The European Committee for Treatment and Research in MS (ECTRIMS) annual meeting presented new data that helped to clarify the mode of action of anti-CD20 agents and address some safety issues that have arisen during the COVID-19 pandemic.
The efficacy of anti-CD20 therapies is well-established and there is growing evidence that earlier use will improve outcomes. For example, a study of national MS registries compared treatment approaches in Denmark, in which 92.4% of patients start treatment with a lower-efficacy DMT, and Sweden, in which 62.4% start with a lower-efficacy agent; the proportion of patients started on rituximab in the two countries was 0.1% and 17.9%, respectively (Spelman et al. ECTRIMS 2021; P815). At four years, the rate of 24-week confirmed disability progression (CDP) was 29% lower in Sweden and time to first relapse was delayed 56%. The Swedish COMBAT study also reported that the risk of relapse and new MRI lesions was lowest when treatment was initiated with an anti-CD20 agent (Alping et al. ECTRIMS 2021; 034).
Two studies have examined the long-term efficacy of anti-CD20 agents. In the extension of the OPERA trials, the annualized relapse rate (ARR) remained low (0.03) in patients on continuous ocrelizumab for 7.5 years (Giovannoni et al. ECTRIMS 2021; P723). The proportion of patients with 6-month confirmed CDP was 25.2% at week 384. The proportion reaching EDSS >6.0 confirmed at 24 weeks was 8.5%.
Long-term data are not yet available for ofatumumab. Mathematical modelling of ASCLEPIOS data estimated that ofatumumab-treated patients would spend 66% of their time at EDSS <3.0 over the first 10 years of therapy. Overall, 11.3% of patients would progress to EDSS >7.0 with ofatumumab compared to 15.0% with teriflunomide at 10 years (Vudumula et al. ECTRIMS 2021; P913).
Updated analyses of MS patient databases indicate that the risk of severe COVID is significantly elevated in patients treated with rituximab and ocrelizumab. In the Italian MS Registry, the odds ratio was 1.89 versus no therapy, with the risk increasing according to the duration of treatment: the odds ratio with ocrelizumab or rituximab versus no treatment was 1.56 with <6 months of treatment, 1.74 with 1-2 years, and 2.75 with >2 years of treatment (Sormani M. ECTRIMS 2021). In the Global Data Sharing Initiative database, there was a higher risk of COVID-related hospitalization (OR 1.90), ICU admission (OR 2.87) and death (OR 1.37) with ocrelizumab compared to all other DMTs (Simpson-Yap et al. ECTRIMS 2021; 098). The seropositivity rate following COVID-19 infection was reported to be 39.5% in patients on an anti-CD20 agent compared to 85.0% for those on other DMTs (Klineova et al. ECTRIMS 2021; P640).
COVID-19 outcomes with ofatumumab were not reported by the Global Sharing Initiative but preliminary findings were available from the phase III ALITHIOS study (Cross et al. ECTRIMS 2021; P982). The overall rate of COVID-19 infection was 8.2%. The rates of severe, life-threatening and fatal outcomes were 4.3%, 1.4% and 0.7%, respectively. Overall, 96% of COVID-19 cases recovered within 20 days. In post-marketing reports, 11.8% of COVID-infected patients on ofatumumab developed severe disease. There were no deaths.
A number of studies have now reported significant attenuation of the B cell response to vaccination with ocrelizumab (Capuano et al. ECTRIMS 2021; P651. Karussis et al. ECTRIMS 2021; P940). For example, one study found that the seropositivity rate post-vaccination was 44.7% for MS patients on anti-CD20 therapy compared to 76.6% with other DMTs (Jaber et al. ECTRIMS 2021; P671). However, in the Italian CovaXiMS study (N=1339), a higher antibody response was seen if mRNA vaccination was administered at least 143 days (4.8 months) after the last ocrelizumab infusion (Sormani M. ECTRIMS 2021; 099); other studies have recommended delaying vaccination at least 6 months to allow for B cell repopulation (Disanto et al. ECTRIMS 2021; P961).
Several groups have now reported little to no increase in relapses or new MRI activity when the next ocrelizumab infusion was delayed 1-3 months (Allen et al. ECTRIMS 2021; P826. Fan et al. ECTRIMS 2021; P839. Smoot et al. ECTRIMS 2021; P639). Similarly, only 1.9% of patients showed radiological disease activity when managed with a personalized dosing regimen (van Lierop et al. ECTRIMS 2021; P757). CD19+ B cell counts were obtained every 4 weeks and ocrelizumab was administered when B cell counts were >10 cells/µL, which resulted in a median dosing interval of 34 weeks (8.5 months).
The response to vaccination has drawn attention to the issue of hypogammaglobulinemia during treatment with anti-CD20 agents. A U.S. study reported that ocrelizumab was associated with IgG hypogammaglobulinemia in 16% of patients at three years; 41% developed IgM hypogammaglobulinemia (Khatri et al. ECTRIMS 2021; P747). A separate study found low serum IgG levels in 10% and low IgM levels in 25% of ocrelizumab-treated patients (Arslan et al. ECTRIMS 2021; P695). Mean lymphocyte counts and immunoglobulin levels were lower in patients who developed COVID-19: 8% of patients with normal IgM levels developed COVID-19 versus 50% with low IgM levels.
In contrast, immunoglobulin levels appear to be minimally affected during treatment with ofatumumab, which is administered at a lower monthly dose by subcutaneous injection. In phase III trials and extensions of ofatumumab, serum IgG showed a transient decline then remained stable for up to 3.5 years (Wiendl et al. ECTRIMS 2021; P931). There was a greater change from baseline in IgM at 48 and 168 weeks of ofatumumab (-31.8% and -46.0%, respectively) but IgM levels remained above the lower limit of normal throughout the treatment course. The risk of serious infections remained low (2.5%). At present, there are insufficient data to determine the risk of severe COVID-19 or the response to COVID-19 vaccination with ofatumumab. A multicentre study in the U.S. and the KYRIOS study in Germany are currently assessing the vaccine response in patients receiving ofatumumab (Chitnis et al. ECTRIMS 2021; P777. Ziemssen et al. ECTRIMS 2021; P660).
An emerging issue, however, is whether serum antibody levels adequately represent the vaccine immune response. Several groups have now reported a robust T cell response following vaccination, which may provide some measure of protection against severe COVID-19 infection (Kakara et al. ECTRIMS 2021; 129). One study found that while only 30% of patients mounted an antibody response to COVID-19 vaccination, 80% showed a significant T cell response (Kister et al. ECTRIMS 2021; P926).
A separate study found that a decline in IgM corresponded to an increase in CD8+ T cells, suggesting a compensatory mechanism of clearing virus-infected cells (Mazziotti et al. ECTRIMS 2021; P684). There are some data to suggest that B cell depletion is associated with an increase in naive CD4+ T cells and recent thymic emigrants (Becker et al. ECTRIMS 2021; P953). In addition, recent data suggest that ocrelizumab can induce an upregulation of T cell genes associated with inflammation and antiviral activity (e.g. Th17) (Fong et al. ECTRIMS 2021; P614). However, while these findings suggest that some degree of antiviral activity by CD8+ cells is preserved, there remains an attenuated follicular T cell response, which likely contributes to the reduction in memory B cell response that has been reported with sustained B cell depletion (Apostolidis et al. Nat Med 2021; epublished September 14, 2021).