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Open Access 01-12-2023 | Gaucher Disease | Research

Real life data: follow-up assessment on Spanish Gaucher disease patients treated with eliglustat. TRAZELGA project

Authors: Irene Serrano-Gonzalo, Laura López de Frutos, Carlos Lahoz-Gil, Francisco Delgado-Mateos, María Ángeles Fernández-Galán, Montserrat Morales-Conejo, María Victoria Calle-Gordo, Daiana Ibarretxe-Gerediaga, Andrés Madinaveitia-Ochoa, Antonio Albarracin-Arraigosa, José Balanzat-Muñoz, Patricia Correcher-Medina, Luis Javier García-Frade, Jesús María Hernández-Rivas, Francesca Labbadia, Jesus Miguel López-Dupla, María Luisa Lozano-Almela, Elvira Mora-Casterá, María Soledad Noya-Pereira, María Ángeles Ruíz-Guinaldo, María del Mar Tormo-Díaz, Isidro Vitoria-Miñana, Isidro Arévalo-Vargas, Marcio Andrade-Campos, Pilar Giraldo

Published in: Orphanet Journal of Rare Diseases | Issue 1/2023

Abstract

Background

The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to choose the best personalized therapy for their patients.

Aims

To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice.

Methods

We designed a real-life study with 2 years of follow-up (TRAZELGA [GEE-ELI-2017-01]) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant.

Main Results

Thirty patients were enrolled in the study. The median age was 41.5 years and the male–female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy.

Conclusion

In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.

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Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, Levade T, Astudillo L, Serratrice J, Brassier A, Rose C, de Villemeur TB, Berger MG. A review of gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci. 2017;18(2):441. https://doi.org/10.3390/ijms18020441.CrossRefPubMedPubMedCentral

Grabowski GA, Zimran A, Ida H. Gaucher disease types 1 and 3: phenotypic characterization of large populations from the ICGG Gaucher registry. Am J Hematol. 2015;90(Suppl 1):S12–8. https://doi.org/10.1002/ajh.24063.CrossRefPubMed

Nalysnyk L, Rotella P, Simeone JC, Hamed A, Weinreb N. Gaucher disease epidemiology and natural history: a comprehensive review of the literature. Hematology. 2017;22:65–73. https://doi.org/10.1080/10245332.2016.1240391.CrossRefPubMed

Baris HN, Cohen IJ, Mistry PK. Gaucher disease: the metabolic defect, pathophysiology, phenotypes and natural history. Pediatr Endocrinol Rev. 2014;12(Suppl 1):72–81.PubMedPubMedCentral

Agencia Española del Medicamento y Productos Sanitarios “Cerezyme(®)”. Ficha Técnica o Resumen de Las Características Del Producto. Agencia Española del Medicamento y Productos Sanitarios; Madrid, Spain: 2012

Agencia Española del Medicamento y Productos Sanitarios .”Vpriv(®)”. Ficha Técnica o Resumen de Las Características Del Producto. Agencia Española del Medicamento y Productos Sanitarios; Madrid, Spain: 2020.

Agencia Europea del Medicamento .”Zavesca(®)”. Ficha Técnica o Resumen de Las Características Del Producto. Agencia Europea del Medicamento; Madrid, Spain: 2018.

Agencia Española del Medicamento y Productos Sanitarios.”Cerdelga(®)”. Ficha Técnica o Resumen de Las Características Del Producto. Agencia Española del Medicamento y Productos Sanitarios; Madrid, Spain: 2020.

Mehta A. Gaucher disease: unmet treatment needs. Acta Paediatr. 2008;97(457):83–7. https://doi.org/10.1111/j.1651-2227.2008.00653.x.CrossRefPubMed

10.

Hughes D, Mikosch P, Belmatoug N, Carubbi F, Cox T, Goker-Alpan O, Kindmark A, Mistry P, Poll L, Weinreb N, Deegan P. Gaucher disease in bone: from pathophysiology to practice. J Bone Miner Res. 2019;34(6):996–1013. https://doi.org/10.1002/jbmr.3734.CrossRefPubMed

11.

EMA. Eliglustat (Cerdelga®) summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/cerdelga-epar-product-information_en.pdf

12.

Mistry PK, Lukina E, Ben Turkia H, Amato D, Baris H, Dasouki M, Ghosn M, Mehta A, Packman S, Pastores G, Petakov M, Assouline S, Balwani M, Danda S, Hadjiev E, Ortega A, Shankar S, Solano MH, Ross L, Angell J, Peterschmitt MJ. Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial. JAMA. 2015;313:695–706. https://doi.org/10.1001/jama.2015.459.CrossRefPubMedPubMedCentral

13.

Pleat R, Cox TM, Burrow TA, Giraldo P, Goker-Alpan O, Rosenbloom BE, Croal LR, Underhill LH, Gaemers SJ, Peterschmitt MJ. Stability is maintained in adults with Gaucher disease type 1 switched from velaglucerasealfa to eliglustat or imiglucerase: a sub-analysis of the eliglustat ENCORE trial. Mol Genet Metab Rep. 2016;9:25–8. https://doi.org/10.1016/j.ymgmr.2016.08.009.CrossRefPubMedPubMedCentral

14.

Lukina E, Watman N, Dragosky M, Lau H, Avila Arreguin E, Rosenbaum H, Zimran A, Foster MC, Gaemers SJM, Peterschmitt MJ. Outcomes after 8 years of eliglustat therapy for Gaucherdisease type 1: final results from the Phase 2 trial. Am J Hematol. 2019;94(1):29–38. https://doi.org/10.1002/ajh.25300.CrossRefPubMed

15.

Cox TM, Drelichman G, Cravo R, Balwani M, Burrow TA, Martins AM, Lukina E, Rosenbloom B, Goker-Alpan O, Watman N, El-Beshlawy A, Kishnani PS, Pedroso ML, Gaemers SJM, Tayag R, Peterschmitt MJ. Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy. Blood. 2017. https://doi.org/10.1182/blood-2016-12-758409.CrossRefPubMedPubMedCentral

16.

Mistry PK, Balwani M, Charrow J, Kishnani P, Niederau C, Underhill LH, McClain MR. 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):1038–46. https://doi.org/10.1002/ajh.25875.CrossRefPubMedPubMedCentral

17.

Stulnig TM. Long-term eliglustat treatment of Gaucher patients over up to 10 years in Vienna. Wien KlinWochenschr. 2022;134(11–12):471–7. https://doi.org/10.1007/s00508-022-02021-2.CrossRef

18.

Kleytman N, Ruan J, Ruan A, Zhang B, Murugesan V, Lin H, Guo L, Klinger K, Mistry PK. Incremental biomarker and clinical outcomes after switch from enzyme therapy to eliglustat substrate reduction therapy in Gaucher disease. Mol Genet Metab Rep. 2021;28(29):100798. https://doi.org/10.1016/j.ymgmr.2021.100798.CrossRef

19.

Giraldo P, de Frutos LL, Cebolla JJ. Biomarker combination is necessary for the assessment of Gaucher disease? Ann Transl Med. 2018;6(suppl 1):S81. https://doi.org/10.21037/atm.2018.10.69.CrossRefPubMedPubMedCentral

20.

Guo Y, He W, Boer AM, Wevers RA, de Bruijn AM, Groener JE, Hollak CE, Aerts JM, Galjaard H, van Diggelen OP. Elevated plasma chitotriosidase activity in various lysosomal storage disorders. J Inherit Metab Dis. 1995;18(6):717–22. https://doi.org/10.1007/BF02436762.CrossRefPubMed

21.

Boot RG, Verhoek M, de Fost M, Hollak CE, Maas M, Bleijlevens B, van Breemen MJ, van Meurs M, Boven LA, Laman JD, Moran MT, Cox TM, Aerts JM. Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood. 2004;103(1):33–9. https://doi.org/10.1182/blood-2003-05-1612.CrossRefPubMed

22.

Dekker N, van Dussen L, Hollak CE, Overkleeft H, Scheij S, Ghauharali K, van Breemen MJ, Ferraz MJ, Groener JE, Maas M, Wijburg FA, Speijer D, Tylki-Szymanska A, Mistry PK, Boot RG, Aerts JM. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response. Blood. 2011;118:e118–27. https://doi.org/10.1182/blood-2011-05-352971.CrossRefPubMedPubMedCentral

23.

Jian J, Chen Y, Liberti R, Fu W, Hu W, Saunders-Pullman R, Pastores GM, Chen Y, Sun Y, Grabowski GA, Liu CJ. Chitinase-3-like Protein 1: a progranulin downstream molecule and potential biomarker for gaucher disease. EBioMedicine. 2018;28:251–60. https://doi.org/10.1016/j.ebiom.2018.01.022.CrossRefPubMedPubMedCentral

24.

Mistry PK, Liu J, Yang M, Nottoli T, McGrath J, Jain D, Zhang K, Keutzer J, Chuang WL, Mehal WZ, Zhao H, Lin A, Mane S, Liu X, Peng YZ, Li JH, Agrawal M, Zhu LL, Blair HC, Robinson LJ, Iqbal J, Sun L, Zaidi M. Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proc Natl AcadSci USA. 2010;107(45):19473–8. https://doi.org/10.1073/pnas.1003308107.CrossRef

25.

Afinogenova Y, Ruan J, Yang R, Kleytman N, Pastores G, Lischuk A, Mistry PK. Aberrant progranulin, YKL-40, cathepsin D and cathepsin S in Gaucher disease. Mol Genet Metab Sep-Oct. 2019;128(1–2):62–7. https://doi.org/10.1016/j.ymgme.2019.07.014.CrossRef

26.

Lefebvre T, Reihani N, Daher R, de Villemeur TB, Belmatoug N, Rose C, Colin-Aronovicz Y, Puy H, Le Van KC, Franco M, Karim Z. Involvement of hepcidin in iron metabolism dysregulation in Gaucher disease. Haematologica. 2018;103(4):587–96. https://doi.org/10.3324/haematol.2017.177816.CrossRefPubMedPubMedCentral

27.

Medrano-Engay B, Irún P, Gervas-Arruga J, Andrade-Campos M, Andreu V, Alfonso P, Pocovi M, Giraldo P. Iron homeostasis and infIammatory biomarker analysis in patients with type 1 Gaucher disease. Blood Cells Mol Dis. 2014;53(4):171–5. https://doi.org/10.1016/j.bcmd.2014.07.007.CrossRefPubMed

28.

Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ 3rd, Khaltaev N. A reference standard for the description of osteoporosis. Bone. 2008;42(3):467–75. https://doi.org/10.1016/j.bone.2007.11.001.CrossRefPubMed

29.

Roca M, Mota J, Alfonso P, Pocoví M, Giraldo P. S-MRI score: A simple method for assessing bone marrow involvement in Gaucher disease. Eur J Radiol. 2007;62:132–7. https://doi.org/10.1016/j.ejrad.2006.11.024.CrossRefPubMed

30.

de Frutos LL, Alfonso P, Lahoz C, Irún P, Giraldo P. Allelic and phenotypic characterization of CYP2D6 and its encoded P450 cytochrome enzyme in a serie of Spanish type 1 Gaucher disease patients. Med Clin (Barc). 2020;155(12):529–34. https://doi.org/10.1016/j.medcli.2020.01.032.CrossRef

31.

Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. ClinPharmacolTher. 2008;83:234–42. https://doi.org/10.1038/sj.clpt.6100406.CrossRef

32.

Alonso J, Prieto L, Antó JM. The Spanish version of the SF-36 Health Survey (the SF-36 health questionnaire): an instrument for measuring clinical results. Med Clin. 1995;104(20):771–6.

33.

Hollak CE, van Weely S, van Oers MH, Aerts JM. Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest. 1994;93:1288–92. https://doi.org/10.1172/JCI117084.CrossRefPubMedPubMedCentral

34.

Irún P, Cebolla JJ, de Frutos LL, De Castro-Orós I, Roca-Espiau M, Giraldo P. LC-MS/MS analysis of plasma glucosylsphingosine as a biomarker for diagnosis and follow-up monitoring in Gaucher disease in the Spanish population. Clin Chem Lab Med. 2020;58(5):798–809. https://doi.org/10.1515/cclm-2019-0949.CrossRefPubMed

35.

Andrade-Campos M, Alfonso P, Irun P, Armstrong J, Calvo C, Dalmau J, Domingo MR, Barbera JL, Cano H, Fernandez-Galán MA, Franco R, Gracia I, Gracia-Antequera M, Ibañez A, Lendinez F, Madruga M, Martin-Hernández E, O’Callaghan MDM, Del Soto AP, Del Prado YR, Sancho-Val I, Sanjurjo P, Pocovi M, Giraldo P. Diagnosis features of pediatric Gaucher disease patients in the era of enzymatic therapy, a national-base study from the Spanish Registry of Gaucher Disease. Orphanet J Rare Dis. 2017;12(1):84. https://doi.org/10.1186/s13023-017-0627-z.CrossRefPubMedPubMedCentral

36.

Giraldo P, Andrade-Campos M, Morales M, SEGA (SEguimiento del paciente de GAucher, Gaucher patient follow‐up) Group. Recommendations on the follow-up of patients with Gaucher disease in Spain: results from a Delphi survey. JIMD Rep. 2022;64(1):90–103. https://doi.org/10.1002/jmd2.12342.CrossRefPubMedPubMedCentral

37.

Istaiti M, Becker-Cohen M, Dinur T, Revel-Vilk S, Zimran A. Real-life experience with oral eliglustat in patients with gaucher disease previously treated with enzyme replacement therapy. J Clin Med. 2022;11(21):6265. https://doi.org/10.3390/jcm11216265.CrossRefPubMedPubMedCentral

38.

Elstein D, Belmatoug N, Deegan P, Göker-Alpan Ö, Hughes DA, Schwartz IVD, Weinreb N, Bonner N, Panter C, Fountain D, Lenny A, Longworth L, Miller R, Shah K, Schenk J, Sen R, Zimran A. Development and validation of Gaucher disease type 1 (GD1)-specific patient-reported outcome measures (PROMs) for clinical monitoring and for clinical trials. Orphanet J Rare Dis. 2022;17(1):9. https://doi.org/10.1186/s13023-021-02163-y.CrossRefPubMedPubMedCentral

39.

Elstein D, Mellgard B, Dinh Q, Lan L, Qiu Y, Cozma C, Eichler S, Böttcher T, Zimran A. Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naïve and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: data from phase 3 clinical trials. Mol Genet Metab. 2017;122(1–2):113–20. https://doi.org/10.1016/j.ymgme.2017.08.005.CrossRefPubMed

40.

Mylin AK, Abildgaard N, Johansen JS, Nordic Myeloma Study Group. Serum YKL-40: a new independent prognostic marker for skeletal complications in patients with multiple myeloma. Leuk Lymphoma. 2015;56(9):2650–9. https://doi.org/10.3109/10428194.2015.1004168.CrossRefPubMed

41.

Ringsholt M, Høgdall EV, Johansen JS, Price PA, Christensen LH. YKL-40 protein expression in normal adult human tissues–an immunohistochemical study. J Mol Histol. 2007;38(1):33–43. https://doi.org/10.1007/s10735-006-9075-0.CrossRefPubMed

42.

Labbus K, Henning M, Borkham-Kamphorst E, Geisler C, Berger T, Mak TW, Knüchel R, Meyer HE, Weiskirchen R, Henkel C. Proteomic profiling in Lipocalin 2 deficient mice under normal and inflammatory conditions. J Proteomics. 2013;14(78):188–96. https://doi.org/10.1016/j.jprot.2012.11.021.CrossRef

43.

Borkham-Kamphorst E, Drews F, Weiskirchen R. Induction of lipocalin-2 expression in acute and chronic experimental liver injury moderated by pro-inflammatory cytokines interleukin-1beta through nuclear factor-kappaB activation. Liver Int. 2011;31:656–65. https://doi.org/10.1111/j.1478-3231.2011.02495.x.CrossRefPubMed

44.

Gervas-Arruga J, Cebolla JJ, de Blas I, Roca M, Pocovi M, Giraldo P. The influence of genetic variability and proinflammatory status on the development of bone disease in patients with Gaucher disease. PLoS ONE. 2015;10(5):e0126153. https://doi.org/10.1371/journal.pone.0126153.CrossRefPubMedPubMedCentral

Title: Real life data: follow-up assessment on Spanish Gaucher disease patients treated with eliglustat. TRAZELGA project
Authors: Irene Serrano-Gonzalo
Laura López de Frutos
Carlos Lahoz-Gil
Francisco Delgado-Mateos
María Ángeles Fernández-Galán
Montserrat Morales-Conejo
María Victoria Calle-Gordo
Daiana Ibarretxe-Gerediaga
Andrés Madinaveitia-Ochoa
Antonio Albarracin-Arraigosa
José Balanzat-Muñoz
Patricia Correcher-Medina
Luis Javier García-Frade
Jesús María Hernández-Rivas
Francesca Labbadia
Jesus Miguel López-Dupla
María Luisa Lozano-Almela
Elvira Mora-Casterá
María Soledad Noya-Pereira
María Ángeles Ruíz-Guinaldo
María del Mar Tormo-Díaz
Isidro Vitoria-Miñana
Isidro Arévalo-Vargas
Marcio Andrade-Campos
Pilar Giraldo
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Gaucher Disease
Gaucher Disease
Gaucher Disease
Biomarkers
Published in: Orphanet Journal of Rare Diseases / Issue 1/2023
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-023-02939-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Real life data: follow-up assessment on Spanish Gaucher disease patients treated with eliglustat. TRAZELGA project

Abstract

Background

Aims

Methods

Main Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Aims

Methods

Main Results

Conclusion

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