Abstract Details

Title MS Relapse Redefined: Distinguishing True Relapses from Pseudoexacerbations in the ULTIMATE I and II Trials Comparing Ublituximab vs Teriflunomide

Topic Multiple Sclerosis

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 6-001

Background The primary endpoint in relapsing multiple sclerosis (MS) trials involves reducing annualized relapse rate (ARR), which may be prone to noise from pseudoexacerbations: symptom recrudescence events meeting relapse criteria without focal inflammation. This leads to a paradox in high efficacy therapy trials where relapses outnumber MRI lesions.

Objective To develop a methodology to reduce the impact of pseudoexacerbations on annualized relapse rates in the ULTIMATE trials.

Design/Methods A higher stringency relapse definition was tested post-hoc in ULTIMATE: Criteria 1: increase of >0.5 points in EDSS score (unless EDSS=0, then increase of ≥1 point). [AND] Criteria 2: ≥2 points increase on one appropriate symptom-matched FS or 1 point on ≥2 appropriate FS. [AND] Criteria 3 & 4: EDSS or FSS change must be higher than prior scores. [AND] Criteria 5: confirmed relapse cannot have occurred within 2-months before/after any infection event. [AND] Criteria 6: relapse excluded if negative for Gd+ or n/e T2 lesions within 5 weeks of symptomatic event. Relapse counts were modeled using generalized estimating equations.

Results Re-baselining at week 24 decreased the proportion of ublituximab-treated participants with n/e T2 lesions by 93% (44.8% vs 3.1%), but only reduced the proportion of participants with relapse by traditional criteria by 16% (13.5% vs 11.4%), suggesting a contribution by pseudoexacerbations. Original ARR reduction in the ULTIMATE trials (ublituximab vs teriflunomide) was 54.2%. After applying the redefined relapse criteria, overall ARR reduction (0-96 weeks) increased to 60.1% (rate ratio [RR] 0.399[0.274, 0.580], p<0.0001; ARR: teriflunomide 0.138, and ublituximab 0.055), which further increased at 48-96 weeks to 66.4% (RR 0.336[0.204, 0.551], p<0.0001; ARR: teriflunomide 0.142, and ublituximab 0.048), aligning closer to MRI results.

Conclusions Increased stringency of MS relapse definition provides a truer assessment of clinical efficacy, and the improved signal to noise ratio of relapse outcomes has implications for relapsing MS trial design and power calculations.

Authors/Disclosures
Stephen Krieger, MD, FAAN (Mount Sinai Dept of Neurology) PRESENTER	Dr. Krieger has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Krieger has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. Dr. Krieger has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Krieger has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Krieger has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for TG Therapeutics. Dr. Krieger has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Krieger has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Expert Witness. The institution of Dr. Krieger has received research support from Novartis. The institution of Dr. Krieger has received research support from Bristol Myers Squibb.
Karthik Bodhinathan, PhD (TG Therapeutics)	Dr. Bodhinathan has received personal compensation for serving as an employee of TG Therapeutics. Dr. Bodhinathan has stock in TG Therapeutics.
Yihuan Xu (TG Therapeutics)	No disclosure on file
Hari Miskin (TG therapeutics)	No disclosure on file
Lily Lee, PhD	Dr. Lee has nothing to disclose.
Enrique Alvarez, MD, PhD (University of Colorado)	Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Alvarez 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. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Alvarez 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. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celgene/BMS. The institution of an immediate family member of Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. The institution of Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon.