Gerry Lee, MD (Host): Hello, everyone. And welcome to another episode of Allergy Talk, a roundup of the field of Allergy Immunology from American College of Allergy, Asthma and Immunology. For today's episode, we'll be viewing more articles from Allergy Watch, a bimonthly publication, which provides research summaries to college members from the major journals of allergy and immunology.

And we have a video version now. So, please check us out on the YouTube channel. Thanks, Sara, at, youtube.com/alergis And don't forget about CME credit. You can earn CME credit by listening to this podcast, and head over to the learning management system at education.acai.orgy/alergytalk. And finally, we can continue the conversation on DocMatter, So, check us out on the DocMatter app.

Well, hello everyone. My name is Jerry Li. I'm an Associate Professor at Emory University and the Assistant Editor of Allergy Watch. And once again, I'm once again joined by Dr. Sham Joshi, the Editor-In-Chief of Allergy Watch, and Associate Professor and Section Chief at Oregon Health and Science University. Sham, welcome back to Allergy Talk.

Shyam Joshi: I am so excited to be here and have some really great articles to talk about.

Gerry Lee, MD (Host): And for the third chair, we are excited to be once again joined by Dr. Sara Sprie, a staff allergist immunologist at Augusta Military Medical Center, an Associate Program Director of the Allergy Immunology Fellowship at Walter Reed and Associate Professor a Pediatrics at Uniform Services University, and an Assistant at ERM Allergy Watch.

Sara, welcome back to Allergy Talk.

Sarah Spriet, DO: Great to be with you gentlemen today.

Gerry Lee, MD (Host): Well, we have some really interesting stuff coming on the pike. I am so excited about this first one selected, Tom. We have new bispecific molecules to treat asthma. Tell us all about it.

Shyam Joshi: Yeah. This is an article that stood out to me just because we have so many new things that are coming down the pipeline. And I think this is one of the ones I'm most excited about. So, the article name was A proof of mechanism Trial in Asthma with lensicamig,

I think I pronounced that correctly, a bispecific nanobody molecule. And so, it was a paper that was written in the European Respiratory Journal and reviewed by one of our assistant editors in Allergy Watch, Tim Chao. I do want to note that this study was funded by Sanofi. It was a phase 1b single dose study to evaluate subcutaneous lunsicameg 400 milligrams versus placebo. And what's interesting about this molecule is it's not a monoclonal antibody. It's has high affinity variable domains that can be strung together. So, these are essentially the variable regions of our monoclonal antibodies that you can string together in a pretty long sequence. And what they're trying to do here is include an anti–IL-13 component and an anti- TSLP in the same molecule. So, we're inhibiting both of those pathways with a single molecule. And these domains are actually relatively small. They're about one-tenth the size of a monoclonal antibody. So, you can string these together and they're still not extremely large.

So, this was, again, like I said, a phase I, be single dose, randomized two to one, double-blind proof of mechanism study. So, it's only 36 patients, so very small right off the bat. And these were mild to moderate patients with asthma that were actually well-controlled. So, they're not at the stage yet where they're trying to take these patients that are poorly controlled. These are well-controlled patients with asthma. They had 24 patients in the treatment arm and 12 patients in the placebo. This was done for patients between the ages of 18 and 60 in Germany and the UK and nearly all the patients were white.

Most had childhood asthma and known allergic rhinitis. And they were either inhaled corticosteroid-naive, which is about 50% of the patients. these are milder patients with asthma or they're on low to medium-dose ICS. But they did have a history of bronchodilator response or bronchoconstrictor response.

To meet the criteria to get into this study, they had to have a pheno of greater than 25. So, we have some information of eosinophilic inflammation and FEV1 of greater than 60s. They didn't want anybody with severe asthma. And with the baseline population, they had an average pheno of 60, which is pretty significant, and blood eosinophil counts around 250 the patients that they selected for the study. And their FEV1 to FEC ratio was right around 0.67. And their primary endpoint, was is looking at can patients tolerate this at 71 days, right? This is a phase IB study. But their secondary endpoint was change in baseline at FeNO at day 29. They also looked at some other T2 blood markers and lung function.

And so, just want to highlight a few results here. So, they did clearly show a decrease in Pheno starting as early as day eight and continuing all the way through day 57 of about a cut of 33, which is around 53% reduction in pheno at day eight, which is really fast actually. And if you compare that to the tezepelumab phase one, two studies, they showed a decrease in FeNO of around 13 at day 29. So, 13 versus 33. Again, totally different studies, different inclusion criteria. The baseline pheno for the TESI study was they had lower baseline pheno, so you can't compare, they're not apples to apples. But it's still interesting enough, they did show a decrease in blood eosinophil counts and improvement in FEV1 as early as day eight of about 350 milliliters, which again is pretty significant. And they found that the patients that had a lower baseline FEV1 had a greater improvement, which absolutely makes sense.

But the main purpose of this study was really to look at safety. And across the board, they looked at many of the same risk factors sa- kind of markers that we're looking at for any of the biologic studies.

And the only thing that stood out was an increase in injection site reactions. About 20% of the patients on the treatment group had it versus 0% on the placebo group. That's really the only thing that stood out to me.

And so, I'm just excited, righ? In the late 2010s, we had these biologics that came in And we had a lot of options. And now, we just hadpamocumab approved. And so, with these newer molecules, inhaled anti- TSLPs coming out down the pipeline, there's just gonna be so many more options for us. And I think for patients who have had issues with other biologics or not completely treated, I think, this is a very interesting one coming down the pipeline in the next few years.

Sarah Spriet, DO: Yeah, I agree. I think that's having the ability to target multiple pathways with one nanobody is tremendously exciting and to have multiple different delivery options for it. It also look like with some of the preclinical studies that it's generally considered low immunogenicity too, right? So, we don't have to worry about the antibodies to the agent developing, which is also great.

Shyam Joshi: Yeah. I, hope it plays out with the human studies going forward that it remains the case. But it does seem like the way that they designed it.

Gerry Lee, MD (Host): I'm just gonna be so curious about what the additional benefit of blocking IL-13. gives you an above just blocking TSOP. As you know, since TSOP is upstream, a lot of the T22 cytokines maybe incorrectly, I kind of lump them together. But I'm so curious, has anyone sort of speculated what's the additional sort of bang for the buck of blocking IL-13 if blocking TSOP might help that by itself.

Shyam Joshi: Yeah. So, a quick plug for the next Allergy Talk podcast, because we're gonna talk about how anti-IL-13s also play an important role in the neuroimmune response. And by modulating the neuronal system and how it interacts with the inflamma- or the immune system can actually change. We're gonna talk more about it on the itch side of things, but they've shown in asthma as well that that interaction between eosinophils and nerve endings play an important role. And IL-13 does play an important role in how the neurons develop and could be the additional benefit. But there may be some others that I'm not aware of as- as well.

Gerry Lee, MD (Host): I appreciate the plug. See? Now, you're locked in. You have to listen to the next one. Okay. Awesome. So anyways, no, thanks for bringing that up. And again, that's what makes this feel so exciting. There's all this new technology on how we can really make a huge difference on inflammation and get to the root cause of what caused a lot of these conditions. So, I'm very interested to see the next chapter.

Okay. Well, let's go to you, Sara. I think we're also talking about therapeutics for another disease, chronic spontaneous urticaria. We have a lot of tools, but it's always hard to choose which one is best. What does this systematic use tell us?

Sarah Spriet, DO: Yeah. Thanks for the segue, Jerry. So, this article is entitled Comparative Efficacy and Safety of Biologics and Systematic Immunomodulatory Treatments for Chronic Urticaria. It was published in Jackie in October, 2025 by Chuan colleagues. And it was reviewed by Dr. Jerry Li. As our audience knows, our current practice parameter was published in 2014. We are definitely due for the update, which is coming. And this systematic review was part of that process to support the newer practice parameter. And a total of 93 studies with more than 11,000 participants were reviewed. And these studies assessed a total of 42 interventions ranging from things like vitamin D, narrow UV band phototherapy, up to the newest, latest, greatest BTK inhibitors. And the reviewers really prioritize patient-important outcomes, including things like urticaria activity scores angioedema activity scores, quality of life and adverse events. And the quality of evidence was evaluated using the grade approach.

So, of the 93 studies, 83 of these were randomized controlled trials, and 54 included only adult subjects. A few of them included adolescents and only one had patients under 12 years of age. So, I think that's important to remember.

Standard dose omalizumab and rimrutinib were among the most effective for both urticaria activity and angioedema-free periods. I think that's an important point to take away from this article. There's only a few studies that include angioedema outcomes like angioedema scores and quality of life. And they also found that dupilumab demonstrated improvement in urticaria activity, but there wasn't outcomes related to angioedema that were significantly changed. Cyclosporine associated was associated with risk of more frequent adverse events, which is no surprise to our listeners. And none of the randomized controlled trials currently address combination therapies.

So, I think the main takeaway point from this really is this is gonna help inform clinical decision-making as we have more tools that are FDA-approved for treatment of our patients who suffer from antihistamine, refractory chronic uricaria. And I know I'm certainly looking forward to a new practice parameter as we move forward in taking care of these patients.

Gerry Lee, MD (Host): So, I'm just curious, I think omalizumab has sort of dominated the first line, and now we see these newer agents. I would love for you, Sara, to start. I mean, for individuals who you're considering going to advanced therapy, I think, I've heard about biomarkers that predict  omelimab response. Now, that we have these other agents, do you think omalizumab is still your go- to? Are you using biomarkers to maybe suggest starting with a different agent? What has been your approach. And, I guess, what's your thoughts on these new up and coming treatments?

Sarah Spriet, DO: Yeah, Thanks for that question. I do get biomarkers for most of my refractory patients to include total IgE. I like to see where their eosinophil count is to begin with. Look at their besophil count as well. I'm still starting with standard dose omalizumab in my practice. And checking for treatment response after the third month. And then, we make a shared decision if they're refractory. Are we up dosing the omalizumab? If there's a strong preference for oral therapy, would likely opt for a rimbrutinib sooner than later. But I think all of that would be in the context of shared decision-making.

Shyam Joshi: Yeah. It's a tough question and something that we were just talking to our fellows about the other day, because we reviewed a very similar article for our journal club. And think I'm very similar to Sarah that I'm not ordering testing right off the bat for most of my patients unless they're really refractory, because I don't know if there's enough information out there about how the biomarkers really affect our decision-making yet. I think we all want biomarkers to be more relevant. We're just not quite there yet.

The a- YACI guidelines clearly state that, yes, you should be getting some basic lab work, right? A CBC and IgE inflammatory markers, thing like that. and curious to see what the joint task force is gonna come out with in terms of recommendations. I do think IgE has some predictive value depending on who you ask. But I do think does play potentially a role in trying to push the dose of omalizumab, which I do think is very underutilized.

think it's a problem because every other omalizumab indication is weigh-based and IgE-based. And then, for a chronic urticaria, we're like, "Oh, it doesn't matter." But it does matter. We know that patients who are obese, patients who are older, they generally require a higher dose. And if you push the dose, you can get very good response. I usually don't go above 600 every four weeks or 300 every two weeks The- There doesn't seem to be much data to support anything higher than that. But up to there, I still find it really helpful.

Gerry Lee, MD (Host): Yeah. I think we certainly need guidance with the practice parameters. We do need more systemic reviews about what best to do. So, I really appreciate reading these articles you y'all sharing your advice. I think my approach has been very similar to yours. Obviously, with omalizumab refractory patients, we do have choices. We do the shared decision-making, I think updosing omalizumab definitely has been what my first choice is. Though, I have to say that part of that probably is how I present remibrutinib. I think obviously, when you talk about shared decision-making, at least my patient population, probably an inner city population, not really excited about new things as much as maybe other populations. I think that I'm just gonna speak individually. I think speed is something people care about, unfortunately. As, you know, bupima may take a litle bit longer, and I do tell people that. So, I think every patient has their own individual preference. And again, I just give them the information I know. And then, as you know, e- everyone's gonna make a different decision based on their preferences.

So, again, I think we're gonna continue these conversations. Certainly, I'm just excited that we have all these treatments available versus the dark-ages where I was given people like cyclosporine or something. Does that make sense? Like we have definitely progressed, which is fantastic.

Okay, well, I want to round this out, this sort of biologic, themed episode with one more article. And this one is entitled Food Allergy Clinical Course in Children and Adolescents Treated With Dupilumab for Atopic Dermatitis. This was published in anals, and this is coming out of Vanderbilt.

And so, I think we have talked about all the indications for biologics like dupilumab. We use it for a lot of the conditions we use, asthma and nasal polyps and eczema and atopic dermatitis. And we've all noticed the one that is missing is fu- ... Well, I mean, rhinitis, but we're not gonna treat it with a runny nose. But like food allergy, right? Food allergy is the one that's missing. And last year, think we all saw that phase two trial that was published in Allergy, that they attempted the peanut to treat children with peanut allergy. And unfortunately, there was only two patients who responded to the medication, which was unfortunately considered a failure after 24 weeks of dupilumab.

But another part of that study showed that there was a significant drop in their total IgE and their peanut IG. And so, this is sort of raises this point that we're noticing that, yes, if you give dupilumab therapy, there seems to be a disconnect between clinical reactivity and testing. And I think this study wanted to add to that literature. And so, this is a study looking at 60 children, six-months to 18 years of age who had food allergy. And so, they had skin prick testing and IgE testing. These patients received treatment for a significant amount of time. I think the median range of treatment for  tepima for the skin prick test was 14 months. And then, for the specific IG, was 17 months. And as expected, just like the previous phase II trial, there was a sig- significant reduction in the allergy test to the food with dupilumab treatment. So, the mean reduction in specific IgE was 66.4%. And skin prick test did decrease as well, but at a lesser extent, which was 28%.

Now, what was also interesting is the trend over time and what the trend over time showed was that for every month of treatment of dupilumab, there was a 6% decrease in the specific IgE, but the skin prick test was stable. So, that was interesting, right? There was actually a disconnect between the testing over time, depending on what you used. Now in terms of the clinical reactivity question, this study wasn't equipped to measure dupilumab's effect on introducing food back in the diet. They just reported their overall pass rate for food challenges, which was 76%.

Now, overall, that aligns with other centers, just generically treatment or not giving the suggestion that because they have a pass rate similar to other centers, it probably didn't move the needle on improving that pass rate. I think obviously the study wasn't designed to measure that, but they're sort of making the case that at least we didn't see more patients pass food challenges with, you know, at least a year of therapy of tepilumab. So, I think the conclusion from this study was that we often see patients with both atopic dermatitis and food allergy. And so, they want relief from their symptoms, and Dupilumab is one of those options. But then, the typical metrics we use to monitor for resolution to make decisions about oral food challenges if we're using serum IgE. Clearly, this is another story shows that disconnect where we lose the reliability of that test, you know, that declining of that test over time, which could be completely an artifact of the drug rather than showing the patient is now a- a- able to tolerate the food. Though there may be a role of skin pr- testing, at least in this study, would suggest that that was more resistant to prolonged use of this medication, though I think further studies need to be borne out. And certainly, we need to be educated about how best to carefully evaluate these patients and not erroneously assume that dupilumab is fixing their food allergy, because the testing artifact, unfortunately, is a misleading.

Shyam Joshi: Yeah, this actually came up earlier this week. I had a patient who's a kido, atopic derm on dupilumab, IgE to Peanut, was over a hundred, came back and has been on dupi for over a year now. And specific IG came back around 50. And mom was so excited and was like, "Oh, it's going the right direction. I think he's gonna outgrow his peanut allergy." And I think having data like this is important, because then we can bring it back up to the patient and be like, "Yes, the number looks better on this test, but let's do the skin testing." And unfortunately, skin testing didn't budge at all. And so, what I've seen really reflects exactly what this paper is showing and just a really important topic for clinicians to understand, because this is gonna be a common thing that we talk with patients about.

Sarah Spriet, DO: Yeah, I echo that sentiment. All my patients who are on dupilumab, I have to think about like, "Yep, that total IgE is trending downward. How do I interpret the specific IgEs?" And so, I do like having at least this paper that tells me, "Yep, stick with the skin testing. It's gonna give you a more important indicator as we follow these patients with food allergy over time, potentially."

Gerry Lee, MD (Host): Yeah, I mean, there's a certain convenience to doing blood testing and I think giving that specific number and getting the components has sort of shifted us toward blood testing. But I think we have some pretty good evidence now that we really should be doing both assessments, especially in the context of these biologics.

And I think, as long as we set upfront the expectations, then also as you're suggesting parents and caregivers will also be aware of what the testing means. Because it- it is very confusing. And I think that that's one thing that we really wanna make sure that the parents understand what's going on.

So, again, if you have thoughts on the best treatment for urticaria, about your experiences with dupilumab and food allergy or testing, we'd love to hear your comments. You can either interim, at the YouTube channel, you can email us at allergytalkword@acai.org. We will also like your feedback and your suggestions. And again, if you like what you're hearing, please rate us on Apple Podcasts or on YouTube. And don't forget, you can earn CME credit. That is education.acai.org/alergytalk, And of course, all the issues of Allergy Watch we did not review is on the main website, college.ac.orgy/publications/alergywatch. Well, I enjoy this immensely. I always learn a lot. Sara, Sham, thank you so much for the discussion. And I hope you enjoy the rest of your day.

Sarah Spriet, DO: Thanks.

Shyam Joshi: care.

Sarah Spriet, DO: fun.

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.