Impact of Fenebrutinib Treatment on MRI Outcomes and Cerebrospinal Fluid Penetrance in Multiple Sclerosis: Results from the Phase II FENopta Study
Amit Bar-Or1, Michal Dufek2, Hrvoje Budincevic3, Jelena Drulovic4, Mario Habek5, Le H Hua6, Martin S. Weber7, Piia Thomas8, Julie Napieralski8, David Clayton8, Denison Kuruvilla8, Qi Qi8, Yan Xu8, Alexandra Goodyear8, Jiwon Oh9
1University of Pennsylvania, 2St. Anne’s University, 3Sveti Duh University Hospital, 4University Clinical Center of Serbia, 5University Hospital Center Zagreb and University of Zagreb, School of Medicine, 6Lou Ruvo Center for Brain Health, 7Institute of Neuropathology and Department of Neurology, University Medical Center, 8Genentech Inc., 9St. Michael’s Hospital, University of Toronto
Objective:
To evaluate the effects of fenebrutinib on MRI outcomes and the ability of fenebrutinib to enter cerebrospinal fluid (CSF) in the ongoing Phase II study FENopta (NCT05119569).
Background:
Fenebrutinib is a potent, highly selective, noncovalent, reversible Bruton’s tyrosine kinase (BTK) inhibitor being investigated for multiple sclerosis (MS) treatment. BTK is implicated in peripheral and central nervous system inflammation in MS, which may drive progressive disease biology.
Design/Methods:
Patients with relapsing MS (pwRMS) were randomized 2:1 to receive fenebrutinib (200 mg, twice daily) or placebo for 12 weeks. The primary endpoint was total new T1 gadolinium-enhancing (Gd+) MRI lesions at Weeks 4, 8 and 12. Key secondary endpoints evaluated the treatment effect on number of MRI lesions (e.g. new/enlarging T2 [NET2] lesions) and safety. Exploratory endpoints assessed fenebrutinib concentrations in CSF.
Results:
Of 106 randomized pwRMS with evaluable MRI, 70 received fenebrutinib, and 36 received placebo. At Weeks 4, 8 and 12 (combined), fenebrutinib patients had a 69% reduction in total new Gd+ lesions and a 74% reduction in total NET2 lesions vs placebo patients. Relative reductions in Gd+ and NET2 lesions were observed at Week 8 (92% and 90%, respectively) and Week 12 (90% and 95%, respectively). Mean fenebrutinib CSF concentration in 11 pwRMS after 12 weeks of continuous fenebrutinib administration was 43.1 ng/mL, which is higher than the mean IC50 (active range) in CD63 (10.0 ng/mL), phospho-BTK (7.5 ng/mL) and CD69 (5.3 ng/mL) whole blood assays. The safety profile was favorable with no serious adverse events or deaths reported.
Conclusions:
These data from FENopta highlight the potential of fenebrutinib for treating RMS by reducing MRI lesions with a favorable safety profile. Early findings show CSF penetration and indicate that fenebrutinib was detected in CSF at clinically relevant concentrations to impact mechanisms underlying chronic progressive disease biology in MS.