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The management of multiple sclerosis has begun to shift away from the traditional escalation model – intensifying therapy in response to ongoing disease activity or progression – to one in which high-efficacy DMTs are used earlier in the clinical course.
High-efficacy DMTs have been shown to be superior to platform agents in slowing disability progression in recent trials such as OPERA I/II (Hauser et al. N Engl J Med 2017;376:221-234) and ASCLEPIOS I/II (Hauser et al. N Engl J Med 2020;383:546-557), although not in earlier studies such as TRANSFORMS (Cohen et al. N Engl J Med 2010;362:402-415) and CARE-MS I (Cohen et al. Lancet 2012;380:1819-1828.).
In the OPERA trials, a significantly lower proportion of patients had 12-week confirmed disability progression (CDP) (9.1% vs. 13.6%) with ocrelizumab compared to interferon beta-1a at 96 weeks (Hauser 2017). In the ASCLEPIOS trials, the proportion with 3-month CDP was significantly lower with ofatumumab compared to teriflunomide (10.9% vs. 15.0%) at a median 1.6 years (Hauser 2020).
Early initiation of a higher-efficacy therapy was supported by a subgroup analysis of newly-diagnosed treatment-naïve patients from ASCLEPIOS. In that analysis, 6-month CDP was 46% lower with ofatumumab compared to teriflunomide (Gartner et al. Mult Scler 2022;28:1562-1575).
Long-term outcomes with an early intensive therapy (EIT) approach were compared to an escalation approach in a retrospective cohort study for the period 1998-2016 (Harding et al. JAMA Neurol 2019;76:536-541). The mean five-year change in EDSS score was lower in the EIT group compared to the escalation group (0.3 vs. 1.2). The median time to sustained accumulation of disability was also significantly longer (6.0 vs. 3.14 years). An interesting finding was that in the escalation group, a first switch to a high-efficacy DMT did not substantially improve the outcome (median time 3.3 years to sustained disability); this may have been attributable to the disability that had already accrued before the switch was made.
Also noteworthy was an MSBase analysis which found that initial treatment with a high-efficacy DMT was associated with a lower risk of SPMS onset compared to platform therapies; the five-year risk was 7% versus 12% (Brown et al. JAMA 2019;321:175-187).
Evaluating benefit-risk
The conventional wisdom is that higher efficacy translates to a higher risk of adverse effects. As such, higher-efficacy DMTs have been largely kept in reserve for patients with aggressive disease: the risks were offset by the need for additional benefit. This was an appropriate strategy with first-generation high-efficacy agents such as natalizumab and alemtuzumab, which were associated with a significant side-effect burden and serious adverse events.
However, the benefit-risk calculation has arguably shifted with second-generation high-efficacy agents such as ocrelizumab, ofatumumab and cladribine.
In the seven-year safety analysis for ocrelizumab, the frequency of serious adverse events was 7.3 per 100 patient-years; the rates of serious infections (2.1/100 PY) and malignancies (0.46/100 PY) were low (Hauser et al. Neurology 2021;97:e1546-e1559). For ofatumumab, in the safety analysis at 3.5 years, the most common serious adverse events were infections, such as appendicitis (0.6%), pneumonia (0.5%), COVID-19 pneumonia (0.4%) and urinary tract infection (0.3%) (Hauser et al. Mult Scler 2022;28:1576-1590).
As a result, recent reviews have concluded that the long-term safety profile of high-efficacy DMTs does not differ substantially from that of platform therapies (Filippi et al. J Neurol 2022;269:5382-5394).
This view suggests that a reappraisal of the benefit-risk of early high-efficacy treatment is overdue. The benefit of more potent anti-inflammatory agents may be more evident in younger patients with more active disease; while the risks appear to be comparable to those associated with platform therapies.
Two recent studies illustrate this point. A retrospective cohort study compared the benefit-risk profiles of 305 RMS patients started on a high-efficacy DMT (MAbs, mitoxantrone or cladribine) or a lower-efficacy agent (injectables, teriflunomide, DMF or fingolimod) (Rojas et al. Clin Neuropharmacol 2022;45:45-51). High-efficacy DMTs were associated with a lower risk of EDSS progression (hazard ratio 0.62), relapses (HR 0.66) and new MRI activity (HR 0.55). When the frequency of specific adverse events was compared, no significant differences were seen between the two groups. Secondly, a meta-analysis of 21 DMT studies reported that the greatest benefit in three-month CDP occurred with ocrelizumab and ofatumumab; and the highest rate of adherence was seen with ofatumumab (Liu et al. Autoimmun Rev 2021;20:102826).
While long-term safety data for second-generation high-efficacy agents appear to be generally favourable, the safety of chronic B cell suppression is not known – an issue highlighted by the COVID-19 pandemic. A retrospective study recently reported that the incidence of hypogammaglobulinemia with ocrelizumab increased from 2.8% at baseline to 13.5% (both for IgG and IgM) after five cycles, although the infection risk appeared to be modest (median 1 infection/patient including COVID-19) (Habek et al. Mult Scler Relat Disord 2022;62:103798). A similar impact on Ig has been reported with rituximab (Perriguey et al. Neurol Neuroimmunol Neuroinflamm 2022;9:e1115) but not with ofatumumab (Hauser 2022), which may suggest a dose effect.
A number of strategies have been proposed to address these and other safety concerns. Alternative dosing regimens (e.g. lower doses, less frequent dosing) are now being investigated. Early use of high-efficacy DMTs may also permit drug-free intervals (as with cladribine) or de-escalation to a less intensive maintenance regimen. Such adjustments may serve to facilitate the shift to the earlier use of high-efficacy DMTs as the new standard of care.