Lunsumio

“Cynomolgus monkey was selected as the appropriate animal species for assessing the nonclinical safety, pharmacokinetic (PK), and pharmacodynamic (PD) properties of mosunetuzumab and 2H7v16/40G5c.”

“2H7v16/40G5c displays the same properties as mosunetuzumab, as it cross-reacts with CD20 and CD3 in both humans and cynomolgus monkeys, but not in rodents.”

“Mosunetuzumab is produced from Chinese hamster ovary (CHO) cells; the functionally equivalent antibody, referred to as 2H7v16/40G5c and the proof-of-concept (POC) molecule, referred to as 2H7v16/UCHT1v9, were produced from E. coli.”

“In the pivotal 26-week GLP toxicity study (16-1815), exposure was maintained in 7/7 animals in the 0.5 mg/kg target-dose group, and in 4/7 surviving animals past TK Day 84 in the 0.1 mg/kg group.”

“A step-up mosunetuzumab dosing regimen was used in the 4-week DRF study and the pivotal GLP 26-week repeat-dose toxicity studies (Study 16-2088 and 16-1815) by splitting the first 1 mg/kg dose to Day 1 (0.2 mg/kg) and Day 2 (0.8 mg/kg)”

“Mosunetuzumab and 2H7v16/40G5c were investigated after repeated dosing up to 26 weeks in cynomolgus monkeys following IV administration (slow bolus injection (½-1 min) or infusion (1h)) or SC injection.”

“In accordance with the current ICH guidance (ICH S6(R1) 2011), genotoxicity studies have not been conducted with mosunetuzumab because the potential of biotechnology products, in particular high molecular weight monoclonal antibodies, to elicit DNA damage in somatic or germ cells via electrophilic reactions is unlikely.”

“No carcinogenicity studies have been conducted with mosunetuzumab and are not planned for the intended oncology indication, as per Guidance for Industry S6R1.”

“A briefing book, including the WOE-based risk assessment and a request to waive a non-human primate embryo-fetal and prenatal/postnatal development study, was submitted to the FDA (dated 3 April 2018; Reference ID: 4277993).”

“Cardiovascular effects were investigated as part of the single dose GLP study in monkeys (Study 14- 1246).”

“The results (EC20 values) were used to inform the starting dose in the first in human study.”

“As CRS related effects were observed at all dose levels, a LOAEL was derived for all studies at the lowest dose levels resulting in an overall LOAEL of 0.01 mg/kg/day in cynomolgus monkeys.”

“Observed toxicities in GLP-study 14-1246 were largely attributed to a dose-dependent release of cytokines which occurred 2-6 hours post-dosing and returned to baseline values at 24 hours post-dose.”

“Vss-values were greater than estimated serum volume of cynomolgus monkeys, most likely due to specific binding of mosunetuzumab to its target cells.”

“The main findings were acute toxicities related to cytokine-release syndrome (CRS) primarily attributed to the first dose, vascular/perivascular inflammatory cell infiltrates mainly observed in the CNS and increased susceptibility to infection following chronic dosing.”