Advertisement

Hormones, Blood Products, and Therapeutic Enzymes

  • Ana Catarina SilvaEmail author
  • Cládia Pina Costa
  • Hugo Almeida
  • João Nuno Moreira
  • José Manuel Sousa Lobo
Chapter
Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 171)

Abstract

Therapeutic uses of biological medicines are diverse and include active substances from different classes. This chapter provides an overview on the clinical applications of biological medicines containing hormones, blood products, and therapeutic enzymes. Currently, therapeutic hormones have 78 approved medicines, including insulin and analogs, glucagon and analogs, growth hormone, gonadotropins (follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin), thyroid-stimulating hormone, and parathyroid hormone. In contrast, recombinant blood products, and particularly blood factors, anticoagulants, and thrombolytic agents, incorporate 49 approved biological medicines. Regarding recombinant therapeutic enzymes, there are 22 approved medicines. Among the referred biological medicines, there are six biosimilar hormones, and no biosimilars have been approved for recombinant blood products and therapeutic enzymes, which is unexpected.

Current investigations on recombinant hormones, recombinant blood products, and therapeutic enzymes seem to follow the same directions, searching for alternative non-injectable administration routes, development of new recombinant molecules with improved pharmacokinetic properties and discovering new clinical applications for approved medicines. These approaches are showing positive results and new medicines are expected to reach clinical approval in the coming years. Future prospects also include the approval of more biosimilar medicines.

Graphical Abstract

Keywords

Anticoagulants Blood factors Glucagon Gonadotropins Growth hormone Insulin Therapeutic enzymes Thrombolytic agents 

Notes

Acknowledgments

This work was supported by the Applied Molecular Biosciences Unit-UCIBIO and FP-ENAS, which are financed by national funds from FCT/MCTES (UID/Multi/04378/2019 and UID/Multi/04546/2019, respectively).

References

  1. 1.
    Chen YC, Yeh MK (2018) Introductory chapter: biopharmaceuticals. In: Yeh MK, Chen YC (eds) Biopharmaceuticals. IntechOpen, LondonGoogle Scholar
  2. 2.
    Walsh G (2013) Pharmaceutical biotechnology: concepts and applications. Wiley, HobokenGoogle Scholar
  3. 3.
  4. 4.
  5. 5.
    Kesik-Brodacka M (2018) Progress in biopharmaceutical development. Biotechnol Appl Biochem 65(3):306–322PubMedGoogle Scholar
  6. 6.
    Vass P, Démuth B, Hirsch E, Nagy B, Andersen SK, Vigh T et al (2019) Drying technology strategies for colon-targeted oral delivery of biopharmaceuticals. J Control Release 296:162–178PubMedGoogle Scholar
  7. 7.
    Permutt MA, Chirgwin J, Rotwein P, Giddings S (1984) Insulin gene structure and function: a review of studies using recombinant DNA methodology. Diabetes Care 7(4):386–394PubMedGoogle Scholar
  8. 8.
    Walsh G (2007) Therapeutic hormones. Pharmaceutical biotechnology: concepts and applications. Wiley, Hoboken, pp 291–328Google Scholar
  9. 9.
    Shaikh IM, Jadhav KR, Ganga S, Kadam VJ, Pisal SS (2005) Advanced approaches in insulin delivery. Curr Pharm Biotechnol 6(5):387–395PubMedGoogle Scholar
  10. 10.
    Rhodes CJ, White MF (2002) Molecular insights into insulin action and secretion. Eur J Clin Invest 32(Suppl 3):3–13PubMedGoogle Scholar
  11. 11.
    Docherty K (1997) Gene therapy for diabetes mellitus. Clin Sci 92(4):321–330PubMedGoogle Scholar
  12. 12.
    Auricchio A, Gao GP, Yu QC, Raper S, Rivera VM, Clackson T et al (2002) Constitutive and regulated expression of processed insulin following in vivo hepatic gene transfer. Gene Ther 9(14):963–971PubMedGoogle Scholar
  13. 13.
    Mane K, Chaluvaraju K, Niranjan M, Zaranappa T, Manjuthej T (2012) Review of insulin and its analogues in diabetes mellitus. J Basic Clin Pharm 3(2):283–293PubMedPubMedCentralGoogle Scholar
  14. 14.
    Bristow AF (1993) Recombinant-DNA-derived insulin analogues as potentially useful therapeutic agents. Trends Biotechnol 11(7):301–305PubMedGoogle Scholar
  15. 15.
    Johnson IS (1983) Human insulin from recombinant DNA technology. Science 219(4585):632–637PubMedGoogle Scholar
  16. 16.
    Herring R, Russell-Jones DDL (2018) Lessons for modern insulin development. Diabet Med 35(10):1320–1328PubMedGoogle Scholar
  17. 17.
    Vajo Z, Fawcett J, Duckworth WC (2001) Recombinant DNA technology in the treatment of diabetes: insulin analogs. Endocr Rev 22(5):706–717PubMedGoogle Scholar
  18. 18.
    Brange J, Langkjoer L (1993) Insulin structure and stability. Pharm Biotechnol 5:315–350PubMedGoogle Scholar
  19. 19.
    Beals JM, Kovach P (2008) Insulin. In: Healthcare I (ed) Pharmaceutical technology: fundamentals and applications. Wiley, HobokenGoogle Scholar
  20. 20.
    Sanchez-Garcia L, Martin L, Mangues R, Ferrer-Miralles N, Vazquez E, Villaverde A (2016) Recombinant pharmaceuticals from microbial cells: a 2015 update. Microb Cell Factories 15:33Google Scholar
  21. 21.
  22. 22.
    Walsh G (2005) Therapeutic insulins and their large-scale manufacture. Appl Microbiol Biotechnol 67(2):151–159PubMedGoogle Scholar
  23. 23.
  24. 24.
  25. 25.
  26. 26.
  27. 27.
  28. 28.
  29. 29.
  30. 30.
  31. 31.
  32. 32.
  33. 33.
  34. 34.
  35. 35.
  36. 36.
  37. 37.
  38. 38.
  39. 39.
  40. 40.
  41. 41.
  42. 42.
  43. 43.
  44. 44.
  45. 45.
  46. 46.
  47. 47.
  48. 48.
  49. 49.
  50. 50.
  51. 51.
  52. 52.
  53. 53.
  54. 54.
  55. 55.
  56. 56.
  57. 57.
  58. 58.
  59. 59.
  60. 60.
  61. 61.
  62. 62.
  63. 63.
  64. 64.
  65. 65.
  66. 66.
  67. 67.
  68. 68.
  69. 69.
  70. 70.
  71. 71.
  72. 72.
  73. 73.
    Bhatia A, Tawade S, Mastim M, Kitabi EN, Gopalakrishnan M, Shah M et al (2018) Comparative evaluation of pharmacokinetics and pharmacodynamics of insulin glargine (Glaritus((R))) and Lantus((R)) in healthy subjects: a double-blind, randomized clamp study. Acta Diabetol 55(5):461–468PubMedGoogle Scholar
  74. 74.
  75. 75.
    Davies M, Dahl D, Heise T, Kiljanski J, Mathieu C (2017) Introduction of biosimilar insulins in Europe. Diabet Med 34(10):1340–1353PubMedPubMedCentralGoogle Scholar
  76. 76.
    Agency EM (2015) Orphan designation: treatment of short bowel syndrome. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3151532
  77. 77.
    Muheem A, Shakeel F, Jahangir MA, Anwar M, Mallick N, Jain GK et al (2016) A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives. Saudi Pharm J 24(4):413–428PubMedGoogle Scholar
  78. 78.
    Shahani S, Shahani L (2015) Use of insulin in diabetes: a century of treatment. Hong Kong Med J 21(6):553–559PubMedGoogle Scholar
  79. 79.
    Asquetiv (2019) MonoSol Rx announces initiation of phase 2a trial for oral insulin film. https://aquestive.com/monosol-rx-announces-initiation-of-phase-2a-trial-for-oral-insulin-film/
  80. 80.
    Trials C (2017) Comparison of insulin tregopil (IN-105) with insulin aspart in type 2 diabetes mellitus patients. https://clinicaltrials.gov/ct2/show/NCT03430856
  81. 81.
    Cengiz E, Bode B, Van Name M, Tamborlane WV (2016) Moving toward the ideal insulin for insulin pumps. Expert Rev Med Devices 13(1):57–69PubMedGoogle Scholar
  82. 82.
    Schaepelynck P (2019) The implantable insulin pump. Handbook of diabetes technology. Springer, Berlin, pp 47–55Google Scholar
  83. 83.
    Bally L, Thabit H, Hovorka R (2017) Finding the right route for insulin delivery – an overview of implantable pump therapy. Expert Opin Drug Deliv 14(9):1103–1111PubMedGoogle Scholar
  84. 84.
    Bally L, Thabit H, Kojzar H, Mader JK, Qerimi-Hyseni J, Hartnell S et al (2017) Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study. Lancet Diabetes Endocrinol 5(4):261–270PubMedPubMedCentralGoogle Scholar
  85. 85.
    Renard E, Tubiana-Rufi N, Bonnemaison-Gilbert E, Coutant R, Dalla-Vale F, Farret A et al (2019) Closed-loop driven by control-to-range algorithm outperforms threshold-low-glucose-suspend insulin delivery on glucose control albeit not on nocturnal hypoglycaemia in prepubertal patients with type 1 diabetes in a supervised hotel setting. Diabetes Obes Metab 21(1):183–187PubMedGoogle Scholar
  86. 86.
    Heinemann L, Nosek L, Flacke F, Albus K, Krasner A, Pichotta P et al (2012) U-100, pH-neutral formulation of VIAject((R)): faster onset of action than insulin lispro in patients with type 1 diabetes. Diabetes Obes Metab 14(3):222–227PubMedGoogle Scholar
  87. 87.
    Hompesch M, McManus L, Pohl R, Simms P, Pfutzner A, Bulow E et al (2008) Intra-individual variability of the metabolic effect of a novel rapid-acting insulin (VIAject) in comparison to regular human insulin. J Diabetes Sci Technol 2(4):568–571PubMedPubMedCentralGoogle Scholar
  88. 88.
    Steiner S, Hompesch M, Pohl R, Simms P, Flacke F, Mohr T et al (2008) A novel insulin formulation with a more rapid onset of action. Diabetologia 51(9):1602–1606PubMedPubMedCentralGoogle Scholar
  89. 89.
    Home PD (2015) Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes? Diabetes Obes Metab 17(11):1011–1020PubMedPubMedCentralGoogle Scholar
  90. 90.
  91. 91.
    Danne T, Heinemann L, Bolinder J (2019) New insulins, biosimilars, and insulin therapy. Diabetes Technol Ther 21(S1):S57–S78PubMedGoogle Scholar
  92. 92.
    Lilly E (2019) Regulatory review: ultra-rapid lispro. https://www.lilly.com/discovery/pipeline
  93. 93.
    Heise T, Hovelmann U, Brondsted L, Adrian CL, Nosek L, Haahr H (2015) Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart. Diabetes Obes Metab 17(7):682–688PubMedPubMedCentralGoogle Scholar
  94. 94.
    Nordisk N (2015) Novo Nordisk completes phase 3a trials comparing faster-acting insulin aspart with NovoRapid® in people with type 1 and type 2 diabetes. https://www.novonordisk.com/bin/getPDF.1906174.pdf
  95. 95.
    Morrow L, Muchmore DB, Hompesch M, Ludington EA, Vaughn DE (2013) Comparative pharmacokinetics and insulin action for three rapid-acting insulin analogs injected subcutaneously with and without hyaluronidase. Diabetes Care 36(2):273–275PubMedPubMedCentralGoogle Scholar
  96. 96.
    Garg SK, Buse JB, Skyler JS, Vaughn DE, Muchmore DB (2014) Subcutaneous injection of hyaluronidase with recombinant human insulin compared with insulin lispro in type 1 diabetes. Diabetes Obes Metab 16(11):1065–1069PubMedGoogle Scholar
  97. 97.
    Lilly E (2019) Medicines in development. https://www.lilly.com/discovery/pipeline
  98. 98.
  99. 99.
    Committee NCCCMCM, Ansite J, Balamurugan AN, Barbaro B, Battle J, Brandhorst D et al (2017) Purified human pancreatic islets, CIT culture media with lisofylline or exenatide. CellR4 Repair Replace Regen Reprogram 5(3):e2377Google Scholar
  100. 100.
    Wu T, Rayner CK, Marathe CS, Jones KL, Horowitz M (2018) Glucagon receptor signalling – backwards and forwards. Expert Opin Investig Drugs 27(2):135–138PubMedGoogle Scholar
  101. 101.
  102. 102.
    Hayashi Y, Seino Y (2018) Regulation of amino acid metabolism and alpha-cell proliferation by glucagon. J Diabetes Investig 9(3):464–472PubMedCentralGoogle Scholar
  103. 103.
    Burrin DG, Petersen Y, Stoll B, Sangild P (2001) Glucagon-like peptide 2: a nutrient-responsive gut growth factor. J Nutr 131(3):709–712PubMedGoogle Scholar
  104. 104.
  105. 105.
    Administration FaD (1998) Recombinant Glucagon. https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20928.pdf
  106. 106.
    Agency EM (2019) Orphan designation: noninsulinoma pancreatogenous hypoglycaemia syndrome. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3182091
  107. 107.
    Agency EM (2019) Orphan designations: congenital hyperinsulinism. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3141342
  108. 108.
    Agency EM (2012) Orphan designations: congenital hyperinsulinism. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu312960
  109. 109.
    Agency EM (2018) Glucagon analogue linked to a human immunoglobulin Fc fragment (also known as HM15136). https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3182022
  110. 110.
  111. 111.
  112. 112.
  113. 113.
  114. 114.
  115. 115.
  116. 116.
  117. 117.
  118. 118.
  119. 119.
  120. 120.
  121. 121.
    Agency EM (2019) Orphan designation: human glucagon-like peptide-2 analogue linked to a human immunoglobulin Fc fragment. https://www.ema.europa.eu/en/documents/orphan-designation/eu/3/18/2126-public-summary-opinion-orphan-designation-human-glucagon-peptide-2-analogue-linked-human_en.pdf
  122. 122.
    Hovelmann U, Bysted BV, Mouritzen U, Macchi F, Lamers D, Kronshage B et al (2018) Pharmacokinetic and pharmacodynamic characteristics of dasiglucagon, a novel soluble and stable glucagon analog. Diabetes Care 41(3):531–537PubMedGoogle Scholar
  123. 123.
  124. 124.
    Company ELa (2015) Intranasal glucagon: phase III clinical trials. http://lilly.mediaroom.com/index.php?s=9042&item=137474
  125. 125.
    Pharmaceuticals X (2018) Xeris Pharmaceuticals announces positive phase 3 clinical trial data on its investigational ready-to-use glucagon rescue pen. https://investors.xerispharma.com/node/6566/pdf
  126. 126.
    Caicedo A, Rosenfeld R (2018) Challenges and future for the delivery of growth hormone therapy. Growth Hormon IGF Res 38:39–43Google Scholar
  127. 127.
    Marian MO, Growth Hormones J (2008) In: Healthcare I (ed) Pharmaceutical technology: fundamentals and applications. Wiley, Hoboken, pp 281–292Google Scholar
  128. 128.
    Lal RA, Hoffman AR (2018) Long-acting growth hormone preparations in the treatment of children. Pediatr Endocrinol Rev 16(Suppl 1):162–167PubMedPubMedCentralGoogle Scholar
  129. 129.
  130. 130.
  131. 131.
  132. 132.
  133. 133.
  134. 134.
  135. 135.
  136. 136.
  137. 137.
  138. 138.
  139. 139.
  140. 140.
  141. 141.
  142. 142.
  143. 143.
  144. 144.
  145. 145.
  146. 146.
    Agency EM (2000) Orphan designation: somatropin for AIDS wasting. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu300001
  147. 147.
    Yuen KCJ, Miller BS, Biller BMK (2018) The current state of long-acting growth hormone preparations for growth hormone therapy. Curr Opin Endocrinol Diabetes Obes 25(4):267–273PubMedGoogle Scholar
  148. 148.
  149. 149.
    Strasburger CJ, Vanuga P, Payer J, Pfeifer M, Popovic V, Bajnok L et al (2017) MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a phase 2 study in growth hormone-deficient adults. Eur J Endocrinol 176(3):283–294PubMedGoogle Scholar
  150. 150.
    Ku CR, Brue T, Schilbach K, Ignatenko S, Magony S, Chung YS et al (2018) Long-acting FC-fusion rhGH (GX-H9) shows potential for up to twice-monthly administration in GH-deficient adults. Eur J Endocrinol 179(3):169–179PubMedGoogle Scholar
  151. 151.
    ClinicalTrials.gov USNLoM (2018) Trial to compare the efficacy and safety of NNC0195-0092 (Somapacitan) with placebo and Norditropin® FlexPro® (Somatropin) in adults with growth hormone deficiency. https://clinicaltrials.gov/ct2/show/NCT02229851
  152. 152.
    Banker MJ, Hinduja R, Sathe S, Arora S (2019) Infertility and assisted reproductive technology1st edn. Jaypee Brothers Medical Publishers, New DelhiGoogle Scholar
  153. 153.
    Ben-Menahem D (2018) Preparation, characterization and application of long-acting FSH analogs for assisted reproduction. Theriogenology 112:11–17PubMedGoogle Scholar
  154. 154.
    Bernard DJ, Li Y, Toufaily C, Schang G (2019) Regulation of gonadotropins. Oxford University Press, OxfordGoogle Scholar
  155. 155.
    Sam T (2008) Follicle-stimulating hormones. In: Healthcare I (ed) Pharmaceutical technology: fundamentals and applications. Wiley, Hoboken, pp 399–404Google Scholar
  156. 156.
    Anderson RC, Newton CL, Anderson RA, Millar RP (2018) Gonadotropins and their analogs: current and potential clinical applications. Endocr Rev 39(6):911–937PubMedGoogle Scholar
  157. 157.
  158. 158.
  159. 159.
  160. 160.
  161. 161.
  162. 162.
  163. 163.
  164. 164.
  165. 165.
  166. 166.
  167. 167.
  168. 168.
  169. 169.
  170. 170.
  171. 171.
    Majumdar A, Sachan R, Nandanwar YS, Mayekar RV, Soni N, Banker MR et al (2019) A multicenter, randomized, equivalence trial of a new recombinant human chorionic gonadotropin preparation versus ovitrelle((R)) for ovulation in women undergoing intrauterine insemination following ovarian stimulation. J Hum Reprod Sci 12(1):53–58PubMedPubMedCentralGoogle Scholar
  172. 172.
    Zander-Fox D, Lane M, Hamilton H, Tremellen K (2018) Sequential clomiphene/corifollitrophin alpha as a technique for mild controlled ovarian hyperstimulation in IVF: a proof of concept study. J Assist Reprod Genet 35(6):1047–1052PubMedPubMedCentralGoogle Scholar
  173. 173.
    Cozzolino M, Vitagliano A, Cecchino GN, Ambrosini G, Garcia-Velasco JA (2019) Corifollitropin alfa for ovarian stimulation in in vitro fertilization: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril 111(4):722–733PubMedGoogle Scholar
  174. 174.
    Szkudlinski MW, Fremont V, Ronin C, Weintraub BD (2002) Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev 82(2):473–502PubMedGoogle Scholar
  175. 175.
    Goltzman D (2018) Physiology of parathyroid hormone. Endocrinol Metab Clin 47(4):743–758Google Scholar
  176. 176.
  177. 177.
  178. 178.
  179. 179.
  180. 180.
  181. 181.
  182. 182.
  183. 183.
  184. 184.
  185. 185.
    Williams AJ, Jordan F, King G, Lewis AL, Illum L, Masud T et al (2018) In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1-34 for the treatment of osteoporosis. Int J Pharm 535(1–2):113–119PubMedGoogle Scholar
  186. 186.
    Cho M, Han S, Kim H, Kim KS, Hahn SK (2018) Hyaluronate – parathyroid hormone peptide conjugate for transdermal treatment of osteoporosis. J Biomater Sci Polym Ed 29(7–9):793–804PubMedGoogle Scholar
  187. 187.
    Avecilla ST (2019) Coagulation factor products. In: Shaz BH, Hillyer CD, Reyes Gil M (eds) Transfusion medicine and hemostasis3rd edn. Elsevier, Amsterdam, pp 251–260Google Scholar
  188. 188.
    Walsh G (2007) Recombinant blood products and therapeutic enzymes. In: Wiley (ed) Pharmaceutical biotechnology: concepts and applications. Wiley, Hoboken, pp 329–370Google Scholar
  189. 189.
    Bhopale GMN, Recombinant RK (2005) DNA expression products for human therapeutic use. Curr Sci 89(4):614–622Google Scholar
  190. 190.
    Steinberg FM, Raso J (1998) Biotech pharmaceuticals and biotherapy: an overview. J Pharm Pharm Sci 1(2):48–59PubMedGoogle Scholar
  191. 191.
    Modi NB (2008) Recombinant coagulation factors and thrombolytic agents. In: Crommelin DJASR, Meibohm B (eds) Pharmaceutical biotechnology: fundamentals and applications: informa healthcare, pp 293–308Google Scholar
  192. 192.
    Frampton JE (2016) Efmoroctocog alfa: a review in haemophilia A. Drugs 76(13):1281–1291PubMedGoogle Scholar
  193. 193.
    Hoy SM (2017) Eftrenonacog alfa: a review in haemophilia B. Drugs 77(11):1235–1246PubMedGoogle Scholar
  194. 194.
    BioMarin (2019) Current clinical trials: hemophilia A. https://www.biomarin.com/hemophilia-a
  195. 195.
    Therapeutics S (2019) Hemophilia B: FIXtendz study and hemophilia A: ALTA study 2019. https://www.sangamo.com/clinical-trials
  196. 196.
    uniQure (2019) GENE THERAPY: hemophilia. http://www.uniqure.com/gene-therapy/hemophilia.php
  197. 197.
  198. 198.
    EMA (2019) NovoSeven (eptacog alfa): an overview of NovoSeven and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/novoseven-epar-medicine-overview_en.pdf
  199. 199.
  200. 200.
    EMA (2018) EPAR summary for the public: Advate® (octocog alfa). https://www.ema.europa.eu/en/documents/overview/advate-epar-summary-public_en.pdf
  201. 201.
    EMA (2018) EPAR summary for the public: Kogenate Bayer (octocog alfa). https://www.ema.europa.eu/en/documents/overview/kogenate-bayer-epar-summary-public_en.pdf
  202. 202.
    EMA (2018) EPAR summary for the public: Helixate NexGen (octocog alfa). https://www.ema.europa.eu/en/documents/overview/helixate-nexgen-epar-summary-public_en.pdf
  203. 203.
    EMA (2018) EPAR summary for the public: Kovaltry (octocog alfa). https://www.ema.europa.eu/en/documents/overview/kovaltry-epar-summary-public_en.pdf
  204. 204.
    EMA (2016) EPAR summary for the public: Iblias (octocog alfa). https://www.ema.europa.eu/en/documents/overview/iblias-epar-summary-public_en.pdf
  205. 205.
    EMA (2018) NovoEight (turoctocog alfa): an overview of NovoEight and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/novoeight-epar-medicine-overview_en.pdf
  206. 206.
    EMA (2017) EPAR summary for the public: Afstyla (lonoctocog alfa). https://www.ema.europa.eu/en/documents/overview/afstyla-epar-summary-public_en.pdf
  207. 207.
    EMA (2015) EPAR summary for the public: Obizur (susoctocog alfa). https://www.ema.europa.eu/en/documents/overview/obizur-epar-summary-public_en.pdf
  208. 208.
    EMA (2018) EPAR summary for the public: Adynovi (rurioctocog alfa pegol). https://www.ema.europa.eu/en/documents/overview/adynovi-epar-summary-public_en.pdf
  209. 209.
    EMA (2018) Jivi (damoctocog alfa pegol): an overview of Jivi and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/jivi-epar-medicine-overview_en.pdf
  210. 210.
    EMA (2018) Elocta (efmoroctocog alfa): an overview of Elocta and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/elocta-epar-medicine-overview_en.pdf
  211. 211.
    EMA (2016) EPAR summary for the public: ReFacto AF (moroctocog alfa). https://www.ema.europa.eu/en/documents/overview/refacto-af-epar-summary-public_en.pdf
  212. 212.
    EMA (2018) EPAR summary for the public: Nuwiq (simoctocog alfa). https://www.ema.europa.eu/en/documents/overview/nuwiq-epar-summary-public_en.pdf
  213. 213.
    EMA (2019) Vihuma (simoctocog alfa): an overview of Vihuma and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/vihuma-epar-medicine-overview_en.pdf
  214. 214.
    EMA (2018) Veyvondi (vonicog alfa): an overview of Veyvondi and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/veyvondi-epar-medicine-overview_en.pdf
  215. 215.
    EMA (2016) EPAR summary for the public: Alprolix (eftrenonacog alfa). https://www.ema.europa.eu/en/documents/overview/alprolix-epar-summary-public_en.pdf
  216. 216.
    EMA (2015) EPAR summary for the public: BeneFIX (nonacog alfa). https://www.ema.europa.eu/en/documents/overview/benefix-epar-summary-public_en.pdf
  217. 217.
    EMA (2015) EPAR summary for the public: Rixubis (nonacog gamma). https://www.ema.europa.eu/en/documents/overview/rixubis-epar-summary-public_en.pdf
  218. 218.
    EMA (2017) EPAR summary for the public: Refixia (nonacog beta pegol). https://www.ema.europa.eu/en/documents/overview/refixia-epar-summary-public_en.pdf
  219. 219.
    FaDA (2017) Prescribing information for IDELVION®. https://www.fda.gov/media/96526/download
  220. 220.
    EMA (2016) EPAR summary for the public: Idelvion (albutrepenonacog alfa). https://www.ema.europa.eu/en/documents/overview/idelvion-epar-summary-public_en.pdf
  221. 221.
    Baker DE (2018) Coagulation factor Xa (Recombinant), inactivated-zhzo (Andexanet Alfa). Hosp Pharm 53(5):286–291PubMedPubMedCentralGoogle Scholar
  222. 222.
  223. 223.
  224. 224.
    EMA (2012) EPAR summary for the public: NovoThirteen (catridecacog). https://www.ema.europa.eu/en/documents/overview/novothirteen-epar-summary-public_en.pdf
  225. 225.
  226. 226.
    FaDA (2004) Prescribing information for REFLUDAN®. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020807s011lbl.pdf
  227. 227.
  228. 228.
    FaDA (2014) Prescribing information for IPRIVASK®. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021271s006lbl.pdf
  229. 229.
  230. 230.
    EMA (2016) EPAR summary for the public: ATryn (antithrombin alfa). https://www.ema.europa.eu/en/documents/overview/atryn-epar-summary-public_en.pdf
  231. 231.
    EMA (2009) EPAR summary for the public: Xigris (drotrecogin alfa (activated)). https://www.ema.europa.eu/en/documents/overview/xigris-epar-summary-public_en.pdf
  232. 232.
  233. 233.
  234. 234.
  235. 235.
    EMA (2016) EPAR summary for the public: rapilysin (reteplase). https://www.ema.europa.eu/en/documents/overview/rapilysin-epar-summary-public_en.pdf
  236. 236.
  237. 237.
    EMA (2005) Tenecteplase Boehringer Ingelheim Pharma GmbH Co. KG (tenecteplase). https://www.ema.europa.eu/en/medicines/human/EPAR/tenecteplase-boehringer-ingelheim-pharma-gmbh-co-kg
  238. 238.
    EMA (2014) EPAR summary for the public: Metalyse (tenecteplase). https://www.ema.europa.eu/en/documents/overview/metalyse-epar-summary-public_en.pdf
  239. 239.
  240. 240.
    Dutta TK, Verma SP (2014) Rational use of recombinant factor VIIa in clinical practice. Indian J Hematol Blood Transfus 30(2):85–90PubMedGoogle Scholar
  241. 241.
    Moorkens E, Meuwissen N, Huys I, Declerck P, Vulto AG, Simoens S (2017) The market of biopharmaceutical medicines: a snapshot of a diverse industrial landscape. Front Pharmacol 8:314PubMedPubMedCentralGoogle Scholar
  242. 242.
    Biron-Andreani C, Schved J-F (2019) Eptacog beta: a novel recombinant human factor VIIa for the treatment of hemophilia A and B with inhibitors. Expert Rev Hematol 12(1):21–28PubMedGoogle Scholar
  243. 243.
    Ezban M, Vad K, Kjalke M (2014) Turoctocog alfa (NovoEight(R))--from design to clinical proof of concept. Eur J Haematol 93(5):369–376PubMedPubMedCentralGoogle Scholar
  244. 244.
    Ahmadian H, Hansen EB, Faber JH, Sejergaard L, Karlsson J, Bolt G et al (2016) Molecular design and downstream processing of turoctocog alfa (NovoEight), a B-domain truncated factor VIII molecule. Blood Coagul Fibrinolysis 27(5):568–575PubMedPubMedCentralGoogle Scholar
  245. 245.
    Takedani H, Hirose J (2015) Turoctocog alfa: an evidence-based review of its potential in the treatment of hemophilia A. Drug Des Devel Ther 9:1767–1772PubMedPubMedCentralGoogle Scholar
  246. 246.
    Lieuw K (2017) Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches? J Blood Med 8:67–73PubMedPubMedCentralGoogle Scholar
  247. 247.
    Baunsgaard D, Nielsen AD, Nielsen PF, Henriksen A, Kristensen AK, Bagger HW et al (2018) A comparative analysis of heterogeneity in commercially available recombinant factor VIII products. Haemophilia 24(6):880–887PubMedGoogle Scholar
  248. 248.
    Keating GM, Dhillon S (2012) Octocog alfa (Advate(R)): a guide to its use in hemophilia A. BioDrugs 26(4):269–273PubMedGoogle Scholar
  249. 249.
    Tiede A, Brand B, Fischer R, Kavakli K, Lentz SR, Matsushita T et al (2013) Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost 11(4):670–678PubMedGoogle Scholar
  250. 250.
    Wynn TT, Gumuscu B (2016) Potential role of a new PEGylated recombinant factor VIII for hemophilia A. J Blood Med 7:121–128PubMedPubMedCentralGoogle Scholar
  251. 251.
    Peyvandi F, Kouides P, Turecek PL, Dow E, Berntorp E (2019) Evolution of replacement therapy for von Willebrand disease: from plasma fraction to recombinant von Willebrand factor. Blood Rev.  https://doi.org/10.1016/j.blre.2019.04.001 PubMedGoogle Scholar
  252. 252.
    Peyvandi F, Mamaev A, Wang J-D, Stasyshyn O, Timofeeva M, Curry N et al (2019) Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery. J Thromb Haemost 17(1):52–62PubMedGoogle Scholar
  253. 253.
    Crowther M, Levy GG, Lu G, Leeds J, Lin J, Pratikhya P et al (2014) A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Blood 124(21):4269Google Scholar
  254. 254.
    Korte W (2014) Catridecacog: a breakthrough in the treatment of congenital factor XIII A-subunit deficiency? J Blood Med 5:107–113PubMedPubMedCentralGoogle Scholar
  255. 255.
    Sottilotta G, Luise F, Oriana V, Piromalli A, Santacroce R, Lelio AD (2019) Use of Catridecacog in a patient with severe factor XIII deficiency undergoing surgery. Hematol Rep 11(1):7912PubMedPubMedCentralGoogle Scholar
  256. 256.
    Fenton JW, Ofosu FA, Brezniak DV, Hassouna HI (1998) Thrombin and antithrombotics. Semin Thromb Hemost 24(02):87–91PubMedGoogle Scholar
  257. 257.
    EMA (2016) EPAR summary for the public: thorinane (enoxaparin sodium). https://www.ema.europa.eu/en/documents/overview/thorinane-epar-summary-public_en.pdf
  258. 258.
  259. 259.
    EMA (2019) EPAR summary for the public: Inhixa (Enoxaparin sodium). https://www.ema.europa.eu/en/documents/overview/inhixa-epar-summary-public_en.pdf
  260. 260.
  261. 261.
    Lee S, Gibson CM (2007) Enoxaparin in acute coronary syndromes. Expert Rev Cardiovasc Ther 5(3):387–399PubMedGoogle Scholar
  262. 262.
    Greinacher A, Warkentin TE, Chong BH (2019) Heparin-induced thrombocytopenia. In: Michelson AD (ed) Platelets4th edn. Academic Press, Cambridge, pp 741–767Google Scholar
  263. 263.
    Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C et al (1990) The structure of a complex of recombinant hirudin and human alpha-thrombin. Science 249(4966):277–280PubMedGoogle Scholar
  264. 264.
    Rydel TJ, Tulinsky A, Bode W, Huber R (1991) Refined structure of the hirudin-thrombin complex. J Mol Biol 221(2):583–601PubMedGoogle Scholar
  265. 265.
    Lubenow N, Eichler P, Lietz T, Greinacher A (2005) Lepirudin in patients with heparin-induced thrombocytopenia – results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost 3(11):2428–2436PubMedGoogle Scholar
  266. 266.
    Tardy B, Lecompte T, Boelhen F, Tardy-Poncet B, Elalamy I, Morange P et al (2006) Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood 108(5):1492–1496PubMedGoogle Scholar
  267. 267.
    El-Mowafi H, El Araby A, Kandil Y, Zaghloul A (2018) Randomized, double-blind, placebo-controlled, interventional phase IV investigation to assess the efficacy and safety of r-hirudin gel (1120I.U) in patients with hematomas. Res Pract Thromb Haemost 2(1):139–146PubMedGoogle Scholar
  268. 268.
    Corral J, de la Morena-Barrio ME, Vicente V (2018) The genetics of antithrombin. Thromb Res 169:23–29PubMedGoogle Scholar
  269. 269.
    Echelard Y, Meade HM, Ziomek CA (2008) The first biopharmaceutical from transgenic animals: ATryn®. Wiley, Hoboken, pp 995–1020Google Scholar
  270. 270.
    EMA (2013) EPAR summary for the public: Fabrazyme (agalsidase beta). https://www.ema.europa.eu/en/documents/overview/fabrazyme-epar-summary-public_en.pdf
  271. 271.
    EMA (2015) EPAR summary for the public: Replagal (agalsidase alfa). https://www.ema.europa.eu/en/documents/overview/replagal-epar-summary-public_en.pdf
  272. 272.
    FaDA (2018) Prescribing information: Fabrazyme (agalsidase beta). https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103979s5303lbl.pdf
  273. 273.
    Vellard M (2003) The enzyme as drug: application of enzymes as pharmaceuticals. Curr Opin Biotechnol 14(4):444–450PubMedGoogle Scholar
  274. 274.
    FaDA (2018) Prescribing information for Activase (alteplase). https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103172s5259lbl.pdf
  275. 275.
    EMA (2018) Oncaspar (pegaspargase): an overview of Oncaspar and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/oncaspar-epar-medicines-overview_en.pdf
  276. 276.
    EMA (2015) EPAR summary for the public: Spectrila (asparaginase). https://www.ema.europa.eu/en/documents/overview/spectrila-epar-summary-public_en.pdf
  277. 277.
    FaDA (2013) Prescribing information: ELSPAR® (asparaginase). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/101063s5169lbl.pdf
  278. 278.
    EMA (2012) Public summary of opinion on orphan designation: pegylated recombinant Erwinia chrysanthemi L-asparaginase for the treatment of acute lymphoblastic leukaemia. https://www.ema.europa.eu/en/documents/orphan-designation/eu/3/11/889-public-summary-opinion-orphan-designation-pegylated-recombinant-erwinia-chrysanthemi-l_en.pdf
  279. 279.
    FaDA (2011) Prescribing information: ERWINAZE (asparaginase Erwinia chrysanthemi). https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125359lbl.pdf
  280. 280.
  281. 281.
    EMA (2009) Public summary of positive opinion for orphan designation of L-asparaginase encapsulated in erythrocytes for the treatment of pancreatic cancer. https://www.ema.europa.eu/en/documents/orphan-designation/eu/3/09/633-public-summary-positive-opinion-orphan-designation-l-asparaginase-encapsulated-erythrocytes_en.pdf
  282. 282.
    EMA (2013) Public summary of opinion on orphan designation: L-asparaginase encapsulated in erythrocytes for the treatment acute myeloid leukaemia. https://www.ema.europa.eu/en/documents/orphan-designation/eu/3/13/1106-public-summary-positive-opinion-l-asparaginase-encapsulated-erythrocytes-treatment-acute_en.pdf
  283. 283.
    FaDA (2014) Prescribing information: PULMOZYME® (dornase alfa). https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/103532s5175lbl.pdf
  284. 284.
    EMA (2014) EPAR summary for the public: Vimizim (elosulfase alfa). https://www.ema.europa.eu/en/documents/overview/vimizim-epar-summary-public_en.pdf
  285. 285.
    FaDA (2014) Prescribing information: VIMIZIM (elosulfase alfa). https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125460s000lbl.pdf
  286. 286.
    EMA (2010) EPAR summary for the public: Naglazyme (galsulfase). https://www.ema.europa.eu/en/documents/overview/naglazyme-epar-summary-public_en.pdf
  287. 287.
    FaDA (2013) Prescribing information: Naglazyme (galsulfase). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125117s111lbl.pdf
  288. 288.
    EMA (2016) EPAR summary for the public: Elaprase (idursulfase). https://www.ema.europa.eu/en/documents/overview/elaprase-epar-summary-public_en.pdf
  289. 289.
    FaDA (2018) Prescribing information: ELAPRASE® (idursulfase). https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125151s197lbl.pdf
  290. 290.
    EMA (2015) EPAR summary for the public: Aldurazyme (laronidase). https://www.ema.europa.eu/en/documents/overview/aldurazyme-epar-summary-public_en.pdf
  291. 291.
  292. 292.
    EMA (2010) EPAR summary for the public: Cerezyme (imiglucerase). https://www.ema.europa.eu/en/documents/overview/cerezyme-epar-summary-public_en.pdf
  293. 293.
    FaDA (2003) Proposed text of the labeling of the drug: cerezyme (imiglucerase for injection). https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/20367s066lbl.pdf
  294. 294.
    EMA (2016) EPAR summary for the public: VPRIV (velaglucerase alfa). https://www.ema.europa.eu/en/documents/overview/vpriv-epar-summary-public_en.pdf
  295. 295.
    FaDA (2010) Prescribing information for VPRIV™ (velaglucerase alfa for injection). https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022575lbl.pdf
  296. 296.
    EMA (2015) EPAR summary for the public: Fasturtec (rasburicase). https://www.ema.europa.eu/en/documents/overview/fasturtec-epar-summary-public_en.pdf
  297. 297.
  298. 298.
    EMA (2018) Lamzede (velmanase alfa): an overview of Lamzede and why it is authorised in the EU. https://www.ema.europa.eu/en/documents/overview/lamzede-epar-summary-public_en.pdf
  299. 299.
    Harmatz P, Cattaneo F, Ardigò D, Geraci S, Hennermann JB, Guffon N et al (2018) Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): novel global treatment response model and outcomes in patients with alpha-mannosidosis. Mol Genet Metab 124(2):152–160PubMedGoogle Scholar
  300. 300.
    Collen D, Lijnen RH (2005) Thrombolytic agents. Thromb Haemost 93(04):627–630PubMedGoogle Scholar
  301. 301.
    Hilleman DE, Tsikouris JP, Seals AA, Marmur JD (2007) Fibrinolytic agents for the management of ST-segment elevation myocardial infarction. Pharmacotherapy 27(11):1558–1570PubMedGoogle Scholar
  302. 302.
    FaDA (2019) Drugs@FDA: FDA approved drug products – search results for “alteplase”. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process
  303. 303.
    Moussaddy A, Demchuk AM, Hill MD (2018) Thrombolytic therapies for ischemic stroke: triumphs and future challenges. Neuropharmacology 134:272–279PubMedGoogle Scholar
  304. 304.
    Kunamneni A, Ogaugwu C, Goli D (2018) Enzymes as therapeutic agents. In: Nunes CS, Kumar V (eds) Enzymes in human and animal nutrition. Academic Press, Cambridge, pp 301–312Google Scholar
  305. 305.
    FaDA (2003) Prescribing information for ELSPAR ® (asparaginase). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/101063s5169lbl.pdf
  306. 306.
    EMA (2015) EPAR summary for the public: Xiapex (collagenase clostridium histolyticum). https://www.ema.europa.eu/en/documents/overview/xiapex-epar-summary-public_en.pdf
  307. 307.
    EMA (2012) Prescribing information for CREON (pancrelipase). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020725s016lbl.pdf#page=16
  308. 308.
    FaDA (2010) Prescribing information for PANCREAZE™ (pancrelipase). https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022523lbl.pdf
  309. 309.
    FaDA (2009) Prescribing information for ZENPEP (pancrelipase). https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022210s000lbl.pdf
  310. 310.
    FaDA (2012) Prescribing information for PERTZYE (pancrelipase). https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022175s000lbl.pdf
  311. 311.
    FaDA (2012) Prescribing information for VIOKACE (pancrelipase). https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022542s000lbl.pdf

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ana Catarina Silva
    • 1
    • 2
    Email author
  • Cládia Pina Costa
    • 1
  • Hugo Almeida
    • 1
  • João Nuno Moreira
    • 3
    • 4
  • José Manuel Sousa Lobo
    • 1
  1. 1.UCIBIO, REQUIMTE, MEDTECH, Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of PharmacyUniversity of PortoPortoPortugal
  2. 2.FP-ENAS (UFP Energy, Environment and Health Research Unit), CEBIMED (Biomedical Research Centre), Faculty of Health SciencesFernando Pessoa UniversityPortoPortugal
  3. 3.CNC – Center for Neuroscience and Cell Biology, Faculty of Medicine (Pólo I)University of CoimbraCoimbraPortugal
  4. 4.FFUC – Faculty of Pharmacy, Pólo das Ciências da Saúde, CoimbraUniversity of CoimbraCoimbraPortugal

Personalised recommendations