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TITLE: Enzyme Replacement Therapy for Rare Diseases: A Review of Clinical Efficacy DATE: 02 September 2011 CONTEXT AND POLICY ISSUES: Rare diseases are an important medical and social issue because of the burden that these conditions place on patients and their families, and the difficulty often encountered in finding timely and specialized medical care.1 Moreover, evidence for the efficacy of therapies for rare conditions is often limited because of the small number of patients that are available to participate in clinical trials, and the few resulting clinical studies.2,3 Lysosomal storage disorders (LSDs) are a group of more than 50 genetically distinct, but biochemically related, inherited conditions.4,5 They generally result from the malfunction of lysosomal enzymes and are characterized by the accumulation of undigested or partly digested macromolecules, leading to cellular dysfunction and various clinical manifestations.4,5 The age of onset of these conditions and the types and severity of clinical symptoms that develop may vary greatly even within a specific disease, and often include organ involvement, musculoskeletal disorders, and neuropathology.4,6,7 LSDs are rare, with reported prevalence rates among neonates ranging from 1 per 57,000 live births to 1 per 4.2 million live births depending on the condition.5,8 Enzyme replacement therapy (ERT) has been used as an intervention in various LSDs and involves replacement of the missing or malfunctioned enzyme with a functional enzyme molecule. As such, ERT addresses the underlying metabolic defects in LSDs, rather than providing symptomatic management.9 ERT in LSDs is lifelong and costly, estimated at USD$200,000 to USD$300,000 per patient, per year.6,9 The objective of the present review is to summarize the evidence regarding the efficacy of ERT in selected LSDs, specifically late-onset Pompe disease, mucopolysaccharidosis type I (MPS-I or Hurler Syndrome), mucopolysaccharidosis type II (MPS-II or Hunter Syndrome), and Gaucher disease, with a view to informing policy decisions regarding their treatment.

Enzyme Replacement Therapy for Rare Diseases 2

RESEARCH QUESTIONS:

1. What is the clinical efficacy of alglucosidase alpha for the treatment of late-onset Pompe disease?

2. What is the clinical efficacy of laronidase for the treatment of mucopolysaccharidosis type I?

3. What is the clinical efficacy of idursulfase for the treatment of mucopolysaccharidosis type II?

4. What is the clinical efficacy of imiglucerase or veraglucerase alpha for the treatment of Gaucher disease?

KEY MESSAGE: Limited evidence for the treatment of selected liposomal storage disorders with enzyme replacement therapy suggests efficacy in some of these conditions. The rare occurrence of liposomal storage disorders poses a challenge for obtaining efficacy data. METHODS: Literature Search Strategy A limited literature search was conducted on key resources including PubMed, Medline, EMBASE, The Cochrane Library (2011, Issue 7), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and abbreviated lists of 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 and randomized controlled trials. The search was also limited to English language documents published between Jan 1, 2006 and Aug 10, 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. Table 1: Selection Criteria

Population

Patients with adult-onset Pompe disease (Type II glycogenosis)

Patients with Mucopolysaccharidosis Type I (MPS-I or Hurler Syndrome)

Patients with Mucopolysaccharidosis Type II (MPS-II or Hunter Syndrome)

Patients with Gaucher disease

Intervention

alglucosidase alpha (Myozyme) for adult-onset Pompe disease

laronidase (Aldurazyme) for Mucopolysaccharidosis Type I

idursulfase (Elaprase) for Mucopolysaccharidosis Type II

imiglucerase (Cerezyme) for Gaucher disease

veraglucerase alpha (VPRIV) for Gaucher disease


Comparator

alglucosidase alpha (Myozyme) for adult-onset Pompe disease

laronidase (Aldurazyme) for Mucopolysaccharidosis Type I

idursulfase (Elaprase) for Mucopolysaccharidosis Type II

imiglucerase (Cerezyme) for Gaucher disease

veraglucerase alpha (VPRIV) for Gaucher disease Or Placebo

Outcomes

Clinical efficacy

Study designs

Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs)

Exclusion Criteria Observational studies and foreign language studies were excluded from this review. Critical Appraisal of Individual Studies The Downs and Black instrument10

was used to assess the methodological quality of randomized studies, and the AMSTAR tool11 was used to assess the methodological quality of systematic reviews. Each report’s fulfillment of the relevant criteria was described and summarized. SUMMARY OF EVIDENCE: Quantity of Research Available A total of 43 citations were retrieved from the literature search. The abstracts for these reports were reviewed and 20 studies that could potentially fulfill the selection criteria were identified for further screening. Five additional references were retrieved from the grey literature. The screening process resulted in the selection of seven reports for inclusion in the present review. A summary of the screening results is provided in Appendix 1. Of the seven selected reports, one12 was a health technology assessment with systematic review, one8 was a systematic review with a meta-analysis, and five13-17 were randomized trials. The selection criteria for this review excluded foreign language reports and observational studies, however given the limited number of eligible studies, additional articles of potential interest are provided in Appendix 2 Summary of Study Characteristics A summary of the characteristics of the studies included in this report is provided in Tables A3.1 (systematic reviews) and A3.2 (randomized studies) of Appendix 3. Of the seven included reports, one13 was in Pompe disease, two8,12 were in mucopolysaccharidosis type I (MPS-I), two14,15 were in mucopolysaccharidosis type II (MPS-II), and two16,17 were in Gaucher disease. The two systematic reviews8,12 were in MPS-I and in both cases reported the same single relevant placebo-controlled clinical trial (Wraith et al (2004)18), however one8 reported estimates for primary outcomes in greater detail and one12 presented secondary outcomes as well, and so both systematic reviews are reported here. As such, there is only one relevant unique randomized study in MPS-I and a total of six unique randomized


studies in the present review. No studies of veraglucerase alpha in Gaucher disease were identified. Three8,12-14 of the six reviewed randomized studies were placebo-controlled. A fourth study compared different doses of the same drug,15 and the other two16,17 were dose frequency studies. The sample sizes of the reviewed studies ranged from 11 patients16 to 96 patients,14 (average sample size = 58). The duration of the intervention period ranged from 26 weeks8,12 to 24 months,17 (average duration 60 weeks). Among the outcomes considered by the six trials were included pulmonary function tests,8,12-15 the six-minute walk test (6MWT),8,12-15 urinary glycosaminoglycans (GAG) excretion,8,12,14,15 liver or spleen volume tests,8,12,14-17 musculoskeletal function studies,8,12-15,17 hemoglobin and platelet counts,16,17 sleep studies,8,12,15 and health status assessments.8,12,13,17 Summary of Critical Appraisal A detailed summary of the critical appraisal of the studies included in the report is provided in Table A4 in Appendix 4. The two systematic reviews8,12 were generally of good quality, each having conducted a comprehensive literature search based on predefined criteria, providing details of included and excluded studies, as well as an assessment of the scientific quality of the included study by Wraith et al.18 Both reviews noted limitations in the description of allocation concealment and blinding in that study. The review by El Dib et al.8 provided a limited description of the study characteristics of Wraith et al., and the review by Connock et al.12 used only one reviewer for the main study selection and data extraction, however the results were verified by a second reviewer. The quality of the randomized trials was variable. The studies of the highest quality were those by Van der Ploeg et al.13 and by Muenzer et al.,14 both of which were double-blind placebo-controlled studies, and which provided descriptions of their losses to follow-up and reported adverse events. Both studies were adequately powered for the primary outcomes versus placebo. Of the remaining three15-17 trials, all were unblinded, two15,16 did not appear to have conducted sample size calculations and included a small number of patients (n = 1116 and n = 1215), and one17 conducted a sample size calculation however subsequent losses to follow-up resulted in a non-statistically-significant between-group difference for the primary outcome. One15 study included only patients with less severe disease and was thus limited in its generalizability, two16,17 did not clearly report their findings, and one16 did not report adverse events. Given that patients with rare conditions often have difficulty in finding specialized care, it was unclear if the care received by patients in each of the five randomized studies was representative of treatment of the majority of such patients. Summary of Findings A detailed summary of the results of the studies included in this report is provided in Tables A5.1 (systematic reviews) and A5.2 (randomized studies) of Appendix 5.

Alglucosidase alpha in late-onset Pompe disease


A single randomized double-blind placebo-controlled trial of 90 patients with Pompe disease, which included patients with a mean age at symptom onset of 28 years, reported significant improvements the 6MWT (difference: 28.12 meters, 95% Confidence Interval [CI]: 2.07 to 54.17) and percent predicted forced vital capacity (%FVC), (difference: 3.4%, 95% CI: 1.03 to 5.77) over an 18-month period. Among secondary outcomes, significant differences were also found in quantitative muscle testing (QMT) of the leg and in maximum expiratory pressure. Differences in arm QMT, maximum inspiratory pressure, and ST-36 scores were not statistically significant. Laronidase in MPS-I A single placebo-controlled trial of 45 patients by Wraith et al.18 that was reported in the two systematic reviews8,12 found significant improvement in %FVC (difference: 4.62%, 95%CI: 0.64 to 8.59), but no significant improvement in the 6MWT at 26 weeks. Secondary outcomes showed significantly greater mean reductions in urinary GAG excretion (54.1% versus 47.3%, P-value not reported) and liver volume (20.2% difference, P-value = 0.001) in the laronidase group. Post-hoc analyses in sleep apnoea and shoulder mobility among subsets of patients suggested better outcomes in the laronidase group. No significant differences were noted in the Health Assessment Questionnaire. Idursulfase in MPS-II Muenzer et al. reported two14,15 studies on MPS-II. The first study14 was a randomized double-blind placebo-controlled trial of 96 patients (mean age approximately 14 years) that compared two dosing frequencies (weekly and every-other-week [EOW]) of 0.5 milligrams per kilogram of idursulfase with placebo over 53 weeks. Based on a composite outcome comprised of %FVC and the 6MWT, the authors reported statistically significant differences for both dosing frequencies compared with placebo. Among secondary outcomes, the authors also reported significantly decreased liver volumes, spleen volumes, and urine GAG excretion among both frequencies of idursulfase compared with placebo. The second study by Muenzer et al.15 was a randomized double-blind trial of three doses of idursulfase for 23 weeks that was followed by an open-label extension and continued for an additional 25 weeks, at which point outcomes were assessed. Average age of patients was 14 years. Because the total sample size of this trial was small (12 patients), it lacked the statistical power to demonstrate important differences between the three doses of idursulfase, and thus no comparative assessment could be made. Imiglucerase in Gaucher disease The two studies in Gaucher disease16,17 were randomized, unblinded, dose-frequency trials. The study by Kishani et al17 randomized 95 patients (approximately 45 years of age at randomization) already on 70 IU per kilogram of body weight per week of imiglucerase to receive this same dose either EOW or every 4 weeks (E4W) for 24 months. The primary outcomes in this trial were composite endpoints based on the percentage of patients that fulfilled each of five criteria: haemoglobin level, platelet count, liver and spleen volumes, bone disease progression and bone crises, defined as bone pain with acute onset requiring immobilization, narcotics, having increased white blood cell count, peritoneal elevation, fever or debilitation for more than 3 days). While this study did perform a sample size calculation, it experienced losses to follow-up which may have rendered reported differences in the two treatment groups not statistically significant. The percentage of patients meeting the primary composite endpoint in the EOW and E4W groups was 80.8% and 63.2%, respectively. The


percentage of patients meeting a therapeutic success goals-based composite endpoint in the EOW and E4W groups was 100% and 89%, respectively. No significant between-group differences were noted in the SF-36 Health Survey. De Fost et al.16 randomized 11 patients (between the ages of 34 and 75) already receiving between 15 and 50 IU per kilogram of body weight of imiglucerase every one-to-two weeks (E1-2W) to continue the same dosing regimen or to receive the same dose E4W for an additional 12 months. The authors reported no significant between-group difference in the percent change in the ratio of liver volume to body weight (baseline: 100%, E1-2W: 102%, E4W: 98%). The authors noted that the typical ERT maintenance dose is higher than the one used in their study. Two patients experienced treatment failure, both of which were in the E4W group. Data on secondary outcomes were not clearly summarized by treatment group.

Limitations Few randomized studies on each of the four indications were identified and no studies of veraglucerase alpha in Gaucher disease were identified. The two systematic reviews8,12 identified only one unique study between them. Most of the studies are of a small sample size, with three15-17 lacking sufficient power to detect differences in their primary outcomes. There is a risk of bias among the included trials. Three15-17 of the randomized studies were unblinded and the extent to which allocation concealment was attempted or successful in each of the six trials was unclear. Between-group differences were not clearly reported in one study,16 and the extent to which the type of care received by the patients in the reviewed studies was representative of the care received by patients with LSDs in general is unclear. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: The evidence suggests that certain ERT interventions may be efficacious in the treatment of selected LSDs. Specifically, the findings of three randomized placebo-controlled studies suggest that alglucosidase is associated with improved mobility and lung function in Pompe disease,13 laronidase is associated with decreased mucopolysaccharide degradation and lung function in MPS-I,18 and idursulfase is associated with improved mobility, organ volume, and decreased mucopolysaccharide degradation in MPS-II.14 Due to limitations in sample size as well as other factors, the two studies of varying dosing frequency of imiglucerase in Gaucher disease16,17 are inconclusive. These results should be interpreted with caution, given the limited evidence for the efficacy of ERT in each of the selected LSDs, and weighed with understanding that more and larger randomized trials are difficult given the rare occurrence of these conditions. High-quality observational studies may be useful in assessing the evidence base for ERT in LSDs. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

http://www.cadth.ca/


REFERENCES: 1. Schieppati A, Henter JI, Daina E, Aperia A. Why rare diseases are an important medical

and social issue. Lancet. 2008 Jun 14;371(9629):2039-41.

2. Gerss JW, Köpcke W. Clinical trials and rare diseases. Adv Exp Med Biol. 2010;686:173-90.

3. Day S. Evidence-based medicine and rare diseases. Adv Exp Med Biol. 2010;686:41-53.

4. Kruer MC. Lysosomal storage disease [database on the Internet]. In: eMedicine. New York: WebMD; 2011 Jun 28 [cited 2011 Aug 23]. Available from: http://emedicine.medscape.com/article/1182830-overview.

5. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA [Internet]. 1999 Jan 20 [cited 2011 Aug 23];281(3):249-54. Available from: http://jama.ama-assn.org/content/281/3/249.long

6 . Deegan P. Gaucher disease: Treatment. 2011 Mar 9 [cited 2011 Aug 23]. In: UpToDate [database on the Internet]. Version 19.2. Waltham (MA): UpToDate, Inc.; c1994 - . Available from: http://www.uptodate.com Subscription required.

7. Kakkis E, Wraith E. Complications and management of the mucopolysaccharidoses. 2011 Jun 10 [cited 2011 Aug 23]. In: UpToDate [database on the Internet]. Version 19.2. Waltham (MA): UpToDate, Inc.; c1994 - . Available from: http://www.uptodate.com Subscription required.

8. El Dib RP, Pastores GM. Laronidase for treating mucopolysaccharidosis type I. Genetics and Molecular Research [Internet]. 2007 [cited 2011 Aug 11];6(3):667-74. Available from: http://www.funpecrp.com.br/gmr/year2007/vol3-6/pdf/GMR0370.pdf

9. Bailey L. An overview of enzyme replacement therapy for lysosomal storage diseases [Internet]. Online Journal of Issues in Nursing. 2008 Jan 1 [cited 2011 Aug 23];13(1). Available from: http://www.nursingworld.org/MainMenuCategories/ANAMarketplace/ANAPeriodicals/OJIN/TableofContents/vol132008/No1Jan08/EnzymeReplacementTherapy.aspx

10. 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.

11. 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 Jul 29];7:10. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

12. Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, et al. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry's disease and mucopolysaccharidosis type I. Health Technol Assess [Internet]. 2006 Jun [cited 2011 Aug 11];10(20):iii-113. Available from: http://www.hta.ac.uk/execsumm/summ1020.htm

http://emedicine.medscape.com/article/1182830-overview

http://jama.ama-assn.org/content/281/3/249.long

http://www.uptodate.com/

http://www.uptodate.com/

http://www.funpecrp.com.br/gmr/year2007/vol3-6/pdf/GMR0370.pdf

http://www.nursingworld.org/MainMenuCategories/ANAMarketplace/ANAPeriodicals/OJIN/TableofContents/vol132008/No1Jan08/EnzymeReplacementTherapy.aspx

http://www.nursingworld.org/MainMenuCategories/ANAMarketplace/ANAPeriodicals/OJIN/TableofContents/vol132008/No1Jan08/EnzymeReplacementTherapy.aspx

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

http://www.hta.ac.uk/execsumm/summ1020.htm


13 . van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, et al. A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med [Internet]. 2010 Apr 15 [cited 2011 Aug 11];362(15):1396-406. Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMoa0909859

14. Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006 Aug;8(8):465-73.

15. Muenzer J, Gucsavas-Calikoglu M, McCandless SE, Schuetz TJ, Kimura A. A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome). Mol Genet Metab. 2007 Mar;90(3):329-37.

16. 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 Aug 11];92(2):215-21. Available from: http://www.haematologica.org/cgi/reprint/92/2/215

17. 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.

18. Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J Pediatr. 2004 May;144(5):581-8.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa0909859

http://www.haematologica.org/cgi/reprint/92/2/215


APPENDICES: APPENDIX 1: Selection of Included Studies

23 citations excluded

20 potentially relevant articles retrieved for scrutiny (full text, if

available)

5 potentially relevant reports retrieved from other sources (grey

literature, hand search)

25 potentially relevant reports

18 reports excluded: -irrelevant population (1) -wrong comparator (1) -not a RCT, HTA, SR, MA (12) -published in language other than English (4)

7 reports included in review

43 citations identified from electronic literature search and screened


APPENDIX 2: Further Information Non-English-language systematic reviews Comitè d'Avaluació de Medicaments d'Utilització Hospitalària (CAMUH). Alglucosidase alpha (Myozyme®) for treatment of patients with late-onset Pompe disease [Internet]. Barcelona: Catalan Agency for Health Information, Assessment and Quality; 2011. Available from: http://www.gencat.cat/salut/depsan/units/aatrm/html/en/dir393/doc14001.html English executive summary Comitè d'Avaluació de Medicaments d'Utilització Hospitalària (CAMUH). Idursulfase (Elaprase) in the treatment of mucopolisacaridosis II [Internet]. Barcelona: Catalan Agency for Health Information, Assessment and Quality; 2010. Available from: http://www.gencat.cat/salut/depsan/units/aatrm/html/en/dir393/doc13714.html English executive summary Comitè d'Avaluació de Medicaments d'Utilització Hospitalària (CAMUH). Laronidase (Aldurazyme®) for the treatment of mucopolysaccharidosis I [Internet]. Barcelona: Catalan Agency for Health Information, Assessment and Quality; 2010. Available from: http://www.gencat.cat/salut/depsan/units/aatrm/html/en/dir393/doc13715.html English executive summary Pichon-Riviere A, Augustovski F, Garcia Marti S, Bardach A, Lopez A, Regueiro A, Glujovsky D, Alcaraz A, Aruj P, Calcagno J, Colantonio L. Idursulfase for the treatment of Hunter syndrome [Internet]. Ciudad de Buenos Aires: Institute for Clinical Effectiveness and Health Policy (IECS); 2007. Available from: http://www.iecs.org.ar/iecs-visor-publicacion.php?cod_publicacion=677&origen_publicacion=publicaciones

Observational studies Muenzer J, Beck M, Eng CM, Giugliani R, Harmatz P, Martin R, et al. Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. Genet Med. 2011 Feb;13(2):95-101. (Study extension with no control group) Schulze-Frenking G, Jones SA, Roberts J, Beck M, Wraith JE. Effects of enzyme replacement therapy on growth in patients with mucopolysaccharidosis type II. J Inherit Metab Dis. 2011 Feb;34(1):203-8. Bembi B, Pisa FE, Confalonieri M, Ciana G, Fiumara A, Parini R, et al. Long-term observational, non-randomized study of enzyme replacement therapy in late-onset glycogenosis type II. J Inherit Metab Dis. 2010 Dec;33(6):727-35.

Clarke LA, Wraith JE, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. 2009 Jan;123(1):229-40. (Study extension with no control group) Sims KB, Pastores GM, Weinreb NJ, Barranger J, Rosenbloom BE, Packman S, et al. Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study. Clin Genet. 2008 May;73(5):430-40.

http://www.gencat.cat/salut/depsan/units/aatrm/html/en/dir393/doc14001.html



http://www.iecs.org.ar/iecs-visor-publicacion.php?cod_publicacion=677&origen_publicacion=publicaciones

http://www.iecs.org.ar/iecs-visor-publicacion.php?cod_publicacion=677&origen_publicacion=publicaciones


APPENDIX 3: Characteristics of Included Reports

Table A3.1: Characteristics of Systematic Reviews

First author, year of publication

Indication, study eligibility criteria Comparators, sample size, duration of intervention, study quality

Outcomes evaluated

El Dib8 (2007) MSP-I

Randomized and quasi-randomized controlled trials (blind and non-blinded without language restriction. Considered studies of laronidase versus other interventions or no interventions or placebo, or different doses of laronidase.

One study met the inclusion criteria of this review (Wraith et al.

18)

Laronidase 100 U/kg (0.58 mg/kg) (n = 22) versus Placebo (n = 23), administered intravenously on a weekly basis, for 26 weeks Study quality classified as B according to Cochrane Collaboration Handbook, based on the absence of descriptions of the randomization process (allocation concealment or allocation generation) and of the blinding process in relation to the evaluated outcome.

Vital capacity at 26 weeks, and mean differences at 26 weeks compared with baseline; six-minute walk test at 26 weeks, and mean differences at 26 weeks compared with baseline; adverse events.

Connock12

(2006)

MSP-I Case series, prospective and retrospective cohort studies, and RCTs with at least 10 patients. Considered different ERT or no ERT as comparator.

The only comparative study to meet the inclusion criteria was the study by Wraith et al (2004) as reported in the systematic review by El Dib et al.

8

The authors also noted that the method used for randomization or how the allocation of treatment was concealed was not explained, nor was the method of blinding. A rating of study quality was not provided.

In addition to the outcomes described by Dib et al.

8, the

authors reported Wraith et al.’s secondary outcomes: GAG excretion, liver volume, sleep studies, shoulder mobility (flexion), and the disability component of the adult and child version of the HAQ.

ERT: enzyme replacement therapy; GAG: glycosaminoglycans; HAQ: Health Assessment Questionnaire; MSP-I: mucopolysaccharidosis type I; RCT: randomized controlled trial


Table A3.2: Characteristics of Randomized Trials

First author, year of publication, country of origin

Indication, patient eligibility criteria Study design, comparators, sample size, duration of intervention

Outcomes evaluated

Van der Ploeg

13

(2010) Netherlands / USA / France

Late-onset Pompe disease Patients eight years of age or older, able to walk 40 meters on the six-minute walk test (assisted if needed), had a percentage of the predicted FVC within the range of 30% to <80% in the upright position, with a postural drop in FVC (in litres) of 10% or more (from upright to supine), and had evidence of muscle weakness in the extremities. Patients requiring any invasive ventilation or noninvasive ventilation while awake and upright were excluded.

Randomized, double-blind, placebo-controlled, multi-center trial. alglucosidase alpha (20 mg/kg) (n = 60) placebo (n = 30) IV administration 78 weeks duration

Primary: Meters walked on the 6-minute walk test; percentage of predicted FVC in the upright position. Secondary and tertiary: changes in the percentages of predicted QMT leg score and QMT arm score, maximum inspiratory pressure, maximum expiratory pressure. The physical component of the Medical Outcomes Study Short Form-36 (SF-36) survey was also administered to patients aged 14 years and over. Adverse events

Muenzer14

(2006) USA / UK / Germany

MPS-II Patients aged 5 to 31 years with a diagnosis of MPS-II based on both clinical and biochemical criteria. Patients had to be able to reproducibly perform pulmonary function testing and have a forced vital capacity of <80% of predicted. Patients who had a tracheostomy, bone marrow, or cord blood transplant were excluded.

Randomized, double-blind, placebo-controlled, multi-center trial. idursulfase 0.5 mg/kg weekly (n = 32) idursulfase 0.5 mg/kg EOW (n = 32) placebo (n = 32) IV administration 53 weeks duration

Primary: a single two-component composite variable combining %FVC and 6MWT. Secondary: change in the individual components of the composite primary outcome, absolute FVC, liver and spleen volumes measured by abdominal MRI, urine GAG excretion, and passive joint range of motion. Adverse events

Muenzer15

(2006b) USA

MPS-II Patients aged ≥5 years with a diagnosis of MPS-II based on both clinical and biochemical criteria. Patients with severe MPS-II were

Randomized double-blind trial, followed by an open-label extension study. The randomized trial compared 3 patients in each treatment group. Patients received either placebo, idursulfase 0.15

Primary: reduction in urinary GAG excretion Secondary: liver and spleen size, 6MWT, pulmonary function, joint mobility, heart size and function, and a sleep study.





Outcomes evaluated

excluded. mg/kg EOW, idursulfase 0.50 mg/kg EOW, or idursulfase 1.5 mg/kg EOW by IV administration. The three patients initially randomized to placebo were later assigned to the differing doses of idursulfase, resulting in 4 patients per idursulfase group. Patients randomized to idursulfase continued on their assigned doses for the trial extension. For patients initially on placebo and assigned to idursulfase for the extension, their last placebo visit became their baseline 23-week randomized trial followed by 25-week open label study, with assessment done at 48 weeks

Safety assessments were performed at every visit

Kishani17

(2008) USA / UK / Italy

Gaucher disease type I (GD1) Patients aged ≥18 years with confirmed diagnosis of Gaucher disease and ≥2 years imiglucerase therapy (20-60 U/kg EOW ≥6 months prior to enrollment) and evidence of stable GD1 at baseline

Randomized, open-label, multicenter dose-frequency trial imiglucerase EOW (n = 33) versus imiglucerase E4W (n = 62) 24 month duration

Primary: proportion of patients who successfully maintained baseline level of clinical response at month 24 to each of the 5 following criteria: 1. Hemoglobin ≥1.25 g/dl for women and

≥1.5 for men; 2. Platelet count ≥25% of baseline and

≥80,000 mm3;

3. Liver and spleen volumes not >20% of baseline values;

4. No new findings or progression of bone





Outcomes evaluated

disease; 5. No bone crises during study. Secondary: proportion of patients meeting all therapeutic success goals-based endpoints, defined as: 1. Hemoglobin >11 g/dL for women and

>12 g/dL for men; 2. Platelets >100.000 mm

3;

3. Liver volume <1.25 MN 4. Spleen volume <8 MN 5. Skeletal assessments as described for

the primary composite endpoint. Patient-reported health status was also assessed using the SF-36 Health Survey Adverse events

De Fost16

(2007) Netherlands

Gaucher disease type I (GD1) Patients aged ≥18 years with proven GD1 as evidenced by physical and neurological evaluation and documentation of deficient glucocerebrosidase activity in leukocytes and genotyping, and had to have received ERT for ≥2 years prior to study enrollment. All patients had to have mild, stable GD1 in the 24 months prior to screening.

Randomized, unblinded, dose-frequency trial. Pre-randomization dose of imiglucerase E1-2W (n = 5) versus pre-randomization dose of imiglucerase E4W (n = 6) 12 month duration

Primary: change in liver ratio (mL/kg body weight) Secondary: spleen volume, hemoglobin level, platelet count, lumbar bone marrow fat, white cell count, plasma levels of ferritin, chitotriosidase, liver enzymes, and angiotensin-converting enzyme

6MWT: six-minute walking test; E1-2W: every one-to-two weeks; E4W: every four weeks; EOW: every other week; FVC: forced vital capacity; GAG: glycosaminoglycans; GD1: Gaucher disease type 1; IV: intravenous; MN: multiples of normal; MPS-II: mucopolysaccharidosis type II; MRI: magnetic resonance imaging; QMT: quantitative muscle testing;


APPENDIX 4: Critical Appraisal based on AMSTAR11 and Downs and Black10

Table A4: Critical Appraisal Summary First author, year of publication

Strengths Limitations

Systematic reviews

El Dib8 (2007) Comprehensive literature search based on pre-

defined criteria

Grey literature included

List of included and excluded studies provided

Scientific quality of studies assessed

Summary of study characteristics not detailed

Connock12

(2006)

Comprehensive literature search based on pre-defined criteria

Grey literature included

Summary of study characteristics and list of included and excluded studies provided

Scientific quality of studies assessed

Study selection and data extraction conducted by single reviewer (however verified by second reviewer)

Randomized studies

Van der Ploeg13

(2010)

Losses to follow-up described

Adequate randomization method

Patients and outcome assessors blinded

Adverse events described

Unclear if care received is representative of treatment of majority of patients

Muenzer14

(2006)



Patients and outcome assessors blinded



Muenzer15

(2006b)





Patients representative of cases with less severe disease

Patients and outcome assessors not blinded for extension study

Insufficient power: significant finding attained with pooling of three doses and extension of study

Kishani17

(2008) Adequate randomization method Unclear if care received is representative of treatment


Table A4: Critical Appraisal Summary First author, year of publication

Strengths Limitations

Adverse events described of majority of patients

Actual values for some secondary outcomes not reported

Patients and outcome assessors not blinded

Reasons for losses to follow-up not completely described

Although a sample size calculation was made, losses to follow up resulted in loss of statistical power

De Fost16

(2007)


Patients randomized to intervention groups

Distribution of principal confounders not clearly described

Main study findings not clearly described and random variability not estimated

Adverse events not reported


Patients and outcome assessors not blinded

Unclear if appropriate statistical tests were used or if study had sufficient statistical power to detect between-group differences


Appendix 5: Results of Included Studies

Table A5.1: Results of Systematic Reviews

First author, Publication Year

Study results Authors’ conclusions

El Dib8

(2007) Vital capacity, total at 26 weeks: Weighted mean difference (WMD): 4.62 (95%Confidence Interval [CI]: 0.64 to 8.59) Vital capacity, mean differences at 26 weeks compared with baseline: WMD: 5.60 (95%CI:1.25 to 9.96) 6MWT, total at 26 weeks: 27.60 (95%CI:-7.52 to 62.72) 6MWT, mean differences at 26 weeks compared with baseline: 38.10 (95%CI:-1.68 to 77.88) There were no statistically significant differences in any of the subcategories of adverse events. No serious adverse events or deaths were reported with laronidase, and the majority of events were associated with underlying MPS-I disease.

The authors concluded that based on the results of Wraith et al.

18, laronidase was safe and

effective compared with placebo for MPS-I because of the findings in urinary excretion of GAGS and improvement in vital capacity, after 26 weeks. Of note, El Dib et al.

8 did not

describe the findings on urinary GAG excretion in their review.

Connock12

(2006)

The results on vital capacity and 6MWT were reported by el Dib et al.8

Urinary GAG excretion: mean decrease of 54.1% in laronidase, and mean increase of 47.3% in placebo (statistically significant, P-value not reported). Decrease in laronidase group occurred in first four weeks of treatment and then stayed low for duration of treatment. Liver volume: mean decrease of 18.9% in laronidase, and mean increase of 1.3% in placebo (P = 0.001). Rates of change in liver volume and method for determining liver volume not given. Sleep studies: number of events of sleep apnea decreased in the laronidase group by 3.6 events per hour compared with the placebo group (not statistically significant). Post-hoc analysis of cases whose baseline levels were suggestive of sleep apnea indicated a difference of 11.4 events per hour in favor of laronidase (statistically significant, P-value not reported). Shoulder mobility (flexion): no difference between groups at 26 weeks, however post-hoc subgroup analysis in most severely affected patients suggests that laronidase improved mean range of movement, while patients on placebo experienced a mean decline in range of movement. HAQ: no important or significant between-group differences in mean scores at week 26.

The authors concluded that the study by Wraith et al.

18

demonstrated treatment benefit over placebo for most of the outcomes assessed.

6MWT: six minute walking test; CI: confidence interval; GAG: glycosaminoglycans; HAQ: Health Assessment Questionnaire; MPS-I: mucopolysaccharidosis type I; WMD: weighted mean difference


Table A5.2: Results of Randomized Trials First author, year of publication

Patient characteristics Study results Authors’ conclusions

Van der Ploeg13

(2010)

Alglucosidase alpha / placebo Sample size: 60 / 30 Age at first infusion (years, mean ± SD): 45.3 ± 12.4 / 42.6 ± 11.6 Sex (male, %): 57% / 37% Age at symptom onset (years, mean ± SD): 30.3 ± 12.3 / 23.9 ± 11.0 Disease duration (years, mean ± SD): 9.0 ± 6.3 / 10.1 ± 8.4 Normal GAA activity (%, mean ± SD): 10.8 ± 8.2 / 10.1 ± 7.8 Use of walking device (%): 38% / 53% Use of ventilator support (%): 33% / 37% SF-36 Physical Component (mean ± SD): 34.33 ± 8.93 / 34.91 ± 7.26 6MWT (meters, mean ± SD): 332.2 ± 126.7 / 317.9 ± 132.3 FVC (% predicted, mean ± SD): 55.4 ± 14.4 / 53.0 ± 15.7

Alglucosidase alpha / placebo 6MWT (meters, mean change): 25.13 / -2.99, difference: 28.12 (95%CI: 2.07 to 54.17) FVC (%predicted, mean change): 1.20 / -2.20, difference: 3.40 (95%CI: 1.03 to 5.77) QMT leg (% predicted, mean change): 1.18 / -2.00, difference: 3.18 (95%CI: 0.73 to 7.08) QMT arm (% predicted, mean change): 5.05 / 1.47, difference: 3.57 (95%CI: -1.83 to 8.97) maximum inspiratory pressure (% predicted, mean change): 3.48 / -0.35, difference: 3.83 (95%CI: -0.60 to 8.26) maximum expiratory pressure (% predicted, mean change): 3.24 / -0.56, difference: 3.80 (95%CI: 0.27 to 7.33) SF-36 Physical Component (mean change): 0.80 / 1.16, difference: 0.37 (95%CI: -3.83 to 3.09) Between-group frequencies of adverse events, serious adverse events, treatment-related adverse events, and infusion-related reactions were similar. Most reactions were mild-to-moderate severity and none required patient withdrawal from study.

The authors concluded that treatment with alglucosidase alpha was associated with improved walking distance, and stabilization of pulmonary function, with possible impacts on proximal limb stability and respiratory muscle strength, over an 18-month period.

Muenzer14

(2006)

idursulfase weekly / idursulfase EOW / placebo

Composite primary outcome score:

Authors concluded that compared with placebo,




Sample size: 32 / 32 / 32 Age (years, mean ± SD): 13.1 ± 1.22 / 14.4 ± 1.2 / 15.1 ± 1.11 Age at diagnosis (months, mean ± SD): 57.1 ± 9.4 / 52.3 ± 6.9 / 62.1 ± 9.1 6MWT (meters, mean ± SD): 392 ± 19 / 401 ± 18 / 392 ± 19 FVC (% predicted, mean ± SD): 55.6 ± 2.2 / 55.1 ± 2.5 / 55.3 ± 2.8 FVC (absolute, litres, mean ± SD): 1.09 ± 0.09 / 1.17 ± 0.10 / 1.19 ± 0.10 Urine GAG (μg/mg creatinine, mean ± SD): 419 ± 34 / 338 ± 21 / 326 ± 26 Liver volume (mL, mean ± SD): 1198 ± 48 / 1191 ± 48 / 1262 ± 50 Spleen volume (mL, mean ± SD): 288 ± 30 / 251 ± 26 / 316 ± 39

idursulfase weekly versus placebo, difference: 18.96 ± 6.47, P = 0.0049 idursulfase EOW versus placebo, difference: 12.86 ± 6.17, P = 0.0416 idursulfase weekly versus idursulfase EOW, difference: 10.84 ± 7.11, P = 0.1329 Secondary outcomes, change from baseline (placebo / idursulfase EOW / idursulfase weekly): 6MWT (meters, mean ± SD): 7.3 ± 9.5 / 30.3 ± 10.3 / 44 ± 12.3* FVC (% predicted, mean ± SD): 0.75 ± 1.71 / 0.004 ± 1.32 / 3.45 ± 0.0650 Liver volume (mL, mean ± SD): -0.8 ± 1.6 / -24 ± 1.7* / -25.1 ± 2.4* Spleen volume (mL, mean ± SD): 7.2 ± 4.2 / -19.8 ± 3.2* / -25.1 ± 2.4* Urine GAG (% change, mean ± SD): 21.4 ± 11.6 / -44.7 ± 4.0* / -52.5 ± 5.3* *statistically significant versus placebo Passive joint range of motion: an improvement in elbow mobility in the idursulfase weekly group was seen compared with placebo (P = 0.476). Data were not reported.

the use of weekly infusions of idursulfase in the treatment of MSP-II produced clinical benefit as demonstrated through improvements in a composite score, the 6MWT, and %FVC.




Treatment with idursulfase was well-tolerated. Of the adverse events considered to be related to the active treatment, the most common were infusion-related. The rate of serious adverse events was similar in the three groups (18 SAEs in 9 patients in the placebo group, 18 SAEs in 8 patients in the EOW group, and 13 SAEs in 9 patients in the weekly group).

Muenzer15

(2006b)

idursulfase (mg/kg): 0.15 / 0.50 / 1.50 Sample size: 4 / 4 / 4 Age (mean, range): 14 (6 to 20) Hepatomegaly: 75% of patients when normalized to body weight FVC (% predicted, range): 15% to 86%

idursulfase (mg/kg): 0.15 / 0.50 / 1.50 / pooled Urinary GAG excretion Baseline: 386 ± 124 / 364 ± 50 / 445 ± 101 / 398 ± 94 6 months: 230 ± 76 / 211 ± 110 / 168 ± 61 / 203 ± 82* 12 months: 203 ± 55 / 209 ± 98 / 178 ± 32* / 200 ± 18* *P < 0.0001 compared to baseline Liver and spleen size: after 6 and 12 months, liver volumes were significantly decreased in the pooled study population (P < 0.0001). Idursulfase-treated patients had decrease in spleen volume in double-blind phase of study, but no consistent dose-related changes in spleen volume seen. In the open-label part of the study, spleen volumes were significantly lower in the pooled study population after 6 months (P = 0.0043) and 12 months (P < 0.0001), and all treated patients had spleen volumes within normal limits.

The authors found idursulfase to be generally well-tolerated and associated with reductions in urine GAG excretion levels and organ size, as well as an increased 6-minute walk distance.




6MWT: Pooled analysis: average walking distance increased from 398±117 meters to 445±124 meters after 12 months (P = 0.013) Pulmonary function: lung function test values were highly variable and no significant differences were noted. Joint mobility: No consistent significant findings were noted. Sleep study results suggested some benefit with idursulfase in as subset of patients, and heart size and function tests were inconclusive. Safety: one year of treatment was well-tolerated, with most adverse events being consistent with those expected in MPS-II patients.

Kishani17

(2008)

Imiglucerase EOW / imiglucerase E4W Sample size: 33 / 62 Age at diagnosis (median [range]): 23.7(2 to 88) / 29.7(4 to 73) Gender (% male): 60.6% / 45.2% Age at first imiglucerase infusion (median [range]): 35.9 (10 to 74) / 41.9 (11 to 75) Years of imiglucerase prior to enrollment (median [range]): 5.9 (2 to 12) / 5.3 (2 to 13)

Imiglucerase EOW/imiglucerase E4W Primary composite endpoint: 80.8% / 63.2%, difference: 27.6% (95%CI: -17.6 to 35.7; P = 0.058) Therapeutic success goals-based composite endpoint: 100%/89%, difference 11% (noted as not statistically significant) SF-36 Health Survey: no significant differences between groups in the physical and mental components Majority of adverse events reported were judged by the principal investigator to be unrelated to imiglucerase therapy. Adverse events occurring at

Authors’ conclusions were that imiglucerase infusions E4W may be a safe and effective option for the majority of clinically stable patients with GD1 but may not be appropriate for all GD1 patients, and that comprehensive monitoring must be provided in all cases. They recommended continued monitoring in patients treated with E4W to assess long-term effectiveness.




Pre-enrollment imiglucerase dose (IU/kg/week, mean ± SD): 70.4 ± 24.9 / 69.7 ± 21.3 Hemoglobin (g/dL) (median [range]):14.1 (12 to 17) / 14.1 (12 to 17) Platelets (x10/mm

3) (median [range]):

182.0 (108 to 411) / 187.5 (101 to 428) Liver volume (MN) (median, [range]): 1.0 (0 to 1.5) / 1.0 (0 to 2.0) Spleen volume (MN) (median, [range]): 4.6 (2 to 51) / 3.2 (1 to 9) Intact spleen: 69.7% / 74.2% Bone crisis: 0/0 Medullary infarction (%): 45.5% / 37.1%

different frequencies between groups were largely associated with the progression of Gaucher disease.

De Fost16

(2007)

Imiglucerase E1-2W / E4W Sample size: 6 / 5 Age range (years) 34 to 75 Gender (% male): 55% Liver ratio (mL/kg body weight) range: 18 to 32 Dose of imiglucerase at randomization (IU/kg/E4W) range:15 to 50 Baseline characteristics were not summarized, but only individual values for each patient were provided.

No significant between-group difference in percent change in liver volume-to-body weight ratio at 12 months was found (102% in E1-2W group, and 98.1% in E4W group [baseline = 100%]). Patients with treatment failure: E1-2W:0 / E4W:2 Data on secondary outcomes were not clearly summarized by treatment group.

The authors concluded that ERT E4W in adult GD1 maintained stable disease in most but not all patients with stable and minimal disease, and that close monitoring of all disease parameters for early detection of disease and dosage frequency adjustment is mandatory.

6MWT: six minute walking test; CI: confidence interval; E1-2W: once every one-to-two weeks; E4W: every four weeks; EOW: every other week; FVC: forced vital capacity; GAA: acid α glucosidase; GAG: glycosaminoglycans; GD1: Gaucher disease type I; IU: international units; MN: multiples of normal; MSP-II: mucopolysaccharidosis type II; QMT: quantitative muscle testing; SD: standard deviation

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