Author Of 2 Presentations
P0211 - Examination of fenebrutinib, a highly selective BTKi, on disease progression of multiple sclerosis (ID 1225)
Preventing multiple sclerosis (MS) disease progression is critical in preserving function and quality of life. Fenebrutinib is a potent, highly selective Bruton’s tyrosine kinase (BTK) inhibitor with a dual mechanism of action. Fenebrutinib targets acute and chronic aspects of MS by decreasing B-cell activation and limiting myeloid proinflammatory responses. This profile and studies of fenebrutinib in patients with other inflammatory diseases suggest a potentially favorable benefit-risk ratio, although there are no studies yet in patients with MS.
To describe the unique design aspects of the Phase III fenebrutinib clinical trial program as they relate to understanding disease progression across the MS spectrum.
We developed a Phase III program that will assess disease progression in two identical clinical trials in relapsing MS (RMS) and one trial in primary progressive MS (PPMS).
To understand the effects of fenebrutinib on disease progression, all three trials include 12-week composite Confirmed Disability Progression (cCDP12) as a primary endpoint; the RMS trials also include annualized relapse rate as a co-primary endpoint. The cCDP12 requires at least one of the following: (1) an increase in Expanded Disability Status Score (EDSS) score of ≥1.0 point from a baseline (BL) score of ≤5.5 points, or a ≥0.5 point increase from a BL score of >5.5 points; (2) a 20% increase from BL in time to complete the 9-Hole Peg Test; (3) a 20% increase from BL in the Timed 25-Foot Walk Test. The cCDP12 is a more sensitive assessment of disability than the EDSS, especially at early disease stages, as it provides a quantitative assessment of upper limb function. Comparator arms will include active disease-modifying treatments with known effects on disability progression (PPMS=ocrelizumab; RMS=teriflunomide). Treatment assignments will be 1:1, with estimated enrollment of 734 patients in each of the RMS trials and 946 in the PPMS trial. Study durations will be event driven, with the primary analysis occurring after a prespecified number of cCDP12 events (≥96 or ≥120 weeks in the RMS and PPMS trials, respectively).
Fenebrutinib will be investigated in RMS and PPMS and may offer a unique approach to slowing disease progression in MS. Furthermore, the use of the cCDP12 as a primary endpoint may provide a clearer, more complete picture of disability progression or improvement than the EDSS alone.
P0338 - Fenebrutinib, a noncovalent, highly selective, long residence time investigational Btk inhibitor for the treatment of MS (ID 1864)
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.
To assess the potency, selectivity and kinetics of inhibition of Btk by FEN.
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.
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.
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.