Sanofi and Kymera's second-generation IRAK4 degrader enters Phase I for hidradenitis suppurativa

Sanofi has initiated [a first-in-human study](https://app.allsci.com/clinical-trial/ASC-CT-0000001179588-1.0-1780665940) of SAR447971 (also known as KT-485), an oral small-molecule IRAK4 targeted protein degrader discovered by Cambridge, Massachusetts-based Kymera Therapeutics (Nasdaq: KYMR), in patients with hidradenitis suppurativa — a chronic, painful inflammatory skin disease with limited oral treatment options. The trial is notable because SAR447971 is a second-generation compound, developed explicitly to improve on the potency and selectivity profile of its predecessor, KT-474 (SAR444656), which Sanofi had previously advanced into Phase II before discontinuing that program. ### Trial design and population The Phase I program (NCT07629336) comprises three sequential substudies enrolling approximately 114 participants in total at a single site in Leiden, Netherlands. The first two cohorts — a single ascending dose study (SAD20411, up to 46 healthy volunteers) and a multiple ascending dose study (MAD20412, up to 48 healthy volunteers) — are randomized, double-blind, and placebo-controlled, with the SAD arm also incorporating a food effect evaluation to characterize how fed versus fasted conditions affect oral absorption. A third open-label multiple ascending dose cohort (MAD24339) will enroll up to 20 patients with confirmed HS, defined by lesions in at least two distinct anatomic areas with at least one site at Hurley Stage II or III and a total abscess and nodule count of four or more. Primary completion is anticipated in Q1 2028. Primary endpoints across all three cohorts assess safety and tolerability through adverse event incidence, laboratory abnormalities, vital sign changes, and ECG parameters. The Sanofi clinical trial is registered under [NCT07629336 ](https://clinicaltrials.gov/study/NCT07629336)according to the trial record. ### Mechanism and research context IRAK4 is a serine/threonine kinase that sits at a convergence point in innate immune signaling, mediating downstream inflammatory responses triggered by Toll-like receptors and interleukin-1 family cytokines. In HS, dysregulated innate immune activation drives the follicular inflammation, abscess formation, and sinus tract development that characterize the disease. SAR447971 is described by Kymera as a second-generation compound with increased potency and selectivity relative to KT-474, developed using Kymera's proprietary Pegasus degrader discovery platform. The predecessor compound KT-474/SAR444656 had reached Phase II in both atopic dermatitis and HS before Sanofi [discontinued that program](https://www.fiercebiotech.com/biotech/kymera-suffers-sanofi-setback-secures-750m-gilead-deal) and elected to advance the second-generation molecule instead. SAR447971's improved selectivity profile is the stated rationale for the generational switch. Under the collaboration structure established in July 2020, Kymera discovered and characterized SAR447971 preclinically; Sanofi holds global inflammation and immunology development and commercialization rights. Kymera retains oncology rights and holds an option to co-develop and share US profits on a 50/50 basis. Kymera is eligible for up to USD 975 million in collaboration milestones, according to the company's [investor disclosures](https://investors.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-announces-sanofi-irak4-collaboration-update). Among active programs, Eli Lilly's [povorcitinib ](https://app.allsci.com/clinical-trial/ASC-CT-0000001017129-1.0-1757352443)(LY3471851), a selective IRAK4 kinase inhibitor currently in Phase III for HS, represents the closest mechanistic comparator in the same indication, though it acts through inhibition rather than degradation and therefore preserves IRAK4 scaffolding function. SAR447971's differentiation claim rests on whether complete protein elimination produces meaningfully greater or more durable pathway suppression. *** This article was generated with AI assistance and reviewed and edited by the AllSci editorial team Explore more at AllSci News: [https://allsci.com/news/](https://allsci.com/news/) --- Spot something wrong? [Report an issue with this article](https://newsgen-prod.reframedata.com/feedback/irak4-degrader-hidradenitis-suppurativa)