Amy Paller, MD: Long-Term Outlook for EB, Ichthyosis and Netherton Syndrome Treatment

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With drug breakthroughs reaching epidermolysis bullosa, Paller considers what may come next for other rare skin diseases.

As previously discussed with HCPLive, there has been a number of notable breakthroughs in the treatment of the rare skin disease epidermolysis bullosa (EB) in the last year—including a gene therapy, a topical treatment, and a cell-based graft therapy that which is awaiting US Food and Drug Administration (FDA) decision.

In the second half of a Q&A with HCPLive during the American Academy of Dermatology (AAD) 2024 Annual Meeting in San Diego, CA, this week, Amy Paller, MD, chair of dermatology at Northwestern Medicine, discussed the application of strategy observed in EB treatment toward other rare dermatoses like ichthyosis. Paller additionally highlighted some current and anticipated breakthroughs in these disease spaces, as well.

HCPLive: In instances like this, where a market is essentially emerging before our eyes, what consideration can we make toward the potential benefit and value of these agents in the long-term?What do you think exactly that may be, in 3 - 5 years?

Paller: I think the biggest thing we have to be concerned about is risks of side effects down the road. We haven't seen this to be a problem with shorter-term trials. But I think what we're most concerned about when you're introducing a new protein into someone who has a recessive disease, and perhaps hasn't seen it or seen much of it, is whether there will be over time the development of an immune response with antibodies that are either negate the response or very importantly, will lead to an alternative blistering disorder that is autoimmune. There have been some people, for example, who have started developing more blisters over time; is that just because the treatment's not working anymore or have they possibly developed a form of EB acquisitive, for example?

And I think that's something that we just really don't know what the long term is going to be. And as I mentioned, we don't know what the long term is going to be for reducing the risk of developing some of these long-term problems. We're hoping the risk of carcinoma will be reduced. But I will also add we're excited about the New England Journal of Medicine article about the use of the topical gene therapy—not just for skin, but also for inaccessible areas, like the eye.

HCPLive: We've covered a good amount of EB subjects. Is there anything else you want to highlight in other rare dermatoses right now?

Paller: In ichthyosis, we don't have anything new out. But there are some studies in development. There's a phase 3 study right now looking at a new topical retinoid—tropical isotretinoin—and if approved, it would be the first on-label indication for a topical retinoid for ichthyosis, which would be pretty exciting to have. We also have some exciting studies moving forward now in development that build on the recognition that these patients have immune activation—systemic as well as involving their skin, but probably coming from the skin. There's a trial right now looking at the interleukin 36 (IL-36) receptor because IL-36 is sky-high across many of these forms of ichthyosis. In the studies that we've done, it's the highest differentially expressed gene. So we're trying to target that and see how things go. We'll hopefully see those results coming out pretty soon.

Then also for Netherton syndrome, we've the recognition that the kallikrein activations—and specific kallikreins at that—are responsible for the manifestations of Netherton syndrome. There was a very early phase trial looking at a topical kallikrein inhibitor. And there are others moving forward, ranging from topicals to a biologic, to even replacement with the missing protein product itself for Netherton syndrome. I think those are going to be pretty exciting. I'm hoping that that the topical gene therapy approach for dystrophic EB will be applied for some of the ichthyosis: Harlequin ichthyosis, and hopefully Lamellar ichthyosis in the future.

HCPLive: It sounds like if there's some form of symptomatic resolve and benefit with a gene therapy that addresses a similar primary mechanism of action in these rare diseases, it could help an entire spectrum of patients.

Paller: Yes. I talk about this all the time: we need to look downstream at the gene, because there's a lot going on between the gene defect and the clinical manifestations. And if you can understand those various steps in the pathway and block something that's in excess, you may abort the clinical manifestations from happening. So that's what we need to think about with all of these genetic disorders, and why it's so important to recognize the genes that underlie them and the mechanism of action.