AAN2020. A CNS penetrant B cell targeting agent.

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Today we had the good news that people with X-linked agammaglobulinaemia (XLA) can recover from COVID-19. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies (also called immunoglobulins), which defend the body from infections, in particular with extracellular, encapsulated bacteria. People with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton’s tyrosine kinase (BTK) gene that leads to a severe block in B cell development (at the pre-B cell to immature B cell stage) and a reduced immunoglobulin production in the serum. BTK is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor . There is significant decrease in all immunoglobulins including IgG, IgA and IgM that is probably secondary to not producing antibody cell precursors. There is a lack of circulating CD19 B cells so it clearly stops memory B cells from being produced. Will it stop their activity once formed.

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Because B cells are important for the control of MS as evidenced by the effect of ocrelizumab, pharma have come up with the idea of targeting Bruton’s tyrosine kinase, with inhibitors.

Evobrutinib is one such tyrosine kinase inhibitor

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.Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med. 2019 Jun 20;380(25):2406-2417

Evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity meaning once bound it is stuck and the kinase wont work….So this could mean inhibition for ever, but the kinase is remade so you still need to keep giving drug. It was found that 25mg was enough to block the kinases but you can see above that this level was not good enough to stop MS. What does it do in EAE there is a small inihibition, but this may be put down to an effect via macrophage inhibition.

At the AAN2020 we have had data from the new kid on the block which is another BTK which was designed to me more CNS-penetrant (SAR442168)

Design of a Phase 2b Dose-finding Trial to Evaluate Safety and Efficacy of the CNS-penetrant BTK Inhibitor SAR442168 in Patients with Relapsing Forms of Multiple Sclerosis
Anthony Traboulsee.

Background
With an increasing number of MS therapies available, to justify placebo arms in clinical trials is becoming difficult, and using alternative approaches is necessary. MRI outcomes in phase 2 trials are well-established predictive biomarkers for clinical outcomes in phase 3 MS drug development.

Objective
To describe the design of a phase 2b, proof-of-concept, dose-finding trial of the CNS-penetrant Bruton’s tyrosine kinase inhibitor SAR442168 in patients with relapsing MS, which implements important design elements intended to improve efficiency and reduce exposure to placebo.

Design Methods
The phase 2b trial (DRI15928, NCT03889639) was a 16-week, placebo-controlled, crossover trial testing four SAR442168 doses (5, 15, 30, or 60 mg q.d., administered orally) in patients with relapsing MS. Patients were assigned to receive placebo for 4 weeks (weeks 1–4) then one of four doses of SAR442168 (weeks 5–16), or to receive SAR442168 (weeks 1–12) then placebo (weeks 13–16), in a double-blinded fashion.

Results
Our modeling approach could provide ≥89% power to detect a maximum 85% risk reduction in the number of new Gd-enhancing T1-hyperintense lesions using a total of 120 patients (26 per dose, assuming 15% drop-out rate) with a 2-sided α=0.05.

Conclusions
By applying modern trial design elements, we developed a compact, MRI-based trial for proof-of-concept and dose-finding for SAR442168 in patients with relapsing MS without the need for a placebo-only arm.

Was was going to stay up to watch the presentation in the Wee hours of the morning but they I thought hey why boother I will just look at the “press release” The results are from Sanofi website

The phase 2 study was designed to assess the dose-response relationship after 12 weeks of treatment with SAR442168, by measuring the number of new brain lesions on MRI. The study evaluated four doses ranging from 5mg – 60mg after 12 weeks and used placebo data obtained at four weeks. In the primary objective measuring the number of new Gd-enhancing T1 hyperintense lesions. The treatment effect of SAR442168 at the 60mg dose was 85% relative reduction of new Gd-enhancing T1 hyperintense lesions. For the secondary objective measuring the number of new or enlarging T2 hyperintense lesions resulted in an 89% relative reduction. The most frequent adverse events (AEs) were headache (3 to 13%), upper respiratory tract infection (3 to 6%) and nasopharyngitis (3 to 9%).

It has been announced that relapsing and progressive trials are planned, will they compare to Best in Class of go against placebo or low hanging fruit? I guess we can guess the answer:-(

Bet they won’t tell us what is does to the B cell populations. But if active I have to bring it in to the B memory cell world or change ideas. Looking forward to the papers to tell us that T cells express BTK

data from bio.gps.org..Memory B cells have message

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