Elosulfase alfa

Mucopolysaccharidoses comprises a group of lysosomal storage disorders caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). MPS IVA is characterised by the absence or marked reduction in N-acetylgalactosamine-6-sulfatase activity. The sulfatase activity deficiency results in the accumulation of the GAG substrates, KS and chondroitin 6 sulphate (C6S), in the lysosomal compartment of cells throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. Elosulfase alfa is intended to provide the exogenous enzyme N-acetylgalactosamine-6-sulfatase that will be taken up into the lysosomes and increase the catabolism of the GAGs KS and C6S. Enzyme uptake by cells into lysosomes is mediated by cation independent mannose-6-phosphate receptors leading to restored GALNS activity and clearance of KS and C6S.

The pharmacokinetic parameters of elosulfase alfa were evaluated in 23 patients with MPS IVA who received weekly intravenous infusions of 2 mg/kg of elosulfase alfa over approximately 4 hours for 22 weeks and the parameters at Week 0 and Week 22 were compared. At Week 22, the mean AUC_0-t and C_max increased by 181% and 192%, respectively, when compared to Week 0.

Pharmacokinetic properties:

^* AUC_0-t, area under the plasma concentration-time curve from time zero to the time of last measurable concentration;
^† C_max, observed maximum plasma concentration;
^‡ CL, total clearance of elosulfase alfa after intravenous administration;
^§ t_1/2, elimination half-life;
^¶ T_max, time from zero to maximum plasma concentration

Biotransformation

Elosulfase 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 elosulfase alfa.

Elimination

Renal elimination of elosulfase alfa is considered a minor pathway for clearance. Mean half-life (t_1/2) increased from 7.52 minutes at Week 0 to 35.9 minutes at Week 22. Male and female patients had comparable elosulfase alfa clearance, and clearance did not trend with age or weight at week 22. Impact of antibodies on elosulfase alfa pharmacokinetics was assessed. No association was apparent between the total antibody titre and elosulfase clearance. However, patients with positive neutralizing antibodies responses had decreased total clearance (CL) values and prolonged t_1/2. Despite the alteration of the pharmacokinetics profile, presence of neutralizing antibodies did not affect pharmacodynamics, efficacy, or safety of the patients who were treated with elosulfase alfa. No accumulation of elosulfase alfa in plasma was evident following weekly dosing.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology evaluating central nervous, respiratory and cardiovascular systems, single-dose and repeated-dose toxicity in rats and monkeys or fertility and embryo-foetal development in rats or rabbits. The evaluation of the peri- and postnatal development study in rats is hampered due to subsequent administration of DPH, and therefore of limited relevance.

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with elosulfase alfa. Reproduction studies have been performed in rats at doses up to 10 times the human dose and have revealed no evidence of impaired fertility or reproductive performance.