Judith Rommer

Judith Rommer asked about the targeted nature of Kymera's IRF5 degrader (KT-579), specifically inquiring about the risk of pan-IRF inhibition, given concerns about off-target effects on other IRFs like IRF8.

Answer

CEO Nello Mainolfi explained that Kymera's IRF5 degrader, KT-579, is designed for pristine selectivity, binding only to IRF5 variants without affecting other IRFs, thus mitigating risks of pan-IRF inhibition. CMO Jared Gollob added that IRF5's restricted expression and context-specific activation allow for safe, deep, and chronic degradation without broad immunosuppression, citing mouse knockout data and 4-week GLP toxicology studies in non-human primates and rats that showed no adverse events or increased infection susceptibility.

Judith Rommer asked about the distinction between IRF5 degradation and inhibition, and whether there is a risk of pan-IRF inhibition, specifically mentioning IRF8, with Kymera's targeted degrader.

Answer

Nello Mainolfi, Founder, President, and CEO, explained that Kymera's molecule is designed to selectively bind only to IRF5 (all splicing variants) and not other IRFs, ensuring pristine selectivity and no pan-IRF inhibition. Jared Gollob, Chief Medical Officer, added that IRF5's restricted expression to specific immune cell subtypes and its context-specific activation mean that deep and chronic degradation does not lead to broad immunosuppression or infectious adverse events. He noted that IRF5 mouse knockouts show no susceptibility to infections, and preclinical tox studies (4-week GLP in NHP and rats) showed no adverse findings or infection susceptibility.