Friday, 13 March 2015

Blocking B cells can sometimes make MS worse

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 . pii: S0022-510X(15)00086-6. doi: 10.1016/j.jns.2015.02.019. [Epub ahead of print]

The 36-week ATON study compared the efficacy and safety of atacicept with matching placebo in 34 patients with unilateral optic neuritis as a clinically isolated syndrome. Atacicept (150mg) was administered twice weekly for 4weeks (loading period), then once weekly for 32weeks. The ATON study was terminated prematurely by the sponsor when an independent Data and Safety Monitoring Board review observed increased multiple sclerosis (MS)-related disease activity in the atacicept arms of the concurrent ATAcicept in MS (ATAMS) study. Analysis of the prematurely terminated ATON study showed that the mean (standard deviation) change from baseline in retinal nerve fiber layer thickness at last observed value in the affected eye was -8.6 (10.1) μm in patients treated with atacicept (n=15) compared with -17.3 (15.2) μm in patients treated with placebo (n=16). In the atacicept treatment group, a higher proportion of patients converted to clinically definite MS during the double-blind period compared with placebo (35.3% [6/17] vs 17.6% [3/17]). Treatment-emergent adverse events were similar across both treatment groups in the double-blind period. A dichotomy emerged with more atacicept-treated patients converting to relapsing-remitting MS compared with placebo-treated patients, despite the same patients experiencing less axonal loss after an optic neuritis event.

Pharma have the herding mentality and once there is is a hit in one therapeutic area then they all follow so as anti-CD20 wih rituximab spawned a couple of of others, another company is trying anti-CD19 anti-B cell therapy but then there was atacicept. This blocks a B cell growth factor but rather than stopping MS, it made MS worse and so in this stuy in optic neuritis it also appeared to make MS worse as it enhanced the occurrence of the second symptom leading to a diagnosis of MS. However in this study they found that there was a suggestion that less nerve loss occurred. This disconnect is yet another example that there are different mechanisms at play when it comes to nerve damage and it cannot be assume that something that blocks nerve damage will be good for stopping the inflammatory response that drives relapsing disease.

The important point is that we need to understand why this went wrong as it is a key how to realise how to make things work. It is also shows that trials can sometimes go wrong and we have to be grateful that some people will take this risk to ensure that progress ultimately occurs.

5 comments:

  1. Is it possible that this drug fails where Rituxan succeeds because Atacicept simply inhibits B cell activity and Rituxan actually destroys the cells? This idea would play well with the hypothesis that the EBV infecting B cells plays a role in activating the disease. Perhaps blocking the immune response of B cells while leaving them intact multiplies the disease activation qualities of EBV, since the nasties are still resident in the body within the now emasculated B cells… Or is this going too far out on a limb?

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    1. Many B cells only have a show life span measured in weeks so if you block growth and leave them, they will still die and I think news one should not get made to replace them so it should deplete, but there are cells that may be left and these are the important ones

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    2. Did Atacicpet deplete b-cell?

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  2. Probably a really basic question, but if B cells have a short life, what happens to the EBV within them when they die, and how does it persist for your whole life?

    Also, I thought there was a study that showed B cells infected with EBV were immortal?

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