SPECIAL REPORT
Over the past 15 years, most MS treatment trials have used an active control, which has generated substantial data with which to compare the efficacy and safety of starting treatment with a higher-efficacy versus lower-efficacy disease-modifying therapy (DMT).
Studies using interferon-β as the active comparator included TRANSFORMS (fingolimod), CARE-MS I and II (alemtuzumab), SUNBEAM (ozanimod), and OPERA I and II (ocrelizumab). Later studies used teriflunomide as the comparator, such as ASCLEPIOS I and II (ofatumumab), OPTIMUM (ponesimod) and ULTIMATE I and II (ublituximab). These studies demonstrated the short-term superiority of higher-efficacy DMTs compared to platform therapies, including in the subgroup of previously untreated patients.
Of particular interest were trials of anti-CD20 therapies (rituximab and ublituximab are not approved in Canada for MS and will not be discussed). In OPERA I/II, the annualized relapse rate (ARR) was about 46% lower with ocrelizumab versus interferon-β-1a (Rebif) (Hauser et al. N Engl J Med 2017;376:221-234). There was a significant 40% reduction in the rate of 24-week confirmed disability progression (CDP) with ocrelizumab (6.9% vs. 10.5%). The number of gadolinium-enhancing lesions per scan was about 94% lower with ocrelizumab.
In a subgroup analysis of OPERA patients with no treatment in the previous two years, ARR was 0.16 with ocrelizumab (0.15 in the previously treated group) (Turner et al. J Neurol 2019;266:1182-1193). The number of 3-month CDP events was 40% lower in the previously untreated ocrelizumab subgroup versus interferon-β; the number of CDP events in the previously treated subgroup was 39% lower but did not achieve significance.
Similar results were seen in the ASCLEPIOS I/II trials using an oral drug comparator. ARR was 51-58% lower with ofatumumab compared to teriflunomide (Hauser et al. N Engl J Med 2020;383:546-557). The risk of 6-month CDP was 32% lower with ofatumumab (8.1% vs. 12.0%). Ofatumumab was also superior to teriflunomide with respect to the number of gadolinium-enhancing lesions per scan (94-97% lower) and concentration of serum neurofilament light chain (NfL) (26% lower at 12 months).
One-third of the ASCLEPIOS cohort was newly-diagnosed and previously untreated, and an analysis was subsequently performed on this subgroup (Gartner et al. Mult Scler 2022;28:1562-1575). Overall treatment efficacy was comparable when ofatumumab was used as a first-line therapy. Ofatumumab reduced ARR by 50% versus teriflunomide (0.09 vs. 0.18), delayed 6-month CDP by 46% (5.4% vs. 10.0%), and reduced the number of Gd+ lesions by 95% in newly-diagnosed/untreated patients. Mean sNfL levels were 23% lower with ofatumumab versus teriflunomide at 12 months. Regarding progression independent of relapse activity (PIRA), the proportion with 6-month PIRA events was significantly lower with ofatumumab compared to teriflunomide (3.6% vs. 7.7%).
The longer-term benefits of starting with a high-efficacy therapy have been examined in several recent observational studies. A Danish MS registry study reported that the risk of 6-month EDSS worsening at four years was reduced 47% (16.7% vs. 30.1%) with a higher- versus moderate-efficacy starting therapy (Buron et al. Neurology 2020;95:e1041-e1051). A Swedish MS registry study found that starting a high-efficacy DMT within the first two years was associated with a 1-point difference in EDSS score at 10 years compared to later escalation to a high-efficacy DMT (He et al. Lancet Neurol 2020;19:307-316). Similarly, a single-centre study observed that when escalation to a higher-efficacy DMT was delayed >2 years, 80% experienced 6-month CDP within four years; in contrast, no patient in the early escalation group had 6-month CDP at four years (Popiel et al. Neurol Neurochir Pol 2023; epublished December 19, 2023).
Also noteworthy are two recent studies that have examined the impact on clinical and economic outcomes of starting treatment with an anti-CD20 agent versus escalation. A health claims database analysis found that first- versus subsequent-line treatment with ocrelizumab (i.e. early intensive therapy vs. escalation) was associated with a lower rate of annual relapse-associated events (0.37 vs. 0.56), a lower rate of hospitalization (0.021 vs. 0.050 in 1 year), fewer non-DMT-related outpatient visits (22.8 vs. 27.9) and a lower economic burden on the healthcare system (all cause non-DMT costs: USD$16,782 vs. $28,275) (Geiger et al. Neurol Ther 2023;12:1709-1728).
Bhan and colleagues also modelled the 10-year economic and social impact of ofatumumab used as a first- versus second-line agent in Canada (Bhan et al. J Comp Eff Res 2023;12:e220175). Patients initiated on ofatumumab had fewer relapses, less disability, and slower progression to EDSS 7.0 compared to patients switching to ofatumumab after three or five years. For patients started on ofatumumab, 67.47% of the time was spent with mild disability (EDSS <3). In contrast, patients escalated at five years from a platform therapy (injectable, teriflunomide) to ofatumumab had a shorter duration of mild disability (<60% in the mild disability health state).
Also noteworthy in this study was that the rate of employment at 10 years was highest in patients receiving ofatumumab (35.6%), natalizumab (34.8%) or ocrelizumab (34.7%) compared to those receiving teriflunomide (28.9%), dimethyl fumarate (30.8%) or a platform injectable (29.4%).
These results suggest that initiating treatment with an anti-CD20 agent may be associated with clinically significant reductions in disease activity and disability worsening, resulting in improved productivity and quality of life in patients with MS.