Abstract Details

Title Clinically Meaningful Decline on SDMT Primarily Occurs Independently of Relapses and Is Slowed by Ocrelizumab in Patients with Multiple Sclerosis: Results from the Pooled OPERA Studies

Topic Multiple Sclerosis

Presentation(s) S40 - Multiple Sclerosis: Clinical Trials (2:12 PM-2:24 PM)

Poster/Presentation
Number 007

Background

Cognitive impairment in relapsing multiple sclerosis (RMS) is common, disabling and may be measured by SDMT. Recent research shows that SDMT can decline in association with acute disease activity, i.e. relapses. The Phase III OPERA studies in RMS demonstrated consistent beneficial effect of ocrelizumab on SDMT improvement, and a reduction of SDMT decline versus interferon-beta-1a (IFNβ1a). Overall disability progression in OPERA was driven mainly by PIRA rather than RAW. The degree to which SDMT results are influenced by relapses in OPERA is unknown.

Objective

To assess: (i) relapse-associated worsening (RAW) of cognitive decline, measured by the Symbol Digit Modalities Test (SDMT), and SDMT progression independent of relapse activity (PIRA) in OPERA I (NCT01247324) and OPERA II (NCT01412333); (ii) the effect of ocrelizumab on these measures.

Design/Methods

24-week confirmed SDMT decline (≥4-point reduction) and its association with relapses (RAW-SDMT) or SDMT progression independent of relapse activity (PIRA-SDMT) was assessed in the pooled OPERA population. RAW-SDMT events were defined as confirmed SDMT worsening occurring ≤90 days after onset of a protocol-defined relapse. SDMT scores were ‘re-baselined’ ≥30 days after each relapse, and PIRA-SDMT events were defined as confirmed SDMT worsening that occurred independently of relapse activity.

Results

24-week confirmed SDMT decline was almost exclusively related to PIRA-SDMT, with events occurring in 11.3% of IFNβ1a-treated patients and 7.0% of ocrelizumab-treated patients, versus RAW-SDMT, experienced by 0.3% of all patients. Ocrelizumab significantly reduced the risk of 24-week confirmed SDMT worsening (hazard ratio [HR] 0.57; 95% CI 0.39–0.82; p=0.003) and 24-week confirmed PIRA-SDMT worsening (HR 0.58; 95% CI 0.39–0.86); p=0.006) versus IFNβ1a. No differences were seen in 24-week confirmed RAW-SDMT.

Conclusions

SDMT decline in OPERA primarily occurred independently of relapses, similar to gradual physical disability worsening, or PIRA. Ocrelizumab was superior to IFNβ1a in preventing the gradual cognitive decline that characterizes RMS.

Authors/Disclosures
Ralph H. Benedict, PhD (University At Buffalo) PRESENTER	Dr. Benedict has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Benedict has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Roche. Dr. Benedict has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Benedict has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Benedict has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bristol Meyers Squibb. Dr. Benedict has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Benedict has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Benedict has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Brystal Mier Squibb. Dr. Benedict has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for EMD Serono. The institution of Dr. Benedict has received research support from Genzyme. The institution of Dr. Benedict has received research support from Biogen. The institution of Dr. Benedict has received research support from Bristol Myer Squib. Dr. Benedict has received intellectual property interests from a discovery or technology relating to health care.
Jerome De Seze	Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma.
Stephen L. Hauser, MD (UCSF Weill Institute for Neurosciences)	Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NGM Bio. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BD. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pheno Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nurix Therapeutics. Dr. Hauser has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gilead. Dr. Hauser has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Accure. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alector. Dr. Hauser has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Annexon. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hinge Therapeutics. Dr. Hauser has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Neurona. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Roche that is relevant to AAN interests or activities. Dr. Hauser has a non-compensated relationship as a Clinical Trial/Primary Investigator with Novartis that is relevant to AAN interests or activities.
Hans-Peter Hartung, MD, FAAN (Heinrich Heine University Medical Faculty)	Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS Celgene. Dr. Hartung has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Geneuro. Dr. Hartung 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. Hartung 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. Hartung 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. Hartung has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Hartung 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. Hartung has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers Neurology.
Ludwig Kappos, MD, FAAN (RC2NB, University Hospital Basel)	The institution of Dr. Kappos has received research support from Bayer. The institution of Dr. Kappos has received research support from Biogen. The institution of Dr. Kappos has received research support from Genentech. The institution of Dr. Kappos has received research support from Genzyme. The institution of Dr. Kappos has received research support from Janssen. The institution of Dr. Kappos has received research support from Merck Serono. The institution of Dr. Kappos has received research support from Minoryx. The institution of Dr. Kappos has received research support from Novartis. The institution of Dr. Kappos has received research support from Roche. The institution of Dr. Kappos has received research support from Sanofi. The institution of Dr. Kappos has received research support from Santhera. The institution of Dr. Kappos has received research support from Swiss MS Society, Swiss National Research Foundation, European Union, Roche Research Foundation, Innosuisse. The institution of Dr. Kappos has received research support from Shionogi. The institution of Dr. Kappos has received research support from Japan Tobacco. The institution of Dr. Kappos has received research support from Auriga Vision AG. The institution of Dr. Kappos has received research support from EMD Serono. The institution of Dr. Kappos has received research support from Glaxo Smith Kline. The institution of Dr. Kappos has received research support from Wellmera AG. The institution of Dr. Kappos has received research support from Eli Lilly (Suisse) SA. The institution of Dr. Kappos has received research support from Bristol Myers Squibb. The institution of Dr. Kappos has received research support from Celltrion Inc. Dr. Kappos has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
Harold Koendgen, MD	Dr. Koendgen has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd. Dr. Koendgen has received stock or an ownership interest from F. Hoffmann-La Roche Ltd .
Qing Wang	Qing Wang has nothing to disclose.
Annette Sauter, PhD (F. Hoffmann-La Roche Ltd)	Dr. Sauter has received personal compensation for serving as an employee of F.Hoffmann-La Roche .
Marianna Manfrini	No disclosure on file
Stanley L. Cohan, MD, PhD, FAAN	Dr. Cohan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Cohan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AbbVie. Dr. Cohan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Cohan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Genentech. Dr. Cohan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bristol Myers Squibb (Celgene). Dr. Cohan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Icometrix. Dr. Cohan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. Dr. Cohan has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Cohan has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for sanofi genzyme. Dr. Cohan has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Novartis. Dr. Cohan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Roche Genentech. Dr. Cohan has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. Cohan has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Serono. Dr. Cohan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Icometrix.

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