Genentech, Inc.

Author Of 1 Presentation

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0338 - Fenebrutinib, a noncovalent, highly selective, long residence time investigational Btk inhibitor for the treatment of MS (ID 1864)

Speakers
Presentation Number
P0338
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Bruton tyrosine kinase (Btk) has the potential to play a role in the acute and chronic inflammation that leads to disease progression in multiple sclerosis (MS) by B-cell and myeloid cell activation. Optimized molecular properties of targeted therapies in chronic conditions like MS are important to limit off-target adverse effects and maximize efficacy. Fenebrutinib (FEN) is a noncovalent investigational Btk inhibitor for the treatment of MS.

Objectives

To assess the potency, selectivity and kinetics of inhibition of Btk by FEN.

Methods

Btk inhibitory potency (IC50) and kinase selectivity of FEN, evobrutinib (EVO) and tolebrutinib (TOL) were assessed in a panel of 219 human kinases. FEN, TOL and EVO were screened at 1 µM; EVO was also tested at 10 µM due to its weaker Btk IC50. IC50 values were determined for all kinases inhibited by ≥50%. FEN was also tested in human whole blood for its ability to block activation of B cells (CD69) and myeloid cells (CD63). The rate of FEN release from the Btk•FEN complex was quantified in a preincubation-dilution experiment, where Btk activity was recovered with a rate constant koff and residence time 1/koff.

Results

FEN potently inhibits Btk (IC50=2.3 nM); TOL has an IC50 of 1.4 nM, whereas EVO has an IC50 of 32 nM. In whole blood, FEN potently blocks activation of B cells (CD69 IC50=8 nM) and basophils (CD63 IC50=31 nM). In the kinase panel, FEN (1 µM) inhibits only 3 of 218 off-target kinases by >50%, whereas TOL (1 µM) inhibits 19 of 218 off-target kinases. EVO inhibits 3 of 218 off-target kinases at 1 µM and 18 of 218 off-target kinases at 10 µM. On the basis of kinase IC50 values, FEN is >130-fold more selective against all 218 kinases tested, whereas EVO and TOL were found to be less selective. Finally, in a preincubation-dilution assay, the Btk•FEN complex is very stable; FEN dissociates very slowly from Btk and shows a residence time of 18.3 hours bound to Btk.

Conclusions

The high selectivity and potency of FEN has the potential to be associated with fewer off-target adverse events and an improved MS therapeutic index compared with less selective Btk inhibitors. FEN’s long residence time bound to Btk may also improve the MS therapeutic index by mimicking the durable pharmacological inhibition of a covalent inhibitor but without the safety risks of covalent Btk inhibitors.

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Presenter Of 1 Presentation

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0338 - Fenebrutinib, a noncovalent, highly selective, long residence time investigational Btk inhibitor for the treatment of MS (ID 1864)

Speakers
Presentation Number
P0338
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Bruton tyrosine kinase (Btk) has the potential to play a role in the acute and chronic inflammation that leads to disease progression in multiple sclerosis (MS) by B-cell and myeloid cell activation. Optimized molecular properties of targeted therapies in chronic conditions like MS are important to limit off-target adverse effects and maximize efficacy. Fenebrutinib (FEN) is a noncovalent investigational Btk inhibitor for the treatment of MS.

Objectives

To assess the potency, selectivity and kinetics of inhibition of Btk by FEN.

Methods

Btk inhibitory potency (IC50) and kinase selectivity of FEN, evobrutinib (EVO) and tolebrutinib (TOL) were assessed in a panel of 219 human kinases. FEN, TOL and EVO were screened at 1 µM; EVO was also tested at 10 µM due to its weaker Btk IC50. IC50 values were determined for all kinases inhibited by ≥50%. FEN was also tested in human whole blood for its ability to block activation of B cells (CD69) and myeloid cells (CD63). The rate of FEN release from the Btk•FEN complex was quantified in a preincubation-dilution experiment, where Btk activity was recovered with a rate constant koff and residence time 1/koff.

Results

FEN potently inhibits Btk (IC50=2.3 nM); TOL has an IC50 of 1.4 nM, whereas EVO has an IC50 of 32 nM. In whole blood, FEN potently blocks activation of B cells (CD69 IC50=8 nM) and basophils (CD63 IC50=31 nM). In the kinase panel, FEN (1 µM) inhibits only 3 of 218 off-target kinases by >50%, whereas TOL (1 µM) inhibits 19 of 218 off-target kinases. EVO inhibits 3 of 218 off-target kinases at 1 µM and 18 of 218 off-target kinases at 10 µM. On the basis of kinase IC50 values, FEN is >130-fold more selective against all 218 kinases tested, whereas EVO and TOL were found to be less selective. Finally, in a preincubation-dilution assay, the Btk•FEN complex is very stable; FEN dissociates very slowly from Btk and shows a residence time of 18.3 hours bound to Btk.

Conclusions

The high selectivity and potency of FEN has the potential to be associated with fewer off-target adverse events and an improved MS therapeutic index compared with less selective Btk inhibitors. FEN’s long residence time bound to Btk may also improve the MS therapeutic index by mimicking the durable pharmacological inhibition of a covalent inhibitor but without the safety risks of covalent Btk inhibitors.

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