Lunsumio
mosunetuzumab
Species
Monkey
Longest study
26 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
“Cynomolgus monkey was selected as the appropriate animal species for assessing the nonclinical safety, pharmacokinetic (PK), and pharmacodynamic (PD) properties of mosunetuzumab and 2H7v16/40G5c.”
Why that species
Cross-reacts with CD20 and CD3 in human and cynomolgus monkey, not rodents; comparable CD3 binding and B-cell killing potency
“2H7v16/40G5c displays the same properties as mosunetuzumab, as it cross-reacts with CD20 and CD3 in both humans and cynomolgus monkeys, but not in rodents.”
Surrogate molecule
Yes: functionally equivalent E. coli-made precursor 2H7v16/40G5c used in early monkey studies; pivotal 26-week study used mosunetuzumab
“Mosunetuzumab is produced from Chinese hamster ovary (CHO) cells; the functionally equivalent antibody, referred to as 2H7v16/40G5c and the proof-of-concept (POC) molecule, referred to as 2H7v16/UCHT1v9, were produced from E. coli.”
Species: general tox
Cynomolgus monkey only
“Cynomolgus monkey was selected as the appropriate animal species for assessing the nonclinical safety, pharmacokinetic (PK), and pharmacodynamic (PD) properties of mosunetuzumab and 2H7v16/40G5c.”
Species: DART
Not conducted; NHP EFD and pre/postnatal study waived on weight of evidence (FDA agreed)
“A briefing book, including the WOE-based risk assessment and a request to waive a non-human primate embryo-fetal and prenatal/postnatal development study, was submitted to the FDA (dated 3 April 2018; Reference ID: 4277993). In a written communication from the FDA dated 14 June 2018, the Agency agreed to the waiver request.”
Species: carcinogenicity
Not conducted (oncology indication, ICH S6(R1))
“No carcinogenicity studies have been conducted with mosunetuzumab and are not planned for the intended oncology indication, as per Guidance for Industry S6R1.”
Surrogate used in
No species-specific surrogate; functionally equivalent analogue 2H7v16/40G5c (same human/monkey cross-reactivity) used in some studies
“2H7v16/40G5c displays the same properties as mosunetuzumab, as it cross-reacts with CD20 and CD3 in both humans and cynomolgus monkeys, but not in rodents.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“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.”
Pivotal GLP studies
GLP single-dose IV/SC monkey (7-week observation); 4-week step-up DRF; GLP 26-week weekly IV step-up monkey study (16-1815)
“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)”
Route in tox
IV (slow bolus or 1-h infusion, step-up dosing) and SC
“Mosunetuzumab and 2H7v16/40G5c were investigated after repeated dosing up to 26 weeks in cynomolgus monkeys following IV administration (slow bolus injection (½-1 min) or infusion (1h)) or SC injection.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“In accordance with the current ICH guidance (ICH S6(R1) 2011), genotoxicity studies have not been conducted with mosunetuzumab because the potential of biotechnology products, in particular high molecular weight monoclonal antibodies, to elicit DNA damage in somatic or germ cells via electrophilic reactions is unlikely.”
Carcinogenicity
Not conducted (ICH S6R1, oncology indication)
“No carcinogenicity studies have been conducted with mosunetuzumab and are not planned for the intended oncology indication, as per Guidance for Industry S6R1.”
Reproductive & developmental
Not conducted (dedicated DART); NHP EFD/PPND waived on weight of evidence; no reproductive organ effects in 26-week monkey study
“A briefing book, including the WOE-based risk assessment and a request to waive a non-human primate embryo-fetal and prenatal/postnatal development study, was submitted to the FDA (dated 3 April 2018; Reference ID: 4277993).”
Safety pharmacology
Incorporated into GLP single-dose (telemetry CV) and repeat-dose monkey studies
“Cardiovascular effects were investigated as part of the single dose GLP study in monkeys (Study 14- 1246).”
Genotox: Ames
Not conducted (ICH S6(R1))
“In accordance with the current ICH guidance (ICH S6(R1) 2011), genotoxicity studies have not been conducted with mosunetuzumab because the potential of biotechnology products, in particular high molecular weight monoclonal antibodies, to elicit DNA damage in somatic or germ cells via electrophilic reactions is unlikely.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“In accordance with the current ICH guidance (ICH S6(R1) 2011), genotoxicity studies have not been conducted with mosunetuzumab because the potential of biotechnology products, in particular high molecular weight monoclonal antibodies, to elicit DNA damage in somatic or germ cells via electrophilic reactions is unlikely.”
Genotox: in vivo
Not conducted (ICH S6(R1))
“In accordance with the current ICH guidance (ICH S6(R1) 2011), genotoxicity studies have not been conducted with mosunetuzumab because the potential of biotechnology products, in particular high molecular weight monoclonal antibodies, to elicit DNA damage in somatic or germ cells via electrophilic reactions is unlikely.”
Carcinogenicity model
Not conducted (oncology indication, ICH S6(R1))
“No carcinogenicity studies have been conducted with mosunetuzumab and are not planned for the intended oncology indication, as per Guidance for Industry S6R1.”
Carcinogenicity timing
Not required; none conducted or planned for the oncology indication
“No carcinogenicity studies have been conducted with mosunetuzumab and are not planned for the intended oncology indication, as per Guidance for Industry S6R1.”
hERG / QT
No hERG; monkey telemetry: heart-rate-dependent PR/QT shortening, no QTc change vs pre-dose
“When corrected for heart-rate, no significant differences were noted in the QT intervals (QTc) compared with pre-dose levels. It appears that effects on QT were heart-rate dependent and not indicative of an effect of mosunetuzumab on ventricular repolarization kinetics, which is accepted.”
First doseopen answer page →
First-in-human starting dose
MABEL-type: EC20 from in vitro human PBMC cytokine release / T-cell activation assay
“The results (EC20 values) were used to inform the starting dose in the first in human study.”
NOAEL / key findings
No NOAEL; overall LOAEL 0.01 mg/kg (CRS effects at all doses); CNS perivascular infiltrates, liver, infections, one convulsion
“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.”
Risksopen answer page →
Immune & cytokine safety
Dose-dependent cytokine release 2-6 h post-dose; step-up dosing mitigated CRS; high ADA in monkeys; B-cell depletion infections
“Observed toxicities in GLP-study 14-1246 were largely attributed to a dose-dependent release of cytokines which occurred 2-6 hours post-dosing and returned to baseline values at 24 hours post-dose.”
Biodistribution & persistence
Vss above serum volume due to target binding; dose-dependent target-mediated clearance
“Vss-values were greater than estimated serum volume of cynomolgus monkeys, most likely due to specific binding of mosunetuzumab to its target cells.”
Modality-specific risk
First-dose CRS, CNS perivascular inflammation/convulsion, and infections from B-cell depletion
“The main findings were acute toxicities related to cytokine-release syndrome (CRS) primarily attributed to the first dose, vascular/perivascular inflammatory cell infiltrates mainly observed in the CNS and increased susceptibility to infection following chronic dosing.”
Anti-drug antibodies: animals
26-week monkey study: ADA in 5/8 (0.1 mg/kg) and 4/8 (0.5 mg/kg); lower exposure in ADA-positive animals at 0.1 mg/kg only
“ADA was detected in 5 of 8 animals in Group 2 (0.1 mg/kg) and in 4 of 8 animals in Group 3 (0.5 mg/kg) dosed with mosunetuzumab. Exposure appeared to be lower in ADA-positive animals in Group 2 (0.1 mg/kg), while exposure was not consistently impacted in ADA-positive animals in Group 3 (0.5 mg/kg).”
Anti-drug antibodies: patients
No patients (N = 418) developed anti-mosunetuzumab antibodies in Study GO29781
“During treatment in Study GO29781 (up to 12 months) [see Clinical Studies (14) ] , using an enzyme-linked immunosorbent assay (ELISA), no patients (N = 418) treated with LUNSUMIO developed anti-mosunetuzumab-axgb antibodies.”
Label warnings
Boxed warning: Cytokine release syndrome
- Cytokine Release Syndrome
- Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome
- Infections
- Hemophagocytic Lymphohistiocytosis
- Cytopenias
- Tumor Flare
- Risk of Medication Errors with Incorrect Product Use
- Embryo-Fetal Toxicity
Cytokine release syndromeNeurotoxicityInfectionsImmune-mediated reactionsCytopeniasSecondary malignancyEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US, Republic of Korea, Canada: dose-escalation part (Group A) of study GO29781 in patients with R/R B-cell NHL
“● Group A (n=33): United States 25 (5), Republic of Korea 7 (2), Canada 1 (1).”
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-type: EC20 from in vitro human PBMC cytokine release / T-cell activation assay
“The results (EC20 values) were used to inform the starting dose in the first in human study.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week GLP cynomolgus monkey study (IV step-up then weekly); recovery phase not stated
“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.”
Pivotal GLP studies
GLP single-dose IV/SC monkey (7-week observation); 4-week step-up DRF; GLP 26-week weekly IV step-up monkey study (16-1815)
“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)”
DART package
Species: DART
Not conducted; NHP EFD and pre/postnatal study waived on weight of evidence (FDA agreed)
“A briefing book, including the WOE-based risk assessment and a request to waive a non-human primate embryo-fetal and prenatal/postnatal development study, was submitted to the FDA (dated 3 April 2018; Reference ID: 4277993). In a written communication from the FDA dated 14 June 2018, the Agency agreed to the waiver request.”
Reproductive & developmental
Not conducted (dedicated DART); NHP EFD/PPND waived on weight of evidence; no reproductive organ effects in 26-week monkey study
“A briefing book, including the WOE-based risk assessment and a request to waive a non-human primate embryo-fetal and prenatal/postnatal development study, was submitted to the FDA (dated 3 April 2018; Reference ID: 4277993).”
PPND / ePPND: when
Monkey EFD/prenatal-postnatal study waived by FDA on weight of evidence
“A briefing book, including the WOE-based risk assessment and a request to waive a non-human primate embryo-fetal and prenatal/postnatal development study, was submitted to the FDA (dated 3 April 2018; Reference ID: 4277993). In a written communication from the FDA dated 14 June 2018, the Agency agreed to the waiver request.”
Carcinogenicity
Species: carcinogenicity
Not conducted (oncology indication, ICH S6(R1))
“No carcinogenicity studies have been conducted with mosunetuzumab and are not planned for the intended oncology indication, as per Guidance for Industry S6R1.”
Carcinogenicity model
Not conducted (oncology indication, ICH S6(R1))
“No carcinogenicity studies have been conducted with mosunetuzumab and are not planned for the intended oncology indication, as per Guidance for Industry S6R1.”
Carcinogenicity timing
Not required; none conducted or planned for the oncology indication
“No carcinogenicity studies have been conducted with mosunetuzumab and are not planned for the intended oncology indication, as per Guidance for Industry S6R1.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL; CRS and infections in monkeys at exposures 0.008-1.84x human AUC
“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.”
NOAEL / key findings
No NOAEL; overall LOAEL 0.01 mg/kg (CRS effects at all doses); CNS perivascular infiltrates, liver, infections, one convulsion
“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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human CD20/CD3 double-transgenic mice: peripheral and tissue B-cell depletion and T-cell activation (comparable to analogue 2H7v16/40G5c)
“In the double-transgenic mouse model, it was also shown that 2H7v16/40G5c and mosunetuzumab have comparable profiles in potently depleting peripheral and tissue B cells as well as activation of T cells.”
Why that model
Cross-reacts with CD20 and CD3 in humans and cynomolgus monkeys but not in rodents
“2H7v16/40G5c displays the same properties as mosunetuzumab, as it cross-reacts with CD20 and CD3 in both humans and cynomolgus monkeys, but not in rodents.”
Reviewer's view of the efficacy data
EMA: pharmacology thoroughly described in the non-clinical package
“The pharmacology of mosunetuzumab was thoroughly described in the provided non-clinical package.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
Monkey embryo-fetal and pre-/postnatal development study waived; weight-of-evidence assessment using other anti-CD20 antibodies
Why: Further monkey testing unlikely to add information; anti-CD20 class effects known · Weight of evidence · Class precedent · Within the guideline
“A briefing book, including the WOE-based risk assessment and a request to waive a non-human primate embryo-fetal and prenatal/postnatal development study, was submitted to the FDA (dated 3 April 2018; Reference ID: 4277993).”
“Based on the justification provided by the Applicant, and in accordance with ICH S6 (R1) it is agreed that no further testing is required in order to elucidate the reproductive toxicity of mosunetuzumab in cynomolgus monkeys, as it is not likely it will add further information to the current nonclinical and clinical knowledge to support the mitigation of this risk in humans.”
Safety marginVerdict not stated
No NOAEL; CRS and infections in monkeys at exposure multiples of 0.008 to 1.84
“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.”
OtherVerdict not stated
No tissue cross-reactivity study: no robust IHC assay could be developed
Why: Poor analytical sensitivity and specificity of the antibody as an IHC reagent
“Due to technical limitations it was not possible to develop a robust, reproducible and accurate IHC assay to assess specific tissue binding and determine the potential cross-reactivity of mosunetuzumab in human and cynomolgus monkey tissue, as mosunetuzumab exhibits poor analytical sensitivity and specificity as an IHC reagent.”
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