The ocrelizumab phase II extension trial suggests the potential to improve the risk: Benefit balance in multiple sclerosis.

Highlights

• Ocrelizumab phase II trial extension data has 18-month post-drug follow-up.

• Annualized relapse rate seems to remain low during the drug-free follow-up.

• Infections and adverse events seem to be reduced during drug-free follow-up.

• Extended interval dosing may be possible that maintains efficacy and allows for more successful vaccination to new infections.

• Extended interval dosing may afford a drug-free pregnancy.

Abstract

Objective

Ocrelizumab inhibits relapsing multiple sclerosis when administered every six months. Based on potential similar memory B cell depletion mechanisms with cladribine and alemtuzumab, we hypothesised that CD20-depletion of B cells by ocrelizumab may exhibit a duration of response exceeding the current licenced treatment interval.

Methods

Internet-located information from regulatory submissions and meeting reports relating to the unpublished open-label, phase II ocrelizumab extension trial (NCT00676715) were reviewed. This followed people (54–55/arm) with MS, who switched from placebo or interferon-beta to ocrelizumab for three 600 mg treatment cycles (week 24, 48, 72) or people treated with ocrelizumab for four 600 mg treatment cycles (week 0–72), followed by an 18 month treatment-free period.

Results

CD19+ B cells were rapidly depleted within 2 weeks and slow CD19+ B cell repopulation began about 6 months after the last infusion with median-repletion of over 15 months. The reduced annualized relapse rate during the published efficacy study appeared to be maintained in the extension study and there were no new T1 gadolinium-enhancing or T2 lesions detected in the treatment-free period. Importantly, within these extension cohorts, there appeared to be fewer adverse events and infections events.

Conclusions

Ocrelizumab appears to induce durable relapsing disease inhibition, within 3 treatment cycles Therefore, it may be possible to reduce the frequency of dosing to maintain efficacy, whilst limiting infection and other risks associated with continuous immunosuppression and could allow more effective vaccination against new pathogens. Further studies are now clearly required to determine whether this data is robust.

Introduction

Multiple sclerosis (MS) is the major demyelinating disease of the central nervous system. Although considered to be a T cell-mediated disease, CD20 B cell–depleting antibodies exhibit high efficacy in MS (Bar-Or et al., 2008; Kappos et al., 2011; Hauser et al., 2017). Indeed, we have suggested that agents that inhibit relapsing MS all target memory B cell populations (Baker et al., 2017a; Baker et al., 2017b; Ceronie et al., 2018). These may act directly on B cells or may target T cells indirectly through loss of B cell help for T cells (Bar-Or et al., 2008; Baker et al., 2017a; Palanichamy et al., 2014; Lovett-Racke et al., 2019). Although the B cell subset depletion potential of ocrelizumab has yet to be fully reported, ocrelizumab and rituximab potently deplete memory B cells (Bar-Or et al., 2008; Palanichamy et al., 2014; Fernandez Velasco et al., 2019). Efficacy of CD20-depletion develops within a few weeks of treatment-onset and is typically administered in 6 monthly cycles to permanently deplete CD19+ B cell populations, which includes memory B cells (Bar-Or et al., 2008; Hauser et al., 2017; Palanichamy et al., 2014; Barkhof et al., 2019). However, memory B cell depletion can last for years following treatment, probably due to their slow repopulation kinetics (Palanichamy et al., 2014; Baker et al., 2018). This suggests that there may be durable efficacy beyond 6 months, as suggested from studies with rituximab (Bar-Or et al., 2008). Furthermore, marked memory B cell depletion appears to be a common mechanism contributing to the efficacy of alemtuzumab and cladribine (Baker et al., 2017b; Ceronie et al., 2018). These are considered immune-reconstitution therapies with long-term efficacy from a short-term treatment cycle (Havrdova et al., 2017; Giovannoni and Soelberg Sorensen, 2018; Giovannoni, 2018), so we hypothesized that ocrelizumab could similarly induce benefit extending beyond a six-monthly treatment cycle.

This is important, because while ocrelizumab use has been well-tolerated in MS (Hauser et al., 2017), B cells form a central part of immunity. As such, continuous B cell depletion is associated with eventual hypogammaglobulinaemia creating an increased risk of infection and reduced vaccination efficacy (Giovannoni, 2018; Nicolini et al., 2019; Derfuss et al., 2019; Stokmaier et al., 2018). These risks appear to be significant, as the development of ocrelizumab was terminated in other CD20-responsive autoimmunities because of infection-related fatalities adversely affecting the risk: benefit balance (Emery et al., 2014). It is therefore important to determine whether efficacy can be maintained and complications de-risked by reduced-frequency dosing. This strategy is currently being tested using natalizumab with a view to reduce the risk of developing progressive multifocal leucoencephalopathy (Zhovtis Ryerson et al., 2016). Furthermore, preliminary studies with rituximab may suggest that dosing to memory B cell population kinetics can reduce dosing frequency whilst maintaining efficacy (Novi et al., 2019).

Despite policies to make trial-data available, trial-information presented at major international conferences are not always followed by peer-reviewed publications (Baker et al., 2017b; Dubuisson et al., 2018). Therefore, information cannot easily be searched or interrogated by internet engines and fails to become common knowledge and perhaps allows people to be unwittingly exposed to unnecessary safety issues (Dubuisson et al., 2018). Although the phase II (NCT00676715) and phase III (NCT03599245) ocrelizumab efficacy MS studies are published (Kappos et al., 2011; Hauser et al., 2017), the extension study data remain unpublished, except in abstract form (Kappos et al., 2012; Hauser et al., 2013; Hauser et al., 2018). Whilst the phase III extension study examined the influence of 6-monthly dosing (Hauser et al., 2018), the phase II extension study followed people during an 18 month treatment-free period (Kappos et al., 2012; Hauser et al., 2013). This suggests that clinical benefits are maintained for some time after treatment cessation, which may have risk:benefit implications.