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Current Pharmaceutical Biotechnology

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ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

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Research Article

Feasibility Study for Bedside Production of Recombinant Human Acid α-Glucosidase: Technical and Financial Considerations

Author(s): Mohammed H. Aldosari*, Marcel den Hartog, Hubertina Ganizada, Martijn J.W. Evers, Enrico Mastrobattista and Huub Schellekens

Volume 21, Issue 6, 2020

Page: [467 - 479] Pages: 13

DOI: 10.2174/1389201021666200217113049

Price: $65

Abstract

Objective: The high cost of orphan drugs limits their access by many patients, especially in low- and middle-income countries. Many orphan drugs are off-patent without alternative generic or biosimilar versions available. Production of these drugs at the point-of-care, when feasible, could be a cost-effective alternative.

Methods: The financial feasibility of this approach was estimated by setting up a small-scale production of recombinant human acid alpha-glucosidase (rhGAA). The commercial version of rhGAA is Myozyme™, and Lumizyme™ in the United States, which is used to treat Pompe disease. The rhGAA was produced in CHO-K1 mammalian cells and purified using multiple purification steps to obtain a protein profile comparable to Myozyme™.

Results: The established small-scale production of rhGAA was used to obtain a realistic cost estimation for the magistral production of this biological drug. The treatment cost of rhGAA using bedside production was estimated at $3,484/gram, which is 71% lower than the commercial price of Myozyme ™.

Conclusion: This study shows that bedside production might be a cost-effective approach to increase the access of patients to particular life-saving drugs.

Keywords: Affordability, bedside production, orphan drug, Pompe disease, rare disease, rhGAA.

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[1]
Field, M.J.; Boat, T.F. Profile of Rare Diseases; National Academies Press: Washington, D.C., 2010.
[2]
Hall, A.K.; Carlson, M.R. The current status of orphan drug development in Europe and the US. Intractable Rare Dis. Res., 2014, 3(1), 1-7.
[http://dx.doi.org/10.5582/irdr.3.1] [PMID: 25343119]
[3]
Gülbakan, B.; Özgül, R.K.; Yüzbaşıoğlu, A.; Kohl, M.; Deigner, H-P.; Özgüç, M. Discovery of biomarkers in rare diseases: innovative approaches by predictive and personalized medicine. EPMA J., 2016, 7(1), 24.
[http://dx.doi.org/10.1186/s13167-016-0074-2] [PMID: 27980697]
[4]
Puiu, M.; Dan, D. Rare diseases, from European resolutions and recommendations to actual measures and strategies. Maedica (Buchar.), 2010, 5(2), 128-131.
[PMID: 21977136]
[5]
Lochmüller, H.; Torrent I Farnell, J.; Le Cam, Y.; Jonker, A.H.; Lau, L.P.; Baynam, G.; Kaufmann, P.; Dawkins, H.J.; Lasko, P.; Austin, C.P.; Boycott, K.M. The International Rare Diseases Research Consortium: Policies and Guidelines to maximize impact. Eur. J. Hum. Genet., 2017, 25(12), 1293-1302.
[http://dx.doi.org/10.1038/s41431-017-0008-z] [PMID: 29158551]
[6]
Giannuzzi, V.; Conte, R.; Landi, A.; Ottomano, S.A.; Bonifazi, D.; Baiardi, P.; Bonifazi, F.; Ceci, A. Orphan medicinal products in Europe and United States to cover needs of patients with rare diseases: an increased common effort is to be foreseen. Orphanet J. Rare Dis., 2017, 12(1), 64.
[http://dx.doi.org/10.1186/s13023-017-0617-1] [PMID: 28372595]
[7]
Gammie, T.; Lu, C.Y.; Babar, Z.U-D. Access to Orphan Drugs: A Comprehensive Review of Legislations, Regulations and Policies in 35 Countries. PLoS One, 2015, 10(10)e0140002
[http://dx.doi.org/10.1371/journal.pone.0140002] [PMID: 26451948]
[8]
Degtiar, I. A review of international coverage and pricing strategies for personalized medicine and orphan drugs. Health Policy, 2017, 121(12), 1240-1248.
[http://dx.doi.org/10.1016/j.healthpol.2017.09.005] [PMID: 29033060]
[9]
Detiček, A.; Locatelli, I.; Kos, M. Patient Access to Medicines for Rare Diseases in European Countries. Value Health, 2018, 21(5), 553-560.
[http://dx.doi.org/10.1016/j.jval.2018.01.007] [PMID: 29753352]
[10]
Orphan Drug Report 2018; EvaluatePharma: London, United Kingdom, 2018.
[11]
Jacquemart, R.; Vandersluis, M.; Zhao, M.; Sukhija, K.; Sidhu, N.; Stout, J. A single-use strategy to enable manufacturing of affordable biologics. Comput. Struct. Biotechnol. J., 2016, 14, 309-318.
[http://dx.doi.org/10.1016/j.csbj.2016.06.007] [PMID: 27570613]
[12]
The Next Generation of Biotech Manufacturing., https://www.amgenscience.com/features/the-next-generation-of-biotech-manufacturing/
[13]
Schellekens, H.; Aldosari, M.; Talsma, H.; Mastrobattista, E. Making individualized drugs a reality. Nat. Biotechnol., 2017, 35(6), 507-513.
[http://dx.doi.org/10.1038/nbt.3888] [PMID: 28581491]
[14]
European Directorate for the Quality of Medicines Quality and Safety Standards in Pharmaceutical Practices and Pharmaceutical Care: Resolutions., https://www.edqm.eu/en/Quality-Safety-Standards-Resolutions-1588.html [accessed Jun 1, 2018].
[15]
Orphan Drugs in the United States; Durham, NC, 2018, p. 25.
[16]
Personalised Medicine Produced in a “Bionexpresso”. https://www.uu.nl/en/news/personalised-medicine-produced-in-a-bionexpresso
[17]
FDA approves first treatment for Pompe disease. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/125141s000_MyozymeTOC.cfm
[18]
Myozyme., https://www.ema.europa.eu/en/medicines/human/EPAR/myozyme
[19]
Kishnani, P.S.; Steiner, R.D.; Bali, D.; Berger, K.; Byrne, B.J.; Case, L.E.; Crowley, J.F.; Downs, S.; Howell, R.R.; Kravitz, R.M.; Mackey, J.; Marsden, D.; Martins, A.M.; Millington, D.S.; Nicolino, M.; O’Grady, G.; Patterson, M.C.; Rapoport, D.M.; Slonim, A.; Spencer, C.T.; Tifft, C.J.; Watson, M.S. Pompe disease diagnosis and management guideline. Genet. Med., 2006, 8(5), 267-288.
[http://dx.doi.org/10.1097/01.gim.0000218152.87434.f3] [PMID: 16702877]
[20]
Leslie, N.; Tinkle, B.T. Glycogen storage disease type II Pompe disease. Gene Reviews; Pagon, R.A.; Adam, M.P.; Ardinger, H.H.; Wallace, S.E.; Amemiya, A.; Bean, L.J.; Bird, T.D., Eds.; University of Washington, Seattle: Seattle, WA , 1993.
[21]
Kishnani, P.S.; Howell, R.R. Pompe disease in infants and children. J. Pediatr., 2004, 144(5)(Suppl.), S35-S43.
[http://dx.doi.org/10.1016/j.jpeds.2004.01.053] [PMID: 15126982]
[22]
Hoefsloot, L.H.; Willemsen, R.; Kroos, M.A.; Hoogeveen-Westerveld, M.; Hermans, M.M.; Van der Ploeg, A.T.; Oostra, B.A.; Reuser, A.J. Expression and routeing of human lysosomal alpha-glucosidase in transiently transfected mammalian cells. Biochem. J., 1990, 272(2), 485-492.
[http://dx.doi.org/10.1042/bj2720485] [PMID: 2268275]
[23]
Moreland, R.J.; Jin, X.; Zhang, X.K.; Decker, R.W.; Albee, K.L.; Lee, K.L.; Cauthron, R.D.; Brewer, K.; Edmunds, T.; Canfield, W.M. Lysosomal acid α-glucosidase consists of four different peptides processed from a single chain precursor. J. Biol. Chem., 2005, 280(8), 6780-6791.
[http://dx.doi.org/10.1074/jbc.M404008200] [PMID: 15520017]
[24]
Maga, J.A.; Zhou, J.; Kambampati, R.; Peng, S.; Wang, X.; Bohnsack, R.N.; Thomm, A.; Golata, S.; Tom, P.; Dahms, N.M.; Byrne, B.J.; LeBowitz, J.H. Glycosylation-independent lysosomal targeting of acid α-glucosidase enhances muscle glycogen clearance in pompe mice. J. Biol. Chem., 2013, 288(3), 1428-1438.
[http://dx.doi.org/10.1074/jbc.M112.438663] [PMID: 23188827]
[25]
McVie-Wylie, A.J.; Lee, K.L.; Qiu, H.; Jin, X.; Do, H.; Gotschall, R.; Thurberg, B.L.; Rogers, C.; Raben, N.; O’Callaghan, M.; Canfield, W.; Andrews, L.; McPherson, J.M.; Mattaliano, R.J. Biochemical and pharmacological characterization of different recombinant acid α-glucosidase preparations evaluated for the treatment of Pompe disease. Mol. Genet. Metab., 2008, 94(4), 448-455.
[http://dx.doi.org/10.1016/j.ymgme.2008.04.009] [PMID: 18538603]
[26]
Myozyme Becomes Lumizyme After Biologics Scale-up, https://www.in-pharmatechnologist.com/Article/2009/02/16/ Myozyme-becomes-Lumizyme-after-biologics-scale-up
[27]
Ratner, M. Genzyme’s lumizyme clears bioequivalence hurdles. Nat. Biotechnol., 2009, 27, 685.
[http://dx.doi.org/10.1038/nbt0809-685a]
[28]
Genzyme. Genzyme Receives Label Expansion for Lumizyme (Alglucosidase Alfa) in the United States for the Treatment of Pompe disease, https://news.sanofigenzyme.com/press-release/genzyme-receives-label-expansion-lumizyme-alglucosidase-alfa-united-states-treatment-p
[29]
FDA expands approval of drug to treat Pompe disease, http://journals.lww.com/neurotodayonline/blog/breakingnews//pages/post.aspx?PostID=342
[30]
Forbes. The World’s Most Expensive Drugs, http://www.forbes.com/2010/02/19/expensive-drugs-cost-business-healthcare-rare-diseases.html
[31]
Kanters, T.A.; Hoogenboom-Plug, I.; Rutten-Van Mölken, M.P.; Redekop, W.K.; van der Ploeg, A.T.; Hakkaart, L. Cost-effectiveness of enzyme replacement therapy with alglucosidase alfa in classic-infantile patients with Pompe disease. Orphanet J. Rare Dis., 2014, 9(1), 75.
[http://dx.doi.org/10.1186/1750-1172-9-75] [PMID: 24884717]
[32]
Patents, G. Treatment of Pompe’s disease., https://patents.google.com/patent/US7351410B2/en
[33]
Blackstone, E.A.; Joseph, P.F. The economics of biosimilars. Am. Health Drug Benefits, 2013, 6(8), 469-478.
[PMID: 24991376]
[34]
Geuijen, K.P.M.; Halim, L.A.; Schellekens, H.; Schasfoort, R.B.; Wijffels, R.H.; Eppink, M.H. Label-free glycoprofiling with multiplex surface plasmon resonance: a tool to quantify sialylation of erythropoietin. Anal. Chem., 2015, 87(16), 8115-8122.
[http://dx.doi.org/10.1021/acs.analchem.5b00870] [PMID: 26192159]
[35]
Freeze, H.H. Lectin affinity chromatography. Curr. Protocols Protein Sci.,, 1995. (1), 9.1.1-9.1.9.
[36]
Liu, H.F.; Ma, J.; Winter, C.; Bayer, R. Recovery and purification process development for monoclonal antibody production. MAbs, 2010, 2(5), 480-499.
[http://dx.doi.org/10.4161/mabs.2.5.12645] [PMID: 20647768]
[37]
Soper, A.S.; Aird, S.D. Elution of tightly bound solutes from concanavalin A Sepharose. Factors affecting the desorption of cottonmouth venom glycoproteins. J. Chromatogr. A, 2007, 1154(1-2), 308-318.
[http://dx.doi.org/10.1016/j.chroma.2007.03.126] [PMID: 17449042]
[38]
DePhillips, P.; Lenhoff, A.M. Determinants of protein retention characteristics on cation-exchange adsorbents. J. Chromatogr. A, 2001, 933(1-2), 57-72.
[http://dx.doi.org/10.1016/S0021-9673(01)01275-4] [PMID: 11758747]
[39]
Janson, J-C. Protein Purification: Principles, High Resolution Methods, and Applications; John Wiley & Sons: Hoboken, NJ, 2012.
[40]
Castonguay, A.C.; Lasanajak, Y.; Song, X.; Olson, L.J.; Cummings, R.D.; Smith, D.F.; Dahms, N.M. The glycan-binding properties of the cation-independent mannose 6-phosphate receptor are evolutionary conserved in vertebrates. Glycobiology, 2012, 22(7), 983-996.
[http://dx.doi.org/10.1093/glycob/cws058] [PMID: 22369936]
[41]
Olson, L.J.; Castonguay, A.C.; Lasanajak, Y.; Peterson, F.C.; Cummings, R.D.; Smith, D.F.; Dahms, N.M. Identification of a fourth mannose 6-phosphate binding site in the cation-independent mannose 6-phosphate receptor. Glycobiology, 2015, 25(6), 591-606.
[http://dx.doi.org/10.1093/glycob/cwv001] [PMID: 25573276]
[42]
Cardone, M.; Porto, C.; Tarallo, A.; Vicinanza, M.; Rossi, B.; Polishchuk, E.; Donaudy, F.; Andria, G.; De Matteis, M.A.; Parenti, G. Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts. PathoGenetics, 2008, 1(1), 6.
[http://dx.doi.org/10.1186/1755-8417-1-6] [PMID: 19046416]
[43]
Preinreich, G.A.D. The economic life of industrial equipment. Econometrica, 1940, 8(1), 12-44.
[http://dx.doi.org/10.2307/1906860]
[44]
Wiebe, M.E.; May, L.H. Cell banking. Bioprocess Technol., 1990, 10, 147-160.
[PMID: 1367056]
[45]
Hoyle, M. Accounting for the drug life cycle and future drug prices in cost-effectiveness analysis. Pharmacoeconomics, 2011, 29(1), 1-15.
[http://dx.doi.org/10.2165/11584230-000000000-00000] [PMID: 21142275]
[46]
GE Healthcare Life Sciences. Single-use Ready to Process Wave Cellbag Bioreactors, https://www.gelifesciences.com/en/se/shop/ cell-culture-and-fermentation/rocking-bioreactors/consumables-and-accessories/single-use-readytoprocess-wave-cellbag-bioreactors-p-00346
[47]
GE Healthcare Life Sciences. HyClone CDM4CHO Cell Culture Media, https://www.gelifesciences.com/en/se/shop/cell-culture-and-fermentation/media-and-feeds/specialty-media/hyclone-cdm4cho-cell-culture-media-p-06206
[48]
GE Healthcare Life Sciences. Disposable Cellbag Bioreactors for Wave Bioreactor Systems, https://www.gelifesciences.co.jp/ catalog/pdf/WAVECellbag_28951136AG.pdf
[49]
Sammlung von Mikroorganismen, D.; Zellkulturen, G.H. Characteristics of CHO-K1 cell line., https://www.dsmz.de/collection/ catalogue/details/culture/ACC-110
[50]
Repligen. KrosFlo KML, https://www.repligen.com/ technologies/tff/lab/kml
[51]
GE Healthcare Life Sciences. Permeate Volume and Process Time calculator for Cross-flow Filtration, https://www.gelifesciences. com/ko/kr/support/online-tools/crossflow-and-normal-flow-filtration/permeate-volume-and-process-time-calculator
[52]
Repligen. MIDIKROS 65CM 10K MPES, https://store. repligen.com/products/midikros-65cm-10k-mpes-1mm-fll-x-fll-1-pk-sterile
[53]
GE Healthcare Life Sciences. ÄKTA Ready Single-Use System, https://www.gelifesciences.com/en/kr/shop/chromatography/chromatography-systems/akta-ready-single-use-system-p-05843
[54]
GE Healthcare Life Sciences. Con A Sepharose 4B, https://www.gelifesciences.com/en/se/shop/chromatography/resins/affinity-specific-groups/con-a-sepharose-4b-p-05883
[55]
GE Healthcare Life Sciences. DEAE Sepharose Fast Flow Anion Exchange Chromatography Resin, https://www.gelifesciences.com/ en/se/shop/deae-sepharose-fast-flow-anion-exchange-chromatography-resin-p-04396
[56]
Van Hove, J.L.; Yang, H.W.; Oliver, L.M.; Pennybacker, M.F.; Chen, Y.T. Purification of recombinant human precursor acid alpha-glucosidase. Biochem. Mol. Biol. Int., 1997, 43(3), 613-623.
[PMID: 9352080]
[57]
Aseptic Technologies. M1 Filling Station, https://www.aseptictech. com/products/m1-filling-station
[58]
Type A2 Biosafety Cabinets, https://www.fishersci.com/shop/ products/1300-series-a2-class-ii-type-a2-bio-safety-cabinets-without-accessories-17/p-4529313
[59]
Total Jobs. Average Pharmacist Salary., https://www.totaljobs. com/salary-checker/average-pharmacist-salary
[60]
GE Healthcare Life Sciences. Ready to Process Wave 25 Rocker, https://www.gelifesciences.com/en/us/shop/cell-culture-and-fermentation/rocking-bioreactors/systems/readytoprocess-wave-25-rocker-p-05542
[61]
Liquid Chromatography (HPLC & UHPLC) Instruments, http://www.perkinelmer.com/category/liquid-chromatography-hplc-uhplc-instruments
[62]
Austin, C.P.; Cutillo, C.M.; Lau, L.P.L.; Jonker, A.H.; Rath, A.; Julkowska, D.; Thomson, D.; Terry, S.F.; de Montleau, B.; Ardigò, D.; Hivert, V.; Boycott, K.M.; Baynam, G.; Kaufmann, P.; Taruscio, D.; Lochmüller, H.; Suematsu, M.; Incerti, C.; Draghia-Akli, R.; Norstedt, I.; Wang, L.; Dawkins, H.J.S. Future of rare diseases research 2017-2027: An IRDiRC perspective. Clin. Transl. Sci., 2018, 11(1), 21-27.
[http://dx.doi.org/10.1111/cts.12500] [PMID: 28796445]
[63]
Cohen, J.; Milne, C-P. Is the increasing cost of treating rare diseases sustainable? Expert Opin. Orphan Drugs, 2013, 1(8), 581-583.
[http://dx.doi.org/10.1517/21678707.2013.819289]

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