When B cell inhibiton simply is not good enough. Bruton’s tyrosine kinase inhibitors?

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Once you know that B cells are an important target you find ways to inhibit them. One approach is to make depleting monoclonal antibodies. Another way is to to stop B cell signalling. In this study they block Bruton’s tyrosine kinase.

ProfG and I spent some time trying to get our hands on one a few years ago but the company wasn’t interested in MS and expected us to pay for all the development work. Needless to say it did not happen.

However, under my radar a company had done a trial. It is now published.

Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis.Montalban X, Arnold DL, Weber MS, Staikov I, Piasecka-Stryczynska K, Willmer J, Martin EC, Dangond F, Syed S, Wolinsky JS; Evobrutinib Phase 2 Study Group. N Engl J Med. 2019 May 10. doi: 10.1056/NEJMoa1901981

BACKGROUND: Bruton’s tyrosine kinase (BTK) regulates the functions of B cells and myeloid (macrophages) cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo.

METHODS: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS).

RESULTS: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib.

CONCLUSIONS: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).

So it was positive and better than dimethyl fumarate…Yipee. However let’s look at the effect on MRI lesions, it inhibits by about 70% inhibion, which is about as good, or bad, as interferon beta and miles worse than CD20 depletion. The relapse rate inhibition is 0.08, which isn’t bad and about as good as alemtuzumab, cladribine, ocrelizumab,etc. However, one has to take this all the time, so what’s the adantage?

Any company with interest in B cells has one of these. I do not know much about evobrutininib but there are loads of others. Genzyme has a brain penetrant version. If you put this head to head against rutiximab, ocrelizumab, ocrelizumab, would it cut the mustard?..Based on MRI not really, so you have to think where you would position this. It is apparently non-depleting so you could stop it and I guess things could reverse, until a depleting antibody.

However the T cell brigade will no need to explain how this works, is BTK in T cells?

However, one thing it does it sthat it targets macrophages, maybe this could be useful in progressive MS. Will it be tried?

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