Mirvetuximab soravtansine

Mirvetuximab soravtansine is an antibody-drug conjugate. The antibody is an engineered IgG1 directed against folate receptor alpha (FRα). The function of the antibody portion is to bind to FRα expressed on the surface of ovarian cancer cells. DM4 is a microtubule inhibitor attached to the antibody via a cleavable linker. Upon binding to FRα, mirvetuximab soravtansine is internalised followed by intracellular release of DM4 via proteolytic cleavage. DM4 disrupts the microtubule network within the cell, resulting in cell cycle arrest and apoptotic cell death.

Cardiac electrophysiology

At the approved recommended dose, mirvetuximab soravtansine did not cause mean increases >10 msec in the QTc interval based on the results of concentration-QTc analysis.

The pharmacokinetics were characterised after patients were administered mirvetuximab soravtansine 0.161 mg/kg to 8.71 mg/kg AIBW doses (i.e., 0.0268 times to 1.45 times the approved recommended dose of 6 mg/kg AIBW), unless otherwise noted.

Mirvetuximab soravtansine summarises the exposure parameters of mirvetuximab soravtansine, unconjugated DM4, and its metabolite S-methyl-DM4 following administration after the first cycle (3-weeks) of mirvetuximab soravtansine 6 mg/kg to patients. Peak mirvetuximab soravtansine concentrations were observed near the end of intravenous infusion, while peak unconjugated DM4 concentrations were observed on the second day after administration of mirvetuximab soravtansine, and the peak S-methyl-DM4 concentrations were observed approximately 3 days after administration of mirvetuximab soravtansine. Steady state concentrations of mirvetuximab soravtansine, DM4, and S-methyl-DM4 were reached after 1 treatment cycle. Accumulation of the mirvetuximab soravtansine, DM4, and S-methyl-DM4 was minimal following repeat administration of mirvetuximab soravtansine.

Exposure parameters of mirvetuximab soravtansine, unconjugated DM4, and S-methyl DM4 after first treatment cycle of 6 mg/kg of mirvetuximab soravtansine:

C_max = maximum concentration, AUC_tau = area under the concentration vs. time curve over the dosing interval (21 days).

Absorption

Mirvetuximab soravtansine is administered as an intravenous infusion. There have been no studies performed with other routes of administration.

Distribution

The mean (±SD) steady state volume of distribution of mirvetuximab soravtansine was 2.63 (±2.98) L. Human plasma protein binding of DM4 and S-methyl DM4 was >99%, in vitro.

Biotransformation

The monoclonal antibody portion of mirvetuximab soravtansine is expected to be metabolized into small peptides by catabolic pathways. Unconjugated DM4 and S-methyl-DM4 undergo metabolism by CYP3A4. In human plasma, DM4 and S-methyl DM4 were identified as the main circulating metabolites, accounting for approximately 0.4% and 1.4% of mirvetuximab soravtansine AUCs, respectively.

Elimination

The mean (±SD) total plasma clearance of mirvetuximab soravtansine was 18.9 (±9.8) mL/hour. The mean terminal phase half-life of mirvetuximab soravtansine after the first dose was 4.9 days. For the unconjugated DM4, the mean (±SD) total plasma clearance was 14.5 (±4.5) mL/hour and the mean terminal phase half-life was 2.8 days. For S-methyl-DM4, the mean (±SD) total plasma clearance was 5.3 (±3.4) L/hour and the mean terminal phase half-life was 5.1 days. In vitro and nonclinical in vivo studies indicate that DM4 and S-methyl-DM4 are primarily metabolised by CYP3A4 and eliminated via biliary excretion in the faeces.

Special populations

No clinically significant differences in the pharmacokinetics of mirvetuximab soravtansine were observed based on age (32 to 89 years), race (White, Black, or Asian), body weight (36 to 136 kg), mild hepatic impairment (total bilirubin ≤ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST), or mild to moderate renal impairment (CLcr ≥30 and <90 mL/min). The pharmacokinetics of mirvetuximab soravtansine in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN with any AST) or severe renal impairment (CLcr 15 to 30 mL/min) is unknown.

Drug interaction studies

In vitro studies

Cytochrome P450 (CYP) enzymes: Unconjugated DM4 is a time-dependent inhibitor of CYP3A4. Unconjugated DM4 and S-methyl DM4 are not direct inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. DM4 and S-methyl DM4 are not inducers of CYP1A2, CYP2B6, or CYP3A4.

Transporter systems: Unconjugated DM4 and S-methyl DM4 are substrates of P-gp but are not inhibitors of P-gp.

Target organs identified with single-dose administration of mirvetuximab soravtansine in cynomolgus monkeys were limited to skin and cellular depletion of the bone marrow and lymphoid tissue. Repeat dosing in cynomolgus monkeys and Dutch-belted rabbits also indicated ophthalmic findings including corneal microcysts, pigmentation, attenuation and degeneration/necrosis of the corneal epithelium. These findings were dose intensity (dose and schedule) dependent with fewer overall findings and recovery of those findings observed in the 3-week dosing schedule (the clinical dosing schedule).

Carcinogenicity studies have not been conducted with mirvetuximab soravtansine or DM4.

DM4 and S-methyl DM4 were not mutagenic in the bacterial reverse mutation (Ames) assay. DM4 and S-methyl DM4 resulted in micronuclei in polychromatic erythrocytes.

No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine.

Fertility studies have not been conducted with mirvetuximab soravtansine or DM4. There are no data on the effect of mirvetuximab soravtansine on human fertility. However, given the mechanism of action of mirvetuximab soravtansine leads to microtubule disruption and death of rapidly dividing cells, there is the potential for drug-related fertility effects.