Clyde E. Markowitz, MD: In the ocrelizumab extension trial, they looked at patients who were originally on the OPERA I and OPERA II trials. These were the relapsing-remitting multiple sclerosis studies, and they followed patients out after they either converted over from the interferon cohort onto active treatment with ocrelizumab or stayed on ocrelizumab from the beginning. They followed them out to 6 years. 
 
The question we’ve always been asking about these patients is, “Do the patients who switch over gain a benefit like the patients who originally started on ocrelizumab from the beginning, or is it not really going to help?” The reality is you follow these people out, you look at the patients who remain on ocrelizumab from the beginning, you see how their relapse rate numbers look, and then you look at the patients who switched over and what happened to them. Do they ever catch up? How do things go? 
 
They looked at both relapse-rate reduction and disability progression. The results that came out of this are that the patients who converted over from interferon gained the benefit of relapse-rate reduction similar to the population you start on ocrelizumab from the beginning, but they never seem to catch up. You don’t get to the level of disability progression reduction as the patients who started ocrelizumab from the beginning.  
 
I think the take-home message for us—we’ve seen this with many different clinical trials—is that whatever the more effective therapy is from the beginning, if it started the earliest, it’s going to have the greatest outcome in suppressing disease activity and ultimately in slowing the disability progression that we’re most concerned about. These data really confirmed that as well. 
 
From a practical standpoint you have to ask the question, “Am I going to start a patient on a more effective therapy from the beginning, or am I going to put them on something that may have a more tolerable safety profile or something that’s a little milder. Overall, after we’ve done so many clinical trials with the different agents that have a higher efficacy, we have learned that you’re best off starting with the most effective therapies. Even though there could be a safety question that you are worried about, those are manageable at this point.  
 
We know what the safety concerns are. We know how to identify patients at greatest risk, and we’re able to figure out how to manage that. The bottom line is that the field overall is saying we need to be starting with a more aggressive therapy from the beginning. Because you aren’t going to catch up if you wait.