Elahere
mirvetuximab soravtansine
Species
MonkeyMouseRabbit
Longest study
10 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Cynomolgus monkey (general tox); rabbit for ocular tox; DM4 payload in monkey and mouse
“The monkey was demonstrated to be the most appropriate animal species for toxicological evaluation of MIRV based on FOLR1 gene sequence homology assessments, in vitro binding assays, and IHC analysis of FRα protein expression on fresh frozen tissue sections using MIRV.”
Why that species
Binds human and monkey FRα with similar affinity (98% homology); no binding to mouse or rat FRα; similar TCR staining
“MIRV (and M9346A) cross-reacts only with rhesus and cynomolgus monkey FRα, out of toxicological species.”
Surrogate molecule
No surrogate; clinical ADC in monkey and rabbit (ocular); free DM4 in non-GLP single-dose studies
“A 10-week GLP compliant repeat-dose toxicity study with mirvetuximab soravtansine was conducted in cynomolgus monkey using the clinical IV route of administration, and the payload DM4 was assessed in cynomolgus monkey in a non-GLP single IV dose toxicity study.”
Study lengthopen answer page →
Longest pivotal study
10 weeks
“A 10-week GLP compliant repeat-dose toxicity study with mirvetuximab soravtansine was conducted in cynomolgus monkey using the clinical IV route of administration”
Pivotal GLP studies
10-week GLP monkey (2, 4, 8 mg/kg q3w IV, 5-week recovery); single-dose monkey; GLP rabbit ocular 4-week weekly and 12-week q3w
“IMGN853 at doses of 0, 2, 4, and 8 mg/kg/dose was administered intravenously (slow push) to cynomolgus monkeys once every 3 weeks for up to 10 weeks (a total of 4 doses) with a 5- week recovery period (n=6/sex/group).”
Route in tox
IV (slow push in monkey; infusion in rabbit), clinical route
“A 10-week GLP compliant repeat-dose toxicity study with mirvetuximab soravtansine was conducted in cynomolgus monkey using the clinical IV route of administration”
Skipped studiesopen answer page →
Genotoxicity
Not conducted with ADC; DM4 and S-methyl-DM4 Ames negative, rat bone marrow micronucleus positive
“DM4 and S-methyl-DM4 were negative in the vitro bacterial reverse mutation assay but positive in the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”
Reproductive & developmental
Not conducted (ICH S9); DM4 genotoxic, embryotoxicity expected; FRα mutations linked to birth defects
“No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine.”
Safety pharmacology
Incorporated into repeat-dose monkey study (ECG, clinical observation); DM4/S-methyl-DM4 hERG IC50 >60 µM
“Additionally, mirvetuximab soravtansine did not have effects on the nervous, cardiovascular, or respiratory systems in monkeys after repeated IV dosing up to 8 mg/kg (4-fold the exposures at the recommended dose based on AUC) based on ECG analysis and clinical observation.”
First doseopen answer page →
First-in-human starting dose
Rationale not stated; FIH Study 0401 escalated from 0.15 mg/kg (TBW) to 7.0 mg/kg
“MIRV: Dose escalation: 0.15 mg/kg TBW to 7.0 mg/kg TBW (n = 44 Q3W; n = 25 QW)”
NOAEL / key findings
10-week monkey NOAEL 4 mg/kg q3w (Cmax margin ~1); single-dose HNSTD 10 mg/kg, NOAEL 3 mg/kg; cornea, skin, bone marrow
“In a 10-week toxicity study in monkeys a mid-dose of 4 mg/kg/dose Q3W of MIRV was selected to characterize potential toxicity at an exposure metric which was predicted to be similar to that of the IV dose (6 mg/kg, AIBW) utilized for the registrational studies. This dose was considered as NOAEL.”
Risksopen answer page →
Immune & cytokine safety
No ADA in any monkey up to 8 mg/kg; bone marrow and lymphoid depletion; no stand-alone immunotox
“All monkeys administered mirvetuximab soravtansine at doses up to 8 mg/kg/dose tested negative for the presence of anti-drug antibodies (ADAs).”
Biodistribution & persistence
Rat radiolabel: liver, bone marrow, lung, kidney, spleen highest; slow ocular clearance; testis penetration; brain <3%; fecal elimination
“The eye:plasma ratio increased through the duration of the study, suggesting that drug clearance from the eyes was slower than from plasma.”
Modality-specific risk
DM4 payload ocular toxicity (corneal degeneration/keratopathy) plus myelosuppression and skin toxicity; dedicated rabbit ocular studies
“Due to ocular toxicities observed in both animal toxicity studies and in patients, the Applicant also conducted GLP compliant repeated-dose toxicity studies to evaluate ocular toxicity of mirvetuximab soravtansine in male rabbits.”