Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Ultragenyx Germany GmbH, Friedrichstr. 191, 10117, Berlin, Germany
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes
ATC code: A16AB18
Mucopolysaccharidosis VII is a lysosomal storage disorder characterized by the deficiency of betaglucuronidase (GUS) that results in glycosaminoglycans (GAGs) accumulation in cells throughout the body leading to multisystem tissue and organ damage.
Vestronidase alfa is a recombinant form of human GUS and is intended to provide exogenous GUS enzyme for uptake into cellular lysosomes and subsequent catabolism of accumulated GAGs in affected tissues.
The clinical program for vestronidase alfa included 23 treatment naïve patients with MPS VII from 4 clinical trials, aged 5 months to 25 years, who received vestronidase alfa at doses up to 4 mg/kg once every two weeks for up to 132 weeks. Nineteen patients were younger than 18 years of age.
In a multi-centre, randomized, placebo-controlled, Blind-Start, single-crossover Phase 3 trial (Study UX003-CL301, referred to as Study 301), 12 patients with MPS VII received vestronidase alfa 4 mg/kg every two weeks for 24 to 48 weeks. The patients were randomized in a blinded manner into 4 groups: 3 patients received vestronidase alfa immediately for 48 weeks (Group A), 3 patients received placebo for 8 weeks then vestronidase alfa for 40 weeks (Group B), 3 patients received placebo for 16 weeks then vestronidase alfa for 32 weeks (Group C), and 3 patients received placebo for 24 weeks then vestronidase alfa for 24 weeks (Group D). Patients who were enrolled in Study 301 were eligible to roll over to Study UX003-CL202 (referred to as Study 202), an open-label extension trial in which patients received additional doses of vestronidase alfa at 4 mg/kg intravenously every other week for up to 144 weeks.
Of the 12 patients enrolled in the UX003-CL301, 4 were male and 8 were female and ranged in ages from 8 to 25 years (median 14 years). Nine patients were younger than 18 years of age. MPS VII diagnosis was confirmed by GUS enzyme activity assay for 5 patients, by genotyping for 3 patients, and via both enzyme assay and genotyping for 4 patients. Patients with MPS VII who received Hematopoietic Stem Cell Transplant therapy were excluded in this study. The extremely small population of patients with MPS VII globally necessitated the enrolment of all patients able to participate in this clinical trial, resulting in a highly variable group. Clinical endpoints were not assessable in some patients due to their extent of disease, age or level of cognition (23 out of 72 assessments [~32%] in 6 domains for 12 patients were non-assessable at baseline).
The primary endpoint was the percent reduction in urinary GAG excretion (Dermatan Sulfate, DS) before and after 24 weeks of treatment with vestronidase alfa. The key secondary endpoint was the multi-domain clinical responder index (MDRI) score consisting of six domains [six-minute walk test (6MWT), forced vital capacity (FVC), shoulder flexion, visual acuity, Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) fine motor and gross motor function] after 24 weeks of treatment and fatigue total score as measured by the Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL).
Minimal important differences (MIDs) were pre-specified for the six MDRI domains plus fatigue, which are: 6MWT (≥23 meters and ≥10% change from baseline), FVC (5% absolute change or 10% relative change from baseline in FVC%pred), shoulder flexion (20 degree change of both shoulder range of motion), visual acuity (3 lines (corrected, both eyes), BOT-2 fine motor (fine motor precision: change of 0.72, and manual dexterity: change of 1.47), BOT-2 gross motor (balance: 0.57, and running speed and agility: 0.59), and fatigue (10 points of total score).
For the clinical (secondary) endpoints, beneficial responses were observed although not in all patients. After 24 weeks of vestronidase alfa treatment, the overall MDRI results, both pre-specified and post-hoc (6 MDRI domains plus fatigue domain) analyses, were positive with an increase of +0.5 domains (p=0.0527) and +0.8 domains (p=0.0433) including fatigue, respectively (t-test).
Study UX003-CL201 (referred to as Study 201) was a single arm, open-label, dose exploration trial that enrolled three MPS VII patients, ranging in age from 5 years to 25 years. After 120 weeks of exposure to vestronidase alfa, 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 treatment.
Study UX003-CL203 (referred to as Study 203) is an ongoing open-label, uncontrolled single arm study that enrolled eight patients less than 5 years of age at a dose of 4 mg/kg vestronidase alfa every two weeks for 48 weeks of treatment period and additional weeks during optional continuation period to evaluate reduction of urinary GAG excretion, growth velocity and hepatosplenomegaly.
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease, it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
The pharmacokinetics of vestronidase alfa were evaluated in a total of 19 MPS VII patients including 15 paediatric patients and 4 adults from 3 clinical trials. After repeated dosing of 4 mg/kg every other week, the maximal serum concentration (Cmax) was 20.0 ± 8.1 µg/mL (mean ± s.d.; range: 6.6 to 34.9 µg/mL) and the area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) was 57.4 ± 23.9 µg*h/mL (mean ± s.d.; range: 18.8 to 97.0 µg*h/mL). The pharmacokinetics of vestronidase alfa are time independent with repeat dosing. The limited pharmacokinetic data at steady state suggest dose proportional increase in exposure of vestronidase alfa over the dose range of 1 – 4 mg/kg every other week.
After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation the total volume of distribution (Vss) was 0.26 ± 0.13 L/kg (range: 0.10 to 0.60 L/kg).
Vestronidase alfa is a recombinant human enzyme and is therefore eliminated by proteolytic degradation into small peptides and amino acids.
After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total clearance (CL) was 0.079 ± 0.045 L/h/kg (range: 0.038 to 0.20 L/h/kg); the mean ± standard deviation of the elimination half-life (t1/2) was 2.6 ± 0.6 hours (range: 0.9 to 3.6 hours).
No excretion studies have been conducted in humans. Vestronidase alfa is not expected to be eliminated through renal or faecal excretion.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single-dose toxicity in rats, repeated dose toxicity in MPS VII mice and juvenile monkeys, or fertility and embryo-foetal development in rats or rabbits. Studies on pre- and post-natal development have not been performed.
Genotoxicity studies and carcinogenicity studies have not been performed with vestronidase alfa. Based on mechanism of action, rhGUS is not expected to be tumorigenic.
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