The budget impact of enzyme replacement therapy in type 1 Gaucher disease in the United States

Abstract

Aim

Gaucher disease (GD) is a rare autosomal recessive condition. Type 1 GD (GD1) is the most prevalent form of GD in Western countries; enzyme replacement therapy (ERT) is a treatment option for patients with GD1. To understand the economic value of the GD1 ERT velaglucerase alfa, a budget impact model (BIM) was developed from a United States (US) payer perspective.

Methods

We estimated the budget impact of velaglucerase alfa for a 10-million-member US health plan by comparing the annual total costs of therapy between a scenario using current velaglucerase alfa uptake to a projected scenario with increased velaglucerase alfa uptake. Total drug costs for both scenarios were estimated as the sum of the product of the number of eligible patients on each treatment and the annual per-patient cost of each medication. Average per-patient costs for ERTs were calculated by adding the yearly drug acquisition, drug administration, and site-of-care markup costs. The budget impact was measured over years 1–3.

Results

An estimated 65 patients would receive velaglucerase alfa treatment in year 1, increasing to 90 patients by year 3. Across analyses, cost savings were realized with velaglucerase alfa compared with imiglucerase ($115,909) and taliglucerase alfa ($80,401). An annual total budget savings of $8.67 million could be realized for a hypothetical 10-million-member US health plan with increased velaglucerase alfa uptake. The per-member per-month costs decreased by $0.0241 across years 1–3.

Conclusions

BIM results show that increased velaglucerase alfa uptake for GD1 treatment is cost-saving for US health plans.

PLAIN LANGUAGE SUMMARY

Type 1 Gaucher disease (GD1) is a rare inherited condition. Long-term enzyme replacement therapy (ERT) can reverse and prevent complications. Imiglucerase, taliglucerase alfa, and velaglucerase alfa are 3 ERTs used to treat GD1. In this study, we estimated how increasing uptake of velaglucerase alfa vs. the other ERTs would impact the budget of a hypothetical US healthcare plan. The results show that increased uptake of velaglucerase alfa is cost-saving for US health plans.

Keywords:

• Budget impact model
• Gaucher disease
• enzyme replacement therapy
• ERT
• velaglucerase alfa

JEL CLASSIFICATION CODES:

• C13
• C1
• C
• C01

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Re: The budget impact of enzyme replacement therapy in type 1 gaucher disease in the United States

Re: Response letter to Sanofi’s communication related to “the budget impact of enzyme replacement therapy in type 1 Gaucher disease in the United States”

Introduction

Gaucher disease (GD) is a rare autosomal recessive condition resulting from mutations in the glucosylceramidase beta (GBA) gene encoding the glucosylceramidase enzyme¹. The estimated prevalence of GD is 1 to 2 cases per 100,000 in the general population, with higher rates reported among people of Ashkenazi Jewish descent². The estimated birth incidence of GD in the general population (including data from North America, Asia, Europe, Africa, and Australia) ranges from ∼0.39 to 5.80 cases per 100,000 births².

Type 1 GD (GD1) is the most prevalent form of GD in Western countries, accounting for 95% of cases¹. The prevalence of GD1 is higher in individuals of Ashkenazi Jewish ethnicity, with a birth incidence of ∼1 in 850^3,4. Patients with GD1 have normal brain development and no central nervous system involvement¹. These patients may exhibit thrombocytopenia, anemia, hepatosplenomegaly, delayed growth in children, and various skeletal abnormalities, although signs and symptoms vary considerably among patients¹.

Key assessments for GD include quantitative volumetric imaging of the liver and spleen, measurement of bone mineral density, and evaluation for skeletal abnormalities⁵. Additionally, there is evidence that elevated levels of the lysosomal storage product and sphingolipid, glucosylsphingosine (lyso-Gb1), a direct metabolite of Gb1, are pathogenic to cells in GD; lyso-Gb1 is now used as a long-term prognostic biomarker in GD⁶. Another regular biomarker testing is outlined in the GD Delphi consensus publication⁵. Past management of GD often included splenectomy for life-threatening thrombocytopenia or hypersplenism. This practice is now quite rare as management of the disease has changed with the advent of enzyme replacement therapy (ERT), which generally reverses GD clinical symptoms, including symptomatic splenomegaly. ERT prevents progressive manifestation of GD and ameliorates GD-associated anemia, thrombocytopenia, organomegaly, bone pain, and bone crises⁷.

Intravenous (IV) ERT with recombinant human acid ß-glucosidase (imiglucerase; Cerezyme; Genzyme Corporation, Cambridge, MA) was approved in 1994, and for more than two decades has been the standard of care for GD1^8,9. Treatment with ERT reverses and prevents many of the manifestations of GD and can prevent disease progression¹⁰. More recently, velaglucerase alfa (VPRIV; Shire Human Genetic Therapies, Inc., Cambridge, MA) and taliglucerase alfa (Elelyso; Pfizer Inc., New York, NY) have been introduced into clinical practice^11,12. These treatments were developed to replace or supplement deficient endogenous enzyme activity in affected individuals and enhance the breakdown of the accumulated substrate⁸.

Early treatment of GD1 with ERT during childhood can potentially prevent some complications of GD, including progression of irreversible skeletal manifestations. Results from a long-term, phase 3 extension study enrolling patients who were treatment naïve before initiating velaglucerase alfa therapy showed continued improvement in signs and symptoms of GD1 in patients who received more than 2 years of therapy^13,14. To understand the economic value of velaglucerase alfa in the treatment of GD1, a budget impact model (BIM) was developed from a United States (US) payer perspective.

Methods

Model framework and assumptions

Model structure

A BIM was developed in Microsoft Excel (Microsoft Corp., Redmond, WA, USA) to estimate the financial impact of increased velaglucerase alfa uptake to a formulary of a hypothetical US payer. The target population was defined as patients diagnosed with GD1 and eligible for treatment with ERT.

The budget impact of velaglucerase alfa was estimated by comparing the annual total costs of therapy between two scenarios over a 3-year time horizon, which is commonly used in US models and is consistent with the budgeting/planning periods of US budget holders^15,16 (Figure 1). The projected scenario reflects an increase in velaglucerase alfa use. The total drug costs for both scenarios were estimated as the sum of the product of the number of eligible patients for each treatment and the annual per-patient cost of each specific medication. Average per-patient costs for ERTs were calculated by adding the yearly drug acquisition, drug administration, and site-of-care markup costs. The model estimated the budget impact over the course of 1–3 years.

Figure 1. Model flow diagram. Abbreviations. GD1, Gaucher disease type 1; ERT, enzyme replacement therapy.

A four-step process was used to calculate the budget impact. First, the total target population using ERT was estimated using epidemiology and treatment use data obtained from the published literature. Second, the number of patients treated with a specific ERT in the current and projected market scenarios was determined. The target population receiving treatment with ERTs was subdivided into specific ERT treatments based on the market share of each treatment in the current and projected scenarios. Third, the number of patients on each ERT was multiplied by the annual per-patient cost of each specific ERT—including drug acquisition, site-of-care markups, and drug administration costs—to calculate total costs in both market scenarios. Lastly, the difference in total costs between the two scenarios was estimated as the difference in total costs between the current scenario and the scenario with increased velaglucerase alfa uptake (i.e. projected scenario).

Model assumptions

The model included the following assumptions:

• Patient age distribution, patient weight, dose administered, site-of-care utilization, and markups were assumed equal among all ERTs.

• All ERTs were assumed administered 26 times per year.

• Markups were assumed different depending on the site of treatment (i.e. home infusion, infusion clinic, hospital outpatient).

• The population consisted of patients aged ≥4 years in accordance with product labels.

• Separate analyses for children, adolescents, and adults were allowed by the model.

• Adverse event and monitoring costs were not assumed different among ERTs, and therefore were not included in the model.

• Switching between ERTs during the same year was not explicitly modeled; switches in subsequent years were included as market share changes over time.

• In the current scenario, market shares were not assumed to change over time.

Model inputs

An overview of model inputs for the base case analysis is provided in Table 1.

Table 1. Base case model inputs.

Model assumption	Description
Perspective	US payer
Plan size	10 million members
Time horizon	3 years
Patient population	Patients diagnosed with GD1 eligible for ERT
Age distribution	≤11 years: 7.37% ≥18 years: 87.94%
Eligible for treatment	97.18% of GD1 prevalent population
GD1 prevalence	1.33 cases per 100,000 population
Velaglucerase alfa use	Current market share (see Table 2)
Drug acquisition costs	Wholesale acquisition costs (year 2021)
Site-of-care markup costs	Average markup: 29%

Abbreviations. GD1, type 1 Gaucher disease; ERT, enzyme replacement therapy; US, United States.

Model perspectives

The model calculates the budget impact of velaglucerase alfa for GD1 compared to other ERTs from a US payer perspective. All cost inputs were included as expenses to the payer.

Eligible treatment population

Plan size

The model assumed a total health plan size of 10 million members to simulate a large US health plan with a sufficient number of patients, due to the rarity of GD.

Age distribution

The GD1 child, adolescent, and adult age distributions were calculated using the age distributions in an international GD1 patient study and assumed that 7.37% of the GD1 population was aged ≤11 years and 87.94% was aged ≥18 years¹⁷.

Eligible treatment population

The eligible treatment population was assumed to be 97.18% of the GD1 prevalent population. This was based on the proportion of patients in the US receiving GD1 treatment as asymptomatic patients with mild genetic mutations, such as N370S (i.e. c.1226A > G; p.N409S), may not require treatment¹⁷. The eligible treatment population for the present analysis was defined as the proportion of GD1 patients in the US that received treatment in the Gaucher Outcome Survey International Disease-Specific Registry.

GD1 prevalence

The target population consisted of patients with GD1. A prevalence of 1.33 cases per 100,000 population was incorporated into the model obtained from a systematic literature review of GD epidemiology performed by Nalysnyk et al. in 2015². Prevalence was assumed constant over the modeled period.

Dosing

Patient weight

The cost of an IV-administered drug can vary by over 100% based on patient weight, as the dosage is individualized¹⁸. To account for differences in the weight of children, adolescents, and adults, the total drug dose was calculated for each age category using the US Centers for Disease Control and Prevention (CDC)-reported average weights by age¹⁹. Average weights were assumed to match the US national average from 1999–2000 to 2015–2016 reported by the CDC in Fryar et al.¹⁹. The average weight for children aged ≤11 years was 30.8 kg, for adolescents aged 12–17 years was 63.9 kg, and for adults aged ≥18 years was 83.5 kg. Children aged <4 years were not included in the base case scenario weight calculation.

Dosing for ERT

The number of infusions administered yearly and ERT dosing were based on label-advised doses.

Drug acquisition cost

Wholesale acquisition costs (WACs; year 2021)—i.e. a manufacturer’s list price for sale to direct purchasers or wholesalers, without discounts, rebates, or incentives²⁰—were used for ERT in the base case model²⁰. The model was also run using average sales price (ASP), a pricing method for drugs and biologics covered by Medicare Part B that is based on manufacturer-reported data on actual selling prices, inclusive of rebates, discounts, and other price concessions²¹. Yearly ERT drug acquisition costs were calculated by multiplying the number of vials used per infusion by the cost per package (the cost for 1 infusion) by the number of annual infusions. The number of vials used per infusion was determined by multiplying the patient weight by the patient dose and dividing the total dose by the number of units per vial.

Site-of-care markup costs

In the US, the cost of an IV-administered drug varies depending on where patients receive their infusions (i.e. home setting, infusion clinic, or hospital outpatient setting) because of the different drug markups applied. Providers seeking reimbursement from insurers for drug administration will include additional costs beyond the drug price; this site-of-care markup tends to be highest with hospital administration. Site-of-care markups were sourced from internal data. We calculated the yearly site-of-care cost by multiplying the yearly drug acquisition cost by the average markup (29%). The average markup was the sum of the products of site-of-care distribution and site-of-care markups.

Market share

The budget impact of velaglucerase alfa was estimated by comparing the total costs between two scenarios. The projected scenario reflects a hypothetical new formulary with greater velaglucerase alfa uptake. In the projected scenario, a market shift was assumed from imiglucerase and taliglucerase alfa to velaglucerase alfa (Table 2).

Table 2. ERT market share: current and projected scenarios.

	Patients, %
	Year 1	Year 2	Year 3
Current scenario (children and adolescents)
Velaglucerase alfa	40.0	40.0	40.0
Imiglucerase	53.0	53.0	53.0
Taliglucerase alfa	7.0	7.0	7.0
Current scenario (adults)
Velaglucerase alfa	40.0	40.0	40.0
Imiglucerase	53.0	53.0	53.0
Taliglucerase alfa	7.0	7.0	7.0
Projected scenario (children and adolescents)
Velaglucerase alfa	50.0	60.0	70.0
Imiglucerase	44.2	35.3	26.5
Taliglucerase alfa	5.8	4.7	3.5
Projected scenario (adults)
Velaglucerase alfa	50.0	60.0	70.0
Imiglucerase	44.2	35.3	26.5
Taliglucerase alfa	5.8	4.7	3.5

Abbreviation. ERT, enzyme replacement therapy.

Results

Budget impact velaglucerase alfa

Treated patient population

In a hypothetical 10-million-member US health plan for the projected scenario, 65 patients were estimated to be treated with velaglucerase alfa in year 1, 78 patients in year 2, and 90 patients in year 3 (Figure 2).

Figure 2. The treated patient population in the current and projected scenarios.

Yearly cost per patient

Regardless of age group, treatment with velaglucerase alfa was cost saving compared to imiglucerase ($115,909 annual cost savings per patient) and taliglucerase alfa ($80,401 annual cost savings per patient) (Figure 3). Cost savings were driven by the drug acquisition costs as administration costs were similar among the ERTs.

Figure 3. Yearly cost per patient with GD1 by age group and ERT therapy^a. ^aDetermined using wholesale acquisition costs (year 2021). ^bWeighted average of the yearly cost per patient, weighted by the proportion of children (N = 10), adolescents (N = 6), and adults (N = 114). Weighted averages were not calculated for drug acquisition, administration, or site-of-care markup costs. Abbreviations. ERT, enzyme replacement therapy; GD1, type 1 Gaucher disease; USD, United States dollar.

When ASP as opposed to WAC was incorporated into the model, the average annual treatment cost per patient did not change substantially (velaglucerase alfa, $576,123; imiglucerase, $719,625; taliglucerase alfa, $679,854); the cost savings with velaglucerase alfa were $143,502 compared with imiglucerase and $103,731 compared with taliglucerase alfa. Average annual treatment costs per patient for velaglucerase alfa were $238,046 for children, $470,562 for adolescents, and $610,072 for adults.

Budget impact

Results from the BIM showed that for a hypothetical 10-million-member US health plan, an increase in the uptake of velaglucerase alfa decreased the annual total budget impact by $8.67 million and the per-member per-month costs by $0.0241 across the first 3 years (Figure 4).

Figure 4. PMPM budget impact for payers with current vs. projected velaglucerase alfa uptake scenario^a. ^aDetermined using wholesale acquisition costs (year 2021). Costs are presented in United States dollars. ^bAverage of years 1–3. Abbreviation. PMPM, per-member per-month.

Discussion

Patients with GD have a lysosomal enzyme deficiency resulting in a buildup of glucocerebroside¹. For patients with symptomatic disease, long-term treatment with either ERT or substrate reduction therapy is needed⁸. ERT provides the enzymes needed to break down glucocerebrosides whereas substrate reduction therapy blocks the production of glucocerebrosides. Currently, several formulations of ERT are administered intravenously, usually once every 2 weeks. The three commercially available formulations of ERTs are not biosimilar; similarities and dissimilarities between imiglucerase, velaglucerase alfa, and taliglucerase alfa have been presented earlier²². Of the available ERTs, only velaglucerase alfa is produced by gene activation via a human cell line²². The resulting protein produced is identical in amino acid sequence to the naturally occurring enzyme. Differences in glycosylation patterns and manufacturing process from a human cell line may explain the lower immunogenicity of velaglucerase alfa, contributing to its improved efficacy²². More recently, studies have shown a steeper and faster decrease of lyso-Gb1 levels, a key GD-specific biomarker in velaglucerase alfa as compared to other ERTs⁶.

The goal of GD treatment is to achieve major hematologic, organomegaly, and skeletal manifestation goals within 1–2 years of treatment initiation²³. ERT is considered a first-line treatment for patients with GD1 as ERT may reverse inflammation and the hematologic effects of GD through supplementation of the defective/deficient enzyme²⁴. Early initiation of ERT therapy may delay and prevent complications and, therefore, ERT should be initiated early in the disease course²⁵.

Among patients with GD1 who are treated with ERT, results from this BIM show that velaglucerase alfa was cost-saving compared to imiglucerase and taliglucerase alfa. The estimated annual cost savings per patient was $115,909 compared with imiglucerase and $80,401 compared with taliglucerase alfa. Overall, the model estimated an ∼$8.7 million cost savings annually with increased velaglucerase alfa uptake for a hypothetical 10-million-member US health plan. The estimated cost savings were driven primarily by drug acquisition costs as administration costs were similar among all ERTs. Results were similar when the model incorporated ASP compared with WAC.

Limitations

As real-world use of ERT in GD1 may vary, our results may not be generalizable to all settings. Although baseline drug utilization data were based on the product label and published literature, actual drug utilization may be substantially different due to differences in standards of care and the use of other interventions that impact each patient population. We found that markup costs were a significant contributor to the annual cost of care per patient. As we sourced site-of-care markups from internal data, site-of-care markups may vary across the different institution and payer settings. We found that drug acquisition costs were the main driver of cost savings for velaglucerase alfa compared to other ERTs. As these costs can be affected by rebates and discounts, results may differ for specific payers or by locality. This model used a rudimentary forecast of potential market share shift based on assumptions and therefore may not accurately reflect changes in market share. Finally, adverse event and monitoring costs were assumed to be similar among ERTs and therefore were not included in the model. Since ERTs for patients with GD1 rarely result in adverse events⁸, any potential bias due to this assumption is likely minimal.

Conclusions

Results from this budget impact analysis suggest potential cost savings for a 10-million-member US health plan with increased use of velaglucerase alfa for GD1. The potential cost-saving estimates may vary depending on drug pricing, market shift to velaglucerase alfa, and treatment and patient dosage assumptions.

Transparency

Declaration of funding

Takeda provided funding for this study.

Declaration of financial/other relationships

SF is a full-time employee of Takeda and a stockholder of Takeda Pharmaceuticals Company Limited. Takeda provided medical writing support in relation to this work.

TJI is a former full-time employee of OPEN Health. OPEN Health received funding from Takeda for medical writing support in relation to this work.

GP is a former full-time employee of OPEN Health. OPEN Health received funding from Takeda for medical writing support in relation to this work.

EW is a full-time employee of Takeda and a stockholder of Takeda Pharmaceuticals Company Limited. Takeda provided medical writing support in relation to this work.

RRP is a full-time employee of Takeda and a stockholder of Takeda Pharmaceuticals Company Limited. Takeda provided medical writing support in relation to this work.

MB is a full-time employee of Takeda and a stockholder of Takeda Pharmaceuticals Company Limited. Takeda provided medical writing support in relation to this work.

A reviewer on this manuscript has disclosed that they have acted as an adviser and speaker for all three companies but have no formal or ongoing affiliations. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

SF, TJI, and MB: concept and design. SF, TJI, GP, EW, RRP, and MB: analysis and interpretation of the data, drafting of the paper or revising it critically for intellectual content, and final approval of the version to be published. All authors agree to be accountable for all aspects of this work.

Acknowledgements

Medical writing support was provided by Beth Lesher, PharmD, BCPS, from OPEN Health, Bethesda, MD, and funded by the study sponsor.