Ocrelizumab Reduces Disease Progression in MS
Unknown Mechanism of Action
The mechanism by which B-cell depletion slows disability progression is not fully understood. It “may be multifunctional, because B cells have important roles in antibody secretion, antigen presentation, and the release of effector cytokines,” said Dr. Calabresi. By virtue of their number, B cells may be more important than other antigen-presenting cells in MS.
One potential reason that ocrelizumab showed positive effects in ORATORIO is that the patient population was relatively young (mean age, 45) and had active MRI scans (more than 25% of the population had gadolinium-enhancing lesions). These factors enabled the demonstration of a measurable anti-inflammatory effect of ocrelizumab in patients with inflammation at an early, reversible stage of the disease. “Another possible explanation is that B cells may mediate pathologic processes by secretion of cytokines or by deposition of immunoglobulins after they enter the CNS,” said Dr. Calabresi. “B cells and plasma cells secrete antibodies that may target CNS antigens such as myelin, neurons, and glia, which could accelerate neurodegeneration or inhibit myelin repair. The continued separation of disability progression curves in the ORATORIO trial beyond 52 weeks, when anti-inflammatory effects have been maximized, and success in the relatively noninflammatory disorder of primary progressive MS suggest that additional mechanisms of action may be operational, and further study is warranted.”
Because ocrelizumab appears to entail a higher risk of herpes reactivation and of neoplasms, “clinicians are urged to carefully consider which patients might benefit the most from ocrelizumab and to stay vigilant with regard to monitoring for side effects that could be managed effectively if detected early,” Dr. Calabresi concluded.
—Erik Greb
Suggested Reading
Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].
Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].
Calabresi PA. B-cell depletion - a frontier in monoclonal antibodies for multiple sclerosis. N Engl J Med. 2016 Dec 21 [Epub ahead of print].
