CLINICAL PHARMACOLOGY
Mechanism Of Action
Mucopolysaccharidosis VII (MPS VII or Sly syndrome) is a lysosomal disorder characterized by the
deficiency of GUS that results in GAG accumulation in cells throughout the body leading to
multisystem tissue and organ damage.
Vestronidase alfa-vjbk is a recombinant form of human GUS and is intended to provide exogenous
GUS enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the
oligosaccharide chains allow binding of the enzyme to cell surface receptors, leading to cellular
uptake of the enzyme, targeting to lysosomes and subsequent catabolism of accumulated GAGs in
affected tissues.
Pharmacodynamics
In all patients evaluated, MEPSEVII treatment resulted in reduction of urinary excretion of GAGs
including chondroitin sulfate and dermatan sulfate, which was sustained with continued treatment.
Pharmacokinetics
The pharmacokinetics of vestronidase alfa-vjbk were evaluated in a total of 19 MPS VII patients
including 15 pediatric patients and 4 adults. Serum exposures of vestronidase alfa-vjbk appeared to
increase approximately proportionally from 1 mg/kg (0.25 times the approved recommended dosage)
to 2 mg/kg (0.5 times the approved recommended dosage), and 4 mg/kg (the recommended dosage).
After repeated dosing of 4 mg/kg every other week, the mean ± standard deviation of maximal
concentration (Cmax) was 20.0 ± 8.1 mcg/mL (range: 6.6 to 34.9 mcg/mL); and the mean ± standard
deviation of area under the concentration-time curve from time zero to the last measurable
concentration (AUC0-t) was 3440 ± 1430 mcg*min/mL (range: 1130 to 5820 mcg*min/mL).
Vestronidase alfa-vjbk concentrations in pediatric patients less than 5 years of age were similar to the
concentrations in older children and adults.
Distribution
After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard
deviation of the total volume of distribution (Vss) was 260 ± 130 mL/kg (range: 97 to 598 mL/kg).
Elimination
After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard
deviation of the total clearance (CL) was 1.3 ± 0.7 mL/min/kg (range: 0.6 to 3.3 mL/min/kg); the mean
± standard deviation of the elimination half-life (t1/2) was 155 ± 37 minutes (range: 51 to 213 minutes).
The inter- and intra-subject variability (coefficient of variation) in total clearance (CL) was 59% and
13%, respectively.
Metabolism
Vestronidase alfa-vjbk is a recombinant human enzyme and is therefore eliminated by proteolytic
degradation into small peptides and amino acids.
Excretion
No excretion studies have been conducted in humans. Vestronidase alfa-vjbk is not expected to be
eliminated through renal or fecal excretion.
Clinical Studies
The clinical program for MEPSEVII included 23 patients with MPS VII, 17 of whom were evaluable for
efficacy, 20 for safety, and 23 for immunogenicity. Patients were enrolled in clinical trials and
expanded access protocols receiving treatment at doses up to 4 mg/kg once every two weeks for up
to 164 weeks. The patients ranged in age from 5 months to 25 years. Sixteen patients were younger
than 18 years of age.
Studies 301 And 202
Study UX003-CL301 (referred to as Study 301, NCT02230566) was a randomized start trial of
MEPSEVII 4 mg/kg every two weeks in patients with MPS VII. Twelve patients were randomized to
one of four placebo durations before crossing over to active treatment. Three patients received
MEPSEVII immediately for a duration of 48 weeks, 3 patients received placebo for 8 weeks then
MEPSEVII for 40 weeks, 3 patients received placebo for 16 weeks then MEPSEVII for 32 weeks, and
3 patients received placebo for 24 weeks then MEPSEVII for 24 weeks. Of the 12 patients enrolled in
the trial, 4 were male and 8 were female and ranged in age from 8 to 25 years (median 14 years).
Nine patients were younger than 18 years of age. The majority of the patients were white (75%), with
50% of Hispanic or Latino ethnicity. Patients who were enrolled in Study 301 were eligible to roll over
to Study UX003-CL202 (referred to as Study 202, NCT02432144), an open-label extension trial in
which patients received additional doses of MEPSEVII at 4 mg/kg intravenously every other week for
up to 124 weeks.
In Study 301, motor function, forced vital capacity, and visual acuity were assessed after 24 weeks of
MEPSEVII treatment and measured against pre-specified minimal important differences. The
extremely small population of patients with MPS VII globally necessitated the enrollment of all
patients able to participate resulting in a highly heterogeneous group. Clinical endpoints were not
assessable in some patients due to their extent of disease, age or level of cognition. Repeated
assessments of the six minute walk test (6MWT) were feasible in ten of 12 patients and are described
further below. Of the three patients who improved on their 6MWT (Figure 1, left panel), two also were
noted to have improvement in balance and gross motor proficiency as assessed by the Bruininks-
Oseretsky Test of Motor Proficiency (BOT-2).
In this trial, the mean difference in 6MWT distance between MEPSEVII and placebo treatment
periods in patients able to perform the test at baseline and subsequent visits through Week 24 is
shown in Table 3. The mean difference in 6MWT distance increases with increased treatment
duration, however, due to the small size of the trial, standard errors are large.
Table 3. Mean Difference in 6MWT Distance (meters) Between MEPSEVII and Placebo
Treatment (Study 301) in Patients with MPS VII
Duration of MEPSEVII
Treatment |
LS mean 6MWT (meters)
(± Standard Error)* |
Number and Treatment Assignment of
Patients Included in Analyis** |
8 weeks |
-11 (± 24) |
5 placebo period; 8 MEPSEVII period |
16 weeks |
13 (± 32) |
5 placebo period; 8 MEPSEVII period |
24 weeks |
18 (± 33) |
5 placebo period; 8 MEPSEVII period |
*ANCOVA analysis of change from baseline in least squares (LS) mean between placebo and MEPSEVII for different
periods, after adjusting for study cohort, age, and baseline 6MWT distance. Patients who used assistive devices were
imputed as zeros in the analysis.
**Number and treatment assignment of patients included in the analysis was based upon a randomized start trial design
and patient ability to complete testing. Due to no placebo period for the three patients who received 48 weeks of
MEPSEVII in the first cohort of the randomized start design, more data were available for analyses during the treatment
period (n=8) than during the placebo period (n=5). While data from 8 participants were available at each time point, due to
missing observations, the 8 participants were not the same across all time points. |
The observed individual 6MWT distances for the 10 patients who could perform the test in Study 301
and Study 202 through Week 120 are presented in Figure 1. The course of three patients with
improvement in distance walked of at least 60 meters compared to the start of MEPSEVII treatment
(Week 0) is shown in the left panel; the relatively stable course in the remaining seven patients,
including those who used assistive devices, is shown in the right panel.
Figure 1. 6MWT Distance for MPS VII Patients in Studies 301 and 202
 |
Patient 10 did not use an assistive device at baseline but started using an assistive device post-baseline from Treatment
Week 8. Patients 6 and 9 consistently used an assistive device at all visits. A solid line indicates the unassisted
assessments and a dotted line indicates the assisted assessments. |
Liver And Spleen Volume
In Study 301, imaging by MRI or ultrasound to assess liver and spleen volume was performed in
seven of the 12 patients. Most liver volumes were normal or below normal size at baseline (mean
1,591 mL, range 742 to 2,207 mL), and on average were unchanged after treatment (mean 1,459 mL,
range 876 to 1,851 mL).
Spleen volumes generally were normal or below normal size at baseline (mean 325 mL, range 131 to
491 mL) and on average were unchanged after treatment (mean 360 mL, range 200 to 582 mL).
Other Investigations
Study UX003-CL201 (referred to as Study 201, NCT01856218) was a single arm, open-label, dose
exploration trial completed outside the United States that enrolled three MPS VII patients, ranging in
age from 5 years to 25 years. Two patients were male; two patients were white and one was Asian.
After 120 weeks of exposure to MEPSEVII, one patient demonstrated a 21% improvement over
baseline in forced vital capacity (FVC% predicted) on pulmonary function testing in addition to a 105
meter improvement in the 6MWT. Two other patients with baseline hepatosplenomegaly had
reduction in liver volume (24% and 53%) and spleen volume (28% and 47%) after 36 weeks of
MEPSEVII treatment.
Expanded access to MEPSEVII treatment was provided to a pediatric patient with MPS VII who
required continuous ventilatory support at the start of treatment and was subsequently able to tolerate
9 hours daily off ventilator support after 164 weeks of MEPSEVII treatment.