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Pharmacology: Pharmacodynamics: Mechanism of action: Tagraxofusp is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT) fusion protein that targets CD123-expressing cells. Tagraxofusp irreversibly inhibits protein synthesis of target cells by inactivating elongation factor 2 (EF2), resulting in apoptosis (cell death).
Clinical efficacy and safety: Study STML-401-0114 was a multi-stage (stage 1 dose escalation, stage 2 expansion, stage 3 confirmatory, stage 4 continued access), non-randomised, open-label, multi-centre study of ELZONRIS. ELZONRIS was administered to 65 previously-untreated and 19 previously treated adult patients with BPDCN according to the WHO classification who received a 12 mcg/kg dose on days 1-5 of multiple 21-day cycles (Table 1). Patients who had known active or suspected CNS leukaemia were not included in the study. The primary endpoint was the rate of complete response (CR; complete resolution of the disease)/clinical complete response (CRc; CR with residual skin abnormality not indicative of active disease). Across all 65 previously untreated patients ELZONRIS resulted in a CR/CRc rate of 56.9% (95% CI: 44.0, 69.2), this included 13 patients in the confirmatory efficacy cohort where the CR/CRc rate was 53.8% (95% CI: 25.1, 80.8). (Table 2).
Patient baseline characteristics are presented in Table 1 and key efficacy measures in Table 2. (See Tables 1 and 2.)
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Click on icon to see table/diagram/imagePharmacokinetics: The pharmacokinetics of tagraxofusp has been evaluated in 43 patients with BPDCN. Most patients (n=38) had pre-existing anti-drug antibodies (ADA) against the diphtheria toxin (DT) component, due to previous vaccination. Pre-existing ADAs resulted in higher clearance and lower tagraxofusp concentrations. During treatment, all patients developed high ADA titres, and substantially reduced free tagraxofusp levels (see as follows). All data referred to as follows are based on free tagraxofusp concentrations in BPDCN patients without pre-existing anti-drug antibodies (ADA, n=5) in the first treatment cycle. Descriptive information is included for BPDCN patients with pre-existing ADAs (n=38).
Distribution: Following administration of ELZONRIS 12 mcg/kg via 15-minute infusion in patients with BPDCN without pre-existing anti-drug antibodies (ADA, N=5), the mean (SD) unbound area under the plasma drug concentration over time curve (AUCunbound) of free tagraxofusp on Day 1 of the first cycle of treatment (C1D1) was 230 (123) hr*mcg/L and maximum unbound plasma concentration (Cmax) was 162 (58.1) mcg/L.
The mean (SD) volume of distribution of free tagraxofusp on C1D1 was 5.1 (1.9) L in 4 patients with BPDCN without pre-existing ADA.
Elimination: Tagraxofusp is expected to be degraded into peptides and its constituent amino acids through proteolysis, with no involvement of CYP or transporters.
The mean (SD) clearance of free tagraxofusp at C1D1 was 7.1 (7.2) L/hr in 4 patients with BPDCN without pre-existing ADA, and the mean (SD) terminal half-life of tagraxofusp was 0.7 (0.3) hours.
Anti-drug antibody formation affecting pharmacokinetics: Patients with pre-existing ADA had lower unbound tagraxofusp plasma concentrations (AUC and Cmax) at C1D1 than patients without pre-existing ADA. Due to the limitation of the bioanalytical method in the presence of ADA, quantitative pharmacokinetic parameters in these patients cannot be given.
Pharmacokinetic/pharmacodynamic relationship: Data collected during Cycle 3 showed increased titres of ADAs and substantially reduced free tagraxofusp concentrations. However, clinical efficacy has been demonstrated beyond Cycle 1 despite the reduced exposure. Due to the limitation of the bioanalytical method, the utility of free tagraxofusp concentrations as a predictor of response is limited.
Pharmacokinetics in special populations: Due to the limitation of the bioanalytical method, the pharmacokinetics of tagraxofusp in patients with renal or hepatic impairment and the effect of body weight, age, and gender are considered unknown.
Paediatric population: The pharmacokinetics of tagraxofusp have not been studied in the paediatric population.
Toxicology: Preclinical safety data: Carcinogenicity or genotoxicity studies have not been performed with tagraxofusp. Tagraxofusp is a recombinant protein and is therefore not expected to interact directly with DNA.
At human equivalent doses greater than or equal to 1.6 times the recommended dose based on body surface area, severe kidney tubular degeneration/necrosis was observed in cynomolgus monkeys. At human equivalent doses equal to the recommended dose, degeneration/necrosis of the choroid plexus in the brain was observed in cynomolgus monkeys. These findings were generally noted after 5 days of daily dosing. The reversibility of this finding was not assessed at lower doses, but the finding was irreversible and became progressively more severe at a human equivalent dose 1.6 times the recommended dose, 3 weeks after dosing stopped. These findings in kidney and choroid plexus are considered likely relevant for the clinical situation.
No fertility studies have been conducted with tagraxofusp. A literature-based risk assessment suggests that exposure to exogenous IL-3 or blockade of IL-3 signaling may have embryotoxic effects on foetal haematopoiesis and embryo-foetal development. The effects of diphtheria toxin exposure on placental and embryo-foetal development are unknown.
