Thursday, 21 December 2017

A new B cell drug on the way

Academics are saying "La, La, La, La, La, T cells, T cells, T cells"
and take no notice of our ravings, lucky for you Pharma is not that blinkered.

They can see the value of hitting the B cell and secretly they have been planning on targeting the B cell with some small molecule inhibitors. Want to know more?




The hot target of the year is
Bruton's tyrosine kinase (abbreviated Btk or BTK). This  is an enzyme that plays a crucial role in B-cell development.

Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C, which in turn hydrolyzes PIP2, a phosphatidylinositol, into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which then go on to modulate the activity of downstream proteins during B-cell signalling

Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia); People with XLA have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. Bruton's tyrosine kinase was discovered in 1993 and is named for Ogden Bruton, who first described XLA in 1952

Simply put, they are B cell selective agents that target immature B cells in the bone marrow, but also memory B cells and importantly can hit plasma cells too. It is also on moncytes and macrophages, but T cells have low levels.







Hopefully they have done a bit more homework after the mess made with Acaticept which made MS worse. This was made on the assumption that they were blocking B cells and as B cell activating factor makes B cells why not block it and B cells go away.

However, as we suggested blocking BAFF will get rid of plasma cells and mature B cells but is does not get rid of memory B cells and appears to makes more of them. If they had thought that memory B cells were a problem them maybe the trials would not have been done as the memory B cell resistance was known.

Benson MJ, Dillon SR, Castigli E, Geha RS, Xu S, Lam KP, Noelle RJ. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol. 2008; 180: 3655.

However it does tell us that the mature B cells are not the problem and may likewise suggest that the plasma cells in the periphery (those in the brain may be a different story)  may not be the problem.

Merck have Evobrutinib in trial and have enrolled 250 pwMS across 55 sites and are fully-recruited. PwMS have been placed into three doses of drug, placebo or dimethyl fumarate for 24 weeks. 

Sanofi have entered the fray as they have just bought PRM226 a BTK inhibitor that is designed to enter the brain and the spinal cord. If this can get rid of oligoclonal bands, will the progressive MS be dealt with?


AbbVie has Imbruvica (ibrutinib).

There are many more companies with BTK inhibitors, which they are developing for B cell cancers.

The question for the BTK inhibitors is do you need to deplete the B cells or block the memory B cell function? I suspect that you will need to deplete the B cells so the non-depleters may not work. We will see.

How convinced are you about B cells?

HPRN2246





15 comments:

  1. Crossing fingers for those. They seem very promising.

    ReplyDelete
  2. I wonder if these trials are successful the T cell mafia will finally wave the white flag of surrender?
    Probably just after the first porcine squadron does a fly-by ;-) Reputations to lovingly protect for posterity.....................:-(

    ReplyDelete
  3. "How convinced are you about B cells?"

    Half convinced:)

    Dr " B cell" is also half convinced

    Dr Hauser:
    We believe the relapsing phase is related to an autoimmune attack mediated by the adaptive immune system, namely T cells and B cells

    https://jamanetwork.com/journals/jama/fullarticle/2666528?utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jama&utm_content=olf&utm_term=121317

    Obrigado
    Bom natal

    ReplyDelete
    Replies
    1. Steve Hauser would appear to be too scared of upsetting his T cell mates to really tell it like it is, the data is there and is increasingly overwhelming;-)
      Nadolig llawen Luis.

      Delete
    2. MD2, T-cell disease in mice, B-cell disease in humans. Is this the end of EAE in the lab? Do we need a new model? I know EAE papers have padded many CVs:-)

      Delete
  4. Regardless of whether it's b or t cells. It's still not a cure. Of all the drugs in clinical trials. Would you say if successful GNbAC1 is the cure ms patients been waiting for? They've just received payment from their sponsors for reaching a milestone in phase 2.

    ReplyDelete
    Replies
    1. GNbAC1 is a antibody you need a small molecule as antibodies are not going to easily get inside a cell or the CNS. There are enough people who have taken this and it is clearly not a cure for all.

      Delete
  5. Thanks MD. Anything in the pipeline that excites you ? You think will be a game changer for ms? Or for that matter any neuroegenteative disease trial that will benefit ms.

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  6. "The purpose of this signal study was to characterize the role of evobrutinib in patients with a broad range of disease activity. The study did not reach the statistical criteria across all patients enrolled, however, there was a clear positive outcome in the pre-specified patient population conventionally studied across RA pivotal trials, which is the population to be enrolled in the Phase IIb dose-finding study."
    From Merck site

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  7. There are already 14 BTK inhibitors in the market for cancer, their mechanism is already known in the pharma ind. They play a safe game after anti CD20 therapies for MS and they are designing special MS drugs with SPECIAL prices.

    ReplyDelete
  8. "How convinced are you about B cells?"

    About B cells doing what, exactly? No matter how much evidence of B-cell involvment you gather, the question that matters is not addressed:

    Is their action pro-active or re-active? A suppressed immune response leads to less inflammation and less stress to surrounding tissue, so the argument that the action is pro-active because vaguely "MS gets better" is actually irrelevant: MS would got better even if the B-cell action was re-active. Disprove this and you have an argument that holds.

    ReplyDelete
    Replies
    1. Exactly. The thing always goes "but it works" (haha) and then ad-hominem attacks to researchers who disagree. Can a B-cell therapy stop progression? MS is one disease, not two. HSCT can halt the total of MS, can a B cell therapy do that? It will take 15 years to know if Sanofi's new miracle can do that, but I highly doubt it.

      Delete
  9. For cancer:
    "The Bruton tyrosine kinase (BTK)-targeting drug ibrutinib has demonstrated substantial success as a single agent in advancing the treatment of B-cell malignancies, and a number of novel BTK-targeting agents are now hot on its heels. Yet the ultimate development of resistance to these inhibitors limits long-term curative potential.

    Despite the impressive clinical efficacy and tolerability of BTK-targeted agents, further research is required to identify optimal dosing schedules and patients who are most likely to benefit from this type of therapy. Furthermore, BTK inhibitor monotherapy is not curative; approximately one-third of patients do not respond to ibrutinib therapy at all, and the majority of those who do ultimately develop resistance.

    Results from a variety of preclinical and early-stage clinical studies suggested that combination therapy with ibrutinib might provide additional benefit and potentially be curative by helping to overcome resistance."

    http://www.onclive.com/publications/oncology-live/2015/june-2015/novel-btk-inhibitors-and-combos-may-hold-the-key-to-b-cell-malignancies

    ReplyDelete

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