Recombinant enzyme intended to replace deficient endogenous lysosomal β-glucuronidase

Catabolizes accumulated GAGs systemically

Significantly reduces uGAG excretion from baseline to 24 weeks, with most patients having a clinically meaningful improvement in ≥ 1 MDRI domain

Maintains clinical benefits during longer-term therapy

Mucopolysaccharidosis VII (also known as Sly syndrome) is an extremely rare, autosomal recessive lysosomal storage disorder caused by mutations in the GUSB gene [1, 2]. GUSB encodes β-glucuronidase [3], an enzyme that plays an essential role in the degradation of specific glycosaminoglycans (GAGs) in lysosomes, namely chondroitin sulfate, dermatan sulfate, and heparan sulfate [1, 4]. In patients with mucopolysaccharidosis VII, the enzymatic activity of β-glucuronidase is deficient [2], resulting in partial degradation and accumulation of GAGs in numerous tissues throughout the body, with consequent cellular damage and organ dysfunction [1, 4]. Although the exact prevalence of mucopolysaccharidosis VII is unknown, it is estimated to be < 1 in 1,000,000 individuals [5].

The clinical presentation and onset of mucopolysaccharidosis VII varies greatly, ranging from earlier onset (e.g. at birth) to a later onset (e.g. during childhood) of clinical manifestations [6, 7]. Patients who present in childhood typically exhibit mild skeletal abnormalities, coarse facial features, and corneal clouding; those who present at birth typically have short stature and greater skeletal dysplasia, hepatosplenomegaly, macrocephaly, gingival hypertrophy, hernias, frequent ear infections, and cognitive impairment [7]. Irrespective of age, patients may also have cardiovascular impairments, decreased pulmonary function, and limited mobility [7]. The phenotype of individuals most profoundly impacted is characterized by the presence of non-immune hydrops fetalis (an excessive accumulation of fluid within fetal body cavities and extravascular compartments) [7]. The life expectancy of patients with mucopolysaccharidosis VII is shortened, with the specifics dependent on the nature of clinical manifestations, and ranges from infancy to adulthood [6, 7].

Enzyme replacement therapy (ERT) with vestronidase alfa (Mepsevii™), a recombinant form of human β-glucuronidase, is the first disease-specific treatment for mucopolysaccharidosis VII [8–10]. Its development was based on the success of ERT in patients with other types of mucopolysaccharidoses [11–16], as well as promising preclinical data of ERT using recombinant mouse β-glucuronidase in murine models of mucopolysaccharidosis VII [17–19]. Intravenous vestronidase alfa is approved for the treatment of mucopolysaccharidosis VII in pediatric and adult patients in the USA [8], the EU (non-neurological manifestations only) [9], and Brazil [10]. This article reviews the efficacy and tolerability of vestronidase alfa in this indication, and summarizes its pharmacological properties.

Vestronidase alfa, a recombinant homotetramer with the same amino acid sequence as that of human β-glucuronidase, acts as an exogenous source of β-glucuronidase [8, 9]. The mannose-6-phosphate (M6P) residues on its oligosaccharide chains bind to the cation-independent M6P receptor on cell surfaces [8, 20]. Vestronidase alfa is subsequently internalized into cell lysosomes, where it acts to catabolize accumulated GAGs in affected tissues [8, 9].

In clinical trials in patients with mucopolysaccharidosis VII, significant reductions in urinary GAG (uGAG) excretion occurred following multiple doses of vestronidase alfa (Sect. 3). According to population pharmacokinetic (PPK) analyses, the relationship between uGAG excretion (both urinary chondroitin sulfate and urinary dermatan sulfate) and vestronidase alfa serum exposure is described by an inhibitory maximal effect model [21]. Treatment with vestronidase alfa 4 mg/kg once every other week [recommended dosage (Sect. 5)] was associated with greater pharmacodynamic responses and pharmacokinetic exposure than dosages of 1 or 2 mg/kg once every other week. A flat exposure-response relationship was seen with vestronidase alfa serum exposures above a cut-off value that approximately corresponds to the area under the concentration-time curve at 40 μg·h/mL. This cut-off exposure level is exceeded with a 4 mg/kg dose, indicating that uGAG reduction had likely reached a plateau, with any increase in dose > 4 mg/kg not predicted to improve treatment outcomes [21].

Vestronidase alfa exhibited approximately proportional serum exposure within a 1−4 mg/kg dose range in patients with mucopolysaccharidosis VII [8]. With repeated dosing, its pharmacokinetics were time-independent [9]. In patients receiving vestronidase alfa 4 mg/kg every other week, the mean maximal serum concentration was 20 μg/mL [9, 20]. Drug concentrations in patients aged < 5 years were similar to those in older children (aged ≥ 5 years) and adults [8]. Vestronidase alfa has a mean total volume of distribution of 0.26 L/kg [8, 9] or 0.19 L/kg (based on PPK analyses) [21], indicating that the distribution of the drug into the extravascular space is limited [21].

Vestronidase alfa is eliminated by proteolytic degradation into amino acids and small peptides [8, 9]. The mean total clearance of vestronidase alfa is ≈ 0.079 L/h/kg [8, 9] with an inter- and intra-subject variability of 59 and 13% [8]. Vestronidase alfa has a short mean elimination half-life (t_½) of 2.6 h in patients with mucopolysaccharidosis VII [8, 9], and an extensive intracellular t_½ of ≈ 40 d in mucopolysaccharidosis VII fibroblasts in vitro (supporting the recommended dosing frequency; Sect. 5) [20]. No excretion studies of vestronidase alfa have been conducted in humans; the drug is not expected to be eliminated through fecal or renal excretion [8, 9].

In PPK analyses, the only covariate that significantly altered the pharmacokinetics of vestronidase alfa was baseline bodyweight [21]. Estimates of allometric baseline bodyweight scalars for clearances and volumes were 0.59 and 0.48, supporting an infusion rate of vestronidase alfa based on bodyweight (Sect. 5) [21].

The efficacy of intravenous vestronidase alfa (≈ 4 h infusion) in 23 treatment-naive pediatric and/or adult patients (aged 5 months to 25 years at enrollment; 19 were aged < 18 years) with confirmed mucopolysaccharidosis VII was investigated in an open-label, dose-exploration phase 1/2 trial [22] and its ongoing long-term extension (Sect. 3.3), an open-label phase 2 trial [23] (Sect. 3.3), and a pivotal, randomized, placebo-controlled, blind start, multicenter, phase 3 trial [24] (Sect. 3.1) and its ongoing open-label extension [25] (Sect. 3.2). The dosage of vestronidase alfa in the phase 3 trial was based on the optimal regimen in the dose-exploration phase 1/2 trial [26] (Sect. 3.3).

Eligible patients had uGAG excretion levels that were a minimum of twofold (phase 1/2 [22] and phase 2 [23]) or threefold (phase 3 [24]) above the mean normal for age at screening. In the phase 3 trial, other key inclusion criteria were no prior vestronidase alfa treatment and the presence of clinical signs of lysosomal storage disease (i.e. ≥ 1 of the following: joint limitations, airway obstruction/pulmonary problems, enlarged liver and spleen, and/or limitation of mobility while still ambulatory) [26, 27]. Two patients in each trial had non-immune hydrops fetalis [26]. Key exclusion criteria included a previous successful bone marrow transplant (BMT) or any degree of detectable chimerism in donor cells and/or a concurrent disease or condition that would interfere with the participation of the study or affect the safety of the patient [22, 23, 27].

Intravenous vestronidase alfa had a manageable tolerability profile in the four clinical trials discussed in Sect. 3, with the following discussion focusing on a pooled analysis of these trials (duration ≤ 132 weeks as of the data lock point) [26]. Most adverse reactions were mild to moderate in severity [9]. No patient withdrew from a study or discontinued treatment with vestronidase alfa as a result of an adverse event (AE) or serious AE (SAE), and no deaths were reported [26]. No clinically significant changes in vital signs were observed in any patient exposed to vestronidase alfa [26].

In the pooled analysis (n = 23, where patients from the phase 3 and open-label extension trials were only counted once), treatment-emergent AEs were reported in 96% of patients, the most common of which were vomiting (48%), cough (48%), upper respiratory tract infection (44%), infusion site extravasation (35%), and diarrhea, rash, and pyrexia (all 30%) [26]. Two patients had anaphylactic reactions following treatment with vestronidase alfa, with subsequent infusions tolerated without recurrence [8, 10]. Anaphylaxis can be life-threatening and it is recommended that vestronidase alfa is administered in the presence of appropriate medical support [8–10].

Eight patients experienced SAEs across all trials [26]. Four of which were considered to be related to vestronidase alfa treatment including: a febrile convulsion occurring in a patient within 3 days of a diphtheria, tetanus, and pertussis (DTP) vaccination, which subsequently resolved (and was assessed as possibly related to treatment due to temporal association with the infusion); an anaphylactoid reaction in a patient after inadvertent bolus infusion of vestronidase alfa, which resolved and the infusion was completed in the same day without recurrence of symptoms; and urticaria and bronchospasm experienced by a patient during infusion of the drug, which resolved with medical treatment [26].

Seventy percent of patients (16 of 23) developed anti-recombinant human β-glucuronidase antibodies, and on at least one occasion, nine of these patients further developed neutralizing antibodies [9]. The high proportion of patients who developed anti-recombinant human β-glucuronidase antibodies was consistent with the proportion of patients in clinical trials who developed antibodies to ERTs for other mucopolysaccharidosis [12, 14, 15]. No definitive correlation has been reported between antibody titer and the development of neutralizing antibodies, and the presence of anti-drug antibodies does not appear to affect reductions in uGAG excretion [9].

Intravenous vestronidase alfa is indicated in pediatric and adult patients for the treatment of mucopolysaccharidosis VII in the USA [8] and Brazil [10] or non-neurological manifestations of mucopolysaccharidosis VII in the EU [9]. Its effects on neurological manifestations originating in the CNS have not yet been established [8, 10]. Vestronidase alfa is not expected to cross the blood-brain barrier, and is therefore not likely to impact neurological manifestations of the disorder [9].

The recommended dosage of vestronidase alfa is 4 mg/kg of bodyweight administered by intravenous infusion every other week [8–10]. The infusion should be administered over ≈ 4 h. To minimize the risk of hypersensitivity reactions, administration of a non-sedating antihistamine with or without an antipyretic medicinal product is recommended 30–60 min before initiating infusion of vestronidase alfa [8–10]. Administration of vestronidase alfa may be slowed, temporarily interrupted or discontinued if hypersensitivity reactions occur [9, 10] (e.g. a severe systemic reaction [8]). In the EU, it is recommended that treatment with vestronidase alfa is periodically evaluated, and discontinuation of vestronidase alfa should be considered in patients where clear benefits (including stabilization of disease manifestations) are not observed [9]. Local prescribing information should be consulted for the recommended infusion rate by patient bodyweight guidelines, and additional warnings and precautions.

Despite a relatively comprehensive understanding of the underlying pathophysiology of mucopolysaccharidosis VII, the development of effective therapeutic options for the disease has, until recently, been slow. This largely reflects the rarity and heterogeneous clinical presentations of the disease, which has hindered the use of traditional study design approaches [24]. Prior to the approval of vestronidase alfa, there were no disease-specific treatments for mucopolysaccharidosis VII, and disease management predominantly focused on symptomatic and supportive care (e.g. physiotherapy and hydrotherapy) [37–39]. BMTs have been performed in a small number of patients with mucopolysaccharidosis VII, some of whom experienced marked clinical improvements, especially in motor function, although effects on neurological manifestations were equivocal [7, 38–40]. There are considerable limitations with BMT and its efficacy is variable in this population [7, 38–40].

ERT with vestronidase alfa is the first disease-specific therapy approved for patients with mucopolysaccharidosis VII [8–10]. In the pivotal phase 3 trial in pediatric and adult patients (which utilized a novel blind start design), treatment with vestronidase alfa for 24 weeks significantly reduced uGAG excretion levels compared with baseline (Sect. 3.1), with results from phase 1 and 2 trials supporting these data (Sect. 3.3). Most assessable patients treated with vestronidase alfa experienced an improvement in ≥ 1 domain of the MDRI over 24-week primary assessment period in the pivotal trial (Sect. 3.1; Table 1). Although the clinical relevance of these effects remains to be established, most patients showed a positive trend towards improvement, or at least stabilization, of some disease symptoms, which are considered beneficial for the patient [26]. These clinical benefits were sustained or further improved during longer-term treatment (≤ 120 weeks) in an ongoing open-label extension study, as was the reduction in uGAG excretion (Sect. 3.2). There is limited data on the use of vestronidase alfa for ≥ 120 weeks [26] and further clinical experience is essential to fully elucidate the long-term efficacy of the drug, along with its efficacy on various clinical manifestations such as pulmonary function for which available data were too limited to draw conclusions in the pivotal trial (Sect. 3.1).

Vestronidase alfa had a manageable tolerability profile in clinical trials, with most adverse reactions being mild to moderate in severity (Sect. 4). Given the global rarity of mucopolysaccharidosis VII, the safety data for vestronidase alfa was considered to be adequate [26, 34].

Despite the clinical benefits of vestronidase alfa therapy in patients with mucopolysaccharidosis VII, it is also associated with several limitations. Firstly, like other ERTs, vestronidase alfa therapy is limited by the need for life-long intravenous treatment [41], which may be associated with infusion-related reactions. Secondly, the effects of vestronidase alfa on neurological manifestations originating in the CNS have not yet been determined; however, vestronidase alfa is not expected to cross the blood brain barrier (Sect. 5). A further limitation of vestronidase alfa therapy is the financial burden (e.g. the long-term cumulative cost); the manufacturer has provided a treatment access scheme to assist with financial support for vestronidase alfa therapy when needed [42].

There are currently no global treatment guidelines available for mucopolysaccharidosis VII [43]; however, vestronidase alfa is indicated for patients of all ages (Sect. 5). It is argued that ERT should be initiated as early as possible following a diagnosis of mucopolysaccharidosis, including before the onset of clinical disease, in order to obtain better long-term treatment outcomes [44]. The mucopolysaccharidosis VII DMP, which is currently recruiting patients, will provide a prospective, comprehensive, standardized dataset, alongside long-term efficacy and safety data for vestronidase alfa therapy, and is likely to lead to a greater understanding of the disease [36] (Sect. 3.3).

Given the rarity of the disease, there are no available data pertaining to the use of vestronidase alfa in specific populations (i.e. pregnant or breastfeeding women, and patients with hepatic and/or renal impairment) or its effect on fertility in humans [9, 26]. In preclinical studies, treatment with vestronidase alfa during organogenesis stages in pregnant animals resulted in no adverse developmental outcomes at doses ≤ 20 mg/kg [9]. There was also no impact of vestronidase alfa on fertility in males and female animals [10].

In conclusion, given the lack of treatment options and the clinical benefits it provides, vestronidase alfa is an important emerging ERT for pediatric and adult patients with mucopolysaccharidosis VII.