Discussion
infection, neuroaxonal injury, disability, reduction of
REGRESSION, EVENTS, INFECTION
This interim analysis provides new insights into the longer-term efficacy and safety of ofatumumab in RMS, supporting a favorable benefit–risk profile. The low rate of relapses with ofatumumab, as identified in ASCLEPIOS I/II,Early initiation of high-efficacy treatment for RMS improves longer-term outcomes compared with delayed initiation or switching from lower efficacy therapies.The 3mCDW and 6mCDW rates at 36 and 48 months, and the cumulative number of events, indicate that early ofatumumab treatment leads to superior disability outcomes that cannot be recovered in patients initially randomized to teriflunomide. These findings are consistent with recent studies of the longer-term benefits of early initiation of high-efficacy DMTs and disability outcomes in MS.The results also illustrate the value of switching from a low efficacy therapy to ofatumumab. In the newly switched ofatumumab group, there was a marked reduction in the ARR, together with almost complete suppression of Gd+ T1 lesion activity, a pronounced reduction of neT2 lesions, sustained reduction of neuroaxonal injury (sNfL), and increased likelihood of maintaining NEDA-3 status.Treatment with biological drugs may trigger an immune response that leads to the formation of anti-drug antibodies (ADAs).The cumulative safety data indicate that extended ofatumumab treatment is well tolerated in patients with RMS, with no new risks identified. Ofatumumab tolerability was reflected by a high level of adherence and a low rate of discontinuation throughout the core and extension periods. The EAIRs of AEs and SAEs were consistent with those previously reported in ASCLEPIOS I/II.The analyses of longer-term efficacy data presented here for the open-label ALITHIOS extension study (including data from the start of the blinded ASCLEPIOS I/II studies) are subject to the limitations of any open-label study, including lack of a comparator arm beyond the core studies. As such, the conclusions related to longer-term clinical efficacy outcomes may be limited due to the potential influence of regression to the mean. Also, as blinding is not maintained during an open-label extension study, the risk of rater assessment bias may increase.In addition, upon completion of the core studies, participation in ALITHIOS was voluntary and patients were free to discontinue due to any reason, creating the potential for selection bias. This seems unlikely, however, as an equal proportion of patients from the ASCLEPIOS I/II teriflunomide (72.3%) and ofatumumab (72.9%) arms enrolled into ALITHIOS; 88.8% of whom were still receiving ofatumumab at data cut-off. Furthermore, in ALITHIOS, the rate of discontinuations was identical for both the ofatumumab and teriflunomide arms (11.2%) and reasons for discontinuation were similar (for example, discontinuations due to AEs: 4.2% vs 3.8%, respectively; patient/guardian decision: 3.6% vs 4.3%, respectively), with low rates of discontinuations due to lack of efficacy (0.6% vs 0.9%, respectively; see The ongoing ALITHIOS study coincided with the global outbreak of COVID-19. People with MS are at increased risk of serious infection,Our findings of sustained reductions in cumulative number of relapses, MRI lesion activity, and risk of CDW with ofatumumab treatment add to a growing body of evidence that supports the value of early initiation of high-efficacy therapies in RMS,