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TITLE: Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase Or A

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TITLE: Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase Or A TITLE: Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase or a Combination of These for the Treatment of Gaucher Disease: A Review of Clinical Effectiveness and Safety DATE: 22 December 2011 CONTEXT AND POLICY ISSUES Gaucher disease is an inherited lysosomal storage disease caused by a deficiency of the enzyme glucocerebrosidase. This deficiency results in an accumulation of glucocerebroside in the lysosomes of macrophages, predominantly in the reticuloendothelial system. 1 Gaucher disease is classified into three subtypes based on the presence of central nervous system involvement. Type 1 (non-neuropathic) is the most prevalent form of Gaucher disease (90% of all cases) and is associated with a range of clinical consequences including: hematological effects (e.g., anemia, thrombocytopenia); visceral effects (e.g., hepatosplenomegaly); and skeletal effects (e.g., reductions in bone density). Type 2 (acute neuronopathic) has an early onset involving severe neurologic effects and typically results in death by age three. Type 3 (sub-acute neuronopathic) is associated with neurological effects that are less severe than type 2.1 Canadian guidelines recommend that enzyme replacement therapy (ERT) should be the first choice of treatment for patients with Gaucher disease.2,3 Imiglucerase (Cerezyme) and velaglucerase alfa (Vpriv) are the two forms of ERT that are authorized for use in Canada. Substrate reduction therapy (SRT) is an alternative treatment option that involves reducing the biosynthesis of glucocerebroside. SRT is currently indicated for use in patients for whom ERT is not a therapeutic option. Miglustat (Zavesca) is the only form of SRT which is currently approved for use in Canada. Eliglustat tartrate is an SRT that is currently in clinical development and is not approved for use in Canada. Specific Health Canada approved indications for ERT and SRT are described in Appendix 1. Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions. RESEARCH QUESTIONS 1. What is the comparative clinical effectiveness of eliglustat tartrate, miglustat, imiglucerase, velaglucerase or a combination of these for the treatment of Gaucher disease? 2. What is the comparative safety of eliglustat tartrate, miglustat, imiglucerase, velaglucerase or a combination of these for the treatment of Gaucher disease? KEY MESSAGE Limited evidence supports the use of enzyme replacement for Type 1 Gaucher disease and shows no additional benefit of combination with substrate reduction treatment. The evidence is insufficient to draw conclusions regarding the safety and efficacy of substrate reduction treatment for Type 1 Gaucher disease. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2011, Issue 11), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, and safety data. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 1996 and November 24, 2011. Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications and evaluated the full-text publications for the final article selection according to criteria presented in Table 1. Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase or a Combination for the Treatment of Gaucher Disease 2 Table 1: Selection Criteria Population Individuals with Type 1 or Type 3 Gaucher disease Intervention Eliglustat tartrate Miglustat Imiglucerase Velaglucerase alfa Combination therapy with ERT and SRT Comparator Eliglustat tartrate Miglustat Imiglucerase Velaglucerase alfa Combination therapy with ERT and SRT Placebo No comparator Outcomes Efficacy Harms Study Designs Health technology assessments, systematic reviews, meta- analyses, randomized controlled trials (RCTs), non- randomized studies (in the absence of any controlled trials) Exclusion Criteria Studies meeting any of the following criteria were excluded: case series, case reports, or non- English language publications. Non-randomized primary studies were included if there were no RCTs identified for a particular intervention. Critical Appraisal of Individual Studies Critical appraisal of the included studies was performed according to study design. Full-text appraisal of primary studies was performed using the criteria described by Downs and Black.4 Reviews conducted by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMEA) were consulted to assist in appraising study HGT-GCB-039 (unpublished)5 and OGT-918-004.6 Systematic reviews were assessed using the AMSTAR criteria.7 SUMMARY OF EVIDENCE Quantity of Research Available A total of 496 citations were retrieved from the literature search. The abstracts for these reports were reviewed and 12 studies that could potentially fulfill the selection criteria were identified for further screening. Four additional references were retrieved from the grey literature. The screening process resulted in the selection of 13 reports. A summary of the screening results is provided in Appendix 2. Of the 13 selected reports, one was a health technology assessment with a systematic review,1 one was a systematic review with a meta-analysis,8 two reported the results of an uncontrolled clinical trial,9,10 and nine articles reported the results of six randomized controlled trials.5,6,11-17 Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase or a Combination for the Treatment of Gaucher Disease 3 Summary of Study Characteristics A summary of the characteristics of the included studies is provided in Table 9 for systematic reviews and Table 10 for primary studies (Appendix 3). Systematic reviews Connock et al (2006) conducted a health technology assessment to evaluate the clinical effectiveness and cost-effectiveness of ERT in the treatment of symptomatic Gaucher disease.1 The review included primary studies of any design that evaluated the clinical effectiveness of ERT in at least ten patients diagnosed with type 1 or type 3 Gaucher disease. Piran et al (2010) conducted a systematic review and meta-analysis to assess the effects of ERT and SRT on bone marrow infiltration (BI) and bone mineral density (BMD) in type 1 Gaucher disease.8 Randomized and non-randomized studies of any design were eligible for inclusion if they evaluated the effect of ERT or SRT on BI or BMD in patients with type 1 Gaucher disease. Key exclusion criteria included review articles, letters to the editors, abstracts, comments, case reports, and studies on types 2 and 3 Gaucher disease. The literature search of both systematic reviews predated the approval of velaglucerase; therefore, imiglucerase and alglucerase were the only forms of ERT considered. The review by Piran et al (2010) also included studies investigating the use of SRT; however, the evidence is limited to studies involving miglustat. Of the 68 studies included in the review by Connock et al (2006) and 17 included in the review by Piran et al (2010), there were four studies that were included in both reviews. Randomized controlled trials All of the included studies involved treatment with imiglucerase (or alglucerase). One non- inferiority trial, compared velaglucerase alfa to imiglucerase.5 Two studies investigated the use of combination therapy with miglustat and imiglucerase against treatment with imiglucerase alone or miglustat alone.6,12 Two studies compared different higher and lower frequency dosing regimens for administration of imiglucerase (i.e., every two weeks versus every four weeks).11,14 One three-arm study compared treatment
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