Abstract Details

Title Design of a Phase 2b Dose-finding Trial to Evaluate Safety and Efficacy of the CNS-penetrant BTK Inhibitor SAR442168 in Patients with Relapsing Forms of Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) S40 - Multiple Sclerosis: Clinical Trials (2:36 PM-2:48 PM)

Poster/Presentation
Number 009

Background With an increasing number of MS therapies available, to justify placebo arms in clinical trials is becoming difficult, and using alternative approaches is necessary. MRI outcomes in phase 2 trials are well-established predictive biomarkers for clinical outcomes in phase 3 MS drug development.

Objective To describe the design of a phase 2b, proof-of-concept, dose-finding trial of the CNS-penetrant Bruton’s tyrosine kinase inhibitor SAR442168 in patients with relapsing MS, which implements important design elements intended to improve efficiency and reduce exposure to placebo.

Design/Methods The phase 2b trial (DRI15928, NCT03889639) was a 16-week, placebo-controlled, crossover trial testing four SAR442168 doses (5, 15, 30, or 60 mg q.d., administered orally) in patients with relapsing MS. Patients were assigned to receive placebo for 4 weeks (weeks 1–4) then one of four doses of SAR442168 (weeks 5–16), or to receive SAR442168 (weeks 1–12) then placebo (weeks 13–16), in a double-blinded fashion. The Multiple Comparison Procedure with Modeling was selected to assess the dose-response relationship based on the reduction in the number of new gadolinium (Gd)-enhancing T1-hyperintense lesions; this method will greatly increase the power of dose-finding exercises based on the a priori assertion that the dose-response relationship is best described by one of six prespecified models (2 E_max, linear, quadratic, logistic, exponential).

Results Our modeling approach could provide ≥89% power to detect a maximum 85% risk reduction in the number of new Gd-enhancing T1-hyperintense lesions using a total of 120 patients (26 per dose, assuming 15% drop-out rate) with a 2-sided α=0.05.

Conclusions By applying modern trial design elements, we developed a compact, MRI-based trial for proof-of-concept and dose-finding for SAR442168 in patients with relapsing MS without the need for a placebo-only arm.

Authors/Disclosures
Anthony Traboulsee, MD (University of British Columbia) PRESENTER	Dr. Traboulsee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Traboulsee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Traboulsee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Traboulsee has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Traboulsee has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for EMD Serono. Dr. Traboulsee has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Roche. The institution of Dr. Traboulsee has received research support from Roche. The institution of Dr. Traboulsee has received research support from Genzyme. The institution of Dr. Traboulsee has received research support from Consortium of MS Centers. The institution of Dr. Traboulsee has received research support from MS Canada. Dr. Traboulsee has received personal compensation in the range of $500-$4,999 for serving as a Workshop Chair with Consortium of MS Centers.
Christopher C. LaGanke, MD (North Central Neurology Associates, PC)	Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. LaGanke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sanofi. Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Novartis. Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for GSK. Dr. LaGanke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Serono EMD. Dr. LaGanke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Genentech. Dr. LaGanke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. LaGanke has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for TG Therapeutics.
Xavier Montalban, MD, PhD, FAAN (Vall Hebron University Hospital-Multiple Sclerosis Centre of Catalonia)	The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck/ EMD Serono. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Hoffmann-La Roche. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion/ Janssen Pharmaceuticals. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for BMS/ Celgene. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi/ Genzyme. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BIAL PD. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PeerVoice. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Samsung Biosys. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zenas BioPharma. Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion/ Janssen Pharmaceuticals. Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS/ Celgene. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck/ EMD Serono. Dr. Montalban 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. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffmann-La Roche. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi-Genzyme. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic Therapeutics. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viatris/ Mylan. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. The institution of Dr. Montalban has received research support from Biogen. The institution of Dr. Montalban has received research support from Hoffmann-La Roche. The institution of Dr. Montalban has received research support from Sanofi/ Genzyme. The institution of Dr. Montalban has received research support from Merck/ EMD Serono. The institution of Dr. Montalban has received research support from Novartis. The institution of Dr. Montalban has received research support from Teva Pharmaceuticals. The institution of Dr. Montalban has received research support from Actelion/ Janssen Pharmaceuticals. The institution of Dr. Montalban has received research support from BMS/ Celgene.
Sibyl E. Wray, MD (Hope Neurology)	Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Wray has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squibb/Celgene. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi/Genzyme. Dr. Wray has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for EMD Serono. Dr. Wray has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Roche/Genentech. Dr. Wray has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi/Genzyme. The institution of Dr. Wray has received research support from Biogen. The institution of Dr. Wray has received research support from Atara Biotherapeutics. The institution of Dr. Wray has received research support from Bristol Myers Squibb/Celgene. The institution of Dr. Wray has received research support from Novartis. The institution of Dr. Wray has received research support from Roche/Genentech. The institution of Dr. Wray has received research support from Sanofi/Genzyme. The institution of Dr. Wray has received research support from TG Therapeutics. The institution of Dr. Wray has received research support from EMD Serono. The institution of Dr. Wray has received research support from Pharmaceuticals Corp..
	No disclosure on file
Andre P. Matta, MD (Eisai)	Dr. Matta has received personal compensation for serving as an employee of Sanofi. Dr. Matta has received stock or an ownership interest from Sanofi.
Timothy J. Turner	Timothy J. Turner has received personal compensation for serving as an employee of Sanofi. Timothy J. Turner has stock in Sanofi. Timothy J. Turner has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file

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