Journal of The Korean Society of Inherited Metabolic disease (대한유전성대사질환학회지)

The Korea Society of Inherited Metabolic Disease (대한유전성대사질환학회)
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A New Treatment Option for Gaucher Disease Type 1: Substrate Reduction Therapy

제1형 고셔병 환자의 새로운 치료로서의 기질 감소 치료

  • Sohn, Young Bae (Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine)
  • 손영배 (아주대학교 의과대학 의학유전학과)
  • Published : 2016.12.31
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Abstract

제1형 고셔병(Gaucher disease type 1)은 리소좀 효소인 산성 ${\beta}$-글루코시다아제(acid ${\beta}-glucosidase$)의 결핍으로 인한 리소솜 축적 질환이다. 효소 활성도가 감소되어 기질이 축적되어, 간비종대, 빈혈, 혈소판감소증 및 골질환을 포함한 전신 증상이 발생한다. 재조합 효소 단백을 정맥 주입하는 효소 대체요법(Enzyme replacement therapy)는 지난 20년 넘게 고셔병의 표준 치료법이었다. 그러나 성공적인 효소 대체요법에도 불구하고, 심각한 폐증상과 골격 증상 등 고셔병 치료에 여전히 해결되지 않는 문제들이 남아 있다. 기질 감소 치료(Substrate reduction therapy)는 기질의 생합성을 억제하여 축적을 감소시킨다. 최근 새로운 경구용 기질감소 치료제인 엘리글루스타트(eliglustat)가 적합한 CYP2D6 대사 표현형을 가진 고셔병 성인 환자를 위한 1차 치료제로 미국과 유럽에서 승인되었다. 엘리글루스타트가 아직 한국에서는 쓰이지 않고 있지만, 본 종설에서는 문헌 검토를 통해 고셔병의 새로운 치료로서의 효소 대체요법을 소개하고자 한다. 아직 확고한 결론을 도출하기에는 연구 결과가 제한적이기는 하지만, 현재까지의 데이터에 따르면 엘리글루스타트는 임상 효능에 있어서 효소 보충 요법에 비열등성을 보인다. 장기 결과에 대한 추가 연구가 필요하지만, 엘리글루스타트의 승인은 해당 1형 고셔병 성인 환자들에게 경구 치료제라는 새로운 선택을 가능하게 하였다. 향후 국내에서 엘리글루스타트가 처방 가능해 지면, 각 환자 마다 철저한 평가를 통해 치료법을 선택할 수 있도록 해야 할 것이다. 나아가, 국내 1형 고셔병 환자들을 위해 엘리글루스타트의 사용에 관한 임상적 지침 또한 조만간 개발될 필요가 있다.

Keywords

References

  1. Grabowski GA, Andria G, Baldellou A, Campbell PE, Charrow J, Cohen IJ, et al. Pediatric non-neuronopathic Gaucher disease: presentation, diagnosis and assessment. Consensus statements. Eur J Pediatr 2004;163:58-66. https://doi.org/10.1007/s00431-003-1362-0
  2. Kaplan P, Baris H, De Meirleir L, Di Rocco M, El-Beshlawy A, Huemer M, et al. Revised recommendations for the management of Gaucher disease in children. Eur J Pediatr 2013;172:447-58. https://doi.org/10.1007/s00431-012-1771-z
  3. Chen M, Wang J. Gaucher disease: review of the literature. Arch Pathol Lab Med 2008;132:851-3.
  4. Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet 2008;372:1263-71. https://doi.org/10.1016/S0140-6736(08)61522-6
  5. Cox TM. Eliglustat tartrate, an orally active glucocerebroside synthase inhibitor for the potential treatment of Gaucher disease and other lysosomal storage diseases. Curr Opin Investig Drugs 2010;11:1169-81.
  6. Shayman JA. ELIGLUSTAT TARTRATE: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease. Drugs Future 2010;35:613-20. https://doi.org/10.1358/dof.2010.035.08.1505566
  7. Cox T, Lachmann R, Hollak C, Aerts J, van Weely S, Hrebicek M, et al. Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 2000;355:1481-5. https://doi.org/10.1016/S0140-6736(00)02161-9
  8. Cox TM, Amato D, Hollak CE, Luzy C, Silkey M, Giorgino R, et al. Evaluation of miglustat as maintenance therapy after enzyme therapy in adults with stable type 1 Gaucher disease: a prospective, openlabel non-inferiority study. Orphanet J Rare Dis 2012;7:102. https://doi.org/10.1186/1750-1172-7-102
  9. Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013;93:402-8. https://doi.org/10.1038/clpt.2013.2
  10. Balwani M, Burrow TA, Charrow J, Goker-Alpan O, Kaplan P, Kishnani PS, et al. Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States. Mol Genet Metab 2016;117:95-103. https://doi.org/10.1016/j.ymgme.2015.09.002
  11. Belmatoug N, Di Rocco M, Fraga C, Giraldo P, Hughes D, Lukina E, et al. Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe. Eur J Intern Med 2016.
  12. Choi JH, Lee BH. A phase 2 multi-center, open-label, switch-over trial to evaluate the safety and efficacy of Abcertin(R) in patients with type 1 Gaucher disease 2015;30:378-84.
  13. 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;122:1182-90. https://doi.org/10.1542/peds.2007-2144
  14. van Dussen L, Biegstraaten M, Dijkgraaf MG, Hollak CE. Modelling Gaucher disease progression: long-term enzyme replacement therapy reduces the incidence of splenectomy and bone complications. Orphanet J Rare Dis 2014;9:112. https://doi.org/10.1186/s13023-014-0112-x
  15. Smid BE, Ferraz MJ, Verhoek M, Mirzaian M, Wisse P, Overkleeft HS, et al. Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients. Orphanet J Rare Dis 2016;11:28. https://doi.org/10.1186/s13023-016-0413-3
  16. Brand M, Muller A, Alsop J, van Schaik IN, Bembi B, Hughes D. Results from a 9-year Intensive Safety Surveillance Scheme (IS(3)) in miglustat (Zavesca(R))-treated patients. Pharmacoepidemiol Drug Saf 2015;24:329-33. https://doi.org/10.1002/pds.3760
  17. Lukina E, Watman N, Arreguin EA, Dragosky M, Iastrebner M, Rosenbaum H, et al. Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study. Blood 2010;116:4095-8. https://doi.org/10.1182/blood-2010-06-293902
  18. Mistry PK, Lukina E, Ben Turkia H, Amato D, Baris H, Dasouki M, et al. 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
  19. Lukina E, Watman N, Dragosky M, Pastores GM, Arreguin EA, Rosenbaum H, et al. Eliglustat, an investigational oral therapy for Gaucher disease type 1: Phase 2 trial results after 4 years of treatment. Blood Cells Mol Dis 2014;53:274-6. https://doi.org/10.1016/j.bcmd.2014.04.002
  20. Cox TM, Drelichman G, Cravo R, Balwani M, Burrow TA, Martins AM, et al. Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial. Lancet 2015;385:2355-62. https://doi.org/10.1016/S0140-6736(14)61841-9
  21. Lee SJ, Lee SS, Jung HJ, Kim HS, Park SJ, Yeo CW, et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 2009;37:1464-70. https://doi.org/10.1124/dmd.108.022368
  22. Lee SY, Sohn KM, Ryu JY, Yoon YR, Shin JG, Kim JW. Sequence-based CYP2D6 genotyping in the Korean population. Ther Drug Monit 2006;28:382-7. https://doi.org/10.1097/01.ftd.0000211823.80854.db
  23. Shayman JA. The design and clinical development of inhibitors of glycosphingolipid synthesis: will invention be the mother of necessity? Trans Am Clin Climatol Assoc 2013;124:46-60.
  24. Ibrahim J, Underhill LH, Taylor JS, Angell J, Peterschmitt MJ. Clinical response to eliglustat in treatmentnaive patients with Gaucher disease type 1: Post-hoc comparison to imiglucerase-treated patients enrolled in the International Collaborative Gaucher Group Gaucher Registry. Mol Genet Metab Rep 2016;8:17-9. https://doi.org/10.1016/j.ymgmr.2016.06.003