Pivekimab sunirine

Pivekimab sunirine is a CD123 (alpha-subunit of the interleukin-3 receptor)-directed antibody-drug conjugate (ADC). The antibody is a humanized anti-CD123 IgG1. Pivekimab sunirine binds to CD123 expressing cells and upon intracellular processing releases a cell membrane-permeable payload, FGN849, leading to DNA alkylation, single-strand DNA breaks, apoptosis, and cell death. The payload, FGN849, is a member of the indolinobenzodiazepine pseudodimer (IGN) class of cytotoxic molecules. Pivekimab sunirine exhibited antitumor activity in in vitro and in vivo models of BPDCN.

Exposure-Response Relationships

Higher FGN849 (cytotoxic component of pivekimab sunirine) exposure was associated with increased rates of Grade ≥2 infusion-related reactions.

Cardiac Electrophysiology

There is insufficient information to characterize the effect of pivekimab sunirine-pvzy on the QTc interval.

In 116 patients who received pivekimab sunirine 0.045 mg/kg once every 3 weeks in CADENZA, 0.9% of patients had QTcF greater than 500 ms.

Pivekimab sunirineand FGN849 pharmacokinetics were observed at Cycle 1 in patients in CADENZA at the approved recommended dosage and are presented as mean (CV%), unless otherwise specified. The exposure parameters of pivekimab sunirine(ADC) and unconjugated FGN849 are summarized in the table below. The C_max and AUC of the ADC increased more than proportionally over a dose range of 0.045 to 0.18 mg/kg (the approved recommended dose to 4 times the recommended dose). ADC time to maximum concentrations (T_max) occurred approximately at the end of the infusion, while FGN849 T_max occurred approximately 2 hours after the end of infusion. There was no accumulation of the ADC or FGN849 in Cycle 3.

Cycle 1 Exposure parameters of pivekimab sunirineand unconjugated FGN849 at Pivekimab sunirine 0.045 mg/kg Every 3 Weeks:

C_max=maximum concentration, AUC_last=area under the concentration from time zero to the last quantifiable concentration

Distribution

Pivekimab sunirinevolume of distribution is 5.4 L (39).

FGN849 plasma protein binding is 99.6% in vitro.

Elimination

Pivekimab sunirineelimination half-life is approximately 1.5 hours at the 0.045 mg/kg every 3 weeks dosage.

Pivekimab sunirineclearance is 1.8 L/hour (76).

Metabolism

Pivekimab sunirineis expected to be catabolized into small peptides and amino acids. FGN849 is primarily metabolized by CYP3A.

Specific Populations

No clinically significant differences in the pharmacokinetics of pivekimab sunirineor FGN849 were observed for age (19 to 91 years), body weight (45 to 160 kg), mild hepatic impairment (total bilirubin >ULN to 1.5 times ULN and any AST), or CLcr 60 to <90 mL/min (estimated by Cockcroft-Gault). Higher pivekimab sunirineexposure and lower FGN849 exposure were observed in female patients compared to those in male patients.

The pharmacokinetics of pivekimab sunirinein patients with moderate to severe hepatic impairment (total bilirubin >1.5 times ULN with any AST) or CLcr <60 mL/min is unknown.

Drug Interaction Studies

No dedicated clinical studies evaluating the drug-drug interaction potential of pivekimab sunirinehave been conducted.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: FGN849 is primarily a CYP3A substrate but is not a significant substrate of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. FGN849 is an inhibitor of CYP3A and CYP2C8 but is not an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6.

Transporter systems: FGN849 is a substrate of P-gp and BCRP but is not a substrate of MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. FGN849 is not an inhibitor of P-gp, BCRP, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2.