Cytokine Signalling Forum


April 21

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Estupiñán HY, Berglöf A, Zain R, Smith CIE.
Front. Cell Dev. Biol. 9:630942 DOI: 10.3389/fcell.2021.630942

Understanding of the B-cell receptor signalling pathway led to the identification of a suitable drug target to addresses autoimmunity and inflammation in areas such as MS, RA, pemphigus and SLE. There are currently 22 BTKis in various stages of clinical development. However, AEs such as cardiovascular and bleeding side effects, as well as rash, diarrhoea and infections have been associated with the inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Based on clini...

May 20

Fenebrutinib versus Placebo o Adalimumab en Artritis Reumatoide: Un estudio doble ciego aleatorizado de fase II (Estudio ANDES)

Cohen S, Tuckwell K, Katsumoto TR, Zhao R, Galanter J, Lee C, Rae J, Toth B, Ramamoorthi N, Hackney JA, Berman A, Damjanov N, Fedkov D, Jeka S, Chinn LW, Townsend MJ, Morimoto AM, Genovese MC.
Arthritis Rheumatol. 2020 Sep; 72(9): 1435–1446.

In this randomised phase II trial with MTX treatment-refractory RA patients, greater efficacy was observed with fenebrutinib 150 mg once daily or 200 mg twice daily compared to placebo, while response rates were numerically similar to those observed with adalimumab. BTK inhibitors have demonstrated clinical efficacy in B cell malignancies and multiple sclerosis, although there is limited clinical evidence of its efficacy in RA. Fenebrutinib (FEN) an orally active and selective non-covalent inh...

Keywords: BTK, Clinical, Phase 2

Translated by: Igor Koz

January 20

Seguridad, Tolerabilidad, Farmacocinética, Ocupación de Blanco y Análisis del Intervalo QT del Nuevo Inhibidor BTK Evobrutinib en Voluntarios Sanos

Becker A, Martin EC, Mitchell DY, Grennigloh R, Bender AT, Mackenzie H and Johne A.
Clin Transl Sci . 2020 Mar;13(2):325-336. doi: 10.1111/cts.12713. Epub 2019 Nov 29.

In this first in-human phase I, double-blind, placebo-controlled trial, the Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib was well-tolerated, showed linear and time-independent PK, induced long-lasting BTK inhibition, and was not associated with prolongation of QT/QTc interval in healthy subjects. Evobrutinib is an oral BTK inhibitor that has demonstrated efficacy in pre-clinical and autoimmune disease models. BTK is a key regulator of B cell receptor and Fc receptor signalling, an...

Keywords: BTK, Clinical, Safety

Translated by: Igor Koz

June 19

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

Haselmayer P, Camps M, Liu-Bujalski L, Nguyen N, Morandi F, Head J, O’Mahony A, Zimmerli SC, Bruns L, Bender AT, Schroeder P, Grenningloh.
J Immunol 2019;202:2888–2906. DOI: 10.4049/jimmunol.1800583

BTK is involved in both adaptive and innate immune responses and mediates signalling of several immune receptors of relevance to RA and SLE pathogenesis. Targeting BTK is a promising approach therefore for autoimmune disorders with aberrant B cell responses. Evobrutinib is a novel, highly specific, and irreversible BTK inhibitor. In vivo and animal models showed that evobrutinib modulated B cell and innate immune cell activation, was efficacious, and prevented joint damage. The potency of evob...

May 14

Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants

Hartkamp LM, Fine JS, van Es IE et al.
Ann Rheum Dis Published Online First 24 April 2014 doi:10.1136/annrheumdis-2013-204143

Bruton’s tyrosine kinase, a downstream target of PI3K signalling, has been shown to be crucial in the B lymphocyte and myeloid cell contribution to murine models of arthritis. Synovial tissue samples were taken from biologically naïve RA (n=16) and PsA (n=12) patients in order to assess the expression of BTK. Separate RA synovial explants (n=8) were used to assess the effects of the specific BTK inhibitor RN486. BTK was expressed at equivalent levels in both RA and PsA synovial tissu...

January 14

Inhibición de PI3K-δ y PI3K-γ mediante IPI-145 anula las respuestas inmunes y suprime la actividad en modelos de enfermedades autoinmunes e inflamatorias

Winkler DG, Faia KL, DiNitto JP et al.
Chemistry and Biology Nov 13 20, 1364-1374

Phosphoinositide-3 kinases (PI3K) are cell signalling proteins that act as a central node for relaying signals from cell surface receptors and downstream mediators. Specifically they phosphorylate phosphatidylinositol to phosphatidylinositol-3,4,5-trisphosphate (PIP3). This acts a docking site for signalling proteins, leading to the activation of downstream effectors such as BTK. Therefore, inhibition of the PI3K-d and PI3K-? isoforms (PI3K-a and PI3K-ß demonstrated embryonic lethality in ...

Keywords: Cytokine Signalling, Preclinical, MOA

Ibrutinib (PCI-32765), el inhibidor de la Btk disponible oralmente, protege contra la pérdida ósea mediada por osteoclastos

Shinohara M, Chang BY, Buggy JJ et al.
Bone 2014;60:8-15

Ibrutinib is a first-in-class, orally available Btk (Bruton’s tyrosine kinase) inhibitor which has been shown to be effective in the treatment against certain types of leukemia and autoimmune disorders. Btk regulates the expression of genes involved in the differentiation and function of osteoclasts, and therefore inhibiting Btk suppresses osteoclastic bone resorption. Results from in vitro testing showed the suppressive effects on osteoclasts and murine models of RA showed ibrutinib treat...

Keywords: BTK, Preclinical, MOA