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JANUARY 7, 2014

Patients and physicians have contacted the National Gaucher Foundation regarding recent discussions and decisions by US insurance carriers and specifically United Health Care to establish a preferred status category for one of the three enzyme replacement therapies currently approved by FDA for treatment of patients with Gaucher disease. The position of the National Gaucher Foundation and its Medical Advisory Board is as follows:

Imiglucerase, velaglucerase alfa, and taliglucerase alfa are bio-similar products that are not bio-identical. They are all highly purified pharmacologic recombinant human glucocerebrosidase glycoproteins produced using different technologies and derived from different cell lines: Imiglucerase (Chinese hamster ovary cell line); Velaglucerase alfa (human fibroblasts derived from a fibrosarcoma cell line): Taliglucerase (carrot root cell line). Although the conformational crystal structures of all three appear to be similar, there are minor differences in primary amino acid structure and more significant differences in glycosylation.1,2 Globally since 1994, more than 5,000 phenotypically and genotypically diverse Gaucher disease patients have been treated with imiglucerase with an extensive observational record of efficacy and safety. Since 2010, other enzyme therapies for Gaucher disease, velaglucerase alpha and taliglucerase, were also approved by the FDA. Randomized and observational clinical trials comprising a few hundred treatment-naïve and "switch" patients suggest that, during the initial 1-3 years of treatment, velaglucerase alfa and taliglucerase are arguably safe and of comparable efficacy to imiglucerase for reversing disease manifestations such as anemia, thrombocytopenia, and hepatosplenomegaly, for reduction of biomarkers and, in the case of velaglucerase alfa, for maintaining therapeutic gains in patients previously treated with imiglucerase.3-14 Velaglucerase alfa and taliglucerase appear to reduce bone marrow Gaucher cell infiltration measured indirectly with quantitative chemical shift MRI imaging similarly to imiglucerase.8,15,16 Compared to imiglucerase, currently published clinical trial and post-marketing data for velaglucerase alfa and taliglucerase with respect to patient-centered outcomes, such as osteopenia, osteonecrosis, fractures, need for hospitalization for splenectomy, and health-related quality of life are rudimentary.17-23 Although taliglucerase is currently authorized for use only in adults, imiglucerase and velaglucerase alfa are approved for pediatric use. However, published data showing that ERT reverses Gaucher disease-associated growth and development retardation in pre-pubertal children are only available for imiglucerase.24,25 Finally, in stable patients during the "maintenance" phase of treatment, the safety and efficacy of infusion schedules less frequent than every two weeks is supported by clinical trial evidence only for imiglucerase.26

Before endorsing a position that imiglucerase, velaglucerase alfa, and taliglucerase are interchangeable or that one ERT should be granted preferential status over the others, we believe further study and clinical experience is warranted and advisable. Differences in antigenicity and seroconversion (apparently less likely with velaglucerase compared with imiglucerase and taliglucerase) to date appear to have little overall effect on safety and efficacy although some severe adverse reactions have been reported.6,7,9-13,27 The long term effect of antigenic variation, if any, is not known. Differences in safety profiles not directly related to the recombinant enzymes themselves but rather to some other aspect of the variant manufacturing process are also possible and may explain atypical late-onset severe adverse events that are beginning to appear in the literature.28 Because imiglucerase has had much longer "exposure time" than either velaglucerase or taliglucerase, the reports of late onset events are largely confined to that product. That pattern may not necessarily hold up in the future.

In vitro and animal studies of differential cellular uptake of the three ERTs have been inconsistent although most studies were not done using Gaucher monocytes or macrophages or in Gaucher animal models.1,2,29,30 In the D409V/null Gaucher mouse model, "significant differential molecular responses were observed in direct transcriptome (the set of all RNA molecules, including mRNA, rRNA, tRNA, and other non-coding RNA) comparisons from imiglucerase- and velaglucerase-treated tissues."31 Whether these cellular differences may ultimately relate to different long-term clinical outcomes including late onset complications of Gaucher disease such as cancers and Parkinson disease is also currently unknown.

We understand that the United Health Care decision to assign preferential status to a single ERT was heavily, if not entirely, based on important and legitimate financial considerations. We strongly endorse efforts to reduce personal and societal costs of health care, including therapies for rare, orphan diseases such as Gaucher disease. However, should each insurance company have a preferential and exclusive ERT, patients may have to switch treatments every time a new negotiation is concluded and every time they change from one health insurance company to another, possibly with a change in physician as well! Furthermore, should it turn out that a large number of insurance companies choose the same preferential product so that other manufacturers cut back on unneeded inventory, there would be an effective reversion to the single product era of 2009 when the Gaucher patient community was devastated by a supply interruption due to a major manufacturing malfunction.

For the past 29 years, the National Gaucher Foundation has represented thousands of individuals and families who are affected by Gaucher disease. Its Medical Advisory Board, comprised of experts in the diagnosis, management and treatment of Gaucher disease, collectively has more than 50,000 patient-years of clinical experience with this rare disease. We firmly believe that treatment for Gaucher disease should not only be evidence-driven but also personalized based on patient history and unique disease characteristics. Premature assignment of preferential placement of one ERT for Gaucher disease (as exemplified by the new United Healthcare policy) undermines the value of expert physician judgment, unnecessarily interferes with the physician-patient relationship and limits our ability to comprehensively understand the effect of treatment on long-term clinical outcomes. Historically, patients and families affected by Gaucher disease and other rare disorders were severely underserved. Remarkable progress has been achieved. This is not the time for policy changes that have the potential to reverse the gains of the past and limit the prospects for the future.


1. Brumshtein B, Salinas P, Peterson B, Chan V, Silman I, Sussman JL, Savickas PJ, Robinson GS, Futerman AH. Characterization of gene-activated human acid-beta-glucosidase: crystal structure, glycan composition, and internalization into macrophages. Glycobiology. 2010;20:24-32. doi: 10.1093/glycob/cwp138.

2. Tekoah Y, Tzaban S, Kizhner T, Hainrichson M, Gantman A, Golembo M, Aviezer D, Shaaltiel Y. Glycosylation and Functionality of Recombinant ß-Glucocerebrosidase from Various Production Systems. Biosci Rep 2013 Aug 28 [Epub ahead of print]; PMID 23980545.

3. Grabowski GA, Barton NW, Pastores G, Dambrosia JM, Banerjee TK, McKee MA, Parker C, Schiffmann R, Hill SC, Brady RO. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med 1995;122:33-39.

4. Weinreb NJ, Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, Rosenbloom BE, Scott CR, Wappner RS, Zimran A. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med. 2002;113:112-119.

5. Weinreb NJ, Goldblatt J, Villalobos J, Charrow J, Cole JA, Kerstenetzky M, Vom Dahl S, Hollak C. Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment. J Inherit Metab Dis. 2013:36:543-553.

6. Zimran A, Altarescu G, Philips M, Attias D, Jmoudiak M, Deeb M, Wang N, Bhirangi K, Cohn GM, Elstein D. Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience. Blood. 2010;115:4651-46566. doi: 10.1182/blood-2010-02-268649.

7. Burrow TA, Grabowski GA. Velaglucerase alfa in the treatment of Gaucher disease type 1. Clin Investig (Lond). 2011 Feb;1(2):285-293.

8. van Dussen L, Cox TM, Hendriks EJ, Morris E, Akkerman EM, Maas M, Groener JE, Aerts JM, Deegan PB, Hollak CE. Effects of switching from a reduced dose imiglucerase to velaglucerase in type 1 Gaucher disease: clinical and biochemical outcomes. Haematologica. 2012;97:1850-1854. doi: 10.3324/haematol.2011.059071.

9. Zimran A, Pastores GM, Tylki-Szymanska A, Hughes DA, Elstein D, Mardach R, Eng C, Smith L, Heisel-Kurth M, Charrow J, Harmatz P, Fernhoff P, Rhead W, Longo N, Giraldo P, Ruiz JA, Zahrieh D, Crombez E, Grabowski GA. Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase. Am J Hematol. 2013;88:172-178. doi: 10.1002/ajh.23383.

10. Gonzalez DE, Turkia HB, Lukina EA, Kisinovsky I, Dridi MF, Elstein D, Zahrieh D, Crombez E, Bhirangi K, Barton NW, Zimran A. Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized, double-blind, multinational, Phase 3 study. Am J Hematol. 2013;88:166-171. doi: 10.1002/ajh.23381.

11. Ben Turkia H, Gonzalez DE, Barton NW, Zimran A, Kabra M, Lukina EA, Giraldo P, Kisinovsky I, Bavdekar A, Ben Dridi MF, Gupta N, Kishnani PS, Sureshkumar EK, Wang N, Crombez E, Bhirangi K, Mehta A. Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease. Am J Hematol. 2013;88:179-184. doi: 10.1002/ajh.23382.

12. Pastores GM, Rosenbloom B, Weinreb N, Goker-Alpan O, Grabowski G, Cohn GM, Zahrieh D. 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. 2013. doi: 10.1038/gim.2013.154.

13. Zimran A, Brill-Almon E, Chertkoff R, Petakov M, Blanco-Favela F, Muñoz ET, Solorio-Meza SE, Amato D, Duran G, Giona F, Heitner R, Rosenbaum H, Giraldo P, Mehta A, Park G, Phillips M, Elstein D, Altarescu G, Szleifer M, Hashmueli S, Aviezer D. Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood. 2011;118:5767-5773. doi: 10.1182/blood-2011-07-366955.

14. Hollak CE. An evidence-based review of the potential benefits of taliglucerase alfa in the treatment of patients with Gaucher disease. Core Evid. 2012;7:15-20. doi: 10.2147/CE.S20201.

15. Maas M, van Kuijk C, Stoker J, Hollak CE, Akkerman EM, Aerts JF, den Heeten GJ. Quantification of bone involvement in Gaucher disease: MR imaging bone marrow burden score as an alternative to Dixon quantitative chemical shift MR imaging--initial experience. Radiology. 2003;229:554-561.

16. van Dussen L, Zimran A, Akkerman EM, Aerts JM, Petakov M, Elstein D, Rosenbaum H, Aviezer D, Brill-Almon E, Chertkoff R, Maas M, Hollak CE. Taliglucerase alfa leads to favorable bone marrow responses in patients with type I Gaucher disease. Blood Cells Mol Dis. 2013;50:206-211. doi: 10.1016/j.bcmd.2012.11.001.

17. Charrow J, Dulisse B, Grabowski GA, Weinreb NJ. The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1 Gaucher disease. Clin Genet 2007: 71: 205–211.

18. Sims KB, Pastores GM, Weinreb NJ, Barranger J, Rosenbloom BE, Packman S, Kaplan P, Mankin H, Xavier R, Angell J, Fitzpatrick MA, Rosenthal D. 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;73:430-440.

19. Mistry PK, Deegan P, Vellodi A, Cole JA, Yeh M, Weinreb NJ. Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis. Br J Haematol. 2009;147:561-570.

20. Mistry PK, Weinreb NJ, Kaplan P, Cole JA, Gwosdow AR, Hangartner T. Osteopenia in Gaucher disease develops early in life: Response to imiglucerase enzyme therapy in children, adoslescents and adults. Blood Cells Mol Dis 2011; 46:66-72.

21. Khan A, Hangartner T, Weinreb NJ, Taylor JS, Mistry PK. Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease - a study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry. J Bone Miner Res. 2012;27:1839-1848.

22. Elstein D, Foldes AJ, Zahrieh D, Cohn GM, Djordjevic M, Brutaru C, Zimran A. Significant and continuous improvement in bone mineral density among type 1 Gaucher disease patients treated with velaglucerase alfa: 69-month experience, including dose reduction. Blood Cells Mol Dis. 2011;47:56-61. doi: 10.1016/j.bcmd.2011.04.005.

23. Weinreb NJ, Barranger J, Packman S, Prakash-Cheng A, Rosenbloom B, Sims K, Angell J, Skrinar A, Pastores GM. Imiglucerase (Cerezyme) improves quality of life in patients with skeletal manifestations of Gaucher disease. Clin Genet 2007: 71: 576–588.

24. Kaplan P, Mazur A, Manor 0, Charrow J, Esplin J, Gribble TJ, Wappner RS, Wisch JS, Weinreb NJ: Acceleration of retarded growth in children with Gaucher disease after treatment with alglucerase. J Pediatrics 1996;129:149-153.

25. Andersson H, Kaplan P, Kacena K, Yee J. Eight-year clinical outcomes of long-term enzyme replacement therapy for 884 children with Gaucher disease type 1. Pediatrics. 2008;122:1182-1190. doi: 10.1542/peds.2007-2144.

26. Kishnani PS, DiRocco M, Kaplan P, Mehta A, Pastores GM, Smith SE, Puga AC, Lemay RM, Weinreb NJ. 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; 96:164-170.

27. Starzyk K, Richards S, Yee J, Smith SE, Kingma W. The long-term international safety experience of imiglucerase therapy for Gaucher disease. Mol Genet Metab. 2007;90:157-163.

28. Vairo F, Netto C, Dorneles A, Mittelstadt S, Wilke M, Doneda D, Michelin K, Ribeiro CB, Quevedo A, Vieira T, Nalin T, Lueska S, Schwartz IV. 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. doi: 10.1007/8904_2013_214.

29. Berger J, Stirnemann J, Bourgne C, Pereira B, Pigeon P, Heraoui D, Froissart R, Rapatel C, Rose C, Belmatoug N, Berger MG. The uptake of recombinant glucocerebrosidases by blood monocytes from type 1 Gaucher disease patients is variable. Br J Haematol. 2012;157:274-277. doi: 10.1111/j.1365-2141.2011.08989.x.

30. Xu YH, Sun Y, Barnes S, Grabowski GA. Comparative therapeutic effects of velaglucerase alfa and imiglucerase in a Gaucher disease mouse model. PLoS One. 2010;5(5):e10750. doi: 10.1371/journal.pone.0010750.

31. Dasgupta N, Xu YH, Oh S, Sun Y, Jia L, Keddache M, Grabowski GA. Gaucher Disease: Transcriptome Analyses Using Microarray or mRNA Sequencing in a Gba1 Mutant Mouse Model Treated with Velaglucerase alfa or Imiglucerase. PLoS One. 2013;8(10):e74912. doi: 10.1371/journal.pone.0074912.