Betsey Zbyszynski: I am Betsey Zbyszynski. I head of Clinical Operations here at Vial, and today we are excited to be speaking with Dr. Amy Paller. Our topic of today is pediatric and rare dermatology indications. And hi Dr. Paller, thanks for joining.
Dr. Amy Paller: Hi, Betsey. I’m Amy Paller. I’m the Chair of Dermatology at Northwestern University Feinberg School of Medicine, and I practice as a Pediatric Dermatologist. I’ve run the pediatric clinical trials unit here for more than 25 years.
Betsey Zbyszynski: Wow, great. So I’ll start out with a couple questions. You work in pediatrics, you also work in rare disease. What are some common pitfalls that you see in protocol designs with pediatric and/or rare disease dermatology trials?
Dr. Amy Paller: I think the biggest pitfall is not thinking about the patient and the family. You just can’t put into pediatric trials and same problem to some extent with rare diseases because they’re often pediatric. The same kind of expectations for the patient that you would in an adult trial. For example too many visits are a much bigger problem when families have to coordinate schedules, when a child has to be pulled out of school when people have to come from a distance, which is often the case with something that’s a rare skin disease. So being creative and trying to minimize the number of in-person visits and possibly instituting more teledermatology visits with more photography, or even sending a nurse to the home, to be able to gather samples and really establish what is almost as good as an in-person visit, are creative ways to try to minimize how many times that family has to be disrupted to come sometimes a long distance.
Of course, laboratory tests are another big item. No child likes pain, and it’s very hard for a family to subject a child to pain in their effort hopefully to make a child better. So having blood draws as infrequently as possible, and using technologies that are noninvasive is really what’s coming and what needs to be done for getting people interested in doing trials. There are a lot of other things too, for example, thinking about what your exclusion and inclusion characteristics are. And if they’re realistic, thinking about what medications have to be stopped during a trial. If you’ve got somebody let’s say with very dry skin, and you say, you can’t use moisturizers. Or someone who has recurrent infections, who finds at certain bathing techniques, or really helpful for that, and you say, “Can’t do it.” You’re going to have people who are gonna be very hesitant to break with routine. And it’s likely that these aren’t gonna even affect the results of the trial. So you have to think carefully about that.
You might have patients, for example, with epidermolysis bullosa, rare blistering disorder. And if you say that they can’t introduce any new oral medications, and yet they’re in terrible pain ’cause they have a large blister and they can’t even take Tylenol or ibuprofen, that’s a real problem. These have all come up in trials that I’ve done, and I think, thinking about the burden and what’s realistic is of critical importance. I would also add too, that burden comes from time. Many times when you’ve got somebody with kids, when you’ve got somebody with a rare disease, there’s already a huge burden just taking care of that disease or just taking care of other children at home.
And to think about how long things take that you’re asking people to do at home. Thinking about how long visits take needs to be part of that consideration as well. We love to get patient reported outcome. That is critical. But if you take too much time doing that, is another burden that’s gonna be making it very hard, not just recruitment, but certainly retention as well. And if you can’t get to getting your results because you can’t keep people in a trial long enough, that’s another problem. I think a very important question is rescue. We really wanna do monotherapy trials as much as possible, but that means for somebody on placebo, [00:05:00] particularly if they’ve had to wash out from something before starting and we wanna keep those washouts as short as possible, of course, but when they come into a trial and they’ve already got that period and they’re in bad shape to meet criteria, you’ve gotta figure out how to keep them in a trial and what’s gonna be meaningful.
And we’ll often think about not rescuing, for example, in the first month or even two months to really get an idea of how well a medication’s working and then allowing rescue and what do you do with those results? Are they valid? And can you keep somebody in for at least safety, if that’s a major part? I think the other thing that, that we might wanna think about with respect to other agents in treating is just any tricks to reducing misery for patients. So even travel can be a problem, figuring out ways to pay for travel that is comfortable. Someone may live two hours away and you may say, oh, and you can drive in, but wouldn’t it be easier for that person to have somebody drive them?
So maybe you have an adult with a rare genetic disease coming a distance, and they’re already losing hours in the office during the clinic visit, think about putting a little extra budget in so that people from a distance can fly and fly comfortably, that people drive them around. Of course, the routine, having a hotel and meals and things, but particularly for patients who have rare diseases, if you wanna attract them, you’ve gotta make that trip as comfortable as possible. So those are just a few things off the top of my head. You’ve gotta put in the budget that makes it fun for them, little gifts for the kids never hurts. You’ve gotta put in enough that it makes it worth the while. The burden is huge for being in a trial and often the benefit is limited. And of course you’ve gotta accommodate to the needs of patients who live anything other than a very close trip.
Betsey Zbyszynski: Yeah, those are all really good points. We’ve, really taken that into consideration too. I’ve run some pediatric derm trials and it’s very different trying to recruit those than you are when you recruit an adult population. Again, taking the burden off the parents, they may have other children, they might need childcare for the, their other children coming to the visits. There’s so many factors in there that affect the whole family. So I agree, just really being aware of the patient’s time, the family’s time, and the caregiver during the trial.
Dr. Amy Paller: And of course rare disease versus pediatrics, that can be very different. You can be talking about a relatively common pediatric disease and it’s and you’re talking about a rare disease and there aren’t that many people in the entire United States. So I think rare disease is a whole different area where creativity is really needed. I would say with rare diseases if there is an advocacy group, you really wanna work closely with that advocacy group to figure out how you can reach the greatest number of patients and have focus sessions talk to people up front to really understand the disease, understand what the burdens are, understand what would make a trial attractive to individuals with that and what you’d have to do to bend over backwards to get these patients recruited and staying in.
And when there are very many patients, it’s sometimes hard to just do a routine placebo control trial. You may have to think about left, right comparisons. You may have to think about having someone flip over from one arm to another, to be able to guarantee and you certainly also may not even understand the natural history of the disease and need to have a preliminary trial where you’re just studying the natural history. I have seen many anecdotal reports and then you do a clinical trial and you do not realize how much there is fluctuation in the natural history of the disease until you do the trial and you find out, oh, this person was at a peak when coming in on placebo and got better. It wasn’t because of placebo, it was because of the natural course of the disease itself. So these are all things that are really important.
I would say one of the most important things to remember is that you gotta have some benefit for the individual who’s in the trial. And they have to understand that there’s something for them at the end of the road. People are often miserable with some of these rare diseases. They can be itchy, they can be in pain, they want something that’s gonna work for them. They may not be that altruistic that they’re going to be in something for the next [00:10:00] generation. So think about what’s in it for the individual and really important to that is especially if there’s a placebo arm early on that they’re gonna get the real thing at the end and they’re gonna get it for a while.
There’s nothing more discouraging and it’s one of the reasons it’s hard to fill studies, when you’re just putting it on one arm, but your entire body’s affected and you can’t use anything anywhere else. Or, it’s going to be a 12 week study and you may be on the placebo arm and you get nothing at the end. So something to try to help them out, even if it’s a guarantee that they can just have the open label once the safety is guaranteed is very important.
Betsey Zbyszynski: Yeah. Patients with rare disease, their lives are already so challenging. So now you’re inviting them to participate in a clinical trial, which could upheaval their life a little bit. So yeah, agreed.
Dr. Amy Paller: It will affect their life. People work, they can’t miss too many days outta work. And, we’re sometimes talking about a situation where they have a disease that already threatens their ability to get to work every day. You take them out of that environment and they could lose their jobs. They certainly are already spending sometimes hours a day, just caring for their skin, and now on top of this, you are throwing in extra hours that take them away from all the things that they must do during the day and also potentially introducing stress, the stress of having to travel, the stress of having to deal with traffic, parking, navigating the hospital system, where they’re seeing, etc.
Betsey Zbyszynski: Yeah. Patient focused is very important and very important to keep in mind when designing protocols. What is the most exciting development in rare pediatric dermatology disease trials that you did not expect?
Dr. Amy Paller: Oh my gosh.
Betsey Zbyszynski: [laughs]
Dr. Amy Paller: Uh, Well, [laughs] we always hope for good results. We don’t always get them. [laughs] So I would say more the ones that we’re disappointed by are the ones we don’t expect, ’cause we’re very optimistic. I’m pretty excited about some of the studies that are involving repurposing and really treating based on pathogenesis. I’m certainly excited as well about early gene therapy or gene manipulating types of studies and watching them as they unfold. So I think those are the two areas that I’m keeping an eye on, whether we’re talking topically or systemically, repurposing based on understanding pathogenesis and then anything we can do that’s gene therapy and hopefully over time curing ’cause that’s what the patients want.
Betsey Zbyszynski: Yeah. I’m seeing more and more gene therapy trials or new small biotech companies popping up with gene therapy. Do you think that’s becoming more popular with dermatology indications?
Dr. Amy Paller: I think that the word gene therapy is both exciting and scary to patients and gene therapy has been used fairly broadly. Gene therapy can be putting something into cells, growing skin cells into a sheet and grafting that onto the skin, and those studies are ongoing. Gene therapy has also been used to be the term to not permanently changing the gene, but introducing gene as a pharmacologic tool and allowing our own skin then to be the factory that takes that gene product, turns it into a protein rather than giving a recombinant protein.
So it can mean several different things and it’s not necessarily a cure. For example the, last one I mentioned is very innovative. It may be more cost effective. It may allow you to do something right then and there on the skin. So it may be delivering it right to the correct place, but it’s not a cure and requires as with any pharmacologic intervention, recurrent application, if it’s topical or administration, if it doesn’t incorporate into the genome.
Betsey Zbyszynski: Interesting. It’s a good area and I only see it progressing more, at least from 10 years ago we got this far, so that’s pretty good.
Dr. Amy Paller: This is where I hope we’re going. So-
Betsey Zbyszynski: Yeah. I think a lot of physicians too. Okay. The year is 2027. What is everyone talking about in rare dermatology disease circles?
Dr. Amy Paller: Well, I would be incredibly optimistic to talk about the topical application of genetic material that can pass through intact skin, get [00:15:00] just where it’s supposed to go, and produce the product there, turn around the genetic disease and make perfectly beautiful looking skin. But I think I’m enough of a realist to say that in 2027, we’ll have made progress towards that, but I very much doubt that we’re even gonna be there in trials. Maybe optimistically I’ll say 10 years. So I think that in 2027, people will be talking about technologies that are in the lab that will allow one to actually do what I just talked about. Maybe talking about some ways to systemically deliver and allow it to target to skin with systemic delivery. Maybe that’ll get it to mucosal surfaces in certain diseases where that needs to be happening, but I just don’t think we’re going to be in the clinic yet in anything that’s going to be more than where we are right now with some of these new technologies that are looking at transplants, that are looking at topically applied ways to deliver genes.
I think those will advance and I’m hoping that they’re going to be expanded to a lot of genetic skin disorders. I think one of the issues is that type of technology is very expensive and for treating small body surface areas, if we’re talking about topical delivery, it’s makes a lot of sense. But when we start to talk about the fact that many of our genetic skin disorders may involve the entire body, then just treating a small part is not going to adequately improve the quality of life for patients. We need to figure out how to do this less expensively and more practically for our patients. And that’s where I’d like to be in five years. I will add to that, that I really do love the progress that I’m already seeing with thinking about pathogenesis and not treating at the genetic level, but rather treating at the downstream level of changing pathways or increasing what is missing.
So we’ve already seen this in so many examples as early developments that have been helpful. Back in 2011, for example, knowing that child syndrome, a scaling disorder that also affects bones as well as skin was clearly mapped to the cholesterol biosynthesis pathway. And we were able to show that blocking the upstream rate limiting step, which we can do with its statin and treating by adding back cholesterol, which may be less important here actually, together in a topical product, took care of everybody with that disease. And then when another set of diseases called porokeratosis, again, a scaling disorders came along and was shown to map to that pathway. The same combination was started and now is the treatment of choice. We’ve learned that we can repurpose some of the medications that block, for example the MAPK ERK I pathway or that block the mTOR pathway and use this for either systemic or more localized mosaic disorders that involve activation of that pathway. That’s incredibly exciting.
We’ve learned also that in some disorders like some of the forms of ichthyosis again, some scaling disorders that based on what we found in terms of immune shifts, we can actually turn around the lifelong disease of many patients who are red, itchy, scaling and make their lives better. So we have some early changes in therapy based on understanding pathogenesis and changing the outcome phenotypically because of these repurposing of products that are already on the market for more common skin disorders. I think that there will be more of that, more testing of that and more recognition of the pathways that are in between the gene and what we see clinically. Very excited, for example, about all the attention now being paid to Netherton syndrome, which we know is a disorder where there is a missing inhibitor and as a result, you have activation of chemicals called calcineurin.
We know from mouse studies, the pathogenesis. So we’re now seeing companies that have developed inhibitors of calcineurin and they may be introduced topically. They may be introduced systemically. One may go [00:20:00] upstream and introduced the inhibitor. And I’m waiting to see the very first studies and their results, but this is the direction that I think rare skin disease treatment will be going over the next few years and I’d like to see more of it by 2027 and some actual results. But I do wanna say one thing, and that is that there are great ideas out there, but unless you can get patients to buy in to being in these trials and have good trial design that encourages patients to be recruited and to be retained, the best ideas will never come to market and will never be available for patients.
Betsey Zbyszynski: Well, really nice talking to you today, Dr. Paller. Learned a lot of course, and I really like your vision for the future.
Dr. Amy Paller: Thanks. My pleasure.
