Editor’s note: This is the first story in a three-part report examining the question, “Is rituximab a reasonable alternative treatment for MS?”, which was a topic discussed at this year’s Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Here, we provide a synopsis of the argument.
More than two years after the approval of Ocrevus (ocrelizumab), B-cell therapies continue to be seen as promising approaches for multiple sclerosis (MS). But it has been debated if rituximab — a B-cell therapy used off-label in MS and also marketed by Genentech — could provide similar or even superior benefits compared with Ocrevus, and at a lower cost.
This question was the focus of a hot topic discussion at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held Sept. 11–13 in Stockholm, where a group of researchers and neurologists voiced their opinions about whether or not rituximab is a reasonable alternative to Ocrevus for people with relapsing MS.
Immune cells homing to the brain and spinal cord (the central nervous system, or CNS) to trigger local inflammation, demyelination (loss of myelin, the protective coat of neurons), and nerve cell death are central for MS. And B-cells, a type of white blood cells, have been identified as relevant players in this process.
For this reason, immunosuppressive treatments that target B-cells have emerged as important therapeutic strategies for MS.
Efforts have been focused on so-called anti-CD20 therapies — antibodies that pinpoint a specific protein on the surface of B-cells called CD20, targeting them for destruction and resulting in B-cell depletion.
Genentech’s Ocrevus is one of these therapies, and the only approved treatment for both relapsing and primary progressive MS (PPMS). It is an engineered (made in the lab) anti-CD20 antibody, given by intravenous (into-the-vein) infusion.
In clinical trials, Ocrevus demonstrated clear benefits. It reduced the rate of relapses and disease activity in patients with relapsing MS, compared with Rebif (interferon beta-1a), and lowered the risk of disability progression in people with PPMS, compared with placebo.
Rituximab is another lab-made anti-CD20 antibody, on the market long before Ocrevus, since 1997. It is indicated, alone or in combination, for the treatment of certain blood cancers, rheumatoid arthritis, and certain types of vasculitis (inflammation of blood vessels).
Rituximab has been used “off-label” — within the U.S. and, particularly, outside the country — to treat several immune-mediated conditions, including MS. Clinical trials have shown that the medicine effectively reduces relapses, limits new inflammation in the CNS, and may also limit disease worsening.
Much controversy has surrounded the use of Ocrevus and rituximab in MS, as they both are anti-CD20 therapies and work through the same principle.
Ocrevus was proposed as a rebranded version of rituximab. But Genentech argues there are molecular differences between the two medicines that make them interact differently with the immune system. Ocrevus may have fewer toxic side effects and reduce the chances that patients may develop antibodies against the medicine, which make therapies less effective over time.
B-cell therapies make sense
At ECTRIMS, the discussion started with neuroimmunologist David Baker, PhD, a professor at the Barts and The London School of Medicine and Dentistry in the U.K., speaking about the rationale for B-cell therapy in MS.
“For many years, we’ve been told that MS is mediated by CD4+ Th17 T-cells,” Baker said, referring to a class of immune cells called T-cells, which are known to promote inflammation and play a role in the development of autoimmune diseases.
But “if MS is a T-cell mediated disease, how and why do CD20 B-cell therapies work?” he asked.
Baker believes that B-cells, specifically memory B-cells, play a central role in MS. In his opinion, lower amounts of these cells in the CNS explain the response MS patients have to B-cell therapies, and possibly the origin and progression of the disease. Thus, therapies that target memory B-cells make sense and are promising avenues to pursue.
The importance of memory B-cells
Memory B-cells are cells that enable our body to build a long-lasting “immune memory.” When they re-encounter a prior threat (e.g., recurring infections) or a factor mistakenly seen as a threat, they proliferate and differentiate into antibody-producing cells (plasma cells).
Baker believes that MS therapies are only effective if they limit the ability of memory B-cells to enter the CNS.
“If you do not deplete memory B-cells, you don’t seem to work in multiple sclerosis,” he said, giving as examples atacicept and tabalumab, two experimental B-cell-targeting treatments that could not prevent (rather, they increased) the accumulation of memory B-cells in the CNS.
Baker emphasized that anti-CD20 therapies have durable effects and suggested that this might be linked to the fact that “it takes 18 months to four years to form a B-cell memory pool.” In fact, in some conditions, following CD20 depletion, “it may take five years for those B-cells to repopulate, and maybe that’s why you get a durability” of treatment, he added.
Other observations also support the role of memory B-cells in MS, Baker said. For instance, the number of memory B-cells drop in the blood during a relapse, while they accumulate within the CNS, including in the cerebrospinal fluid (CSF), which is consistent with the idea that memory B-cells migrate from the blood to the CNS during active disease.
Furthermore, a genetic variant associated with MS is linked to increased production of memory B-cells. Many other MS susceptibility genes with presumed functions on immune T-cells are produced by or act on the growth and survival of B-cells.
Additionally, Epstein-Barr virus (EBV), a proposed risk factor for MS, “affects essentially everybody with multiple sclerosis,” and EBV proteins can “activate many of the autoimmune risk genes, and induce memory B-cells.”
Baker believes that “B-cells are instrumental in targeting what drives the active lesions, which occur in relapsing and progressive MS.” B-cells drive MS progression by producing cytokines [small protein messengers of the immune system], and may also “produce antibodies which … keep the microglia [white blood cells residing in the CNS] in an activated state.”