Pegunigalsidase alfa

The active substance of pegunigalsidase alfa is pegunigalsidase alfa. Pegunigalsidase alfa is a pegylated recombinant form of human α-galactosidase-A. The amino acid sequence of the recombinant form is similar to the naturally occurring human enzyme.

Pegunigalsidase alfa supplements or replaces α-galactosidase-A, the enzyme that catalyses the hydrolysis of the terminal α-galactosyl moieties of oligosaccharides and polysaccharides in the lysosome, reducing the amount of accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3).

Plasma pharmacokinetic (PK) profiles of pegunigalsidase alfa were characterized during the course of the clinical development at 0.2, 1, and 2 mg/kg administered every two weeks in adult patients with Fabry disease. The pharmacokinetic results for all three dose levels demonstrated that the enzyme was available throughout the 2-week intervals with a plasma half-life (t_1/2) ranging from 53-134 hours across dose groups and visit day. The mean value for AUC_0-∞ increased with increasing dose on Day 1 and throughout the study. Mean values for dose-normalized AUC_0-2wk were similar for all dose levels, indicating linear dose-proportionality. For patients who received 1 and 2 mg/kg pegunigalsidase alfa, there were increases in mean t_1/2 and AUC_0-∞ with increasing duration of treatment and corresponding decreases in Cl and Vz, suggesting a saturated clearance.

Pegunigalsidase alfa is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of pegunigalsidase alfa in a clinically significant way. The molecular weight of pegunigalsidase alfa is ~116 KDa, which is twice the cut-off value for glomerular filtration, thus excluding filtration and/or proteolytic degradation in kidneys.

There are no animal studies to assess the carcinogenic or mutagenic potential of pegunigalsidase alfa.

In the 6-month chronic toxicity study in mice, an increased incidence and/or mean severity of multifocal nephropathy and interstitial lymphocytic infiltration in the kidneys, hepatocytic vacuolation and hepatocyte necrosis in the liver, were confined to males and females administered the high-dose of 40 mg/kg/injection (3.2-fold human exposure, in terms of AUC, following a dose of 1 mg/kg); in monkeys, an increased incidence of Kupffer cell hypertrophy was noted in the liver (7.6-fold above AUC reached in humans following a dose of 1 mg/kg); all findings resolved during the recovery period.

Animal studies demonstrated low systemic exposure in foetus (between 0.005 and 0.025% of dams' systemic exposure) and suckling pups (maximum 0.014% compared to mother’s systemic exposure) following repeated treatment of the dams or mothers with pegunigalsidase alfa. Fertility and embryofoetal developmental toxicity studies did not show evidence of impaired fertility, embryotoxicity or teratogenicity. However, prenatal and postnatal developmental toxicity studies were not performed with pegunigalsidase alfa and the risks for foetus and pups during the late pregnancy and lactation are unknown.