Multiple sclerosis (MS) is a chronic and disabling disease, in which a person’s central nervous system (brain, spinal cord and optic nerves) is attacked by their immune system, causing inflammation and onsets of neurological dysfunction, and over time results in progressive disability. Inflammations can be identified as inflammatory lesions by performing MRI scans on the brain and due to the progressiveness of the disease patients suffer relapses in neurological dysfunctions. More common in women and Caucasians, MS generally manifests itself in young adulthood.
According to an article published Online First in The Lancet a phase 2 randomized, open label, placebo-controlled trial demonstrated the new monoclonal antibody ocrelizumab successfully targets B cells, immune cells implicated in multiple sclerosis, and rapidly reduces disease-related, inflammatory brain lesions and clinical attacks. Ocrelizumab is a recombinant, humanized, monoclonal antibody, developed to selectively target CD20-positive B cells. (CD20 is a cell surface protein expressed on select B cells).
T cells of the body’s immune system govern cell-mediated immune responses, such as activation of natural killer cells, whereas B cells govern antibody-related or ‘humoral’ immune response. Scientists used to believe the inflammation in MS was exclusively controlled by T cells, however, according to recent evidence, B cells are thought to drive the abnormal immune response in these patients.
The author Professor Ludwig Kappos of the Departments of Neurology and Biomedicine at the University Hospital Basel in Switzerland and his team evaluated the efficacy and safety of two dose regimens of ocrelizumab in patients with relapsing-remitting multiple sclerosis and compared ocrelizumab with the standard MS treatment of once-a-week administration of interferon beta-1a, which is thought to reduce inflammation.
The international multi-center study (79 centers in 20 countries) was conducted on 218 patients aged 18-55 years with relapsing-remitting multiple sclerosis. The participants were split into 4 different groups.
The first group consisted of 54 patients receiving placebo, whilst the second group and third group each containing 55 participants received either a low-dose (600 mg) or a high-dose (2000 mg) of ocrelizumab, and 54 patients in the fourth group received the standard once-weekly treatment of intramuscular interferon beta-1a (30μg). The dose ratio was determined as 1:1:1:1. At week 24, the first (placebo), second (ocrelizumab 600mg) and fourth (beta-1a) group received 600 mg of ocrelizumab, whilst the dose of the third, the high-dose group, was reduced to 1000 mg of ocrelizumab. The study’s primary endpoint was determined as the total number of active (contrast enhancing) lesions per group that were established with MRI scans of the brain at 12, 16, 20, and 24 weeks.
Researchers discovered at week 24 that the number of active lesions was 89% lower in the 600 mg ocrelizumab low-dose group and 96% lower in the 2000 mg high-dose group compared with the placebo group. The exploratory evaluation demonstrated that both ocrelizumab groups performed better compared with the interferon beta-1a group by equal margins, however, further confirmation is required in future studies.
Annual relapse rates were substantially lower in both ocrelizumab groups, with 80% in the 600 mg group and 72% in the 2000 mg group compared with the placebo group. Although serious adverse events were rare and comparable in all four groups, one patient in the ocrelizumab 2000 mg died. At this time it is still unclear whether the death could be linked to the study drug.
The researchers comment: “Our findings show that ocrelizumab rapidly suppresses inflammatory activity as depicted by contrast enhancing lesions in frequent MRIs, and by clinical relapses. With caution needed when results are compared between different trials, the effect size in our study on MRI and relapse activity compares favorably with established treatments, and to most of the other compounds in development. In the observation period of 48 weeks, this rapid and pronounced effect was associated with a benign safety profile.”
They summarize saying: “Large, long-term studies are warranted to establish the risk-benefit ratio and the place of this innovative therapeutic approach in the increasing armamentarium of multiple sclerosis treatments.”
Dr Jeremy Chataway at the National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust and Imperial College London, UK, and Prof David Miller, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust and Institute of Neurology, University College London, UK, discuss questions arising from powerful immunological drugs like ocrelizumab, such as potency and serious adverse events together with the difficulties in deciding the best implementation strategies, even when licensed by regulatory bodies.
They say in a linked comment: “Should these drugs be used very early (in clinically isolated syndrome and early relapsing-remitting multiple sclerosis) and aggressively to completely abolish the inflammation, or, with gradual escalation, in view of individual disease activity? Therapeutic potency will have to be balanced against early or late risk, both known and unknown. The equation is difficult to solve.”
Written by: Petra Rattue