KT-474 reduces inflammation in patients with hidradenitis suppurativa, atopic dermatitis
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Key takeaways:
- KT-474 is an IL-1 receptor-associated kinase 4 degrader for the treatment of inflammatory diseases.
- KT-474 exhibited a favorable safety profile while targeting degradation.
Results from a phase 1 study show that KT-474 reduced disease-relevant inflammatory biomarkers in the blood and skin of patients with hidradenitis suppurativa or atopic dermatitis, according to a Kymera Therapeutics press release.
KT-474 is a potent, highly selective, orally bioavailable interleukin-1 receptor-associated kinase 4 (IRAK4) degrader that is being developed for the treatment of immune-inflammatory diseases. In a phase 1 trial, researchers assessed the safety, pharmacokinetics, pharmacodynamics and clinical activity of KT-474 and found the drug normalized hidradenitis suppurativa (HS) and AD skin lesions.
“The results show that IRAK4 can be safely and effectively degraded in the blood and skin of patients with HS and AD, resulting in a systemic anti-inflammatory effect and initial signals of clinical activity including improvement in skin lesions and disabling symptoms such as pain and pruritus,” Jared Gollob, MD, chief medical officer of Kymera Therapeutics, told Healio.
Researchers initially investigated the dose range of KT-474 in single ascending doses in 105 healthy subjects, which was followed by 14 days of studying multiple ascending dose escalations also in healthy subjects to determine a safe dose. Finally, 21 patients with HS and AD then received daily dosing of KT-474 for 28 days.
Blood tests showed that healthy volunteers achieved mean IRAK4 degradations greater than or equal to 93% after a single dose of 600 mg to 1,600 mg. After 14 daily doses of 50 mg to 200 mg, IRAK4 degradation was greater than or equal to 95%.
Blood from patients treated with 75 mg of KT-474 also exhibited IRAK4 degradation. IRAK4 was also normalized in skin lesions that were previously overexpressed relative to healthy volunteers.
Blood and skin samples from patients with HS and AD exhibited a reduction in disease-relevant inflammatory biomarkers which coincided with an improvement in skin lesions and symptoms.
KT-474 was well tolerated by patients and researchers reported no drug-related infections.
According to the press release, this is the first published clinical trial of a heterobifunctional degrader. The company reports that this proof-of-concept study will be followed by placebo-controlled phase 2 trials.
“These promising results have led to the initiation of phase 2, randomized, placebo-controlled trials in moderate to severe HS and AD to further evaluate the therapeutic potential of IRAK4 targeting with KT-474,” Gollob said.
Reference:
A Single and Multiple Ascending Dose Trial of KT-474 in Healthy Adult Volunteers and Patients With Atopic Dermatitis (AD) or Hidradenitis Suppurativa (HS). https://www.clinicaltrials.gov/study/NCT04772885?term=NCT04772885&rank=1. Updated Oct. 24, 2022. Accessed Nov. 17, 2023.
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