Abstract Details

Title Effect of the Sphingosine 1-Phosphate Receptor Agonist ONO-4641 on Circulating Lymphocytes in Patients with Relapsing-Remitting Multiple Sclerosis: Results from the Phase 2 DreaMS Trial

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 153

Objective

Background BACKGROUND: ONO-4641 is an oral, selective sphingosine-1-phosphate (S1P) receptor-1 and -5 agonist. In the Phase 2, placebo-controlled DreaMS (Drug Research EvaluAtion for Multiple Sclerosis) trial (NCT01081782), all ONO-4641 doses demonstrated significant efficacy on all key magnetic resonance imaging (MRI) measures of disease activity and were generally well tolerated with no unexpected adverse events.

Design/Methods DESIGN/METHODS: Patients with active RRMS (aged 18-55 years, Expanded Disability Status Scale scores ?5.5) were randomized (1:1:1:1) to placebo or ONO-4641 (0.05, 0.10, 0.15 mg) once daily for 26 weeks. Circulating absolute lymphocyte counts (ALC; all patients) and lymphocyte subset counts (subset of patients) were determined at baseline (pretreatment), Week 2, 4-weekly to Week 26, and a 4-week off-treatment follow-up (FU) visit.

Results RESULTS: ALC decreased with increasing ONO-4641 dose; the decrease from baseline was detectable at Week 2 and remained at [sim]40%, [sim]60%, and [sim]65% with 0.05-, 0.10-, and 0.15-mg, respectively, throughout treatment. CTCAE grade 3 lymphopenia occurred in 6 (5.9%), 50 (49%), and 62 patients (62%) with 0.05, 0.10, and 0.15 mg, respectively; 5 patients had grade 4 lymphopenia (0.10 mg, 1 patient; 0.15 mg, 4 patients). Dose-dependent decreases from baseline were also seen for CD3+CD4+ (helper T), CD19+CD20+ (B), and CD3+CD8+ (cytotoxic T) cell counts. CD4/CD8 ratio decreased by [sim]15%, [sim]40%, and [sim]55% with 0.05, 0.10, and 0.15 mg doses, respectively. In patients completing 4-week FU, ALC and subset counts returned to pretreatment levels in all treatment groups. ONO-4641 had no clear effect on CD3-CD16+CD56+ (natural killer) cells.

Conclusions CONCLUSIONS: ONO-4641 treatment rapidly, dose-dependently, and reversibly reduced lymphocyte counts, particularly the CD3+CD4+ and CD19+CD20+ subsets. Even the 40% reduction in ALC achieved with the 0.05-mg dose was associated with a positive effect on MRI outcomes.

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 Biogen. 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 as a Consultant for cabaletta. 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.
Frauke Zipp, MD (University Medical Center Mainz)	Dr. Zipp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celgene. Dr. Zipp has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen. Dr. Zipp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Octapharma. Dr. Zipp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Zipp 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. Zipp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TEVA. The institution of Dr. Zipp has received research support from BMBF. The institution of Dr. Zipp has received research support from DFG. The institution of Dr. Zipp has received research support from PMSA. The institution of Dr. Zipp has received research support from Sanofi Genzyme. The institution of Dr. Zipp has received research support from UCB. The institution of Dr. Zipp has received research support from Eisai. The institution of Dr. Zipp has received research support from SK Life Science. The institution of Dr. Zipp has received research support from Abbott. The institution of Dr. Zipp has received research support from Actelion. The institution of Dr. Zipp has received research support from Bayer. The institution of Dr. Zipp has received research support from Servier. Dr. Zipp has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with Novartis. Dr. Zipp has received personal compensation in the range of $0-$499 for serving as a Reviewer with Universite de Geneve. Dr. Zipp has received personal compensation in the range of $5,000-$9,999 for serving as a Reviewer with Oppenheim Förderpreis für Multiple Sklerose. Dr. Zipp has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with EKFS. Dr. Zipp has a non-compensated relationship as a Associate Editor with Brain that is relevant to AAN interests or activities. Dr. Zipp has a non-compensated relationship as a Advisor with Science Translational Medicine that is relevant to AAN interests or activities.
Selmaj Krzysztof, PhD (Uniwersytet Medyczny)	No disclosure on file
Bryan R. Due, PhD (Ono Pharma USA)	No disclosure on file
Timothy L. Vollmer, MD, FAAN	The institution of Dr. Vollmer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen IDEC. The institution of Dr. Vollmer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech/Roche. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Siranax. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Celgene. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Meyers Squib. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Viela Bios. The institution of Dr. Vollmer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. The institution of Dr. Vollmer has received research support from Rocky Mountain MS Center. The institution of Dr. Vollmer has received research support from Biogen. The institution of Dr. Vollmer has received research support from Actelion. The institution of Dr. Vollmer has received research support from Genentech/Roche. The institution of Dr. Vollmer has received research support from Anokion. The institution of Dr. Vollmer has received research support from TG Therapeutics.
Michaela Tyblova (Nurologicka Klinika 1 LF UK)	No disclosure on file

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