NAV

Mirvetuximab soravtansine

Identification

Summary

Mirvetuximab soravtansine is a folate receptor alpha-directed antibody and microtubule inhibitor conjugate used to treat folate receptor alpha positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Brand Names
Elahere
Generic Name
Mirvetuximab soravtansine
DrugBank Accession Number
DB12489
Background

Mirvetuximab soravtansine-gynx (IMGN853) is an antibody-drug conjugate (ADC) formed by a monoclonal antibody (M9346A) that targets folate receptor alpha (FRα), covalently joined by a cleavable disulfide linker to the genotoxic compound DM4 (also known as soravtansine or ravtansine).3,5 DM4 is conjugated to the antibody with a drug-to-antibody ratio of 3.5:1.2

The antibody component of mirvetuximab soravtansine-gynx binds to FRα, a receptor overexpressed on the surface of epithelial tumor cells, characteristic of ovarian, endometrial, triple-negative breast and non-small-cell lung cancers.1 After an ADC/receptor complex is formed, mirvetuximab soravtansine-gynx is internalized, and DM4 is released inside the cell. DM4 leads to cell-cycle arrest and apoptosis and is also able to diffuse into neighboring cells and induce further cell death.1

On November 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for the treatment of adult patients with FRα–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1-3 prior systemic treatment regimens. This decision was supported by findings from the phase 3 SORAYA trial (NCT04296890).5,6

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
150000.0 Da (approximate)
Sequences
>Heavy chain
QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYDGDTFY
NQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWGQGTTVTVSSAS
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPG
>Light chain
DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIYRASNLEA
GVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYTFGGGTKLEIKRTVAAPSVF
IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS
STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. WHO: International Nonproprietary Names for Pharmaceutical Substances (INN) [Link]
Download FASTA Format
Synonyms
  • Anti-FOLR1-monoclonal-antibody-maytansinoid-conjugate-IMGN-853
  • Mirvetuximab soravtansine
  • Mirvetuximab soravtansine-gynx
External IDs
  • IMGN-853
  • IMGN853

Pharmacology

Indication

Mirvetuximab soravtansine is indicated for the treatment of adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Patients are selected for therapy based on an FDA-approved test.5

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.5

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

There is an exposure-response relationship for mirvetuximab soravtansine-gynx. The increased exposure of mirvetuximab soravtansine-gynx was associated with a higher incidence of ocular adverse reactions and peripheral neuropathy grade 2 or higher. Mirvetuximab soravtansine-gynx did not cause large QTc increases (>10 msec) at the approved recommended dose.5 The use of mirvetuximab soravtansine-gynx has been associated with severe ocular adverse reactions, such as visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis. Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, as well as peripheral neuropathy, may also occur in patients treated with mirvetuximab soravtansine-gynx. Since mirvetuximab soravtansine-gynx contains DM4, a genotoxic compound, the use of this drug may cause embryo-fetal harm in pregnant women.5

Mechanism of action

Mirvetuximab soravtansine-gynx is an antibody-drug conjugate (ADC) formed by three components: a chimeric IgG1 antibody against folate receptor alpha (FRα), the small molecule anti-tubulin agent DM4 (a maytansine derivative) and a sulfo-SPDB linker that joins DM4 to the mirvetuximab antibody.5 FRα is expressed on the cell surface and has a restricted distribution in normal tissues. However, abnormally high levels of FRα have been detected in serous and endometrioid epithelial ovarian cancer, endometrial adenocarcinoma, and non–small cell lung cancer of the adenocarcinoma subtype. In ovarian cancer patients, its expression is maintained in metastatic foci and recurrent carcinomas.4 Mirvetuximab soravtansine-gynx binds with high affinity to FRα and is then internalized through antigen-mediated endocytosis. Inside FRα-expressing tumor cells, DM4 is released via proteolytic cleavage. DM4 disrupts the microtubule network within the cell, leading to cell cycle arrest and apoptosis.1,5 Since DM4 is electrically neutral and lipophilic, it is able to diffuse across cell membranes and lead to the death of neighboring antigen-negative cells. This "bystander effect" is an important component of mirvetuximab soravtansine-gynx, allowing it to exert a cytotoxic effect even in cells that do not express FRα on their surface.2,4

TargetActionsOrganism
AFolate receptor alpha
binder
Humans
Absorption

The pharmacokinetic parameters of mirvetuximab soravtansine-gynx were evaluated in patients given a 6 mg/kg adjusted ideal body weight (AIBW) dose administered during the first treatment cycle (3 weeks). Mirvetuximab Soravtansine-gynx, the unconjugated DM4, and S-methyl-DM4 had a corresponding Cmax of 137.3 µg/mL, 4.11 ng/mL and 6.98 ng/mL, and a corresponding AUCtau of 20.65 h⋅mg/mL, 530 h⋅ng/mL and 1848 h⋅ng/mL.5 The peak concentration of mirvetuximab soravtansine-gynx was observed near the end of intravenous infusion, while DM4 and S-methyl-DM4 concentrations peaked 2 and 3 days after mirvetuximab soravtansine-gynx administration. After one treatment cycle, mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 reached steady-state concentrations. Following the repeated administration of mirvetuximab soravtansine-gynx, the accumulation of mirvetuximab soravtansine-gynx, DM4, and S-methyl-DM4 were minimal.5

Volume of distribution

Mirvetuximab soravtansine-gynx has a steady-state volume of distribution of 2.63 L.5

Protein binding

Based on in vitro studies, the plasma protein binding of the mirvetuximab soravtansine-gynx component DM4 and its metabolite S-methyl DM4 is higher than 99%.5

Metabolism

After mirvetuximab soravtansine-gynx binds the folate receptor alpha (FRα) and is internalized via antigen-mediated endocytosis, the DM4 agent is released via proteolytic cleavage. The monoclonal antibody portion of this drug is expected to be metabolized by catabolic pathways into small peptides. Unconjugated DM4 is reduced and S-methylated to form S-methyl-DM4. DM4 and S-methyl-DM4 are the main circulating metabolites of mirvetuximab soravtansine-gynx and correspond to approximately 0.4% and 1.4% of mirvetuximab soravtansine-gynx AUCs. Both DM4 and S-methyl-DM4 undergo metabolism by CYP3A4.5

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Route of elimination

Mirvetuximab soravtansine-gynx metabolites S-methyl DM4 and DM4-sulfo-SPDB-lysine were detected in urine within 24 hours of infusion as the main metabolites.5

Half-life

After the first dose, the geometric mean terminal phase half-life of mirvetuximab soravtansine-gynx is 4.8 days.5 The geometric mean terminal phase half-lives of the unconjugated DM4 and its metabolite, S-methyl-DM4, are 2.8 and 5.0 days, respectively.5

Clearance

The total plasma clearance of mirvetuximab soravtansine-gynx is 18.9 mL/hour.5 The unconjugated DM4 has a total plasma clearance of 13.8 L/hour, while its metabolite, S-methyl-DM4, has a total plasma clearance of 4.3 L/hour.5

Adverse Effects
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Toxicity

Toxicity information regarding mirvetuximab soravtansine-gynx is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as ocular toxicity, pneumonitis and peripheral neuropathy.5 Symptomatic and supportive measures are recommended.

Carcinogenicity studies with mirvetuximab soravtansine-gynx or DM4 have not been performed. An in vivo rat bone marrow micronucleus study showed that DM4 and its metabolite, S-methyl DM4, are clastogenic. DM4 and S-methyl DM4 did not show evidence of mutagenicity in the bacterial reverse mutation (Ames) assay. The effects of mirvetuximab soravtansine-gynx or DM4 on fertility studies have not been evaluated.5

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Mirvetuximab Soravtansine.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Mirvetuximab Soravtansine.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Mirvetuximab Soravtansine.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Mirvetuximab Soravtansine.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Mirvetuximab Soravtansine.
AmbroxolThe risk or severity of methemoglobinemia can be increased when Mirvetuximab soravtansine is combined with Ambroxol.
AmiodaroneThe serum concentration of Mirvetuximab Soravtansine can be increased when it is combined with Amiodarone.
AmivantamabThe risk or severity of adverse effects can be increased when Mirvetuximab Soravtansine is combined with Amivantamab.
AmprenavirThe serum concentration of Mirvetuximab Soravtansine can be increased when it is combined with Amprenavir.
AnifrolumabThe risk or severity of adverse effects can be increased when Anifrolumab is combined with Mirvetuximab Soravtansine.
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Food Interactions
No interactions found.

Products

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International/Other Brands
Elahere (ImmunoGen, Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ElahereInjection, solution100 mg/20mLIntravenousImmunoGen, Inc.2022-11-14Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
98DE7VN88D
CAS number
1453084-37-1

References

Synthesis Reference

Payne, G. et al. (2016). Methods for formulating antibody drug conjugate compositions. World Intellectual Property Organization WO 2016/036861 A1. Available at: https://patentimages.storage.googleapis.com/81/ac/da/92f7eb5933228f/WO2016036861A1.pdf

General References
  1. Moore KN, Martin LP, O'Malley DM, Matulonis UA, Konner JA, Vergote I, Ponte JF, Birrer MJ: A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer. Future Oncol. 2018 Jan;14(2):123-136. doi: 10.2217/fon-2017-0379. Epub 2017 Nov 3. [Article]
  2. Nerone M, Grande MD, Sessa C, Colombo I: Advancing antibody-drug conjugates in gynecological malignancies: myth or reality? Explor Target Antitumor Ther. 2022;3(2):149-171. doi: 10.37349/etat.2022.00077. Epub 2022 Apr 19. [Article]
  3. Martin-Sabroso C, Lozza I, Torres-Suarez AI, Fraguas-Sanchez AI: Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives. Pharmaceutics. 2021 Oct 15;13(10). pii: pharmaceutics13101705. doi: 10.3390/pharmaceutics13101705. [Article]
  4. Ab O, Whiteman KR, Bartle LM, Sun X, Singh R, Tavares D, LaBelle A, Payne G, Lutz RJ, Pinkas J, Goldmacher VS, Chittenden T, Lambert JM: IMGN853, a Folate Receptor-alpha (FRalpha)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRalpha-Expressing Tumors. Mol Cancer Ther. 2015 Jul;14(7):1605-13. doi: 10.1158/1535-7163.MCT-14-1095. Epub 2015 Apr 22. [Article]
  5. FDA Approved Drug Products: ELAHERE (mirvetuximab soravtansine-gynx) injection for intravenous use [Link]
  6. OncLive: FDA Approves Mirvetuximab Soravtansine-gynx for FRα+ Platinum-resistant Ovarian Cancer [Link]
PubChem Compound
131704323
PubChem Substance
347828725
ChemSpider
64873336
RxNav
2621548
Wikipedia
Mirvetuximab_soravtansine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentEpithelial Ovarian Cancer / Fallopian Tube Cancer / Peritoneal Cancer1
3CompletedTreatmentEpithelial Ovarian Cancer / Fallopian Tube Cancer / Ovarian Cancer / Primary Peritoneal Carcinoma1
3CompletedTreatmentEpithelial Ovarian Cancer / Fallopian Tube Cancer / Peritoneal Cancer1
3RecruitingTreatmentEpithelial Ovarian Cancer / Fallopian Tube Cancer / Peritoneal Cancer1
3RecruitingTreatmentFallopian Tube Cancer / Ovarian Cancer / Peritoneal Cancer1
2Active Not RecruitingTreatmentFallopian Tube Cancer / Ovarian Cancer / Peritoneal Cancer1
2CompletedTreatmentAnatomic Stage II Breast Cancer AJCC v8 / Anatomic Stage IIA Breast Cancer AJCC v8 / Anatomic Stage IIB Breast Cancer AJCC v8 / Anatomic Stage III Breast Cancer AJCC v8 / Anatomic Stage IIIA Breast Cancer AJCC v8 / Anatomic Stage IIIB Breast Cancer AJCC v8 / Anatomic Stage IIIC Breast Cancer AJCC v8 / Anatomic Stage IV Breast Cancer AJCC v8 / Estrogen Receptor Negative / Folate Receptor Alpha Positive / HER2/Neu Negative / Progesterone Receptor Negative / Prognostic Stage 2 Breast Cancer AJCC v8 / Prognostic Stage IIA Breast Cancer AJCC v8 / Prognostic Stage IIB Breast Cancer AJCC v8 / Prognostic Stage III Breast Cancer AJCC v8 / Prognostic Stage IIIA Breast Cancer AJCC v8 / Prognostic Stage IIIB Breast Cancer AJCC v8 / Prognostic Stage IIIC Breast Cancer AJCC v8 / Prognostic Stage IV Breast Cancer AJCC v8 / Triple Negative Breast Carcinoma1
2RecruitingTreatmentEndometrial Cancer2
2RecruitingTreatmentFallopian Tube Cancer / High Grade Ovarian Cancer / Primary Peritoneal Cancer1
2RecruitingTreatmentFallopian Tubes / Ovarian Cancer / Primary Peritoneal Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous100 mg/20mL
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Targets

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Details1. Folate receptor alpha
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Receptor activity
Specific Function
Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analo...
Gene Name
FOLR1
Uniprot ID
P15328
Uniprot Name
Folate receptor alpha
Molecular Weight
29818.94 Da
References
  1. Moore KN, Martin LP, O'Malley DM, Matulonis UA, Konner JA, Vergote I, Ponte JF, Birrer MJ: A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer. Future Oncol. 2018 Jan;14(2):123-136. doi: 10.2217/fon-2017-0379. Epub 2017 Nov 3. [Article]
  2. Ab O, Whiteman KR, Bartle LM, Sun X, Singh R, Tavares D, LaBelle A, Payne G, Lutz RJ, Pinkas J, Goldmacher VS, Chittenden T, Lambert JM: IMGN853, a Folate Receptor-alpha (FRalpha)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRalpha-Expressing Tumors. Mol Cancer Ther. 2015 Jul;14(7):1605-13. doi: 10.1158/1535-7163.MCT-14-1095. Epub 2015 Apr 22. [Article]
  3. FDA Approved Drug Products: ELAHERE (mirvetuximab soravtansine-gynx) injection for intravenous use [Link]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Curator comments
DM4, the small molecule component of mirvetuximab soravtansine, is metabolized by CYP3A4. In vitro, DM4 is also a time-dependent inhibitor of CYP3A4; however, this effect has not been detected in vivo.
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Davis JA, Rock DA, Wienkers LC, Pearson JT: In vitro characterization of the drug-drug interaction potential of catabolites of antibody-maytansinoid conjugates. Drug Metab Dispos. 2012 Oct;40(10):1927-34. doi: 10.1124/dmd.112.046169. Epub 2012 Jun 29. [Article]
  2. FDA Approved Drug Products: ELAHERE (mirvetuximab soravtansine-gynx) injection for intravenous use [Link]

Transporters

Details1. P-glycoprotein 1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
In vitro studies have shown that DM4, the small molecule component of mirvetuximab soravtansine, is a substrate of P-glycoprotein. However, this effect has not been detected in vivo.
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: ELAHERE (mirvetuximab soravtansine-gynx) injection for intravenous use [Link]

Drug created at October 20, 2016 22:35 / Updated at December 06, 2022 13:40