REBLOZYL Powder for solution for injection Ref.[10651] Active ingredients: Luspatercept

Absorption

In healthy volunteers and patients, luspatercept is slowly absorbed following subcutaneous administration, with the C_max in serum often observed approximately 7 days post-dose across all dose levels. Population pharmacokinetic (PK) analysis suggests that the absorption of luspatercept into the circulation is linear over the range of studied doses, and the absorption is not significantly affected by the subcutaneous injection location (upper arm, thigh or abdomen). Interindividual variability in AUC was approximately 38% in MDS patients and 36% in β-thalassaemia patients.

Distribution

At the recommended doses, the mean apparent volume of distribution was 9.68 L for MDS patients and 7.08 L for β-thalassaemia patients. The small volume of distribution indicates that luspatercept is confined primarily in extracellular fluids, consistent with its large molecular mass.

Biotransformation

Luspatercept is expected to be catabolised into amino acids by general protein degradation process.

Elimination

Luspatercept is not expected to be excreted into urine due to its large molecular mass that is above the glomerular filtration size exclusion threshold. At the recommended doses, the mean apparent total clearance was 0.516 L/day for MDS patients and 0.437 L/day for β-thalassaemia. The mean half-life in serum was approximately 13 days for MDS patients and 11 days for β-thalassaemia patients.

Linearity/non-linearity

The increase of luspatercept C_max and AUC in serum is approximately proportional to increases in dose from 0.125 to 1.75 mg/kg. Luspatercept clearance was independent of dose or time.

When administered every three weeks, luspatercept serum concentration reaches the steady state after 3 doses, with an accumulation ratio of approximately 1.5.

Haemoglobin response

In patients who received <4 units of RBC transfusion within 8 weeks prior to the study, Hb increased within 7 days of treatment initiation and the increase correlated with the time to reach luspatercept C_max. The greatest mean Hb increase was observed after the first dose, with additional smaller increases observed after subsequent doses. Hb levels returned to baseline value approximately 6 to 8 weeks from the last dose (0.6 to 1.75 mg/kg). Increasing luspatercept serum exposure (AUC) was associated with a greater Hb increase in patients with MDS or β-thalassaemia.

Special populations

Elderly

Population PK analysis for luspatercept included patients with ages ranging from 18 to 95 years old, with a median age of 72 years for MDS patients and of 32 years for β-thalassaemia patients. No clinically significant difference in AUC or clearance was found across age groups (<65, 65-74, and ≥75 years for MDS patients; 18-23, 24-31, 32-41, and 42-66 years for β-thalassaemia patients).

Hepatic impairment

Population PK analysis for luspatercept included patients with normal hepatic function (BIL, ALT, and AST ≤ ULN; N=207), mild hepatic impairment (BIL >1–1.5 x ULN, and ALT or AST > ULN; N=160), moderate hepatic impairment (BIL >1.5–3 x ULN, any ALT or AST; N=138), or severe hepatic impairment (BIL >3 x ULN, any ALT or AST; N=40) as defined by the National Cancer Institute criteria of hepatic dysfunction. Effects of hepatic function categories, elevated liver enzymes (ALT or AST, up to 3 x ULN) and elevated total BIL (4–246 mol/L) on luspatercept clearance were not observed. No clinically significant difference in mean steady state C_max and AUC was found across hepatic function groups. PK data are insufficient for patients with liver enzymes (ALT or AST) ≥3 x ULN.

Renal impairment

Population PK analysis for luspatercept included patients with normal renal function (eGFR ≥90 mL/min/1.73 m²; N=315), mild renal impairment (eGFR 60 to 89 mL/min/1.73 m²; N=171), or moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m²; N=59). No clinically significant difference in mean steady state C_max and AUC was found across renal function groups. PK data are not available for patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage kidney disease.

Other intrinsic factors

The following population characteristics have no clinically significant effect on luspatercept AUC or clearance: sex and race (Asian versus White).

The following baseline disease characteristics had no clinically significant effect on luspatercept clearance: serum erythropoietin level, RBC transfusion burden, MDS ring sideroblasts, β-thalassaemia genotype (β0/β0 versus non-β0/β0) and splenectomy.

The volume of distribution and clearance of luspatercept increased with increase of body weight, supporting the body weight-based dosing regimen.

Single and repeat-dose toxicity

Following repeated administration of luspatercept in rats, toxicities included: membranoproliferative glomerulonephritis; congestion, necrosis and/or mineralisation of the adrenal glands; hepatocellular vacuolation and necrosis; mineralisation of the glandular stomach; and decreased heart and lung weights with no associated histology findings. A clinical observation of swollen hindlimbs/feet was noted in several studies in rats and rabbits (including juvenile and reproductive toxicity studies). In one juvenile rat, this correlated histopathologically with new bone formation, fibrosis, and inflammation. Membranoproliferative glomerulonephritis was also seen in monkeys. Additional toxicities in monkeys included: vascular degeneration and inflammatory infiltrates in the choroid plexus.

For the 6-month toxicity study, the longest duration study in monkeys, the no-observed-adverse-effect level (NOAEL) was 0.3 mg/kg (0.3-fold of clinical exposure at 1.75 mg/kg every 3 weeks). A NOAEL was not identified in rats and the lowest-observed-adverse-effect-level (LOAEL) in the rat 3-month study was 1 mg/kg (0.9-fold of clinical exposure at 1.75 mg/kg every 3 weeks).

Carcinogenesis and mutagenesis

Neither carcinogenicity nor mutagenicity studies with luspatercept have been conducted. Haematological malignancies were observed in 3 out of 44 rats examined in the highest dose group (10 mg/kg) in the definitive juvenile toxicity study. The occurrence of these tumours in young animals is unusual and the relationship to luspatercept therapy cannot be ruled out. At the 10 mg/kg dose, at which tumours were observed, the exposure represents an exposure multiple of approximately 4 times the estimated exposure at a clinical dose of 1.75 mg/kg every three weeks.

No other proliferative or pre-neoplastic lesions, attributable to luspatercept, have been observed in any species in other non-clinical safety studies conducted with luspatercept, including the 6-month study in monkeys.

Fertility

In a fertility study in rats, administration of luspatercept to females at doses higher than the currently recommended highest human dose reduced the average number of corpora lutea, implantations and viable embryos. No such effects were observed when exposure in animals was at 1.5 times the clinical exposure. Effects on fertility in female rats were reversible after a 14-week recovery period.

Administration of luspatercept to male rats at doses higher than the currently recommended highest human dose had no adverse effect on male reproductive organs or on their ability to mate and produce viable embryos. The highest dose tested in male rats yielded an exposure approximately 7 times the clinical exposure.

Embryo-foetal development (EFD)

Embryo-foetal developmental toxicology studies (range-finding and definitive studies) were conducted in pregnant rats and rabbits. In the definitive studies, doses of up to 30 mg/kg or 40 mg/kg every week were administered twice during the period of organogenesis. Luspatercept was a selective developmental toxicant (dam not affected; foetus affected) in the rat and a maternal and foetal developmental toxicant (doe and foetus affected) in the rabbit. Embryofoetal effects were seen in both species and included reductions in numbers of live foetuses and foetal body weights, increases in resorptions, post-implantation loss and skeletal variations and, in rabbit foetuses, malformations of the ribs and vertebrae. In both species, effects of luspatercept were observed in the EFD studies at the lowest dose tested, 5 mg/kg, which corresponds to an estimated exposure in rats and rabbits of approximately 2.7 and 5.5 times greater, respectively, than the estimated clinical exposure.

Pre- and post-natal development

In a pre- and post-natal development study, with dose levels of 3, 10, or 30 mg/kg administered once every 2 weeks from gestational day (GD) 6 through post-natal day (PND) 20, adverse findings at all doses consisted of lower F₁ pup body weights in both sexes at birth, throughout lactation, and post weaning (PND 28); lower body weights during the early premating period (Week 1 and 2) in the F₁ females (adverse only at the 30 mg/kg/dose) and lower body weights in F₁ males during the premating, pairing and post-mating periods; and microscopic kidney findings in F₁ pups. Additionally, non-adverse findings included delayed male sexual maturation at the 10 and 30 mg/kg/dose. The delay in growth and the adverse kidney findings, in the F₁ generation, precluded the determination of a NOAEL for F₁ general and developmental toxicity. However, there was no effect on behavioural indices, fertility or reproductive parameters at any dose level in either sex, therefore the NOAEL for behavioural assessments, fertility and reproductive function in the F₁ animals was considered to be the 30 mg/kg/dose. Luspatercept is transferred through the placenta of pregnant rats and rabbits and is excreted into the milk of lactating rats.

Juvenile toxicity

In a study in juvenile rats, luspatercept was administered from postnatal day (PND) 7 to PND 91 at 0, 1, 3, or 10 mg/kg. Many of the findings seen in repeat-dose toxicity studies in adult rats were repeated in the juvenile rats. These findings included glomerulonephritis in the kidney, haemorrhage/congestion, necrosis and mineralization of the adrenal gland, mucosal mineralization in the stomach, lower heart weights, and swollen hindlimbs/feet. Luspatercept-related findings unique to juvenile rats included tubular atrophy/hypoplasia of the kidney inner medulla, delays in the mean age of sexual maturation in males, effects on reproductive performance (lower mating indices), and nonadverse decreases in bone mineral density in both male and female rats. The effects on reproductive performance were observed after a greater than 3-month recovery period, suggesting a permanent effect. Although reversibility of the tubular atrophy/hypoplasia was not examined, these effects are also considered to be irreversible. Adverse effects on the kidney and reproductive system were observed at clinically relevant exposure levels and seen at the lowest dose tested and, thus, an NOAEL was not established. In addition, haematological malignancies were observed in 3 out of 44 rats examined in the highest dose group (10 mg/kg). These findings are all considered potential risks in paediatric patients.