Kymera Study Validates IRAK4 as Viable Protein Degradation Target

 Kymera Therapeutics announced positive interim results from its Phase I placebo-controlled trial of targeted protein degradation for anti-inflammation.

At this week’s 4^th Annual Targeted Protein Degradation Summit, Kymera presented data from a Single Ascending Dose portion of a Phase I study demonstrating robust IRAK4 degrader activity of their drug candidate, KT-474.

KT-474 targets and degrades IRAK4, which is a previously “undruggable” target implicated in several inflammatory and immune diseases like arthritis and Alzheimer’s Disease. Previous anti-inflammatory therapies have aimed to block single downstream cytokines, which is not sufficient to prevent disease symptoms.

Out of 57 healthy volunteer patients, randomly sorted into placebo or a single KT-474 dose, robust IRAK4 reduction was seen for up to six days. Mean reduction, as measured in peripheral blood mononuclear cells, was measured to be 93-96% at the three highest dosage levels, achieved at 48 hours after dosing. Additionally, KT-474 was well-tolerated with no serious adverse events reported, although with some probable side effects noted to be headache and nausea.

Kymera was able to demonstrate for the first time proof-of-biology ex vivo (outside of the body) using whole blood from one of their KT-474 treated patient cohorts. After stimulating the whole blood with R848 or LPS, which ordinarily would induce pro-inflammatory cytokines, levels of these inflammatory cytokines (ex. IL6, IL10, TNF-alpha) were significantly decreased from baseline in the KT-474 treated whole blood samples.

“Importantly, we have now shown that IRAK4 knockdown of ≥ 85% in vivo in circulating PBMC leads to profound TLR/IL-1R pathway inhibition, as demonstrated by up to 97% suppression of ex vivo response of whole blood to TLR agonists,” explained Dr. Jared Gollob, MD, chief medical officer of Kymera.

These proof-of-biology results validated the protein degrader activity of KT-474 in targeting IRAK4 as a master regulator of inflammatory cytokines. This confirms the efficiency of the drug to inhibit multiple pro-inflammatory cytokines, as opposed to just one.

“The proof-of-mechanism and proof-of-biology that have been achieved with just single doses of KT-474 attest to the potency of this drug and validates the strategy of targeting IRAK4 with a degrader to maximize blockade of TLR/IL-1R signaling,” said Kymera President and CEO Dr. Nello Mainolfi, Ph.D..

Kymera is currently conducting a multiple ascending dose trial as another part of its KT-474 study, with results expected by the end of 2021. Following this, the company plans to evaluate the therapeutic profile of KT-474 in an open-label cohort of patients with hidradenitis suppurativa, a skin condition characterized by painful bumps under the skin, and atopic dermatitis.

“The potent, broad effect of IRAK4 knockdown observed on multiple different proinflammatory cytokines implicated in a variety of autoimmune inflammatory diseases highlights the potential for KT-474 to be a best-in-class oral anti-inflammatory drug, especially in a shifting external landscape for safe, broadly active small molecule anti-inflammatory agents,” Mainolfi said.

https://www.biospace.com/article/kymera-study-validates-irak4-as-viable-protein-degradation-target-/