How was the first-in-human dose set for approved bispecifics?

“A pharmacokinetic-pharmacodynamic (PK/PD) model for cytokine excursions in cynomolgus monkeys, particularly interleukin 6 (IL-6), was built and translated to humans. The human starting dose was selected to keep the predicted IL-6 excursion below a predefined threshold in patients”

“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,”

“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.”

“The proposed clinical starting dose of 0.5 mg/eye is supported by the nonclinical data but the high dose of 6.0 mg/eye is not.”

“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 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”

“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.”

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

“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.”

“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.”

“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 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).”

“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.”

“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.”

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

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

“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.”