Emerging therapies at AAN – the B cell movement

Neurologist and leading MS researcher Dr. Amit Bar-Or from the Montreal Neurological Institute at McGill University presented data on an emerging MS treatment called ofatumumab at the American Academy of Neurology Annual Meeting last week. Ofatumumab is a monoclonal antibody targeted against a protein commonly found on B cells called CD20. It is currently indicated for the treatment of chronic lymphocytic leukemia, but has been recently identified as a potential treatment of autoimmune diseases such as MS.

Dr. Bar-Or presented results from a phase II clinical trial looking at the safety, efficacy and dose response of ofatumumab in people with relapsing-remitting MS.

The study recruited 231 participants who were randomly assigned to one of 5 treatment groups: 3mg every 3 months, 30mg every 3 months, 60mg every 3 months, 60mg every month, and placebo (mock treatment). Participants were given ofatumumab via under-the-skin injections over a period of 6 months and also took part in follow-up studies. The efficacy – ability to produce a beneficial effect – of ofatumumab was determined by its ability to reduce lesions as observed on MRI.

At 12 weeks, treatment with ofatumumab resulted in a significant reduction in the number lesions compared to placebo. The reduction in lesions was observed for all doses. Researchers also reported a linear relationship between suppression of B cell activity and residual disease activity, with 1 new lesion per year with treatment versus 16 new lesions per year without treatment. The drug showed a good safety profile, with reports of some adverse events including injection-site reactions. There were no serious infections, PML cases or immunogenicity (immune reactions against the drug) observed.

Ofatumumab, which is currently being developed by pharmaceutical company GlaxoSmithKline, adds to the growing list of MS therapies in the pipeline. It is also one of two emerging MS therapies targeting B cells, the other being ocrelizumab. Like ofatumumab, ocrelizumab targets the CD20 protein and is currently in phase III trials led by scientists at Roche.

B cells have gained increasing interest among the MS research community over the years. When trials involving B-cell targeted treatments showed marked improvements in people with MS, researchers acknowledged that B cells are important players in MS disease. Last year, the MS Society and MS Scientific Research Foundation launched a $3.6 million dollar collaborative, multi-site study led by Dr. Bar-Or which seeks to understand how different types of B-cells impact the development and progression of MS, how they may have a role in progressive MS, and how they can be therapeutically targeted to improve health without harming other parts of the immune system. I had a chance to chat with Dr. Bar-Or after his presentation at the conference to get a more in-depth look at ofatumumab and B cells.

Here is what he shared with me.

1. What is ofatumumab and what is its mechanism of action in the body?

Ofatumumab is an antibody that is administered subcutaneously and binds very specifically to a molecule called CD20, which is expressed on the surface of B cells of the immune system. When administered to patients, ofatumumab binds to B cells and quickly removes them.

2. What were the major findings of the most recent clinical trial with ofatumumab?

A unique aspect of this study was the assessment of multiple different doses and regimens of ofatumumab. This provides, for the first time, an opportunity to assess the effects of different degrees of B cell depletion on new MS disease activity. Ofatumumab was very efficient at depleting B cells, and did so in a dose-dependent manner, which resulted in a dose-dependent effect of limiting development of new MS brain lesions. Importantly, decreases of greater than 90% in new MS brain lesions were also seen at several of the lower doses of ofatumumab that only partially depleted B cells. These lower doses of ofatumumab may therefore strike a better balance between benefit and safety compared to other agents, which will be important for long-term treatment. Ofatumumab is also administered by simple subcutaneous injection once a month or even less frequently, so patients can inject themselves.

3. Has ofatumumab been evaluated in trials with progressive MS patients?

Not yet

4. This drug adds to a growing list of B-cell targeted treatments for MS. Why are B cells only being looked at now and how important are they in MS disease?

Prior work largely focused on the role of T cells, and largely because T cells are more involved in the most commonly used animal model in MS, known as experimental autoimmune encephalomyelitis (EAE). We now appreciate that B cells are very important, in part because of their interaction with T cells. Recent studies point to an important ability of B cells to influence T cell responses and we believe that the substantial benefit (decreased new relapses) of selectively removing B cells in people with MS is due to removal of the capacity of MS B cells to abnormally activate T cells. So it’s not about T cells OR B cells, it’s about the interactions between them.

5. Are all types of B cells considered ‘bad guys’ in MS?

No. In fact some B cells may be ‘good guys’ – these have been called regulatory B cells or ‘Bregs’. People with MS seem to have too few of these, and too many of the ‘bad guy’ cells that can abnormally activate T cells. An important goal is to understand better who are the good guys and who are the bad guys, including how their profiles differ across individuals, what generates and activates them, what regulates them, and what different treatments do to them.

6. Are B cells contributing to the development of progressive forms of MS?

Quite possibly. We now know that an important part of the injury in MS that has not been appreciated is injury to the cortex (‘grey matter’) and particularly to regions of the cortex that are very close to the surface of the brain. This injury appears to have a different pattern and therefore a different cause than the typical lesions (or plaques) that occur around vessels in the ‘white matter’. The distribution of this cortical injury suggests something happening from the surface in. It is now also appreciated that along the surface of the brain, there are immune cell collections in the ‘meninges’ (the membranes wrapping around the brain). These immune cell collections seem to be close to regions of most substantial cortical injury and , interestingly, are rich in B cells. We have shown that secreted products from MS B cells can injure brain cells and so it is quite possible that B cells, within these meningeal collections, contribute to the cortical injury that results in progressive MS.

7. What are the next steps in research on ofatumumab?

To choose the optimal ofatumumab dose that will be investigated in Phase III clinical trials of MS and to consider how ofatumumab can be evaluated in people with progressive forms of MS.

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