I'm Mark Lebwal. I'm Dean for Clinical Therapeutics at Mount Sinai, where I served as chairman of the Department of Dermatology for nearly 25 years. This is my list of disclosures. Most of the dollars here go to the Department for Clinical Trials that we do in the department, not to myself. And I do work at Mount Sinai full time. And here is a view from my window. And obviously psoriasis is an area of expertise for me, as are other inflammatory skin diseases. But we see every kind of skin disorder, including acne and warts and skin cancer, and have done trials in all of those areas. So here are the reasons why dermatologists should be involved in clinical trials and industry relationships. First of all, it helps you provide the best care for your patients. Nobody comes out with a new drug because it's the second best. They are always trying to make the best drug. Secondly, it builds your reputation. Thirdly, it helps the specialty and the world and helps patients around the world. And finally, clinical research income is financially worthwhile and should be above criticism. When we do clinical trials, it helps everyone in dermatology. So let me start out with it helps you provide the best care for your patients and give you some examples of that. And this is a patient who I had taken care of for a number of years. The patient had a metastatic basal cell carcinoma, usually fairly rapidly lethal. And he was sent to me to put him on a retinoid to shrink the tumor and keep it in control, which we did as best we could. He had radiation therapy and Mohs surgery. But the tumor was kept in control for a period of time. And then I learned about the Vismodegib trials taking place. I contacted the company that made the made Vismodegib. They awarded us the trial at Mount Sinai and I really did it for my patient. This patient, you can see a tumor over here. And what you see, here's the paper about the one of the first papers about the hedgehog pathway. And what it showed is in 33 patients with very locally advanced or metastatic basal cells, 16 were had partial and two complete responses. It did have a number of side effects. Here are some of the photos from those patients at baseline and at week 32. And here's a photo of my patient and you see the blue arrow pointing to the tumor on his CT scan. And here it is after he went on Vismodegib, the tumor has disappeared. And this patient now we're 15 years later is still alive. He's on hedgehog inhibitors intermittently, most recently Sonodegib, which may be a little better tolerated, but has maintained remission since that time. So here's a double blind placebo control trial of Sonodegib, another hedgehog inhibitor. And that's what we have been using actually recently. And the reason that we've been using it is because patients get severe muscle cramps and also alopecia as a result of hedgehog inhibitors. And those are usually the side effects that prevent us from using these more often. However, they usually take several months to occur. And in particular, the muscle cramps, which can be awful, take several months to occur and you can delay them further by starting L-carnitine, which we did with this individual. This individual, by the way, is a physician and actually gave me permission to even tell you his name, which I won't, but but there's no, I'm not bound by any HIPAA rules because I am released to show his photos. So here's his, here's a patient before Sonodegib. He came to me and said, you know, they told me I'm going to have a deforming scar and they're going to cut my tear duct. What can you do for me? We put him on Sonodegib and I told him, when you start to get the muscle cramps, we're going to do Mohs surgery. But hopefully it will be much smaller than what you need now. So here he is after four weeks. He does not have any muscle cramps at all, no symptoms at all, no side effects at all. After four weeks of Sonodegib and you see how much smaller the tumor already is. Here he is eight weeks later. And again, you see how much smaller the tumor is. And here he is at 18 weeks. He is just beginning to get muscle cramps. And at that point we did Mohs surgery. And of course the excision is dramatically smaller than it would have been. And he ended up with a beautiful scar. So a very small scar, thanks to Sonodegib. And we are routinely doing this for basal cells that are likely to leave a deforming scar. You can make those much smaller. Okay. And that's actually something we're doing right now. And I'm very excited about the fact that we're doing it right now because it really helps patients with a disease that can be very common and very deforming. Okay. It builds your reputation as the second bullet. So this is actually one of my most cited papers. And we had figured out when calcipotriene was introduced and the only treatment used before then was halabetasol, we figured out that the combination of the two was better than each one individually. And here we showed that in a trial. You see that patients who had halabetasol in the evening and calcipotriene in the morning did statistically significantly better than patients on halabetasol only twice a day or calcipotriene only twice a day. And this was in a limited period trial, but then we followed patients for months, six months. And we compared the combination of calcipotriene with weekend therapy with halabetasol to just placebo and weekend halabetasol. And you see the placebo line in green, the remission is substantial, the plaques get worse compared to the combination line where for the six months the patient maintained, the patients maintained their remission. Now we also at that time, people were mixing steroids and calcipotriene together and we knew that they weren't compatible. So we actually did a, this was an in the lab study where we had a chemist analyze the survival of calcipotriene in combination with other topical medicines. And what we showed here is, first of all, if you add salicylic acid gel, another at that time, another commonly used psoriasis treatment to calcipotriene, it inactivated the calcipotriene immediately. In fact, we had to raise the pH of the solution by adding sodium hydroxide in order to get any stability at all. And even then, the calcipotriene was degraded over a few hours. We also showed that hydrocortisone valerate, a topical steroid use at the time, inactivated calcipotriene over a matter of hours. And then we showed other agents that were indeed compatible with the two, and that actually led to the development of medications like the combination products with calcipotriene and betamethicone dipropionate, which were put in special vehicles to minimize the acidity of the combination in order to allow the calcipotriene to survive. We also showed the combination of calcipotriene with ultraviolet light. So at that time, a lot of my career depended on this new topical therapy that had been developed at this point nearly 30 years ago, and many of my articles were in fact cited. Here's one where when PUVA was being used, we showed that UVA inactivated some of the calcipotriene, and conversely, we showed that calcipotriene inactivated, calcipotriene blocked UVA so that it told us you had to apply the medication after light treatments, not before. We also showed it in combination with UVB. So for many years, a lot of my career depended on my working with pharma to show how we could impact psoriasis beneficially in combinations of therapy that were used. Subsequently, infliximab was developed. It was used for Crohn's disease first and arthritis, and by its mechanism, we suspected that it would work for psoriasis. And here's one where I wasn't able to get the infliximab from the drug company, but I managed to find a patient with Crohn's disease who also had psoriasis who needed to be treated, and we showed that indeed the infliximab cleared psoriasis in this patient who also had Crohn's disease. Subsequently, we did many trials looking at the combinations of the use of TNF blockers in patients who had psoriasis, and those emerged for a long time as leading treatments for psoriasis. When tacrolimus first came out, it was approved for atopic dermatitis, and I knew simply by trying samples in patients with psoriasis that indeed it was very effective, specifically on the face and in intertrigenous areas. Those are thinner skin parts of the body that respond more readily to treatments, and we then subsequently showed that pimacrolimus cream also was effective, another topical calcineurin inhibitor, specifically for facial and intertrigenous areas, and those are areas where we don't like using topical steroids because they thin the skin too much. So here's one of the first patients I treated, and you can see she has psoriasis under her breasts. Here she is one to two weeks later. Here's a patient with psoriasis in the groin. All of these photos are taken at a maximum of two weeks difference, so they were quickly in those areas, here again before and after two weeks. Our next point is that involvement of dermatologists with clinical trials and industry relation helps the specialty and the world, and this is a photo of a patient, and I'll never forget what she said to me. She was an oncology nurse here at Mount Sinai. She had dozens of actinic keratoses, and I prescribed 5-FU, which was the only treatment we had at the time for widespread AKs, and she came back and she said, I can tell you what the FU stands for. This is a miserable treatment. Now at the time, imiclomide was developed for genital warts, and we knew its mechanism of action. It caused release and increase of interferons, and indeed that was shown in animal studies, so we went into this knowing it. Now, intralesional interferon was also available, was actually approved first for genital warts, and here Libby Edwards and her colleagues showed that when you inject intralesional interferon into actinic keratoses, they resolve. The problem about injecting it, though, is that many of the patients would develop flu-like symptoms or neutropenia from the interferon injections, something which only happened in massive overdoses of imiclomide cream. So, and she then showed that topical interferon had an impact on actinic keratoses as well, and so at the time, I actually had developed an actinic keratosis myself. We had samples of imiclomide for genital warts in our sample closet, and I tried it on myself knowing that interferon was good for AKs, and indeed I probably overdid it, but the AK disappeared in a short period of time. I told that to a patient who was a physician at Mount Sinai, and he said, oh, I want to try it. Now, this is a patient who had probably not gone more than two months without a squamous cell carcinoma or numerous actinic keratoses on his very sun-damaged scalp, and he applied the imiclomide samples, and he actually applied them every day for a month, and he called me up, and he said, you better look at this, and here's what his scalp looked like, but here's what it looked like when we stopped the imiclomide, and he did not get another AK or squamous cell for more than five years, so a very dramatic benefit. We took that information and did a bilateral comparison control trial where we showed that we used imiclomide on one side and vehicle on the other side, and you see here the vehicle-treated side still has actinic keratoses on the right hand. The imiclomide-treated side on the left hand is clear, and they had similar amounts of AKs before. Again, this is the vehicle-treated side and the imiclomide-treated side. Here is a side of a forehead which was symmetrically studded with actinic keratoses. On the imiclomide-treated side, we've cleared them. On the vehicle-treated side, they are still there. Again, here's the vehicle-treated side. Here's the imiclomide-treated side, so we then approached the company that made it at the time. It was 3M Pharmaceuticals, and we said, you know, we'd like to do a placebo-controlled trial to go after approval. We did that, and indeed, I was the lead author on that. It helped me, but more importantly, it helped patients everywhere. For many years, this became a leading treatment and still is a leading treatment for actinic keratoses, and now even is used to treat basal cell carcinomas. Another reason to pursue clinical trials and interact with industry. Here's yet another one that was done at Mount Sinai and at two other sites, Michigan and Pearl Grimes in Detroit worked on it, and we treated patients with afomelanotide, which is an MSH analog, thinking that that might help vitiligo, and we did it in combination with narrowband UVB phototherapy. The drug is now approved for erythropoietic protoporphyria. That is what it was developed for, but we convinced the manufacturer to try it in vitiligo, and here's our data. This is in combination with narrowband UVB in 24 weeks. We never see this kind of repigmentation, and with afomelanotide, we did. So, very dramatically effective treatment. Not yet approved for vitiligo, but hopefully one day will be. Okay. This is actually the study of infliximab that I showed you earlier, where we used infliximab to treat pyoderma gangrenosum. So, I'm going to close with a series of letters. The bottom line for all of this is when it helps our patients, it helps us, and it helps a specialty, and these are three letters I got right around Christmas time in 2016. They were holiday letters, but beautifully written, and they just made me feel wonderful, and there you see, you know, thank you for the care. You've always made us feel well taken care of. Words are insufficient to express, and so on, and I just love getting those letters, but the bottom line reminds us that what we're here for. I'm going to close with this slide, which tells you my point of view about clinical trials. So, the optimist says this glass is half full. The pessimist says it's half empty. The realist says it's half full and half empty. Be an opportunist. Dear pessimist, optimist, and realist, while you were busy arguing about the glass of water, I drank it. Sincerely yours, the opportunist. Take advantage of the fact that we have so much development in dermatology, and you see that many of the things that launched my career were off-label uses of drugs that were already developed. You may have your own ideas. You may have new ideas, or you can simply use drugs that are out there to further expand their uses, and that has held me very well, and I hope and think it will help you. Thank you very much.

clinical trials

dermatology

new treatments

Mark Lebwell

patient care

dermatology advancements

off-label drug use

patient care innovation

Mark Lebwal