Fred Lublin, MD: In Europe, England and Germany, is this approved for primary progressive MS [multiple sclerosis]?
Sven Meuth, MD, PhD: Yes, it is approved, and based on the experiences in Europe with the ocrelizumab, especially from Sweden, it entered the market, and there was already a very positive feeling when an approved B-cell depleting agent entered the field. This is why it’s also quite frequently used, but I agree. It’s more used in patients with relapsing-remitting MS where it has a significant impact on the disease course. However, we are now starting to treat more patients with PPMS [primary progressive MS] because there is a lack of alternatives, and the hypothesis behind to interfere with the B-cell compartment and maybe to get, sooner or later, more B cells out of the brain is intriguing, in my opinion. However, we have a bit of a problem. We are wondering, when do we stop ocrelizumab in a PPMS patient, because as already mentioned before, we are not claiming that progression is fully stopped. It is somehow slowed, but when do we see a point in time to say, “In this given patient, the efficacy is not as expected?” This is, for me in the clinics, quite difficult to define, and I would be happy to learn your strategy of when to start ocrelizumab, but also when you think about cessation.
Fred Lublin, MD: Wallace?
Wallace Brownlee, MBChB, PhD, FRACP: We use ocrelizumab method for primary progressive MS in the United Kingdom. We’ve also had discussions about this issue around time and activity, and in the United Kingdom, active has to have been in the last 3 years. To initiate on ocrelizumab, patients need to have had either a Gad-enhancing lesion or new T2 lesions appearing on their scan in the last 3 years, and be ambulatory, and be in the early stages of primary progressive MS to try to recapitulate the clinical features that seemed to be associated with greatest benefit in the trials.
Like Sven, a big dilemma in treating both relapsing and primary progressive MS with ocrelizumab is when do you stop treatment? Because over time, we’re seeing increasing reports of low immunoglobulin levels in patients who had been treated with B-cell depleting agents for a prolonged period, and we are aware that the pharmacodynamic effect on B cells lasts much longer than the licensed dosing interval of 6 months. Whether there is an opportunity for an adaptive dosing or personalized dosing based on, for example, CD19 counts, these are all areas of uncertainty with this drug.
Fred Lublin, MD: How did they come up with the 3-year definition?
Wallace Brownlee, MBChB, PhD, FRACP: The 3-year definition of activity was taken as a line in the sand, and I think 3 years is not unreasonable. We know the activity is less common in people with primary progressive MS than it is in, say, early relapsing MS. There are different risks to this treatment, and you want to try to identify patients who are likely to benefit on the basis of recent inflammatory activity. Three years is not an unreasonable line in the sand.
Fred Lublin, MD: I’m intrigued and often puzzled about how regulators come up with these numbers because they don’t necessarily comport with the clinical data that are available. My experience with this is, one little paradox, and that is when I’m evaluating a primary progressive patient, and I tell them I want them to go out and get an MRI, they look at me a little funny when I say, “I hope I see a Gad-enhancing lesion,” because normally, you don’t want to see them, certainly not in our relapsing-remitting population. As Patricia alluded to, there was a hint. It wasn’t statistically significant, but there was a hint that if you had activity on your MRI, that you would do better. This was the whole business with siponimod, which we talked about, but it is a little paradoxical. I want to see something change. I’d feel a little more comfortable.
My experience is that I have some people who do very well on it, and then some people who don’t. The ones who continue to progress, those are the ones I take off: I stop it. If someone’s doing OK, I continue it. I think from a pharmacobiology point of view, we still have a lot to learn about these self-depleters, just as you folks alluded to, in terms of the durability of the effect and even trying to get a better understanding on the nature of the B cells that return, initially, as they’re returning and whether they may be a more protective population. That will more rationally guide our re-dosing, which right now is not done terribly rationally, but there is a lot more to learn with that.
Wallace Brownlee, MBChB, PhD, FRACP: Maybe that’s something that COVID-19 is going to teach us, Fred, in that we have large numbers of patients around the world who are deferring further courses of B-cell depleting agents because of fears that immunosuppression might be associated with a higher risk of developing COVID-19 infection or a higher risk of more severe infection. Maybe we’re going to start getting some of these data from real-world practice in 2020.
Fred Lublin, MD: That’s a very interesting thought because that’s exactly what we’re doing. We are delaying, and we’re delaying not only because of the concern of immunosuppression but also because of the capacity of our infusion centers to distance people. The number of patients they can deal with has gone down. And we’re trying to limit trips to the hospital and to the infusion center. We should hopefully learn something good from that.