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.

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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 with ERT (imiglucerase or alglucerase) against treatment with calcitriol or a combination of ERT and calcitriol.15

Five RCTs were conducted in patients with type 1 Gaucher disease5,6,11,14,15 and one study was conducted in the patients with type 3 Gaucher disease.12 Open-label trials (N = 5) were more common than double-blind trials (N = 1). The sample size for included trials ranged from 11 to 95 patients. Two studies included patients who were naïve to treatment with ERT5,15 and four required patients to have been stabilized on ERT at the time of screening.6,11,12,14 All studies reported changes hematological endpoints (i.e., hemoglobin and platelets) and visceral endpoints (e.g., liver and spleen volume) and three studies reported changes in skeletal manifestations of Gaucher disease (e.g., bone marrow density).11,14,15 The studies ranged from 6 to 24 months in duration.

Uncontrolled clinical trials

One uncontrolled, phase 2, multicenter study, single-arm study investigated the use of eliglustat tartrate (50 or 100 mg TID) in 26 patients with type 1 Gaucher disease. Follow-up was reported at one9 and two years.10

Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase or a Combination for the Treatment of Gaucher Disease 4

Summary of Critical Appraisal

A detailed summary of the critical appraisal is provided in Table 11 for systematic reviews and Table 12 for RCTs (Appendix 4).

Systematic reviews

The health technology assessment conducted by Connock et al (2006) included a high quality systematic review of the literature.1 The review was conducted according to a protocol prepared in advance and included a comprehensive literature search involving multiple databases and without language restrictions. The literature search strategy was well reported; however, it did not specify whether or not grey literature was reviewed. The review included an appropriate risk of bias assessment and the quality of the evidence was considered throughout the review. A list of included and excluded studies was provided and key characteristics of the relevant studies were presented and discussed in the report.

The review by Piran et al, 2010 also included a comprehensive literature search the methods were well reported in the publication.8 The literature search strategy does not indicate whether or not grey literature was reviewed. Additional limitations with the methodology and reporting for this systematic review included failure to specify if study selection was performed in duplicate or by one reviewer, poor reporting of characteristics from the included studies, and lack of a formal risk of bias assessment. The authors did not specify if they performed an assessment of publication bias. However, given the limited number of studies which were pooled, any formal assessment of publication bias would have limited statistical power.

Randomized controlled trials

Common limitations of the identified RCTs include the use open-label designs (one RCT was double-blind); small sample sizes; poor reporting of methods for randomization and allocation concealment; and short duration which may not be reflective of long-term clinical use. With the exception of one RCT,14 the baseline characteristics within each of the studies were similar between the different treatment groups. The two trials which investigated the use of miglustat in combination with imiglucerase required patients to have been stably treated with imiglucerase at the time of screening.6,12 This may limit the generalizability of these trials to the Canadian setting where miglustat is only indicated for use in patients for whom ERT is considered inappropriate.

Dosing of the investigational products was generally within the range recommended in the Canadian product monographs.18-20 In the trial reported by Schiffmann et al (2007)12 adults with type 3 Gaucher disease were given 200 mg of miglustat three times daily (TID) which is greater than the dosage recommended for use in type 1 Gaucher disease (i.e., 100 mg TID); however, since miglustat is not indicated for use in the treatment of type 3 Gaucher disease in Canada, there is no recommended dose range for this patient population. The cumulative dose of ERT was substantially different in the two trials which compared higher and lower frequencies of imiglucerase dosing. No patient in the trial reported by De Fost et al (2007)14 received more than 50 U/kg every four weeks and a majority received 30 U/Kg or less. In contrast, the mean dose in the trial reported by Kishani et al (2009)11 was approximately 70 U/kg every four weeks. De Fost et al (2007) noted that the cumulative monthly dose of imiglucerase used in their study was relatively low and unlikely to be reflective of the typical dosage of imiglucerase used elsewhere.

Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase or a Combination for the Treatment of Gaucher Disease 5

A full-text publication of trial HGT-GCB-039 was unavailable; therefore, critical appraisal is limited to the information reported in the FDA Medical Review17 and the European Public Assessment Report for Vpriv.16 EMEA reviewers concluded that the following elements of this RCT were acceptable and consistent with their expectations for a trial in this patient population: inclusion and exclusion criteria; sample size calculation; primary and secondary endpoints; non- inferiority margin; and the comparator. There was a 0.8 g/dL difference in median hemoglobin between the two treatment groups at baseline which could be indication of differing disease severity at baseline. This discrepancy was investigated by EMEA reviewers who noted the following: 1) an analysis adjusting for the baseline hemoglobin concentration was similar to the primary efficacy analysis; and 2) the baseline difference was considered to be to the disadvantage of the efficacy of velaglucerase alfa rather than imiglucerase (i.e., the risk of bias would favour imiglucerase).

Uncontrolled clinical trials

The primary limitation with the study by Lukina et al (2010)9,10 is the absence of any control groups. In terms of a single-arm study, this trial was well conducted and well reported.

Summary of Findings

Systematic reviews

The systematic review by Connock et al (2006)1 included a total of 63 studies with two RCTs, two studies that were described as being “cohort-like” studies, one case-control study, and 58 case series. The primary outcomes of interest for this review were mortality and patient quality of life; however, the authors stated that few studies reported these endpoints. The majority of studies reported hematological and visceral endpoints. With respect to hematological outcomes, data from 16 studies suggested that the hemoglobin levels of patients treated with ERT approached the lower end of the normal range following one year of treatment. In addition, the mean platelet levels in patients treated with ERT increased in all 16 studies. Data from three studies indicated improvement in patients’ global disease severity score.

The report stated that, despite poor quality of the evidence, ERT appears to be effective in treating the visceral symptoms but that there remains uncertainty regarding the effectiveness of ERT in preventing some of the skeletal manifestations of type 1 Gaucher disease. They noted that weak quantitative evidence suggested that ERT appears to have a positive effect on bone pain, bone crises, and bone fractures. However, they stated the results should be interpreted with caution as the available data also suggested the possibility that ERT may exacerbate depletion in bone density. Overall, the authors concluded that all studies were suggested that ERT was beneficial in patients with Gaucher disease.

The review by Piran et al (2010)8 included 17 studies with 15 prospective cohort studies, one case-control study, and one pooled analysis of three open-label clinical trials. A brief summary of the characteristics and results for each of the included studies is shown in Appendix 5. After assessing relevant study characteristics (e.g., age of patients), the authors conducted a limited number of meta-analyses to assess the effects of ERT on bone marrow infiltration and bone mineral density (femoral and lumbar) in type 1 Gaucher disease (Table 2). One pooled analysis of two uncontrolled studies showed a statistically significant improvement in bone marrow burden in 27 patients who were treated for a mean of 49 months with ERT (P = 0.004). Meta- analysis of three studies (n = 54) measuring changes in BMD Z-score in the lumbar spine

Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase or a Combination for the Treatment of Gaucher Disease 6

showed no statistically significant change from baseline (P = 0.09). Pooling of two studies measuring changes in BMD Z-score of the femur also demonstrated no statistically significant change from baseline (P = 0.48).

Due to a limited number of published reports, the authors did not conduct any meta-analyses for the effects of SRT on skeletal complications. Two small studies (n = 2 and n = 6) showed no statistically significant changes from baseline for bone marrow infiltration following SRT treatment. This systematic review included one pooled analysis of three open-label studies (Pastores et al, 2007) which suggested that BMD Z-scores for both the femur and lumbar spine improved following 6, 12, and 24 months of treatment with miglustat. Overall, the authors of this review concluded that further investigations are needed to evaluate the effects of ERT and SRT on skeletal manifestations of type 1 Gaucher disease.

Table 2: Summary of meta-analyses for skeletal manifestations8 Endpoint (∆ from BL) Intervention No. Studies (N) WMD (95% CI) Bone marrow burden ERT 2 (27) -4.96 (-8.38, -1.57) BMD lumbar (Z-score) ERT 3 (54) 0.37 (-0.05, 0.79) BMD femur (Z-score) ERT 2 (43) 0.16 (-0.29, 0.61) BMD=bone marrow density; BL=baseline; CI=confidence interval; ERT=enzyme replacement therapy; N=number of patients in meta-analysis; WMD=weighted mean difference; ∆=change

Randomized Controlled Trials

Velaglucerase alfa versus Imiglucerase

A single RCT compared velaglucerase alfa against imiglucerase. Trial HGT-GCB-039 was a multi-centre, phase III, double-blind, parallel-group, non-inferiority RCT with a duration of nine months. The trial included 34 treatment-naïve patients with type 1 Gaucher disease. Eligible patients were randomized (1:1) to receive either velaglucerase alfa 60 U/kg E2W or imiglucerase 60 U/kg E2W. The primary outcome was the difference in mean absolute change in hemoglobin from baseline to week 4. Secondary endpoints included between-group differences in the mean and percent changes from baseline in platelet count, liver and spleen volumes, plasma chitotriosidase activity, and plasma chemokine ligand 18 (CCL18) levels.

The results of trial HGT-GCB-039 are summarized in Table 3. The mean change from baseline in hemoglobin was similar between the velaglucerase and imiglucerase treatment groups and the predefined non-inferiority criterion was achieved for both the ITT and PP analysis. There was no statistically significant difference between the two groups for liver volume, spleen volume, plasma chitotriosidase, platelet counts, and plasma CCL18.17 At least one adverse event was reported in 94.1% of patients in both treatment groups. Three patients in the velaglucerase group (17.6%) experienced at least one serious adverse event compared with none in the imiglucerase group. Overall, efficacy data from trial HGT-GCB-039 suggests that velaglucerase at a dose of 60 U/kg E2W is non-inferior to imiglucerase at a dose of 60 U/kg in treatment naïve patients. Reviewers for the EMEA concluded that the overall adverse profile appears to be comparable between velaglucerase and imiglucerase.

Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase or a Combination for the Treatment of Gaucher Disease 7

Table 3: Summary of Efficacy Results from HGT-GCB-0395 Outcome Change from Baseline - Mean (SE) Mean Difference Velaglucerase Imiglucerase (97.5% or 95% CI)* Hemoglobin (g/dL) - ITT 1.624 (0.223) 1.488 (0.281) 0.135 (-0.596, inf)* Hemoglobin (g/dL) - PP 1.677 (0.249) 1.520 (0.273) 0.157 (-0.599, inf)* Platelet Count (X109 cells/L) 110.41 (17.159) 144.38 (22.760) -38.71 (-88.42, 10.99)* P. Chitotriosidase (nmol/mL/h) 34,711.9 35,109.5 -703.6 (-11,762, 10,355) NLV (% of BW) -1.31 -1.10 -0.07% (-0.43, 0.29) NSV (% of BW) -1.34 -2.45 0.08% (-0.52, 0.68) Plasma CCL18 (ng/ml) -926.2 -1153.4 145.7 (-186.6, 480.0) BW=body weight; CI=confidence interval; inf= ;ITT=intention to treat; NLV=normalized liver volume; NSV=normalized spleen volume; P.=plasma; PP=per-protocol; SE=standard error *indicates 97.5% confidence interval

Miglustat in Combination with Imiglucerase

Elstein et al (2007) reported the results of trial OGT 918-004, a single-centre, phase II, open- label, parallel-group RCT comparing the efficacy and safety of miglustat, imiglucerase, or a combination of miglustat and imiglucerase over a period of 6 months.6 The trial included 36 patients with type 1 Gaucher disease who had been treated with imiglucerase for a minimum of 2 years. The patients were randomized to one of the following groups: 1) switch to miglustat at a dose of 100 mg TID; 2) addition miglustat at a dose of 100 mg TID to their existing treatment with imiglucerase; or 3) continue their existing treatment with imiglucerase.

There were no statistically significant differences between the treatment groups for mean changes in hemoglobin or spleen volume. There was a statistically significant reduction in liver volume favouring the combination group versus the imiglucerase group (-4.9% versus 3.6%; P = 0.047). There was a statistically significant difference in the mean change from baseline in platelet count favouring the imiglucerase group compared to the miglustat group (15.3 X 109/L vs. -21.6 X 109/L; P = 0.035). Safety assessments were only reported for patients treated with miglustat. The authors concluded that combining miglustat with imiglucerase did not provide any substantial benefit in patients stably treated with ERT.

Table 4: Summary of findings from trial OGT-918-0046,13 Change from Baseline Outcomes Statistical Significance* MIG IMG MIG + IMG Liver volume (%) -2.9 3.6 -4.9 P=0.047 for IMG vs. MIG + IMG Spleen volume (%) -4.8 -2.1 -8.5 No significant differences Haemoglobin (g/dl) -0.31 -0.15 -0.10 No significant differences Platelet count (x109/L) -21.6 15.3 2.7 P=0.035 for MIG vs. IMG Chitotriosidase activity (%) 33.0 -0.3 -3.9 P=0.004 for MIG vs. IMG P=0.001 for MIG vs. MIG + IMG IMG=imiglucerase; MIG=miglustat *P-values calculated with an Analysis of Covariance (ANCOVA) model Table adapted from EPAR Scientific Discussion for Zavesca13

Schiffmann et al, 2008 reported the results of a phase I/II, open-label, parallel-group RCT compared miglustat versus no miglustat in patients with type 3 Gaucher disease treated with ERT.12 Thirty patients were randomized (2:1) to receive miglustat in addition to their ongoing ERT (n = 21) or to continue with their ERT without miglustat treatment (n = 9) for a period of 12

Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase or a Combination for the Treatment of Gaucher Disease 8

months. Patients 12 years or older received a 200 mg TID dosage of miglustat and patients younger than 12 years received a lower dosage adjusted to their body surface area. To be eligible for the study, patients were required to have been stable on ERT for at least 6 months (n = 29) or have successfully undergone a bone marrow transplant at least one year prior to study entry (n = 1). The primary efficacy end point was the change in vertical saccadic eye movements (VSEM) velocity from baseline to month 12. Secondary endpoints included a range of neuropsychological and neurological assessments, systemic endpoints (e.g., liver and spleen volume), hematological assessments (e.g., hemoglobin and platelet counts), and clinical laboratory assessments

The authors reported that the addition of miglustat had no effect on VSEM which was the primary outcome of the study. They also reported that there were no statistically significant differences between the two treatment groups in secondary eye movement parameters or neurological evaluations (neurological examinations or cognitive tests) at the end of randomized phase. There were no statistical comparisons provided for any of the systemic or biochemical endpoints; however, the authors reported that liver volume, spleen volume, hemoglobin levels and platelet counts remained stable in both treatment groups at all-time points with no notable differences were observed between treatment groups (Table 5). Safety assessments were only reported for patients treated with miglustat. Diarrhea (72%), tremor (38%), abdominal pain (34%), and cough (34%) were the most commonly reported adverse events. At least one serious adverse event was reported for six patients (21%) treated with miglustat.

Table 5: Summary of systemic disease endpoints from Schiffmann et al, 200712 Miglustat No miglustat Endpoints Time point n Mean (95% CI) n Mean (95% CI) Forced vital capacity Baseline 9 75.1 (62.0, 88.2) 6 79.5 (61.3, 97.6) (% actual / predicted) Month 12 9 81.1 (65.7, 96.5) 6 81.3 (62.7, 99.9) Liver volume Baseline 11 0.72 (0.6, 0.8) 6 0.69 (0.6, 0.8) (L / height in cm x 100) Month 12 11 0.69 (0.6, 0.8) 6 0.64 (0.5, 0.8) Spleen volume Baseline 7 0.19 (0.1, 0.2) 6 0.13 (0.1, 0.2) (L / height in cm x 100) Month 12 7 0.17 (0.1, 0.2) 6 0.15 (0.1, 0.2) Hemoglobin Baseline 18 126.7 (121.4, 132.1) 9 122.8 (116.2, 129.3) (g/L) Month 12 18 129.4 (125.2, 133.6) 9 126.9 (121.2, 132.6) Platelet count Baseline 18 243.1 (212.2, 274.0) 9 244.0 (160, 343) (x 109//L) Month 12 18 240.9 (214.7, 267.1) 9 241.6 (134, 348) CI=confidence interval; n=number of patients

High versus Low Frequency of Imiglucerase

Kishnani et al (2008) conducted a multicentre, 24 month, open-label, parallel-group, phase 4 RCT to assess the safety and efficacy of imiglucerase infused once every four weeks (E4W) compared to once every two weeks (E2W) at the same cumulative monthly dose.11 102 adults with type 1 Gaucher disease were randomized (2:1) to E4W dosing (n = 65) or E2W dosing (n = 37). The primary endpoint was the proportion of patients who successfully maintained their baseline level of clinical response at month 24 or at the time of discontinuation. Clinical response was defined by a composite outcome of the following hematological, skeletal, and visceral measures: hemoglobin does not fall below the baseline more than 1.25 g/dL for women or 1.5 g/dL for men, platelet count does not fall more than 25% below baseline or does not fall below 80,000 mm3, liver and spleen volumes are not greater than 20% above baseline, no evidence of bone disease progression, including no incidence of pathologic fractures, medullary infarctions, lytic lesions or avascular necrosis, and no bone crises. A secondary composite

Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase or a Combination for the Treatment of Gaucher Disease 9

outcome, based on modified criteria published after initiation of the trial, was included in the report: hemoglobin >11 g/dl (women) and >12 g/dl (men); platelets > 100,000 mm3; liver volume >1.25 multiples of normal (MN); spleen volume <8 MN; and skeletal manifestations were the same the primary outcome. Health-related quality of life was assessed using the SF-36.

The authors reported that there were no statistically significant differences in the proportion of patients who met the response criteria for either the primary or secondary composite outcomes (Table 6). The authors also reported that there were no statistically significant differences between the groups in the mean composite scores of the SF-36. Overall adverse events were more commonly reported for patients in the E4W group compared with the E2W group (84% versus 64%, P-value not reported); however, serious adverse events occurred more frequently in the E2W group compared with the E4W group (21% versus 6.4%, P-value not reported).

Table 6: Summary of findings from Kishnani et al, 200811 Proportion of Responders - n/N (%) E4W vs. E2W Endpoint E4W E2W (95% CI) Primary Composite 36/57 (63) 21/26 (81) -17.6% (-35.7, 5.8) Secondary Composite 46/52 (89) 24/24 (100) -11.5% (-23.1, 6.0) CI=confidence interval; E2W=every two weeks; E4W=every four weeks; n=number of responders; N=total number of patients *87% and 92% of patients were included in the ITT analysis for the E2W and E4W groups, respectively.

De Fost et al (2007), conducted a 12-month, open-label RCT to evaluate whether patients with stable type 1 Gaucher disease could be maintained with ERT dosing E4W.14 Eleven patients who had been treated with imiglucerase were randomized to either continue their current dosing schedule (once every week, n = 4; or once every 2 weeks, n = 1) or to switch a lower frequency dosing schedule of once E4W (n = 6). The cumulative monthly dosage of imiglucerase was unchanged during the trial. After 12 months of treatment there were no statistically significant differences between the high and low frequency dosage regimens for any of the following outcomes: liver volume, spleen volume, hemoglobin level, platelet count, chitotriosidase, white cell count, and ferritin. Two patients in the low frequency group were considered treatment failures due to measureable disease progression versus none in the higher frequency group. However, the relevance of this finding is questionable given that the low frequency treatment group had more severe Gaucher disease at baseline. Overall, the authors concluded that low frequency ERT sufficiently maintained a stable disease state in most, but not all, adult patients with type 1 Gaucher disease.

ERT versus non-ERT

One trial was identified that compared patients treated with ERT against patients not treated with ERT.15 Schiffmann et al (2002) reported the results of a six-month, three-arm, open-label RCT comparing the use of ERT alone, ERT in combination with calcitriol, or calcitriol alone in splenectomized adults with type 1 Gaucher (n = 29). Hematological, visceral, and skeletal outcomes were reported in this trial (results summarized in Table 7). Relative to the calcitriol alone treatment group, patients treated with ERT demonstrated statistically significant improvements in platelet counts (ERT alone group), hemoglobin (ERT with calcitriol group) and bone marrow fat fraction (both ERT groups).

Eliglustat Tartrate, Miglustat, Imiglucerase, Velaglucerase or a Combination for the Treatment of Gaucher Disease 10

Table 7: Summary of findings from Schiffmann et al, 200215 Change from BL to 6 months Outcomes Statistical Significance ERT CAL ERT + CAL Liver volume (%) -24.9% -5.6% -6.2% No significant differences Hemoglobin (g/dl) 2.76% -3.5% 8.3% P < 0.01 for CAL vs. ERT + CAL Platelet count (x109/L) 34% -4% 37% P < 0.05 for CAL vs. ERT BM fat fraction 99% -41% 67% P < 0.001 for CAL vs. ERT P < 0.001 for CAL vs. ERT + CAL BMD SECT (mg/m3) -6.2% -2% -5.2% No significant differences BMD DECT (mg/m3) -6% 0% -7.8% No significant differences BL=baseline; BM=bone marrow; BMD=bone mineral density; CAL=calcitriol; ERT=enzyme replacement therapy; DECT=dual-energy computerized tomography; SECT=single-energy computerized tomography Table adapted from results presented in Connock et al, 20061

Uncontrolled clinical trials

Eliglustat tartrate

There were no RCTs identified for eliglustat tartrate; therefore, an uncontrolled phase 2 study was included in this review. Lukina et al 2010 reported the one year9 and two year results10 of an open-label, single-arm study where 26 patients with type 1 Gaucher disease were treated with eliglustat tartrate at a dose of 50 or 100 mg TID (dose selected based on plasma drug concentrations). All patients had an intact spleen and had not been treated with imiglucerase or miglustat for a period of at least 12 months prior to the trial. The primary efficacy end point was a composite outcome which required patients to show improvement from baseline to one year in at least two of the following: a reduction of at least 15% in spleen volume; increase of at least 0.5 g/dL in hemoglobin level; and increase of at least 15% in platelet count.

Following one year of treatment, the primary composite endpoint was achieved by 77% (95% CI 58% to 89%) of patients in the ITT analysis and 91% (95% CI 72% to 98%) of patients in the per-protocol analysis. Statistically significant improvements were also reported for changes in hemoglobin, platelet counts, spleen volume, and lumbar spine bone mineral density (Table 8). The authors reported that median SF-36 scores were increased for physical functioning, general health, and for the physical component (all P < 0.01). Twenty patients enrolled in the second year of the trial. Following two years of treatment with eliglustat tartrate, there were statistically significant improvements from baseline in the following endpoints (percentage ± standard deviation): hemoglobin (20% ± 15%), platelet counts (81% ± 56%), spleen volume (-52% ± 11%), liver volume (-24% ± 13%), and lumbar spine bone mineral density (7.8% ± 10.6%).

Over the course of the two year study period, 88.4% of patients experienced a total of 126 adverse events. In the first year of the study, 85% of patients experienced at least one adverse event and three patients experienced a total of five serious adverse events. Two patients withdrew as a result of adverse events. In the second year, 70% of patients experienced at least one adverse event. There were no serious adverse events or withdrawals due to adverse events reported in the second year of the trial.

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Table 8: Summary of findings from Lukina et al, 20109 Outcome Change from BL (95% CI) Mean hemoglobin (g/dl) 1.62 (1.05, 2.18) Platelet counts (% change) 40.3% (23.7, 57.0) Spleen volume (% change) -38.5% (-43.5%, -33.5%) Liver volume (% change) -17.0% (-21.6%, 12.3%) Lumbar spine BMD (Z-score) 0.31 (0.09, 0.53) Femur BMD (Z-score) 0.01 (-0.19, 0.20) BL=baseline; CI=confidence interval; BMD=bone mineral density

Limitations

There are limited data concerning the comparative effectiveness of newer agents; no RCTs were identified for eliglustat tartate and a single RCT with 35 patients has compared velaglucerase with imiglucerase. Eliglustat tartate is not currently approved for use in Canada, the United States, or Europe; therefore, it is currently an experimental medicine with limited efficacy and safety data. There was also limited evidence for the use of ERT or SRT in patients with type 3 Gaucher; a single RCT was identified for patients with type 3 Gaucher disease, all the other studies included patients with type 1 Gaucher disease.

There are important limitations with the RCTs included in this review, such as the use open- label designs (one double-blind RCT was identified); small sample sizes; and poor reporting of methods for randomization and allocation concealment. In addition, the trials were of relatively short duration which may not be reflective of long-term clinical use. Limitations, such as the small sample sizes and low number of RCTs, are likely attributable to the fact that Gaucher disease is a relatively rare condition making it difficult to recruit patients for clinical trials. The two trials which investigated the use of miglustat in combination with imiglucerase required patients to have been stably treated with imiglucerase at the time of screening.6,12 This may limit the generalizability of these trials to the Canadian setting where miglustat is only indicated for use in patients for whom ERT is considered inappropriate.

Overall, there is considerable heterogeneity in the literature related to Gaucher disease with studies differing in design (e.g., controlled versus uncontrolled), interventions (e.g., dosage and concomitant treatments), outcomes (e.g., hematological, visceral, skeletal, and others) and patient characteristics (e.g., age, disease severity, and previous therapy). Many published reports lacked a clear description of the study design. Connock et al (2006)1 stated that they had difficulty in determining whether some studies were conducted prospectively or retrospective. They also noted that it was not always clear if a published report was a case series or an uncontrolled clinical trial.

CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING

Randomized and non-randomized studies support the efficacy of the ERT in the management of hematological and visceral symptoms of type 1 Gaucher disease. However, evidence from one systematic review and meta-analysis suggests that more evidence, preferably in the form of longer-term controlled clinical trials, is needed to fully evaluate the effects of ERT and SRT on the skeletal manifestations of type 1 Gaucher disease. With respect to different forms of ERT, evidence from one RCT has shown that velaglucerase alfa is similar to imiglucerase for the management of hematological and visceral endpoints in type 1 Gaucher disease. The adverse event profiles also appear to be similar; however, longer term follow-up may be needed to

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confirm these findings. Evidence regarding the use of combination therapy with both ERT and SRT is limited to single RCTs in patients with type 1 and type 3 Gaucher disease and both studies suggested that there is no additional benefit to combination treatment. There was insufficient evidence to assess the comparative safety of SRT alone or in combination with ERT.

One study was identified that investigated the use of miglustat in patients with type 1 Gaucher disease. This study was conducted in a patient population that was stably treated with ERT, which is inconsistent with the Canadian indication for product. The other form of SRT included in this review, eliglustat tartrate, is not approved for use by Health Canada, the FDA, or the EMEA. The evidence regarding the use of eliglustat tartrate is limited to a single uncontrolled study; therefore, more evidence is required to determine if this agent has a place in the treatment of Gaucher disease. Overall, the evidence included in this review is insufficient to draw conclusions regarding the safety and efficacy for the use of SRT in the treatment of type 1 Gaucher disease.

PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

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REFERENCES

1. Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher's disease: a systematic review. Health Technol Assess [Internet]. 2006 Jul [cited 2011 Dec 7];10(24):iii-152. Available from: http://www.hta.ac.uk/fullmono/mon1024.pdf

2. Canadian guidelines for treatment of Gaucher disease by enzyme replacement with imiglucerase or substrate reduction therapy with miglustat [Internet]. Version 9. Montreal: The Garrod Association; 2011 Aug [cited 2011 Nov 24]. Available from: http://www.garrod.ca/wp-content/uploads/ONTARIO-GUIDELINES-FOR-TREATMENT- OF-GAUCHER-August-2011-2.pdf

3. Canadian guidelines for treatment of Gaucher disease by enzyme replacement with imiglucerase or substrate reduction therapy with miglustat [Internet]. Version 8. Montreal: The Garrod Association; 2007 [cited 2011 Nov 24]. Available from: http://www.garrod.ca/data/attachments/RevisedGaucherGuidelinesV8Mar26-07.pdf

4. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998 Jun;52(6):377-84.

5. National Library of Medicine (US). Clinicaltrials.gov [Internet]. Study of gene-activated® human glucocerebrosidase (GA-GCB) ERT compared with imiglucerase in type I Gaucher Disease [Internet]. Bethesda (MD): National Library of Medicine (US); 2000 Feb 29- [cited 2011 Dec 21]. Available from: http://clinicaltrials.gov/ct2/show/NCT00553631?term=HGT- GCb-039&rank=1.

6. Elstein D, Dweck A, Attias D, Hadas-Halpern I, Zevin S, Altarescu G, et al. Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement. Blood [Internet]. 2007 Oct 1 [cited 2011 Nov 30];110(7):2296-301. Available from: http://bloodjournal.hematologylibrary.org/content/110/7/2296.full.pdf+html

7. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 [cited 2011 Nov 28];7:10. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

8. Piran S, Amato D. Gaucher disease: a systematic review and meta-analysis of bone complications and their response to treatment. J Inherit Metab Dis. 2010 Jun;33(3):271-9.

9. Lukina E, Watman N, Arreguin EA, Banikazemi M, Dragosky M, Iastrebner M, et al. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood. 2010 Aug 12;116(6):893-9. Available from: http://bloodjournal.hematologylibrary.org/content/116/6/893.full.pdf+html?sid=08fce199- 5588-40ec-b3ef-4658018b8317

10. Lukina E, Watman N, Arreguin EA, Dragosky M, Iastrebner M, Rosenbaum H, et al. Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease

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type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study. Blood. 2010 Nov 18;116(20):4095-8. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993616

11. Kishnani PS, DiRocco M, Kaplan P, Mehta A, Pastores GM, Smith SE, et al. A randomized trial comparing the efficacy and safety of imiglucerase (Cerezyme) infusions every 4 weeks versus every 2 weeks in the maintenance therapy of adult patients with Gaucher disease type 1. Mol Genet Metab. 2009 Apr;96(4):164-70.

12. Schiffmann R, Fitzgibbon EJ, Harris C, DeVile C, Davies EH, Abel L, et al. Randomized, controlled trial of miglustat in Gaucher's disease type 3. Ann Neurol [Internet]. 2008 Nov [cited 2011 Nov 30];64(5):514-22. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605167

13. Scientific discussion: Zavesca [Internet]. London: European Medicines Agency [Internet] 2005. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Scientific_Discussion/human/000435/WC500046721.pdf

14. de Fost M, Aerts JM, Groener JE, Maas M, Akkerman EM, Wiersma MG, et al. Low frequency maintenance therapy with imiglucerase in adult type I Gaucher disease: a prospective randomized controlled trial. Haematologica [Internet]. 2007 Feb [cited 2011 Nov 30];92(2):215-21. Available from: http://www.haematologica.org/content/92/2/215.full.pdf+html

15. Schiffmann R, Mankin H, Dambrosia JM, Xavier RJ, Kreps C, Hill SC, et al. Decreased bone density in splenectomized Gaucher patients receiving enzyme replacement therapy. Blood Cells Mol Dis. 2002 Mar;28(2):288-96.

16. Assessment report for VPRIV [Internet]. London: European Medicines Agency [cited 2011 Dec 22] 2010. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Public_assessment_report/human/001249/WC500096489.pdf

17. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Medical review(s) [Internet]. In: Vpriv (Velaglucerase alfa) Injection. Shire Human Genetic Therapies, Inc. Application No.: 022575. Approval Date: 2/26/2010. Bethesda: Food and Drug Administration; 2010 Feb 12 [cited 2011 Dec 13]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022575s000medr.pdf.

18. Drug Product Database. Ottawa: Health Canada. Shire Human Genetic Therapies Inc. PrVPRIV™ velaglucerase alfa: Powder for Solution for Injection 400 U/vial. 2011 Aug 12 ;c2009 - .

19. Drug Product Database. Ottawa: Health Canada. PrZavesca® Miglustat Capsule 100 mg: Professed Standard Glucosylceramide Synthase Inhibitor. 2011 Mar 3; c2009 - .

20. Drug Product Database. Ottawa: Health Canada. PrCerezyme® Imiglucerase for injection (Recombinant human ß-glucocerebrosidase analogue) Lyophilized Powder 200 Units/vial and 400 Units/vial. 2011 Dec 10; c2009 - .

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APPENDICES:

Appendix 1: Treatments for Gaucher Disease Included in this Review

Treatment Health Canada Indications Enzyme replacement therapy Imiglucerase Long-term enzyme replacement therapy in patients with a confirmed diagnosis of non-neuronopathic (Type 1) or chronic neuronopathic (Type 3) Gaucher disease who exhibit non-neurological manifestations of the disease.

Velaglucerase alfa Long-term enzyme replacement therapy for pediatric and adult patients with type 1 Gaucher disease. Substrate reduction therapy Miglustat Treatment of adult patients with mild to moderate Type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to constraints such as allergy, hypersensitivity, or poor venous access). Eliglustat tartrate Not approved for use in Canada

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Appendix 2: Selection of Included Studies

496 citations identified from electronic literature search and screened

484 citations excluded

12 potentially relevant articles retrieved for scrutiny (full text, if available)

4 potentially relevant reports retrieved from other sources (grey literature, hand search)

16 potentially relevant reports

3 reports excluded:

- Irrelevant comparator (2)

- Review articles (1)

13 reports included in review

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Appendix 3: Characteristics of the Included Studies

Table 9: Characteristics of Included Systematic Reviews Author, Year Description Comparators Outcomes Population 8 Piran, 2010 SR with MA Imiglucerase Skeletal Type 1 GD 17 studies Miglustat Children or adults Randomized and No comparator non-randomized

1 Connock, 2006 HTA with SR Imiglucerase Hematological Type 1 GD 63 studies Alglucerase Visceral Type 3 GD Randomized and No comparator Skeletal Children or adults non-randomized HRQoL Cost-effectiveness

GD=Gaucher disease; HRQoL=health-related quality of life; HTA=health technology assessment; MA=meta-analysis; SR=systematic review

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Table 10: Summary of Characteristics of Included Clinical Trials Author/Trial ID, Description Comparators Outcomes Eligible Population Year, Country Randomized controlled trials

HGT-GCB-039 9 months Velaglucerase (60 U/kg Hematological Type 1 GD 5 2010 Multicentre E2W) Visceral Treatment Naive Phase III Imiglucerase (60 U/kg Safety USA, UK, India, Non-inferiority E4W) Argentina, Israel, Double-blind Paraguay, Spain, Parallel-group Russia, Tunisia N = 35 11 Kishnani 2009 24 months Imiglucerase (E2W) Hematological Type 1 GD Multicentre Imiglucerase (E4W) Visceral Treated with a USA, UK, Brazil, Phase IV Skeletal stable dose of Canada, Italy, Open-label HRQoL imiglucerase (20- Poland, Spain Parallel-group Safety 60 U/kg E2W) for N = 95 ≥ 6 months Schiffmann 12 months Imiglucerase (ED) Saccadic eye Type 3 GD 12 2007 Open-label Miglustat (200 mg TID) + movements Treated with ERT Parallel-group Imiglucerase (ED) Neuropsychological for ≥ 6 months (no OGT-918-006 Phase I/II Neurological dosage specified) N = 21 Hematological USA, UK Visceral Safety 6 Elstein 2007 6 months Miglustat (100 mg TID) Hematological Type 1 GD Single center Imiglucerase (ED) Visceral Treated with ERT OGT-918-004 Open-label Miglustat (100 mg TID) + Safety for ≥ 24 months Parallel-group Imiglucerase (ED) HRQoL (no dosage Israel N = 36 specified) With or without intact spleen 14 De Fost 2007 12 months Imiglucerase (E2W) Hematological Type 1 GD Single center Imiglucerase (E4W) Visceral Treated with ERT Netherlands Open-label Skeletal for ≥ 24 months Parallel-group (no dosage N = 11 specified) With or without intact spleen Schiffmann 6 months ERT (60 U/kg E2W) Hematological Type 1 GD 15 2002 Open-label Calcitriol (0.25-3 µg/day) Visceral Treatment Naïve Parallel-group ERT (60 U/kg E2W) + Skeletal Splenectomized USA N = 29 Calcitriol (0.25-3 µg/day) Uncontrolled clinical trials Lukina, 20109 2 years Eliglustat (50-100 mg Hematological Type 1 GD Open-label TID) Visceral Treatment Naïve USA, Argentina, Single-arm Skeletal With intact spleen Israel, Mexico, N = 26 HRQoL Russia Safety E2W=every two weeks; E4W=every four weeks; ED=existing dose; ERT=enzyme replacement therapy; GD=Gaucher disease; HRQoL=health-related quality of life; TID=three times daily

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Appendix 4: Summary of Critical Appraisal

Table 11: Critical Appraisal of Systematic Reviews Author, Strengths Limitations Year Piran, 2010 Comprehensive literature search Predated the approval of velaglucerase 8 Literature search strategy well reported Literature search strategy did not indicate Key study characteristics presented whether or not grey literature was reviewed. Unclear if study selection was performed in duplicate or by one reviewer No formal risk of bias assessment Limited to English language studies

Connock, Protocol specified in advance Predated the approval of velaglucerase 1 2006 Comprehensive literature search Unclear if grey literature was reviewed No language restrictions Study selection was performed by one Literature search strategy well reported reviewer; however, a second reviewer Appropriate risk of bias assessment verified the results Quality of the evidence considered throughout the review Included and excluded studies provided Key study characteristics presented

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Table 12: Critical Appraisal of Primary Studies Trial ID, Year, Strengths Limitations Country Randomized Controlled Trials HGT-GCB- Treatments were double-blind Study is not published; however, the results 5 039, 2010 EMEA reviewers concluded that the following have been posted on clinicaltrials.gov elements of this RCT were acceptable and 0.8 g/dL difference in median hemoglobin USA, UK, consistent with their expectations for a trial in between the two treatment groups at baseline Argentina, this patient population: inclusion and which could be indication of differing disease India, Israel, exclusion criteria; sample size calculation; severity at baseline Paraguay, primary and secondary endpoints; NI Russia, margin.13 Spain, 91% of patients completed the trial Tunisia Both ITT and PP analyses conducted Exposure to IPs was similar in both groups High level of compliance in both groups

Kishnani Objective and methods clearly stated Treatments were open-label 11 2009 Sample size calculations provided Poor reporting of methods for randomization Eligibility criteria were well described and allocation concealment USA, UK, Baseline characteristics described and were Primary ITT analysis did not include all Brazil, similar between the two treatment groups randomized patients Canada, Adverse events reported Patient disposition was well-reported; however, Italy, Poland, Exposure to ERT was similar between the two the reasons for discontinuation were not Spain groups during the trial completely described 24 month duration Loss to follow up resulted in an evaluable sample size which was below the amount specified in the sample size calculations Post-hoc adjustments made to the primary and secondary composite outcomes Actual values for some secondary outcomes not reported (e.g., SF-36)

Schiffmann Objective and methods clearly stated Treatments were open-label 12 2007 Eligibility criteria were well described Poor reporting of methods for randomization Sample size calculations provided and allocation concealment OGT-918- Baseline characteristics were described and Majority of patients were being treated with 006 were similar between the two groups imiglucerase at the time of screening Patient disposition was well described Dosage of imiglucerase was not reported USA, UK All patients completed the randomized phase Results were not clearly stated and there is limited information about the random variability Exposure to IPs and compliance were not reported

Elstein Objective and methods clearly stated Treatments were open-label 6 2007 Eligibility criteria were well described Poor reporting of methods for randomization Patient disposition was well reported and allocation concealment OGT-918- Baseline characteristics were described and Patients treated with imiglucerase for a 004 were similar between the two groups minimum period of 2 years at screening Dosage of IPs within the recommended range No formal sample size calculations13 Israel Baseline characteristics were similar between No pre-specified primary endpoint the three treatment groups No adjustments for multiple comparisons 92% of patients completed the randomized Did not include an ITT analysis phase of the trial Safety data only for miglustat-treated patients Adverse events reported

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Trial ID, Year, Strengths Limitations Country De Fost Objective and methods clearly stated Treatments were open-label 14 2007 Eligibility criteria were well described Limited sample size (n = 11) Sample size calculations provided Poor reporting of methods for randomization Netherlands Baseline characteristics described and allocation concealment Patient disposition was well described Statistically significant differences in patient characteristics between the two groups at baseline Results were not clearly stated and there was no indication of random variability Safety assessments not reported

Schiffmann Objective and methods clearly stated Treatments were open-label 15 2002 Eligibility criteria were well described Sample size calculations were not reported Randomization was concealed Results were not clearly stated and there is USA Baseline characteristics described and were limited information about the variability of the similar between the three treatment groups results Patient disposition was well reported Adverse events reported

Uncontrolled clinical trials

Lukina 2010 Objective and methods clearly stated No control group 10 Sample size calculations provided Treatment was open-label Both ITT and PP analyses conducted USA, Baseline characteristics well described Argentina, 85% completed one year on study and 77% Israel, completed two years on study Mexico, 24 month duration Russia EMEA=European Medicines Agency; ERT=enzyme replacement therapy; IPs=investigational products; ITT=intention to treat; NI=non-inferiority; PP=per protocol

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Appendix 5: Summary of studies included in the review by Piran et al 20108

Study Treatment Dose N Duration Findings Elstein et al 2004 Miglustat 100 mg TID 2 3 years NS for change in fat fraction (P=0.12) Rosenthal et al 1995 ERT 60 U/kg/E2W 12 42 months Increase in fat fraction (P<0.0001) Hollak et al 2001 ERT 15-120 U/kg/month 12 4 years Increase in fat fraction (P=0.0004) Maas et al 2003 ERT NA 12 40 months Increase in fat fraction (P=0.0001) Giraldo et al 2006 Miglustat 100 mg TID 25 1 year No statistical analysis Terk et al 2000 ERT 7 U/kg/week 16 1-4.7 years 75% responded to ERT for BM infiltration 30-60 U/kg/E2W Poll et al 2002 ERT 20-60 U/kg/E2W 30 36 months 63% responded to ERT for BM infiltration Olsen et al 2003 ERT NR 9 NR 22% responded to ERT for BM infiltration El-Beshlawy et al 2006 ERT 60 μg/kg/E2W 11 11.2 months 36% responded to ERT for BM infiltration Wilson et al 2007 ERT 7.5 U/kg/E2W 11 5 years 64% responded to ERT for BM infiltration Mikosch et al 2008 Miglustat 100 mg TID 6 6-18 months NS for change in BMB (P=0.82) Robertson et al 2007 ERT 26–51 U/Kg/E2W 15 4.75 years No statistical analysis Pastores et al 2007 Miglustat 100 mg TID 72 2 years Increase in BMD lumbar Z-score (P=0.015) Increase in BMD femur Z-score (P=0.039) Lebel et al 2004 ERT 30 U/kg/month 10 24-108 months NS for change in BMD femur Z-score (P=0.91) NS for change in BMD lumbar Z score (P=0.7) Ciana et al 2005 ERT 6.8-30 U/kg/E2W 11 4.5 years Increase in BMD femur Z-score (P=0.005) Wenstrup et al 2007 ERT 15-60 U/kg/E2W 111 8 years No statistical analysis Sims et al 2008 ERT 60 U/kg/E2W 33 4 years Increase in BMD femur Z-score (P=0.035) NS for change in BMD lumbar Z-score (P=0.042) ERT=enzyme replacement therapy; E2W=every two weeks; N=number of patients; NR=not reported; NS=not significant, TID=three times daily

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