Stewart Tepper, MD: I’d like to say a few basic things, because I think the questions that our neurologists ask us, besides the issue of what happens if it doesn’t work, are: Are they safe, and how effective are they, and are they different from what we have now?
Stephen Silberstein, MD: Well, you’re going to have your talk about fremanezumab and eptinezumab, so you can talk about those briefly.
Stewart Tepper, MD: OK. The first question is safety. And…with some of these monoclonal antibodies now—for example, with erenumab—we are beyond 4 years in patient exposures, over 200 patients beyond 4 years. Thousands of patients have been exposed for years to fremanezumab and to erenumab and galcanezumab, so we really are beginning to have a very large safety database. And for the subcutaneous injected ones, which are galcanezumab, erenumab, and fremanezumab, there’s some irritation at the injection site that’s more than placebo. There are a few sniffles that occur with some of them and some constipation, but we’re really not seeing significant safety adverse events. And erenumab in particular was given in a study for patients with what I would have called unstable angina—patients having angina every month—and did not appear to worsen angina or change exercise tolerance tests when compared with placebo.
So on the safety side, although we’re always monitoring and these are new drugs, I think we have every reason to be encouraged, and tolerability, as David said, is excellent.
Peter Goadsby, MBBS: And no liver enzyme issues…
Jessica Ailani, MD: Yes, it’s not metabolized…
Peter Goadsby, MBBS: It’s worthwhile saying, across the entire development program.
Jessica Ailani, MD: Right, or kidney issues, and it doesn’t interact with...
Stewart Tepper, MD: Metabolized through the reticular endothelial system.
Jessica Ailani, MD: Right, and they don’t interact with other drugs.
Stewart Tepper, MD: And it’s a beautiful thing, not having drug–drug interactions.
Jessica Ailani, MD: Just going to the 1 thing about cardiac safety: I think it’s important that we recognize that patients with significant cardiac issues were not in these clinical trials. So there is that small trial with erenumab in patients with stable angina, but it was a very small group of patients in that. As clinicians, we need to be aware of that and consider that if we’re thinking about prescribing this in a patient…who’s had a heart attack in the last several months or who had a stroke last year. Because we don’t have information at this point about if there are going to be any complications, and I think that’s important to realize.
David Dodick, MD: I think it’s important to back up and ask ourselves why we are even having this conversation, right? And it’s all about antagonizing the effect of a potent vasodilator. I’ll say a couple of things. One is that it’s not the only potent vasodilator in the human body. There’s a lot of redundancy in the system for good reason. That would be No. 1. So if you antagonize the effect of 1, you may not affect vasomotor tone.
No. 2, when you apply the receptor antagonist or the antibodies to an isolated blood vessel, whether it’s a coronary or you name it, it doesn’t constrict the vessel, so it’s not a direct vasoconstrictor effect. And the concern is that if someone’s already having mild cardio ischemia or cerebrovascular ischemia and they’re going to have a stroke or myocardial infarction, could you expand or increase the size of the infarction because you’ve taken out something that might provide dilation of collateral blood vessels? I think that’s the concern.
And so people should be aware of the fact that these don’t directly constrict blood vessels. And the only reason we’re talking about it is because it antagonizes the effect of 1 vasodilator in the human body.
Stephen Silberstein, MD: Very important issue. And then the article that was published using erenumab in angina patients: There was a letter to the editor by the Scandinavian group criticizing the trial and basically claiming that, yes, they believe the results, but perhaps these are people with fixed stenotic lesions, were not vasospastic, and it may not apply to everybody.
So I think here’s the way I would look at it: There’s definitely no evidence that they cause any problems. But as somebody once said, the absence of evidence doesn’t prove anything.
Peter Goadsby, MBBS: Interestingly, in terms of safety, the endocrinologists talk about this because of the MS [multiple sclerosis] monoclonals. These antibodies have been engineered on the FCN not to interact with the immune system. They simply don’t have any immune-modulating effects, so there’s no baggage for infections and such.
Stephen Silberstein, MD: You’ve got to stop at that point. That is a crucial issue. If you listen to television, half the ads are for an antibody, and you hear people say, “You’re going to get tuberculosis or this or that.” I always say, “It’s not the antibody that causes the problems—it’s what the antibody does for a living that causes the problem.” And basically, if antibodies are dangerous, we’d be all dead because we have tons of antibodies. The concentration of our own antibodies is a thousand-fold what we give when we give a monoclonal antibody. The, top interacts with the antigen, the bottom of the Y is what can cause problems. It has all, as Peter said, been genetically engineered to not interact with the immune system, so therefore, by definition, they do not cause those problems.
Peter Goadsby, MBBS: And we need to think about this as immunopharmacology, not immune modulation. Let’s say the fragment pharmacology on CGRP pathways without any FC and immune modulation. It’s very important because our colleagues are so used to these concerns. And one of the most exciting things about this release is it’s a completely different way of thinking.
Stewart Tepper, MD: Which brings us back to efficacy.
Stephen Silberstein, MD: Yes.
Stewart Tepper, MD: And how do they differ from the preventive medicines we were talking about, besides the fact that they’re designed, besides the fact that they’re clean, besides the fact that they appear so far safe and tolerable? They have a number of features from an efficacy standpoint that are extremely hopeful for our patients.