2. Academic Validation
  3. IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial

  • Nat Med. 2023 Dec;29(12):3127-3136. doi: 10.1038/s41591-023-02635-7.
Lindsay Ackerman 1,  Gerard Acloque 2,  Sandro Bacchelli 3,  Howard Schwartz 4,  Brian J Feinstein 5,  Phillip La Stella 6,  Afsaneh Alavi 7,  Ashwin Gollerkeri 8,  Jeffrey Davis 8,  Veronica Campbell 8,  Alice McDonald 8,  Sagar Agarwal 8,  Rahul Karnik 8,  Kelvin Shi 8,  Aimee Mishkin 8,  Jennifer Culbertson 8,  Christine Klaus 8,  Bradley Enerson 8,  Virginia Massa 8,  Eric Kuhn 8,  Kirti Sharma 8,  Erin Keaney 8,  Randy Barnes 8,  Dapeng Chen 8,  Xiaozhang Zheng 8,  Haojing Rong 8,  Vijay Sabesan 8,  Chris Ho 8,  Nello Mainolfi 8,  Anthony Slavin 8,  Jared A Gollob 9
Affiliations

Affiliations

  • 1 Medical Dermatology Specialists, Phoenix, AZ, USA.
  • 2 Encore Medical Research, LLC, Hollywood, FL, USA.
  • 3 Encore Medical Research, LLC, Weston, FL, USA.
  • 4 CenExel RCA, Hollywood, FL, USA.
  • 5 Encore Medical Research, LLC, Boynton Beach, FL, USA.
  • 6 TKL Research, Fair Lawn, NJ, USA.
  • 7 Mayo Clinic, Rochester, MN, USA.
  • 8 Kymera Therapeutics, Inc., Watertown, MA, USA.
  • 9 Kymera Therapeutics, Inc., Watertown, MA, USA. jared@kymeratx.com.
PMID: 37957373 DOI: 10.1038/s41591-023-02635-7
Abstract

Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 Degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600-1,600 mg and after 14 daily doses of ≥95% at 50-200 mg. In patients, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885 .

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