The Irak-4 approach has a wobble

 Irak-4 inhibition in autoimmune disease took a knock yesterday, with Pfizer quietly discontinuing its contender PF-06650833 in hidradenitis suppurativa. Kymera paid a big price, its stock losing 24%; the Irak-4 project KT-474 is Kymera’s lead, and analysts had been looking to Pfizer’s data to handicap KT-474’s own phase 1 atopic dermatitis/hidradenitis suppurativa update, due in the second half. Then again, Kymera did not help itself, coincidentally revealing that its phase 1 protocol had been amended to increase dosing from 14 to 28 days and add clinical endpoints, and disclosing that 10-20msec QTc prolongation had been observed in the study. The last point was not serious enough to be graded an adverse event, but one risk is that it might be exacerbated by continuous dosing. Stifel analysts said Pfizer’s move called into question Irak-4 as an autoimmune target. Still, the molecules act differently: PF-06650833 is a straight inhibitor whereas KT-474 is a degrader. Sentiment will not have been helped by the FDA placing Curis’s Irak-4 inhibitor emavusertib – focused on oncology – on clinical hold last month. Pfizer continues to list PF-06650833 as a rheumatoid arthritis project, but no active trials here are ongoing.

Selected Irak-4 projects in clinical development
Project	Company	Mechanism	Status
GS-5718	Gilead	Irak-4 inhibitor	Ph2 in rheumatoid arthritis
Zimlovisertib/ PF-06650833	Pfizer	Irak-4 inhibitor	Ph2 combo in rheumatoid arthritis completed; discontinued for hidradenitis suppurativa without revealing ph2 data
Emavusertib/ CA-4948	Curis	Irak-4 inhibitor	Ph1/2 lymphoma study on partial US hold
R289 (R835 prodrug)	Rigel	Irak-1 & 4 inhibitor	Ph1 for myelodysplastic syndromes
BAY1830839	Bayer	Irak-4 inhibitor	Ph1 in autoimmune disease
KT-474/ SAR444656	Kymera/Sanofi	Irak-4 degrader	Ph1 for atopic dermatitis/hidradenitis suppurativa
KT-413	Kymera	Irak-4 imid	Ph1 for lymphoma
EVO101	Evommune (ex Lilly)	Irak-4 inhibitor	Ph1 volunteer study started Mar 2022
Source: EvaluatePharma & clinicaltrials.gov. https://www.evaluate.com/vantage/articles/news/snippets/irak-4-approach-has-wobble