Columvi
glofitamab
Sources:FDA multi-discipline review ↗
Species
Monkey
Longest study
4 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Conducted Stated
Speciesopen answer page →
Species
Cynomolgus monkey only
“The cynomolgus monkey is a relevant species for toxicology studies based on glofitamab binding to CD20 and CD3 on cynomolgus monkey B- and T-cells.”
Why that species
Comparable binding to human and monkey B- and T-cells (EC50 4.3/2.3 nM B, 21.1/13.2 nM T); no rodent, dog, minipig cross-reactivity
“Glofitamab bound to human and monkey B-cells with EC50 values of 4.3 and 2.3 nM respectively and bound to human and monkey T-cells with EC50 values of 21.1 and 13.2 nM respectively. This justified use of the cynomolgus monkey for general toxicology studies.”
Surrogate molecule
No surrogate; clinical molecule tested in monkey (obinutuzumab pretreatment used in some studies)
“The cynomolgus monkey is a relevant species for toxicology studies based on glofitamab binding to CD20 and CD3 on cynomolgus monkey B- and T-cells.”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“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.”
Pivotal GLP studies
GLP cynomolgus 2-week IV (2 weekly doses) and 4-week IV/SC step-up (every other day) studies with recovery
“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.”
Route in tox
IV (slow bolus) and SC
“Route of administration: IV (slow bolus) injection and SC”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“genotoxicity studies have not been conducted with glofitamab. It is not expected that glofitamab would interact directly with DNA or other chromosomal material.”
Carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies with glofitamab have not been conducted and are not planned. Glofitamab is intended for the treatment of patients with advanced cancer.”
Reproductive & developmental
Not conducted (weight-of-evidence assessment; B-cell depletion and cytokine release risk to pregnancy)
“While no animal studies were conducted to assess the reproductive and developmental risks of glofitamab, a weight of evidence (WoE)-based risk assessment report was submitted.”
Safety pharmacology
Incorporated into repeat-dose monkey studies (CNS, respiratory, CV); cytokine-related heart rate increase
“No specific safety pharmacology studies have been conducted with glofitamab. Effects on the central nervous, respiratory, and cardiovascular systems were evaluated in repeat-dose toxicity studies in cynomolgus monkeys.”
First doseopen answer page →
First-in-human starting dose
MABEL: monkey PK/PD IL-6 excursion model plus in vitro human/monkey whole-blood cytokine data; 5 ug flat dose
“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”
NOAEL / key findings
HNSTD 30/100 ug/kg step-up (2-week); B-cell depletion, cytokine release, lymphoid hypocellularity; CRS deaths at 100 ug/kg first dose
“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,”
Risksopen answer page →
Immune & cytokine safety
Marked dose-dependent cytokine release (IL-6 >581-fold); step-up dosing/obinutuzumab mitigated; high ADA incidence limited exposure
“Gpt resulted in the attenuation of cytokine release allowing higher doses to be administered in cynomolgus monkeys. Administration of a low-dose prior to administering higher doses (step-up dosing) also mitigated the dose-limiting cytokine response.”
Biodistribution & persistence
No dedicated distribution studies (ICH S6); TMDD via CD20 with fast clearance in monkeys
“No dedicated studies have been performed to investigate the in vivo tissue distribution of glofitamab in animals, as per ICH S6(R1).”
Modality-specific risk
Cytokine release syndrome (dose-limiting first-dose CRS), mitigated by step-up dosing and obinutuzumab pretreatment
“Three of 7 males in the 0.1 mg/kg group were euthanized on day 1 due to clinical signs associated with cytokine release syndrome.”