Abstract Details

Title Impact of Fenebrutinib Treatment on MRI Outcomes and Cerebrospinal Fluid Penetrance in Multiple Sclerosis: Results from the Phase II FENopta Study

Topic Multiple Sclerosis

Presentation(s) S31 - Multiple Sclerosis: Therapeutics and Clinical Decision Making (1:36 PM-1:48 PM)

Poster/Presentation
Number 004

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.

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).

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.

Authors/Disclosures
Amit Bar-Or, MD, FRCPC (University of Pennsylvania) PRESENTER	Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Genentech. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen/Actelion. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Atara Biotherapeutics. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merk/EMD Serono. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Atara Biotherapeutics. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck/EMD Serono. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi/Genzyme. The institution of Dr. Bar-Or has received research support from Novartis. The institution of Dr. Bar-Or has received research support from Biogen. The institution of Dr. Bar-Or has received research support from Roche/Genentech. The institution of Dr. Bar-Or has received research support from Merck/EMD Serono.
Michal Dufek, PhD	Dr. Dufek has nothing to disclose.
Hrvoje Budincevic	No disclosure on file
Jelena Drulovic	Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Jelena Drulovic has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hemofarm. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck Serono. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Actavis TEVSA. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Hemofarm. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Medis. Jelena Drulovic has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Zentiva. Jelena Drulovic has received research support from Ministry of Science, educaton and technological development of the Republic of Serbia.
Mario Habek (University Hospital Center Zagreb)	No disclosure on file
Le Hua, MD, FAAN (Cleveland Clinic)	Dr. Hua has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Hua has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Hua has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Horizon. Dr. Hua has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Hua has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genzyme. Dr. Hua has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hua has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Hua has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for TG Therapuetics. The institution of Dr. Hua has received research support from Genentech.
Martin Weber, MD (Universitätsmedizin Göttingen)	Dr. Weber has nothing to disclose.
Piia Thomas, MD (Genentech)	Dr. Thomas has received personal compensation for serving as an employee of Genentech. Dr. Thomas has stock in F. Hoffman-La Roche Ltd..
Julie Napieralski	Julie Napieralski has received personal compensation for serving as an employee of Genentech/Roche.
David Clayton	David Clayton has received personal compensation for serving as an employee of Genentech/Roche. David Clayton has received stock or an ownership interest from Roche. An immediate family member of David Clayton has received publishing royalties from a publication relating to health care.
Denison Kuruvilla (Genentech)	No disclosure on file
Qi Qi (Genentech)	No disclosure on file
Yan Xu (Genentech)	No disclosure on file
Alexandra L. Goodyear, MD (Genentech)	Dr. Goodyear has received personal compensation for serving as an employee of Genentech. Dr. Goodyear has received personal compensation for serving as an employee of Novartis. Dr. Goodyear has stock in Novartis. Dr. Goodyear has stock in Genentech.
Jiwon Oh, MD, FAAN (St Michael's Hospital)	Dr. Oh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. The institution of Dr. Oh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen-Idec. Dr. Oh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Oh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD-Serono. Dr. Oh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Oh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Oh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Oh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Horizon Therapeutics. Dr. Oh has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Oh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen-Idec. Dr. Oh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi-Genzyme. The institution of Dr. Oh has received research support from Biogen-Idec. The institution of Dr. Oh has received research support from Roche.