FCGR3A Polymorphisms on the Therapeutic Response to Rituximab. JAMA Neurol. 2015;72(9):989-95. I think its impressive.

It is not perfect, but the number of relapses were reduced by 96%
from 2.4 (2 a year) to 0.1 (one every ten years). They administered another dose when the frequency of CD19+, CD27+ memory B cells within the CD19+ population reached 0.05% in the first two years and 0.1% in the second. This is reduced from normally about 20-30% of CD19 B cells (Switched =IgD- & Unswitched = IgD+) in the the healthy situation (click here. They should use absolute numbers per microlitre as it is more risky to use percentages).

In yet new another recent study 


Cohen M, Romero G, Bas J, Ticchioni M, Rosenthal M, Lacroix R, Brunet C, Rico A, Pelletier J, Audoin B, Lebrun C. Monitoring CD27+ memory B-cells in neuromyelitis optica spectrum disorders patients treated with rituximab: Results from a bicentric study. Neurol Sci. 2017;373:335-338. Set a level at 0.05% and they could drop the infusions from every 6 months to 7.4 months with no loss of efficacy.


Could this be used in MS?

Based on the unpublished (actually read our paper as it is no longer unpublished:-) Phase II Extension data for Ocrelizumab, it appears that 6 monthly dosing (read our paper) may be more frequent that needed for some people.

The data above is also directly relevant to MS, because of rituximab is being used frequently in places such as Sweden. 

There they are doing the COMBAT-MS study to determine the effectiveness of rituximab.


If you can read or understand Swedish (Click).  

Antibodies kill via either complement fixation or via antibody-dependent cellular cytotoxicity (ADCC). This latter method of killing is used predominantly by alemtuzumab and ocrelizumab also, in fact ocrelizumab is more dependent on this than rituximab.

This occurs because phagocytic cell/natural killer cells bind to the Fc (tail) of the antibody by an Fc Receptor. 


Interestingly a genetic variant of one of the Fc Receptor links to activity.

Kim et al. 2015 found factors that influenced depletion of the memory B cells and one factor was notably a variant of a gene FCGR3A (Fc receptor gamma 3A). 

If there was a phenyalanine (F) amino acid at position 158 of the molecule compared to the usual  valine (V) the receptor had a lower binding capacity for IgG (If you are heterozgous (F/V) or homozygous (F/F), there was a reduced response to (V/V) B cell depleting response. The residue at position 158 directly interacts with the lower hinge region of IgG1


If you had the F/F variant you depleted B cells less well and were at a greater risk of relapse.

What is going to happen in the PCORI (at the Karolinska Institute home of MS genetics in Sweden) study? 

Surely they should be genotyped to link genotype with depletion/clinical efficacy.

This genotype can influence the efficacy of other IgG1 antibodies

What is it going to do with daclizumab and notably alemtuzumab (there is no influence with the cancer dose, but based on rituximab the influence of FCG3A is antibody dose-dependent) and ocrelizumab? 


What’s your Fc Receptor genotype?

Are you going to be a good depletor?

Currently CD19+, CD27+ and genotyping are not routine maybe they will be in the future

15 comments:

  1. Nice is changing its review process as of next month. Any drug costing.more than 20 million will automatically go to 2nd review lasting upto 3 years. Further driving pressure on pharma to cut prices. So Ocrelizumab is at least another 3 years away if and when EMA approve it. So sad. Patient lives are now just cost driven

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  2. Or: NICE would say there is enough evidence to say that rituximab is also an option in RRMS. Cost effective option. Adjust your pricing to the real world, dear pharma.

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    1. As NICE is dependent on high cost pharma drugs they are not going to say use rituximab.

      You have probably to spend a few million writing the report in a format that NICE understands there will be companies (probably Ex-NICE staff) that do this for pharma for a fat fee. You have to collect the cost benefit data from your studies.

      This is all part of the world that pharma support in their drug development.

      I can't tell you properly because I don't know whats entailed but I do know further done the pipeline and there are lots of remora feeding off scraps created by the pharma shark.

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    2. As NICE is dependent on high cost pharma drugs they are not going to say use rituximab.

      You have probably to spend a few million writing the report in a format that NICE understands there will be companies (probably Ex-NICE staff) that do this for pharma for a fat fee. You have to collect the cost benefit data from your studies.

      This is all part of the world that pharma support in their drug development. I think profG said 6% of our GDP. This is why perhaps the US and other countries Governments supports high cost drugs, because of the infrastructure and jobs it creates

      I can't tell you properly because I don't know whats entailed but I do know further down the pipeline and there are lots of remora feeding off scraps created by the pharma shark.

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    3. I know, MD, I know. And I know how Pharma dances round politicians, KOL, doctors in general etc. etc. But at the end the system will collapse under its own weight, it cannot continue like this forever. And all players in this game know it.

      As I was doing my afternoon balance routine I was thinking the following: there are usually some questions I have to consider before I prescribe a drug... and in that order:
      1. Is it safe?
      Rituximab: millions of patient years of exposure in different conditions, we are aware what the problems are and there are no real show-stoppers.
      Ocrelizumab: potentially a better, more humanized molecule. But what is the experience ine the real world? Well...a few hundred patients in clinical studies.

      2. Does it work?
      Rituximab: seems to do the job, they have considerable proportion of MSers using biologics in Sweden actually on it for years with good results. US centers have also been using it for years( I guess for people who cannot afford the expensive drugs).
      Ocrelizumab: Cannot compare it head-to-head as there are no studies like that, but that is true of all newer drugs as head-to-head studies are with interferons/copaxone only.Effective, but we don't know if it is better,equal or worse than rituximab.

      3. Price to the patient?
      Rituximab: it is not very cheap, but of the biologic drugs it is probably one of the cheapest, even before generic copies

      Ocrelizumab: ???? My guess would be a tad cheaper than alemtuzumab per year, but not much. Can my patients afford it? Not unless they re-morgage the house.

      So it is the question of where and how public money should be spent to deliver most health for the buck.

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    4. Love Roche folk. They are always on time, professional, would never leave you standing in the rain, the perfect Swiss machine.
      But I am getting weird deja vu with artistic visions of colourful lymphocytes dancing to mesmerising music... I'll go read some pubmed to recover.

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    5. Most health for their buck.


      Indeed this is why Sweden gives rituximab to most people with MS.

      I think it could be possible that we should start everyone on generic cladribine and see how they do.Maybe an idea too early for some but once oral cladribine gets licenced the side effect profile is more clear and people are comfortable using it then maybe not so crazy. why not start on oral cladribine. It will depend on the licence they seek and get. If it is for active MS it will be second line.

      Bye Bye CRAB drugs.


      Every one starts on an effective treatment.Then you decide what you do with the failures, retreat or if you take the view that action is via CD20 B cells obvious one is ritiximab ocrelizumab as taking out other cells adds to problem. If you are the T cell fan the choice is more complex.

      The landscape will change once the first small molecule becomes generic

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    6. Swedes are cold and pragmatic. But even in Sweden there is a lobby trying to push for ocrelizumab rather than rituximab. So what are they going to do when Ocrevus comes? Take people off rituximab and start them on Ocrevus?
      Will there be a ban on the use of rituximab in new MS patients but the ones who are on rituximab will be allowed to continue? (that would affacet Karolinska as well)
      Would Roche do the Campath/Lemtrada trick and withdraw rituximab form the market for a while? But what happens then to all of the RA/SLE/GPA patients as Ocrevus has no licence for other conditions than MS.
      2017 will be an interesting year so stay tuned, everybody!

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    7. I think the Swedes may have something to say about being labelled cold, but agree the situation in Sweden will be interesting once orevus gets a licence.

      Rituximab is a 7 billion dollar drug

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  3. I went to your article and there Lemtrada depleted memory B cells. EMA product information for Lemtrada says: rise in memory B and T cells.
    Funny how all those cells always know how to dance to the tune that the Pharma Orchestra is currently playing ;-).

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    1. As we will soon see that is a load of rubbish. This is a Chinese Whisper and more Cambridge myth (data handling) that is created by using percentages rather than absolute numbers just as we saw the other day with Tregs going up from 3-13% (of CD4 cells) whilst actually going from 30,000 cels/ml down to 2cells/ml. All of the cells decrease by 80-95% in absolute terms. CD4 T cells are 70% depleted for over 2 years after you start lemtrada.

      I guess we need to publish a different world reality

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    2. If you look at any depletion in CD4 the memory pool looks less touched than the naive population because they recover this has led to idea of driving T cell repopulation via thymus.I think this is the wrong approach and rather than stopping secondary autoimmunity i fear it will make it worse
      The trial has been done we shall see.

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    3. MD if you look on Prof Coles' blog.
      The the trial has been stopped early, last year, because it didn't work.

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    4. That's very interesting stopped not working or stopping making things worse.

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