Mirvetuximab soravtansine

Mirvetuximab soravtansine is an antibody-drug conjugate (ADC). The antibody is a chimeric IgG1 directed against folate receptor alpha (FRα). The small molecule, DM4, is a microtubule inhibitor attached to the antibody via a cleavable linker. Upon binding to FRα, mirvetuximab soravtansine is internalized 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.

Exposure-Response Relationships

An exposure-response relationship between mirvetuximab soravtansine and overall response rates was observed. Higher incidence of Grade ≥2 ocular adverse reactions and Grade ≥2 peripheral neuropathy occurred with increasing mirvetuximab soravtansine exposure.

Cardiac Electrophysiology

At the approved recommended dose, mirvetuximab soravtansine did not cause large mean increases (>10 msec) in the QTc interval.

The pharmacokinetics were characterized after patients were administered mirvetuximab soravtansine 0.161 mg/kg to 8.71 mg/kg adjusted ideal body weight (AIBW) dosages, (0.0268 times to 1.45 times the approved recommended dosage of 6 mg/kg AIBW), unless otherwise noted.

Table 6 summarizes 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.

Table 6. 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).

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.

Elimination

Total plasma clearance (geometric mean [CV%]) of mirvetuximab soravtansine was 18.9 mL/hour (51.9%). The geometric mean terminal phase half-life of mirvetuximab soravtansine after the first dose was 4.8 days leading to a steady state at approximately 24 days. For the unconjugated DM4, the total plasma clearance (geometric mean [CV%]) was 13.8 L/hour (31.1%) and the geometric mean terminal phase half-life was 2.8 days. For S-methyl-DM4, the total plasma clearance (geometric mean [CV%]) was 4.3 L/hour (63.6%) and the geometric mean terminal phase half-life was 5.0 days.

Metabolism

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.

Excretion

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

Specific Populations

No clinically significant differences in the pharmacokinetics of mirvetuximab soravtansine were observed based on age (34 to 89 years), 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

Clinical studies and model informed approaches

No clinical studies evaluating the drug-drug interaction potential of mirvetuximab soravtansine have been conducted.

However, in 3 clinical trials, there were no differences in exposure between patients who received concomitant weak or moderate CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors and those who did not.

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.