Q&A: Study Highlights KT-474's Effectiveness in Targeting IRAK4 for Hidradenitis Suppurativa and Other Inflammatory Diseases

Kymera Therapeutics recently shared that findings from a non-interventional trial involving its agent, KT-474, were published in the Journal of Investigative Dermatology under the title, "Interleukin 1 receptor-associated kinase 4 is overexpressed in hidradenitis suppurativa skin and correlates with inflammatory biomarkers."¹

The research revealed that the IRAK4 protein is overexpressed in active hidradenitis suppurativa (HS) lesions, linking its signaling pathway to increased inflammation in the disease. KT-474, an IRAK4 degrader, has been shown to reduce IRAK4 levels and inhibit inflammatory cytokines, suggesting it could be effective for HS, atopic dermatitis (AD), and other similar inflammatory conditions.

Sanofi is now advancing KT-474 into phase 2 trials and plans to accelerate development based on promising preliminary results.

Dermatology Times recently spoke with Jared Gollob, MD, chief medical officer of Kymera Therapeutics, to discuss the role of IRAK4 expression and degradation in HS, as well as the potential of KT-474 in immuno-inflammatory diseases.

Q&A

Q: Could you elaborate on the significance of the recent JID publication regarding IRAK4 expression in patients with HS? What does this study add to our understanding of HS?

A: We've understood from the literature that was already out there that toll-like receptors (TLR) and IL-1 receptors, IL-1 family cytokines, play an important role in the inflammation that you see with a disease like HS, and that was one of the reasons why we were interested in IRAK4, because IRAK4 is an important part of that, of those pathways, of the TLR and IL-1R pathways, and a very important signaling node. We felt that an IRAK4-targeted drug, like a degrader, was a very good fit for a disease like HS, where the sort of pleiotropic, severe inflammation is being driven by the activation of toll-like receptors and by IL-1 receptors. But what wasn't out there was any information around direct or expression in skin lesions in HS patients, so that was something that we wanted to understand better before we conduct our first clinical trial with KT-474, which is targeting IRAK4, really, to further understand the role that IRAK4 plays in HS.

That was really the premise around this non-interventional study where we essentially collaborated with a NHS clinician, a key opinion leader in this space, Dr Afsaneh Alavi. She used to be at a site in Canada where we did the study. Now she's at the Mayo Clinic, but she sees many of these HS patients, and so we designed this study in conjunction with Dr Alavi, where we essentially had HS patients coming in with mild, moderate, or severe disease, and we then undertook biopsies of the skin in these patients, as well as taking blood from the patients, to allow us to study IRAK4 expression. We ended up bringing on 30 patients with with HS across those different disease severities.

Importantly, what we found was that in these skin biopsies, we could readily measure IRAK4 in the skin lesions. But if we compared the skin lesions of these patients to normal skin of healthy volunteers, we saw that there was significant upregulation or overexpression of IRAK4 protein in these skin lesions. What was also very interesting is that that over expression of IRAK4 correlated strongly with the overexpression of many different pro-inflammatory gene transcripts that we know drive the disease pathogenesis, including transcripts like IL-17, IL-1, and tumor necrosis factor, among many others. This was very important for us to learn; here, we find that in these skin lesions causing the disease, IRAK4 is upregulated relative to normal skin and that, in conjunction with that, we see upregulation of all these inflammatory gene transcripts. We also looked at IRAK4 in the blood in these patients, and also saw that IRAK4 was expressed in the blood, although, interestingly, not at higher levels compared to what you see in healthy subjects. The over expression of IRAK4 is really what we saw, predominantly in the active disease areas, which provided the rationale for why we would want to go after IRAK4 and lower IRAK4 to try to treat the disease.

Q: How does KT-474 function as an IRAK4 degrader, and what mechanisms allow it to decrease IRAK4 protein levels and inhibit inflammatory cytokine production?

A: There are different ways that you can potentially inhibit IRAK4. The traditional way has been to just inhibit its activity with a kinase inhibitor, and a number of big pharma companies developed a kinase inhibitor to IRAK4, including companies like Pfizer and Bayer. But we and others have known all along that if you can just inhibit the kinase activity of IRAK4, you're only able to partially block its activity, and therefore only partially block the signaling through the toll-like receptors and IL-1 receptors.

We've shown, I think fairly convincingly, that only by degrading IRAK4 can you completely shut off the signaling downstream for the toll-like receptors and IL-1 receptors. That's the reason why our purpose has been to go after this target with the degrader. These degraders are small molecules, but these are special small molecules. We call them heterobifunctional small molecules, that bind to IRAK4, and they also bind to what's called an E3 ligase. They bring these 2 proteins together so that the E3 ligase can ubiquitinate IRAK4 and then tag it for degradation. Because these are small molecules, they can go broadly throughout the body and get to all the different tissues, not just blood, but skin and whatever tissues might be affected by a particular disease. As small molecules, these degraders can freely travel to these different disease sites, get into a variety of different cells, and within those cells, then tag IRAK4 for degradation. We've been able to show in our phase 1 study in healthy volunteers and then in patients with HS, that we're able to degrade IRAK4 by upwards of 98% and almost completely obliterate IRAK4 from these different tissues. We've also shown that we're able to then shut off inflammation, both in the skin and also systemically in the blood.

Q: In what ways do the findings from the non-interventional trial support the potential of KT-474 in treating HS, AD, and potentially other TLR/IL-1R-driven immuno-inflammatory diseases?

A: The non-interventional study was the first time we or anybody else have shown that a signaling protein like IRAK4 is actually upregulated in the context of inflammatory disease; in this case, the specific inflammatory disease of the skin, HS. Now, whether that means that IRAK4 is also upregulated in other inflammatory diseases that are driven by toll-like receptors and IL-1 receptors, remains to be shown. But it's not inconceivable that might also be the case.

This all came before initiation of our phase 1 study. Within our phase 1 study that we published last year in Nature Medicine, we showed that KT-474 was able to effectively degrade IRAK4 in blood and skin of healthy volunteers. Then, importantly, we showed that in HS and AD patients, both these 2 different inflammatory skin diseases, we could also strongly degrade downregulate IRAK4 in skin lesions and in blood, that was associated with down regulation of markers of inflammation in the skin and blood. Then, importantly, we actually saw improvement in these diseases. In both HS and AD, we saw a decrease in skin lesions, and we saw a decrease in symptoms for HS patients. Pain is a horrible symptom that comes with this disease, and we saw very dramatic reductions in pain following just 28 days of treatment with our drug. Then in atopic dermatitis, we saw very robust reductions in itching, or pruritus, in addition to the effects on these skin lesions.

For us, it was very important proof of concept that an oral drug, which is a degrader, can be safely administered to healthy volunteers and patients really [do] not have any adverse effects, hit the target very hard, result in a systemic anti-inflammatory effect, and that then translated into improvement in clinical outcomes, including signs and symptoms of the disease. This was really our flagship immunology program, so the first time that a degrader was actually used in immunology, or even in public volunteers, for that matter. There were a lot of important firsts in that phase 1 study with KT 474, and of course, now that has led to Sanofi, who's our partner on this program going forward, and in the midst of 2 substantial phase 2 trials, placebo control studies in HS and AD, that will then give us a more definitive answer as to the activity of the drug in those diseases.

Q: What does the expansion of the ongoing trials mean for the development timeline of KT-474, and what are the key objectives of the phase 2 trials?

A: These 2 phase 2 studies really are designed to answer whether or not in a placebo-controlled manner KT-474 is truly impacting the disease. In both HS and AD, both of these studies enroll moderate to severe patients with HS and AD. It involves 16 weeks of daily dosing with the drug, and it includes placebo as well as several different dose levels of KT-474, where the primary endpoints of these studies are the measurement of skin lesions. In HS, it's looking at what's called abscess and nodule count, and in AD, it's looking at EASI score. But both of these trials also include a number of other important clinical endpoints, such as pain in HS and itching in AD. These studies were initially designed as proof of concept phase 2 studies with relatively limited exploration of different doses.

Sanofi recently undertook an interim analysis looking at safety and efficacy across both of these studies, with the aim of after looking at efficacy and safety, determining whether they would want to then go ahead and expand these phase 2 studies to allow more dose range finding, so that these studies could essentially evolve from being proof of concept phase 2a studies to more seamless 2a, 2b studies, so that you have in 1 study the ability to do the dose range finding that's needed to then get to the next stage of development, which is phase 3.

The expansion of these studies is going to happen because the interim analysis of safety and efficacy led Sanofi to have the confidence to now want to go ahead and further expand these studies, which is a great outcome, I think, for both trials and for the program. By now including additional doses in these studies, and having more dose range finding, these can then qualify as essentially phase 2b studies, and then could allow us to go directly from this type of a study to a phase 3 study after registration. Although the phase 2 study now becomes larger, and so the readout will now take a bit longer. We initially had said these studies would read out in the first half of 2025, and now it will take longer for that to happen. Overall, it will accelerate the time to registration, because this will allow these studies to serve as the only phase 2 studies that we need prior to going on to phase 3. For all those reasons, we see this as a very positive development for the program.

Reference

1. McDonald A, Karnik R, Campbell V, et al. Interleukin 1 receptor-associated kinase 4 is overexpressed in hidradenitis suppurativa skin and correlates with inflammatory biomarkers. J Invest Dermatol. July 17, 2024. doi: 10.1016/j.jid.2024.04.035