Gaucher disease (GD) is a rare disorder linked to the absence/deficiency of glucocerebrosidase. GD can be treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The aim of this systematic review (SR) is to assess the effectiveness of drugs used for GD treatment.
Data Sources:
Searches were conducted in PubMed and Scopus, in April 2021. The search strategies encompassed the name of the disease and of the drug treatments. Manual search was also conducted.
Study Selection and Data Extraction:
Observational and interventional longitudinal studies evaluating ERT and SRT for GD were included. Single mean meta-analyses were conducted for each drug using R.
Data Synthesis:
The initial search retrieved 2246 articles after duplicates were removed. Following screening and eligibility assessment, 68 reports were included. The studies evaluated imiglucerase, velaglucerase alfa, taliglucerase alfa, miglustat, and eliglustat. The results showed that ERT is effective as a treatment in both naïve and experienced patients. Miglustat did not significantly improve blood outcomes in naïve patients and resulted in a decrease in the platelet levels of experienced patients. Eliglustat was mainly assessed for experienced patients and resulted in stable outcome values.
Relevance to Patient Care and Clinical Practice:
This extensive SR confirms the effectiveness of GD treatments in short- and long-term follow-ups.
Conclusions:
The results were favorable for all ERTs and for eliglustat. Based on the assessed evidence, miglustat did not achieved expressive results. However, all evidence should be interpreted considering its limitations and does not replace well-conducted randomized trials.
NalysnykLRotellaPSimeoneJCHamedAWeinrebN. Gaucher disease epidemiology and natural history: a comprehensive review of the literature. Hematology. 2016;22(2):65-73. doi:10.1080/10245332.2016.1240391.
BarisHNCohenIJMistryPK. Gaucher disease: the metabolic defect, pathophysiology, phenotypes and natural history. Pediatr Endocrinol Rev. 2014;12(suppl 1):72-81.
4.
GrabowskiGAAndriaGBaldellouA, et al. Pediatric non-neuronopathic Gaucher disease: presentation, diagnosis and assessment. Eur J Pediatr. 2004;163(2):58-66. doi:10.1007/S00431-003-1362-0.
5.
PastoresGMWeinrebNJAertsH, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004;41:4-14. doi:10.1016/j.seminhematol.2004.07.009.
6.
StirnemannJÔBelmatougNCamouF, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci. 2017;18(2):1-30. doi:10.3390/ijms18020441.
7.
ZimranAElsteinD. Gaucher disease and the clinical experience with substrate reduction therapy. Philos Trans R Soc Lond B Biol Sci. 2003;358(1433):961-966. doi:10.1098/RSTB.2003.1272.
8.
BennettLLTurcotteK. Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease. Drug Des Devel Ther. 2015;9:4639-4647. doi:10.2147/DDDT.S77760.
9.
ConnockMBurlsAFrewE, et al. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review. Health Technol Assess. 2006;10(24):iii-ivix. doi:10.3310/hta10240.
10.
PiranSAmatoD. Gaucher disease: a systematic review and meta-analysis of bone complications and their response to treatment. J Inherit Metab Dis. 2010;33(3):271-279. doi:10.1007/s10545-010-9071-0.
11.
DonedaDNettoCBMoulinCCSchwartzIVD. Effects of imiglucerase on the growth and metabolism of Gaucher disease type I patients: a systematic review. Nutr Metab. 2013;10:34. doi:10.1186/1743-7075-10-34.
12.
NabizadehAAmaniBKadivarM, et al. The clinical efficacy of imiglucerase versus eliglustat in patients with Gaucher’s disease type 1: a systematic review. J Res Pharm Pract. 2018;7(4):171-177. doi:10.4103/jrpp.JRPP_18_24.
13.
ShemeshEDeromaLBembiB, et al. Enzyme replacement and substrate reduction therapy for Gaucher disease. Cochrane Database Syst Rev. 2015;27(3):CD010324. doi:10.1002/14651858.CD010324.
14.
HigginsJPTThomasJChandlerJ, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Published Online 2022. www.training.cochrane.org/handbook.
15.
BorensteinMHedgesLVHigginsJPRH. Introduction to Meta-analysis. Hoboken, NJ: John Wiley & Sons; 2009.
16.
Al-TaiMAl-AsadyDHamidR. Response to enzyme replacement therapy in patients with Gaucher disease type I. Ann Trop Med Public Heal. 2019;22(S6): 103-117. doi:10.36295/ASRO.2019.220613.
17.
Arikan-AyyildizZYüceAEmreSBaysoyGSaltik-TemizelINGürakanF. Outcome of enzyme replacement therapy in Turkish patients with Gaucher disease: does late intervention affect the response. Turk J Pediatr. 2011;53(5):499-507.
18.
Cerón-RodríguezMBarajas-ColónERamírez-DevarsLGutiérrez-CamachoCSalgado-LozaJL. Improvement of life quality measured by Lansky Score after enzymatic replacement therapy in children with Gaucher disease type 1. Mol Genet Genomic Med. 2018;6(1):27-34. doi:10.1002/mgg3.339.
19.
ChoiJHLeeBHKoJM, et al. A phase 2 multi-center, open-label, switch-over trial to evaluate the safety and efficacy of Abcertin® in patients with type 1 Gaucher disease. J Korean Med Sci. 2015;30(4):378-384. doi:10.3346/jkms.2015.30.4.378.
20.
CoxTMDrelichmanGCravoR, et al. Eliglustat compared with imiglucerase in patients with Gaucher’s disease type 1 stabilised on enzyme replacement therapy: a phase 3, random-ised, open-label, non-inferiority trial. Lancet. 2015;385(9985):2355-2362. doi:10.1016/S0140-6736(14)61841-9.
21.
ElsteinDDweckAAttiasD, et al. Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement. Blood. 2007;110(7):2296-2301. doi:10.1182/blood-2007-02-075960.
22.
ElsteinDAbrahamovAHadas-HalpernIMeyerAZimranA. Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease. QJM. 1998;91(7):483-488. doi:10.1093/qjmed/91.7.483.
23.
FostMAertsJMGroenerJE, et al. Low frequency maintenance therapy with imiglucerase in adult type I Gaucher disease: a prospective randomized controlled trial. Haematologica. 2007;92(2):215-221. doi:10.3324/haematol.10635.
24.
GrabowskiGABartonNWPastoresG, et al. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med. 1995;122(1):33-39. doi:10.7326/0003-4819-122-1-199501010-00005.
25.
KrugBCSchwartzIVLopes De OliveiraF, et al. The management of Gaucher disease in developing countries: a successful experience in Southern Brazil. Pub Heal Genom. 2009;13(1):27-33. doi:10.1159/000217793.
26.
IbrahimJUnderhillLHTaylorJSAngellJPeterschmittMJ. Clinical response to eliglustat in treatment-naïve patients with Gaucher disease type 1: post-hoc comparison to imiglucerase-treated patients enrolled in the International Collaborative Gaucher Group Gaucher Registry. Mol Genet Metab Rep. 2016;8:17-19. doi:10.1016/j.ymgmr.2016.06.003.
27.
LeeNCChienYHWongSL, et al. Outcome of early-treated type III Gaucher disease patients. Blood Cells Mol Dis. 2014;53(3):105-109. doi:10.1016/j.bcmd.2014.05.007.
28.
LeeBHAbdallaAFChoiJH, et al. A multicenter, open-label, phase III study of Abcertin in Gaucher disease. Med (United States). 2017;96(45):1-7. doi:10.1097/MD.0000000000008492.
29.
MitrovicMAnticDElezovicI, et al. Haemostatic abnormalities in treatment-nave patients with Type 1 Gaucher’s disease. Platelets. 2012;23(2):143-149. doi:10.3109/09537104.2011.597526.
30.
MitrovicMSumaracZAnticD, et al. Markers of coagulation activation and enhanced fibrinolysis in Gaucher type 1 patient: effects of enzyme replacement therapy. Blood Cells Mol Dis. 2012;49(1):58-59. doi:10.1016/j.bcmd.2012.03.003.
31.
NagralAMewawallaPJagadeeshS, et al. Recombinant macrophage targeted enzyme replacement therapy for Gaucher disease in India. Indian Pediatr. 2011;48(10):779-784. doi:10.1007/s13312-011-0128-4.
32.
PleatRCoxTMBurrowTA, et al. Stability is maintained in adults with Gaucher disease type 1 switched from velaglucerase alfa to eliglustat or imiglucerase: a sub-analysis of the eliglustat ENCORE trial. Mol Genet Metab Rep. 2016;9:25-28. doi:10.1016/j.ymgmr.2016.08.009.
33.
SánchezKLNodarseRFModroñaPLOteroAGNúñezAA. Experiencia cubana en la terapia de reemplazo enzimático en la Enfermedad de Gaucher Cuban experience in enzymatic replacement therapy in Gaucher disease. Rev Cuba Hematol, Inmulog y Hemoter. 2015;31(2):187-194.
34.
SchiffmannRFitzgibbonEJHarrisC, et al. Randomized, controlled trial of miglustat in Gaucher’s disease type 3. Ann Neurol. 2008;64(5):514-522. doi:10.1002/ana.21491.
35.
ShehiBBoçariGVyshkaGXhepaRAlushaniD. Gaucher’s disease in Albanian children: casuistics and treatment. Iran J Pediatr. 2011;21(1):1-7.
36.
Grigorescu SidoPDruganCCretV, et al. Outcome of enzyme replacement therapy in patients with Gaucher disease type I. J Inherit Metab Dis. 2007;30(5):783-789. doi:10.1007/s10545-007-0621-z.
37.
Grigorescu-SidoPDruganCAlkhzouzC, et al. Baseline characteristics and outcome in Romanian patients with Gaucher disease type 1. Eur J Intern Med. 2010;21(2):104-113. doi:10.1016/j.ejim.2009.11.005.
38.
SimsKBPastoresGMWeinrebNJ, 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;73(5):430-440. doi:10.1111/j.1399-0004.2008.00978.x.
39.
ThejealRFKadhumAJ. Gaucher disease in Iraqi children (Clinical, diagnostic & therapeutic aspects). Pakistan J Med Sci. 2016;32(2):319-323. doi:10.12669/pjms.322.9316.
40.
TukanIHadas-HalpernIAltarescuGAbrahamovAElsteinDZimranA. Achievement of therapeutic goals with low-dose imiglucerase in Gaucher disease: a single-center experience. Adv Hematol. 2013;2013:151506. doi:10.1155/2013/151506.
41.
TurkiaHBGonzalezDEBartonNW, et al. Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease. Am J Hematol. 2013;88(3):179-184. doi:10.1002/ajh.23382.
42.
ZahranAMElsayhKIEl-DeekSEEl-BazMA. Oxidative stress, trace elements, and circulating microparticles in patients with Gaucher disease before and after enzyme replacement therapy. Clin Appl Thromb Hemost. 2015;21(1):58-65. doi:10.1177/1076029613489595.
43.
ZimmermannAGrigorescu-SidoPRossmannH, et al. A prospective study of insulin resistance in Gaucher disease type 1 patients with normal weight, under enzyme replacement therapy. Acta Endocrinol (Copenh). 2015;11(2):180-188. doi:10.4183/aeb.2015.180.
44.
ZimranAElsteinDLevy-LahadE, et al. Replacement therapy with imiglucerase for type 1 Gaucher’s disease. Lancet. 1995;345(8963):1479-1480. doi:10.1016/S0140-6736(95)91038-7.
45.
ElsteinDAltarescuGMaayanH, et al. Booster-effect with velaglucerase alfa in patients with Gaucher disease switched from long-term imiglucerase therapy: early access program results from Jerusalem. Blood Cells Mol Dis. 2012;48(1):45-50. doi:10.1016/j.bcmd.2011.09.009.
46.
ElsteinDMehtaAHughesDA, et al. Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 Gaucher disease. Am J Hematol. 2015;90(7):592-597. doi:10.1002/ajh.24007.
47.
GonzalezDETurkiaHBLukinaEA, et al. Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: results from a randomized, double-blind, multinational, Phase 3 study. Am J Hematol. 2013;88(3):166-171. doi:10.1002/ajh.23381.
48.
HughesDAGonzalezDELukinaEA, et al. Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: long-term data from phase III clinical trials. Am J Hematol. 2015;90(7):584-591. doi:10.1002/ajh.24012.
49.
IdaHTanakaAMatsubayashiT, et al. A multicenter, open-label extension study of velaglucerase alfa in Japanese patients with Gaucher disease: results after a cumulative treatment period of 24 months. Blood Cells, Mol Dis. 2016;59:140-147. doi:10.1016/j.bcmd.2015.10.002.
50.
SerratriceCBengherbiaMAlessandriniM, et al. Effects of switching from imiglucerase to velaglucerase alfa without dose reduction nor wash out in type 1 Gaucher disease. Blood Cells Mol Dis. 2014;53(1-2):94-96. doi:10.1016/j.bcmd.2013.12.004.
51.
SmithLRheadWCharrowJ, et al. Long-term velaglucerase alfa treatment in children with Gaucher disease type 1 naïve to enzyme replacement therapy or previously treated with imiglucerase. Mol Genet Metab. 2016;117(2):164-171. doi:10.1016/j.ymgme.2015.05.012.
52.
Van DussenLCoxTMHendriksEJ, et al. Effects of switching from a reduced imiglucerase to velaglucerase in type 1 Gaucher disease: clinical and biochemical outcomes. Haematologica. 2012;97(12):1850-1854. doi:10.3324/haematol.2011.059071.
53.
ZimranAAltarescuGPhilipsM, et al. Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-Month experience. Blood. 2010;115(23):4651-4656. doi:10.1182/blood-2010-02-268649.
54.
ZimranAPastoresGMTylki-SzymanskaA, et al. Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase. Am J Hematol. 2013;88(3):172-178. doi:10.1002/ajh.23383.
55.
ZimranAWangNOggCCrombezECohnGMElsteinD. Seven-year safety and efficacy with velaglucerase alfa for treatment-naïve adult patients with type 1 Gaucher disease. Am J Hematol. 2015;90(7):577-583. doi:10.1002/ajh.24040.
56.
ZimranAElsteinDGonzalezDE, et al. Treatment-naïve Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4 years in phase 3 trials. Blood Cells Mol Dis. 2018;68:153-159. doi:10.1016/j.bcmd.2016.10.007.
57.
ZimranARevel-VilkSBecker-CohenM, et al. Rapid intravenous infusion of velaglucerase-alfa in adults with type 1 Gaucher disease. Am J Hematol. 2018;93(9):E246-E248. doi:10.1002/ajh.25205.
58.
KuterDJWajnrajchMHernandezBWangRChertkoffRZimranA. Open-label, expanded access study of taliglucerase alfa in patients with Gaucher disease requiring enzyme replacement therapy. Blood Cells Mol Dis. 2020;82:102418. doi:10.1016/j.bcmd.2020.102418.
59.
PastoresGMPetakovMGiraldoP, et al. A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase. Blood Cells Mol Dis. 2014;53(4):253-260. doi:10.1016/j.bcmd.2014.05.004.
60.
PastoresGMShankarSPPetakovM, et al. Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase. Am J Hematol. 2016;91(7):661-665. doi:10.1002/ajh.24399.
61.
ZimranABrill-AlmonEChertkoffR, et al. Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood. 2011;118(22):5767-5773. doi:10.1182/blood-2012-01-408054.
62.
ZimranAGonzalez-RodriguezDEAbrahamovA, et al. Safety and efficacy of two dose levels of taliglucerase alfa in pediatric patients with Gaucher disease. Blood Cells Mol Dis. 2015;54(1):9-16. doi:10.1016/j.bcmd.2014.10.002.
63.
ZimranADuránGMehtaA, et al. Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease. Am J Hematol. 2016;91(7):656-660. doi:10.1002/ajh.24369.
64.
ZimranAGonzalez-RodriguezDEAbrahamovA, et al. Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase. Blood Cells Mol Dis. 2018;68:163-172. doi:10.1016/j.bcmd.2016.10.005.
65.
ZimranADuránGGiraldoP, et al. Long-term efficacy and safety results of taliglucerase alfa through 5 years in adult treatment-naïve patients with Gaucher disease. Blood Cells Mol Dis. 2019;78:14-21. doi:10.1016/j.bcmd.2016.07.002.
66.
CoxTLachmannRHollakC, et al. Novel oral treatment of Gaucher’s disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet. 2000;355(9214):1481-1485. doi:10.1016/S0140-6736(00)02161-9.
67.
CoxTMAmatoDHollakCE, et al. Evaluation of miglustat as maintenance therapy after enzyme therapy in adults with stable type 1 Gaucher disease: a prospective, open-label non-inferiority study. Orphanet J Rare Dis. 2012;7(1):102. doi:10.1186/1750-1172-7-102.
68.
ElsteinDHollakCAertsJM, et al. Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease. J Inherit Metab Dis. 2004;27(6):757-766. doi:10.1023/B:BOLI.0000045756.54006.17.
69.
GiraldoPLatrePAlfonsoP, et al. Short-term effect of miglustat in every day clinical use in treatment-naïve or previously treated patients with type 1 Gaucher’s disease. Haematologica. 2006;91(5):703-706.
70.
GiraldoPAlfonsoPAtutxaK, et al. Real-world clinical experience with long-term miglustat maintenance therapy in type 1 Gaucher disease: the ZAGAL project. Haematologica. 2009;94(12):1771-1775. doi:10.3324/haematol.2009.008078.
71.
HeitnerRElsteinDAertsJWeelySvZimranA. Low-dose N-butyldeoxynojirimycin (OGT 918) for type I Gaucher disease. Blood Cells Mol Dis. 2002;28(2):127-133. doi:10.1006/bcmd.2002.0497.
72.
MikoschPReedMBakerR, et al. Changes of bone metabolism in seven patients with Gaucher disease treated consecutively with imiglucerase and miglustat. Calcif Tissue Int. 2008;83(1):43-54. doi:10.1007/s00223-008-9143-4.
73.
PastoresGMBarnettNLKolodnyEH. An open-label, noncomparative study of miglustat in type I Gaucher disease: efficacy and tolerability over 24 months of treatment. Clin Ther. 2005;27(8):1215-1227. doi:10.1016/j.clinthera.2005.08.004.
74.
SmidBEFerrazMJVerhoekM, et al. Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients. Orphanet J Rare Dis. 2016;11(1):1-12. doi:10.1186/s13023-016-0413-3.
75.
CharrowJFragaCGuX, et al. Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: the Phase 3, randomized, double-blind EDGE trial. Mol Genet Metab. 2018;123(3):347-356. doi:10.1016/j.ymgme.2017.12.001.
76.
CoxTMDrelichmanGCravoR, et al. Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy. Blood. 2017;129(17):2375-2383. doi:10.1182/blood-2016-12-758409.
77.
LukinaEWatmanNArreguinEA, et al. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood. 2010;116(6):893-899. doi:10.1182/blood-2010-03-273151.
78.
LukinaEWatmanNArreguinEA. Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-Year results of a phase 2 study. Blood. 2010;116(20):4095-4098. doi:10.1182/blood-2011-04-347146.
79.
LukinaEWatmanNDragoskyM, et al. Eliglustat, an investigational oral therapy for Gaucher disease type 1: phase 2 trial results after 4 years of treatment. Blood Cells Mol Dis. 2014;53(4):274-276. doi:10.1016/j.bcmd.2014.04.002.
80.
LukinaEWatmanNDragoskyM, et al. Outcomes after 8 years of eliglustat therapy for Gaucher disease type 1: final results from the phase 2 trial. Am J Hematol. 2019;94(1):29-38. doi:10.1002/ajh.25300.
81.
MistryPKLukinaETurkiaH, et al. Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial. J Am Med Assoc. 2015;313(7):695-706. doi:10.1001/jama.2015.459.
82.
MistryPKLukinaEBen TurkiaH, et al. Outcomes after 18 months of eliglustat therapy in treatment-naïve adults with Gaucher disease type 1: the phase 3 ENGAGE trial. Am J Hematol. 2017;92(11):1170-1176. doi:10.1002/ajh.24877.
83.
MistryPKBalwaniMCharrowJ, et al. Real-world effectiveness of eliglustat in treatment-naïve and switch patients enrolled in the International Collaborative Gaucher Group Gaucher Registry. Am J Hematol. 2020;95(9):1038-1046. doi:10.1002/ajh.25875.
84.
BiegstraatenMCoxTMBelmatougN, et al. Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease. Blood Cells Mol Dis. 2018;68:203-208. doi:10.1016/j.bcmd.2016.10.008.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
