Ocrelizumab in Primary Progressive MS

Research Summary: Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis

There has been a lot of hype over ocrelizumab as the next ‘wonder drug’ in MS.  This has mostly come from the early discussion that it may be the first treatment to have benefits for people with primary progressive MS (PPMS).  With the trial results being published in The New England Journal of Medicine in late 2016, we thought we would examine them and see if the hype is real.

We start today by discussing the background that led to the development of this trial and the specifics of the trial design.  While there is a tendency to want to skip straight to the results, it is important to understand these aspects to be able to put the findings into context.

The Background

PPMS accounts for approximately 10-15% of all diagnoses of multiple sclerosis.  It is characterised by the gradual worsening of disease from onset without any periods of remission.  Up until now, no trials of treatments for PPMS have been successful, and so no approved disease-modifying therapies currently exists for PPMS.

Recently, B cells have been recognised as an important contributor to the damage seen in people with MS.  It is thought that B cells may be involved in a variety of ways, including helping to activate T cells, producing chemical messengers that stimulate inflammation and through antibodies that can directly damage the myelin.

For these reasons, recent therapies have focussed on depleting or removing B cells as a treatment for MS.  CD20 is a molecule found on the surface of mature B cells that has been used as a target for these novel drugs.  Ocrelizumab is a monoclonal antibody against CD20 that depletes B cells.  Rituximab, another new therapy that targets CD20, was recently unsuccessful in meeting it’s goals in a trial in people with PPMS.  However, it was noted that it seemed to be effective in a smaller group of people within the trial, specifically, those that were younger and exhibited large amounts of inflammation.  This was noted and used to help design the ocrelizumab study.

The Study

The trial encompassed a number of different centres through Europe and North America.  To be included in the study, people had to meet the following criteria:

• Be diagnosed with PPMS
• Be between 18 and 55 years old
• Have an EDSS between 3.0 and 6.5
• Have been diagnosed for less than 10 years if EDSS was below 5, or less than 15 years if EDSS was above 5
• Have evidence of elevated B cell levels or at least one oligoclonal band
• Have had no previous use of immunosuppressive treatments

The participants were then split; two-thirds received ocrelizumab and one-third received the placebo.  The treatment was given through two infusions spaced 14 days apart and repeated every 24 weeks.  The double-blinding of the trial was maintained for at least 5 doses.

The main measure to determine the success of the trial was the percentage of people in each group that showed confirmed disability progression.  Progression was recorded as either an increase in EDSS of 1.0 (if the person started with an EDSS of 5.5 or above) or an increase in EDSS of 0.5 (if the person started with an EDSS below 5.5).  This increase had to be sustained for 12 weeks.

Other factors that were investigated as part of the trial, listed as secondary outcomes, were the timed 25 foot walk, change in lesion and brain volume, as well as a physical health based quality of life component.  Safety, in terms of how well the treatment was tolerated and adverse events, was all studied.

Stay tuned to our Facebook page for the next part of the story, where Brett will discuss the results and outcomes of the trial.