What safety margins were accepted for approved bispecifics?

“obtained exposure levels in toxicology studies conducted without Gpt did not exceed those obtained in the clinical setting, as estimations of exposure multiples resulted in values of 0.03 to 0.28 (based on AUC)”

“Key findings with glofitamab identified in single- and repeat-dose toxicity studies up to 4 weeks in duration in cynomolgus monkeys included B-cell depletion, transient postdose cytokine release, primarily after the first dose,”

“At the NOAEL/LOEL of 0.3 mg/kg, exposure in cynomolgus was well below the human exposure (0.1x or 0.2x).”

“Immunosuppression led to secondary infections and moribund euthanasia at all doses; no NOAEL was identified; dose-dependence was evident by incidence and timing”

“In this study, the no observed adverse effect level (NOAEL) for BiLu is considered to be the low dose (0.2 to 3.0 μg/kg). This mouse dose is equivalent to the catumaxomab dose used in the clinical regimen; the maximum human dose is 100 µg (i.e. 1.43 µg/kg in a 70 kg person).”

“In this study, the no observed adverse effect level (NOAEL) for BiLu is considered to be the low dose (0.2 to 3.0 μg/kg).”

“When applying the corrections of AUC, estimations of exposure multiples resulted in values of 0.008 to 1.84, implying that CRS related effects and immunosuppression leading to infections occur at clinically relevant dose levels.”

“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.”

“the exposure margin at the NOAEL of 0.5 mg/eye/dose (based on the animal immune mediated ocular effects in the 6 month monkey study) with mean AUC(0-72h) = 20200 ng•hr/mL and a mean Cmax = 220 ng/mL on Day 141, is only around 1 when compared to values of human exposure”

“For ocular toxicity, the NOAEL was 0.5 mg/eye (the low dose). The LOAEL was 1.5 mg/eye (the mid-dose), due to ocular inflammation (observed by ophthalmology and confirmed by histopathology).”

“the NOAEL in the SC dosing group was 10 mg/kg. At the highest IV dose of 1 mg/kg, the exposure in males and females was the same as the clinical AUC0-t at steady state. At the highest SC dose of 10 mg/kg, the exposure margins in males and females were 5x the clinical AUC0-t at steady state.”

“In the pivotal 5-week study (503484), the NOAEL in the IV repeat dosing group was 0.1 mg/kg, while the NOAEL in the SC dosing group was 10 mg/kg.”

“Exposures achieved in monkeys at the 120 mg/kg dose level were 5x1 times higher than the AUC in patients (102954 µg*h/mL) at the once weekly dose for 4 weeks, then every 2 weeks clinical dose of 1050 mg.”

“The no-observed-adverse-effect level (NOAEL) in the toxicology studies was 120 mg/kg/week (highest tested dose) for the 6-week and 3-month toxicity GLP studies.”

“In repeat-dose toxicity studies in cynomolgus monkeys (28DTOX and 13WTOX), no mortality or signs of acute toxicity was noted following the first administration of zanidatamab at dose levels up to 150 mg/kg resulting in exposure multiples approximately 10-fold higher than clinically relevant exposure.”

“No adverse effects were observed at any dose tested (up to 150 mg/kg QW) for animals in either the 8-week or 13-week dosing cohorts.”

“The NOAEL dose of 30 mg/kg in the 26-week study (1060134) resulted in a steady state AUC0−168h (AUC0−168h ss) exposure of 8680 µg.d/mL. This is approximately 11-fold above the clinical exposure in a 3 mg/kg QW dosing regimen which is the regimen that is anticipated to yield the highest exposure in patients.”

“This is approximately 11-fold above the clinical exposure in a 3 mg/kg QW dosing regimen which is the regimen that is anticipated to yield the highest exposure in patients.”

“the safety margins (at NOEL 30 mg/kg IV weekly dosing) were adequate, i.e. 48 times the Cmax and 22 times the AUCtau compared to subjects with relapsed/refractory multiple myeloma in Phase 1/2 study MajesTEC-1 (at steady-state exposure at 1.5 mg/kg SC weekly, the recommended weight-based dose regimen).”

“The no-observed-effect level for 5 weekly IV doses of teclistamab-treated monkeys was 30 mg/kg , the highest dose tested”

“The Applicant suggests that these findings were unrelated to zenocutuzumab as comparable findings were not observed in animals that showed higher zenocutuzumab exposure compared to the mid-dose animal”

“The exposure of chimpanzees in term of AUCinf was 2.9 (M) and 5.6 (F) ng.h/mL with Cmax of 0.9 (M) and 1.36 (F) ng/mL, i.e. higher than Css reached at the clinical doses of 9 µg/day (211 pg/mL) and 28 µg/day (621 pg/mL)”

“Following daily administration of the surrogate for 4 or 13 weeks in mice, lymphoid tissues were the target organs of toxicity with decreased spleen weights and decreased cellularity or germinal center development observed in the lymph nodes, Peyer’s patches, and spleen.”

“Tarlatamab-related changes are reversible and clinically monitorable, and the highest non-severely toxic dose was determined to be 4500 µg/kg based on the absence of any tarlatamab-related adverse findings.”

“Tebentafusp demonstrated broad loss of specificity for the target pHLA complex from 1 nM (1,000× MABEL), where consistent evidence of T cell activation (IFNγ release) and/or redirected killing (GrB release) was observed across the different normal cells tested.”

“In the 9- or 14-week study, a NOAEL could not be determined.”

“In the repeat-dose toxicology studies, once weekly IV infusion of up to 1 mg/kg odronextamab for up to 4 weeks was tolerated.”

“The single-dose toxicity studies with BiLu indicate that catumaxomab may cause liver toxicity.”

“No adverse effects on any toxicology or safety pharmacology parameter evaluated at up to the high dose of 30 mg/kg weekly”