Pegzilarginase

ARG1-D is an inherited metabolic disease characterised by deficiency of the arginase 1 enzyme and associated with the persistent elevation of plasma arginine leading to disease manifestations and progression of clinical symptoms.

Pegzilarginase is a cobalt substituted recombinant human arginase 1 enzyme conjugated with 5 kDa mPEG carriers at a degree of substitution of 6-12 moles of mPEG per mole of protein. The molecular mass of the conjugated protein is approximately 224-344 kdA. The mPEG carrier reduces clearance of pegzilarginase resulting in an extended half-life while maintaining the functions of the enzyme. Pegzilarginase is intended to substitute for the deficient human arginase 1 enzyme activity in patients with ARG1-D. Pegzilarginase has been shown to rapidly and sustainably reduce plasma arginine and convert it to urea and ornithine.

The pharmacodynamic effects of pegzilarginase have been evaluated in adults and paediatric subjects with ARG1-D across a range of doses administered both intravenously and subcutaneously.

Intravenous administration of pegzilarginase resulted in early reductions in plasma arginine levels with median time to nadir (lowest arginine level) of 2-5 hours. It is expected that plasma arginine will reach its steady-state on or before Week 8. It is not expected for the time to reach these levels to be influenced by the baseline plasma arginine value or the route of administration.

Plasma arginine levels remained controlled after switching from intravenous to subcutaneous administration at the same dose, and subcutaneous administration led to fewer and shorter episodes of pegzilarginase-induced hypoargininaemia.

Corresponding significant increases in plasma ornithine levels and decreases in plasma guanidino compound levels were demonstrated with pegzilarginase treatment. Treatment with pegzilarginase does not directly target elevated plasma ammonia levels.

The pharmacokinetic (PK) properties of pegzilarginase were evaluated following intravenous and subcutaneous administration in adults and paediatric subjects with ARG1-D. Population PK analysis has been used to characterise the pharmacokinetics of pegzilarginase.

The following PK parameters at steady state were derived using the final population PK model (Table 4). The final PK model was based on data obtained from 20 female and 17 male subjects, aged 2-31 years old with body weights 12.2-76.7 kg. In the clinical trials, the dose range was 0.015-0.2 mg/kg. Simulated dose in the model was 0.1 mg/kg for 5 weeks.

Table 4. Pharmacokinetic parameters at steady state:

Abbreviations: AUC_0-168=area under the concentration-time curve from time 0 to 168 hours; C_max=maximum observed concentration; t_½=half-life; T_max=time to maximum concentration
^* Data displayed are geometric mean and geometric coefficient of variation (%)
^** Data displayed as [median (range)]
^ For intravenous dosing, the Tmax corresponds to the time of the first measured PK sample. In these simulations the first PK sample was set at the end of infusion (0.25 h post-dose) for all subjects with no variability.
Simulations were performed for a patient with a body weight of 31kg.

Absorption

Following subcutaneous administration, the mean absolute bioavailability was 57 % and the maximum concentration was reached approximately 34 hours post-dose. Exposure to pegzilarginase increase in an approximately dose-proportional manner with linear PK over a dose range of 0.04 to 0.2 mg/kg intravenous and 0.06 to 0.2 mg/kg subcutaneous. Negligible accumulation was observed after weekly dosing.

Distribution

Pegzilarginase is mainly distributed in the vascular system, with a total volume of distribution of approximately 47 ml/kg, which is similar to human serum volume. The pharmacokinetics was best described with a population-PK model which comprised two-compartments (central and peripheral).

Elimination

Pegzilarginase is a pegylated recombinant human enzyme. To allow once-weekly administration, PEG has been used as a carrier to prolong the half-life of pegzilarginase compared to endogenous arginase. Based on population PK analysis; pegzilarginase has a half-life of approximately 50 hours. The enzyme is expected to be metabolised into small peptides and amino acids by catabolic pathways. Pegzilarginase utilizes a 5 kDa PEG which is eliminated via renal glomerular filtration in patients with normal renal function.

Special populations

Age and sex were not found to be significant covariates once body weight was taken into account. Anti-PEG ADAs were considered an important covariate on clearance, however, this effect was observed with initial doses and it is expected that exposure at steady-state will not be affected.

Renal impairment

Pegzilarginase has not been studied in patients with renal impairment. It cannot be excluded that elimination of PEG is decreased in patients with impaired renal function.

Hepatic impairment

Pegzilarginase has not been studied in patients with hepatic impairment. Changes in the clearance of the enzyme are expected as pegzilarginase is metabolised by catabolic pathways.

Body weight

Overall, body weight had a minimal impact (<20%) on the exposure of pegzilarginase, when dosing is weight based.

Animal toxicology and/or pharmacology

Dose-dependent and adverse loss of appetite and reductions in body weight gain attributed to marked and sustained arginine depletion below the normal range in normal animals (mice, rats, rabbits and monkeys) was observed in single and repeat dose toxicology studies as well as developmental and reproductive toxicity studies with pegzilarginase. These findings were reversible following cessation of dosing.

In the long-term studies with pegzilarginase, male reproductive toxicities were noted in a single species, healthy juvenile rats. The principal adverse findings at dose levels ≥0.3 mg/kg, included decreased weights of testes, seminal vesicles, epididymides and prostate, atrophy was observed in the seminiferous tubules. The male rat organ weight findings were reversible. Histopathology confirmed findings in the testes and epididymides, which were not reversible in the recovery period of 6 weeks; however, it is worth noting that the normal sperm cycle is 9 weeks. These effects could be due to exaggerated pharmacology in normal animals with normal circulating arginine levels at baseline. However, the relevance for humans is unclear.

Reproductive and developmental toxicology

Studies conducted with pegzilarginase in rats and rabbits with normal circulating arginine levels demonstrated maternal reproductive toxicity that is associated with sustained decreases in plasma arginine concentrations below the normal range during gestation. Toxicities associated with the prolonged exaggerated pharmacology in pregnant animals were decreased maternal body weights, food consumption, and mean gravid uterine weights and associated secondary fetal growth retardation.

In pre- and postnatal development toxicology studies in rats with normal circulating arginine levels, male rat offspring of nursing animals dosed with 1 mg/kg pegzilarginase (approximately 7 times human exposure based on AUC) revealed deficits possibly due to secondary effects related to exaggerated pharmacology in animals with normal circulating arginine levels.

Fertility

During fertility assessments conducted in normal animals with normal circulating arginine levels, male rats dosed at 1 mg/kg showed decreased sperm production and motility. Additionally, in naïve female rats paired with males treated at 1 mg/kg/dose for 8 weeks prior to mating, pegzilarginase-related effects included a significant reduction in uterine implantation sites and increased pre-implantation loss.