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 (1290)

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. 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. 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. Disclosure: Dr. Benedict has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ralph H. B. Benedict is on the speakers’ bureau for EMD Serono, and consults for Biogen Idec, Genentech, Roche, Sanofi/Genzyme, Takeda, NeuroCog Trials, and Novartis.. Dr. Benedict has received royalty, license fees, or contractual rights payments from Psychological Assessment Resources. Dr. Benedict has received research support from Ralph H. B. Benedict has received research support from Accorda, Novartis, Genzyme, Biogen Idec, and Mallinkrodt, and is on the speakers’ bureau for EMD Serono.. Dr. De Seze has nothing to disclose. Dr. Hauser has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alector, Annexon, Bionure, Molecular Stethoscope, Symbiotix. Dr. Hauser has received compensation for serving on the Board of Directors of Neurona. Dr. Hauser has received research support from F. Hoffmann-La Roche Ltd, and Novartis.Dr. Hartung has received personal compensation from Bayer Healthcare, Biogen Idec, CSL Behring, GeNeuro, Genzyme, MedImmune, Merck Serono, Novartis, Opexa, Receptos, Roche, Sanofi, Teva, and Viela Bio.Dr. Kappos has received research support from Bayer, Biogen, Innosuisse, Novartis, the Swiss MS Society, the Swiss National Research Foundation, and the European Union.Dr. Overell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of F. Hoffmann-La Roche Ltd. Dr. Koendgen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with · H Koendgen is an employee and shareholder of F. Hoffmann-La Roche Ltd. Dr. Koendgen has received research support from Employee and shareholder of F. Hoffmann-La Roche. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with I am an employee of F. Hoffman-La Roche Ltd. Dr. Sauter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of F. Hoffmann-La Roche Ltd. Dr. Manfrini has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee and shareholder of F. Hoffmann-La Roche Ltd.. Dr. Cohan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employment, consulting, scientific advisory board, speaking, or other activities (Sanofi Genzyme, Biogen, Acorda, Genentech, Novartis). Advisory Boards, Research Steering Committees, Research Support and Speaking Honoraria, (Biogen, Mallinckrodt, Novartis. Dr. Cohan has received research support from Biogen, Mallinckrodt, Novartis, Roche Genentech, Sanofi Genzyme, MedDay..