Massachusetts-based Photys Therapeutics and China's Polymed Biopharmaceuticals have moved oral IRAK4 degrader PHT-776/HPB-143 into first-in-human testing, becoming the third disclosed oral PROTAC targeting IRAK4 to reach the clinic as developers test whether eliminating the protein can outperform conventional kinase inhibition. The Phase I trial is a single- and multiple-ascending dose study enrolling at Shanghai's Huashan Hospital, affiliated with Fudan University. The companies said they expect clinical data within 12 months.
PHT-776 is being developed under a 2025 licensing agreement in which Polymed granted Photys exclusive rights outside Greater China and Southeast Asia. Polymed retains rights in those territories under its HPB-143 designation. The two companies said preclinical studies showed high oral bioavailability, potent efficacy at low doses across multiple disease models, and no observed cardiovascular effects — a profile they assert differentiates the molecule from other disclosed IRAK4 PROTAC programs.
IRAK4 is a central component of Toll-like receptor and IL-1 receptor signaling, driving downstream NF-κB and MAPK activation through both its kinase activity and a kinase-independent scaffolding function within the Myddosome. That dual role provides the rationale for degradation: conventional inhibitors block IRAK4's catalytic activity while leaving its scaffolding function intact, whereas PROTACs remove the protein altogether.
The approach already has human proof of mechanism from Kymera Therapeutics' KT-474 (SAR444656), partnered with Sanofi. A Phase I study published in Nature Medicine demonstrated IRAK4 degradation in blood and skin alongside reductions in inflammatory biomarkers, and the molecule has since advanced into Phase II studies in hidradenitis suppurativa and atopic dermatitis. Also under development is GS-6791 (NX-0479), a PROTAC originated by Nurix Therapeutics and licensed to Gilead Sciences. The failure of conventional IRAK4 inhibition adds to the mechanistic case for degradation. Pfizer discontinued IRAK4 kinase inhibitor zimlovisertib after Phase II failures in rheumatoid arthritis, while degraders are designed to suppress both catalytic and scaffolding functions.