KT-474 Demonstrates Efficacy and Promise in Atopic Dermatitis and Hidradenitis Suppurativa Study

Kymera Therapeutics recently shared promising results from the phase 1 clinical trial of its lead program, KT-474, marking a significant milestone in the field of targeted protein degradation (TPD). Published in Nature Medicine under the title "IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial," this study represents the first published clinical trial utilizing a heterobifunctional targeted protein degrader.

KT-474, a potent and highly selective orally bioavailable IRAK4 degrader, exhibited potential in treating inflammatory diseases like hidradenitis suppurativa (HS) and atopic dermatitis (AD). The trial demonstrated a reduction of disease-relevant inflammatory biomarkers in the blood and skin of patients, correlating with improvements in skin lesions and symptoms. Notably, the study showcased the ability of targeted protein degradation to unlock the IRAK4 pathway.

With partner Sanofi advancing KT-474 into phase 2 clinical trials for HS and AD, the study underscores the clinical potential of an IRAK4 degrader over small molecule inhibitors.

Jared Gollob, MD, Chief Medical Officer of Kymera Therapeutics, spoke with Dermatology Times to discuss the results of the study and their significance in the development of therapies for HS and AD.

Transcript

Jared Gollob, MD: I am Jared Gollob. I am the Chief Medical Officer here at Kymera Therapeutics, and I've been here for a little over 5 years.

Dermatology Times: What is the significance of these phase 1 trial results?

Gollob: For us, we think that this really is important validation for the actual platform that we're using, the targeted protein degradation platform using heterobifunctional molecules. So really providing one of the first main clinical validation points in a peer-reviewed publication for the technology, for the platform itself. This is the first healthy volunteer study with a heterobifunctional degrader. Also the first study in non-oncology patients: in this case, patients with autoimmune diseases, hidradenitis suppurativa and atopic dermatitis, which are inflammatory skin diseases.

We think that the paper is also important because it provides validation for the target itself, the pathway. Showing we can degrade the target is very important, which in this case is IRAK4, which plays a central role in signaling through toll-like receptors and IL-1 receptors, and it's been potentially implicated in a number of autoimmune diseases because of its place in that pathway. Being able to show that we can degrade this protein, and this protein has a functional effect and anti-inflammatory effect, that's an important first, but also being able to show the first signs of what we believe is clinical activity in these HS and AD patients. In the context of a phase 1 study with this drug, where you're sort of connecting the dots between this drug and its effect on the target in skin and blood. Here's how that translates into an effect on inflammation in blood and skin looking at inflammatory biomarkers. Then just downstream of that, here's the actual potential clinical impact now that one could see, understanding that this is the an early signal of clinical efficacy that has to be confirmed in randomized phase 2 studies that are now ongoing. But I think this really starts to provide validation for the pathway and why we're interested in hitting IRAK4 in addition to this validation for the technology and for heterobifunctional degraders as a whole.

Dermatology Times: How does KT-474 differ from existing treatments for conditions like HS and AD?

Gollob: I think right now, the drugs that have shown the most activity in these diseases, in general, are either injectable biologics. So for example, in HS drugs targeting single cytokines with antibodies, anti-TNF drugs, anti IL-17 drugs, for example, or even an oral drug like a JAK inhibitor has shown activity in HS. In AD, of course, dupilumab, which is the marketed drug that targets the IL-4, IL-13 pathway, has shown considerable activity in AD, as have JAK inhibitors. So again, most of these, are injectable biologics that are targeting either individual cytokines, with the exception being JAK inhibitors. But JAK inhibitors, there have also been issues with safety around JAK inhibition. IRAK4 targeting is different, because by hitting this important signaling node, just downstream of the toll-like receptors and the IL-1 receptors, can allow them to have a very broad anti-inflammatory effect. So very different from going after single cytokines. And we know that many autoimmune diseases, including AD and HS, have pleiotropic inflammation; multiple different cell types are mediating the inflammation, multiple different cytokines and chemokine are mediating the inflammation, and so there may be limitations to going after just a single cytokine. So having a drug that's an oral drug, which KT-474 is an oral degrader of IRAK4, in a drug that can be safe for patients, and we believe our data so far have pointed toward the safety of this approach of hitting IRAK4, so they have a broad oral anti-inflammatory drug that can treat multiple different autoimmune diseases, can be a very different value proposition from having just injectable biologics that are more focused in what part of the inflammatory pathway they're hitting.

We think that this can be a real differentiator for this novel class of drugs. We know that IRAK4 can be targeted safely, we believe, because there are human adults who have no mutations for IRAK4, and those patients do not appear to have immunodeficiencies or susceptibility to infections. And so far, we have not seen infections in our phase 1 study or in our preclinical tox studies. We believe that if we have a drug here that has the convenience of it being an oral drug, is safe and well-tolerated, and has a broad anti-inflammatory effect, it can be a very novel approach to treating HS and AD. We think it could also make a much larger segment of those populations have access to this sort of a drug by having a drug that's oral and safe. Right now, drugs like dupilumab or even anti-TNF drugs, for example, in HS, are probably only reaching maybe less than 10% of the addressable populations. We feel that having a safe oral drug, if it proves to be efficacious in subsequent studies, could really reach a much larger segment of these populations and ultimately help more patients.

Dermatology Times: What improvements were noted in the study, and how do these correlate with a reduction in inflammatory biomarkers?

Gollob: For both the AD and HS patients who were on the final open label portion of the phase 1 study, we saw a reduction in skin lesion burden in these patients; again, in a small controlled study, it's hard to know how that compares with what has been seen in larger controlled studies. But the results we saw were comparable to the metrics one would associate with standard of care agents. But again, we really can't say whether they're as accurate because it's an uncontrolled study. But nonetheless, we thought those results were promising, especially for just 4 weeks of treatment. We only treated these patients with 28 days of dosing, so a daily oral dose for 28 days. Registration endpoints for AD and HS, using clinical endpoints, usually are 16 weekend points. I think we're potentially seeing just the tip of the iceberg in terms of activity with 4 weeks of dosing, but we still saw substantial effects on skin lesion burden, and very importantly, on symptoms. For patients with HS, pain is one of the terrible symptoms these patients have, in addition to itching, but pain leads to depression leads to loss being able to perform daily activities. We saw substantial reductions in pain even with this 28 days of dosing in HS. In AD, itching is really the predominant symptom that ruins quality of life, leads to lots of scratching, skin irritation, infections, and we saw a very profound reductions in itching in the AD patients within 28 days of dosing. To see impact on skin lesion burden and associated impact on the symptoms that matter the most to these patients, and to tie that together with a reduction in circulating biomarkers of inflammation, looking at biomarkers like IL-1 and IL-1 beta and C-reactive protein, where we saw reductions in HS and AD patients. We performed skin biopsies, serial skin biopsies of skin lesions pre and post treatment in these patients and were able to do RNA sequencing to look at various proinflammatory genes. We were able to see the impact of the drug on the expression of proinflammatory genes that are known to be disease relevant for either HS or AD. Putting that all together, being able to show the pharmacology of the drug, target knock down both in the skin and in the blood, because these are these inflammatory diseases, even skin diseases are systemic diseases. These patients have systemic inflammation; they're systemically sick, in addition to having all the problems with the skin lesions and the itching and the pain. To see this sort of a systemic anti-inflammatory effect with the drug, with even 28 days of dosing, and the impact on these key clinical endpoints that really are the sorts of endpoints that are used ultimately in registration studies, because when you're getting a drug approved, you want to show how does this impact how patients feel and function? It's not enough just to show well, skin lesions are getting better. That can be very important for how patients feel and function but also showing that you can affect even more objective measures like pain and itching, we think, is very important.

Dermatology Times: What are the implications of this study for the development of KT-474 for HS and AD?

Gollob: This is a program that is partnered with Sanofi, which obviously has a lot of experience in developing drugs like dupilumabin inflammatory diseases, you know, TH-2 diseases in particular, but especially the success of dupilumab in diseases like AD and now also in COPD and other tissue diseases. We partnered with Sanofi early in this program's history. Even before we were in the clinic, our partnership was such that Kymera ran the phase 1 study with Sanofi's input. They are now responsible for running the phase 2 trials with our input. Right now, these phase 2 studies, the first 2 that have been chosen, the first 2 indications are obviously HS and AD, and these are both randomized placebo-controlled phase 2 studies with a variety of different clinical endpoints as well of safety and pharmacodynamic endpoints. We've already announced that the HS study already has begun dosing its first patients. So that study is now ongoing and enrolling, and we expect the same shortly, this quarter, for the phase 2 study of AD, and right now, are looking at probable readouts for both of those studies in the first half of 2025.

We're very excited that Sanofi is progressing both of these studies. We think there'll be a lot of very important learnings around safety and efficacy in these placebo controlled randomized trials, phase 2 studies, and will hopefully then form a basis for what further development will look like for these 2 indications, if these are positive studies, will also help to inform what other indications Sanofi and Kymera might want to go forward with in the future.

Just to emphasize again, because I think this is true for this program, as well as for additional programs in our pipeline, we have other immunology programs in our pipeline, that we'll be discussing more at an R&D day that we have planned for January 4. For example, we have a program that's targeting a key transcription factor in the IL-4, IL-13 pathway, which could potentially have the potential to phenocopy, which is seen with injectable biologics like dupilumab. We think that this is an important overriding principle that Kymera holds for our pipeline, especially in immunology, which is degraders have the potential, we believe, to allow us to use oral small molecules to really essentially match the power of injectable biologics in terms of having impact on these key clinically validated pathways, but with the convenience of oral dosing, and hopefully, also a very clean safety profile. I think, the ability, whether it's with the IRAK4 program, which is our first program where we think we're moving in that direction, and starting to provide proof of concept for that principle, and then for additional programs in our pipeline, such as the one that I just mentioned, hitting the IL-4, IL-17 pathway, I think really shows the potential power of this technology for using targeted protein degradation to solve big problems, in this case in dermatologic diseases, but to solve those big problems, especially with small molecules that can have the power of biologics of injectable biologics, but with safety that's going to be necessary to be able to expand these treatments into a large segment of the populations of AD and HS, both in moderate to severe patients. Maybe eventually even down the line with an oral and safe drug, maybe being able to get to even patients with even earlier disease, milder disease, with AD and HS, to prevent them from progressing to more advanced stages.

[Transcript has been edited for clarity.]

Reference

Kymera Therapeutics announces publication of phase 1 trial results for KT-474 (SAR444656), a first-in-class IRAK4 Degrader, in Nature Medicine. Kymera Therapeutics, Inc. November 13, 2023. Accessed November 17, 2023. https://investors.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-announces-publication-phase-1-trial-results