Columvi
glofitamab
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.”
Species: general tox
Cynomolgus monkey only
“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.”
Species: DART
Not conducted; weight-of-evidence risk assessment (B-cell depletion, cytokine release)
“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.”
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“Glofitamab is intended for the treatment of patients with advanced cancer. In line with the ICH S9 guideline, no carcinogenicity studies were performed (ICH S9).”
Surrogate used in
No surrogate used; clinical molecule in cynomolgus monkey (obinutuzumab pretreatment 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.”
Genotox: Ames
Not conducted (ICH S6)
“(ICH S6[R1] 2011), genotoxicity studies have not been conducted with glofitamab.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“(ICH S6[R1] 2011), genotoxicity studies have not been conducted with glofitamab.”
Genotox: in vivo
Not conducted (ICH S6)
“(ICH S6[R1] 2011), genotoxicity studies have not been conducted with glofitamab.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“Glofitamab is intended for the treatment of patients with advanced cancer. In line with the ICH S9 guideline, no carcinogenicity studies were performed (ICH S9).”
Carcinogenicity timing
Not required: advanced cancer indication (ICH S9)
“Glofitamab is intended for the treatment of patients with advanced cancer. In line with the ICH S9 guideline, no carcinogenicity studies were performed (ICH S9).”
hERG / QT
No hERG assay; monkey ECG showed no effect on QRS or QTc (cytokine-related heart rate increase only)
“There was no effect of glofitamab administration on QRS duration or corrected QTc interval.”
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.”
Anti-drug antibodies: animals
High ADA incidence in all monkey studies, causing loss of exposure and PD effect; limited study duration to 4 weeks
“In summary, glofitamab was shown to be highly immunogenic in cynomolgus monkeys and to lead to loss of exposure and pharmacological effect in repeat-dose studies. Consequently, no further/longer toxicology studies were conducted, which is accepted.”
Anti-drug antibodies: patients
1.1% (5/448) anti-glofitamab antibodies; neutralizing not reported
“During treatment in Study NP30179 (up to 9 months) [see Clinical Studies (14.1) ] , using an enzyme-linked immunosorbent assay (ELISA), the incidence of anti-glofitamab antibody formation was 1.1% (5/448) in patients treated with COLUMVI.”
Label warnings
Boxed warning: Cytokine release syndrome
- Cytokine Release Syndrome
- Neurologic Toxicity
- Serious Infections
- Tumor Flare
- Embryo-Fetal Toxicity
Cytokine release syndromeNeurotoxicityInfectionsSecondary malignancyEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week IV/SC step-up cynomolgus monkey study with 4-week treatment-free period
“RO7082859: A 4-week intravenous and subcutaneous toxicity and toxicokinetic study in Mauritius cynomolgus monkeys followed by a 4-week treatment-free period”
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.”
DART package
Species: DART
Not conducted; weight-of-evidence risk assessment (B-cell depletion, cytokine release)
“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.”
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.”
PPND / ePPND: when
No PPND or other reproductive animal studies; weight-of-evidence risk assessment instead
“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.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“Glofitamab is intended for the treatment of patients with advanced cancer. In line with the ICH S9 guideline, no carcinogenicity studies were performed (ICH S9).”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“Glofitamab is intended for the treatment of patients with advanced cancer. In line with the ICH S9 guideline, no carcinogenicity studies were performed (ICH S9).”
Carcinogenicity timing
Not required: advanced cancer indication (ICH S9)
“Glofitamab is intended for the treatment of patients with advanced cancer. In line with the ICH S9 guideline, no carcinogenicity studies were performed (ICH S9).”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey exposure below clinical: AUC multiples 0.03-0.28 in studies without obinutuzumab pretreatment
“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)”
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,”
Efficacy evidenceopen answer page →
Efficacy evidence
Human HSC-engrafted NOG/NSG mice, non-tumor-bearing and tumor-bearing
“In vivo activity was investigated in both non-tumor bearing HSC-NOG mice and in tumor-bearing HSG-NOG and HSG-NSG mice.”
Why that model
No cross-reactivity with rodent, dog or minipig CD20 or CD3e; monkey is the only cross-reactive species
“The choice of the cynomolgus monkey as the pharmacological and toxicological species is considered justified as comparable cross-reactivity is observed between human and monkey B cells while no cross-reactivity is observed for rodent, dog or minipig CD20 or CD3ε.”
Reviewer's view of the efficacy data
EMA: in vitro and in vivo pharmacology programme, including disease models, sufficient to support clinical use
“The in vitro and in vivo pharmacology programme, including in disease models, supporting the intended clinical use of glofitamab – is sufficient.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
No repeat-dose study longer than 4 weeks; 13-week monkey study waived
Why: High ADA incidence in monkeys caused loss of exposure and effect; effects similar to other B-cell depleting agents · Pharmacology or kinetics · Class precedent
“Studies longer than 4 weeks were not performed, as glofitamab was highly immunogenic in cynomolgus monkeys leading to loss of exposure and loss of the pharmacologic effect.”
“The waiver for omitting the 13-week study is therefore accepted, also as the observed effects of glofitamab is similar to that observed for other B-cell depleting agents, and no unexpected findings have been observed.”
DARTAccepted
No animal reproductive or developmental toxicity studies; weight-of-evidence risk assessment instead
Why: Weight-of-evidence per ICH S6(R1); further testing unlikely to add to current nonclinical and clinical knowledge · Weight of evidence · Within the guideline · Class precedent
“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.”
“Based on the justification provided, and in accordance with ICH S6 (R1) it is agreed that no further testing is required in order to elucidate the reproductive toxicity of glofitamab in cynomolgus monkeys, as it is not likely it will add further information to the current non-clinical and clinical knowledge to support the mitigation of this risk in humans.”
Safety marginAccepted
Monkey exposures below clinical: AUC multiples 0.03 to 0.28 in studies without obinutuzumab pretreatment
Why: Advanced cancer indication; adverse effects from exaggerated pharmacology; no alternative species besides monkey · Serious disease · Within the guideline · Pharmacology or kinetics
“In summary, 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), implying that CRS-related effects occur at clinically relevant dose levels.”
“The low exposure multiples are considered acceptable, taking into account the indication (advanced cancer), that the expected adverse effects of glofitamab occurs mainly due to exaggerated pharmacology or secondary to it, and that no obvious alternative animal species besides the monkey are available for toxicology studies.”
Similar precedents
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