B cell-directed therapies in MS – POST-ECTRIMS SPECIAL REPORT


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Part 2

Two anti-CD20 therapies (rituximab, ocrelizumab) are currently used for the treatment of multiple sclerosis and one, ofatumumab, is in late-stage development. Part 1 of this series examined the role of B cells in MS (see Update on B cells in MS pathophysiology, NeuroSens, June 29, 2020). Part 2 will summarize the data on the use of anti-CD20 agents in MS.

Rituximab was initially investigated in MS over a decade ago as a means of reducing B cells in cerebrospinal fluid. While it is now generally accepted that anti-CD20 agents have little effect on oligoclonal banding (Monson et al. Arch Neurol 2005;62:258-264), some early reports did find modest reductions in OCBs (Cross et al. J Neuroimmunol 2006;180:63-70). The phase II HERMES trial (n=104) compared two infusions of rituximab 1000 mg (on days 1 and 15) with placebo over 48 weeks; the primary endpoint was evaluated at week 24 (Hauser et al. N Engl J Med 2008;358:676-788). The number of Gd+ lesions was significantly lower with rituximab compared to placebo (mean 0.5 vs. 5.5). However, this regimen was not highly effective: there was no significant difference in annualized relapse rate at week 48 (0.4 vs. 0.7) and 20% of patients relapsed in the first year. A high proportion of patients (rituximab 15.9%, placebo 40%) did not complete the study. Two Cochrane reviews were unaccountably published on the one study (Dian et al. Cochrane Database Syst Rev 2013;(12):CD009130). A more recent meta-analysis reported a relapse-free rate of 86.2% with rituximab at week 96 (Tian et al. J Neuroimmunol 2020;347:577317).

More interesting was the phase II/III OLYMPUS trial in primary-progressive MS (Hawker et al. Ann Neurol 2009;66:460-471). Subjects received rituximab 1000 mg q24 weeks for 96 weeks. Rituximab failed to demonstrate a significant reduction versus placebo in the rate of confirmed disability progression (CDP, 30.2% vs. 38.5%), and no significant difference in brain volume change. However, time to CDP was delayed in the subgroup aged <51 years and those with baseline Gd+ lesions; these findings would guide patient selection for the ocrelizumab PPMS trial. Subsequent studies have reported mixed results in progressive MS. A propensity score matched analysis in younger patients (mean age 49 years) with secondary-progressive MS found a small relative reduction in EDSS worsening (-0.5 points over three years) in patients who received rituximab (Naegelin et al. JAMA Neurol 2019;76:274-281). A phase III comparison of rituximab and glatiramer acetate in SPMS found that both treatments were similarly ineffective in slowly EDSS worsening (Cheshmavar et al. Acta Neurol Scand 2020; epublished September 8, 2020).

As a large molecule, rituximab does not easily cross the blood-brain barrier, but two studies have examined the effects of intrathecal administration. The first looked at focal leptomeningeal contrast inflammation (LCE), present in about one-third of PPMS patients and associated with subpial cortical demyelination and neurodegeneration (Absinta et al. Neurology 2015;85:18-28). Intrathecal administration of rituximab transiently reduced B cells and CXCL-13, a B cell chemoattractant, in CSF but had no effect on leptomeningeal enhancement (Bhargava et al. Mult Scler Relat Disord 2019;30:136-140), which may suggest that rituximab has a limited effect on CNS inflammation. More recently, a phase Ib study found that intrathecal rituximab did not appear to stop progression in PMS patients (Bergman et al. J Neurol 2020; epublished September 8, 2020).

Since rituximab was not put into development as a treatment for MS, there are insufficient data on the optimal dosing, efficacy or safety. One suggestion is that rituximab dosing is too high, and a low-dose regimen (500 mg q6months vs. q12 months) will be studied in the phase III RIDOSE-MS trial (Midaglia et al. ACTRIMS/ECTRIMS 2020; PS01.05).

Ocrelizumab was initially studied in MS a decade ago in a phase II trial that used a dosing regimen similar to that of rituximab: low dose (600 mg) or high dose (2000 mg) by infusion on days 1 and 15 (Kappos et al. Lancet 2011;378:1779-1787). The reduction versus weekly IM interferon-beta in Gd+ lesions was 89% and 96% with the two doses at week 24. The phase III development program comprised two studies in RRMS (OPERA I and II) and the ORATORIO trial in PPMS. In the OPERA studies, ARR was 0.16 with ocrelizumab 600 mg q6monthly compared to 0.29 with interferon-β SC three times/week, a 46% relative reduction (Hauser et al.  N Engl J Med 2017;376:221-234). ARR differences were not significant in patients aged >40 years (Turner et al. J Neurol 2019;266:1182-1193). The pooled rate of 6-month CDP was 6.9% versus 10.5% with ocrelizumab and interferon-β, respectively, calculated to be a 40% reduction. Differences were not significant in the subgroup with EDSS < 2.5 (Turner 2019). The rates of no evidence of disease activity (NEDA) were 47.9% and 47.5% with ocrelizumab in the two studies versus 29.2% and 25.1% with interferon-β. The extension study reported that ARR was 0.04 at 4.5-year follow-up in the continuous ocrelizumab group (Giovannoni et al. ECTRIMS 2020; P0216). The disability endpoint was changed for the extension; 48-week CDP increased from 4.1% at Year 2 to 16% at Year 6.5 with continuous treatment.

In the ORATORIO trial, there was a 25% relative reduction in 6-month CDP with ocrelizumab compared to placebo (29.6% vs. 35.7%) (Montalban et al. N Engl J Med 2017;376:209-220). About 70% of patients receiving ocrelizumab experienced disability progression and/or ongoing disease activity (Wolinsky et al. Ann Neurol 2018;84:527-536). In the open-label extension, the proportion of patients with 48-week CDP increased from 30.5% at week 168 to 54.2% at week 360 with continuous ocrelizumab (Wolinsky et al. ECTRIMS 2020; P0237).

A recent analysis suggested that some patients may benefit from higher doses, so high-dose studies in RMS (MUSETTE) and PPMS (GAVOTTE) will examine ocrelizumab doses of 1200 mg q6monthly and 1800 mg q6monthly (Hauser et al. ECTRIMS 2020; P0230).

This novel anti-CD20 agent received FDA approval (as Kesimpta) in August 2020 for the treatment of RMS. An infusion dosing regimen similar to that used with other anti-CD20 agents was examined in the first phase II trial (100, 300 or 700 mg, weeks 0 and 2) (Sorensen et al. Neurology 2014;82:573-581). New MRI activity was suppressed >99% at week 24. Subcutaneous administration was subsequently studied in the phase II and III trials. The MIRROR study demonstrated that profound B cell depletion was not required to reduce Gd+ lesions by >90% (Bar-Or et al. Neurology 2018;90:e1805-e1814). It was further posited that monthly dosing would prevent B cell repletion; lower doses would allow for more rapid B cell repletion; and that subcutaneous administration might more directly target B cell activity in the lymph nodes (Theil et al. Front Immunol 2019;10:1340).

Accordingly, the phase III ASCLEPIOS I and II trials administered ofatumumab 20 mg/month SC after three loading doses (20 mg on days 1, 7 and 14) and compared it to teriflunomide 14 mg/day for a median of 1.6 years (Hauser et al. N Engl J Med 2020;383:546-557). ARR with ofatumumab was 0.11 and 0.10 in the two studies compared to 0.22 and 0.25 with teriflunomide, a relative reduction of 51-58%. The proportion of patients with 6-month CDP was 8.2% and 8.2% with ofatumumab versus 13.0% and 10.9% with teriflunomide, a relative reduction of 24-39%. The number of new/enlarging T2 and Gd+ T1 lesions was reduced >82% and >99%, respectively, versus the active control. Greater clinical benefit was seen in the subgroup of newly-diagnosed patients: the relative reductions in ARR and 6-month CDP were 50.3% (0.09 vs. 0.18) and 46% (5.9% vs. 10.4%), respectively. MRI outcomes showed similar efficacy in the newly-diagnosed group compared to the full cohort (Gartner et al. ECTRIMS 2020; P0192). The NEDA rate at 12 months was subsequently reported to be 47.0% with ofatumumab compared to 24.5% with teriflunomide (Hauser et al. EAN 2020; LB62).

Also noteworthy was the 12-week APLIOS study, which demonstrated that the proportion of patients free of Gd+ lesions was 87% at week 8 and 94% at week 12 (i.e. after 6 doses) (Bar-Or et al. AAN 2020; P8.1-001). In the ongoing ALITHIOS safety study (cumulative exposure 2118.6 patient-years to date), the incidence of severe infections was 1.8% (Cross et al. ECTRIMS 2020; P0234). No deaths or cases of PML or hepatitis B reactivation have been reported.

B cell-directed therapies in MS – Survey

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