How long were the pivotal tox studies for approved bispecifics?

“A 26-week intermittent dose (once weekly, 27 doses) subcutaneous administration toxicity study of CH5534262 in mature cynomolgus monkeysfollowed by a 13-week recovery period / Study report no. 1060134”

“Repeat-dose toxicity was also evaluated in cynomolgus monkeys dosed once weekly in a 4-week IV dose toxicity study (1060140) and 4- and 13-week SC dose toxicity studies (1060133 and 1060134).”

“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)”

“The 26-week IVT monkey study (report # 1057630) was submitted in draft form on 3/24/2015 (SD # 21), and in final form on 7/27/2015 (SD # 24).”

“Study # 1053361, 2-Month Toxicity and Toxicokinetic Study with RO6867461 Following Intravitreous and Intravenous Administration in Cynomolgus Monkeys with a 4-Week Recovery Phase”

“once weekly IV infusions of 0.1 and 1 mg/kg for 16 weeks (total of 17 doses) with a 14-week recovery period.”

“once weekly IV infusions of 0.01, 0.1, and 1 mg/kg for 4 weeks (total of 5 doses) with a 12-week recovery period”

“The subsequent toxicology study was initially programmed for 26 weeks of treatment but due to declining clinical condition that necessitated early sacrifice of a number of animals for welfare reasons, the study was stopped after 9 (total of 9 doses; 20 mg/kg group) or 14 weeks”

“Study R5458-TX-17179: A 5-Week Intravenous Infusion Toxicity and Toxicokinetic Study in Cynomolgus Monkeys With a 12-Week Dose-Free Recovery Phase”

“The Applicant evaluated the safety of zenocutuzumab in GLP-compliant 1-month and 13-week repeat-dose toxicology studies in cynomolgus monkeys with the intended IV route of administration.”

“In the 13-week repeat-dose toxicology study in monkeys, zenocutuzumab was intravenously administered at 10, 30, and 101 mg/kg once weekly for 13 weeks, followed by a 6-week recovery period.”

“Therefore, in the 13-week repeat-dose toxicology study in mice, BALB/c mice were administered muS103new (0, 1, or 5 mg/kg/day; 0, 2, or 10 mg/kg/day) by subcutaneous injection twice daily with an 8-hour interval between doses for 13 weeks with a 4-week recovery period.”

“For this review, the 4-week (summarized) and 13-week studies of muS103new in mice and the 5-weekly dose study of blinatumomab in chimpanzees were reviewed.”

“In the 3-month repeat-dose SC toxicity study, elranatamab doses of 0.3, 3, and 6 mg/kg/week (total of 14 doses) showed adverse clinical signs that correlated with decreased body weight and food consumption and contributed to mortality.”

“Recovery was not assessed in any of the general toxicology studies.”

“No adverse effects on any toxicology or safety pharmacology parameters evaluated at up to the high dose of 4500 µg/kg weekly for 3 months.”

“The nonclinical safety assessment of tarlatamab was based on a 10-day exploratory as well as 28-day GLP and 3-month GLP repeat-dose IV toxicology studies with once weekly doses of up to 4500 µg/kg.”

“Janssen conducted a GLP-compliant 13-week toxicology study in cynomolgus monkeys. Monkeys received intravenous amivantamab once weekly at doses of 0, 60, or 120 mg/kg.”

“The repeat-dose toxicity of amivantamab in cynomolgus monkeys was evaluated in a 4-week tolerability non-GLP study, and 6-week toxicity with 6-week recovery and 13-week toxicity GLP studies.”

“A comprehensive series of non-GLP and GLP studies have been conducted. The program included tissue cross-reactivity studies in panels of human tissues and IV toxicology studies of up to 13 treatment cycles (13 weeks duration) performed in cynomolgus monkeys.”

“Doses of 0 (vehicle control), 5, 50, and 150 mg/kg QW Route of administration: 1 hour IV infusion Formulation/Vehicle: sucrose, pH Species/Strain: Cynomolgus monkey”

“The toxicity and toxicokinetics (TK) of epcoritamab were evaluated in a 5-week toxicity study in cynomolgus monkeys.”

“Study: A 5-Week Toxicity Study of GEN3013 by Intravenous Infusion and Subcutaneous Injection in Cynomolgus Monkeys with Bioavailability, Local Tolerance, and a 6 Week Recovery Period / 503484 / eCTD location 4.2.3.2”

“The toxicity and toxicokinetics (TK) of teclistamab were evaluated in a 5-week repeat-dose toxicity study in cynomolgus monkeys.”

“Monkeys were administered teclistamab (0 [control], 1, 10, or 30 mg/kg/dose, IV) once weekly for five total doses followed by an 8-week recovery period.”

“Longer duration repeat-dose toxicology studies were not conducted due to the exposure-limiting development of anti-drug antibodies (ADA) in a short dose-range finding study (data not shown) and the 4-week repeat-dose study.”

“The Applicant conducted GLP studies in cynomolgus monkeys, including 2-week and 4-week repeat-dose toxicology studies, via the intravenous (IV) and subcutaneous (SC) routes.”

“The toxicity and toxicokinetics (TK) of JNJ-64024701 were evaluated in a GLP-compliant 1-month repeat”

“JNJ-64024701 (GCDB32 GPRC5DxCD3): A 1-Month GLP Intravenous Toxicity and Toxicokinetic Study in Cynomolgus Monkeys / Study T-2017-009”

“Tebentafusp can only recognize human HLA; therefore, all nonclinical toxicology studies were conducted in vitro.”

“Tebentafusp was also investigated in toxicology studies to assess its cross‐reactivity with normal tissues in a GLP‐compliant tissue cross‐reactivity study.”

“Repeat-dose toxicity studies have not been performed with catumaxomab due to the lack of an appropriate animal species.”

“Therefore, a limited toxicology programme was performed, i.e. single dose toxicity studies with catumaxomab in mice, rats and cynomolgus.”

“Repeat-dose toxicity studies have not been submitted.”

“In the few studies performed in rats, mice and one cynomolgus monkey, no acute toxicity was seen even at very high doses of catumaxomab.”