Sunday, 11 March 2018

Is it the B-cell and/or the T-cell? Prof G eats his hat.

At Barts-MS we have been pushing the B-cell hypothesis based on circumstantial evidence when a lot of genomic, and other data, make it clear that T-cells are also involved in the pathogenesis of MS. Now that the first non-depleting BTKi (Bruton Tyrosine Kinase Inhibitor) is effective in MS does this change our central hypothesis? 


Yes, I am eating my hat. I predicted that unless a BTKi was depleting it would not work in MS. Why? 

I am convinced that EBV causes MS and that the only way to control MS was to deplete the peripheral blood and lymph nodes of B cells, in particular, memory B cells, to reduce the EBV viral load. 

EBV lives in memory B cells and provides these cells with a survival advantage by stimulating a signaling or messaging pathway, which is independent of antigen stimulation. The B cell needs this EBV-induced signal stay alive and proliferate.

Another pathway to keep B cells alive is via antigen stimulation. For the antigen stimulation to work, the B cell needs Bruton tyrosine kinase (BTK) activation, which plays a crucial role in B cell maturation. Mutations in the BTK gene cause a rare primary immunodeficiency syndrome that is X-linked (the gene is on the X-chromosome) called agammaglobulinemia or Bruton's agammaglobulinemia. 

Patients with this type of agammaglobulinemia have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. Based on this genetic disorder many Pharma companies have been targeting BTK as a treatment for lymphoma and autoimmune disease. 

There is a licensed BTKi called Ibrutinib that is licensed for B cell lymphomas. About 2-years ago the Mouse Doctor and I had quite detailed conversations with Abbvie about doing an investigator-led, proof of concept study, to test Ibrutinib in MS. Abbvie were very supportive of this, but Janssen who co-developed Ibrutinib had cold feet, so our proposal never got off the ground. I made the argument that Ibrutinib, a depleting BTKi, would be superior to the non-depleting BTKi in development.

Therefore, I was somewhat surprised to see the press release from Merck last week confirming that the evobrutinib phase 2b study was positive in MS. This is telling us that you don't need to deplete B cells to get a therapeutic effect and that B-cell antigen signalling and presentation are back on the cards. This puts T-cells back on the agenda, possibly downstream of B cells. I personally can't wait to see how effective evobrutinib is at suppressing MS disease activity. It will need to be as good as anti-CD20 therapy to have a chance in the marketplace. Let's hope we get to hear the results of the trial at ECTRIMS. I am also aware of at least two other Pharma companies with their own BTKi about to go into clinical trials in MS. It is quite amazing how Pharma seems to get things much quicker than the wider MS community in terms of therapeutic targets; c'est la vie! 




Now will Merck develop evobrutinib as a monotherapy or will they leverage the mode of action of oral cladribine (Mavenclad)? Cladribine is currently being used as a SIRT (selective immune reconstitution therapy). However, most pwMS will relapse or have a recrudescence of disease activity at sometime after receiving cladribine. Could cladribine be turned into a true induction treatment followed by evobrutinib as a maintenance therapy? 

We have shown that cladribine has a profound effect on B cells, in particular, memory B cells. Could evobrutinib post-cladribine maintain the remission very, very long term? This is how I would develop at least one of the trials in the phase 3 programme. 

What about evobrutinib post-alemtuzumab? With alemtuzumab, I would use a BTKi in parallel. A BTKi may not only be effective in preventing recrudescence of MS disease activity it could possibly prevent the secondary autoimmunity post-alemtuzumab. Maybe this is the logic behind Genzyme's recent licensing agreement with Principia Biopharma to develop PRN2246 a BTKi in MS.

Biogen also has a BTKi (BIIB068) that is currently being tested in lupus. Will they let Merck and Genzyme steal a march on them? As the dominant pharma company in MS, I suspect they won't. 

Evobrutinib appears to have triggered a BTKi Lemming Syndrome (a psychological quasi-condition in which the afflicted person/pharma-company becomes subject to the whims of a portion of popular culture, and bends his/her entire persona/company to conform to the norms dictated by the media-moguls/other pharma companies in charge of a said trend ;-).

Evobrutinib

Who said it wasn't an interesting time to be in MS? We clearly in a new era where we are unpacking the pathogenesis of MS and autoimmunity, in general, using new biological targets. 

Roll on ECTRIMS the evobrutinib results are going to be one of the highlights, if not the highlight of this year's meeting. 

MERCK KGaA
DARMSTADT, Germany, March 7, 2018 /PRNewswire/ -- Primary endpoint met for evobrutinib (Bruton's Tyrosine Kinase Inhibitor - BTK) in relapsing multiple sclerosis (MS)  First proof of concept for BTK inhibitor in MS.

Merck KGaA, Darmstadt, Germany, a leading science and technology company, today announced positive results from its Phase IIb study of evobrutinib (Bruton's Tyrosine Kinase Inhibitor - BTK) in relapsing multiple sclerosis (MS). The study has met its primary endpoint, demonstrating that evobrutinib resulted in a clinically meaningful reduction of gadolinium enhancing T1 lesions measured at weeks 12, 16, 20 and 24 in comparison to patients receiving placebo.

"We are encouraged by these early positive results of evobrutinib in relapsing MS," said Luciano Rossetti, Head of Global Research & Development at the Biopharma business of Merck KGaA, Darmstadt, Germany. "The trial will continue so as to further inform our clinical development strategy for evobrutinib in MS."

Details of this clinical study can be found on ClinicalTrials.gov.

Evobrutinib, discovered by Merck KGaA, Darmstadt, Germany, is also in Phase IIb studies in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

About evobrutinib

Evobrutinib (M2951) is in clinical development to investigate its potential as a treatment for multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It is an oral, highly selective inhibitor of Bruton's Tyrosine Kinase (BTK) which is important in the development and functioning of various immune cells including B lymphocytes and macrophages. Evobrutinib is designed to inhibit primary B cell responses such as proliferation and antibody and cytokine release, without directly affecting T cells. BTK inhibition is thought to suppress autoantibody-producing cells, which preclinical research suggests may be therapeutically useful in certain autoimmune diseases. Evobrutinib is currently under clinical investigation and not approved for any use anywhere in the world.


SANOFI-GENZYME

Sanofi, Principia agree to develop multiple sclerosis drug candidate

• Clinical-stage oral drug candidate (PRN2246) with the potential to treat multiple sclerosis
• Principia to receive $40 million upfront payment, future milestone payments could total $765 million

Thursday, November 9, 2017 7:48 am EST, Paris, France and South San Francisco, Calif

Sanofi will develop Principia Biopharma Inc.’s experimental oral treatment that shows promise in multiple sclerosis (MS) and, potentially, other central nervous system (CNS) diseases.

Under the license agreement signed this week, Sanofi will develop Principia’s Bruton's tyrosine kinase (BTK) inhibitor (PRN2246), which was designed to access the brain and spinal cord by crossing the blood-brain barrier and impact immune cell and brain cell signalling. This may help treat MS and other CNS diseases. PRN2246 is currently in clinical development.

“Our agreement with Principia is an example of Sanofi’s strategic commitment to build our drug discovery and development pipeline in MS and neurological diseases,” says Rita Balice-Gordon, PhD, Global Head of MS/Neuroscience Therapeutic Research Area at Sanofi. “Complementing our own internal R&D expertise, external relationships like this may accelerate delivery of new treatments to patients living with these serious diseases.”

“Sanofi is an ideal partner for PRN2246. The agreement allows Principia to maximize the BTK opportunity in neurology with a strong partner for PRN2246 while focusing internal resources on our lead BTK inhibitor in another therapeutic area.” said Martin Babler, Chief Executive Officer of Principia Biopharma. “PRN2246 is a blood brain barrier crossing, highly potent BTK inhibitor, that we believe is especially well suited for the treatment of MS and other neurological disorders.”

BIOGEN

Biogen sneaks previously unknown lupus drug into the clinic

by Ben Adams Jul 13, 2016 10:49am

...... Analysts at Jefferies have found that Biogen ($BIIB) has quietly sneaked a lupus candidate into the lab for initial testing, coming as it does after the Big Biotech has in recent months cut its lupus research programs.

...... But in a note to clients posted today, Jefferies said that the company has now put forward a Bruton’s tyrosine kinase (Btk) inhibitor, known as BIIB068, into the clinic.

...... According to clinicaltrials.gov, the experimental candidate is targeting systemic lupus erythematosus (SLE) in a Phase I trial of 52 patients, which is expected to enroll by December.

...... Jefferies noted that while lupus “remains a challenging condition,” some Btk inhibitors have shown “signals of promise” in early trials.........


ProfG    

33 comments:

  1. Thanks ProfG! A juicy post!

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    1. Some of you have been asking for more science. Do you understand the science?

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  2. Is this the beginning of the end for b cells in the brain. Then we will get to see if oCB are important.

    More evidence that B cells are better targets.

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    1. Indeed, could we be on the verge of getting rid of long-lived plasma cells in the brain and oligoclonal bands?

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  3. A request for a plain English post as this news is obviously important:

    "This is telling us that you don't need to deplete B cells to get a therapeutic effect and that B-cell antigen signalling and presentation are back on the cards. This puts T-cells back on the agenda, possibly downstream of B cells."

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    1. I will do a simple post to explain what I mean. Yes, this is a very important topic and the results are telling us something fundamental about the role B cells play in MS.

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    2. I have had a look and there is very little literature and until we see some of the background data it is rather difficult, but based on animal studies there is depletion or lack of formation = depletion

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  4. Ok nice article and feels like another landmark step into understanding MS. The article title implies it's not B cell mediated disease. The article content also implies it's not B cell mediated disease. As Btki is non depleting so doesn't effect b memory cells invaded by EBV, and are kept alive by EBV. According to your theory. Therefore a non depleting BTKI should not affect MS progression. Clearly Merck trial counters this? But this fits with why alemtuzumab is superior to Ocrelizumab and Caldribine. Did it really require this trial to make you rethink?

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    1. The drug targets B cells and the influence on T cell function is down stream, let us see that that the drug does not affect memory B cells, if it doesn't we may have to amend our ideas but until then it I assume that this enhances our ideas. Maybe ProfG can get the investigators brochure

      In a memory B cell most of the EBV genes get switched off, does it enhance survival maybe, but put a B cell in culture and it is dead.
      ProfG I think was assuming that you have to kill the B cell to remove the remove the EBV, it may be doing this, I understand that in blood only one in 50,000 cells appears to be infected. if these are being killed you would not it.

      Do T cells help B cells to survive. This is possible if not probable

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    2. In Mixed Cellularity Hodgkin's Lymphoma, the cancer cell is a B cell modified by Epstein Barr virus. However, there are very few of these Reed–Sternberg cells, most of the lymphoma is made up of other immune cells. The infected B cells seriously disrupt the immune system causing effects no where near the lymphoma. A similar effect could be at play here.

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    3. "let us see that that the drug does not affect memory B cells"

      Not directly, when you raise transitional b cells memory b

      cells go down

      X-linked lymphoproliferative disease (XLP) is a severe immunodeficiency associated with a marked reduction in circulating
      memory B cells. Our investigation of the B cell compartment of XLP patients revealed an increase in the frequency of a population
      of B cells distinct from those previously defined. This population displayed increased expression of CD10, CD24, and CD38,
      indicating that it could consist of circulating immature/transitional B cells. Supporting this possibility, CD10 CD24highCD38high
      B cells displayed other immature characteristics, including unmutated Ig V genes and elevated levels of surface IgM; they also
      lacked expression of Bcl-2 and a panel of activation molecules. The capacity of CD24highCD38high B cells to proliferate, secrete Ig,
      and migrate in vitro was greatly reduced compared with mature B cell populations. Moreover, CD24highCD38high B cells were
      increased in the peripheral blood of neonates, patients with common variable immunodeficiency, and patients recovering from
      hemopoietic stem cell transplant. Thus, an expansion of functionally immature B cells may contribute to the humoral immunodeficient
      state that is characteristic of neonates, as well as patients with XLP or common variable immunodeficiency, and those
      recovering from a stem cell transplant. Further investigation of transitional B cells will improve our understanding of human B
      cell development and how alterations to this process may precipitate immunodeficiency or autoimmunity. The Journal of Immunology,
      2006, 176: 1506–1516.


      Do T cells help B cells to survive

      I guess (the memory b cell comptartment)

      Idiopathic CD4 T lymphocytopenia (ICL)
      is a rare heterogeneous disorder defined
      by CD4 T-cell counts below 300 cells/ L
      in the absence of human immunodeficiency
      virus (HIV) infection or other known
      immune deficiency disorders. Here, we
      report the expansion of immature/
      transitional B cells in patients with ICL,
      which is associated with elevated serum
      levels of IL-7. Both the percentage of
      immature/transitional B cells and levels
      of IL-7 were inversely correlated with levels
      of CD4 T-cell counts and directly
      correlated to each other. Further analyses
      of B cells indicated that, in contrast to the
      activating effects of HIV disease on mature
      B cells, the expansion of immature/
      transitional B cells in patients with ICL
      occurred at the expense of memory
      B cells. These findings extend previous
      reports on primary immunodeficiencies
      as well as HIV disease by suggesting that
      CD4 T-cell lymphopenia has an impact
      on human B-cell development either directly
      or indirectly via the associated elevation
      of IL-7 levels. (Blood. 2007;109:
      2086-2088

      Black swan to the rescue :)



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  5. Isn't this all a bit early for celebrations (or eating hats) when only very limited headline data have been presented.

    "... Merck has yet to quantify the difference ... against rival multiple sclerosis drug Tecfidera... gaps in the information released so far leave critical questions about the safety and efficacy of evobrutinib unanswered."

    https://www.fiercebiotech.com/biotech/merck-kgaa-btk-inhibitor-beats-placebo-phase-2-multiple-sclerosis-trial

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    1. Not too early. I predicted this study would be negative as it is a non-depleting agent. I was wrong. Time to eat my hat and to put on a new thinking one.

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    2. True Academic is one who is willing to accept the data and is open to new ideas. I applaud your stand for accepting your long held scientific beliefs maybe incorrect.

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    3. Dr Klaus. It met it's primary and secondary end point on 2 different dosages! Do you really need to wait for the full results? Regardless of how effective. If it's effective when it shouldn't be means you need to re-evalute you hypothesis.

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    4. "True Academic is one who is willing to accept the data and is open to new ideas. I applaud your stand for accepting your long held scientific beliefs may be incorrect."
      Now, if only the hard-core T cell brigade would do the same. I won't be holding my breath just yet ;-)

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    5. "I predicted it is non depleting"...based on the animal data it is indeed depleting.

      So I would like to see the pre-clinical data

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    6. "It met it's primary and secondary end point on 2 different dosages!"

      We need to see more, and look deeper into the data to decide whether this can indeed *not* be reconciled with primarily B cell driven pathophysiology, and if that is the case, then let's see how effective and safe it is compared to other compounds.

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  6. Re: "Who said it wasn't an interesting time to be in MS?"

    Yes, unless you've got advance MS and have been degenerating for ears.

    I remind you: the UK NHS has nothing for modifying our disease course.

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  7. If t cells are the main problem after all is that not why tysabri is so effective?
    Of all the available therapies which are considered the most effective ie lemtrada tysabri cladribine pending ocrelizumab which would you honestly consider to be the best regardless of which type of MS you are on paper considering Ms is really one illness?
    Sorry if this is considered silly question

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    1. There was a head to head real life experience and tysabri did very well, if you have constant control of your immune response then you have control but this can cause side-effect issues.

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  8. Okay, for some trivia and then a question.

    Trivia: are you aware that there is an infamous serial killer here in the US that was known as the BTK killer? He was quite prolific, and was active for several decades. In his case, the initials stood for Bind, Torture, and Kill, which was his modus operandi. He was married, had children, and would sometimes do his killing on his lunch hour from work. Was also very active in his church, and was ultimately called because a note he sent to the police was traced to a church computer.

    And now the question: if these BTK inhibitors keep B cells immature and stuck in the bone marrow, don't they help prove the hypothesis that B cells are fundamental to the MS disease process? Is your problem with these non-depleting drugs the fact that they don't impact the existing population of peripheral B cells, and thus don't deplete Epstein-Barr virus? Would not depriving the body of new B cell lineage eventually reduce EBV load, simply through attrition of existing memory B cells? Or does EBV make infected memory B cells immortal, so that EBV load would not be impacted even though new B cells were not being created?

    Actually, I guess that was more than one question, but I would appreciate any and all insights…

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    1. Dear WK
      Good to see you are thinking straight....this data enhance the B cell hypothesis.

      Time to review the BTK inhibitor literature and them talk I think

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  9. This site has always been dysfunctional concerning MS

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    1. Dear L from leicester
      Thanks for this comment...much appreciated as alawys

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  10. "It will need to be as good as anti-CD20 therapy to have a chance in the marketplace."


    Surely the question should rather be about which therapy has the best risk/benefit profile?

    No one can afford to be too arrogant about their pet MS pathology theories. Not yet.

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    1. Some of these agents get in the brain...do they get rid of OCB?

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  11. Very interesting and very confusing to say the least. MS still seems a mystery. We have found lots of DMT that halt progression. as the pwMS, I am still leery of how much we interfere with the immune system. Deleting mature B-cells, deleting T-cells, Deleting immature B-cells. At what point am I in more danger from having a useless immune system.

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    1. Confusing because we haven't explained it properly

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  12. what about NK cells? you used to bang on about these a lot but have since gone quiet. another failed idea?

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    1. As the saying goes, "When the facts change, i change my mind.....".

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    2. Valuable information can come from a 'failed idea'.

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  13. Good to see you so positive about a result.

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