Hi everyone, I'm really excited to talk to you about one of my favorite topics, clinical trials in atopic dermatitis and practical considerations. I'm coming from Mount Sinai in New York City. These are my disclosures. I'm really proud to be working on multiple drugs with multiple companies. So truthfully, I believe I don't have any conflict because I really work with everybody and I don't have any ownership or financial gain from any atopic dermatitis drug. So atopic dermatitis, we all know, but what we may not know, or maybe we overlooked is this is the most common inflammatory skin condition. About 7% of the adults in the United States, even more of the children, around 15% and some countries in Asia, even up to 25% of the children, up to a third of patients will have moderate to severe disease, still the majority of patients are in the mild to moderate category. So until recently, we had a huge unmet need for long-term disease control, but there is still need for patients for better treatments for long-term disease control. Now the therapeutic drought is finally ending in this disease, but again, there is still need and we need clinical trials with better drugs for our patients with atopic dermatitis. Now the pipeline is super busy for atopic dermatitis patients. There are several drugs in phase 3. We are waiting approval for lebrokismab and nemolizumab, and we have some AX40-AX40 ligand in a late phase 3 that maybe have the potential of disease modification, we'll see. So very busy time. We also have clinical trials that failed in atopic dermatitis, but even from them we learn, right? Such as the IL-17C, IL-33, and others that failed clinical trials in atopic dermatitis. So how did we get to this amazingly successful point that we now have in atopic dermatitis? It wasn't such an easy road as you guys may think, but it was all done through clinical trials. We really needed to have initial studies of pathogenesis that had skin and blood biomarkers. So skin biopsies, skin and blood needed to be taken to really understand the disease phenotype. And then very important, equally if not more important, clinical trials with mechanistic studies. I want to tell you today that mechanistic studies are so important in clinical trials for multiple reasons, but they are also important to inform us about the drugs, the pathway, what really works, what really doesn't work, what differentiates responders and non-responders. Super important. And like everything in life, not only successes, but sometimes even more important are the failures to help frame the pathogenic concepts and the therapeutic direction. And I'll give you a very important example. The interferon gamma study in psoriasis, you may not know, but at that time psoriasis was considered to be a Th1 driven disease, but that study failed miserably. And we learned that psoriasis is not Th1 primarily driven. We learned that it is Th17 driven. So these are really important. Now also in atopic dermatitis, I think the failures taught us that atopic dermatitis is not a primarily eosinophil driven disease. So it's important to remember that because studies with IL-5 failed, and also some studies with keratinocyte derived molecules such as TSLP, IL-33, IL-25, IL-36, and IL-17 failed. So these are also important to really direct us to where we really need to go. Another important concept for us, and it's important as clinicians, but also in clinical trials, that a patient with moderate to severe disease that has substantial body surface area involvement, you cannot just treat them with a topical. You need to give them a systemic. Why is that? Because they have what we call the roof is burning. So they have so much body surface involvement that it leaks to the blood and they have increases in inflammatory markers, including atherosclerosis and cardiovascular related molecules. And that is also very important to consider in clinical trials. It's really important what patient you get into what trial. Now let's dive into do's and don'ts for clinical trial. So first of all, like everything in life, it's good not to be too ambitious to start with. You need to start small and perform really well. That's the general principle. Start with one trial. It may be that in the beginning you don't get the best trial ever, you know, but get a trial and perform really well. What does it mean perform really well? Enroll the right patients, enroll as many patients as you can and do the best possible job and do not take too many trials initially until you are having that confidence that you can do it well, because it's really important initially to build your reputation, right? The reputation is the most important thing you have and initially work very hard to build that reputation. And how do you do that? You build a patient database. Of course, if you are known for a disease or you have patients with that disease, it will be easier for you to enroll. So build a patient database. Let pharma companies know you are interested in clinical trials. That's also important. And again, in the beginning, you may not get the best ones, but you'll start with one. And believe it or not, if you do a good job, you'll have more and more and you'll have better and better studies. Now make sure you familiarize yourself into differences in atopic dermatitis across different phenotypes, different skin types, and the relevance to various scoring systems. For example, in African-American, it's much harder to visualize the scorings of the disease, right? The EZ and SCORA, you really need to understand different skin types and how redness manifests in these skin types or hyperplasia, how it differs between skin types. You really need to do a good job. And sometimes you may not have these patients regularly in your clinic. You still need to learn and understand these differences. Because if you score patients wrong, you get yourself not a good reputation and that's not a good thing. Now try to ensure you increase your reach to include a diverse patient population, including all skin tones and ethnicities. You need to make a really deliberate attempt to this. And train your staff well to recognize these important nuances and their relevance to scoring. Train them well on IGA, EZ, SCORA, NRS, and so on. They need to really know it inside and out. Another important thing that can really set you apart, do mechanistic analysis. That will set you apart and will get you to publish in higher impact factor journals. You don't want to be just one of 500 investigators that doesn't get into a publication. If you do mechanistic analysis, you'll be part of a smaller pool of investigators and your paper will get to be published in higher impact journals and you'll have more publications from that study. So be smart, get what you need. Get a fridge, get a minus 80 freezer, get a centrifuge, so you're really ready to take this on. You don't need a lot of equipment. It's not too expensive, but you need the right equipment, particularly the freezer, the fridge, and the centrifuge, and very little training needed. In fact, you'll get the training on the job, but you just need the equipment and then learn how to do it and do it well and teach your staff how to do it. So that will be really important because, first of all, you'll participate in higher profile studies, you'll get better studies, and tell the industry that you know how to do them and you are up to doing it. Now, sometimes even if you don't have a freezer, you can do them and you can ship in dry ice. So really important to try to get these because you will set yourself apart. Now familiarize yourself well with the collection and the storage of biomarkers and pick trials smartly. A novel mechanism can set you apart with some mechanistic evaluations, and that can lead to premier publications. In the beginning, you cannot be too choosy, but still, I think you can try and set yourself apart and tell companies and representatives that you are interested in these studies. And make sure to train your staff. Your staff are basically your delegates, right? You will be viewed by your staff. So you need to have a very well-trained staff. And make sure to attend in-person all investigator meetings, and make sure you fully understand the protocol inside out and its inclusion and exclusion criteria. And do not be afraid to ask questions. It's better to ask a question, even though you think it's not, it's a silly question, not a smart question, doesn't matter. You want to do a good job. So being a safe than sorry is always what you need to think about. You really need to be the side that stands out. Not in a bad way. You want to stand out in a good way. To be the side that did everything perfect, that really stands out in a good way. Now I want to also talk about an example of a novel mechanistic study being done at our center and how this can help our patients and our understanding. So these are tape strips that actually my lab really spearheaded the use of tape strips as a means to understand biomarkers in a minimally or even non-invasive way. Because at the end of the day, tape strips do not scar. Patients are really amenable to do that. I had quite a few patients say no to biopsies, but I didn't have patients say no to tape strips. They are quick. They don't leave scarring. And they are really a good way for you to be part of mechanistic analysis because it's very patient friendly. So can tape strips be used to evaluate biomarkers of therapeutic response in AD? And I'll show you that the answer is definitely yes. So what are tape strips and what are the principles of tape strips? Tape strips were introduced originally, as you know, as a detection method of melanoma because the pagetoid cells are really superficial. We adapted this method to inflammatory skin diseases and you sample basically until the middle of the stratum granulosa. So you are very superficial, usually high up in the stratum granulosa. And we did several studies, but I want to show you a few of them. Here we did a study, a real life study with dupilumab, real life, not a clinical trial. And here I'm showing you before and after dupilumab in real life. And I want to show you that you can really modify biomarkers really linked to atopic dermatitis, such as the chemokines associated with type 2 immunity, like CCL18, you have CCL17, so TARC and PARC, these are the major biomarkers of atopic dermatitis. And you see here filaggrin, you see IL-19, IL-15, IQOS, so many, many of the biomarkers that we know already from skin biopsies appear here. And the AX40 and AX40 ligand are also here. AX40 has another name, TNF-RSF4, and AX40 ligand is TNF-SF4. So even AX40 and AX40 ligand are here, and so is CCR4. So you can actually evaluate also for new targets using TAFEs. Many markers of general inflammation, TH17, like IL-19, T cell activation, and T cell memory cells, CCR7, IQOS, terminal differentiation. So super exciting that we can evaluate it in such minimally invasive means, such as tape strips. And be sure to understand how these are done. And of course, in different studies, you'll get training by the different companies as well. The TH2 markers, like we discussed, CCL17, CCL18, and CCL13. And we also compared how well the tape strip biomarkers, or those that we get through tape strips, are comparing to those that we get through biopsies. So we compared our real-life study with dupilumab with the biomarker study we've done with dupilumab in the clinical trial. And lo and behold, and these are not the same patients, but pay attention that the results are very similar. The decreases you get in biomarkers with dupilumab in real life with tape strips and in the biopsy study done in the clinical trial are very similar. So definitely tape strips are really good. Now it's not that you don't sometimes need biopsies to verify a particular molecule, but you can do that in a smaller number of patients. So what I usually say, tape strips should be done in all patients, and biopsies in those patients that are willing to give biopsies. And of course, blood should be done also in all patients. Now some other dos, treat your clinical trial patients as if they're part of your family. This is what we do, and they participate in many of our studies. And also allow them some free visits after the trial is finished. They really need to feel that you care, and we really do care. Many times they will return for many other studies if they feel valued. And make sure to include the appropriate patient reimbursement. You do not want your study to fail because you don't have money to pay patients for their travel, for participations in biopsies, in tape strips, in blood. This is a key component to success. Do not forget, you need to reimburse your staff, yourself, but also your patients. Super important. Do not dos. Do not be afraid to ask questions. Experts and the company, you need to be able to ask those questions. And do not hire too many people in the beginning. Do not be too ambitious. First make sure you succeed, and then expand gradually. And do not take too many trials in the beginning. It's better to enroll 10 patients in one single trial and be on a paper rather than two patients in five trials. You would lose money. You would lose reputation, and you'll not be on any paper. You need to build your reputation and start small and expand. Do not hire inexperienced people if you yourself are not experienced enough to train them. Extremely important that in the beginning you associate yourself with experienced people. You cannot rely in the beginning on inexperienced people. And specialize. Now there is a revolution in inflammatory skin diseases, and these trials usually are published in much higher impact journals. So specialize. And do not be overly confident. When you start, there are many things to learn, and good to devote time and effort to do it well. It will pay off later. You cannot want everything from the beginning, because then you'll lose more than what you'll gain. And do not miss phone calls, training in the beginning. Do not just rely on your staff. Be there yourself and attend these. First of all, it will make a good impression. And you need it also. Remember, it's ultimately your, the PI, responsibility. And do not enroll a patient that you have concerns that will not be compliant with the study. Try to minimize your dropouts. I know that sometimes we all want to have patients in the study, but those patients at the end will bring you bad reputation. If you enroll 10 patients and only two or three are sticking to the end, that's not good for you. Now another important concept, be all in or all out. Research is feast or famine. Sometimes you have a lot of trials that are competing with each other, and sometimes you have none. You need to invest wholeheartedly and have a skill team or do not do it at all. You don't have to do trials, but if you do it, be all in. And with that, thank you so much. I hope you enjoy it. I hope you'll enjoy clinical trials and mechanistic studies as I do. I'm a little bit unusual. I'm a physician scientist, so I'm doing some clinical trials. I do many more mechanistic studies, and I like the idea of bridging the clinic and the translational world. I think that's what's benefiting our patients. Thank you so much.

atopic dermatitis

clinical trials

disease control

biomarker analysis

patient management