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
We mentioned the paper
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
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!