Identifying the Biomarkers for the Treatment of Severe Asthma - Episode 9
Neal Jain, MD, FAAP, FAAAAI, FACAAI: So then we see these patients. Let’s say the number is still in the millions, regarding the number of patients in the [United States] who have truly severe disease, which we can show with biomarkers, exacerbations, etc, and need for oral steroids, high-dose inhaled steroids—we’ve excluded all those alternative diagnoses—but they have this truly severe disease, and we start to think about these targeted therapies. So we have these different biologics. I’m curious to know, do you use them in your practice? And how do you decide when it’s time to use those therapies?
Aidan A. Long, MD: If you think about the first 1 we had, anti-IgE, omalizumab, it’s been approved for asthma since about 2003, I think. So there is about 15 or 16 years of experience with it. And this was a remarkable breakthrough in the treatment of asthma. So despite what we’ve all discussed, about trying to manage asthma ideally, the early studies with omalizumab showed that they were able to reduce asthma exacerbations by about 35% to 40% in these patients who were truly allergic asthma patients, who were truly refractory to therapy. And what was remarkable was the more severe the disease, the greater the magnitude of the exacerbation reduction. Really quite extraordinary.
And it actually brings up a very interesting question. How is this drug doing with this? Even though there are different phenotypes and endotypes of asthma, most asthma exacerbations are still virally induced. How would an anti-IgE drug help with that problem? It clearly does. The facts are there. Exacerbations are reduced. And when looked at mechanistically in a severe asthma study that Brad has been a part of, you can show that it decreases virally induced asthma exacerbations.
Bradley Chipps, MD: Both in ICATA and PROSPERO.
Aidan A. Long, MD: Yeah, quite remarkable. And now there’s in vitro testing showing that the impaired antiviral response that we see in allergic asthmatics is restored.
Bradley Chipps, MD: Interferon responses restored, yeah.
Aidan A. Long, MD: By this anti-IgE, and possible by the other biologics too. I think we might find out.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Right. I think you’d expect to see that, given that we think that most of these exacerbations seem to be virally driven, and we’re reducing exacerbations with these therapies. Nic, do you use biologics in your practice?
Nicola A. Hanania, MD, MS: Obviously, yes. But one has to keep in mind that with biologics, right now, just as you mentioned earlier, if we know that a biologic can alter the course of the disease, meaning “cure asthma,” we would be using it right up front. Currently, biologics are used as sort of the last resort if the patient has severe asthma, has failed current therapy, and continues to have symptoms, mainly because of the cost. Of course, it’s a commitment.
So whenever I decide to use a biologic, I sit with the patient. There’s quite a bit of overlap, regarding treatment choice. But there’s definitely a need for a patient’s interaction and feedback on this because we need his or her commitment. This is a long-term commitment. It’s not a onetime deal. Often, they need to come into the office—twice a month sometimes, or once a month. So cost is an issue, and coverage is an issue. So we go over this before we step into it. But I do use biologics. We have a limited number for certain type 2—high asthma, allergic asthma, eosinophilic asthma, and hopefully more to come. As I mentioned earlier, there are several studies ongoing.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Yeah, it’s definitely been an evolution. And I think going from that time 15, 16 years ago, which is around the time I came out of training, to sort of where we are now, there’s been a lot of advancement in our understanding and our options that are available. We also have a lot of challenges that we have to deal with, obviously. You mentioned cost being 1 of them.
Bradley Chipps, MD: To take that a step further, I want to ask the other panelists a question. How many controllers do you think you need to expose a patient to before you consider a biologic?
Nicola A. Hanania, MD, MS: Honestly, in my practice almost all the patients who go on a biologic have been on 2, 3, if not 4 therapies.
Aidan A. Long, MD: I would agree.
Bradley Chipps, MD: I think at least 3, or maybe even 4 controllers if you want to count monthly.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Do we have any concerns about the long-term use of these therapies?
Aidan A. Long, MD: Safety. It’s interesting. The first 1 to come out, and we mentioned omalizumab, did have safety warnings. One of them, for example, was a warning about possible increased risk of malignancies across a broad range of malignancies, including skin, breast, lung, colon. It wasn’t a significant problem in the studies, but it was a numerical difference. However, in the fullness of time, further studies have been done—long-term follow-up—and the EXCEL study ran over 5 years, had a large number of patients, and that issue appeared not to be confirmed. In terms of joint decision making with the patients, that was a really difficult discussion to have. That seems to have been addressed, though.
Bradley Chipps, MD: In the EXCEL study, then the cardiovascular thing.
Aidan A. Long, MD: Although, as Brad is pointing out, another issue appeared to arise: Increased cardiovascular events, venous occlusive disease, arterial occlusive disease. Again, a numerical difference, but something we need to be worried about. With the newer agents, we don’t have that length of experience to guide us. In the early clinical studies, they seemed to be very safe and well tolerated. But yes, these are important.
Nicola A. Hanania, MD, MS: The other thing is anaphylaxis. I’ve never seen it in my patients, but it’s certainly something to be aware of.
Bradley Chipps, MD: I’ve had 2 cases.
Nicola A. Hanania, MD, MS: For several of my patients, I do use epinephrine injections, just for them to carry with them. We monitor these patients the first 3 times they get the injection. They all get the injection in the office, but we keep them longer—like 4 hours. In general, we’re really familiar with omalizumab because it’s been there longer and it has long-term safety studies. Most of the other biologics have 1 year. Actually, more recently with mepolizumab, there are 4-year studies published showing long-term safety.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Just building upon what Aidan had sort of talked about with regards to EXCEL, I think 1 of the challenges is when we look at these open-label trials. There are definitely methodological issues that can sort of come into play when interpreting the data, right? And so we have to be careful, especially with regard to cardiovascular risk, when you compare a moderate population of asthmatics to a severe population of asthmatics. How does that play into the safety? We can read between the lines, but generally speaking, it’s not something that I have thought about.
When I think about these medications, I don’t think about them as being immunosuppressive in any way, as some of the drugs that are used, perhaps, in the rheumatologic space might be. And in general, I think our safety concerns, at least thus far, especially with Xolair, have been limited. Hopefully that is the case with these other therapies.
Transcript edited for clarity.