Pyrukynd: what flexibility did regulators accept, and why?

“The Applicant stated that in vivo studies were conducted in normal C57BL/6 mice and in the murine Hbbth3/+ model of β-thalassemia, another hemolytic anemia, because suitable animal models of PKD were not available during the early development of mitapivat.”

“Although a proof-of-concept from an in vivo model of PKD was not conducted, the beneficial effect of mitapivat on RBC in the mouse model of thalassemia, combined with the ex vivo studies with PK isoforms, and pharmacological rationale (i.e., allosteric activation of a deficient PK enzyme) provides sufficient evidence of potential effectiveness in treating PKD.”

“NOAEL is 25 mg/kg/BID (1.2× MRHD, based on AUC) and 50 mg/kg/BID (2.2× MRHD, based on AUC) in males and females, respectively, based on the occurrence of subcapsular inflammation/necrosis at higher doses.”

“The safety margins are acceptable even if they are low. Indeed, the severity was of relative significance and effects were reversible in most of cases.”