12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mucopolysaccharidoses comprise a group of lysosomal storage disorders caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis IVA (MPS IVA, Morquio A Syndrome) is characterized 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 C6S, in the lysosomal compartment of cells throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. Vimizim 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. Elosulfase alfa uptake by cells into lysosomes is mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of elosulfase alfa to mannose-6-phosphate receptors.

In the absence of an animal disease model that recapitulates the human disease phenotype, elosulfase alfa pharmacological activity was evaluated using human primary chondrocytes from two MPS IVA patients. Treatment of MPS IVA chondrocytes with elosulfase alfa induced clearance of KS lysosomal storage from the chondrocytes.

12.2 Pharmacodynamics

The pharmacodynamic effect of Vimizim was assessed by reductions in urinary KS levels. The relationship of urinary KS to other measures of clinical response has not been established [see Clinical Studies (14)]. No association was observed between antibody development and urinary KS levels.

12.3 Pharmacokinetics

The pharmacokinetics of elosulfase alfa were evaluated in 23 patients with MPS IVA who received intravenous infusions of Vimizim 2 mg/kg once weekly, over approximately 4 hours, for 22 weeks. Eleven patients were aged 5 to 11 years, six were aged 12 to 17 years, and six were aged 18 to 41 years. Table 2 summarizes the pharmacokinetic parameters at Week 0 and Week 22. Mean AUC0‑t and Cmax increased to 2.8- and 2.9-fold, respectively, at Week 22 compared to Week 0. Mean t1/2 increased from 7.5 min at Week 0 to 35.9 min at Week 22. These changes are likely related to the development of neutralizing antibodies in all patients.

Table 2: Pharmacokinetic Parameters

Pharmacokinetic Parameter	Week 0 (N = 22)* Mean (SD)	Week 22 (N = 22)* Mean (SD)
AUC0-t, min x µg/mL†	238 (100)	577 (416)
Cmax, µg/mL‡	1.49 (0.534)	4.04 (3.24)
Tmax, min§	172 (75.3)	202 ( 90.8)
CL, mL/min/kg¶	10.0 (3.73)#	7.08 (13.0)♠
Vdss, mL/kg♥	396 (316) ♦	650 (1842) ♠
t1/2, min♣	7.52 (5.48) #	35.9 (21.5) ♠

* The pharmacokinetics of elosulfase alfa was evaluated in 23 individual patients. However, 1 patient was not tested at Week 0 and another patient was not tested at Week 22.

†AUC0-t, area under the plasma concentration-time curve from time zero to the time of last measurable concentration;

‡Cmax, observed maximum plasma concentration;

§Tmax, time from zero to maximum plasma concentration;

¶CL, total clearance of drug after intravenous administration;

#N = 15;

♠N = 20

♥Vdss, apparent volume of distribution at steady-state;

♦N = 14;

♣t1/2, elimination half-life