Effect of Ozanimod on Symbol Digit Modalities Test Performance in Relapsing MS

Abstract

Background: Cognitive dysfunction, including slowed cognitive processing speed (CPS), is one of the most disabling symptoms of multiple sclerosis (MS). The Symbol Digit Modalities Test (SDMT) is a preferred measure of CPS for MS trials and routine screening. Based on encouraging SDMT results in the phase 3 SUNBEAM trial, these post hoc, exploratory analyses were conducted to further compare effects of the sphingosine 1-phosphate receptor modulator ozanimod versus intramuscular interferon β-1a on CPS in participants with relapsing multiple sclerosis (RMS). Methods: In the phase 3, double-blind, double-dummy, SUNBEAM study, adults (aged 18-55 years) with RMS (N=1,346) were randomized to once-daily oral ozanimod 0.92 or 0.46 mg, or weekly intramuscular interferon β-1a 30 µg. The study continued until the last participant was treated for 12 months. CPS was measured as part of a secondary endpoint using the SDMT. Exploratory, post hoc analyses evaluated SDMT change and percentages of participants with clinically meaningful (≥4-point) SDMT improvement or worsening at months 6 and 12, and relationship between SDMT and brain volume on magnetic resonance imaging. Results: Ozanimod improved SDMT scores compared with interferon β-1a at months 6 and 12. At month 12, least squares mean difference in SDMT z-scores for ozanimod 0.92 mg versus interferon β-1a was 0.102 (95% CI, 0.031-0.174, nominal p = 0.0051; standardized mean difference = 0.1376). A greater percentage of ozanimod 0.92 mg-treated participants had clinically meaningful improvements in SDMT scores versus interferon β-1a at month 6 (30.0% versus 22.2%) and month 12 (35.6% versus 27.9%). Of those with SDMT improvement at month 6, 66.4% of those treated with ozanimod 0.92 mg and 55.9% of those treated with interferon β-1a had sustained Statistician: Hongjuan Liu, Bristol Myers Squibb, Princeton, New Jersey. Nonstandard abbreviations: CPS = cognitive processing speed; PwMS = persons with multiple sclerosis; SMD = standardized mean differences.

Effects on cognition of DMTs in multiple sclerosis: moving beyond the prevention of inflammatory activity

“…In SUNBEAM (NCT02294058), a phase III RCT in RMS, mean change in SDMT Z-score over 1 year was greater for ozanimod-groups (0.5 mg: n = 450; 1.0 mg: n = 447) compared with interferon beta-1a group (n = 448) (mean difference from baseline to month 12 vs interferon β 1a: ozanimod 0.5 mg = 0.082 [95% CI = 0.010;0.153], p = 0.02; ozanimod 1.0 mg = 0.111 [95% CI = 0.039;0.182], p = 0.002) [12]. This was further confirmed in a post hoc analysis of the same RCT [14], which also showed that the 1.0 mg ozanimod-group (n = 444) had a significantly greater proportion of RMS showing ≥ 4-point SDMT improvement at month 6 (30.0% vs. 22.2%, rate ratio = 1.3 [95% CI = 1.08;1.68], p = 0.008) and month 12 (35.6% vs. 27.9%, rate ratio = 1.2 [95% CI = 1.02;1.50], p = 0.03) compared with interferon β 1a-group (n = 446) [14].…”

“…Emerging data also support the beneficial effects on cognitive functions of siponimod [8] and ozanimod [12,14], two selective modulators of sphingosine 1 phosphate receptors, which have been recently approved for secondary progressive (SP) MS and RMS, respectively.…”

OzEAN Study to Collect Real-World Evidence of Persistent Use, Effectiveness, and Safety of Ozanimod Over 5 Years in Patients With Relapsing-Remitting Multiple Sclerosis in Germany

“…The efficacy outcome measures of the OzEAN study complement those of the phase 2 and 3 clinical trials ( Table 5 ), which focused on traditional, physician-reported assessments of relapses (ARR) and disability progression (EDSS), MRI parameters (gadolinium-enhancing lesions, T2 lesions, and brain atrophy), and functional measures [the Multiple Sclerosis Functional Composite (MSFC)( 33 )), which comprises the Timed 25-Foot Walk (lower limb function and walking speed), Nine-Hole Peg Test (upper limb function and dexterity), and either the SDMT or the Paced Auditory Serial Addition Test (cognition) ( 4 , 6 , 7 , 34 , 35 ). QoL was assessed in the phase 3 studies using the MSQOL-54, but no other PROs were employed ( 6 , 7 ).…”

Time to rethink the reported disease-modifying treatment effects on cognitive outcomes: Methods and interpretative caveats

“…While the field researchers are well aware of the practice effects challenges, it is concerning that the studies aimed to assess the effects of DMTs on cognitive evolution have systematically overlooked the practice effects in interpreting their results. For example, the SDMT practice effect is wholly disregarded in the OPERA and the SUNBEAM studies ( 3 , 6 ). Furthermore, these studies expedite and amplify the learning effects by using short and frequent retesting intervals (at 12-week intervals in the OPERA study ( 3 ) and 6-month intervals in the EXPAND ( 5 ) and SUNBEAM ( 6 ) studies), which contribute to exacerbating the improved SDMT performance.…”