Saturday, 11 February 2017

Atacicept Why didn't it work

So to End B memory Cell week (my posts will reduce)

It is all well and dandy coming up with an idea when everything goes the same way, but what happens when things make MS worse  what can this tell us.

Read the paper


http://www.ebiomedicine.com/article/S2352-3964(17)30045-2/pdf

We mentioned the paper


Sergott RC, Bennett JL, Rieckmann P, Montalban X, Mikol D, Freudensprung U, Plitz T, van Beek J; ATON Trial Group..
ATON: results from a Phase II randomized trial of the B-cell-targeting agent atacicept in patients with optic neuritis.
J Neurol Sci. 2015; 351:174-8

We should not forget


Kappos L, Hartung HP, Freedman MS, Boyko A, Radü EW, Mikol DD, Lamarine M, Hyvert Y, Freudensprung U, Plitz T, van Beek J; ATAMS Study Group. Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial.
Lancet Neurol. 2014; 13:353-63


BACKGROUND: Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production.
METHODS: In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18-60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT).
FINDINGS: Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43-1·74; 75 mg, 0·79, 0·40-1·58; 150 mg, 0·98, 0·52-1·81; placebo, 0·38, 0·17-0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97-5·27; 75 mg, 2·30, 1·08-4·92; 150 mg, 2·49, 1·18-5·27; placebo, 3·07, 1·40-6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group
INTERPRETATION: Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted.



Top Left. Mature B cells drop after atacicept. Bottom left IgG levels drop after atacicept in MS. Middle-Memory B cells increase in mice given atacicept-like molecule (TACI-Ig). Right top Blockade of BAFF with antibody increase memory B cells but decrease mature and plasma cells in arthritis

Here, the idea was to block B cell growth factors (BAFF), using a fusion protein of a type of BAFF receptor fused to an antibody (atacicept), and indeed that what is does. It makes naive also known as mature B cells go down and it also kills plasma cells and so immunoglobulin levels go down, but memory B cells go up. MS gets worse. 

So is this a T cell- mediated disease? or 

Does it really tells us that it is the memory B cell?

So for the relapsing disease it does not appear to be the plasma cell or mature B cell as a problem.

Another way to do the same thing is to block B cell activating factor (BAFF) with an antibody. The example in the graph you can see Belimumab in arthritis. As you can see mature (naive) and plasma cells go down memory B cells go up. 

I don't think this was used in MS but another study used another antibody to the same target. This was done by Lilly.

The trial was claim to be completed and presumed failed as it was never reported but there is a suggestion it was terminated...this would suggest worsening, but as it was in development in Lupus at the time is this a reason to keep quiet?

I requested and was refused access to the data by the Lilly Team.
Maybe someone from Lilly or someone with influence can ask them to share data as it speaks to safety.
 
So is MS a T cell disease?..You decide


or would you want your therapies to deplete memory B cells? 

Time to get more data to support or refute the idea!

9 comments:

  1. So, the 'failed' trials ATAMS and ATON have made a huge impact on MS research. Just as well the teams went ahead and published! There has to be a lesson in this ;-)
    I'm shocked to hear about Lilly. Why on earth not release the data to you, presumably it's no use to them now? Perhaps when they see your paper they'll realise how important it is for MS research (and research into other ai diseases). Hey, might even give them a pointer as to what to try next ;-)

    ps paper looks good in published format with pictures in amongst the text. First time I've seen this version :-)

    ReplyDelete
    Replies
    1. I agree those antibodies are gone. Lily have a big B cell programme.

      If it made people worse and they continued with their lupus programme for another few years.it would look bad.

      I think it is scandalous that they don't release the data.

      Delete
  2. http://lilly.co.uk/en/responsibility/transparency/clinical-trial-registry.aspx

    Reading this on Lilly website I can't understand the info wasn't happily shared. Hello Lilly, anyone there?

    ReplyDelete
    Replies
    1. I will look on website and maybe try again. Their excuse was that it was before the 2012 cuttoff after which they have pledged to give access to data.
      Maybe we can track down the person who said it was terminated which suggests bad news. I think they are at Novartis
      Probably a.gag clause.

      Delete
  3. I'm pretty naive but to my mind the spirit of their webpage says data is happily shared for the greater good ;-)
    Good luck MD and thanks again for the paper, it means a lot to us all :-)

    ReplyDelete
    Replies
    1. Thanks I have gone back to ask the where their trial data is disclosed I think on point 2 or 6.

      For point 2 can they argue it wasn't marketed.

      Delete
  4. Its more than b cells clould it be t and b working toghether

    ReplyDelete
  5. B cells
    For a long time, B cells were thought to be important in MS in their capacity
    to differentiate into plasma cells and produce antibodies.36 The advent of B
    cell depleting therapies has challenged this view. It was noted that clinical
    improvement in patients treated with rituximab often preceded reduction in
    autoantibody levels.52 Further, in a phase II trial of atacicept, a fusion protein
    that blocks plasma cell function and the late stages of B cell development,
    treatment was found to aggravate MS.53 This is in contrast to rituximab,
    which in clinical trials has been proven to be effective in MS.54, 55 The above
    suggests that B cells are important in some other capacity than antibody
    production. Rituximab treatment results in a noticeable decline of T cell
    numbers in CNS of treated patients, suggesting that B cells sustain
    pathogenic T cell responses. Recently, it was demonstrated that IL-6
    production is the major mechanism of B cell contribution to the pathogenesis
    of EAE (experimental autoimmune encephalomyelitis, an experimental
    model of MS), and also that this inflammatory pathway was increased in
    RRMS patients.52 Another possibility is that the B cells act as antigen
    presenting cells.56
    Joachim Burman

    ReplyDelete

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