Abstract Details

Title Evolution of Lesions that Shrink or Disappear into Cerebrospinal Fluid (Atrophied T2 Lesion Volume) in Primary-Progressive Multiple Sclerosis: Results from the Phase III ORATORIO Study

Topic Multiple Sclerosis

Presentation(s) MS and CNS Inflammatory Disease Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 151

Objective To investigate the effect of ocrelizumab versus placebo over 120 weeks on the evolution of atrophied T2-lesion volume (aT2-LV) in primary-progressive multiple sclerosis (PPMS) in a double-blind, randomized, phase 3, placebo-controlled study (ORATORIO; NCT01194570).

Background Atrophied T2-LV is an exploratory imaging marker in MS reflecting the volume of periventricular lesions subsumed into cerebrospinal fluid (CSF). This MRI biomarker has been shown to be sensitive to MS progression. Accumulation of aT2-LV is 3- to 5-fold higher in progressive compared to relapsing MS, making it an interesting endpoint for PPMS trials. This is one of the first applications of aT2-LV in an interventional, multicenter study with a 2-year treatment duration.

Design/Methods This exploratory post-hoc, MRI-blinded analysis evaluated 732 PPMS patients participating in ORATORIO randomized to ocrelizumab (488) or placebo (244). Atrophied T2-LV was calculated using T1-weighted and FLAIR acquisitions by overlaying baseline T2-lesion masks on follow-up CSF maps at 24, 48 and 120 weeks. Treatment group comparisons were performed using mixed effect model with repeated measures on log-transformed data. Covariates included baseline T2-LV, EDSS, gadolinium-enhancing lesions, geographical region and age (≤/>45). Sensitivity analysis was performed to account for the influence of unavoidable longitudinal changes to MRI acquisition factors.

Results

Accumulation of aT2-LV in the placebo group (366.1mm³, 120 weeks) was consistent with progressive MS in previous reports. In comparison, ocrelizumab treatment significantly slowed accumulation of aT2-LV (319.4mm³, p=0.013). Similar results were obtained when scanner model, software and protocol changes were included, as additional covariates in the model (p=0.029).

Conclusions

Ocrelizumab showed a significant effect of reducing aT2-LV in PPMS. Additionally, aT2-LV was not affected by scanner-related changes. These data suggest that ocrelizumab may favorably impact mechanisms underlying progressive biology of MS; however, further investigations are needed to validate the connection between aT2-LV and its pathobiology, and to better understand individual clinical relevance.

Authors/Disclosures
Robert Zivadinov, MD, PhD, FAAN (Buffalo Neuroimaging Analysis Center) PRESENTER	The institution of Dr. Zivadinov has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. The institution of Dr. Zivadinov has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Omnicuris. The institution of Dr. Zivadinov has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Myrobalan. Dr. Zivadinov has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Dr. Zivadinov has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Serono. Dr. Zivadinov has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bristol Myers Squibb. The institution of Dr. Zivadinov has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen.
Jinglan Pei	Jinglan Pei has nothing to disclose.
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.
Donna Goldman, MD (Genentech)	Dr. Goldman has received personal compensation for serving as an employee of Genentech. Dr. Goldman has stock in Roche. Dr. Goldman has stock in Bristol Myers Squibb. Dr. Goldman has stock in Amgen. Dr. Goldman has stock in Glaxo Smith Kline. Dr. Goldman has stock in Merck. Dr. Goldman has stock in Haleon. Dr. Goldman has stock in Pfizer. Dr. Goldman has stock in Adaptive Biotechnologies. Dr. Goldman has stock in Organon. Dr. Goldman has stock in Teva. An immediate family member of Dr. Goldman has received personal compensation in the range of $100,000-$499,999 for serving as a Manager, Office of HIV/AIDS with Massachusetts Department of Public Health.
Ryan C. Winger, PhD (Genentech)	Dr. Winger has received personal compensation for serving as an employee of Genentech. Dr. Winger has stock in F. Hoffmann-La Roche Ltd.
	No disclosure on file
Michael G. Dwyer III, MD, PhD (Buffalo Neurological Analysis Center)	Dr. Dwyer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Dwyer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Keystone Heart, Ltd. Dr. Dwyer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Dwyer has received research support from Novartis. The institution of Dr. Dwyer has received research support from Keystone Heart, Ltd. The institution of Dr. Dwyer has received research support from Bristol Myers Squibb. The institution of Dr. Dwyer has received research support from Roche.
Niels Bergsland (Buffalo Neuroimaging Analysis Center / State University of New York At Buffalo)	Prof. Bergsland has nothing to disclose.

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