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.”
Species: general tox
Cynomolgus monkey (10-week GLP study); DM4 payload single-dose in monkey
“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.”
Species: DART
Not conducted
“No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine.”
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”
Surrogate used in
No surrogate used; clinical ADC cross-reacts with rhesus and cynomolgus monkey FRα only
“MIRV (and M9346A) cross-reacts only with rhesus and cynomolgus monkey FRα, out of toxicological species.”
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.”
Genotox: Ames
DM4 and S-methyl DM4: negative in Ames
“DM4 and S-methyl DM4 were not mutagenic in the bacterial reverse mutation (Ames) assay.”
Genotox: in vitro mammalian
Not conducted (in vitro testing limited to bacterial reverse mutation assay)
“DM4 and the active metabolite S-methyl DM4 were assessed in vitro for the genotoxic potential in a bacterial reverse mutation assay and in vivo in Sprague Dawley rats for the clastogenicity.”
Genotox: in vivo
DM4 and S-methyl DM4: positive (clastogenic) in rat bone marrow micronucleus study
“DM4 and the metabolite, S-methyl DM4, were clastogenic in the in vivo rat bone marrow micronucleus study.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”
Carcinogenicity timing
Not required for the advanced cancer indication (ICH S9)
“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”
hERG / QT
ADC not tested; DM4 and S-methyl-DM4 <50% hERG inhibition up to 60 µM
“In safety pharmacology studies, inhibition of hERG channels was not evaluated with mirvetuximab soravtansine; however, up to 60 µM DM4 and metabolite S-methyl-DM4 had < 50% inhibition on hERG potassium channels.”
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.”
Anti-drug antibodies: animals
No ADA in any monkey at doses up to 8 mg/kg
“All monkeys administered mirvetuximab soravtansine at doses up to 8 mg/kg/dose tested negative for the presence of anti-drug antibodies (ADAs).”
Anti-drug antibodies: patients
9% (57/626) developed ADA at 6 mg/kg AIBW Q3W
“In studies 0416, 0417, 0401, and 0403 in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer who received ELAHERE at 6 mg/kg AIBW administered intravenously once every 3 weeks, 9% (57/626) developed anti-drug antibodies.”
Label warnings
Boxed warning: Ocular toxicity
- Ocular Disorders
- Pneumonitis
- Peripheral Neuropathy
- Embryo-Fetal Toxicity
Ocular toxicityImmune-mediated reactionsNeurotoxicityEmbryo-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
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)”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
10-week cynomolgus monkey IV study (every 3 weeks, 4 doses) with 5-week recovery
“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).”
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).”
DART package
Species: DART
Not conducted
“No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine.”
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.”
PPND / ePPND: when
Not conducted: no reproductive or developmental studies (DM4 genotoxic, toxic to dividing cells)
“No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine. The cytotoxic component of ELAHERE, DM4, disrupts microtubule function, is genotoxic, and can be toxic to actively dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”
Carcinogenicity timing
Not required for the advanced cancer indication (ICH S9)
“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 4 mg/kg: AUC margin 0.09 (AUC0-24 vs AUCtau) to 0.57 (AUC0-∞)
“When monkey AUC0-24 was compared to human AUCtau (area under the concentration vs. time curve over the dosing interval 21 days) exposure margin was 0.09; however, when monkey AUC0-∞ was used for comparison the exposure multiple was 0.57.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Ovarian cancer xenograft mouse models (single IV dose)
“In vivo, mirvetuximab soravtansine delayed tumor growth and caused tumor regression in several ovarian cancer xenograft mouse models when mice were administered a single IV dose of mirvetuximab soravtansine containing antibody doses as low as 1.2 mg/kg and DM4 dose of 25 µg/kg.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: pharmacology data generally adequate and in line with guidelines
“The pharmacology data is considered in general adequate; the development program is in line with the regulatory guidelines.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No reproductive or developmental toxicity studies at all, including embryo-fetal development
Why: Cytotoxic payload targets rapidly dividing cells; maytansinoid class has described developmental toxicity · Within the guideline · Class precedent · Pharmacology or kinetics
“The absence of any reproductive or developmental studies was justified by referring to ICH S9.”
“The payload of MIRV, DM4 (and the active metabolite S-methyl DM4), is cytotoxic, targets rapidly dividing cells and belongs to a class of compounds (maytansinoid) for which developmental toxicity/teratogenicity has been described in the literature (Sieber 1978; Issell 1978).”
Safety marginVerdict not stated
No exposure margin at the monkey NOAEL: AUC multiple 0.09 (AUC0-24 vs AUCtau) to 0.57 (AUC0-∞)
“When monkey AUC0-24 was compared to human AUCtau (area under the concentration vs. time curve over the dosing interval 21 days) exposure margin was 0.09; however, when monkey AUC0-∞ was used for comparison the exposure multiple was 0.57.”
Impurity or metaboliteAcceptedBeyond the letter
Maytansinoid impurities qualified with single-dose mouse studies only
Why: Patients are dosed once every 3 weeks · Pharmacology or kinetics
“The impurities were dosed only once in mouse qualification studies; however this can be accepted since posology in patients is once every 3 weeks (21-day cycle).”
Similar precedents
AdcetrisADCs · brentuximab vedotin · CD30Monkey + rodent · 26 wkBesponsaADCs · inotuzumab ozogamicin · CD22Monkey + rodent · 26 wkDatrowayADCs · datopotamab deruxtecan · Trop-2Monkey + rodent · 13 wkDecnupazADCs · pivekimab sunirine · CD123Monkey + rodent · 13 wkEmrelisADCs · telisotuzumab vedotin · c-MetMonkey + rodent · 13 wkEnhertuADCs · fam-trastuzumab deruxtecan · HER2Monkey + rodent · 13 wk