Gerald Lee, MD (Host): Hello everyone, and welcome to another episode of Allergy Talk, a roundup of the latest in the field of Allergy and Immunology by the American College of Allergy, Asthma and Immunology. For today's episode, we'll be reviewing some articles from Allergy Watch, a bimonthly publication, which provides research summaries to college members from the major journals in Allergy and Immunology. And don't forget about CME credit at education.acaai.org/allergytalk, and the ACAAI Community on Doc Matter, where we continue the conversations about these articles.

Well, hello again. My name is Gerry Lee. I'm an Associate Professor at Emory University, an Assistant Editor of Allergy Watch. And once again, I'm joined by the Editor-in-Chief of Allergy Watch, Dr. Stan Fineman.

Stanley M. Fineman, M.D., M.B.A: Hello and thank you. And it's great to be here. I'm Editor-in-Chief of Allergy Watch, as Gerry said. And I'm a past president of the college. I'm also an adjunct faculty at Emory.

Host: And for the third chair, we are once again joined by Dr. Timothy Chow, an Assistant Professor at UT Southwestern, an Assistant Editor at Allergy Watch. Tim, welcome back to the podcast and tell the audience a little about yourself.

Timothy Chow, MD: Yeah, it's a pleasure. I mainly do Pediatric Drug Allergy over here at UT Southwestern. And so, I've loved being a part of Allergy Watch where I mainly review respiratory journals. And so, it's great because I'm always learning new things. So, thanks again for having me.

Host: We got a great slate of articles. Stan, let's kick off with you. I think the field of epinephrine treatment for anaphylaxis has just exploded in the past year, and we have another one on the way. So, tell us about it.

Stanley M. Fineman, M.D., M.B.A: So, this was an article that was published in the Annals of Allergy in May of 2025 that's entitled, Integrated Phase I Pharmacokinetics and Pharmacodynamics of Epinephrine Administered Through Sublingual Film, Autoinjector and Manual Injection. And it was reviewed in Allergy Watch by Iris Otani. And it struck my eye because we know that epinephrine has different forms of administration. We always look to try to make it easier for our patients because we know they're kind of reluctant to carry their epinephrine autoinjectors. They're reluctant to use them.

We know that as of last year in August of 2024, we have an option of using a nasal spray, which many patients prefer, although I don't personally have any experience of a patient who used it, instead of an epinephrine autoinjector. But this is a company that has developed a sublingual film and the company is named Aquestive Therapeutics. And they're naming the product Anaphylm, and it looks kind of like a breath strip. If you get the idea of a breath strip that you put on your tongue, it's the same type of thing, and the product is called AQST‑109, or now they got a name, Anaphylm. So, this report is basically data from two randomized, open label phase I crossover trials that evaluated the PK, the pharmacokinetics, and the PD, that's the pharmacodynamics of epinephrine in 54 healthy volunteers. So, they didn't have other medical conditions. And the products that they compared were the Anaphylm, the sublingual, the pro-drug that's dropped in the tongue; the epinephrine injection by manual injection, 0.3 milligram; also, a generic EpiPen, the brand name EpiPen, and an AUVI‑Q. So, they were literally five different things that they did. And they measured the median time to maximum concentration, that's the Tmax, for the Anaphylm product was 15 minutes compared with EpiPen or generic EpiPen, which was 10 minutes and 15 minutes, and AUVI-Q, which was 30 minutes. And I didn't understand how they found this, but the manual administration of epinephrine intramuscularly was 50 minutes, like almost an hour, which we don't really see that in clinical practice, but that's what they measured in their analysis. But they felt that there was very rapid onset. The oral sublingual performed similar to the intramuscular administrations. And they felt that that was very positive.

Now, one of the things that I thought, one of the most interesting aspects of their report was the fact that they also reported on the effect of the epinephrine administrations on blood pressure, both systolic and diastolic. And we know that, when you have anaphylaxis, you get hypertension. And so, you want to try to preserve that. Well, the Anaphylm, which is that product AQST‑109, had a dramatic increase in diastolic blood pressure rapidly. Whereas the other products, you saw a decrease in your diastolic blood pressure. And with systolic, there was also a much more rapid increase in the Anaphylm than there was with the intramuscular administration.

Now, if I recall, when you did look at the studies with the nasal, again, the nasal seemed able to hold the systolic, and particularly the diastolic better than the intramuscular. And of course, people suspect that it may be related to the fact that you're giving it intramuscularly, you get a vasoconstriction and you may not get that same profound effect. It may affect absorption. And, anyway, it's just another potential administration of epinephrine. It would be a lot easier to carry around a little film. Put it on like a breath strip.

And I did want to have a shout out to Dr. Estelle Simons, who was one of the greats in our research. And that in February of 2006, that's 2006, she reported in JACI, a study where she looked at sublingual epinephrine tablets versus intramuscular injection for the treatment of anaphylaxis. Now, she did this in rabbits and she also did the PK, and found that the sublingual was a good potential. But this was obviously a totally different product. But conceptually, it's the same type of thing, using your mouth to absorb it quickly. And, you know, they're very phase one. They're not approved yet, but it's something that I think allergists need to be aware of. And maybe even tell patients, "Look, we've got intramuscular epinephrine, the autoinjectors available. We have now the nasal spray available. Down the road, hopefully, we'll have other products that make it easier for you to administer epinephrine if you need to.

Host: All the treatment options for food allergy or anaphylaxis keeps on growing and growing. It just seems to come out of nowhere. So, I'm just curious, what have your experiences been with needle-free epinephrine? Tim, what has your been experience with the product and the interest of your patients?

Timothy Chow, MD: We definitely have patients who are interested, but either are not able to kind of get it due to insurance coverage or have difficulties, or patients who sort of are interested, but also want the backup of the EpiPen. And in those settings, it's interesting to think about sort of like the cost effectiveness, especially as both providers and patients kind of increased comfort in sort of this new kind of treatment option.

Host: Yeah, I think we encounter some patients who on principle might be interested, but there's actually some security with the old standby product that they know is going to work. And also, is it worth paying more money for something that they don't use that much anyways? So, I've seen all directions of this, and I do think it's always great we're giving more choices to our patients. But, Stan, what have you seen in your patients?

Stanley M. Fineman, M.D., M.B.A: So, I really haven't had a lot of experience with patients using this product. The limited exposure that I have had with people who've had the nasal spray is that they have it and they've carried it. They haven't needed it yet, in my experience, but they always have an autoinjector as well.

Host: Yeah. And I think it's just a comfort blanket for people who are just interested, but always want that safety net, I think. As time goes on and we get more clinical experience, who knows-- the winds will change-- but just having more options sounds like a fantastic win for all of our patients, especially those who actually are not going to administer epinephrine due to fear of needles. I mean, if we can reduce that barrier, we're absolutely going to save lives with a product like this or any of the needle-free products. So, Stan, that was great.

Let's go to your article, Tim. I think we are always interested in how these new therapeutics are now allowing remission to finally happen in asthma patients. So, what is the data on tezepelumab?

Timothy Chow, MD: Yeah. So, this article title is a bit of a mouthful, but it's the Clinical Response and On-Treatment Clinical Remission with Tezepelumab in a Broad Population of Patients with Severe Uncontrolled Asthma: the Results Over Two Years from the NAVIGATOR and DESTINATION Studies. So, this was published in the European Journal, a respiratory journal in 2024. And so, as you alluded to, in severe asthma, treatment goals are evolving. So, you know, we once were focused on symptom control. But now, we're moving more towards considering possible remission.

And so, this study was led by Michael Wechsler and colleagues exploring essentially the effect of tezepelumab on clinical response and on-treatment clinical remission for this. And so, this data comes as the title mentions from these two large phase III trials. So, NAVIGATOR studied over a thousand patients with severe uncontrolled asthma that were randomized to either tezepelumab or placebo for 52 weeks. DESTINATION was then its extension and followed patients out to two years. And there's a lot of definitions for clinical response, clinical remission on-treatment, and complete remission, that sometimes it's a little bit like comparing apples to oranges across these studies when different definitions are used. And Figure 1 actually provides a really nice summary of various definitions. So, I would encourage our listeners to check that out because it's a nice kind of overview.

But in this study, the investigators defined essentially a clinical response as meeting four criteria. So, at least a 50% reduction in exacerbations, improved lung function, improved asthma control, questionnaire score, and a physician-assessed improvement as well. But then, on-treatment, clinical remission was stricter. So, what they required for that was no exacerbations, no oral steroid use, stable lung function above 95th percentile of baseline and well-controlled symptoms with an ACQ score of 1.5 or lower. And so with that in NAVIGATOR, which again was that initial 52-week study, 46 of patients on tezepelumab achieved a complete clinical response at one-year compared to 24% on placebo and an odds ratio of 2.83.

In the extension DESTINATION, there's no significant difference between clinical remission between tezepelumab and placebo groups. And so, 33% of tezepelumab-treated patients achieved on-treatment clinical remission at some point over that two-year period versus around a quarter in the placebo group. And again, that wasn't statistically significant. Forty-one percent though of those tezepelumab patients who achieved clinical remission maintained it through the end of the year. So, I think tezepelumab significantly improved clinical responses, not necessarily clinical remission rates, at least in a significant way. But of those patients who did achieve that clinical remission on tezepelumab, quite a few of them maintained it throughout the course of that, again, extension study. And so, clinical remission is going to continue to be an outcome of interest in clinicians. I think we should be familiar that different definitions exist, especially as they're beginning to appraise the literature in this manner.

Stanley M. Fineman, M.D., M.B.A: Tim, was the fact that they had 41% maintaining their clinical remission through even the end after two years of treatment and that was a pretty strict definition of clinical remission. I mean, it seems impressive to me. I mean, what do you think?

Timothy Chow, MD: No, I completely agree. Yeah, I think, again, they're pretty stringent, as you mentioned in their definition. So, the fact that this population of severe uncontrolled asthma is able to even reach that degree, I think, it's just telling of just the exciting developments that we've had in the world of asthma over the last few decades.

Host: And I am really glad that we're achieving this goal for our patients. I think a lot of people have normalized this is what asthma is. Asthma is going to involve me going to the doctor and getting oral steroids. Asthma is going to involve me having symptoms every month. And for people to achieve something where you can experience what a regular person can feel without fear of getting sick is amazing.

I think one of the things I grapple with, and I don't know how often this comes up, is once we achieve clinical remission, are we really committing this patient to continuous biologic therapy for the duration of their disease? And, as you know, what's going to come up with that discussion is when we achieve clinical remission with a biologic, that is a significant cost to that patient.

So, how do you, Tim, think about the cost of biologics with the clinical outcomes and weighing what we can offer the patient versus does the patient really want to pay for that?

Timothy Chow, MD: Yeah. That's a great question. And I think, obviously, as physicians, we have a seat at that table. Obviously, there's many other kind of stakeholders who are involved in the ultimate decision-making of that as possible. I think the hope is as we think globally of sort of the-- and again, there's been great work done within our own field by a number of different investigators-- but thinking about sort of the cost effectiveness and taking into account not just the costs of drug, in terms of avoided complications, whether it be admissions, but even risk more globally of like missed work days and missed productivity, I think that a holistic approach in terms of considering these will hopefully help us to define what, again, a healthy tension of that balance will be, and how to best kind of shepherd those resources.

Host: But I think you bring up good point. Like, sometimes we're having a narrow view of what really cost effectiveness is, but it does include quality of life and missed work days and productivity and impact to someone's productivity. So, I really appreciate that nuanced holistic approach, because I think that's the way we should be thinking about it.

 So, I got one more really interesting article. And I know this is like an older one, but it's definitely worth talking about. And this is the CAFETERIA study that came out of Mount Sinai. So, the title of the article is Peanut Oral Immunotherapy in Children With High Threshold Peanut Allergy. This was published in that New England Journal of Medicine Evidence Journal earlier in the spring of '25. And this really gets to the heart of a question we've always had regarding the food-allergic patients who don't pass a food challenge. They had a reaction, but at a pretty high threshold, right? That they were able to consume some of the food. But since they had a reaction, what is our advice to the patient? Or what are the next steps after that food challenge result?

And I think a lot of allergists, because of concerns of co-factors or the uncertainty of the environment would say, "Well, we could try again later, but that we recommend avoidance." But a lot of allergists-- and there's actually a survey that was sent out to allergists in response to a food challenge that said this, they are allowing or incorporating the food into the diet. And so, this study took that a little bit further in the context of what if you did oral immunotherapy for patients who have higher threshold food allergy. And we actually don't have a lot of data on this high-threshold population because they're usually excluded from oral immunotherapy trials. So, this was a great opportunity to say, "Okay, for the patients we've classically excluded from oral immunotherapy, what is the efficacy of oral immunotherapy?" So, the way this study worked is that they enrolled children four to 14 years of age. They underwent double blind placebo control food challenges to peanut. And the high-threshold children were defined as tolerating 143 milligrams of peanut protein. That's approximately like dose four in their challenge, but they had symptoms before the five gram peanut dose, right? Again, five grams is approximately 1-1/2 tablespoons of peanut butter.

Now, they did exclude certain patients in this study. I think one notable exclusion criteria if you had a total peanut IgE over 50. But once they identified this high-threshold population, they were randomized to either avoidance or peanut oral immunotherapy where they took that reactive dose and they dropped it 20-35%, at least one-eighth of a tablespoon of peanut butter. And then, they started daily oral immunotherapy with an up-dosing per protocol every eight weeks to achieve at least one tablespoon of peanut butter. And so, they continued that for about 72 weeks. And then, they did double-blind placebo control challenges after 72 weeks or reaching eight weeks of tolerating one tablespoon of peanut butter a day.

So, interestingly, once they identified patients who achieved desensitization on those oral immunotherapy, which, I mean, I'm just going to skip ahead, all of them did, all of them who completed the study did. I mean they had about 38 children who underwent oral immunotherapy. And 32 of the patients who made it to the end-- and again, there was some dropout due to like anxiety, GI symptoms. Again, six of the 38 did drop out. Of the 32 who did again go through the entire protocol, they all reached the last dose, which was a full 9 grams, essentially a "meal size" amount of peanut. So, they were given the option then if they wish to continue, that they would incorporate into the diet ad lib.

And so, the directions were you could eat it, not daily, but you had to eat at least two tablespoons a week of peanut butter for at least 16 weeks. And then, they did a sustained unresponsive challenge. They stopped it. And then, eight weeks later, they did a double-blind placebo-controlled challenge. And when they did that sustained unresponsiveness challenge, what they found was that 26 out of the 30 were able to meet the endpoint of 9 grams even if they missed it for two months, right? So, we have a group of individuals who were high threshold, they weren't able to tolerate 9 grams. They were able to do this oral immunotherapy protocol, and they were able to incorporate into the diet ad-lib, which was quite impressive.

Now, again, there was some natural resolution. If you look at the placebo group, I believe, I don't want to say the wrong thing, but I think there were a few individuals who did naturally. But it was obviously much greater, about only three in the placebo group achieved the nine grams in the avoidance group. But again, that means at least 27 of the avoidance groups potentially could have benefited with this oral immunotherapy and this population to incorporate into the diet.

So again, this is sort of a smaller study. I think we're all trying to figure out what's the next steps for this. But if we think about what patients want, of course, they want to be safe in their food. But if there's an option to incorporate in the diet, now recognizing this is not cure, I think that is an option we should consider offering to patients, assuming that we do the usual precautions about co-factors as well as, again, trying to make sure they are, in some ways, maintaining the desensitization. Again, eight weeks sustained unresponsiveness challenge is different from like a full remission challenge like they did in the IMPACT study.

Anyways, I thought it was a fascinating way to show evidence about this approach. And I don't know, Tim, if you've had any experience in your patients asking for this sort of treatment or have you tried this sort of strategy?

Timothy Chow, MD: Yeah, that's interesting. I personally haven't. The one thing that I will say that I feel like I run into sometimes is where patients who have kind of reached, we're on kind of that maintenance desensitization kind of dose, that sometimes there still just isn't that much interest in terms of like eating the food ad lib.

And so, what's interesting, I'd be interested to see like, obviously, a very motivated population to be in OIT, Mount Sinai. I'm interested to see just what the interest would be kind of across. I certainly don't think it's zero. I think that, like you said, it's something that a number of patients would be interested at. But I'm curious to see, yeah, just where that fits in in terms of the shared decision-making that we do and what the uptake in our patients would be.

Host: Stan, what have you seen in your practice?

Stanley M. Fineman, M.D., M.B.A: Well, I mean, patients do want to use normal natural foods, I mean, normal foods. They'd rather put small doses of peanut protein either as a powder or a peanut butter or whatever. So, I mean, the fact that they were successful with this, I think, is a major accomplishment. I'm sure other people have done similar type protocols where they used small amounts. And obviously, the patients who have higher thresholds are the ones who are less likely to have anaphylaxis. And so, they're more likely to tolerate this sort of off-label type of oral immunotherapy treatment. So, I think you have to keep that in mind too. This is not for everybody. I think this is only for the higher threshold _____.

Host: Yeah, I mean these were higher threshold individuals. They obviously had lower IgE. I neglected to mention their IgE levels. I mean, the peanut IgE levels in this population were on the lower side. I think the average peanut IgE was like 5.5 with an Ara h 2 of 3.8. So, again, I'm just trying to give you an idea of this population. And they excluded over 50. So, I think we do need to also understand who are the right individuals for this so we aren't overpromising something that, again, may not be applicablefor a different population. I do agree with Tim. We just have to get more data as well.

Stanley M. Fineman, M.D., M.B.A: It's not ready for prime time, I would guess you'd say, or for every patient. You'd have to be very selective.

Host: Okay. Well, those are the articles that we are reviewing today. If you like what you heard, go to your favorite podcast app and give us a review. I think it really helps us a lot. And then, of course, don't forget about that CME Credit. You just want to go to education.acaai.org/allergytalk. And email us any feedback about the articles we reviewed today. What is your experience with high threshold patients? I'd love to hear from you. The email is allergytalk, one word, at acaai.org. I always have fun doing this. Have a wonderful day everybody.

Disclaimer: The ACAAI is presenting this podcast for educational purposes only. It is not medical advice or intended to replace the judgment of a licensed physician. The college is not responsible for any claims related to the procedures, professionals, or products or methods discussed in the podcast. And it does not approve or endorse any products, professional services, or methods that might be referenced.