Abstract Details

Title Delayed-release Dimethyl Fumarate Treatment Shifts the Immune Repertoire in Patients With Relapsing-Remitting Multiple Sclerosis: Results of PROCLAIM, an Open-label Phase 3 Study

Topic Multiple Sclerosis

Presentation(s) P4 - Poster Session 4 (5:30 PM-6:30 PM)

Poster/Presentation
Number 15-053

Objective To characterize longitudinal changes in the immune repertoire, including lymphocyte subsets and immunoglobulins (Igs), during 2 years of delayed-release dimethyl fumarate (DMF) treatment.

Background DMF, an oral disease-modifying therapy approved for treating relapsing-remitting multiple sclerosis (RRMS), has been reported to cause pleiotropic changes in the immune repertoire, including a disproportionate reduction in CD8⁺ T cells.

Design/Methods

In PROCLAIM (EUDRA CT 20015-001973-42), an open-label, multicenter, 96-week phase 3b study, patients aged 18-65 years with RRMS were treated with DMF 240mg twice daily. ALC and changes in lymphocyte subset, Ig, and apoptosis/proliferation/trafficking markers were assessed by flow cytometry at baseline, and Weeks (W) 4, 8, 12, 24, 36, 48, 72, and 96.

Results Of the 218 enrolled patients; 58 (27%) patients discontinued study treatment primarily due to AEs (n=21) and consent withdrawal (n=19). Median ALC was 1.82×10⁹/L and 1.05×10⁹/L at baseline and W96, respectively, representing a 39% reduction. Circulating lymphocyte subset numbers were reduced within the first 6 months of DMF treatment and sustained through W96; CD4⁺ and CD8⁺ T, CD19⁺B, and natural killer (NK) cell median percent change from baseline (CFB) to W96 were -31%, -52%, -13%, -18%, respectively, all P<0.05. At W96, the memory CD4⁺CD45RA^- and CD8⁺CD45RA^-T and CD27⁺IgD⁺B cell compartment was selectively reduced (-70%, -85%, -53% CFB, all P<0.001) compared to naïve CD4⁺CD45RA⁺CCR7⁺ and CD8⁺CD45RA⁺CCR7⁺T cells and CD27^-IgD⁺B cells (-16%, -55%, -16% CFB, P<0.05). Only immunoregulatory CD56^bright NK and transitional CD24^hiCD38^hiB cell numbers increased (+15% and +50% CFB, both P<0.001). Overall, no increases in apoptotic markers were detected, but T-cell proliferation increased initially, then stabilized by W96.

Conclusions

DMF treatment induced a general shift towards a naïve/anti-inflammatory repertoire and away from memory/proinflammatory phenotypes, which was maintained over 2 years.

Study Supported by: Biogen

Authors/Disclosures
Derrick Robertson, MD PRESENTER	Dr. Robertson has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Greenwich Biosciences. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Horizon. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Janssen. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi Genzyme. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for TG Therapeutics. Dr. Robertson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mallinckrodt. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion. Dr. Robertson has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Biogen. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Serono. Dr. Robertson has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Genentech. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi Genzyme. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for PRIME CME. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Janssen. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Horizon. Dr. Robertson has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for TG Therapeutics. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for McVeigh. Dr. Robertson has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Mccumber. Dr. Robertson has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Goodis. The institution of Dr. Robertson has received research support from Biogen. The institution of Dr. Robertson has received research support from EMD Serono. The institution of Dr. Robertson has received research support from Jansenn. The institution of Dr. Robertson has received research support from Genentech. The institution of Dr. Robertson has received research support from Patient-Centered Outcomes Research Institute. The institution of Dr. Robertson has received research support from Novartis. The institution of Dr. Robertson has received research support from Sanofi Genzyme. The institution of Dr. Robertson has received research support from TG Therapeutics. The institution of Dr. Robertson has received research support from Prime. The institution of Dr. Robertson has received research support from Greenwich Biosciences. The institution of Dr. Robertson has received research support from Atara Biotherapeutics. The institution of Dr. Robertson has received research support from CorEvitas. The institution of Dr. Robertson has received research support from Anokion. The institution of Dr. Robertson has received research support from UCB Biosciences. Dr. Robertson has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Consortium of Multiple Sclerosis Centers. Dr. Robertson has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Multiple Sclerosis Association of America.
	No disclosure on file
Mark C. Cascione, MD (Tampa Neurology Associates)	No disclosure on file
Becky J. Parks, MD (Blueprint Medicines)	Dr. Parks has received personal compensation for serving as an employee of Alexion Pharmaceuticals. An immediate family member of Dr. Parks has received personal compensation for serving as an employee of Edward P. Evans Foundation. Dr. Parks has stock in Biogen. An immediate family member of Dr. Parks has stock in Regeneron. Dr. Parks has stock in Blueprint Medicines. Dr. Parks has stock in Sanofi. An immediate family member of Dr. Parks has stock in Vertex. Dr. Parks has stock in AstraZeneca. The institution of an immediate family member of Dr. Parks has received research support from NIH/NCI. The institution of an immediate family member of Dr. Parks has received research support from Leukemia & Lymphoma Society. The institution of an immediate family member of Dr. Parks has received research support from AstraZeneca Scholar Award.
	No disclosure on file
	No disclosure on file
	No disclosure on file

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