Long-term safety and effectiveness of velaglucerase alfa in Gaucher disease: 6-year interim analysis of a post-marketing surveillance in Japan

Rieko Sagara, Masahide Ishigaki, Manami Otsuka, Kei Murayama, Hiroyuki Ida, Jovelle Fernandez, Rieko Sagara, Masahide Ishigaki, Manami Otsuka, Kei Murayama, Hiroyuki Ida, Jovelle Fernandez

Abstract

Background: Gaucher disease (GD) is caused by reduced lysosomal enzyme β-glucocerebrosidase activity. Heterogeneous genotypes and phenotypes have been observed within GD types and across ethnicities. Enzyme replacement therapy is generally recommended for patients with type 1 GD, the least severe form of GD. In Japan, velaglucerase alfa has a broad indication covering type 1, 2 or 3 GD. METHODS: All patients with type 1, 2, or 3 GD administered velaglucerase alfa 60 U/kg every 2 weeks via intravenous infusion after its launch date in Japan in 2014, were enrolled in a non-interventional, observational post-marketing surveillance (PMS). Individual patient data were reported via case report forms (CRFs). Key safety endpoints investigated included the incidence of infusion-related reactions (IRRs), the safety of velaglucerase alfa in patients with types 2 and 3 GD, from patients under one year of age to elderly patients (≥ 65 years of age). Long-term efficacy was also assessed. RESULTS: In total, 53 patients with GD were registered. CRFs were available for 41 (77.4%) patients at the 6-year interim analysis. Fourteen adverse drug reactions (ADRs) were reported in seven patients. All reported ADRs occurred in patients with type 2 GD. ADRs were reported by 63.6% (7/11) of patients with type 2 GD. Ten ADRs were reported in five patients aged < 4 years. No elderly patients experienced any ADR during the surveillance period. Five ADRs occurring in three (10.0%) patients were classified as IRRs, with one case of vomiting (moderate severity) resulting in treatment discontinuation. Ten serious adverse events were reported in five (16.7%) patients. Three fatal events were considered to be unrelated to treatment with velaglucerase alfa. Platelet counts increased after the administration of velaglucerase alfa and were generally maintained within the normal range over the administration period. Among eleven patients tested for neutralizing anti-velaglucerase alfa antibodies, two (18.2%) were assessed as positive results. CONCLUSION: PMS data from patients with types 1-3 GD in Japan indicate that long-term treatment with velaglucerase alfa was well-tolerated and associated with increased platelet counts, which is consistent with observations made in studies outside of Japan.

Trial registration: NCT03625882 registered July 2014.

Keywords: Enzyme replacement therapy; Gaucher disease; Glucosylceramidase; Japan; Post-marketing; Safety; Surveillance; Velaglucerase alfa.

Conflict of interest statement

RS, MI and MO are employees of Takeda Pharmaceutical Company Ltd. JF is an employee of, and owns stock in Takeda Pharmaceutical Company Limited and was formerly employed by, and owns restricted stock in, GlaxoSmithKline as well. KM has nothing to disclose. HI has received honoraria from Sanofi, Takeda Pharmaceutical Company Ltd and JCR Pharmaceuticals Company Ltd; consulting fees from Takeda Pharmaceutical Company Ltd and JCR Pharmaceuticals as well as grants or funds from Sanofi, and Dainippon Sumitomo Pharma Co Ltd.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Patient disposition. Demonstration of the patient progression through the study, from enrollment to allocation within a study group. The number of patients included within each stage are shown. Abbreviation: CRF, case report form
Fig. 2
Fig. 2
Platelet counts for Japanese patients with GD treated with velaglucerase alfa. Box and whisker chart showing the change in platelet count in the patients with GD following treatment with velaglucerase alfa over time. GD Gaucher disease

References

    1. Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, et al. A review of gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci. 2017;18(2):E441.
    1. Van Rossum A, Holsopple M. Enzyme replacement or substrate reduction? A review of gaucher disease treatment options. Hosp Pharm. 2016;51(7):553–563. doi: 10.1310/hpj5107-553.
    1. Mehta A, Kuter DJ, Salek SS, Belmatoug N, Bembi B, Bright J, et al. Presenting signs and patient co-variables in Gaucher disease: outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative. Intern Med J. 2019;49(5):578–591. doi: 10.1111/imj.14156.
    1. Roshan Lal T, Sidransky E. The spectrum of neurological manifestations associated with gaucher disease. Diseases. 2017;5(1):E10.
    1. 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–S18. doi: 10.1002/ajh.24063.
    1. Schwartz IVD, Göker-Alpan Ö, Kishnani PS, Zimran A, Renault L, Panahloo Z, et al. Characteristics of 26 patients with type 3 Gaucher disease: a descriptive analysis from the Gaucher Outcome Survey. Mol Genet Metab Rep. 2018;14:73–79. doi: 10.1016/j.ymgmr.2017.10.011.
    1. Filocamo M, Mazzotti R, Stroppiano M, Seri M, Giona F, Parenti G, et al. Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher patients. Hum Mutat. 2002;20(3):234–235. doi: 10.1002/humu.9058.
    1. Giraldo P, Alfonso P, Irún P, Gort L, Chabás A, Vilageliu L, et al. Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula. Orphanet J Rare Dis. 2012;7:17. doi: 10.1186/1750-1172-7-17.
    1. Feng Y, Huang Y, Tang C, Hu H, Zhao X, Sheng H, et al. Clinical and molecular characteristics of patients with Gaucher disease in Southern China. Blood Cells Mol Dis. 2018;68:30–34. doi: 10.1016/j.bcmd.2016.10.026.
    1. Ida H, Iwasawa K, Kawame H, Rennert OM, Maekawa K, Eto Y. Characteristics of gene mutations among 32 unrelated Japanese Gaucher disease patients: absence of the common Jewish 84GG and 1226G mutations. Hum Genet. 1995;95(6):717–720. doi: 10.1007/BF00209497.
    1. Ida H, Rennert OM, Kawame H, Maekawa K, Eto Y. Mutation prevalence among 47 unrelated Japanese patients with Gaucher disease: identification of four novel mutations. J Inherit Metab Dis. 1997;20(1):67–73. doi: 10.1023/A:1005313724361.
    1. Eto Y, Ida H. Clinical and molecular characteristics of Japanese Gaucher disease. Neurochem Res. 1999;24(2):207–211. doi: 10.1023/A:1022553819241.
    1. Jeong SY, Park SJ, Kim HJ. Clinical and genetic characteristics of Korean patients with Gaucher disease. Blood Cells Mol Dis. 2011;46(1):11–14. doi: 10.1016/j.bcmd.2010.07.010.
    1. Tajima A, Yokoi T, Ariga M, Ito T, Kaneshiro E, Eto Y, et al. Clinical and genetic study of Japanese patients with type 3 Gaucher disease. Mol Genet Metab. 2009;97(4):272–277. doi: 10.1016/j.ymgme.2009.05.001.
    1. Huang Y, Jia X, Tang C, Liu S, Sheng H, Zhao X, et al. High risk screening for Gaucher disease in patients with splenomegaly and/or thrombocytopenia in China: 55 cases identified. Clin Chim Acta. 2020;506:22–27. doi: 10.1016/j.cca.2020.03.016.
    1. Rosenbaum H. Hemorrhagic aspects of Gaucher disease. Rambam Maimonides Med J. 2014;5(4):e0039. doi: 10.5041/RMMJ.10173.
    1. Linari S, Castaman G. Clinical manifestations and management of Gaucher disease. Clin Cases Miner Bone Metab. 2015;12(2):157–164.
    1. Agency EM. Paediatric Gaucher disease. A strategic collaborative approach from EMA and FDA. 6 July 2017. Contract No.: EMA/237265/2017.
    1. Weiss K, Gonzalez A, Lopez G, Pedoeim L, Groden C, Sidransky E. The clinical management of Type 2 Gaucher disease. Mol Genet Metab. 2015;114(2):110–122. doi: 10.1016/j.ymgme.2014.11.008.
    1. Hughes DA, Gonzalez DE, Lukina EA, Mehta A, Kabra M, Elstein D, 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.
    1. Zimran A, Elstein D, Gonzalez DE, Lukina EA, Qin Y, Dinh Q, et al. Treatment-naive 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.
    1. Package insert of CEREZYME® intravenous drip infusion 400 units 2017. Available from .
    1. Package insert of VPRIV® intravenous drip infusion 400 units 2016. Available from .
    1. Brumshtein B, Salinas P, Peterson B, Chan V, Silman I, Sussman JL, et al. Characterization of gene-activated human acid-beta-glucosidase: crystal structure, glycan composition, and internalization into macrophages. Glycobiology. 2010;20(1):24–32. doi: 10.1093/glycob/cwp138.
    1. Tekoah Y, Tzaban S, Kizhner T, Hainrichson M, Gantman A, Golembo M, et al. Glycosylation and functionality of recombinant β-glucocerebrosidase from various production systems. Biosci Rep. 2013;33(5):E00071.
    1. Zimran A, Altarescu G, Philips M, Attias D, Jmoudiak M, Deeb M, 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.
    1. Zimran A, Wang N, Ogg C, Crombez E, Cohn GM, Elstein D. 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.
    1. Gonzalez DE, Turkia HB, Lukina EA, Kisinovsky I, Dridi MF, Elstein D, 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.
    1. Ben Turkia H, Gonzalez DE, Barton NW, Zimran A, Kabra M, Lukina EA, 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.
    1. Zimran A, Pastores GM, Tylki-Szymanska A, Hughes DA, Elstein D, Mardach R, 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.
    1. Pastores GM, Rosenbloom B, Weinreb N, Goker-Alpan O, Grabowski G, Cohn GM, et al. A multicenter open-label treatment protocol (HGT-GCB-058) of velaglucerase alfa enzyme replacement therapy in patients with Gaucher disease type 1: safety and tolerability. Genet Med. 2014;16(5):359–366. doi: 10.1038/gim.2013.154.
    1. Elstein D, Mehta A, Hughes DA, Giraldo P, Charrow J, Smith L, 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.
    1. Smith L, Rhead W, Charrow J, Shankar SP, Bavdekar A, Longo N, 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.
    1. Hosoba S, Kito K, Teramoto Y, Adachi K, Nakanishi R, Asai A, et al. A novel mutation causing type 1 Gaucher disease found in a Japanese patient with gastric cancer: a case report. Medicine (Baltimore). 2018;97(27):e11361. doi: 10.1097/MD.0000000000011361.
    1. Ida H, Tanaka A, Matsubayashi T, Murayama K, Hongo T, Lee HM, 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.
    1. Administration FaD. Highlights of Prescribing Information - VPRIVTM 2019. Available from .
    1. Agency EM. Assessment report for VPRIV. EMEA/H/C/001249 2010. Available from
    1. Ida H, Rennert OM, Ito T, Maekawa K, Eto Y. type 1 Gaucher disease: phenotypic expression and natural history in Japanese patients. Blood Cells Mol Dis. 1998;24(1):73–81. doi: 10.1006/bcmd.1998.0172.
    1. Vairo F, Netto C, Dorneles A, Mittelstadt S, Wilke M, Doneda D, et al. Enzyme replacement therapy in a patient with Gaucher Disease type III: a paradigmatic case showing severe adverse reactions started a long time after the beginning of treatment. JIMD Rep. 2013;11:1–6.
    1. Pastores GM, Turkia HB, Gonzalez DE, Ida H, Tantawy AA, Qin Y, et al. Development of anti-velaglucerase alfa antibodies in clinical trial-treated patients with Gaucher disease. Blood Cells Mol Dis. 2016;59:37–43. doi: 10.1016/j.bcmd.2016.03.004.
    1. Kumano S. GPSP: good post-marketing study practice. Nihon Yakurigaku Zasshi. 2012;140(2):81–84. doi: 10.1254/fpj.140.81.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera