AMS05: Ocrelizumab Discontinuation in Relapsing Multiple Sclerosis

About This Grant

Multiple sclerosis (MS), a chronic, immune-mediated disease affecting the central nervous system (CNS), impacts an estimated 2.5 million people worldwide and nearly 1 million in the USA, primarily young adults with a female predilection. It is a major cause of neurological impairment, characterized by relapses that are driven by aberrant peripheral immune-cell activation and trafficking from the circulation into the CNS. Immune cells that then compartmentalize within the CNS are thought to contribute to subsequent progressive disease. Anti-CD20 (aCD20) therapy, that selectively depletes B cells, is highly effective at limiting relapsing MS, a benefit now understood to reflect removal of abnormally pro-inflammatory B cells that, when present, contribute to aberrant responses of T cells and myeloid cells involved in disease relapse. While now a mainstay treatment in MS, long-term continuous aCD20 treatment is associated with increasing risks. Interestingly, if B cells are allowed to return, both the B cells and non-B cells appear to no longer harbor the same abnormal profiles. The proposed randomized, placebo controlled-discontinuation trial of aCD20 in relapsing MS (AMS05) will test the hypothesis that at least some MS patients who discontinue aCD20 treatment will experience durable remission of relapsing disease, even after B cell reconstitution. Comprehensive mechanistic studies will define cellular mechanisms underlying, and potentially predictive of, durable remission and breakthrough disease. AMS05 will recruit patients with very early active MS, treat them with open-label anti-CD20 (ocrelizumab; OCR) for 24 months, then randomize them to placebo (Arm 1) or continued standard OCR treatment (Arm 2). Frequent brain MRIs will closely monitor for any disease activity and frequent biosampling will enable us to address: (1) Whether prolonged disease quiescence can be achieved after aCD20 discontinuation and B cell reconstitution? (2) What biological mechanisms underlie durable remission vs. disease breakthrough? (3) Can early biomarkers predict which patients will experience these outcomes? The study's two main Aims are: Aim 1: (a) Assess the rate of durable relapsing disease remission following 24 months of initial aCD20 treatment, using serial clinical assessments and high frequency acquisition of co-registered brain MRIs; (b) define biological profiles associated with durable disease remission or breakthrough disease, Aim 2: Evaluate predictors of durable treatment effects following OCR discontinuation by (a) assessing whether outcomes (durable remission or not; breakthrough disease) can be predicted by particular immune cell subset responses, in earlier samples; and (b) explore predictive modeling (accounting for age, sex, race, biological measures) and their interactions, that may better predict outcomes. The AMS05 clinical trial will explore the potential for aCD20 therapy to induce long-term remission in MS, potentially providing a breakthrough treatment paradigm, while also gaining novel insights into roles of B cells in autoimmunity and of cellular mechanisms of human immune tolerance.8. Proj