Introduction

Dr. Anju Peters (Northwestern University): Thank you for joining us. We will talk about Breaking New Ground in Chronic Rhinosinusitis with Nasal Polyps, or CRSwNP: Expert Perspectives on Targeting Epithelial Cytokines.

[00:00:16]

Advances in Targeted Therapy for CRSwNP

We know CRS with nasal polyps or chronic rhinosinusitis with nasal polyps is a type 2 inflammatory disease. These patients have significant inflammation, often undergo sinus surgery, undergo oral steroids, and despite treatment, these patients have disease recurrence.

It is the type 2 inflammation which is the key inflammatory pathway in these patients with CRSwNP. We do have targets that target this type 2 inflammation.

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Biologics for CRSwNP

This slide shows you some of the drugs that are approved for chronic rhinosinusitis with nasal polyps, and another one which in studies has shown benefit but not approved as of yet.

Dupilumab, which targets IL-4 receptor alpha. Mepolizumab, which targets IL-5, and omalizumab, which targets IgE, the allergic antibody. These three are approved for CRSwNP. They are also approved for other comorbid conditions, including asthma.

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Emerging Biologics

In addition to the three that we have currently approved, there are new treatment options that are going to be available hopefully soon. One of them is tezepelumab, which targets TSLP. This is an alarmin that is released from the airway epithelium. It is already approved for asthma and it has positive studies in chronic rhinosinusitis with nasal polyps.

Tezepelumab blocks TSLP and reduces downstream cytokines. We also have a biologic which targets eosinophilic inflammation. It targets IL-5. It is injected every six months and it is depemokimab. There are others that are being studied as well.

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Pipeline Snapshot: What’s Coming Next?

A few that are in the pipeline are currently being studied in addition to tezepelumab, include biologics that target IL-33, which are in phase II. There are also other IL-25 targeting biologics. This is an exciting time for targeting or treating type 2 inflammation in patients with CRS with wNP. We have few that are already approved and others that are on the way.

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Where Are We Headed?

Where are we headed? CRSwNP is entering a precision area for personalized medicine. Our current biologics, as I mentioned, are effective for severe T2-high CRSwNP. There are newer therapies that are targeting upstream cytokines or alarmins, TSLP as well as IL-33. The ongoing trials will reshape the treatment landscape.

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Panel Discussion

I would like to ask the rest of my panel some questions and we can discuss these. Let us start with either Stephanie or Katie, what are some unmet needs with the current biologic armamentarium that target downstream inflammatory mediators for CRSwNP?

Dr. Kathleen Buchheit (Brigham and Women's Hospital): Sure. I am happy to get started. From an allergy perspective, I think this is probably general for both allergists and otolaryngologists. There are a subset of patients who do not have type 2 inflammation driving their disease. For those folks really right now, our current biologics are not particularly efficacious. We do see that there are some non-responders to biologic therapy.

I suspect it is because what is driving their inflammation is more neutrophilic inflammation, potentially driven more by cytokines such as IL-17 or interferon gamma. We do not necessarily hit the right target in every patient. Right now we do not have the tools available to do so for everybody.

Dr. Stephanie Smith (Northwestern Medicine): Yeah. I agree with you, Katie. That is a big unmet need is treating our other patients with nasal polyps and also perhaps those with CRS without polyps.

I think some other unmet needs here are that we do not have perfect, reliable biomarkers just yet to help us predict which patients will respond the best to biologic or surgical therapy.

Dr. Buchheit: Yeah, I would agree with that. I think it would be amazing if we could predict the folks that are going to really not do well with surgery and spare them that. That is just something that right now we do not have any perfect tools to do.

The other area that I am really interested in that is certainly related to this is I see a lot of patients who have aspirin exacerbated respiratory disease and I do not know, Anju, if you are doing this a lot still, but we still do some aspirin desensitization for these patients. There are some patients who do like maybe not all of them, but some patients do really, really well with that.

If we could predict which patients with AERD would do well with surgery paired with an aspirin desensitization, that offers a lot of benefits and that it is readily available and easy to do after they are desensitized, easy to continue taking regularly. That is an area where I wish we had better biomarkers to help us predict which of our patients with AERD would do well with that medical and surgical management plan.

Dr. Peters: I totally agree. I mean, CRSwNP, even in the Western world where we think of this as being type 2 is heterogeneous and there are patients who have mixed inflammation. Right now we do not know which one of them unless they undergo surgery, and then their pathology might help us. But it would be wonderful if before surgery we could say, you have mixed inflammation or you only have type 2 inflammation and you do so well with surgery.

Biomarkers I think are a huge thing, as you mentioned, Stephanie. If we had a way of telling how long someone needs to be on a biologic, my patients always ask me, is this forever? I am like, no, we do not know what is forever. But most patients do not necessarily stay on them long term.

If we could say, you only need it for six months, you may need it for five years. Those type of biomarkers would be wonderful because these drugs are expensive. Potentially, if we can spare someone being on them for a long period of time.

Let us move on to the next question. When and with what criteria do you assess therapeutic response from a biologic? Either one of you.

Dr. Smith: I think the most important thing is how my patients are feeling. From a biologic, I think one of the most outstanding responses they have is with regard to hypoxemia. That will be the first thing a lot of patients will tell me about, or that I will inquire about. We do have standardized patient reported outcomes measures that at my academic institution, we use the SNOT-22 a lot, or a CRS-PRO to help numerically assess how patients are doing.

Then definitely, looking at nasal endoscopy to assess whether polyps are present or big or smaller are the ways that I assess therapeutic response. But I think the biggest thing at the end of the day is how a patient is feeling.

Dr. Buchheit: Yeah, I would 100% agree with that. I mean, the reason to use these is to improve your patient's quality of life. I want them coming back to me, saying that I am less congested. I can smell. I am sleeping better. I am just feeling better overall. All of those things. For folks with comorbidities, saying that my asthma is also better and markers of that are improving as well.

Then from my perspective, I think another huge thing to consider is less use of other medications, specifically systemic corticosteroids. For our patients who are getting multiple courses of oral corticosteroids a year, going to urgent care or primary care doctor and getting these frequently, seeing that that is decreasing is important. Or for our folks who are coming to us and they are on daily oral corticosteroids at baseline being able to wean that.

Then once that happens I am delighted. Then also looking forward to de-escalating some of the intranasal steroid use. Maybe going from irrigations or drops or exhale delivery system down to sprays and patients who are doing really well. Patients prefer that. It is less work for them to manage the less intensive intranasal steroid applications. I am happy for them to do that and they are really delighted about it as well.

Then that is certainly associated with less potential side effects like epistaxis. We worry less about the ocular side effects or theoretical ocular side effects as well if we can taper their intranasal steroids once they are doing beautifully well on a biologic.

Dr. Peters: I totally agree with you guys that it is nice clinically how people do. In addition, I know, Stephanie, you do endoscopy. I do not have the luxury of doing endoscopy in my regular allergy clinic. That is where I feel like I rely on many of my biologic patients doing like a VAS. I just have them score it from zero to 10, with saying 10 is the best. Where are you? In every visit, I will do that for two of the symptoms that I feel like – not just I feel studies have shown bother them the most. You brought up sense of smell and nasal congestion, and then that gives me a really good way of showing the patient also, look, this is where you were when we started you on the biologic and look where you are now. That is a semi objective way I feel of assessing response.

Again de-escalation of therapy. I mean many of them have asthma and now are asthma guidelines say. Many of these patients were high-dose inhaled steroids. Now our most recent GINA guidelines say consider a trial of high-dose inhaled steroids if you really need it on the most severe asthmatics, but then really guide us to bring it down, because we now know those high-dose inhaled corticosteroids have side effects and have systemic absorption.

I do notice that many of my patients have stopped it themselves, including nasal sprays and nasal rinses. Or we definitely try and de-escalate therapy. That is a really good point, too.

Dr. Buchheit: One thing I guess we did not talk about when we would assess therapeutic response, but typically I will see these patients back at some point in the three to six month time interval, definitely at three months for people who are really symptomatic or have poorly controlled asthma as well, or who are getting a lot of systemic corticosteroid, sometimes I will see a patient who is really just predominantly a patient back at the six month time frame. But assessing in that time frame, I think is quite helpful. It gives the drug a good amount of time to work, and for you to really get a sense of whether or not they are getting benefit from it.

Dr. Peters: I totally agree. It is interesting because many patients respond with just even one injection within weeks, their sense of smell will come back or start returning. If they have severe asthma, I will see them sometimes even follow up in six weeks three months nasal polyp wants to. If I start them on biologics, I will see them back initially at three months, then six months. Then over time now it has become yearly and some of these patients.

All right, let us move on to the next one. How and when do you decide to switch to a different therapeutic target?

Dr. Buchheit: Yeah. This is I think, an area where there is not a ton of evidence to guide us necessarily. It depends a little bit for me, obviously on what drugs the patient has tried. Specifically, what biologic the patient has tried. If somebody after six months really has had no benefit at all and they are still quite symptomatic, they do not think that their sense of smell has improved. They do not see that the congestion is any better or mucus production is less. Then they see my colleagues in otolaryngology. Really, there is no change in the endoscopic inflammation that they note, we will consider switching to a different biologic.

For folks who have been on either omalizumab or mepolizumab for polyps specifically, there is good evidence suggesting that if you make the switch from that to dupilumab, that they have some likelihood of improving symptomatically. I think that there is less evidence of switch benefit the other direction. For patients who do not do particularly well on dupilumab, there is less evidence to suggest that switching from dupilumab to mepolizumab or to omalizumab leads to improvement.

That said, anecdotally, I have had patients where I have made switch from agents in all different directions, and I have seen folks who do not respond to one specific one that do beautifully well on a different one. I think that if there is reason to believe either looking at biomarkers, or just clinically knowing your patient and thinking about what is going on, I think it is a reasonable thing to consider.

Dr. Smith: I will say that I am typically working together closely with our allergist and immunologist if we think about switching to a different biologic, to be honest. I think I have seen it switched when perhaps or concerned about rising eosinophil counts. If Anju can speak to that. But otherwise, yeah, I think we give it four to six months typically before thinking that a particular biologic is not effective for the nasal polyps alone.

Dr. Peters: That is exactly. Katie, what you said is, and Stephanie what you said. Mostly we switch patients from omalizumab or mepolizumab to dupilumab. There is definitely evidence for that. But like you said, anecdotally, switching the other way around may work. I think side effects is become more of a reason I have been switching recently. As these biologics have been around, they all work really well, especially in asthma. In nasal polyps, dupilumab does work better than mepolizumab or omalizumab based on great evidence.

But we also do see even though the side effect profile is very safe, there are people who might get arthralgias. There are people who get rashes. If their eosinophilic counts are going really high, and I am concerned that there may be something potentially that EGPA may be in the differential. Those that have abnormal chest CTs or severe asthma, that is getting harder to control on dupilumab all of a sudden and their EOs[?] are going really sky high, I may switch them to mepolizumab and get them evaluated for EGPA.

I am sure you have the same, Katie. I have like three or four patients who are actually on dual biologics, and these are my patients who then went on to develop EGPA. They often for their sinus symptoms are still on dupilumab. But we are also using higher dose anti-IL-5 or 300 milligram mepolizumab or benralizumab to treat their other EGPA manifestations. Rarely dual biologics. Switching them is clinically if they do not do as well.

The next thing that we can talk about is how do you compare these different biologics, especially tezepelumab has amazing data that was published in New England Journal of Medicine in February, how we would compare that to other biologics that target, for example, IL-5.

I think many of us who have been treating asthma with tezepelumab would say we are using asthma as an indication to treat their nasal polyps already. But what do you think? How would you compare, Katie? Because I know you probably have been using quite a bit of tezepelumab.

Dr. Buchheit: Yeah, no, that is a good point. Yes, I think you bring up a good point that for some time now, we have had tezepelumab available to treat asthma. I think since the end of 2021. We have had several years of experience with it. I have a number of patients who have asthma who also have chronic rhinosinusitis with nasal polyps. For a variety of reasons, often, generally side effects, actually, we have had to switch them from another biologic to tezepelumab.

I will say that, again, this is anecdotal, but they have done beautifully well. Continued benefit in terms of both their upper and lower airway symptoms. What has really been great is to actually see the published data from the phase III studies, really reiterating and supporting what we have seen clinically now for a few years with those folks.

I think it is a great option. The data from the phase III study is I think what is really impressive about it is that, yes, it reduces nasal polyps size and improves patient's nasal congestion. There are also pretty substantial improvements in smell, which is something that we see most with dupilumab compared to the other biologics that are currently available that target type 2 cytokines or IgE. That is another exciting thing about targeting TSLP specifically for patients with nasal polyps.

Dr. Peters: I think the fact that in that study that only one person ended up needing surgery who was in the tezepelumab group, as I think I recall. Quality of life with SNOT-22 improved. We do not want to compare these biologics because this was not a direct comparison. But if you just look at all of these different studies and look at how much their SNOT-22 improved, it appears that tezepelumab had more SNOT-22 improvement than the other biologics did in their phase III studies. I do think this is another good option for our patients.

Dr. Buchheit: Yeah, 100%. I think an important caveat is the patients in that study. They did start off with a higher SNOT-22 level. Maybe there was more room for improvement. But I do think that it is super impressive.

You bring up I think a really good point, which is that, and I tell this to all my patients, there is no head to head studies comparing these drugs where we have all the data and results available now. There will be more data coming in that space in the future, which is exciting. I am really looking forward to that.

It really is important to consider differences in the study design and just the patient populations that we are seeing. I think being careful not to directly compare them but get excited about some findings like patients having come back and their symptoms get so much better is definitely something that we can do.

Dr. Peters: Yeah, I think there might be a publication that is comparing like you said. It is I think in press already.

Dr. Buchheit: Yeah.

Dr. Peters: But you know what? They are all phase III studies. They were all similar type of severity. There were small differences in terms of surgery and what their baseline polyp size was, but very similar. I think the more exciting part is that we have another treatment option for our patients with CRS with wNP.

We have been talking about tezepelumab and its positive data that was recently published in New England Journal of Medicine. However, we have a few others that are in the pipeline, including depemokimab which targets IL-5. As you can imagine, there may be some benefits to it. Stephanie, how would you see it in some of our patients that we manage together?

Dr. Smith: I think that one of the highlights of that drug potentially is the Q six-month injection that may be more appealing to patients who shy away from every two to four week injections.

Dr. Peters: Yeah. Katie, I know you have published anti-IL5 effects. We have been on actually the same manuscript that potentially these anti-IL-5 drugs target other cells than just eosinophils. Do you want to comment on that a bit?

Dr. Buchheit: Sure. I can comment on that briefly. I am not caring for patients with nasal polyps, I am really excited about understanding the immune biology of nasal polyps and using these biologics to really knock out, if you will, specific cytokines or markers in patients with nasal polyps. We have learned that IL-5 receptor is expressed on a lot of different cells in nasal polyp tissue.

I think there is emerging evidence that blocking IL-5 has impacts beyond just impacting eosinophil levels and tissue eosinophils and whatnot. It is possible that these drugs are acting through multiple pathways, which makes sense.

We see that even in patients with AERD specifically treating them with an anti-IL-5, we see over time, normalization of the epithelial barrier and improvement in cell to cell adhesion, cilium organization, tight junction transcripts. One, it is a cool time to learn more about nasal polyps and what is driving it. But two, it is an amazing time to learn more about how these drugs are impacting our patients at the cellular and molecular level.

I am excited about learning more about depemokimab, how it works clinically and also mechanistically. I agree with Stephanie that there are folks who would be really happy about Q six-month dosing. I always think about I am in Boston where it is cold. I think about my snowbirds who are spending the winter somewhere warm and want to get it right before they go and when they come back, or college students where, it is hard for them to get injectable medications to them sometimes, or they do not want to do it by themselves away at school. For those folks, every six month drug is really attractive too.

Dr. Peters: Yeah, I think that is a really good point. The other point you mentioned that made me think about it. We have talked about targeting TSLP. There are other alarmins that are being targeted with anti-IL-33. One of the things we think when you target these alarmins, you get broader dampening of the inflammation but improving the epithelial barrier dysfunction which we think underlies a lot of this information, which hopefully these biologics all kind of help with it. But certainly I would think that targeting TSLP and IL-33 probably would do more so. But we will have to understand that a lot more as more studies happen.

Dr. Buchheit: Yeah. No, I think from a translational science point, a really interesting time to learn a lot more about how these drugs function. The work that Stephanie is doing, where you are debulking and removing this polyp tissue, it is an amazing opportunity for scientists to really, I think, study it and understand more about type 2 inflammation and then more about how these interventions are impacting people again, at the immune system level.

Dr. Peters: Absolutely. I mean, again, I know Stephanie, you are the surgeon, but Stephanie and my other surgery colleagues have published and others have published that we know biologics decrease type 2 inflammation. We have plenty of evidence for that, but even surgery decreases type 2 inflammation and potentially modifies how, if you do not have asthma, potentially you have decreased risk of asthma. We know biologics treat both upper and lower airways but so does surgery.

I just think it is so exciting for our patients who we used to have just courses of systemic steroids after systemic steroids. Multiple surgeries now do well with one surgery. If disease comes back, they go on biologics. Many do find just with surgery.

Dr. Buchheit: I guess I have a question maybe for both you and Stephanie about that is, and there need to be more studies in this area. But if you have a patient who undergoes surgery, has a great surgery, and their polyps start recurring after surgery, is there a time point where you think is the most ideal time point at that juncture to initiate biologic therapy? I am curious about that.

Dr. Smith: Katie, most patients do quite well after surgery, but every right now just has that one patient who within one month of surgery, they have got inflammation again. I will admit that I typically treat with systemic steroids at that point and topical steroid rinses.

I do not jump to biologics immediately, but I think that future studies should help us discern what is the appropriate timing. We do also have access to implantable steroid eluting stents that we will sometimes consider in those early recurrences. I do not have an exact time point, but probably looking at maybe the three-month mark is where I would typically start thinking about altering the course.

Dr. Peters: I agree with you. You never know who is going to recur when. When we look at the multicenter DeConde study, they had recurrence quite soon, within a month, three months, and they looked up to 18 months. It appeared 40-some-percent of people recur. But other surgical studies do not show such high recurrence rate.

I tell my patients and I tell my colleagues, just because you are seeing polyp recurrence after surgery does not mean we have to rush to biologics, because many of them, if their polyps stay small and are not that bothered by it, we can just treat them with topical steroids, EDS-FLU, steroid rinses, etc.

I think in three months if they start having more symptoms, especially if they have asthma, then I start thinking of introducing biologics in those patients.

Dr. Buchheit: Yeah.

Dr. Peters: Well, thank you very much for joining me. This was quite informative for me as well.

Dr. Smith: Thank you.

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