DECNUPAZ Powder for solution for injection Ref.[116689] Active ingredients: Pivekimab sunirine

Exposure-Response Relationships

Higher FGN849 (cytotoxic component of DECNUPAZ) 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 DECNUPAZ 0.045 mg/kg once every 3 weeks in CADENZA, 0.9% of patients had QTcF greater than 500 ms.

Pivekimab sunirine-pvzy and 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-pvzy (ADC) and unconjugated FGN849 are summarized in Table 5. 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.

Table 5. Cycle 1 Exposure parameters of pivekimab sunirine-pvzy and unconjugated FGN849 at DECNUPAZ 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 sunirine-pvzy volume of distribution is 5.4 L (39).

FGN849 plasma protein binding is 99.6% in vitro.

Elimination

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

Pivekimab sunirine-pvzy clearance is 1.8 L/hour (76).

Metabolism

Pivekimab sunirine-pvzy is 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 sunirine-pvzy or 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 sunirine-pvzy exposure and lower FGN849 exposure were observed in female patients compared to those in male patients.

The pharmacokinetics of pivekimab sunirine-pvzy in 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 sunirine-pvzy have 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.

Carcinogenesis

Carcinogenicity studies have not been conducted with pivekimab sunirine-pvzy or the small molecule FGN849.

Mutagenesis

FGN849 was mutagenic in the bacterial reverse mutation (Ames) assay and clastogenic in the in vitro and in vivo (rat) micronucleus assays. These results are consistent with the pharmacological mechanism of action of DNA alkylation that induces G2-M phase arrest of dividing cells resulting in cell death.

Impairment of Fertility

Fertility studies have not been conducted with pivekimab sunirine-pvzy or FGN849.

14.1 Treatment-naïve Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

CADENZA (NCT03386513) was a multicenter, open-label, single-arm, clinical trial that included 33 adult patients with treatment-naїve BPDCN with no central nervous system (CNS) involvement. Treatment consisted of DECNUPAZ 0.045 mg/kg intravenously once every three weeks. Patient baseline characteristics are presented in Table 6.

Table 6. Baseline Demographics of Patients with Treatment-naїve BPDCN:

^a PCHM is defined as any previously diagnosed or concurrently present hematologic malignancy at the time of BPDCN diagnosis

The efficacy of DECNUPAZ in patients with treatment-naїve BPDCN was based on the rate of complete remission or clinical complete remission (CR/CRc). Key efficacy measures are presented in Table 7. The median follow-up was 21.5 months (range: 4.2, 27). The median time to CR/CRc was 1.8 months (range: <0.5 to 4). Among the 33 patients with treatment-naїve BPDCN, 13 (39.4%) patients were able to receive post-study treatment HSCT.

Table 7. Efficacy Results in Patients with Treatment-naїve BPDCN:

CI = confidence interval; NE = not estimable
^a CRc is defined as complete remission with residual skin abnormality not indicative of active disease.
^b CR/CRc rate was 77.3% (95% CI: 54.6, 92.2) in patients with de novo BPDCN (N=22).
^c CR/CRc rate was 54.5% (95% CI: 23.4, 83.3) in patients with PCHM (N=11).
^d Kaplan-Meier estimate.
^e Median duration of CR/CRc was 9.8 months (range: 0.9, 23.9+) in 17 patients with de novo BPDCN who achieved CR/CRc.
^f Median duration of CR/CRc was 6.3 months (range: 2.4, 23.2+) in 6 patients with BPDCN with PCHM who achieved CR/CRc.

14.2 Relapsed or Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

CADENZA (NCT03386513) was a multicenter, open-label, single-arm, clinical trial that included 51 adult patients with relapsed or refractory BPDCN without evidence of active CNS disease treated with DECNUPAZ 0.045 mg/kg intravenously once every three weeks. Patient baseline characteristics are presented in Table 8.

Table 8. Baseline Demographics of Patients with Relapsed or Refractory BPDCN:

The efficacy of DECNUPAZ in patients with relapsed/refractory BPDCN was based on the rate of CR/CRc. Key efficacy measures are presented in Table 9. The median follow-up was 24.1 months (range: 0.2 to 30.4). The median time to CR/CRc was 1.7 months (range: 1 to 6). Among the 51 patients with relapsed/refractory BPDCN, 6 (11.8%) patients were able to receive post-study treatment HSCT.

Table 9. Efficacy Results in Patients with Relapsed or Refractory BPDCN:

CI = confidence interval; + = Censor indicator
^a CRc is defined as complete remission with residual skin abnormality not indicative of active disease.
^b Kaplan-Meier estimate.