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BackTable / ENT / Podcast / Transcript #46
Podcast Transcript: Biologics for Nasal Polyps: What’s the Role?
with Dr. Cecelia Damask and Dr. Matthew Ryan
We talk with Dr. Cecelia Damask and Dr. Matt Ryan about the role of Biologics for Nasal Polyps, including patient selection and its place in the treatment plan. You can read the full transcript below and listen to this episode here on BackTable.com.
Table of Contents
(1) The Basics of Biologics and Immunomodulators
(2) Phenotypes and Endotypes of Chronic Rhinosinusitis
(3) Stratifying Patients to Determine Candidacy for Biologics Treatment
(4) Development of Criteria to Recognize T2 Mediated Inflammation
(5) Biologics for Surgery Naive Patients
(6) Steroids for Nasal Polyps
(7) Consulting with Patients About Biologics
(8) Side Effects of Common Biologics
(9) Differences Between Dupilumab, Mepolizumab, and Omalizumab
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[Ashley Agan MD]
Quick introductions. My name is Ashley Agan, and I'm a general ENT in Dallas, Texas.
[Gopi Shah MD]
And my name is Gopi Shaw. I'm a pediatric ENT at UT Southwestern in Dallas, Texas as well. How are you doing this morning Ash?
[Ashley Agan MD]
I'm great. How are you, Gopi?
[Gopi Shah MD]
I'm doing good. Enjoying a little bit of an extra- turn back, fall back. Get the extra hour.
[Ashley Agan MD]
That’s right. Extra hour of sleep, so good.
[Gopi Shah MD]
So the one perk about it, I guess.
[Ashley Agan MD]
That's right.
[Gopi Shah MD]
Well, we have a very exciting show today. We have Dr. Matthew Ryan. He's a professor of otolaryngology at UT Southwestern in Dallas, Texas. His focus is rhinology allergy and skull-base surgery. Dr. Ryan was a past president of the AAOA and was director of CME for the AAOA for several years. You may remember him from the BackTable ENT Episode 26, Allergic Rhinitis and Immunotherapy.
He is here today with Dr. Cecilia Damask. Dr. Cecilia Damask is an otolaryngologist practicing in Lake Mary ENT and Allergy in Lake Mary, Florida. She's a fellow of the American Osteopathic College of Otolaryngology- Head Neck Surgery, as well as a fellow for the American Academy of Otolaryngologic Allergy. She serves as a national member of the Allergy and Immunology Committee for the American Academy of Otolaryngology. And they are here today to talk to us about the use of biologic agents and allergy in otolaryngology. Welcome to the show Dr. Ryan and Dr. Damask.
[Cecelia Damask MD]
Thank you.
[Matthew Ryan MD]
Thanks for having us. This is great.
[Gopi Shah MD]
I guess we'll first start out. If you could tell us a little bit about yourself and your practice.
[Cecelia Damask MD]
Sure. I am a comprehensive otolaryngologist in private practice and I do all spectrum of otolaryngology, but I have a heavy focus on allergy in my practice, and that includes other things like asthma and allergic skin conditions. And so I have a lot of experience with the various biologics and have been doing them in my practice probably, wow, for more than five years, probably for about seven years. And I also do clinical research and I was lucky enough to be a site for two of the different clinical trials for biologics for nasal polyps. I was a site for the NUCALA trial, as well as for the AstraZeneca FASENRA trial.
[Matthew Ryan MD]
Dr. Shaw, Dr. Agan. Thanks for having me, Matt Ryan here. I am a rhinologist at UT Southwest. Not born in Dallas, but raised in Dallas, went away for 20 years and came back to UT Southwestern about 14 years ago to join Brad Marple and have really enjoyed my time in Dallas and developing a rhinology and allergy practice.
And I'm excited to talk about biologics because I think the advent of these new agents is going to change our treatment approach for patients with nasal polyp disease and especially help us in situations where previously we were consigned to failure. And now we've got a new tool that's gonna help us get optimal outcomes for patients. I'm really excited to talk about this.
(1) The Basics of Biologics and Immunomodulators
[Ashley Agan MD]
Awesome. Well, let's get into it. As far as just kind of laying the groundwork for immunomodulators, biologics, what are we talking about as far as this class of medications? How do they work? How is it different than our typical kind of traditional toolkit of what we use to treat allergies?
[Matthew Ryan MD]
So I'll jump in on that one. Dr. Agan, the biologics are monoclonal antibodies that are available for the treatment of a variety of conditions. And we know about many of them through TV ads, because there's a lot of direct-to-consumer marketing being done for these monoclonal antibody therapies that can treat a range of conditions, everything from thyroid eye disease to ulcerative colitis to psoriasis, asthma, skin conditions, and now finally nasal polyp disease.
And they are very different from small molecule pharmaceutical agents that really had been the mainstay of our medical treatment approach, throughout the history of medicine. Small molecules are much easier to produce. Their dosing is in a lot of ways simpler. They can be given orally. I guess, one big distinction with these monoclonal antibody therapies, the biologics, is that they have to be administered parenterally. Usually that's intramuscular though. There are some IV preparations as well. I say intramuscular, I meant subcutaneous actually, right Dr. Damask? Yeah. So they can't be taken orally because they are essentially antibodies.
[Gopi Shah MD]
And Dr. Damask, you've been using this, you said for about the last five years of your practice, for what patients, like what indications have you been using it for in your practice?
[Cecelia Damask MD]
My gateway, I guess, to biologics and what I started with was different skin conditions. So I've been using biologics for chronic spontaneous urticaria for patients who had failed management with high doses of antihistamines to suppress their urticaria. I've been using it for other skin conditions like atopic dermatitis. So patients who have failed management with various topical steroids or calcineurin inhibitors. I have used it a lot for asthma, for allergic asthma, as well as for eosinophilic asthma or asthma that is corticosteroid dependent. And then I have a few patients that I have on biologics for EGPA or what we used to Churg-Strauss. And then most recently I have patients on biologic specifically just for nasal polyps.
[Ashley Agan MD]
For most patients, would you say traditional therapy is still the mainstay and that biologics are really more of a next tier, like when things aren't working or is this something we should be thinking about earlier?
[Matthew Ryan MD]
I would say that for most conditions, the biologics are the last line of therapy. And the reason that we see so many TV ads is because the biologics are very expensive medications. There's a lot of money involved in this. And so, in general for most chronic health conditions for which we have a biologic available, the traditional or standard therapies are really what we rely on. And so it's a select niche group of patients for whom a biologic is appropriate. And that's to some extent, I think function of the cost of these therapies. That's something that we have to consider when we're making decisions about whether or not we want to start a patient on a biologic. What are your thoughts, Cecilia?
[Cecelia Damask MD]
I agree. These are patients who we have tried traditional therapy, whether for asthma, that's doing inhaled corticosteroids or adding on a long acting beta agonist or a LAMA, and these patients are failing and requiring other systemic therapy, like systemic steroids multiple times a year to control their asthma. Then that's someone I would consider for a biologic and same with our nasal polyp patients, it’s someone who has failed other management and the biologics, at least in their PI they're listed as being add-on for maintenance therapy that have failed with intranasal corticosteroid.
[Matthew Ryan MD]
Yeah. So from a regulatory standpoint, the FDA considers them usually these agents to be an add on to other treatments and certainly from a payer standpoint, getting approval from a third-party payer for these agents usually entails documenting a failure or lack of adequate response to the traditional therapy for whatever the condition is. And I think the trade-off from a payer standpoint from a societal standpoint is that while these agents are very expensive, they are sometimes saving healthcare costs. So if you think of asthma patients and you're keeping them out of the emergency room, keeping them out of the hospital, preventing death, then they can be considered of great value if you're just looking at things monetarily.
And then the other aspect is the quality of life impact of these agents, which is difficult to quantify, but for most of these conditions, for which we have a biologic available, there is a significant number of patients who do not get adequate relief with traditional therapies. And so biologics become the thing that actually provides that quality of life benefit that we've sought for so long. And it's hard to put a price tag on that.
[Cecelia Damask MD]
You know, also Matt when you think about costs, I think one thing to think about is what would happen to patients who are on systemic steroids multiple times a year, over many years. And there have been studies that have shown things that we know like avascular necrosis of the hip and cataracts, but then there are other things like sepsis, thrombolytic events that can occur with different versus steroids. And so also controlling patients' disease better and not needing so many bursts of steroids that's also a potential savings and also definitely an improvement in their quality of life as well.
[Ashley Agan MD]
Yeah, absolutely.
[Gopi Shah MD]
In terms of, just focusing it on chronic sinusitis with nasal polyps. I wanted to get into, I feel like, I think, you know, we think of chronic sinusitis with nasal polyps as having a lot of subtypes, right? Depending on whether it's AFS, CRS with nasal polyps, AERD. Is there a certain group that this is good for? Or is this, do we think that this is gonna be beneficial to anybody with chronic sinusitis and nasal polyps? Who's going to benefit?
[Cecelia Damask MD]
So in the trials, when they did the studies, AFS was an eliminating thing that patients or subjects could not be enrolled in the trials, but there were definitely AERD patients that were in the trials. And I think to better answer that question, we kind of want to take a step back and talk about maybe phenotypes and endotypes a little bit, and talk about how to classify and potentially a new classification system of chronic rhinosinusitis.
(2) Phenotypes and Endotypes of Chronic Rhinosinusitis
[Matthew Ryan MD]
So what are the phenotypes, Cecilia, of chronic rhinosinusitis?
[Cecelia Damask MD]
Well, can we back up and talk maybe a little bit about endotypes first and just about what is T2 versus non-T2.
[Matthew Ryan MD]
Sure.
[Cecelia Damask MD]
So when we think about trying to break things down and we look at things that are T2 mediated or non-T2 mediated, things that are T2 mediated can be mediated by different cell types or different cytokines. Like the interleukin four, interleukin five, interleukin 13, and once we identify someone is potentially having a T2 endotype then we can break them down into different phenotypes.
[Matthew Ryan MD]
And the T2 and the type is that similar to Th2, right? I remember hearing about Th1 and Th2 inflammation.
[Cecelia Damask MD]
So similar ish in that there are really different ways that those pathways can be triggered. So you're right. I mean, we have our traditional pathway that we think of as being the allergic pathway where, allergens come along and can activate a mast cell to release different type two cytokines, like interleukin five, interleukin four, and interleukin 13, and then interleukin four can cause B cell class switching and production of IgE. Interleukin five is important for eosinophils and basically tells eosinophils everything to do like mature, to proliferate. And then interleukin 13, we know is involved in things like mucous response or remodeling or cell recruitment, but those same cytokines can be activated by other things. Besides the Th2 cell, they can be activated in an allergy independent manner by this thing called an ILC2 cell.
[Matthew Ryan MD]
So, but otherwise for our purposes, T2, Th2, are almost synonymous. It sounds like. It's the same group of cytokines that are involved.
[Cecelia Damask MD] Yeah. Same group of cytokines.
[Matthew Ryan MD]
And Dr. Agan to get to your question, since we're talking about inflammatory endotypes, the biologics that we have available for treatment of CRS with polyps are specific for those type two cytokines, IL-4 and 13, IL-5 and IgE. And so, I think if we're trying to decide who a biologics for, we want to try to identify a type two endotype and maybe in our discussion, we'll get to that.
But I wanted you to talk about phenotypes, Dr. Damask. The phenotypes of CRS. How's that different from endotype?
[Cecelia Damask MD]
So a phenotype is something that you can observe. It's an observable characteristic, whereas an endotype is a mechanism of how something happened. So a phenotype is something that we could look in and say, oh, we see polyps, or we don't see polyps. But in terms of CRS with NP, different phenotypes would be something like CCAD or AFRS or eosinophilic CRS.
(3) Stratifying Patients to Determine Candidacy for Biologics Treatment
[Ashley Agan MD]
So how do we stratify patients into whether they're a T2 endotype so that we can know, okay, they're a candidate for biologics? Should we be getting labs? Is it based on what our clinical exam looks like? How do we know?
[Cecelia Damask MD]
So I think there are some things that we can see in clinic that might clue us in to someone being a type two patient. And then yes, there are laboratory studies or pathology specimen, but we're not going to have that available to us in a clinical setting. But I think biggest indicators is if someone is steroid responsive. And so if they have a good response to a steroid, then that is someone who most likely has T2 mediated disease.
[Ashley Agan MD]
And does a Medrol dose pack count? Are we talking like a larger dos of prednisone, any steroid?
[Cecelia Damask MD]
Any steroid. Someone that’s steroid responsive most likely has some T2 mediated disease.
[Matthew Ryan MD]
And the other thing I look at Dr. Agan is, if someone does have a history of allergic rhinitis or has a history of asthma, I think those can, sort of point to a type two. There are some labs that I will draw. So I'll get a total serum IgE and I'll get a CBC with diff to look at the peripheral eosinophil count. And in general, if I see really high total serum IgE, or I see a really high peripheral eosinophil count, that makes me think type two. That's not set in stone by any means. I will say for some of the clinical trials of these biologics, they did have certain thresholds for, let's say, an eosinophil count to be accepted into the trial because these agents, some of them, Dr. Damask, I think, can tell us more precisely, but some of them are specifically for CRS with nasal polyps, with an eosinophilic component.
[Cecelia Damask MD]
Definitely for the trials for asthma, they had to have certain cutoffs of peripheral eosinophil levels to be involved in the trials. For omalizumab, for nasal polyps, they did have to have a minimum IgE level of 30 or above, but for the dupilumab and for the Mepo trials, there was no minimum requirement of peripheral eosinophilia. However, when they have done post hoc analysis and looked at response, like in the Mepo trial, they saw that patients who– post hoc, so this is not in the actual trial, but this is analysis afterwards– patients who had peripheral eosinophils over 300, they had a larger improvement in their nasal polyp score or improvement in less need for systemic steroids if their peripherally eosinophils were over 300.
[Matthew Ryan MD]
So that's an interesting thing, so that these trials enrolled people that perhaps didn't have type two inflammation as the etiology of their polyps and for us as clinicians, if we want to get the best results, we need to try to specifically identify those patients who have type two inflammation as the driver and in those folks we can see dramatic improvement.
So there are a variety of other forms of nasal polyp disease that are not type two. So you can think about cystic fibrosis as a great example. So in cystic fibrosis, the development of nasal polyps in those patients is not necessarily driven by abnormal eosinophilic inflammation going on. And so their problem oftentimes is as a consequence of disrupted mucociliary clearance, they have colonization with various bacteria that promote inflammation and a CF patient doesn't necessarily get that great of a benefit with nasal polyps. Do they, or with steroids, do they Dr. Shah?
[Gopi Shah MD]
No, I mean, we traditionally think that they're oral steroid resistant. The polyps don't respond as well. That being said, in terms of topical steroids, we will recommend Flonase or sometimes Pulmicort rinses topically.
[Matthew Ryan MD]
So that's just an example of case of nasal polyps that’s not steroid responsive and type two mediated, and we see the same pattern in adults. That can be sometimes a challenge, but we do see adults with nasal polyps, but they don't respond well to steroids. If you look at them endoscopically, sometimes you'll see some creamy white pus interdigitating among the polyps. It's very different from AFS where we see eosinophilic mucin. So there are some clinical clues. But I think as Dr. Damask mentioned the trial of steroids and assessing steroid treatment responses, a great way to identify the type two polyps.
[Ashley Agan MD]
It also sounds like it would be helpful too, to screen and ask about things like asthma and, skin things, you know, like asking you, do you also happen to have a atopic dermatitis and asthma because if that's positive as well, it sounds like you're leaning more towards, okay, this is a type two patient.
[Cecelia Damask MD]
Exactly.
(4) Development of Criteria to Recognize T2 Mediated Inflammation
[Gopi Shah MD]
Do you think we'll have criteria that develop eventually to help us kind of say, okay, these are the four things we need to say you're type two or not?
[Matthew Ryan MD]
What does the EPOS document say on that or the EUFOREA document? There are some European position papers that have come out, they tend to be really broad in their approach. So they're very inclusive in terms of who should potentially qualify for treatment with a biologic. But there are some criteria that are mentioned in those documents.
[Cecelia Damask MD]
So in EPOS, they listed several different criteria for consideration. And one was a diagnosis of comorbid asthma. One was a significant loss of smell. So anosmia is considered also to be a marker of T2 inflammation. Another criteria was need for systemic steroids. And that was more than two courses of systemic steroids over a year. And then they listed evidence of type two inflammation and an EPOS they define that as blood eos over 250 or a total IgE over 100 or tissue eos of greater than 10 per high power field. And then their last criteria was a significantly impaired quality of life having a SNOT-22 greater than 40. And so according to EPOS they said, if you have three or more of those criteria met, that could be potentially someone to consider for a biologic. If they have bilateral polyp disease and have had previous sinus surgery.
[Matthew Ryan MD]
So somewhat complicated. I think Dr. Agan.
[Ashley Agan MD]
For sure.
[Matthew Ryan MD]
And those are pretty broad inclusion criteria and a peripheral eosinophil count of 250 is within the normal range at our laboratory. That's not what you would consider peripheral eosinophilia by any means.
[Ashley Agan MD]
And when we're talking about tissue eosinophils, is that like a biopsy of polyps in the nose, like from maybe from your sinus surgery that you did or something.
[Matthew Ryan MD]
Yeah, that's based on a surgical specimen. I suppose you could do an office biopsy of a polyp in clinic and use that, but there's a lot of trickiness to that approach. And part of it has to do with sampling, because if you just take a patient who has a nose full of polyps, those polyps are not all the same. They can be quite different. Both grossly and histopathologically, if you look at them under a microscope and where you choose to start counting eosinophils, I think really matters. And so the eosinophils are not necessarily evenly distributed. So it's a tricky thing, and I will tell you our pathologists don't do that. They do not count eosinophils.
[Gopi Shah MD]
I was going to say, do you have to ask them because I don't think I've ever seen that on a report.
[Matthew Ryan MD]
Yeah, there are some medical centers where they're able to work with the pathologist and the pathologist will count eosinophils per high powered field. And there are other disease states in which that sort of approach is standard. So for example, eosinophilic esophagitis with an esophageal biopsy, that's pretty, well-defined what constitutes an abnormal eosinophilia. And we just don't have that yet for nasal polyps. So I don't use that personally, but some people do.
(5) Biologics for Surgery Naive Patients
[Gopi Shah MD]
Okay, so we've had a patient and they come to your clinic. They have nasal polyps, you know, there's a history of asthma. There's some loss of smell. You try them on steroids, they get better, but let's say it's been three months and they're back to see you and their nose is full again. Let's say they’re sinus surgery naive. Is a biologic in your armamentarium just yet? Or, what's your management now? How is biologics weaved into your treatment plans for these patients?
[Matthew Ryan MD]
I'm a sinus surgeon. And so I'll give you my perspective, but I want to hear what Dr. Damask has to say about a surgery naive patient with a temporary response to systemic steroid treatment. How do you bring up this issue of biologics as the next step?
[Cecelia Damask MD]
So with patients, it is a discussion and I do try to encourage patients to have sinus surgery, because this is going to be an ongoing disease that we're going to need to manage. And I want to be able to deliver good topical therapy for them. And I think the best way to do that is to have a good sinus surgery so that we can then better administer topical therapy because we know just doing an intranasal steroids spray, most of it ends up on the inferior turbinate or on the floor. And unless the patient has really bad asthma that isn't controlled, that I would be thinking about a biologic for their asthma, or unless they had a lot of other comorbid conditions that would preclude them from surgery, I typically am going to recommend surgery in a surgery naive patient.
[Matthew Ryan MD]
And I feel the same way Dr. Agan. In general, the treatment for CRS with polyps is topical intranasal steroids, saline irrigations, and a brief courses of systemic steroids. And if I'm seeing a patient initially. And I give them my standard prednisone taper along with intranasal steroids and saline, and those polyps melt away and they do well, we will just follow that patient over time. And if they do start coming back every three months with regrown polyps, that's when, certainly in my mind, surgery is the next step. And the goal of surgery is not just to remove polyps, but to create wide sinus openings for all of the sinuses so that topical steroids can be delivered. And I think of this somewhat like asthma, where in asthma, the primary maintenance therapy is inhaled steroids. And you're delivering the steroid medication down into the small airways exactly where the problem is. We'd like to do the same thing with our polyp patients. And so we need complete surgery so that the steroid that the patient squirts up their nose can get onto all the mucosal services and we can control that inflammation. And so that is my standard treatment approach. And I think is the right one and, and the most cost effective one.
There might be some select circumstances where a surgery is not the right thing. And Dr. Damask mentioned some of that, the co-morbidities that make surgery inadvisable. So a great example would be a patient with a mechanical heart valve who has to be chronically anticoagulated. And they can only be off their anticoagulation for the time of surgery and otherwise need to be back on their standard anticoagulation regimen immediately after surgery. I would treat that patient with a biologic rather than say, just because of the risk of postoperative hemorrhage. so there are some examples like that.
I will tell you, given my track record of doing sinus surgery and watching patients come back with recurrent inflammation and being frustrated by it. I do feel like I've detected a pattern where I can recognize those patients who are going to not do well long-term after surgery. And those are patients who have severe asthma and also have sky high peripheral eosinophil count, like a thousand or more. And so if I'm seeing someone with severe asthma and nasal polyps, and they've got a peripheral eosinophil count over a thousand, I will talk to them about biologics and as an option other than surgery, primarily because I think with those patients, I'm likely to do surgery and ended up starting them on a biologic anyway. And so we can skip the whole surgery part if there's someone like that. But those are pretty rare patients, I would say.
[Ashley Agan MD]
And you, you mentioned your topical nasal steroids. I was just curious since we're talking about it, do you have a topical steroid of choice? And how do you like to deliver it?
(6) Steroids for Nasal Polyps
[Cecelia Damask MD]
So, I mean, I'll do budesonide irrigation. Also, if a patient doesn't like it in that it's not convenient and it takes a lot of time, they travel a lot and they don't want to have to do rinses or irrigations, I will do the EDS fluticasone device.
[Matthew Ryan MD]
Which is called EXHANCE.
[Ashley Agan MD] That's the one where you kind of blow it into your nose so that it, that distribution is supposedly better. Right?
[Matthew Ryan MD]
Yeah, it's this cool asthma inhaler type thing, but you blow a while having the things stuck in your nose and it's essentially double dosed flow now. So that's, that's what it is from a molecular standpoint, but the device distributes the medicine in a way that's much better than a standard Flonase or any other allergy nose spray kind of device. And they've got actual data. We do a lot of off-label stuff, putting steroids up the nose. They've got actual data that shows that their product works for nasal polyps compared to placebo. So they're kind of ahead of the game in that.
I personally like to use budesonide full strength as a nasal drop with the patient having their head inverted and there are a lot of patients that don't like that because it's a hassle to do it from a positioning standpoint. The budesonide vial has two milliliters in it. And so you're essentially putting one milliliter up each nostril, and that's a lot of liquid to go up your nose. If you compare that to a standard nasal steroid spray that has about a hundred microliters per puff. And so, for those patients that don't like doing the budesonide just as a drop up there knows I'll go to the EXHANCE as a much better tolerated treatment approach. I'm not sure which works better though. No idea there.
[Gopi Shah MD]
You said budesonide full dose. It comes in 0.25 milligrams per mL, 0.5 milligrams per mL, 1 [milligram per mL]. Is your go-to 0.25? What's full dose for you?
[Matthew Ryan MD]
Well, I use the 0.5 and that's the most cost-effective for most patients because that's generic. I do have some patients I've gone up to the one milligram dose, but I think that's still branded. And so there can be problems getting that reimbursed or insurance companies balk at that. But anyway, high-dose steroids are the name of the game for the treatment of most patients with nasal polyps. And we can get great treatment results with that for the vast majority of people.
[Ashley Agan MD]
Just to kind of continue to elaborate on that. What is your high dose steroid burst for these patients?
[Matthew Ryan MD]
Well, my standard prednisone taper is 20 days long. And it is 40 milligrams a day for five days, then 30 milligrams a day for five days and then 20 and then 10. And it's very arbitrary. That's what I use for the majority of people. If there are patients who have had adverse responses to systemic steroids, I might go lower. If there's someone who's really big, we have a more powerful taper that's approximately 16 days. So it's a little bit shorter, but we hold them at 60 milligrams for nine days straight. And that's a lot of steroid and there have now been some recommendations that have come out quantifying safe a maximum amount of steroid per year. And I think with my standard treatment approach, if I'm using my 20 day taper three times a year on someone, I am significantly exceeding that. And that's when I've got to be thinking about other treatment approaches.
[Cecelia Damask MD]
I also do 40, but I only do three days at a time. So mine's 12. So I taper down over 12 days.
(7) Consulting with Patients About Biologics
[Ashley Agan MD]
So, yeah, I think continuing with this patient that we were kind of using as our example patient, now that they're back, they've had sinus surgery and we're starting to think of biologics. How does that conversation go?
[Gopi Shah MD]
Yeah. What are the side effects? What do you tell them? How do they do it?
[Matthew Ryan MD]
Well, so if our patient with CRS with polyps and asthma goes through the standard treatment paradigm, I do my surgery on them, start them on high dose steroids and they come back one or two months later and they already have polypoid edema filling their ethmoid cavity and they're starting to notice more mucus secretions, maybe their sense of smell goes away again. Then I'm really frustrated because I'm in a situation where I'm having to give them yet again, another round of systemic steroids. And I'm kind of expecting that it's only going to work for a little.
[Cecelia Damask MD]
Yeah.
[Matthew Ryan MD]
And they're going to be back where they started again and ultimately left alone over time. They're going to regrow their polyps and not only lose their sense of smell, but also become congested and they to have nasal airway obstruction. And I certainly, in my practice, have some nice examples of exactly that scenario, where the patient is coming back after surgery every few months, and I'm giving them more and more steroids. And, we know that's not good. And even if the patient doesn't get any side effects from those steroid bursts, it's not a good treatment approach for a disease that could last 10 years or longer. And so that is precisely the patient in whom I will recommend a biologic and prescribe a biologic.
[Ashley Agan MD]
Cecilia, maybe you can elaborate on what that conversation looks like with the patient. And it sounds like that there's going to be a need for insurance pre-authorization regardless. And, you know, as a patient, I'm sure their concerns are gonna be, how much is this going to cost? Am I going to be on this forever? Is it a pill or do I have to inject? All those types of things I'm sure come up.
[Cecelia Damask MD]
So there are multiple factors and different types of biologics that the patients can be put on. So it is an actual long conversation with a patient to try to decide which one. And then even once we decide which one, is this something that is going to be administered in the office so I can monitor you and make sure that you're compliant, or is this something that you're going to self administer at home or someone's going to administer to you?
And then there's questions about frequency in terms of dosing. So one of them dupilumab, for everybody, is every two weeks and NUCALA or mepolizumab for everybody is every four weeks. Omalizumab can be dosed based on their IgE and their weight, and so it can be variable. It can be something that they might get every two weeks, or it could be something that they might get every four weeks. And also with the omalizumab, the number of injections can vary. So some people could get one injection, some people could get three injections every two or four weeks. So there's that discussion about frequency
And each one of the biologic companies has what I'll call a hub, where you fill out an enrollment form, which basically tells the patient's insurance. It tells some baseline things about the patient. Like they have failed with topical steroids, or they have been on so many bursts of oral steroids. And you sign it kind of like a prescription and the patient signs it saying that they give this hub permission to evaluate the patient's insurance for a benefits investigation. And then that benefits investigation will come back to the office and it will give you information about if the patient has any out-of-pockets, if they have any deductible, how much this would cost. And then also it will tell the office how the patient is to obtain the drug.
So some patients get the drug through what's called a specialty pharmacy. So it's not your local Walgreens or CVS. It's a pharmacy that specializes in taking care of medicines that require special handling because they have to be refrigerated at a, at a certain degree between two to eight degrees Celsius, like our immunotherapy and the specialty pharmacies will coordinate delivery.
Some patients, their insurance, especially our Medicare patients for some of the biologics require what's called “buy and bill.” And so that means the biologic has to be purchased by either your office or by an infusion center and then billed to the insurance. So these hubs are very helpful and we'll sort all that out for you and send it back so that then you know which way the patient would have to go for a particular biologic. And then also what those hubs will do, as long as the patient signs permission for them to do so, they will look into copay assistance or different assistance programs to help the patients. And for all the different manufacturers that are out there, they all have really wonderful copay assistance programs that help the patient, not only for the cost of the drug, but if you do administer in the office for administration in the office as well.
(8) Side Effects of Common Biologics
[Matthew Ryan MD]
So I think for commercial payers there's really minimal out-of-pocket costs for patients. So the companies have arranged it so that it's not painful financially at all for the patient. And the treatments are very expensive, but of course the insurance pays for that. It's a little different with Medicare or Medicaid, because then the copay assistance is not allowed. It's prohibited and so I have found that the biologics can be out of reach for Medicare patients because of what their expected out-of-pocket costs are. But they get back to your question, Dr. Agan, I just tell patients, this is an injection based treatment, kind of like an insulin shot and you can give it yourself at home and It's not that hard to do.
And from a side effect standpoint, these agents are, I think, extraordinarily safe. You'll see, on the TV ads, all sorts of disclaimers and warnings, tell your doctor, if you have a parasitic infection, like, okay, I'm going to do that because I know I've got parasites and so I better not start this you know, immunosuppressing biologic agent. So, the one side effect that I know of is dupilumab can cause some cornea problems, some keratitis, eye irritation, conjunctivitis type symptoms in some patients. But that's really the only practical side effect that I feel like doctors need to know about. At least with dupilumab. Now, omalizumab, mepolizumab, now also available for nasal polyps. Do those have any prominent side effects, Dr. Damask that people ought to know about?
[Cecelia Damask MD]
So for all three of them injection site reaction, you know, big surprise, was a frequent or less than 10% reported side effect. But, interesting for all three of them for nasal polyps, arthralgia was seen as a side effect. For NUCALA oropharyngeal pain came up more frequently than placebo. And for omalizumab, abdominal pain and headache also came up more frequently than placebo.
[Matthew Ryan MD]
But what have you seen in your practice, Dr. Damask? Because I've only seen the eye thing with dupilumab.
[Cecelia Damask MD]
I have seen nothing, other than injection site reactions. They have been really well tolerated. And I will say for dupilumab specifically that I will monitor their peripheral eosinophils before I start them and after I start them, because in the trial, there was some unmasking of EGPA in very small percentage, but I still will monitor. And I have not seen that happen in any of my patients.
[Matthew Ryan MD]
So in general, I would say side effect wise, these are better than steroids.
[Cecelia Damask MD]
Yes, absolutely. Oh, absolutely.
(9) Differences Between Dupilumab, Mepolizumab, and Omalizumab
[Ashley Agan MD]
And how do you pick which one? You have these three to pick from. Are there certain patients that one is better for than the other?
[Cecelia Damask MD]
That's the million dollar question.
[Matthew Ryan MD]
That is a great question. Things were so simple a year ago when all we had was dupilumab available. So the question a year ago was, should we consider a biologic in this patient? Now we have to consider if we're going to do a biologic, which one to prescribe, and we do not have head to head trials. We probably never will. And so this may be a little bit like choosing a nasal steroid spray And we all have our preferred nasal steroid spray for one reason or another. And the reasons may not be great.
[Ashley Agan MD]
And what's the difference between the three of them? Are they targeting different interleukins?
[Cecelia Damask MD]
Yes. So they are targeting different things. So like dupilumab, it targets the IL-4 receptor alpha, which then block signaling for interleukin four and interleukin 13. Omalizumab targets anti-IgE and mepolizumab targets IL-five and blocks IL-5 signaling, which then does not allow binding of IL-5 to the alpha chain receptor.
[Matthew Ryan MD]
But we don't have the ability clinically to assay for these different cytokine levels and decide that we should go after IgE or go after IL-4 as our therapeutic target. And they all work for the same kind of inflammation, the type two inflammation. The clinical trial have their nuances where there's some slight differences in terms of treatment results. And so you'll hear people say, dupilumab shrunk the polyps more than omalizumab in their clinical trials, but you can't really compare trial to trial, at least not in a scientifically rigorous way. And so ultimately we're going to be left having to make the decision. And, some of that I think might be based on, Dr. Damask, comorbid conditions that the patient has or on payers. Perhaps payers are going to start weighing in here and Blue Cross will only pay for dupilumab and Humana will only pay for mepolizumab. We might face a situation like that. But really, I don't think we have an answer to your question, Dr. Agan.
[Cecelia Damask MD]
No, I think it's hard. And then I do think dosing wise, things are different and some patients may prefer different dosing regimen. And so that is one differentiator. And you know, definitely like Dr. Ryan said it is very hard to compare them because with their trials, even the inclusion criteria for who was enrolled in the trial might be a little bit different between the different studies. And so that does make comparison very diffcult.
[Ashley Agan MD]
If a patient is an non-responder to one, is it reasonable to try them on a different one?
[Cecelia Damask MD]
Yes.
[Matthew Ryan MD]
That's done in asthma all the time, where you try one and if it doesn't work, you move on. And interestingly, what I've seen published in terms of appropriate duration of trial, if you will, is six months, which I think is outrageously long because I think with these biologics, you're going to know within a month or two, how well they're working for a patient and, and my experience with dupilumab, since that's what we've had available to us is that patients, oftentimes their sense of smell can be restored as shortly as two weeks later after starting treatment.
[Cecelia Damask MD]
Yeah. The EUFOREA guidelines say four months. But yes. And the patients do get really quick response. So like you said, in the dupilumab trial they saw the sense of smell improve as quickly as two weeks. In the Mepo trial, when they did their first reading, in terms of reporting nasal congestion, they started to see a breakaway in terms of improvement in nasal congestion. So absolutely they do definitely have a very quick onset. I agree.
[Gopi Shah MD]
And then are they on these for lifetime or is it like, okay, this is a two year thing and then we're done or okay, we're going to do it for six months, every other year?
[Matthew Ryan MD]
I heard that said. I'm at a medical meeting right now, down in San Antonio. And, that was said from the podium, if you start a biologic, they gotta be on it for life.
[Gopi Shah MD]
Do you agree?
[Matthew Ryan MD]
Well, let me ask you guys, have you ever tried to prescribe a nasal steroid spray to a patient? And they said, do I have to be on this forever? And what do you say back to them? Well, you probably say, well, let's first see if it works.
[Gopi Shah MD]
But a nasal steroid spray is over the counter, it's not injections and it's topical.
[Matthew Ryan MD]
It's the same principle though. It's the same principle in the sense that, first you find out if it's going to work for the patient and then you keep it going as long as you want to get the benefit from that particular agent. And it doesn't matter whether it's a biologic or a nasal steroid spray.
And the truth is people grow into their disease and they grow out of their disease. And so if you're giving a nasal steroid spray to a 24 year old patient, that doesn't mean they're going to be using that nasal steroid spray when they're 70, there's a good chance that their rhinitis problem's going to improve as they get older. And the same is true with nasal polyp disease. There's a natural history to the disease. It's not necessarily something you take to the grave. And so that's my retort to that lifetime treatment.
[Ashley Agan MD]
And as far as the age appropriate minimum, how old do patients need to be to be able to be a candidate for a biologic? Are pediatric patients eligible?
[Cecelia Damask MD]
For nasal polyps, it's 18 and up, but for other indications, like for asthma, several of them go down to six years of age and up, for atopic dermatitis down to six, and for hives down to 12.
[Matthew Ryan MD]
So we'll probably be seeing these biologics get a pediatric indication for polyps too. Hopefully for you, Dr. Shah.
[Gopi Shah MD]
I'm hoping. Because now I mention it to the families, you know, especially if they're a 14, 15 year old teenage kid, so that when they turn 18, I'm going to be like, please go see Dr. Matt Ryan, because there's something else we can do. And then I'm better about in pediatrics everything's very multi D and allergy immunology, pulmonary, they're all very involved, especially in the kids that have asthma, atypic dermatitis. So if they have any of those, on their problem list and I see polyps, I'll reach out to the pulmonologist or allergist, just to say, hey. Because you know, I'm not prescribing this obviously in our clinic, but many of them are. And so I have seen a handful of kids for other indications get this, and their nose is beautiful and their number of surgeries is down significantly and quality of life so much better. So I'm hopeful as well.
[Ashley Agan MD]
Yeah. I've definitely seen patients who were put on a biologic by their pulmonologist or some somebody else and who were seeing me for allergic rhinitis. And they're like, oh, I'm a hundred percent better like that's not even an issue anymore. So it's pretty amazing.
One last question as we round this out. One thing that we didn't talk about in the algorithm of working up these patients from beginning to potentially biologics is, does allergy immunotherapy, is that a branch anywhere, before you get to biologic or during, or concurrently? How does that overlap or is that opening whole nother podcast?
[Matthew Ryan MD]
That perhaps is opening a whole nother podcast. Well, I think in practice, what are people doing? I think for patients who have rhinitis, rhinosinusitis, doctors are getting allergy testing. They're starting patients on immunotherapy. With the idea that the immunotherapy might help somehow with the inflammatory disease problem and maybe help in the long-term control of something like, AFS. We just don't have high level clinical evidence that that is the case. I would say in my practice, we only would only consider immunotherapy in a patient who has clear, comorbid rhinitis that is coincidental with their CRS, with polyps. And it would kind of be a last ditch treatment approach.
So I would say before the advent of biologics, I would probably be more likely to recommend immunotherapy as another thing as we're piling on anti-histamines and leukotriene receptor antagonists, and every other non-steroid type of medication that we can throw at a patient. I think those days are over now with the advent of biologics. Because in my experience, patients who have clear type two disease, when they get started on a biologic after they've had complete sinus surgery, they do beautifully. And not only do they self discontinue all their topical intranasal treatments, but they self discontinue their asthma medications.
And so literally they're on nothing but their biologic and they feel happy as can be. And so that's the revolutionary thing that we now have available to us. It's very exciting.
[Ashley Agan MD]
Awesome. I think that's a great place to end it, unless there's any other take-home points or pearls that you guys feel like we've missed. We've covered a lot today.
[Matthew Ryan MD]
This is great. Thank you for having us, Dr. Agan.
[Cecelia Damask MD]
Thank you.
[Gopi Shah MD]
Thank you for your time. And again, very nice to meet you. Thank you for coming on Dr. Damask and of course, Dr. Ryan's always wonderful to have these conversations and see you. For our listeners, thank you for stopping by. Any new listeners, thank you for checking us out. You can find us on SoundCloud, Spotify, iTunes, Apple, and Gaana. Please follow us on Instagram and Twitter at _BackTableENT. We love feedback. Reach out to us for topics, ideas, speakers, or if you ever want to come on the show, Ash, am I missing anything?
[Ashley Agan MD]
Like, rate, and subscribe to the podcast. That's very helpful. Thanks for stopping by the show today. That's a wrap.
[Matthew Ryan MD]
Thanks you guys.
[Cecelia Damask MD]
Thank you.
Podcast Contributors
Dr. Cecelia Damask
Dr. Cecelia Damask is a practicing otolaryngologist in the Orlando, Florida area.
Dr. Matthew Ryan
Dr. Ryan is a Professor of Otolaryngology - Head and Neck Surgery at UT Southwestern Medical Center.
Dr. Gopi Shah
Dr. Gopi Shah is a pediatric otolaryngologist and the co-host of BackTable ENT.
Cite This Podcast
BackTable, LLC (Producer). (2022, February 1). Ep. 46 – Biologics for Nasal Polyps: What’s the Role? [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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