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Betsey Zbyszynski: [00:00:00] Hello, I’m Betsey Zbyszynski, Head of Clinical Operations at Vial Health Technologies. And today we are here with Dr. Mark Lebwohl talking about challenges in a atopic dermatitis trials. How are you doing Dr. Lebwohl?
Dr. Mark Lebwohl: I am doing fine. Thank you.
Betsey Zbyszynski: Thanks for joining us. And I’ll give you an opportunity just to introduce yourself and tell a little bit about your background.
Dr. Mark Lebwohl: For the last quarter century, approximately, I have been chairman of the Department of Dermatology at Mount Sinai where we have conducted clinical trials leading to approval of most of the drugs in dermatology. My main area of interest has been inflammatory skin diseases. We have a huge clinical research unit in our department. We’ve been at the forefront of most of the psoriasis drugs that have come to market in the last two decades or more. I recruited Emma Gutman, based actually out a presentation she gave as a resident when she was at Cornell in which she identified essentially all of the cells and cytokines involved in the development of atopic dermatitis and put them together in a map that showed how they work and where they work. I recruited her here right after seeing that. And we were indeed the first to test dupilumab based on her work for the treatment of atopic dermatitis that of course has become a huge success in the form of Dupixent which is now helped tens of thousands, if not hundreds of thousands of patients worldwide, many of the subsequent IL-13 blockers, including tralokinumab, Adbry and lebrikizumab, which will be coming, are based on her work.
And even a lot of the JAK inhibitors, you can see where they are effective for atopic dermatitis based on her work. And some of the other new molecules coming that block TSLP also are based on work she did. So I’m very please that she has stepped into the chairman position and I am now Dean for Clinical Therapeutics across the entire Mount Sinai system.
In every area of clinical research, we have a major advantage in that we take care of about 43% of New York City. And we do have a very active clinical research program, which benefits patients that we take care of. I’m excited about my new position and that has led to a lot of research at Mount Sinai, so that’s my background.
Betsey Zbyszynski: That’s great. Congratulations on your new position. And I didn’t realize Dr. Guttman too. I’m really excited for her. I’ve known her for a while.
Dr. Mark Lebwohl: Wonderful. I’ve been the beneficiary of her being here. She’s great.
Betsey Zbyszynski: That’s great. That’s really, that’s great for the city as well.
Dr. Mark Lebwohl: Yep.
Betsey Zbyszynski: Okay. So let’s get into some of discussion on atopic dermatitis. This may be a question you get asked a lot, I’m sure. But what are some of the common pitfalls in atopic dermatitis protocol?
Dr. Mark Lebwohl: There’s one very specific one and that is especially for topical therapy. The FDA requires as an endpoint clear or almost clear skin with an investigator global assessment tool that goes from zero to four.
Zero is no disease. One is mild disease. Two is moderate disease. Three is severe disease. And four is very severe disease. There are other variations of that scale, so you can have zero is clear. One is almost clear. And that is the most common scale. Two is mild. Three is moderate and four severe. And the FDA on that letter scale requires clear, or almost clear skin — a score of zero or one, with two degrees of improvement. So if your entry criteria is a two going from a two to clear, two to zero is much harder than going from a three to one.
And if you have too many patients who enter with mild disease, it is very hard to achieve that endpoint. Whereas if you have a high proportion of the patients entering with moderate disease, a three on that IGA scale, then it is much easier to go from three to one than from two to zero. And I would say that’s the biggest pitfall and there actually have been drugs that have been denied approval on the basis of not being able to demonstrate a two-point improvement. So that would be probably the most common and major pitfall that I’ve seen. Second very common pitfall, especially in atopic dermatitis is there is a large placebo effect. And as recently as the last couple of years all of the drugs, if they have good vehicles, will have a decent placebo effect. And to have a placebo effect in the 20 to 30 range is not abnormal. Even a 40 range you can get with a placebo, but I would say a big pitfall in the success of a drug that goes up for approval for atopic dermatitis [00:05:00] is investigators that are not good at distinguishing that placebo effect from the therapeutic effect of the molecule that you’re looking at. And in fact, the drug that indeed was approved for psoriasis failed in its first attempt to get approval for atopic dermatitis, even though the mechanism should have worked. And the reason it didn’t was when you look at the investigators, they had investigators who reported a placebo effect of 55%.
And and I have just have to say that you have to then step back and look at. Which investigators, really separated out the placebo from the active drug. And if you went back to those investigators and had them repeat the trial, you’d get an approvable drug. I think picking your investigator is really critical to the success of a clinical research program.
Betsey Zbyszynski: Yeah. Particularly in dermatology too. And yeah, it’s interesting what the placebo effect. I’ve seen that in a lot of acne studies as well, and I think sponsors should take a look at their sample size to make sure that they’re powering it correctly to be sure that they account for that placebo effect as well.
Dr. Mark Lebwohl: Yup. I think that recruitment of investigators is actually key to everything you want to get investigators who are not only good at examining their patients in distinguishing differences in efficacy. And sometimes I hate to bring honesty into it, but, sometimes simply they’re investigators who will rate everyone, even if they’ve not seen them or hardly seen them.
And that is a terrible thing to say, but I believe particularly actually, when that does happen, the second thing that I would say is that the investigators have to be able to recruit adequate numbers of patients. And they also have to be not only well-trained, but they have to see enough of a disease to be able to distinguish the different levels of efficacy on an IGA scale. So all of those factors play into the success of a drug trial.
Betsey Zbyszynski: Yeah. Completely agree. How do you advise sponsors who are concerned about the recruitment for their atopic dermatitis trial? We know the market’s so big right now with atopic dermatitis. It’s very crowded.
Dr. Mark Lebwohl: Yeah, it is very important to pick investigators who take care of a lot of atopic dermatitis. First, because they’re better at using those scales. They use them more often. They see more patients. But secondly, they’re good at recruiting patients and it is true that there are a lot of trials out there.
So when you go to an investigator, you have to ask them what competing trials do you have? Is that going to slow down our recruitment in that’s key. It doesn’t do you any good if you’re planning on your timelines to finish the different phase trials in six months only to see that it takes you two years instead.
So I think that is critical as well. The other reason it’s important to pick good investigators. And I’ll give you an example of a trial in which I was a consultant for a company years ago. And over my objections, they went to a part of the world where we had bad experience before in terms of investigators just reporting every patient as getting. And then you have to question, did they really do the study? So this was a study that was done at five sites and three of the sites were in Eastern Europe. And actually all of the sites were in Eastern Europe at two of the sites, the study result was highly statistically significant enough, so that the overcame, what looked like to be no effect at the other sites. It was actually a combination product. There was an active drug, a placebo, and then a combination product with the active and another ingredient. So at three of the sites, All of them worked including the placebo arm. Now we knew that the placebo was not as good as the active, because that was already an approved drug yet at three of the sites, there was no difference between the placebo and a drug that we knew worked.
So you really have to then sit back and question. I found that very troubling at the time, and I learned a lesson you’ve got to go to investigators, go look at trials, that had good outcomes and use the investigators who were in that trial for the same disease state.
Betsey Zbyszynski: Yeah. And you can look for trends as well. I know during trials, as the data’s coming in and try to combat that at the beginning. Yes. Yeah.
Dr. Mark Lebwohl: And I will say a good CRO does exactly that they go and recruit the trials where they know they have experience where it worked. Sometimes the data is not published.
Sometimes it’s not published because the data’s didn’t warrant the drug to be come successful. Sometimes it’s not published because it’s in press. [00:10:00] Sometimes it takes actually months to years to publish an article. And I’ve actually had good articles that took over a year to get published.
But you need a CRO that will actually do their homework and make sure that they pick good investigators.
Betsey Zbyszynski: Yeah. Especially here in the US. Folks that run dermatology trials, you know who to go to. There’s good investigators.
Dr. Mark Lebwohl: I will say that the reverse is true too. Investigators not to go to as well.
Betsey Zbyszynski: Exactly. What is the most exciting development in a topic dermatitis that you didn’t expect?
Dr. Mark Lebwohl: So I will change that and make an inflammatory skin disease because one very exciting I’ll give you a couple of examples, but one very exciting thing in psoriasis was I had a patient who is going undergoing an inflammatory bowel disease study in our GI department.
And I was seeing her for psoriasis and she came back to me after being in that trial. And this has happened to me a few times. Now that I’m talking about it and she said, my psoriasis cleared up and that was a drug that Abbott had the time, I think it was before they broke Abbvie off of Abbott.
And I called the company and I asked them if they would give me the drug to test for psoriasis and they refused, but sure enough, a couple of years later others must’ve gone to them and they ended up going forward with psoriasis trials. The drug was in fact highly effective, but ended up not being pursued by the company because they had some adverse events that I think they made a mistake in not pursuing that drug, but that was exciting at the time. Another exciting breakthrough that happened to us, we were seeing a patient who we were injecting intralesional with steroids for sarcoids of the skin. And she comes back to me.
And again, this is a trial that was done for systemic sarcoid and she got an IV drug called infliximab and of course her cutaneous sarcoid disappeared. And we realized that TNF blockers of which infliximab is the strongest would be highly effective for sarcoid, and then indeed, that is now used for that.
Another surprise I remember was something that took us by surprise. This was actually the trial where I had recruited Emma Guttman. We actually called Regeneron to get to dupliamab for the treatment of atopic dermatitis. And the first patient in this study was a patient of mine.
And in that study, it was a dose escalation study. So you start with the low dose in every cohort of patients you go up. This was the first patient. He had been a patient of mine for years. He started at the first injection of the lowest dose. And a week later we knew he was better. So that was really unexpected, a major surprise, we’re expecting to go to higher and higher doses before we get a therapeutic response.
And this guy responded at the lowest dose. So we knew right away that dupilumab was going to work. And that in fact was a real home run.
Betsey Zbyszynski: It is now. That’s great.
Dr. Mark Lebwohl: Yeah.
Betsey Zbyszynski: I love those surprises too. I know it’s not in dermatology, but it happened in ophthalmology with that glaucoma drug, Bimatoprost, and they found that it lengthened eyelash.
That was one of those unexpected treatments.
Dr. Mark Lebwohl: Sure. If you think about it, cyclosporine, which was for many years used and still is used for psoriasis, that was discovered in a transplant patient who happened to have psoriasis and it just cleared the patient’s psoriasis.
Betsey Zbyszynski: Wow. And that’s been used in a lot of different dermatology indications.
Dr. Mark Lebwohl: Absolutely, atopic dermatitis and psoriasis. Yep.
Betsey Zbyszynski: When was the last time you changed your mind about a new approach to treating atopic dermatitis?
Dr. Mark Lebwohl: The oral JAK inhibitors have been approved for a variety of indications. First being used, for example, for rheumatoid arthritis and the first one used for a dermatologic indication was the use of Xeljanz or tofacitinib for psoriatic arthritis and Xeljanz indeed was associated with a number of effects, which are not common, but were increased and it got boxed warnings for heart attacks, major adverse cardiovascular events, pulmonary embolism or deep vein thrombosis, cancer and infection. And subsequently, upadacitinib, RINVOQ, was approved for psoriatic arthritis and recently approved for atopic dermatitis, which is abrocitinib, was also approved for atopic dermatitis and Opzelura, which is a topical therapy for atopic dermatitis also got that box warning and the topical therapy I will take out of it because, even though it’s on occasion absorbed to a significant degree, like 8%, I understand why the FDA gave it a box warning.
So I’m taking that drug out of it. I had [00:15:00] been hesitant to use the oral JAK inhibitors based on the box warnings, but in fact, the risks proved to be low. And when I had patients who had particularly severe psoriatic arthritis that I treated with tofacitinib, I went and actually looked into the real risk of those box warnings.
And because there were so low, I started using them not only for psoriatic arthritis, but also for atopic dermatitis and they are quite effective. In fact, I would say both, upadacitinib and abrocitinib are at least as effective or even more effective than dupiliamab. And so on, when I have particularly severe patients, I do use those drugs. I have patients who for a variety of reasons are not good candidates for dupiliamab, I also use those drugs. And I find the number of patients I’m treating with oral JAK inhibitors growing every week. We’re also diagnosing a lot of what I would call psoriasis, PsEma psoriasis plus eczema.
And we have quite a few patients who have features of both. And of course those drugs work for both diseases so I’m using more and more of them for that reason.
Betsey Zbyszynski: That’s really great to hear. I know the JAK inhibitors have been getting a bad rap lately. What about, have you been involved in JAK-2 combination compounds?
Dr. Mark Lebwohl: I have actually, and in fact, I was going to answer the last question you stated with the discussion of deucravacitinib, which is the BMS JAK 1 TYK2 combination. And we were offered that trial. And at first I was very reluctant to bring the early trials to Mount Sinai because I was worried that a small molecule will never be as safe as an injectable molecule that is more targeted.
But they actually created, so they did their early phase trials. And then the phase III, we actually did in the dermatology department at Mount Sinai. The deucravacitinib had a very safe safety profile in its phase II, even though I’d been worried about it. And then when I looked into how the molecule was made, it actually is very different than the JAK inhibitors.
It primarily blocks TYK2. I said JAK-1 and TYK2, that’s wrong. It is a selective TYK2 inhibitor, it hardly has any impact on JAK-1, 2 or 3. And so it’s pretty exclusively a TYK2 inhibitor and TYK2 primarily influences interleukin-12 and interleukin-23 very similar to a ustekinumab, Stelara.
It does also impact interference. So I would say you can’t just call it a Stelara, like drug nonetheless. It has a safety profile that looks like ustekinumab, which is a very good safety profile. So I have been very excited about deucravacitinib and we had no trouble in our clinical trial of it and expected actually to be quite successful when it comes out.
I don’t know if the FDA will give it a box warning that it does give to the other JAK inhibitors, but whether it does or not, this one clearly has distinguished itself. It shows none of the lab abnormalities that you see with the other JAK inhibitors. And I hope it will have a safety profile similar to the to ustekinumab, which is a very safe drug.
Betsey Zbyszynski: Yeah, that’s a, that’s great. I’ve been hearing more and more about those compounds. So I’m hoping that R&D, more development in those. Another question. So on a scale of one to 10, how optimistic are you about the current therapies that are being studied in clinical trials for atopic derm?
Dr. Mark Lebwohl: Oh, very optimistic. So I think some of them are going to fail. Someone will go by the wayside, but I think we are at a point for atopic dermatitis, similar to where we were when etanercept was first approved. And even before that Amevive, alefacept, and Efalizumab, raptiva, were first approved, the latter two drugs were not that effective.
So when etanercept and the TNF blockers entered the stage those stopped being used and were taken off the market. I will say efalizumab also had rare occurrence of a progressive multifocal leukoencephalopathy there were five cases of that among thousands of patients treated. And I think the company withdrew it, not just because of that side effect, but also because the drugs just didn’t work as well.
So the TNF blockers were barely effective. And back then, we thought that a PASI 75, 75% improvement in a psoriasis severity measurement was a home run. Today, we don’t even look at Pepsi 75. We’re looking at PASI 90 and PASI 100. In fact, hopefully to be approved soon, bimekizumab is the first drug we’ve ever used with the majority of patients achieve PASI 100, not a drop of psoriasis left during the [00:20:00] placebo controlled period of their study. And that’s just extraordinary to have more than 50% clearing completely is something we’ve never seen before. Right now if we get an easy 75, that’s the eczema severity score, we consider that a home run, but I’ll predict that, 10 and 20 years from now, we’ll be looking at easy one hundreds just as we did in psoriasis. The other reason I’m optimistic is that we are also now going to start treating effectively alopecia areata, vitiligo and a host of other diseases that would benefit from some of the atopic dermatitis treatments.
Betsey Zbyszynski: Oh, the same treatments for those indications as well.
Dr. Mark Lebwohl: Yes.
Betsey Zbyszynski: Wonderful.
Dr. Mark Lebwohl: On a 1-10 scale, I’d rate it at 10.
Betsey Zbyszynski: Oh great.
Dr. Mark Lebwohl: Maybe an 11.
Betsey Zbyszynski: It goes all the way up to 11.
So the last question here, if you were king for a day and you could allocate $250 million into research and development, what would be your focus.
So I’ll separate that into dermatology and non-dermatology. I think that with my Dean’s hat as Dean for Clinical Therapeutics, the biggest killers today are heart disease, which is actually being addressed fairly well.
Dr. Mark Lebwohl: And there’s certainly room for improvement and there is a lot of work in that area. But cancer, there are still many cancers where we have not much hope. That is getting better by the day. Cancer is becoming more and more of a chronic disease where it is controlled, but it’s still will remain a big killer.
And I think we still need breakthroughs in cancer. And I would allocate a ton to cancer. The other areas that we don’t think about are neurologic diseases that are starting to impair the lives of our older patients. As people are living longer and longer, Alzheimer’s is devastating and we desperately need a treatment for Alzheimer’s disease.
The demyelinating diseases like multiple sclerosis, we still could do better. Parkinson’s disease, a lot of the neurologic diseases, we really still could do much better than we are. So I think that there’s a lot of room in neurologic diseases.
Moving to the dermatology side, we are doing very well in many inflammatory skin diseases. We could still do better in atopic dermatitis and vitiligo, I think is a devastating disease for which we do not yet have any approved therapies. I think that topical ruxolitinib, Opzelura, will get approval for vitiligo. I hope. I do think that we still, when you look at the impact of our current treatments on the quality of life, vitiligo patients, we are getting repigmentation and actually with the Opzelura, a fairly good repigmentation, but it’s still taking too long to get there.
And I think nobody’s going to allow someone to do a three-year long placebo controlled trial, but I think until we get. More and more pigment only then will we see the improvements in the quality of life of patients? Because if they go from, 50% vitiligo or 75% less vitiligo.
There’s still a lot of deep pigmented areas left. And the impact on quality of life is not good enough if you still have a lot of deep pigmented areas left, even though that there are fewer deep pigmented areas. So that I think is a real, a devastating disease. We also need a lot of help in viral diseases.
We are still far from having a routine treatment that can clear warts. We are hopefully soon to get a topical cantharidin that will help molluscum. But I think improvement in viral diseases and specifically cutaneous viral diseases is badly needed. And then there are some common conditions.
Even one associated with atopic dermatitis, for which we don’t have any treatments and that’s keratosis pilaris now it’s not a devastating disease, which vitiligo can be, but there are individual patients who have it severely for which we still definitely need a treatment. The same holds true for ichthyosis.
And again, ichthyosis vulgaris again, associated with atopic dermatitis, but we are not good at treating ichthyosis with chronic treatments you can use long-term. So it’s true that topical retinoids help a little bit, but you really need oral retinoids for severe disease and long-term oral retinoids are difficult to use.
Betsey Zbyszynski: Yeah. And I know a lot of dermatology diseases also come with emotional and mental challenges for these patients.
Dr. Mark Lebwohl: Suicide rates in diseases like a atopic dermatitis, psoriasis and vitiligo are actually dramatically increased. And certainly we certainly understand why patients are debilitated by something that affects their appearance.[00:25:00]
Betsey Zbyszynski: Yeah. Thanks for all your hard work in developing and being a part of some of these clinical trials, Dr. Lebwohl and congratulations again on your new position. That’s really exciting for you. I’m sure there’s going to be a lot of challenges for you there being Dean of the whole current therapies, but thank you for your time today.
It’s always a pleasure to speak to you.
Dr. Mark Lebwohl: My pleasure and it has been rewarding. So I will say yes challenges, but but it’s been rewarding. Thank you very much for having me.