IRAK4 overexpressed in hidradenitis suppurativa, could be downregulated by degrader
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Key takeaways:
- Interleukin-1 receptor-associated kinase 4 protein levels were elevated in hidradenitis suppurativa (HS)lesions.
- KT-474, demonstrated preliminary clinical activity in HS and atopic dermatitis patients.
Researchers confirmed that the interleukin-1 receptor-associated kinase 4 protein plays a role in the pathogenesis of hidradenitis suppurativa and that a degrader treatment may impact the disease, according to a study.
“We knew from existing literature that there was an abundance of evidence that the toll-like receptor and interleukin-1 receptor pathways were involved in the inflammation that you see in a disease like [hidradenitis suppurativa (HS)],” Jared Gollob, MD, chief medical officer of Kymera Therapeutics and one of the study investigators, told Healio. “But nobody had ever looked at whether interleukin-1 receptor-associated kinase 4 (IRAK-4), which is the central signaling node for these pathways, was expressed higher, lower or the same in the skin lesions of patients with HS compared with healthy individuals.”
In their noninterventional study, Gollob and his colleagues investigated the role of IRAK4 in HS. Thirty patients with HS were enrolled. The researchers collected blood samples and biopsies from lesional, perilesional and nonlesional skin.
Results showed that IRAK4 protein levels were elevated in active skin lesions in patients with HS regardless of their disease severity compared with unaffected skin of patients with HS (P .0001) and the skin of healthy individuals.
The study also showed that a targeted degrader of IRAK4, KT-474, robustly lowered IRAK4 in blood samples from HS patients treated ex vivo, and blocked toll-like receptor-induced, pro-inflammatory cytokine and chemokine production by monocytes obtained from healthy subjects.
“This was an important finding that further strengthened our conviction that IRAK4 is an important protein involved in the inflammation driving this disease and that an IRAK4 degrader could downregulate its expression,” Gollob said.
According to the study, these results support the findings from a subsequent phase 1 trial that showed daily, oral treatment with KT-474, a targeted degrader of IRAK4, decreased IRAK4 in peripheral blood immune cells from healthy volunteers and patients with HS and atopic dermatitis (AD).
“We also showed in the phase 1 trial that when you downregulate IRAK4 in active skin lesions, you also downregulate multiple different pro-inflammatory gene transcripts in both HS and AD patients,” Gollob explained. “Even more importantly, we showed that this could have an impact on both diseases, resulting in an improvement in skin lesion burden as well as symptoms.”
KT-474 is currently being evaluated in phase 2 studies in both HS and AD, according to Gollob.
For more information:
Jared Gollob, MD, can be reached at media@kymeratx.com; LinkedIn: Kymera Therapeutics.
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