Evaluation of galsulfase for the treatment of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)

Figures & data

Box 1. Drug summary.

Drug name	Galsulfase (recombinant human N-acetylgalactosamine 4-sulfatase)
Phase	IV
Indication	Patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)
Pharmacology description/mechanism of action	Galsulfase acts by cleaving the sulfate moieties of the glycosaminoglycan (GAG) dermatan sulfate, which are abnormally stored in the lysosomes of cells in patients with mucopolysaccharidosis VI
Route of administration	Intravenous infusion
Pivotal trial(s)	Three clinical studies using recombinant human ASB (rhASB) enzyme replacement therapy have been reported. A Phase I/II study and a Phase II study both showed that weekly infusions of rhASB 1 mg/kg were well tolerated, decreased urinary GAG (uGAG) levels and improved endurance in patients with rapidly progressive disease. The Phase III pivotal trial was a double-blind, randomized, placebo-controlled, multicenter, international study that demonstrated significantly greater improvement in endurance on a 12-min walk test after 24 weeks in the treatment as compared to placebo group. The patients treated with rhASB also showed nearly significant improvement in 3-min stair climb and significant reduction in uGAG levels. A total of 56 MPS VI patients between 5 and 29 years with a mean age of 12 years were included in these trials. In the Phase I/II study, weekly infusions of 1.0 mg/kg galsulfase resulted in a more rapid and robust sustained reduction of GAGs than weekly infusions of 0.2 mg/kg galsulfase (63 vs 51%) reduction at 48 weeks. In the Phase III trial, patients received either infusions of galsulfase (1.0 mg/kg every week) or placebo. Improvements were greater in the treated group; thus, 1.0 mg/kg weekly is the recommended dose

Figure 1. rhASB plasma concentrations during and 2 h after the first infusion with the area under the plasma concentration-time curve (AUC_0-t).

Table 1. Phase III study: summary of effect on primary and secondary endpoints.

Endpoint	Statistical method	Estimated difference rhASB group and placebo group at 24 weeks	p value
Primary variable 12MWT	Longitudinal analysis	92 m mean improvement in favor of rhASB	0.025
6MWT (supportive of primary)	Longitudinal analysis	53 m mean improvement in favor of rhASB	0.007
Secondary variables 3MSC: rate	Longitudinal analysis	5.7 stairs/min mean improvement in favor of rhASB	0.053
3MSC: number of steps (supportive of 3MSC rate)	Longitudinal analysis	16.3 ± 7 mean improvement in favor of rhASB	0.042
Urinary GAG levels	Analysis of variance	-227 µg/mg creatine mean Decrease in favor of rhASB	< 0.001
# of responders with baseline GAG reduced ≥ 50% (supportive of GAG levels)	Fisher's exact test; Exact inversion of two one-sided intervals for confidence intervals	# of responders: 17/19 in rhASB group, 0/19 in the placebo group	< 0.001

Modified from [22].

3MSC: 3-minute stair climb; 6MWT: 6-minute walk test; 12MWT: 12-minute walk test; GAGs: Glycosaminoglicans; rhASB: Recombinant human N-acetylgalactosamine 4-sulfatase.

Table 2. Summary of AEs during study weeks 1 – 48.

Category	# Patients (%)	# Events^§	# Patients (%)	# Events^§
Double-blind (weeks 1 – 24)	rhASB	(n = 19)	Placebo	(n = 20)
Any AEs*	19 (100)	369	20 (100)	344
Deaths	0	–	0	–
Drug-related AEs^‡	11 (58)	92	6 (30)	14
SAEs	3 (16)	3	4 (20)	12
Severe AEs	4 (21)	7	4 (20)	9
AEs during infusion^¶	11 (58)	74	8 (40)	13
IARs (study drug-related AEs during infusion)	10 (53)	60	4 (20)	6
Discontinuation due to AEs	0 (0)		0 (0)
Phase III extension	rhASB/rhASB	(n = 19)	Placebo/rhASB	(n = 19)
Any AEs*	18 (95)	312	19 (100)	272
Deaths	0	–	0	–
Drug-related AEs^‡	8 (44)	100	6 (32)	26
SAEs	1 (6)	2	4 (21)	7
Severe AEs	3 (17)	4	3 (16)	15
AEs during infusion^¶	9 (50)	98	7 (37)	31
IARs (study drug-related AEs during infusion)	7 (39)	95	5 (26)	23
Discontinuation due to AEs	0 (0)		0 (0)

Adapted from [22].

*Includes study drug-related and unrelated AEs.

^‡Possibly, probably, or definitely related to study drug.

^§Multiple events were counted if the patient had the same AE with different onset times.

^¶All infuses AEs (related or unrelated to study drug).

AEs: Adverse events; IARs: Infusing-drug adverse events; rhASB: Recombinant human N-acetylgalactosamine 4-sulfatase; SAEs: Serious AEs.

Table 3. Summary of study populations.

Study	Study design	Study dates	Study duration (weeks)	Patients enrolled/completed	Dose of rhASB (mg/kg)	Age (years)	Sex (M/F)	Main results
Phase I/II	Double-blinded, randomized, dose comparison/open-label extension	January 2001 – December 2005	240	7/5	0.2	7 – 16	4/3	High doses group – larger decrease in uGAGs Increase in 6MWT and shoulder ROM Decrease in pain and arthritis severity scores No drug-related SAE
Phase II	Open-label, nonrandomized	2002 – 2006	144	10/10	1.0	6 – 21	7/3	Decrease pain and stiffness at week 24 Increase > 10% in FVC Improvement in 12MWT and 3MSC Therapy well tolerated
Phase III	Double-blinded, placebo-controlled, randomized/open-label extension	2003 – 2006	96	39/38	1.0	5 – 29	13/26	Decrease in uGAGs Improvement in 12MWT and 3MSC Development of IgG antibodies to rhASB related to more IAR Therapy well tolerated

Adapted from [23].

FVC: Forced vital capacity; GAGs: Glycosaminoglicans; IAR: Infusing-drug adverse events; rhASB: Recombinant human N-acetylgalactosamine 4-sulfatase; ROM: Range of motion; uGAGs: Urinary GAGs.

Harmatz P, Whitley CB, Waber L, et al. Enzyme replacement therapy in mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). J Pediatr 2004;144:574-80

 PubMed Web of Science ®Google Scholar

Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. J Pediatr 2006;148:533-9

 PubMed Web of Science ®Google Scholar

Harmatz P, Giugliani R, Schwartz IV, et al. Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase. Mol Genet Metab 2008;94:469-75

 PubMed Web of Science ®Google Scholar