brainmacromovementin

by Tianli Xiao
figures by Abigail Burrus

Multiple sclerosis begins when a patient is as young as 20. It can start with blurry vision, tingling in the arms or legs, or a persistent feeling of tiredness. MS is a long-term, progressive disease that worsens over time, but there are few drugs available today. Even worse, patients diagnosed with a less common form of MS known as primary progressive multiple sclerosis have no treatments available at all. However, this harsh reality might change soon with the emergence of a new drug called Ocrelizumab.

What is multiple sclerosis?

Multiple sclerosis is a neuroinflammatory disease in which damage to the brain and spinal cord causes brain dysfunction. Normally, the cells in our brain are constantly and rapidly communicating with each other to help us form thoughts and control our bodies. It is this communication that becomes disrupted in multiple sclerosis. Depending on which region of the brain becomes damaged, the symptoms of MS can vary. For instance, MS patients may have difficulty walking, experience poor vision, or encounter bowel problems.

The excitement surrounding Ocrelizumab is that it’s the first drug to show benefit for primary progressive multiple sclerosis. Multiple sclerosis is not one single disease – about 85% of MS patients are grouped into a subset known as “relapsing-remitting multiple sclerosis” who have disappearing and reappearing symptoms, thus earning the relapsing-remitting name. In contrast, 10-15% of patients never experience the relapse-remitting phase; instead, their symptoms progressively worsen over time in a condition known as primary progressive MS (Figure 1). While research and drug development has created several new treatments for relapse-remitting multiple sclerosis, there hasn’t been a drug that showed benefit for primary progressive MS – until now.

Figure 1: Multiple sclerosis is not a single disease. The majority of patients (around 85%) suffer from relapsing-remitting MS, which means they may experience periods when the symptoms get better without any treatment. In contrast, patients suffering from a less common, primary progressive MS, will have continuously worsening disease from the time of diagnosis.
Figure 1: Multiple sclerosis is not a single disease. The majority of patients (around 85%) suffer from relapsing-remitting MS, which means they may experience periods when the symptoms get better without any treatment. In contrast, patients suffering from a less common, primary progressive MS, will have continuously worsening disease from the time of diagnosis.

Ocrelizumab brings new hope to slow primary MS

In December 2016, a phase III clinical trial showed that a drug called Ocrelizumab provides benefits for patients with primary progressive multiple sclerosis. The trial’s goal was to see whether patients who received Ocrelizumab would have slower disease progression than other patients. Thus, they gave patients either Ocrelizumab or an inactive placebo and monitored the time it took for patients to have progression in their symptoms. The study found those receiving the drug are likely to have slower disease progression compared to those who received placebo, although the effect was modest. Ocrelizumab is now being reviewed by the US Food and Drug Administration (FDA) for approval for widespread use.

Unfortunately, like all existing drugs for MS, Ocrelizumab cannot cure multiple sclerosis, but will simply slow down the pace at which the disease gets worse. Although multiple sclerosis is an old disease, known to physicians since 1868, it has taken 148 years before the first drug to show promise for primary progressive MS. Why is MS so difficult to treat?

Why has MS been so hard to treat?

MS is a complicated disease involving many cell types, making it challenging to know which cells should be targeted for treatment. But we do know that the inappropriate activation of the immune system plays an important role in MS. Cells from the normal immune system, such as T cells and B cells, attack the brain, causing damage that leads to MS. You might be thinking that if researchers can understand what triggers the immune system to target the brain, we can design drugs to remove that trigger and cure the disease. Unfortunately, the specific causes of MS have not been identified, and thus existing drugs have not been able to cure MS. Instead they alleviate the symptoms and slow down the disease progression.

Nonetheless, developing drugs that target the immune system has proven beneficial.  Over ten drugs have been approved to treat relapsing-remitting MS, all with a similar goal of dampening the immune response. For instance, some drugs like interferon-beta act on immune cells such as T and B cells to prevent them from attacking; other drugs like Natalizumab and Fingolimod prevent the immune cells from entering the brain.

Treating primary progressive MS has proved very challenging, mostly because scientists are only beginning to understand this form of MS. The fact that progressive MS has very distinct symptoms compared to relapse-remitting MS suggests that immune cells might behave very differently in these two diseases. To complicate the matter further, many clinical trials do not separate relapse-remitting MS from primary progressive MS patients, thus a study might overlook a benefit seen only in progressive MS patients.

What can the success of Ocrelizumab teach us about the disease underlying primary MS? To understand that, we need to know what Ocrelizumab does.

How might the drug work?

Ocrelizumab targets a molecule called CD20 that is expressed on B cells, which marks the B cells to be killed. Normally, B cells are a critical part of our immune system, whose job is to produce antibodies to fight infections. However, B cells are inappropriately activated in MS patients. They move into the brain and promote an immune response in primary progressive MS, there are special structures that continuously supply the brain with immune cells, including B cells, to establish a chronic state of immune overactivation. Thus by killing B cells, Ocrelizumb helps fix this problem.

B cells have several life stages- from an immature B cell in the beginning, to an activated B cell, to eventually become an antibody-producing B cell. Ocrelizumab does not target all B cells – it does not kill antibody-producing B cells, or B cells that have not yet matured. This is a good thing, since we still need antibodies to protect ourselves against infection. Thus Ocrelizumab selectively kills activated B cells in MS patients, and thereby prevents them from activating other immune cells and from producing cytokines in the brain.

Figure 2: B cells in multiple sclerosis; 1) B cells enter the brain in MS patients and produce antibodies against proteins in the brain. Normal brain proteins are labeled by arrow 2. 3) B cells also present proteins to other components of the immune system and activate them, such as a T cell shown here in purple. This contributes to the immune overactivation in the brain. 4) B cells produce signals called cytokines to further increase immune system action. 5) Ocrelizumab recognizes proteins on a subset of B cells, specifically B cells that express CD20. The result of this interaction kills the B cells, thus alleviating the immune overresponse.
Figure 2: B cells in multiple sclerosis; 1) B cells enter the brain in MS patients and produce antibodies against proteins in the brain. Normal brain proteins are labeled by arrow 2. 3) B cells also present proteins to other components of the immune system and activate them, such as a T cell shown here in purple. This contributes to the immune overactivation in the brain. 4) B cells produce signals called cytokines to further increase immune system action. 5) Ocrelizumab recognizes proteins on a subset of B cells, specifically B cells that express CD20. The result of this interaction kills the B cells, thus alleviating the immune overresponse.

What does Ocrelizumab mean for patients?

Despite all the excitement around Ocrelizumab, it’s also important to note several caveats. First of all, while patients receiving Ocrelizumab will likely experience slower disease progression, the effect is not as dramatic as some might hope. Furthermore, the study focused on middle-aged patients with a moderate disease severity, thus whether older patients with more advanced diseases will benefit from the drug remains unknown. Nonetheless, for many patients suffering from primary progressive MS, there will be a drug available for the first time. Furthermore, if the drug is approved for clinical use by the FDA, it will likely spur further interest in developing drugs for this patient group. As for researchers, results from this trial will certainly stimulate further interest in examining the role of B cells specifically in primary progressive MS.

The results of the Ocrelizumab trial, albeit modest, mark an important milestone in treating primary progressive MS. Clearly, a better understanding of the disease biology is needed to design more sophisticated drugs, particularly in primary progressive MS, where the mechanism of disease might be different than relapse-remitting MS. The attention brought by Ocrelizumab to primary progressive MS will certainly help.

Tianli Xiao is a PhD student in the Immunology Program at Harvard University.

For more information:

  1. National Multiple Sclerosis Society: http://www.nationalmssociety.org
  2. Dolgin, E., Therapies: Progressive steps. Nature, 2016. 540(7631): p. S7-S9
  3. Paper describing results of Ocrelizumab: Montalban, X., et al., Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med, 2016.

9 thoughts on “Ocrelizumab: The first treatment for primary progressive multiple sclerosis

  1. After reading this report, does anyone know the clinical criteria for being accepted on this treatment? My mum has PPMS and is 66 years old, still able to walk (although very painful) and is on pregabalin and doculepin.
    Worried that this new drug may only be given to people who are middle aged as report states that trials where conducted on this age group..
    Any answers would appreciated.. 👍

    1. If you have not gotten an answer yet, my father is 65 and has PPMS and his doctor is recommending he start this treatment so your mother should be able to start it as well. It has been approved by the FDA.

  2. I was dx with PPMS in 2011. Tried the rounds of steroids which worked for awhile but then just got h/a from that. Had an autologous stem cell transplant in October 2016; results good at first but now gradual decline. Am l a candidate for any of the new trials?

  3. I’m Paulo, a 40yrs old, patient and diagnosed with MS 11 Ceará ago, Despite the fact that I didn’t have any other relapse (just one in the first year) , I’ve slightly seen my simptoms worses severally.

    Now at 6,5 from kutze escale, I Wonder if this new drug can decrease my current “status”.

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