Review of Natalizumab for MS

Fred D. Lublin, MD: Natalizumab, Stephen?

Stephen C. Krieger, MD: Natalizumab I think was the archetypal high efficacy medicine, and it really dragged us as a field into the modern era of being able to balance risk and benefit. This is a monoclonal antibody. It’s infused classically every 4 weeks. We’re going to talk a little bit about how that might be evolving. It blocks the transmigration of lymphocytes across the blood-brain barrier. So, again, we can think of this as a cell trafficking modulator. So, although the S1Ps [sphingosine 1-phosphate receptor modulators] do that through a very different mechanism, the principle that these are blocking the movement of the lymphocytes of concern is similar with these 2 modalities. I think that’s why the idea of stopping an S1P modulator and stopping natalizumab both are fraught with the concern for disease rebound as those cells are able to cross into their target.

A couple of things to say about natalizumab. As we talked about before, this is the one where we thought that there was a 1 in 1000 risk across the board of PML [progressive multifocal leukoencephalopathy], an opportunistic viral infection of the brain caused by the JC [John Cunningham] virus. But this is also I think the best example of using a couple of simple biomarkers to help us optimize a risk-benefit ratio of a particular medicine for patients. We know that the risk of PML increases the longer a patient is on natalizumab if they are JC virus antibody-positive.

The advent and the dissemination of the JC antibody blood test I think is the single most useful biomarker that we have in some ways. Because simply knowing how long has someone been on the drug, are they JC antibody-positive, and were they exposed to immunosuppressive or chemotherapeutic agents in the past allows us to discriminate PML risk 100-fold, from perhaps a 1 in 100 risk for the highest risk category, to perhaps a 1 in 10,000 risk or lower for those in the lowest category, those who were JC virus antibody-negative. That’s I think incredibly useful, and it really guides the conversation with patients about who’s suitable for this medicine and for whom it could be used early, used first-line in the right circumstances we were talking about earlier.

Now interestingly, natalizumab was studied in secondary progressive MS [multiple sclerosis] in the ASCEND trial, and that was a negative study. So here you’ve got another cohort of secondary progressive MS patients. The outcome measure is accumulation of disability tested in a variety of ways with natalizumab versus placebo, and it was negative. It showed statistically significant benefit on a subcomponent of disability, the function in the upper extremity. That was a negative study.

I think it’s important that this unequivocally high efficacy medicine for disease activity was not successful in secondary progressive MS. And yet with the new FDA categories, it too garnered this active SPMS [secondary progressive multiple sclerosis] indication. And siponimod, which was successful in secondary progressive MS, garnered the same indication. And I think that’s another example of how we’re trying to retrofit the way the FDA has now categorized things on to the data that we have.

The last thing I’ll say about natalizumab is we’ve talked a lot about PML risk stratification on the basis of patient selection. But now where it’s being looked at in our field is whether extending out the interval of the dosing, so in essence, underdosing the medicine over time, can reduce the risk of PML. And some early data with a lot of work presented by Lana Zhovtis Ryerson, MD, at NYU [New York University Langone Health], and collaborative groups, have suggested that extended interval dosings out to the 6-, 7-, 8-week range can meaningfully decrease the risk of PML even in high-risk patients. But I think that there’s real diversity in our field as to whether we believe that and whether that guides our practice. So I’ll just put it out there. That’s what the data look like. I’d be interested to know whether you’ve begun to adopt that or question it.

Amit Bar-Or, MD, FRCP: I think it’s certainly plausible, biologically believable. The issue is what to do with that information. And you made the point that for the same 1 in 1000, there were people who said, “Absolutely, yes,” versus “Absolutely no.” So if you change that from 1 in 1000 to 1 in 200, will that really shift the equation dramatically or will it just nudge it a little bit?

Peter A. Calabresi, MD: I think it makes sense though. We’ve known for over a decade that receptor occupancy differs in patients. It’s just a very difficult assay to perform on a clinical basis. And so right now it feels a little uncomfortable to extend the dosing interval on some patients, and not have a way of necessarily monitoring that. We’ve seen some people feel like they’re starting to reactivate. Of course, it’s probably the right thing to do in people who have been on it for a while and are in that low positive category.

Patricia K. Coyle, MD: I think the TOUCH program data were pretty convincing that extended dosing significantly lowered risk of PML. I think it’s a definite strategy that you can do, and I think the data have supported 6 to 8 weeks. I know there’s a big trial looking at 6 weeks extended dosing. You still have efficacy. The drug seems to hang around longer, so I think that’s a valid step to take to lower PML risk if you continue on it.

Peter A. Calabresi, MD: We need a biomarker. There needs to be a blood test to know who’s a good candidate.

Fred D. Lublin, MD: I’d like to see a prospective study. The TOUCH isn’t prospective, it’s sort of happenstance, so I’d like to see it looked at. I’d like to see it looked at prospectively. But we got at this issue of the label, and we should say cladribine did not get a CIS [clinically isolated syndrome] indication.

Patricia K. Coyle, MD: And this again makes no sense to me. Cladribine had a CIS trial. Cladribine was approved because it doesn’t cause cancer, so why would you say they didn’t give it a CIS approval because they said we’re going to recommend it be used as a second-line agent, that you try another agent beforehand? Totally illogical.

Fred D. Lublin, MD: But they didn’t say it doesn’t cause cancer because they did give it a cancer warning.

Patricia K. Coyle, MD: Well, yes, but you don’t need to do any special cancer screening. In theory, you can have cancer associated with any immunosuppressive agent. It got back on the market because they didn’t have an obvious cancer issue with it.