Robert J. Fox, MD: Ocrelizumab is an anti–B-cell monoclonal antibody that very quickly and effectively kills B cells in the body. The B cells remain gone from the body for many months—upward of 6, 9, and in some patients, even 12 months.
B cells have not traditionally been considered to be a part of MS [multiple sclerosis]. However, this has changed based on more recent findings and a related rituximab trial that found very robust reductions in new lesions and active lesions and relapses following therapy with this drug. Ocrelizumab was evaluated in 2 phase 3 trials in relapsing MS and a third phase 3 trial in primary progressive MS. It was very effective in reducing relapse rates and new lesions on MRI [magnetic resonance imaging].
It reduces new lesions on MRI by upward of 95% or more. So, a very robust reduction in active inflammation. In the primary progressive trial as well as a relapsing MS trial, it slowed the progression of disability. Not only did it decrease inflammation, but it slowed the accumulation of clinical disability in patients with relapsing or primary progressive MS.
There were some risks and some adverse events that were seen with ocrelizumab. There were infusion reactions, mostly hives and itching, that were seen during and shortly after the infusion. There was also an increased risk of infections, particularly respiratory infections and zoster infections, that were seen with this drug. There are also rare reports of PML [progressive multifocal leukoencephalopathy]—a very serious and sometimes fatal brain infection—that have been associated with this drug. Clearly, this drug’s very good efficacy does come with some risks.
Then the question turns to where we use ocrelizumab in clinical practice. It's clearly a highly effective therapy. It has some risks, but risks that are often acceptable to patients, particularly patients who have modest or aggressive disease. We do use it in patients as a first-line therapy, but not as often. It is mostly used as a drug for breakthrough disease activity from the other therapies, or is used in patients who are at high risk for complications to the other therapies. Then, ocrelizumab is a good option.
Similar to what was seen with siponimod, ocrelizumab was found to be more beneficial in patients who are younger and have active inflammation in primary progressive MS. It shows less efficacy in patients who are older and don’t have active inflammation. Also, the ocrelizumab primary progressive MS trial only enrolled patients age 55 or under. So we really didn't get a sense, because the patients weren't enrolled, of how patients would do if they were older with less active inflammation.
As a result, many of us are a little bit more hesitant to use this in patients who are older, who don't have active inflammation, who are more disabled—particularly those who may not have much movement because they're wheelchair bound and the like—and, therefore, may have a higher risk of infections such as respiratory infections. Again, the risk-benefit profile then shifts. The benefits become less, and the risks become higher. Older patients and more disabled patients with primary progressive MS were less likely to use ocrelizumab.