Intro: Please stay tuned to the end of this program or see the show notes for important information regarding today's speakers and the content of this podcast.

Gerry 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 will be reviewing articles from Allergy Watch, a bi- monthly publication which provides research summaries to college members from the major journals in allergy and immunology.

And you can also earn CME credit by listening to this podcast. For information about CME credit, or to read archive issues of Allergy Watch, head over to college.acaai.org/publications/allergywatch and make sure you check out the acaai community on Doc Matter where we can continue the discussion of these articles.

Hello everyone. My name is Gerry Lee. I'm an Associate Professor at Emory University, an Assistant Editor of Allergy Watch, and again, today I'm joined by the Editor in Chief of Allergy Watch, Dr. Stan Feynman.

Stan Feynman, MD: Hello, everybody. It's great to be here. And I'm currently in practice in Atlanta with Atlanta Allergy, and I'm also an Adjunct Professor at Emory. And, I'm the Past President of the American College of Allergy.

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

Timothy Chow, MD: Yeah, thanks again for having me. So I'm down here in Dallas. I run our Pediatric Drug Allergy program here and I really enjoy being a part of Allergy Watch, so it's a pleasure to be here.

Host: All right. So again, we'll start with you, Stan. We continue to see just a whole array of options for our atopic dermatitis patients, and it sounds like you've got one more for us.

Stan Feynman, MD: Yes, so this was an article that was published in the New England Journal of Medicine, in March of 2023, entitled Two Phase Three Trials of Lebrikizumab for Moderate to Severe Atopic Dermatitis. And it was reviewed in Allergy Watch by Samantha Knox. And you know, anytime there's an article about an allergy issue or an allergy product in the New England Journal of Medicine, I kind of look at it a little more carefully because if New England Journal is going to publish an article, then it must have some importance.

But the interesting thing about lebrikizumab, and the reason it piqued my interest, was we did a study using lebrikizumab several years ago for asthma, and unfortunately it didn't meet its endpoints. But it's a really interesting product because it's a high affinity IgG4 monoclonal antibody that targets IL interleukin 13, and it prevents the formation of the interleukin 4r alpha and interleukin 13r alpha 1 hetrodimer receptor signaling complex.

So it really blocks 13, but not really IL 4. So previous 2B trials have shown a critical role in this IL 13 signaling in the pathogenesis of atopic dermatitis. So this article shows the initial results for the two phase 3 trials that are called the Advocate trials. So Advocate 1, Advocate 2, and they're identically designed.

They're randomized trials, enrolling adolescent and adult patients. So the adolescents are 12 to 18. The adults are 18 and above with moderate to severe atopic dermatitis. And they were enrolled with a 2 to 1 ratio to receive lebrikizumab or placebo. They were monitored for a year, 52 weeks, and there were 424 patients in the Advocate 1 trial, and 427 in the Advocate 2 trial.

 And the dosage was lebrikizumab, a 250 milligram sub q every two weeks, although there were loading doses of 500 milligrams at baseline and at two weeks, and then after that it was the 250. The current report includes the outcomes for the first 16 weeks of treatment. So it's not the full data, but it's at least the first 16 weeks because the primary efficacy outcome was at least a two point reduction in the investor's global assessment score.

 It was a zero four global assessment score, uh, and in fact, 43%, 43.1% of the lebrikizumab treated patients in the Advocate 1 and 33.2% in the Advocate 2 achieved that primary efficacy outcome.

The response rates for the placebo was less than half, it was 12.7 in one of the trials, the Advocate 2 was 10.8, so definitely less than half. And the percentages with at least 75 percent improvement in the eczema area and severity index, where 58 percent and 52 percent compared to placebo was way less than half of those 16 percent and 18%.

 So it clearly met its criteria both for primary and the secondary, which is the eczema area and severity index score achieving the 75 percent improvement. So it was associated with improvement in scores for itching and also interference with sleep. It seemed to work very quickly. And the lebrikizumab group did have, unfortunately, a higher rate of conjunctivitis, and that's one of the things I wanted to talk about, because the side effect of conjunctivitis as we all know, we see that a fair amount now with our patients who are treated with atopic dermatitis with dupilumab.

 The ones in this study with lebrikizumab, the incidence of conjunctivitis was 7. 2 percent in the Advocate 1 study and 7. 5 percent in the Advocate 2 study. So they're both fairly high versus 2.8 percent and 2 percent in the placebo groups. So it was really double, but it really wasn't quite as high as the incidence that was reported in the dupilumab study with conjunctivitis.

And, one of the things that they postulated, the authors postulated, was that the conjunctival goblet cell scarcity due to interleukin 13 and interleukin 4 inhibition can affect the homeostasis of the conjunctival mucosal surface resulting in these events. They feel that the inhibiting just the IL 13 may be associated with a lower incidence and severity of conjunctival problems because compared to those products that inhibit both IL 13 and IL 4. So that's how they explained the difference in the conjunctival side effects that they saw in these patients. So, Samantha Knox, did comment on it that felt that, interestingly, the most common adverse event was conjunctivitis. So counseling our patients on the development of ocular symptoms will be important if this new medication gets approved.

Timothy Chow, MD: Yeah, I think that's really interesting, especially with thinking about dupilumab associated ocular surface disease and thinking about like the wide spectrum that that actually can present with, whether it just be some mild eye irritation or dryness, ranging to conjunctivitis to keratoconjunctivitis. I think that these studies are starting to continue to peel back what the underlying mechanism of these are, and it'll be interesting to see, as we get those insights, if we can help manage more effectively when that arises in our patients who are on these drugs.

Host: I'm just so fascinated by all the different approaches people are taking for refractory atopic dermatitis. It just seems to me just out of nowhere, now we're getting choices left and right, and walking through the woods on all of these, I think it's getting more interesting, because, if I think about the levers you can push and pull, we're talking about comorbidities you can treat, injection versus a small molecule or oral, frequency of injection, if you do injection, and of course, the elephant in the room, side effects, right?

Side effects, especially those that require a black box. So, I think it's interesting. I could theoretically be walking into a room and the shared decision making can include like four or five options. And, choice is good, but, I think our patients listen to us very carefully about our recommendations.

And so, it just sort of be interesting to see, once all of these medications come approved, two week injection versus four week injection, oral medication versus injection, lab monitoring, no lab monitoring. These are all factors that I would imagine people have different opinions about.

And our own opinions about, our own trepidation about. I don't know, Stan, how do you feel about, you've seen the whole spectrum of atopic dermatitis and these new treatments. How do patients, do you think, respond to all these different choices and options? Is that overwhelming for them?

Stan Feynman, MD: Well, it is overwhelming because at least right now they're seeing these on TV. And so, everything looks great on the TV and the ads. And, we have to deal with the side effects and any potential long term consequence, obviously age indications and of course, ultimately, which third party carrier is going to help them pay for it.

So, it is getting very complicated, but I think from my standpoint, being in allergy for a long time; I just think it's exciting to see that these targeted therapies are being developed and they're going to be helping our patients. I mean, in this study, particularly, they reported an improvement in itching within two weeks. So, I think it's very hopeful for patients.

Host: So again, more treatments for our patients is extremely important and you mentioned access, so I think that sort of bridges to our next article. So Tim, you're going to alert us about some maybe access issues about allergen immunotherapy.

Timothy Chow, MD: Yeah, so this article is titled Racial and Ethnic Disparities in Allergen Immunotherapy Prescriptions for Allergic Rhinitis. It was published in the Journal of Allergy and Clinical Immunology in Practice in February 2023 online. And the primary objective was really to assess the differences in SCID prescribing practices across different social determinants of health.

So to do this, the authors used the TRINET X multi center medical health record database, and they looked at adults with a diagnosis of allergic rhinitis by ICD 10 codes. And then they used this propensity score matching using non Hispanic white patients as their reference and they created this match cohort for age, sex, other atopic comorbidities such as asthma, asthma severity, presence of atopic dermatitis, and then other comorbidities that may affect you know, SCID prescription, like a history of heart failure or coronary artery disease, beta blocker use or ACE inhibitor use. And then they compared SCID prescriptions across these then matched cohorts over a three year observation period. So in this database, over their study period, there was just over a million patients with allergic rhinitis.

And after propensity score matching, they had just over 150,000 in the non Hispanic white cohort. The same number in the black cohort of black patients and black patients compared to white patients were 60 percent less likely to receive a SCID prescription. They then performed another propensity score matching to compare non Hispanic white patients with Hispanic white patients when they had about 69,000 in each group, and they found that Hispanic white patients were 20 percent less likely to receive a SCID prescription.

And there were no significant differences between Hispanic nonwhite patients and non Hispanic nonwhite patients. So, in a large national patient cohort, Black and Hispanic patients were less likely to have a SCID prescription, for allergic rhinitis compared to white patients. And in her comments in Allergy Watch, Iris Otani notes that reasons for these differences really need to be investigated.

And I wholeheartedly agree. And I would encourage and hopefully future investigators to continue to use significant nuance to tease this out, because there are probably multiple levels in which different social determinants of health can be impacting these disparities. So as we all know, starting SCID is a shared decision making process that incorporates weighing different possible patient goals; such as optimizing symptom control, or potentially preventing further allergic sensitizations, or decreasing potential long term medication use, with risks that may be perceived differently by different patients, like the risk of a SCID reaction, or the risk of lost time from school or workdue to injection schedules. And so, there's a lot of nuance to be able to tease out what components of that patients are valuing with that shared decision making process, and that's kind of not without even mentioning the racial and ethnic disparities that exist with regards to just accessing care in general.

So, all that to say, further nuanced studies will be needed to begin to tease that apart, and I think it's important to note that in other areas where similar kind of complex shared decision making is being performed, such as with food, oral immunotherapy; these racial disparities have already been observed and there have been investigations into diving deeper into that.

And so I think as a field, should be encouraged.

Stan Feynman, MD: The college has made an effort to really make us more knowledgeable about these disparities of healthcare and especially racial disparities. And so, I really give the college credit for addressing that. And, this is just more data, to support, there's a significant problem with certain groups getting the best care that they can get. So, it's a complicated study, but I think it's ultimately good data that we need so that we are more aware of some of these disparities in healthcare.

Host: Yeah, I mean, I completely agree, Stan. What has impressed me the most is leadership from national sides, like the college trying to address these disparities, through education to providers and patients to get even more diversity in the workforce. So for those of you who aren't aware the college was doing SPARC grants for historically black colleges and universities for residents to attend and medical students to attend the college meeting.

 As Tim, you mentioned, the issues could be just access to the allergist who doubts himself, the identification of someone with a similar background as you in terms of the decision making and receptiveness to different treatments. And of course, just the difficulty of doing the treatment as well.

We certainly have so many things we could work on, but raising attention, again, makes us work toward goals to how to close it. So, I love studies like this. And again, it just makes me more emboldened to be more forthcoming and spend extra effort to do outreach in these populations.

 I'm very, very fortunate to work in an institution where we've made accommodations like night clinic for allergy injections. So the Hughes Paul Night Allergy Clinic, we have an after hours shot clinic that was an absolute response to our patient population in inner city Atlanta. So these are the sorts of things, just small things that we're trying to do to make sure we try to improve access as best as we can.

Let's talk about one more article that I thought was really interesting. And I'm going to tell you, if you got an immunology or allergy article that hits Nature of Science or Cell, I think it's worth talking about, like, I think I just, that's just my opinion. So, the title of this article is Human T Cell Generation Restored in CD3 Delta Severe Combined Immune Deficiency Through Adenine Base Editing.

What the heck is that? Okay, so let's talk about this article. So, severe combined immune deficiency due to a CD3 Delta defect. As you know, that's part of your T cell receptor complex. If you don't got this subunit, your T cell receptor don't work. The T cells will just not develop. You'll have T minus B plus NK plus SCID.

And so obviously that is historically something we have addressed through transplant. But you know, if we talk about disparities for immunotherapy, disparities also occur for transplant. There's a limited pool of stem cell donors. Obviously the treatment has a significant mortality, graft versus host disease, what have you.

And so you may have seen these gene therapy trials where they would take a lentiviral vector and you would just insert the functional gene into a stem cell. But again, there have been problems with that approach. That gene could be inserted anywhere and you could have insertal immunogenesis and all these inadvertent side effects.

And so another approach people have been taking, and you may have heard of this new technique, which is called CRISPR. And obviously what it can do is it can, through the process of DNA repair, modify your DNA by just making either a double strand cut or a single cut and either inserting DNA or in this approach, instead of inserting DNA, actually just change a single base nucleotide.

So that's called base editing. So old CRISPR, which is basically you would make a double stranded cut and then you would have this template to do insertion of cDNA. Again, there's some downsides. With that double strand break repairs, you could have inadvertent insertions, deletions, you could have off target effects.

And so in this base editing approach, if you just target just one nucleotide to switch it, you don't need a template, you just do one specific area, and potentially it could be a better approach. So again, this is the objective of the study. They wanted to try this editing base editing approach to fix a single nucleic defect.

It's a C202C to T, mutation that was described in a Menitite founder population. And so they looked at a T cell line, they looked at human stem cells, and they also got stem cells from one of these patients and actually applied the treatment. They didn't infuse it into the patient, it was just sort of a proof of concept.

And so what they found was, is that one of the things about traditional CRISPR that is a flaw, is that it requires the cell to be proliferating for it to work.

The cell has to be in active cell cycle replication. So, the correction efficiency isn't great. Now, base editors does not require that cell to be in active cellular replication.

So, they actually had higher correction efficiency when they use a base editing approach and interestingly, when they look at off target effects, traditional CRISPR, they've been having chromosomal abnormalities occur after it. And so they compared their base editing approach versus traditional CRISPR approach, and there was less chromosomal abnormalities.

Though, one thing that was more common in the base editing approach is that they're trying to fix one nucleotide, but adjacent nucleotides in that area have been modified as well. This sort of an unintended bystander editing, they say. Now, the study attempts to look at what's the significance of this happening.

They actually characterize each bystander edit and tried to determine if it led to any potential effects that were detrimental. And at least this in vitro study didn't seem to suggest that it would affect the function or be oncogenic or that sort of thing. But interestingly, what they were able to find is that once they do this approach and they correct that single nucleotide variant, they were able to get CD T cell receptor expression, it was able to signal, it was able to work appropriately.

They actually had sort of a thymic model where they were able to show that you were able to make naive T cells from these stem cells. So, really interesting work that sort of is thinking about the future of how we're going to be correcting genetic inborn errors in immunity.

Now this is not all roses. There are some limitations to the fact that I think the number one limitation this process is that it has to be absolutely individualized to the patient. So you can't just take this and just give it to everybody. Each person's mutation is unique.

Each person's unique sequence is unique. So again, they have this founder population. So all of them are sort of genetically somewhat similar, but like for a general population, you would have to tailor make this base editing product for their one individual mutation for that individual person.

So that's very challenging. I think that that's going to be one thing they're going to have to work out in the future, but just the fact that all these cool things are happening in the past, I mean in the future, to move the field forward, it's just exciting times and clearly, five, 10 years now we're going to be doing amazing Gattaca like GD manipulation stuff maybe in the future.

I know that's very sci fi, but it seems like sci fi is now. That's what I'm trying to tell you. It's really cool.

Stan Feynman, MD: Gerry, it is very cool. I've read the Codebreaker, which is the book about how the developer of CRISPR, Jennifer Doudna and her crew won the Nobel prize. And of course, now as we're recording this podcast, there's been a lot of press recently about the FDA looking at the use of CRISPR for helping patients with sickle cell disease. Obviously our immune deficient patients have a problem in their genes too.

And I guess this is just a natural extension. It's very complex. It's very difficult for me to understand as a clinician, but it seems like there's a lot of help for our patients in the future.

Timothy Chow, MD: And I'm excited. I think, the word precision medicine gets thrown around a lot, but it's hard to imagine how much more precise you can get than changing like a single nucleotide. And so it's exciting to see as our techniques improve and we can maybe help prevent some of that adjacent nucleotide modification effect, especially for these single nucleotide, leading to nonsense mutation defects. It's super exciting.

Host: So, again, I always learn a lot from Allergy Watch. So, if you liked what you heard on the podcast today, please rate our podcast, it really helps us out, and we're always wanting to hear from you, your feedback, your corrections, your suggestions, our email for that is AllergyTalk, one word, at ACAAI.org.

If you'd like to claim CME credit by listening to this podcast, you just head over to our website. That's college.acaai.org/publication/allergywatch. I immensely enjoy doing this. I learned so much every time. Thanks for the great discussion and we'll hear from you next time.

Thanks for, listening and enjoy your day.

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, products, or methods discussed in the podcast, and it does not approve or endorse any products, professionals, services, or methods that might be referenced.

Today's speakers have the following disclosures. Drs. Lee and Chow have nothing to disclose. And Dr. Feynman has been a speaker for Takeda and has done research for AIMU, DVB, and BioQuest.