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Background: Gaucher disease type 1 (GD1) is a rare, genetic, lysosomal storage disease with no cure. Current treatment options include intravenous (IV) enzyme replacement therapy ([ERT]; imiglucerase, velaglucerase alfa, or taliglucerase alfa) or oral substrate reduction therapy ([SRT]; eliglustat or miglustat). The cost to U.S. payers of an IV-administered drug can vary depending on the site of care (i.e., home, outpatient clinic, or hospital setting). Treatment with oral eliglustat may present an opportunity for cost savings., Objective: To evaluate the budget impact from a U.S. payer perspective associated with transitioning patients receiving ERTs to the oral SRT eliglustat for the treatment of adults with GD1., Methods: A budget impact model estimated the change in pharmaceutical and administration costs resulting from increasing the market share of eliglustat from 12% (current) to 44% (new). The market share for eliglustat was drawn equally from existing shares of imiglucerase (40%) and velaglucerase alfa (40%) and assumed to be static over the analysis period. ERT costs were adjusted to account for site of care-based markup and the proportion of patients receiving infusions in each site of care (home, infusion center, or hospital outpatient). Annual ERT costs were calculated assuming a biweekly dose of 47.4 U per kg, a 72-kg patient weight, and 24 infusions per year. The effect of key variables was tested in the sensitivity analyses. All costs are expressed in 2017 U.S. dollars., Results: In a new plan with 5 million members and 25 GD1 treated patients, increased use of eliglustat resulted in an annual savings of $1,526,710 and a total savings of $4,580,130 (13.6%) over 3 years. The corresponding annual per member per month savings was $0.025. This is further illustrated in the sensitivity and scenario analyses where the use of eliglustat was cost saving in all cases. Shifting more patients receiving ERT in the hospital outpatient setting to eliglustat resulted in increased savings., Conclusions: Based on these analyses, increased use of eliglustat resulted in meaningful cost savings to a payer's overall budget. Cost savings are highest among patients switching from ERT administered in a hospital outpatient setting. The results suggest that cost savings are also likely achievable from initiating patients on oral eliglustat instead of infusion-based therapy from the outset of treatment., Disclosures: This study was sponsored by Sanofi Genzyme. Evidera received funding from Sanofi Genzyme to conduct this study and prepare the manuscript. The sponsor collaborated on the study design, analysis, interpretation of results, and writing of the manuscript. Nalysnyk is an employee of and shareholder in Sanofi Genzyme. Ward, Cele, and Uyei are employees of Evidera, which provides consulting and other research services to biopharmaceutical companies. Sugarman was also an Evidera employee when the study was being conducted and the manuscript written. This study was presented as a poster at the Academy of Managed Care Pharmacy Nexus 2016, October 3-6, 2016; National City, MD, and at the International Society for Pharmacoeconomics and Outcomes Research, 22nd Annual International Meeting; May 20-24, 2017; Boston, MA.

The purpose of this article is to review eliglustat tartrate, a substrate reduction therapy, for the treatment of Gaucher disease type 1 (GD1). GD is an rare inborn error of metabolism caused by accumulation of lipid substrates such as glucosylceramide within the monocyte-macrophage system that affects the body by causing enlargement of the spleen and liver, destruction of bone, and abnormalities of the lungs and blood, such as anemia, thrombocytopenia, and leukopenia. GD is classified into three types: GD1, a chronic and non-neuronopathic disease accounting for 95% of GD cases; and types 2 and 3 (GD2 GD3) which are more progressive diseases with no approved drugs available at this time. Treatment options for GD1 include enzyme replacement therapy and substrate reduction therapy. Eliglustat works by inhibiting UDP-glucosylceramide synthase, the first enzyme that catalyzes the biosynthesis of glycosphingolipids, thus reducing the load of glucosylceramide influx into the lysosome. Eliglustat was approved by the US Food and Drug Administration after three Phase I, two Phase II, and two Phase III clinical trials. The dose of eliglustat is 84 mg twice a day or once daily depending on the cytochrome P450 2D6 genotype of the patient.

Focusing on the benefits of patients with rare disease the authors analysed the aspects of orphan medicines financed in the frame of the Hungarian social insurance system in 2012 in order to make the consumption more rational, transparent and predictable. Most of the orphan drugs were financed in the frame of compassionate use by the reimbursement system. Consequently, a great deal of crucial problems occurred in relation to the unconventional subsidized method, especially in the case of the highest cost enzyme replacement therapies. On the base of the findings, proposals of the authors are presented for access to orphan drugs, fitting to the specific professional, economical and ethical aspects of this unique field of the health care system. The primary goal is to provide a suitable subsidized method for the treatment of rare disease patients with unmet medical needs. The financial modification of orphans became indispensible in Hungary. Professionals from numerous fields dealing with rare disease patients' care expressed agreement on the issue. Transforming the orphan medicines' financial structure has been initiated according to internationally shared principles.

Objective: To evaluate the cost-effectiveness of enzyme replacement therapy (ERT) compared to standard medical care without ERT in the Dutch cohort of patients with type 1 Gaucher disease (GD I)., Design: Cost-effectiveness analysis was performed using a life-time state-transition model of the disease's natural course. Transition probabilities, effectiveness data and costs were derived from retrospective data and prospective follow-up of the Dutch study cohort., Setting: The tertiary referral center for Gaucher disease in the Netherlands., Participants: The Dutch cohort of patients with GD I., Intervention: ERT versus standard medical care without ERT in symptomatic patients., Main Outcome Measures: Years free of end organ damage (YFEOD) (splenectomy, bone complication, malignancy, multiple complications), quality adjusted life years (QALY), and costs., Results: Over an 85 year lifetime, an untreated GD I patient will generate 48.9 YFEOD and 55.86 QALYs. Starting ERT in a symptomatic patient increases the YFEOD by 12.8 years, while the number of QALYs gained increases by 6.27. The average yearly ERT medication costs range between € 124,000 and € 258,000 per patient. The lifetime costs of ERT starting in the symptomatic stage are € 5,716,473 against € 171,780 without ERT, a difference of € 5,544,693. Consequently, the extra costs per additional YFEOD or per additional QALY are € 434,416 and € 884,994 respectively. After discounting effects by 1.5% and costs by 4% and under a reasonable scenario of ERT unit cost reduction by 25%, these incremental cost-effectiveness ratios could decrease to € 149,857 and € 324,812 respectively., Discussion: ERT is a highly potential drug for GD I with substantial health gains. The conservatively estimated incremental cost-effectiveness ratios are substantially lower than for Pompe and Fabry disease. We suggest that the high effectiveness has contributed importantly to acceptance of reimbursement of ERT for GD I. The present study may further support discussions on acceptable price limits for ultra-orphan products.

This paper approaches in a critical way aspects of Brazilian public policies for drugs, emphasizing those classified as high cost and for rare diseases. The lysosomal storage diseases was taken as an example because of their rarity and the international trend for the development of new drugs for their treatment, all at high costs. Three lysosomal storage diseases were approached: Gaucher disease, Fabry disease and mucopolysaccharidosis type I. Gaucher disease has its treatment drug licensed in Brazil and guidelines for its use are established through a clinical protocol by the Ministry of Health. The others have their drug treatments registered in Brazil; however, no treatment guidelines for them have been developed by the government. The objective of the paper was to foster the discussion on the role of health technology assessment for high-cost drugs for rare diseases in Brazil, emphasizing the need for establishing health policies with legitimacy towards these diseases. Despite the difficulties in establishing a health policy for each rare disease, it is possible to create rational models to deal with this growing challenge.

Objectives: The aim of this review is to determine the clinical effectiveness and cost-effectiveness of enzyme replacement therapy (ERT) in the treatment of symptomatic Gaucher's disease., Data Sources: Major electronic databases were searched from their inception to August 2003; and updated from January 2003 to July/August 2004., Review Methods: Databases were searched for studies that met the criteria and selected data were extracted and evaluated. Studies were assessed for their relevance to the UK context and the review objective. The bibliographic databases were also searched to identify existing cost studies, economic evaluations and models. A Markov decision model was constructed based on patients moving between states defined by the modified Severity Score Index (SSI). Most of the parameters were derived from the published literature. ERT was assumed to restore patients to full health in the base case., Results: Sixty-three studies were included, all suggestive of benefit with ERT. However, the way in which the effects translate into patient well-being and survival or the need for services and resources has not been reliably estimated. Quality of life improvements with ERT have been reported. Nonetheless, studies based on the Short Form 36 (SF-36) indicate that patients treated with ERT continue to have reduced health-related quality of life (HRQoL) compared with the general population. No study attached utility values to quality of life measures for ERT-treated patients. Thirty-one studies relevant to the natural history of the disease were found. Sixteen looked at multiple clinical characteristics of a cohort of patients with type I Gaucher's disease. There was considerable within-study and between-study heterogeneity, but all showed that Gaucher's disease was a progressive condition. Some suggested that the disease may become more indolent in adulthood; however, studies were discrepant on this point. Most disease is diagnosed in adulthood, although about one-quarter presented in childhood, these patients having the most severe symptoms and greatest rate of progression. Modelling of natural history was undertaken using the five papers that reported the SSI for each patient, along with patient-level data on age, age at diagnosis, splenectomy status and genotype, to address the question of whether disease stabilises in adulthood and the degree of correlation between phenotype and genotype. Analysis of the available data suggested that disease progression is likely to slow markedly in adulthood and that genotype is a useful predictor of clinical expression of the disease. Five studies looked at quality of life. Data on this topic were also obtained from the registries. The evidence suggests that the vast majority of the clinical characteristics of type I Gaucher's disease have little impact on subjective HRQoL and that therefore for the majority of people with type I Gaucher's disease this may not be a severe condition. Bone and skeletal symptoms contribute most to the morbidity of the disease and can lead to severe pain and immobility. The mean cost per patient treated was approximately pounds sterling 86,000 per annum in England and Wales. The cost per patient varied considerably by dose. Four existing economic evaluations were found, all of which calculated a very high cost per quality-adjusted life-year (QALY). Using the Markov decision model, ERT was assumed to restore patients to full health in the base case. The estimated incremental cost per QALY [incremental cost-effectiveness ratio (ICER)] in the base case ranged from pounds sterling 380,000 to pounds sterling 476,000 per QALY, depending on genotype. Univariate sensitivity analyses examined ERT not restoring full health, more severe disease progression in the untreated cohort, and only treating the most severely affected patients. These produced ICERs of approximately pounds sterling 1.4 million, pounds sterling 296,000 and pounds sterling 275,000 per QALY, respectively. The base-case unit cost of the drug is pounds sterling 2.975. The unit cost would have had to be reduced ten-fold, to pounds sterling 0.30, to obtain an ICER of pounds sterling 30,000 per QALY. At a unit cost of pounds sterling 1 the ICER would be pounds sterling 120,000 per QALY., Conclusions: Although ERT for treating the 'average' Gaucher's disease patient exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over ten-fold, some argue that since orphan drug legislation encouraged the manufacture of Cerezyme, and Gaucher's disease can be defined as an orphan disease, the NHS has little option but to provide it, despite its great expense. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, these were very thin indeed. Nonetheless, even large errors in estimates of the distribution of genotype, genotype--phenotype associations, effectiveness and numbers of patients will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. Further research could help to clarify the many uncertainties that exist. However, although doing so will be of clinical interest, it is questionable whether, within the current pricing environment, such research would have any substantive impact on policy decisions. It is highly improbable that, whatever the findings of such research, the ICER could be brought down by the orders of magnitude required to make ERT an efficient use of health service resources. (The possible exception to this would be investigating the most efficient alternative treatment strategies for using ERT in a paediatric population only.) Moreover, if under equity considerations for orphan diseases the NHS feels it is important to provide this drug, regardless of its cost-effectiveness, then refining the precision of the ICER estimate also becomes superfluous.

Drugs for orphan diseases are often disproportionately costly, although the patient population is by definition small. In Israel, with a high percentage of Ashkenazi Jews and therefore many patients with Gaucher disease, the expense of enzyme replacement therapy for all patients would be prohibitive. For this reason, with approval of enzyme replacement therapy in Israel, the low-dose regimen (30 U/kg/month), less than one quarter of the manufacturer's original recommended dosage, was instituted as the starting regimen. A Gaucher Committee of medical experts under the auspices of the Ministry of Health determines eligibility for enzyme replacement therapy based on criteria of disease severity. At the advent of 2006, 184 patients in Israel receive enzyme replacement therapy, about one third of all known Israeli patients with Gaucher disease. The national budget provides capitation for each patient to each Sick Fund via a health care basket for severe/expensive treatments. After nearly nine years, the benefits of these innovations include availability of budget for patients requiring enzyme replacement therapy, evidence-based data that low dose is safe and effective, and that untreated mildly affected patients generally continue a benign disease trajectory, but if necessary, have recourse to enzyme replacement therapy, that is, patient care is never compromised. Questionnaires of satisfaction with this system highlight good outcome scores. For countries with limited resources, the use of an impartial committee of experts is recommended, as is long-term surveillance of all patients; maintenance protocols or even drug vacations as enzyme-treated patients approach normalization of disease parameters should be considered.

Potential treatment for lysosomal diseases now includes enzyme replacement therapy, substrate reduction therapy, and chaperone therapy. The first two of these have been implemented commercially, and the spectrum of diseases that are now treatable has expanded from Gaucher disease to include several other disorders. Treatment of these diseases is extremely costly. We explore some of the reasons for the high cost and discuss how, by proper selection of patients and appropriate dosing, the economic burden on society of treating these disease may be ameliorated, at least in part. However, the cost of treating rare diseases is a growing problem that society needs to address.

Aim: To evaluate the feasibility of financing the treatment of Gaucher disease with recombinant human imiglucerase in the Croatian health care system., Methods: Treatment with enzyme replacement therapy of 5 patients with Gaucher disease was started on January 2001. In 4 patients the typical signs of Gaucher disease (organomegaly, bone changes, anemia, and thrombocytopenia) were documented at the time of diagnosis. One patient received bone marrow stem cell transplant as treatment for acute myeloid leukemia from a HLA-matching sibling with Gaucher disease. All patients underwent therapy with imiglucerase (Cerezyme) infusion every 14 days. The outcome and actual cost of the treatment were followed during 12 months., Results: After 3 months of therapy, hemoglobin rose above low normal range in 2 patients. After 6 months, 3 patients had platelet count above 100x10(9)/L, and bone pain crises completely disappeared in patients with severe bone involvement. After 12 months, normal blood counts were restored in all patients. At the same time point, bone destruction remained unchanged in 3 patients and showed marked improvement in one. In agreement with the Ministry of Health, the Croatian Institute for Health Insurance restructured its funds and established a special "Fund for expensive drugs." This fund covers the treatment costs for patients with Gaucher disease (approximately 150,000 per patient per year) as well as the cost of treatment for patients with Fabry disease, AIDS, adenosine deaminase deficiency, multiple sclerosis, chronic myeloid leukemia, juvenile arthritis, and ovarian cancer., Conclusion: Collaboration of the institutions in a post-communist transition health care system can provide an effective model for financing expensive treatment for patients with rare diseases in a resource-poor health system.

The authors developed an automated patient interviewing tool to elicit individuals' willingness-to-pay (WTP) utilities under conditions of uncertainty and examined the reliability of this method and its potential usefulness in clinical decision support. We tested this method in 52 healthy volunteers using a computer-based interview that trained subjects in standard gamble (SG) and WTP methods, and elicited preferences for moderate Gaucher disease using WTP and SG. We assessed the validity of the WTP method by calculating the cost-effectiveness threshold implied by subjects' WTP and SG utilities; we also assessed subjects' understanding and comfort with using WTP for decision making by a questionnaire. The WTP method had good test-retest reliability (r = 0.796), and produced a cost-effectiveness ratio and ratings for understanding and clarity that support its validity. Moreover, many subjects felt that WTP was a reasonable (83%) method for therapeutic decision making and expressed comfort (62%) in using the method for their own health care decisions. These results suggest that a probabilistic method for WTP utility assessment is potentially useful for acquiring patient preferences for use in normative decision support systems.

Alglucerase is a modified form of human placental glucocerebrosidase used as enzyme replacement therapy for patients with Gaucher's disease, in whom functional glucocerebrosidase is deficient. Alglucerase has provided a breakthrough in treatment for patients with this relatively rare disease. With alglucerase infusions typical disease manifestations are ameliorated or normalised: hepatosplenomegaly is reduced, haematological parameters improve, and patients experience an increased quality of life usually within 4 to 6 months of treatment. Parameters of bone disease also respond, but generally over a longer period of treatment. Alglucerase is well tolerated by children and adults, with few adverse effects reported. Seroconversion occurs in approximately 15% of patients on high-dose therapy, but does not appear to affect the efficacy of treatment. Several dosage regimens have been used to deliver alglucerase, and the comparative benefits of these remain controversial. High-dose regimens of 60 IU/kg bodyweight administered every 2 weeks are clearly effective; however, smaller dosages given more frequently are also effective and incur a greatly reduced acquisition cost. Patient responses are variable, and the dosage regimen should be tailored to individual needs. Dosage regimens may be considerably reduced for the maintenance phase of treatment, but clinical experience is as yet insufficient to establish the minimum dosages required in the long term. Acquisition cost of alglucerase is $US3.70 per unit (1994 US dollars); thus, a dosage regimen of 60 IU/kg bodyweight administered every 2 weeks for a patient weighing 70kg costs $US404,040 per year. The minimal costs per quality-adjusted life year saved (QALY) have been estimated for 3 dosage regimens over a 10-year period. Cost per QALY was $US147,000 for 60 IU/kg bodyweight administered every 2 weeks, $US75,000 for 30 IU/kg every 2 weeks, and $US49,000 for 2.3 IU/kg administered 3 times per week. These costs were calculated assuming immediate death with no treatment, which suggests that the actual costs per QALY for most patients with type 1 or 3 disease are likely to be much higher. Drug administration costs may become a significant part of the cost during maintenance therapy; in addition, possible cost savings due to increased patient productivity and reduced palliative treatments remain unresolved. Although some patients may obtain increased benefit from high-dosage regimens, the very high cost may preclude general use of these regimens. Healthcare resources consumed by alglucerase therapy represent a large opportunity cost for other therapeutic areas.(ABSTRACT TRUNCATED AT 400 WORDS)