Emma Guttman-Yassky, MD, PhD, presented “Inflammatory Skin Diseases: The Translational Revolution”. At least 1 in 10 people worldwide have immune-mediated inflammatory skin diseases such as psoriasis vulgaris, atopic dermatitis, alopecia areata, vitiligo, and numerous others. Previously, there was a huge unmet need for safer and more effective treatments for atopic dermatitis in both adults and children. Dr. Guttman-Yassky’s research proposed a paradigm shift in the pathogenesis of atopic dermatitis. She discussed her research and clinical trials which led to novel therapeutic developments and what is in the pipeline for future treatments. Hi everyone. My name is Emma Guttman and I'm coming from new york city from the Kimberly and eric Waldmann department of dermatology at the Icahn School of Medicine at Mount Sinai and I'm really pleased today to talk to you about inflammatory skin diseases, the translation of revolution. So it's important to remember that immune mediated inflammatory skin diseases affect many. Many people worldwide. Approximately one out of 10 people will have some inflammatory condition, inflammatory skin conditions such as psoriasis and dermatitis, alopecia Areata, vitiligo and many others. In my talk today I will focus on a topic dermatitis and alopecia Areata but with first need to remember where it all started and it started with the development in psoriasis. And this is how psoriasis patients looked unfortunately approximately 14, 15 years ago. And this is on the right. You see how they look today. Mostly they're clear due to so many advances in our knowledge in psoriasis and psoriasis I think is the most successful case of molecular therapeutic targeting in any human immune mediated disease beyond the skin with a single drug we now can control psoriasis extremely well in approximately 90%. Up 200% actually of patients. And we have now drugs that directly target key pathogenic cytokines that are also part of the genetic genomic risk of psoriasis. And a very good example is this study with recent schism of the targets. I'll 23 p 19 And you see here really mind blowing a passing 75 results that are approaching 100% and also passing 90 results of 80% with recent. So how did we get to this amazing point we now have in psoriasis? We started by increasing our knowledge through bench studies of pathogenesis that had biomarkers both in skin and blood. That really helped formulate a hypothesis. And then we continued with a targeting with clinical trials with targeting agents that also included bio markets in skin and blood. The generated by the markets of therapeutic response. And of course we needed multiple cycles to generate success because as we know for each success story there are many failures. But also the failures are important because they really help us frame pathogenic concepts and get in good therapeutic direction and also rises is known to all of us as a th 17 and I'll 23 center disease. So we now need to ask the question can the success of psoriasis. This very successful psoriasis model bedside to bench model b also apply to other immune mediated inflammatory skin diseases. And the answer is a definite yes but definitely we need a role too Pass and such was the road of a topic dermatitis that we need to remember. This is the most common inflammatory skin disease. It involves up to 7% of the adult population in the US in Europe 3-4% and up to 25% of the Children worldwide. Around the third of these patients very similar to psoriasis have moderate to severe disease. And until very recently we had a huge unmet need for safer and more effective treatments in those adults and Children in with the topic dermatitis. Now, what happened in a topic dermatitis that really prevented the therapeutic development? Was this futile debate in the literature whether it's an inside Out or outside in disease, what does it mean? Inside Out means that it's primarily immune driven, driven by different cytokines that are important in a topic dermatitis such as th two cytokines, or type two cytokines such as aisle four, aisle 13 31 and also ill 22 that is derived from the th 22 axis and the outside in hypothesis suggested that it all starts from the barrier that creates a barrier defect that allows penetration of allergens and microbes creating the disease phenotype. But we would learn that actually these hypotheses are not mutually exclusive and they can go inside together. So in 2012 we proposed a paradigm shift in the pathogenesis of a topic dermatitis, proposing that these a hypothesis are not mutually exclusive and that already in the non regional skin of patients with a topic dermatitis, there is a regulation of multiple immune molecules such as Type two. Type 22 molecules. This process is intensified even more in acute disease and much more in chronic disease and of course there are barrier abnormalities in a topic dermatitis, but some of them are generated actually through the action of cycle whites for example, I'll foreign all 13 inhibit anti microbial peptides. They inhibit barrier molecules such as Phil a green Ukrainian lipids. I'll 31 starts to eat scratch like unification cycle. I'll 22 starts. The onset of pleasure also disrupts the barrier. And together with aisle 17 synergize is to induce the S 100. And this process is perpetuated in the chronic stage of a topic dermatitis. And you recognize many of these molecules as being successfully now targeted in clinical trials are already approved for a topic dermatitis. So how are we testing the contribution of the different immune access to a topic dermatitis very similar to psoriasis through clinical trials with targeted treatments in a topic dermatitis patients. And you know, nothing would have been possible without the very instrumental contribution of the dilemma. Both the first treatment in specific treatment for patients with the topic dermatitis, but also it contributed to dissecting the pathogenesis of a topic dermatitis is a fully human monoclonal antibody that targets I'll for receptor alpha that potently inhibits both aisle four and aisle 13 cytokine signaling. And the first study was a very short study. Four week study with a total of 67 patients, 18 of them participating in the biopsy sub study and it was really helpful to understand the pathogenesis of a topic dermatitis and that continued to face three studies that that we all know the results of the I. G. A 01 or clear or almost clear and easy 75 that were the co primary endpoint at week 16. Both showing success and significance, both in the every week dozing and every other week. Those in for patients with a topic dermatitis. And we have shown in our mechanistic studies in of the diploma clinical trials that diploma not only impacted the clinical response but was also impacting both the information and the barrier dysfunction of a topic dermatitis. And this was very instrumental because it was really the first study that established al foreign L 13 as pathogenic cytokines in a topic dermatitis cementing A. D. As being reversible and immune driven exactly like psoriasis. And really opening the door to all these amazing therapeutic development. We now have we are fortunate to have in a topic dermatitis and just I'm also a clinician and it's important to put what we know. Mechanistic Lee with the clinical world. This is a patient of mine that was enrolled in Phase three, you see very significant disease and this is how the patient looked after the treatment. So certainly made a huge difference in the life of this patient and many other patients worldwide and as we know, the pillow is also improving Children, adolescents and the approval is also now coming in infants and small Children. Now let's talk about 13 in division and I think it's important to ask is 13 in division enough to control a topic dermatitis or do we really need to inhibit both sides. All kinds of type two immune pathway, aisle four and aisle 13. So let's look closely into that because I think we have our answer. So our answer comes from the study with liberalism. That was a clean study. No topical steroids and here and I don't like to compare studies that were not done at the same time. But we see we can definitely say that the results are in the ballpark of the maybe slightly more. But again it's not done at the same time but definitely very similar. So I think we can conclude that other team seems to be the most important site, a kind of the type two pathway. Now, what about Jak inhibition? We need to remember that the topic dermatitis is this heterogeneous disease that not all patients have only type two immune activation while that is common to all of them, some of them have also th one immune activation, th 22 maybe even th 17 in asian patients. So JAK inhibitors come very handy for these patients because they are too targeting more than one cytokine pathway including the type two pathway, but also other cytokines and pathways such as 22 interferon gamma. And I want to show you how we are improving upon the clinical responses will Jack one targeting. And here I want to show you using the example of the city but this is not the only JAK inhibitor or that is approved. Now for a topic dermatitis. So here we see a measure up one and two Easy 75 the validated I G A clear or almost clear how it really pushes the barrel of efficacy. Almost 80% responses with the higher dose in Easy 75 also more than 60% in I g a zero or one. And we see even easy 90 responses. Who would have believed that? We would talk about easy 90 responses. And here we see that in measure up when both doses are inducing more than 50% easy 90 responses will do publicity. Now adverse events. We know that Jak inhibitors do come with some price. We see acne form rashes, some. No, so far range itis a simple K increases. But overall I have to say that generally it seems that Jak inhibitors have a better safety profile in a topic dermatitis compared to other diseases where patients may have other comorbidities such as R A N psoriasis. But certainly we need long studies to a certain longer term safety. Now the pipeline in the topic dermatitis is very busy. We have many successes now from early studies like CCR four in X 40 antagonism with the K H K 4083 name Eliza mom shows a success as well. And you know, we'll see what time in hence for us I think in five years we will really revolutionize the a pipeline and the treatments for patients with the topic dermatitis. And we also have some trailers that we know did not work like L 33 T S L P I L 17 C and I'll 17 8. They did not work in patients with the top democrat itis. Now I want to also talk about another disease that is very dear to my heart alopecia Areata and I want to show you how are we extending the translation of revolution to other inflammatory skin diseases from psoriasis to A. D. And now to alopecia Areata. So alopecia Areata has approximately 2% like the prevalence in the United States over 6.6 million. Almost 100 50 million worldwide. So very sizable population up to 10 to 15% of patients will progress to have total scalp involvement or total body hair involvement. And there is a huge unmet need for safe and effective treatments for patients with. Now we know from in small studies and recent clinical trials that JAK inhibitors are effective in our data and there are several now in trials and I want to show you some data from barry sitting in that is a Jak one Jak two inhibitor, regal sitting in Jack Tree Tech and re positing tick to Jack one from fighter barry sitting with this from eli lilly and I cannot pronounce it but europe's a litany Jak one, Jak two and this is from concert, so different studies that have different times of endpoint as well. Pay attention that barry city has the primary endpoint at week 36. So you cannot compare to what we see for week 24 And then you see a for little city native and a very positive and the euro the primary endpoint is 24. But when you look at the mean south score of these studies, you see very similar population highly severe patients and with to also pay attention to that. The primary endpoint with study was South score less than 20 equal or less than 20 at week 36. Whereas the others are looking at mean change from baseline South score or South 50 response at week 24. And these are the results for the primary endpoint and also other endpoints. And we see here that the South Korea equal or less than 20 with a body city name was significant for the higher dose and also for the second dose at 36 weeks. However, if you look at the graphs, there was no significance at week 24. So they certainly needed that 36 week time and the South responses at week 24. We see nice data for South 50 75 90 with both the studies done by Fizer and by concert, we do see similar to other Jak inhibitor studies in other indica patients, acne, herpes simplex infections and the cPK elevation. So we need to understand what is the best time point. It depends on the efficacy probably for some drugs. 24 weeks for some drugs. 36 weeks. And these are the results the Barber sitting in study as I told you at week 24, there is no significance but there is significance. At week 36. The safety looks good so far. There is some magnet form rushes orange itis, some nausea and some respiratory infections and some hair pathetic signal. But we'll need to see. And also remember this is four mg barry sitting if not the two mg does. That was studied in the United States for a topic dermatitis in europe for milligram, those is approved for a topic dermatitis. Now, this is the study with the pre positive and retail city. Me and this is post hoc analysis showing a south equal or less than 10, remember that's not equal or less than 20. And we see very nice data with significance already achieved quite early for this and much before the 24 weeks. And it's creeping up with both drugs. And here a fighter took to drugs as compared to placebo. In terms of safety of this study done by fighter, you see acne some headache, although not much, not, not more than placebo overall, you see quite a good safety profile for the study for 24 weeks and my life did the mechanistic studies for this and we showed that when you are targeting peixe alopecia areata in scalp. When you look at their scalp lesions in different pathways that we know that are important in alopecia rata. You see modulation of these pathways. You see increases in hair keratin genes, you see decreases in teach one related genes. You see decreases in teach to related genes and also decreases in aisle 12, 23 related genes. And these are important because my group showed that while th one is important in alopecia Areata, as you see here by increases in interferon gamma and related in markets that are also important in other inflammatory skin diseases such as a topic dermatitis and psoriasis. Also, the th to access is also elevated as you see here by increased I'll 13 and also we see increases in sales fell 23 p. 19 and 12 23 P. 14 across the diseases and by the way the is only increased in A. And A. D. Now that brings me to a very important point that starts becoming quite evident by multiple publications now that alopecia Areata is highly associated with atrophy. The highest association is with eczema or dermatitis, but also their associations with other topic conditions such as allergic rhinitis and asthma. And genetic studies also associated Albertine and all four with alopecia Areata. And that brought us to do a study with in patients with to the paper is already published in allergy and this was a hypothesis driven clinical trial in which we wanted to test the contribution of type to access in alopecia Areata And we showed that it worked primarily in the patients with high G and with a top either personal or familial and we expect to see more mechanistic studies from that study and just you know as I said I'm also a clinician, very important for me to see what different drugs are doing to patients. This is a patient with alopecia universally for 23 years and this is how the patient looked after the trial and he tried everything. He even tried cyclosporin that did not grow his hair. So that was certain that the pillow mom helped him and many other patients look like that as well. Just to show you that vitiligo also has now emerging new treatments going into Vitiligo. I think it will follow the other diseases. So very exciting times I think in inflammatory skin diseases And I think generally speaking in the last decade there is a real revolution in inflammatory skin diseases who's highly a successful new treatments going into them that also amplified the current understanding of these diseases. And as I explained this revolution started with psoriasis and now extends to a topic that authorities are officially activity like when other inflammatory skin diseases. And I think the translational research done on tissue samples both in skin scalp and blood really helped us increase our knowledge on disease pathogenesis, further promoting the therapeutic development and with that I'm really thanking you for your time and I hope you join me in appreciating this very exciting times we're now experiencing, are experiencing for a new treatment paradigm for patients with inflammatory skin diseases. Thank you so much and thank you again for the invitation to speak here.