Why did Atacicept make MS worse? Can you be Sherlock?


Response to therapy is the ultimate human experiment. It can tell us so much more than thousands of animal experiments.

A successful trial tells us a load, but likewise a failed trial, if done properly and many failed trials are not done properly I would say, tells us alot.

Now it may tell us something we don’t want to hear and a good example is the effect of anti-CD20 (Ocrelizumab for example). This kills most B cells except plasma (antibody-producing cells, that live in the bone marrow) and the early B cell precursors (that live in the bone marrow also).

Rather than accept the easy view that a B cell expressing CD20 is the central target and the problem in MS, T cell immunologists have come up with all sorts of answers to avoid the obvious and some have desparately tried to convince themselves that CD20+ T cells are the answer. But if T cells are the only answer how does CD19 B cell depleting antibodies work. This kills a few more B cells than CD20 and is effective at blocking MS lesions.

So how does this work?

Again, some will say it is T cells and if you say it confidently and loud enough no-one will question this in public, as they don’t want to cause a scene (I have seen it done)…but there is an very ugly fact that CD19 is not realy expressed by T cells and so this can not be the answer. There are hundreds of papers showing this.

So it ain’t T cells I am guessing..now it may be B cells activating T cells

Now back to those informative experiments

Atacicept usage in MS was one of those experiments.

It was supposed to be a B cell blocker and work like anti-CD20 and stop MS, however

It went wrong in two different MS trials and made MS worse in both cases Therefore, understanding this is going to tell us something very, very fundemental about MS. It really is something we need to get our heads around.

Since the end of 2017, we have been learning about B cells and prodding the T cell immunologists to have a think about what is really going on.

Some are a lost-cause I have to say and could not think themselves out of a paper bag….Yep only joking… but I know some of you want to to have a laugh every now and then…(Thanks Fi for your nice comments)

But we need to do some reading and thinking

Perhaps we can do this together, as I know some of you like abit of detective work and turn up stuff we miss . Let’s see what you can find.

I don’t know the answer?. But once were are done. I’ll write a review on this. Maybe even do an experiment.

Kappos et al. Lancet Neurol. 2014 Apr;13(4):353-63. doi: 10.1016/S1474-4422(14)70028-6. Epub 2014 Mar 6. 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).

So in placebo 0.038 = 0.4 which is 4 relapses in 10 years. In the low dose atacicept it was 0.86 = 0.9 which is 9 relapses in 10 years and at the 150mg dose it was 0.98 = 1.0 which is ten relapses in 10 years or one relapse a year. So the worsening caused about twice the disease activity, but it wasn’t seen in the MRI lesions.

Sergott et al. ATON: results from a Phase II randomized trial of the B-cell-targeting agent atacicept in patients with optic neuritis.

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) (Twice the amount of nerve loss). 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 eve

So Acacicept made things worse and it didnt take many people to see this

Last year we suggested that it may be because if made more memory B cells, but we have had alternative suggestions.

It has got me intriged and we have been told that

  1. Atacicept may have blocked the actions of immunoregulatory antibody-producing cells via an action of blocking BAFF (B cell activating factor). Now we have another idea and this is
  2. Because Atacicept blocked the actions of immunoregulatory astrocytes via an action involving APRIL (A proliferating ligand).

Atacicept is an fusion protein of a receptor called TACI- with immunoglobulin so it will be bind to BAFF and APRIL expressed on cells or mop up any BAFF or APRIL that is floating around.

This will stop stimulation by BAFF binding to three different receptors called BAFF-R, TACI and BMCA and stop the action of APRIL which acts on TACI and BMCA (Don’t worry about this we can reivew this in the future and we can find out what they do and what is expressed by what for example BMCA is expressed by plasma cells, BAFF-R is high on immature cells. Mice CNS cells express different molecules to humans.

Now if you remember we spent some time hassling Ely Lilly to publish their study on tabalumab, which blocked BAFF. Did it make MS worse too?

We have seen the abstract.

Maria Silk & Eric Nantz Efficacy and Safety of Tabalumab in Patients with Relapsing-Remitting Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Study (P3.397). Neurology 2018; 90 (15 Supplement). Of 245 randomized patients, 197 (80%) completed the study. The mean total numbers of Gd-enhancing MRI lesions averaged over Weeks 12, 16, 20, and 24 were 1.521 and 1.758 in the all-tabalumab and placebo groups, respectively; differences overall or between any of the tabalumab groups and placebo were not statistically significant. The proportion of patients reporting at least one treatment-emergent adverse event, serious adverse event, and follow-up emergent adverse event was higher in the all-tabalumab group than placebo (68.1% [n=143] vs 48.6% [n=17], 11% [n=23] vs 5.7% [n=2], and 41.9% [n=88] vs 34.3% [n=12], respectively); however, this was not dose dependent. Conclusions: Treatment with tabalumab was not efficacious in reducing Gd-enhancing MRI lesions in patients with RRMS versus placebo; no specific safety concern was identified.

So apparently no worsening. It was significantly larger than either of the ataciciept trials. But what happened to the memory B cell responses?

We don’t know as the data was not reported, but belimimab is another anti-BAFF blocking antibody and if we look at its affect on memory B cells, we see that there was no effect.

Ramsköld D et al. B cell alterations during BAFF inhibition with belimumab EBioMedicine. 2018 Dec 25. pii: S2352-3964(18)30612-1. doi: 10.1016/j.ebiom.2018.12.035. [Epub ahead of print]

“B cells from peripheral blood of 23 SLE patients initiating belimumab treatment and followed longitudinally for up to three years. B cells decreased during the study period, with a rapid decrease of both naïve at the first follow-up visit, followed by a continuous reduction at subsequent follow-ups. In contrast, plasma cells and switched memory B cells remained stable throughout the study.

There were no more plasma cells either. This perhaps tells us that it is the mature cells that are more BAFF dependent.

Therefore is APRIL (A proliferation-inducing ligand (APRIL), also known as tumor necrosis factor ligand superfamily member 13 (TNFSF13) may be the problem kid?

However, more positive data for the memory B cell hypothesis.

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  • Rather than accept the easy view that a B cell expressing CD20 is the central target and the problem in MS

    Although B-cells have
    known roles in antigen presentation, cytokine production,
    and (once the B-cell matures to a plasma cell) antibody
    production, their exact role in MS pathophysiology remains
    unclear [90]

    Therapeutic Advances and Challenges in the Treatment of Progressive
    Multiple Sclerosis


  • If the B cell expressing CD20 is the central target and the problem in MS

    Why them alemtuzumab is superior to ocrelizumab?

    Should´nt we all be taking anti cd 20 ?


    • Why is alemtuzumab superior…what is the evidence that it is superior?

      ProfGs ramblings?…You need head to head studies to at least compare like with like.
      I am willing to accept it can be superior and then it says you add to the B cell depletion.

      At the moment it seems that most people are taking ocelizumab….profG thinks it is about 8 out of 10 are picking it. This is why ProfG is worried about the time-bomb if there is an atrophy difference. The Swedes will be able to address this because they have enough people first line on rituximab. They however I suspect dont have the alemtuzumab data…speak to a wellknow Swedish Neuro they though it was the Devil’s Tool.

      If Roche can access the data there must be enough firsth line ocrelizumab use.

      When I go to Sweden next month I will be posing this question?…

  • Maybe the obsession with B cells T cells, the immune system reaction, is the problem. Maybe you need to look deeper. Maybe HERVs are where it’s at.

    • I’ll leave the obsessions with HERVs to ProfG and ProfG down-under…did you buy the stuff in the video?.

      If it is an endogenous retrovirus it is everycell, why MS?…A plausible answer and I may put some effort into thing about it.

      • I thought some of what Prof Dolie said is compelling stuff. I’m particularly troubled by the variety of presentations of MS (not least because I seem to have one of the less common) and HERV activation – possibly by EBV and herpes simplex amongst other things – offers a lot of scope for explanation of this. I stumbled across this, although a bit old by now, from 2011:

        Very interesting, particularly the theraputic possibilities. Please do think about HERVs!

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