Kymera Therapeutics, Inc. (NASDAQ:KYMR), a biopharmaceutical company advancing targeted protein degradation to deliver novel small molecule protein degrader therapeutics, today announced the company will present interim data from a non-interventional trial evaluating IRAK4 expression in the skin and blood of patients with HS and atopic dermatitis (AD) as well as the effect of its lead IRAK4 degrader, KT-474, on IRAK4 levels in peripheral blood mononuclear cells (PBMC) following ex vivo treatment. Data will be presented at the 5th Annual Symposium on Hidradenitis Suppurativa Advances (SHSA) on Friday, Oct. 9 at 9:00 AM ET (Poster #P2.20).
“IRAK4 controls signaling through IL-1 receptors (IL-1R) and toll-like receptors (TLR), which play key roles in the pathogenesis of various autoimmune and inflammatory diseases including HS, a painful and debilitating inflammatory skin disease with limited treatment options,” said Jared Gollob, MD, Chief Medical Officer at Kymera Therapeutics. “The goal of conducting a non-interventional study in HS and AD early on was to understand IRAK4 expression in diseased tissues and demonstrate ex vivo proof of mechanism with our lead IRAK4 degrader, KT-474, in patients prior to conducting our first clinical studies. We have completed accrual of HS patients, and these interim data in HS support the relevance of the IRAK4 signaling pathway and the ability of KT-474 to lower IRAK4 levels across all PBMC subsets, thereby differentiating its pharmacodynamic effect from that of IRAK4 kinase inhibitors.”
Conducted in collaboration with Afsaneh Alavi, MD, at York Dermatology Clinic and Research Center in Ontario, Canada, the non-interventional trial is enrolling up to 30 patients with mild, moderate and severe HS and up to 10 patients with moderate or severe AD. IRAK4 levels and the expression of proinflammatory cytokines are measured in skin biopsies obtained from lesional, peri-lesional and non-lesional skin and in blood. The effect of KT-474 or an IRAK4 kinase inhibitor on IRAK4 levels and cytokine production are measured following ex vivo incubation of whole blood. Interim trial results for IRAK4 expression in the skin and blood of 30 HS patients and the impact of KT-474 on IRAK4 levels in HS PBMC are being presented today at SHSA.
“We are highly encouraged by these initial findings which characterize IRAK4 expression in the skin and blood of patients with HS, a debilitating disease with both cutaneous and systemic inflammation. The higher levels of IRAK4 observed in skin from active lesions and in circulating monocytes, a cell type which plays a key role in the pathogenesis of HS, along with the ability of KT-474 to suppress IRAK4 expression in PBMC irrespective of baseline intensity, provide a strong scientific rationale for further evaluation of IRAK4 degraders to treat HS,” said Dr. Alavi, Principal Investigator, formerly at York Dermatology Clinic and Research Center and currently at Mayo Clinic in Rochester, MN. “We look forward to analyzing the full trial results as part of ongoing efforts to advance new therapies for patients with HS and AD with high unmet medical need.”
“This non-interventional trial exemplifies Kymera’s commitment to working with disease area experts from the outset in order to understand target expression and ex vivo pharmacodynamic activity of our degraders in diseased tissue in indications where we intend to develop,” said Nello Mainolfi, PhD, co-founder and CEO, Kymera Therapeutics. “The results to date in HS patients support our plans for clinical development of KT-474, and we are on track to initiate a Phase 1 trial in the first half of 2021.”
SHSA Poster Presentation Highlights
Poster #P2.20, “Interim Results from Non-interventional Study to Evaluate Cutaneous and Circulating Biomarkers for a Novel IRAK4-Targeted Therapeutic in Patients with Hidradenitis Suppurativa,” were presented by Dr. Alavi.
Data presented on the 30 HS patients enrolled showed:
- IRAK4 expression can be quantified in the skin using immunofluorescence (IF) and mass spectrometry (MS), and in PBMC by flow cytometry.
- IRAK4 expression in the skin was higher in lesional and peri-lesional skin compared to unaffected skin.
- IRAK4 was detected in the blood across all PBMC subsets, with the highest expression in monocytes.
- Ex vivo treatment of whole blood with an IRAK4 degrader substantially lowered IRAK4 levels across all PBMC subsets in the blood, whereas ex vivo treatment with an IRAK4 kinase inhibitor increased IRAK4 levels in T and NK cells.
Kymera presented preclinical data earlier this year at the 9th European Hidradenitis Suppurativa Foundation Scientific Conference demonstrating that oral daily dosing of its IRAK4 degraders completely suppressed IRAK4 protein expression in skin and immune cells and inhibited cutaneous inflammation. Preclinical research presented at the American College of Rheumatology meeting last year showed that inhibition of in vitro cytokine and chemokine induction by TLR agonists, alone or combined with IL-1b, was superior for IRAK4 degraders compared to IRAK4 kinase inhibitors.
Select Kymera posters, presentations and publications, including today’s SHSA presentation slides, can be found at this link: https://www.kymeratx.com/scientific-resources/?cat=13&tag=all.