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Can we use an anti-CD20 therapy as an immune constitution therapy (IRT), i.e. 2 years of treatment followed by no treatment unless there is EIDA (evidence of inflammatory disease activity)? This strategy is not new to the field of MS; this is how we use alemtuzumab, cladribine and AHSCT. So why not with ocrelizumab, ofatumumab or rituximab?
The anti-CD20-IRT question really needs an answer. However, many of my colleagues are nervous about not treating pwMS continuously and would therefore prefer to use adaptive dosing of anti-CD20s based on B-cell, or memory B-cell, reconstitution. This is why we proposed doing the ADIOS study (adaptive ocrelizumab dosing study) in 2019 and were in the process of getting this study designed and funded prior to COVID-19.
However, since COVID-19 and the introduction of COVID-19 vaccines have spotlighted the long-term safety signals associated with continuous anti-CD20 therapy and their associated poor vaccine responses we now want to redesign the study. We now want the study to be focused on safety and to add another arm to test using anti-CD20 therapy as induction therapy for 2 years and then following it with a derisking strategy using one of the licensed immunomodulatory or low-risk maintenance therapies, i.e. interferon-beta, glatiramer acetate, teriflunomide or dimethyl fumarate (DMF). This is the so-called IM or induction-maintenance arm.
The proposed primary outcome will be serious Infections, which are those requiring hospitalisation. Secondary outcomes will include the development of hypogammaglobulinaemia, antibiotic and antiviral drug usage as a surrogate for infections, vaccine responses, days off work and healthcare utilisation. With regard to efficacy, we propose assessing change in T2-lesion volume or number and relapses for inflammation and brain volume change and disability progression as end-organ damage markers.
This study will need to be pragmatic and run through a registry, for example, the UK’s OPTIMISE pharmacovigilance platform. We also propose doing some nested or add-on studies in cohorts to do specific vaccine, biomarker, immunology and virology studies. These add-on studies will provide more data on each of the arms being used in the ADIOS-IM study.
Some questions for any readers who are anti-CD20 therapies. Would you volunteer to participate in this study? If there are any HCPs reading this post do you think we have clinical equipoise to do this study or have you already adopted one or more of these strategies to derisk anti-CD20 therapy already in your clinical practice?
Another potential advantage of this study, apart from making your MS treatment safer, is the potential cost-saving in the long term for the NHS or your health insurance provider.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.