Background

Galsulfase (Naglazyme) is available as a 5 mg/5 mL vial of solution for intravenous (IV) infusion at a cost of $1,535 per vial or $307 per mL¹ as long-term enzyme replacement therapy (ERT) in patients with a confirmed diagnosis of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) (MPS VI) (N-acetylgalactosamine-4-sulfatase [ASB] deficiency).

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders of disrupted glycosaminoglycan (GAG) metabolism.^1–3 Each MPS disorder is caused by a deficiency of a specific enzyme required for GAG degradation, which leads to accumulation of partially degraded GAGs.^1,2,4,5 The accumulation of GAGs causes progressive cellular, multi-system damage, organ failure, and reduced life expectancy. MPS VI is a rare, progressive, autosomal recessive disorder with multiple organ and tissue involvement.^1–3

Currently, galsulfase is the only ERT indicated to treat patients with MPS VI. Prior to galsulfase, the management of MPS VI was generally supportive for complications. Standard medical management (SMM) differed based on patient characteristics (such as age, disease severity, and progression). As per the clinical trial identified,^6,7 galsulfase was assessed as a supplement to SMM in clinical practice.

Approach for this review

This review was initiated by the Formulary Working Group for the drug plans participating in the CADTH Common Drug Review (CDR) Program. As part of the CDR procedure, the manufacturer of galsulfase was invited to provide clinical and/or health economic evidence to support the CDR review process. The manufacturer provided Clinical Study Reports for galsulfase and a budget impact analysis (BIA) from the perspective of CDR-participating plans. To complement the limited health economic evidence shared by the manufacturer, CDR assessed the health economic evidence available in the public domain, and was supported by clinical expert inputs.

Cost assessment

Galsulfase was submitted at a marketed price of $307 per mL. The recommended dose is 1 mg per kg per week; therefore, the treatment cost per administration of galsulfase is $307 multiplied by the patient weight. Data from the pivotal clinical trial^6,7 indicated that patient age ranged from five to 29 years, and patient weight ranged from 14 kg to 47 kg; the mean patient weights in the trial were 24.6 kg for galsulfase and 20.8 kg for placebo. However, the patient weight was skewed to the low end due to patient age. The recently published long-term follow-up retrospective observational study of galsulfase⁸ did not present an average weight, although the age ranges may suggest an average weight above the average weight in the pivotal study. Based on the available data on patient weight, CDR had to assume an average weight of 25 kg per patient (per the galsulfase trial treatment group). For an individual weighing 25 kg, at the recommended dose of 1 mg/kg of body weight administered once weekly (over at least four hours as an IV infusion),⁹ the drug cost of galsulfase annually is $399,100. Based on the weight range in the study, for an individual weighing 14 kg, the drug cost of galsulfase decreases to $223,496; and for an individual weighing 47 kg, the drug cost of galsulfase annually increases to $750,308.

The CDR clinical expert indicated that if a five-year-old patient with typical MPS VI received galsulfase, it would be expected that, without a stopping rule applied, the patient would receive treatment for approximately 20 years. Over 20 years, considering the range in patient age (five to 29 years) and weight (14 kg to 47 kg) from the pivotal study, it seems to be appropriate to assume an average weight of 25 kg over the 20-year period.⁶ Based on this, the total average undiscounted lifetime drug cost of galsulfase per patient is approximately $8 million.

There is uncertainty regarding the number of patients who may receive galsulfase. Although the manufacturer estimated that there are approximately 15 to 20 potential patients with MPS VI in Canada,¹⁰ a BIA was also provided by the manufacturer based on a patient population of ▬ patients across Canada receiving galsulfase at baseline (year 0), which ▬ patients at year 3.¹¹ The difference in patient numbers was not justified. Additionally, in the BIA provided by the manufacturer, the assumed patient weight of 22 kg was based on the average weight from the pivotal trial,^6,7 resulting in a budget impact of $▬ at baseline (year 0) ▬ in year 3 (undiscounted). As MPS can range based on age at onset of the condition, CDR developed a scenario analysis increasing the average patient weight to 25 kg (as above). In addition, the CDR scenario considered that all 15 to 20 potential Canadian patients were able to receive treatment. CDR notes that the total cost depends substantially on the patient weight and number of patients, and thus created Table 1 for clarity.

Table 1

Cost of Galsulfase Dependent Upon Weight and Patient Numbers.

Review of the published economic literature

Embase and MEDLINE databases were searched with no date or language restrictions, with the initial search completed on September 28, 2015. Regular search updates were performed until the meeting of the CADTH Canadian Drug Expert Committee (CDEC) on January 20, 2016 (Appendix 3). The review did not identify any published economic literature on galsulfase for the treatment of MPS VI (Appendix 1).

Grey literature was identified by searching relevant websites, including those of health technology assessment (HTA) agencies (Appendix 1). An HTA review from Australia’s Pharmaceutical Benefits Advisory Committee (PBAC) was identified. The PBAC Public Summary Document (PSD) reported that its health economic review was based on a trial-based cost-consequence analysis submitted by the manufacturer in which galsulfase in addition to SMM was compared with SMM alone (Appendix 2). Clinical data were based on the same pivotal study assessed in the CDR Clinical Review.¹² The cost-consequence evidence reported in the PSD indicated that patients receiving galsulfase in addition to SMM could walk farther, climb more stairs, and had fewer hospitalizations and surgical or diagnostic procedures; and that this was associated with an additional annual cost of less than $10 million per patient compared with SMM alone. PBAC concluded that the preliminary economic evaluation suggested the resulting incremental cost-effectiveness ratio would be unacceptably high, but that the submission met the criteria for listing on Australia’s Life Saving Drugs Programme (LSDP).

Health economic assessment

The CDR Clinical Review appraised the results of the identified randomized, double-blind, placebo-controlled clinical study^6,7 assessing the safety and efficacy of galsulfase in addition to SMM over a period of 24 weeks. The CDR clinical expert identified the need for hospitalization, surgical and diagnostic procedures, and wheelchair use as important outcomes that have an impact on health resource utilization, which may be informed by the study.

The following observations were seen in the pivotal study. Three patients (out of 19) in the galsulfase group and three patients (out of 20) in the SMM group were hospitalized during the time of the study, although patients receiving galsulfase plus SMM had fewer hospitalizations in total per patient than patients receiving SMM alone (there were about four times more hospitalizations in the placebo group than in the galsulfase group). Two patients required tracheostomy: one in the galsulfase group and one in the SMM group. Neither was determined to be study-related.⁷ In total three patients in the galsulfase group and four patients in the SMM group had a serious adverse event (SAE) that required a surgical or diagnostic procedure, although patients receiving galsulfase had fewer surgical or diagnostic procedures.⁷ The CDR Clinical Review indicates that wheelchair use was not reported in the study. Resource use was not well reported in the study, and the aforementioned evidence was sourced from SAE patient narratives in the Clinical Study Report.

Given the available data and the short-term nature of the study, it is difficult to make assumptions as to the extent to which health care resource utilization may be affected by the use of galsulfase in addition to SMM. The potential exists that there are cost implications for galsulfase that cannot be assessed given the paucity of data. It can be hypothesized that the introduction of galsulfase may reduce health care resource utilization, such as the potential for fewer hospitalizations, surgeries, and diagnostic procedures, and reduced wheelchair time. The CDR clinical expert did indicate that the use of galsulfase in patients with MPS VI is unlikely to affect the requirement for, or time to, bone marrow transplantation.

While no evaluation was provided to CDR assessing the relative health and economic implications of adding galsulfase to SMM in the Canadian situation, the general findings appear to be broadly similar to those identified by PBAC in its review of galsulfase. Galsulfase appears to be effective and well tolerated in patients with MPS VI (refer to CDR Clinical Review), but at a substantially greater total cost, driven by the cost of galsulfase ($399,100 per year for a 25 kg patient). The potential savings from other resource usage may not be enough to offset the high annual medication cost of adding galsulfase to SMM.

Patient input

Patient input was received as a single joint submission from two patient groups: the Isaac Foundation for Mucopolysaccharide (MPS) Treatment and Research, and the Canadian Society for Mucopolysaccharide and Related Diseases (the Canadian MPS Society). Information was obtained from a variety of sources, including patient interviews, an online survey, an internal review of a patient registry, and published literature.

Information was presented indicating the effect of MPS VI on the musculoskeletal system, leading to significant pain, loss of function, and reduced quality of life (QoL); affecting daily living activities and general enjoyment (e.g., bike riding, playing musical instruments, writing, drawing). Additionally, caregivers of patients with MPS VI are often required to miss work due to extensive care requirements, long hospital stays, multiple surgical interventions, and frequent medical appointments.

For patients without access to galsulfase, it was reported that a long-term palliative approach to managing the disease was taken, managing symptoms as they appeared. All interviewed patients who had received galsulfase, and their caregivers, reported stabilization of their condition and improvement in their QoL following initiation of galsulfase, although the previous impact of the disease persisted.

Patient input on treatment limitations focused on the access to galsulfase and infusion facilities. No serious or life-threatening infusion reactions were reported as a result of galsulfase, and it was reported that mild infusion-related reactions were tolerable and did not result in discontinuation of galsulfase. The weekly, four-hour galsulfase infusions were noted as a concern, as in some cases, two days of infusion per week were required.

Issues for consideration

• CDR was not able to assess the effects of implementing a treatment stopping rule based on efficacy and safety considerations.
• The assumption is that the manufacturer pays for the infusion. If the jurisdiction is required to fund the infusion, this would add further costs to treatment with galsulfase.
• MPS VI is a chronic condition; however, there is limited long-term natural history data to optimally inform the safety and efficacy of galsulfase. Further long-term data on galsulfase treatment and the natural history of the condition may assist decision-makers in their reimbursement policies.
• Patient input indicated that some patients may require more than one infusion per week, which would increase the annual cost of treatment with galsulfase.
• A 10-year cross-sectional follow-up study suggested that there is an association between treatment with galsulfase and prolonged survival; however, the CDR Clinical Review indicated that chance, confounding, or bias cannot be ruled out as alternative explanations for the results.

Conclusions

The annual acquisition cost of galsulfase for a patient weighing 25 kg at the recommended dosing regimen is $399,100. A typical five-year-old patient with MPS VI receiving galsulfase over 20 years would cost approximately $8 million (galsulfase drug cost only; undiscounted).

While no evaluation was provided to CDR assessing the relative health and economic implications of adding galsulfase to SMM in the Canadian situation, the general findings indicate treatment with galsulfase appears to lead to improvements on the 12-minute walk test (12MWT) with numerically fewer SAEs than SMM patients with MPS VI, but at a substantially greater total annual cost driven by galsulfase medication cost.

Cost comparison table

Galsulfase is the first treatment to be indicated for MPS VI, to be used as an add-on to SMM. Clinical experts have determined that there are no appropriate comparator treatments in this context (Table 2). Comparators may be recommended (appropriate) practice versus actual practice. Comparators are not restricted to drugs, but may be devices or procedures. Costs are manufacturer list prices, unless otherwise specified. Existing Product Listing Agreements are not reflected in the table and as such may not represent the actual costs to public drug plans.

Table 2

Cost Comparison Table for Galsulfase for the Treatment of Mucopolysaccharidosis VI.