Prescribing Change: Could Omalizumab Transform Food Allergies?

"Although omalizumab is not a cure, it's a major step forward for patients as the first monoclonal antibody or biologic therapy to become FDA-approved to treat food allergy."   — Dr. Brian Vickery

Is omalizumab set to change the food allergy landscape? And how should clinicians use it in practice? On this episode of The Allergist, Dr. Mariam Hanna sits down with Dr. Brian Vickery, professor of pediatrics and chief of the Division of Allergy and Immunology at Emory University, to break down what allergists need to know about this new FDA-approved biologic for food allergies.

• What makes omalizumab a milestone treatment? The first FDA-approved biologic for food allergies, covering multiple allergens and all age groups from one year and up.

• How does it work? A deep dive into its mechanism, from intercepting free IgE to its broader immunological effects.

• The implications of the OUTMATCH trial: What the numbers really say about efficacy across different foods, including why cashew results looked weaker than peanut but might just be an artifact of study design.

• Who should consider it? A practical look at patient selection—where omalizumab might be an ideal option and where OIT or other strategies may still be preferable.

• Where do we go from here? The future of biologics in food allergy treatment, including whether other monoclonals like dupilumab could play a role down the line.

Join us as we unpack the data, the clinical applications, and the questions still left unanswered.

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The Allergist is produced for CSACI by PodCraft Productions

Transcript

Dr. Mariam Hanna:
Hello, I'm Dr. Mariam Hanna, and this is The Allergist, a show that separates myth from medicine, deciphering allergies and understanding the immune system. Everyone these days wants to talk about OIT. Is my kid eligible? They're not all the simple preschoolers with mild reactions and high thresholds however. Recently, I had a 6-year-old child who came into my office with a profound recent reaction to three bites of a bun made with buttermilk, with a background of milk allergy. She had required three doses of epinephrine because of cyanosis and hypotension, and finally had an epinephrine infusion. Background: terrible asthma. Mom was terrified, wanted to talk about OIT. I was terrified. Milk, terrible asthma. I told her, no way. Let's talk biologics. Curious thing about omalizumab—you don't have the food allergy indication in Canada, but that really hasn't stopped us from being kind of intrigued. So when a recent publication came out about omalizumab implementation in practice after the OUTMATCH trial, I pored over it, reached out to have this conversation.

And with that, it's my pleasure to introduce Dr. Brian Vickery. Dr. Vickery is a professor of pediatrics, Marcus Professor of Pediatric Immunology, and Chief of the Division of Allergy and Immunology at Emory University and Children's Healthcare of Atlanta. Dr. Vickery has over 15-plus years of track record with over a hundred publications in leading journals. He's a nationally prominent clinician scientist focused on improving outcomes for children with allergic disease through the development and implementation of interventions that effectively address unmet medical needs. Dr. Vickery, thank you so much for saying yes to this podcast and welcome to the podcast.

Dr. Brian Vickery:
Mariam, thanks for inviting me. This is something I've really been looking forward to, and I'm excited to be here.

Dr. Mariam Hanna:
Awesome. We're going to start with: What is omalizumab?

Dr. Brian Vickery:
So, omalizumab is a monoclonal antibody directed at IgE that has been on the market for some time, commercially known as Xolair, with the first indication being allergic asthma about 20 years ago, and then a second indication for chronic spontaneous urticaria, and now a third indication for food allergy following the results of the phase three OUTMATCH trial that was completed and published in February of this past year.

Dr. Mariam Hanna:
Perfect. And how does omalizumab work in general for all these diseases?

Dr. Brian Vickery:
So, omalizumab binds very specifically to the heavy chain region on IgE, which means that it binds whatever IgE is floating around in the circulation. It is not targeting any allergen-specific IgE per se because the binding region is on the heavy chain part of the molecule. That means it should have broad action against IgEs with multiple different specificities, and it also means that it doesn't displace IgE that's already bound to mast cells. So it's really intercepting soluble IgE that's in the circulation. What happens though, once you do that, is that you form drug-IgE complexes, and over time free IgE is decreased. When free IgE levels decrease and stay down, what this does secondarily is it changes the behavior of other cells that depend on IgE. So most prominently, that's mast cells. As less IgE is available in the environment, mast cells over time start to downregulate their IgE receptor and basically just calm down. Beyond mast cells, we know that omalizumab has effects on antigen-presenting cells like dendritic cells and also T-cells. So yes, it intercepts IgE as the primary effector molecule in allergy, but it also has important cellular effects on T cells like dendritic cells, mast cells, and T-cells.

Dr. Mariam Hanna:
And if I can push a little bit, over time, what timeframe are you talking about here? Is this just patients that are on maintenance after 16 weeks, or is this longer time periods for that to happen?

Dr. Brian Vickery:
Well, it's a good question. I mean, we know that after a dose of omalizumab, free IgE drops very quickly, within hours to days. But this question about what is the onset of action with respect to clinical desensitization—where we would be able to tell a family how soon does this start working? Is it after the first dose? Do you have to reach some sort of steady state? Does it take weeks or months in terms of the clinical protection we might hope to get out of omalizumab? That's a question that I don't think we really quite have the answer to yet. And we'll get into the data. We don't really have a great idea yet of who responds well to this medication and who doesn't. And so there's clearly some biology here that is more complex than just that rather simple explanation.

Dr. Mariam Hanna:
Okay. Let's get into the trial a little bit. What were the main findings from the OUTMATCH trial?

Dr. Brian Vickery:
The OUTMATCH trial was a fairly complex trial that's still ongoing, but the results that were presented in February were a fairly straightforward first stage of the study, which was effectively a randomized placebo-controlled trial of omalizumab versus placebo in multi-food allergic children, adolescents, and young adults. And this was done at 10 sites in the U.S., including my site. So all the participants had to have peanut allergy, and then they had to have at least two other common allergies from a list that included milk, egg, wheat, cashew, and hazelnut. The patients all had food challenges at the beginning to not only demonstrate that they were allergic but that they were reactive at certain thresholds, as is typically done in research. Then they were randomized to 16 to 20 weeks of omalizumab or placebo for omalizumab, and then the challenges were repeated at that point to each of the foods.

The primary endpoint was tolerating at least 600 milligrams of peanut protein without dose-limiting symptoms after 16 to 20 weeks. And that primary endpoint was met, with 67% in the active group being able to achieve that outcome compared to a small percentage in the placebo group. And then the key secondary endpoints were around tolerating 1,000 milligrams of milk, egg, and cashew as pre-specified secondary endpoints. And all of those endpoints were also met, with statistically significant changes seen in the active group compared to the placebo group, although there was some variation, particularly with cashew. And we will probably talk about why that might've been for those secondary endpoints.

Dr. Mariam Hanna:
Absolutely. And before we talk about those endpoints, how was the Xolair dose determined?

Dr. Brian Vickery:
Well, that's a good question. Essentially, the asthma dosing strategy was adopted for this trial with some modifications. And the modifications included, number one, lower dosing by weight, right? So in asthma dosing, you have a table with body weight in kilograms as the columns of the table. Well, this trial was open to children as young as one year of age, and of course, the lower limit of approval for asthma is six years of age. So there were several additional columns accommodating these children with smaller body sizes down to 10 kilograms. Ten kilograms is the smallest you could be and still be in the study. And then a few additional rows at the bottom, allowing slightly higher total IgEs—up to 1,850 was the total IgE limit in the study for OUTMATCH, which is a little bit higher than the commercial allowance for asthma, but it's essentially a modified asthma dosing strategy. But I do think there is some residual uncertainty about is that the optimal way to use it.

Dr. Mariam Hanna:
Okay. Some foods were more, let's say, successful than others. Why do you think that was?

Dr. Brian Vickery:
So for peanut as the primary endpoint, the participants qualified for the study by having dose-limiting symptoms at or before the 100-milligram dose in the screening challenge. And by convention, a participant like that needs to tolerate 600 milligrams at exit to be considered a treatment responder. And that's kind of a standard regulatory expectation at this point. However, for the non-peanut foods, the decision was made prior to the study to allow them into the study by having dose-limiting symptoms at 300 milligrams or less—the next highest dose in the screening food challenge. And this was done just out of a pragmatic consideration of having to qualify people for multiple foods for the study, including foods like milk or egg, where thresholds might be different. And so this was sort of a pragmatic concession to trying to actually recruit the study. Well, if you let people in at 300 milligrams at their entry threshold, they must tolerate 1,000 milligrams at exit to be considered a responder.

And again, that's a regulatory expectation. So for those non-peanut foods, treatment success was defined by tolerating at least 1,000 milligrams after 16 to 20 weeks with no more than mild symptoms, which is a higher bar. And it turns out that for cashew, 41% of those treated.

were able to tolerate at least a thousand milligrams at exit compared to the 67% for peanut. And that looks like, well, geez, the cashew participants didn’t do as well or cashews are harder to treat. When you actually look at it as a sort of a fold change, at screening, the median tolerated dose for cashew was 10 milligrams. They were actually more sensitive to cashew than the peanut participants were to peanut, and yet they had to get to a thousand to be considered a treatment responder. So that’s a hundred-fold threshold change in 16 weeks, which is a pretty high bar.

And as a result, because the endpoint was read out as a proportion—the proportion of those able to tolerate a thousand milligrams—the proportion was less. It was a higher bar. I think that’s mostly an artifact of the study. I don’t know that there’s anything intrinsically more difficult about cashew. The other thing that is helpful, I think, to look at is the results of the open-label food challenges, which were also published in the same paper. So the first 60 participants in the study, after they did their exit food challenges, went on six additional months of open-label omalizumab again as a regulatory requirement, and then were challenged again after six additional months of treatment. And there, when you see those results, the cashew participants with an additional six months of treatment look exactly the same as all the other foods. And so really for the non-peanut foods, cashew stands out.

Dr. Mariam Hanna:
Absolutely, that the threshold might be lower but would still benefit. And if anything, they’re going to benefit over the long run if you just keep them on the dose.

Dr. Brian Vickery:
That’s right. And so there’s not really an appetite right now to consider fold change as an endpoint, but in reality, that’s what people want to know, right? If you get 50- or 100-fold difference in your threshold, that could well be clinically meaningful for that individual person, even though they don’t meet the definition of treatment success for the study, because that’s really what individual patients care about.

Dr. Mariam Hanna:
So let’s talk about what’s the specific FDA indication that Xolair received for food allergy. Who qualifies?

Dr. Brian Vickery:
So the FDA labeled food allergy for the reduction of allergic reactions, including anaphylaxis, in food allergic patients aged one and above who are allergic to one or more foods. And the label also says that omalizumab is to be used in conjunction with ongoing food allergen avoidance. So there’s a couple of things to point out there. One is it’s aged one and above, so there’s no upper limit. There were not many adults in this trial at all, and there was nobody in their forties, fifties, sixties, but there is really no age range—it’s just one and above. And although there were only a handful of foods studied in OUTMATCH, the label doesn’t reflect that. It just says one or more foods. It doesn’t call out the specific foods that we actually have data on from OUTMATCH.

And so those are two interesting parts of the label. I wasn’t sure how that would happen and whether they would just say, well, for peanut, for milk, for egg, for cashew, whatever. It was just one or more foods. And then that additional statement about to be used in conjunction with ongoing food allergen avoidance.

Dr. Mariam Hanna:
And will that ever be revised?

Dr. Brian Vickery:
I'd have to speculate about that, but my speculation would be no, because the amount and quality of data that you need to go back to a regulatory agency and get a label changed is so onerous that it's probably unlikely to happen. And of course, the FDA does not regulate medical practice. They certainly serve a very important role in the evaluation of these medicines. But then people have used medications off-label, if you will, if that's what the patient needs, for years. And so that's up to us to figure out best practices.

Dr. Mariam Hanna:
Absolutely. Okay. Should all patients consider a threshold or a food challenge before being started on a medication like omalizumab?

Dr. Brian Vickery:
Well, I think my personal opinion is that if you're going to consider a food allergy treatment, you should really strongly consider a challenge beforehand. Now, that's not going to be required by any means, and there are plenty of patients for whom that would be inadvisable, right? I mean, somebody who had a clear history of anaphylaxis last week—the milk patient you described in the entry—you’re not going to challenge that person, right? There's no reason to do that

Dr. Mariam Hanna:
No chance, no.

Dr. Brian Vickery:
That would be, frankly, unethical. But we also know that we see patients who are avoiding foods in many other kinds of clinical scenarios where the likelihood of allergy is far less clear, or there's a potential for a milder phenotype—that is, high-threshold reactivity with mild symptoms—where the benefit of a treatment may not be as clear, right? So I think it’s something to really give strong consideration to.

I think that the additional issue that Xolair brings into play here that might be slightly different than the kinds of decisions that are made with OIT is that here it’s got a multi-food indication, and this is something I’ve been wrestling with in my own practice. So let’s say, for instance, that somebody is clearly allergic to peanut and there’s no doubt about that. They have a clear history of objective anaphylaxis, they have high-titer IgE, but they’re also avoiding all the tree nuts out of precaution because somebody tested them.

And then there’s this egg allergy that is seemingly getting better, the IgE is dropping, and they’re on baked egg, and maybe it looks like they might’ve outgrown their egg allergy. There’s a clear clinical indication for protection against peanut. The tree nuts are all unknown, and then egg looks like it may be going away. Well, as soon as you start that person on omalizumab, then your ability to read out any of those other challenge results is now out the window. But do you deny somebody an effective treatment for their peanut allergy while asking them to undergo challenges to all these other things first? And how do you manage those situations, right?

Dr. Mariam Hanna:
I completely agree with you, and the labor and the resources that are associated with doing multiple food challenges for patients during their life, and then offering this on a population level where you have lots of people with food allergies that are interested in immunotherapy, is daunting for many. What I wanted to point out is the one-year-old that gets started on Xolair for their multi-food allergy—is that child on Xolair forever? Do we not think that there’s a disease modification effect or that you can put immunotherapy kind of under the shield of Xolair and then take it away?

Dr. Brian Vickery:
Well, it’s a great question, and I’m glad you asked it. I think of, in clinical practice, the use of Xolair as kind of having use cases. And so one obvious use case would be, say, like a 17-year-old who’s preparing to go off to university and has multiple allergies, maybe nuts, has a history of severe reaction, and is not necessarily interested in lifelong treatment or cure but wants to be protected as they navigate the challenges ahead—moving to university and traveling and things like that. That’s a pretty good use case for it. I may not take it forever. I may take it for the next four or five years and then get into my adulthood where I can manage my allergies a little easier. 

The young child, particularly where it involves staple foods, is a very distinct kind of use case. So as you talked about, if dietary incorporation, particularly with staple foods—milk, egg, wheat, but not exclusive to those—where those are commonly a goal of, "Let's get these back in the diet," and that's not possible in those younger kids without omalizumab, can you use it in that case to facilitate the introduction, stimulate those allergen-responsive cells by including antigen in the treatment recipe under the safety cover of omalizumab, which you couldn't do without it, and then pull back on the omalizumab to allow them something like either guided or maybe, depending on their outcome, something more like ad-lib eating as they get older?

I think that's something that obviously we'll need more data on, but I think that's a scenario that could play out. But obviously, we're going to need to develop more experience, and it gets into that whole new frontier that we really need to push the field towards in terms of phenotypes and defining that food allergy is not a monolith. There's different kinds of food allergy, and we need to be better about identifying those phenotypes and getting into more sort of a precision medicine approach—like for this phenotype, this is a good approach, for that phenotype, maybe consider something else.

Dr. Mariam Hanna:
So you said it—phenotypes, the biologics companies would like me to think of each different patient phenotype for what biologic I prescribe. Could you see that food immunotherapy and food allergy could be done under the guise of other biologics? Like is omalizumab the only one that would work for this, or could we have the same effect from some of the ones we currently have or ones to come in the future?

Dr. Brian Vickery:
Well, I think that there's two parts to that answer. One is considering the ones that are currently maybe commercially approved for other indications, and the short answer is not of the ones that are otherwise. Now, in current use, I don't think so, although I have to say that I have this personal interest in exploring what a persistent use of dupilumab in young babies, toddlers who have bad eczema might do to their IgE production, and whether or not that could allow for some feeding that might not happen otherwise. That's totally unproven.

Dupilumab was studied in older peanut-allergic participants in a small trial where they were challenged, randomized to dupilumab or placebo, and then challenged again 24 weeks later. And although their peanut IgEs were cut in half by the dupilumab treatment, they were still every bit as reactive 24 weeks later. These are 11-year-olds with persistent peanut allergy, and the conclusion was, dupilumab doesn't work for food allergy as a monotherapy.

We know that it decreases IgE production, but they're still reactive. And we see that in clinical practice when we use it for an eczema indication. Again, that's a phenotype thing. It's possible that it may be a different outcome if you study people early in life before immune memory mechanisms have really fully become established.

That's an exploratory research use. Clinically, I don't really see a lot of opportunity for other biologics now. And then I would also say that the second part of that question is there are many other biologics being developed, and I think it's very likely that one or more of them could become commercially approved down the line, including several others that have anti-IgE functions that are overlapping but also, in some ways, distinct from what omalizumab has.

So I think that's down the road. That still needs to be further developed and demonstrated in clinical trials. But I do think you'll see new biologics coming out with a food allergy indication down the line in addition to some small molecule medicines that might be orally bioavailable and then innovative forms of immunotherapy.

Dr. Mariam Hanna:
A fascinating new frontier. Alright, time to wrap up and ask today's allergist, Dr. Brian Vickery, for his top three key messages to impart to patients and physicians on today's topic: omalizumab in the management of food allergies. Dr. Vickery, over to you.

Dr. Brian Vickery:
Alright, number one, although Xolair is not a cure, it's a major step forward for patients as the first monoclonal antibody or biologic therapy to become FDA-approved to treat food allergy, with the additional advantage of it being a familiar, established medicine in the allergist's repertoire with a 20-year track record of safety in asthma.

Number two, Xolair was also the first product to become approved for the treatment of food allergy across a wide range of ages, from one to adulthood, where we previously had no approvals in adult patients at all, and also the first to be approved for the treatment of one or more allergens.

And number three, Xolair can be considered as an option for desensitization, especially in those for whom OIT was not successful or where it may be difficult to consider. So, for instance, when there are multiple foods involved, or when there is not an immunotherapy available for a more unusual food allergen, perhaps like a crustacean allergy or something. And, or when social or lifestyle circumstances make OIT especially challenging—for example, a busy adolescent with many extracurricular activities, a college student, or an adult who must travel often.

Dr. Mariam Hanna:
Perfect. Thank you, Dr. Vickery, for joining on today's episode of The Allergist.

Dr. Brian Vickery:
Well, Mariam, thanks for having me. I really enjoyed the conversation and look forward to continuing to see where this field goes.

Dr. Mariam Hanna:
Absolutely.

This podcast is produced by the Canadian Society of Allergy and Clinical Immunology. The Allergist is produced for CSACI by PodCraft Productions. The views expressed by our guests are theirs alone and do not necessarily reflect the views of the Canadian Society.

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