Клиническая эффективность и безопасность комбинированного препарата ивакафтор/лумакафтор у пациентов с муковисцидозом: обзор международных исследований

Муковисцидоз — аутосомно-рецессивное заболевание, вызванное нарушением структуры гена трансмембранного регулятора проводимости муковисцидоза (CFTR), характеризующееся тяжелым течением и неблагоприятным прогнозом при отсутствии или неоптимальном лечении. Одобрение для клинического применения в 2012 г. в США препаратов патогенетической терапии — модуляторов белка CFTR (потенциатор и корректоры) снизило летальность, связанную с этим заболеванием. В статье представлен обзор исследований клинической эффективности и безопасности комбинированного препарата ивакафтор плюс лумакафтор (Ива/Лум) — первого лицензированного препарата — модулятора CFTR для пациентов-гомозигот по варианту F508del. Показано, что Ива/Лум повышает функцию легких, снижает количество обострений бронхолегочного процесса, в том числе требующих введения антибиотиков и госпитализации, частично восстанавливает экзокринную функцию поджелудочной железы, увеличивает массу тела и массо-ростовой индекс, повышает качество жизни, что позволяет говорить о его благоприятном влиянии на течение и прогноз муковисцидоза. Отмечено также, что раннее начало применения препарата (с двухлетнего возраста) положительно влияет на прогноз заболевания, увеличивая продолжительность жизни и улучшая ее качество.

1. Муковисцидоз / под ред. Н.Ю. Каширской, Н.И. Капранова, Е.И. Кондратьевой. 2-е изд., перераб. и доп. — М.: ИД «МЕДПРАКТИКА-М»; 2021. — 680 c.

2. Mishra A, Greaves R, Massie J. The relevance of sweat testing for the diagnosis of cystic fibrosis in the genomic era. Clin Biochem Rev. 2005;26(4):135–153.

3. Jentsch TJ, Maritzen T, Zdebik AA. Chloride channel diseases resulting from impaired transepithelial transport or vesicular function. J Clin Invest. 2005;115(8):2039–2046. doi: 10.1172/JCI25470

4. Kogan I, Ramjeesingh M, Li C, et al. CFTR directly mediates nucleotide-regulated glutathione flux. EMBO J. 2003;22(9): 1981–1989. doi: 10.1093/emboj/cdg194

5. Cystic Fibrosis Mutation Database. Available online: http://www.genet.sickkids.on.ca. Accessed on September 9, 2021.

6. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117–133. doi: 10.1159/000029497

7. Dechecchi MC, Tamanini A, Cabrini G. Molecular basis of cystic fibrosis: from bench to bedside. Ann Transl Med. 2018;6(17):334. doi: 10.21037/atm.2018.06.48

8. De Boeck K, Vermeulen F, Dupont L. The diagnosis of cystic fibrosis. Presse Medicale. 2017;46(6 Pt 2):e97–e108. doi: 10.1016/j.lpm.2017.04.010

9. Zaher A, ElSaygh J, Elsori D, et al. A Review of Trikafta: Triple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Therapy. Cureus. 2021;13(7):e16144. doi: 10.7759/cureus.16144

10. Регистр больных муковисцидозом в Российской Федерации. 2019 год / под редакцией Н.Ю. Каширской, Е.И Кондратьевой, С.А. Красовского и др. — М.: ИД «МЕДПРАКТИКА-М»; 2021. — 68 c.

11. Veit G, Avramescu RG, Chiang AN, et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell. 2016;27(3):424–433. doi: 10.1091/mbc.E14-04-0935

12. De Boeck K, Zolin A, Cuppens H, et al. The relative frequency of CFTR mutation classes in European patients with cystic fibrosis. J Cyst Fibros. 2014;13(4):403–409. doi: 10.1016/j.jcf.2013.12.003

13. Кондратьева Е.И., Амелина Е.Л., Чернуха М.Ю. и др. Обзор клинических рекомендаций «Кистозный фиброз (муковисцидоз)» (2020) // Пульмонология. 2021;31(2):135–146. doi: 10.18093/0869-0189-2021-31-2-135-146

14. Van Goor F, Straley KS, Cao D, et al. Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol Lung Cell Mol Physiol. 2006;290(6):L1117–L1130. doi: 10.1152/ajplung.00169.2005

15. Kalydeco® (ivacaftor) Tablets Label. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203188s022l_207925s003lbl.pdf. Accessed on January 15, 2021.

16. Flume PA, Van Devanter DR. State of progress in treating cystic fibrosis respiratory disease. BMC Med. 2012;10:88. doi: 10.1186/1741-7015-10-88

17. Van Goor F, Hadida S, Grootenhuis PDJ, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A. 2011;108(46): 18843–18848. doi: 10.1073/pnas.1105787108

18. Rubin JL, O’Callaghan L, Pelligra C, et al. Modeling longterm health outcomes of patients with cystic fibrosis homozygous for F508del-CFTR treated with lumacaftor/ivacaftor. Ther Adv Respir Dis. 2019;13:1753466618820186. doi: 10.1177/1753466618820186

19. Wang XR, Li C. Decoding F508del misfolding in cystic fibrosis. Biomolecules. 2014;4(2):498–509. doi: 10.3390/biom4020498

20. Wainwright CE, Elborn JS, Ramsey BW, et al. LumacaftorIvacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220–231. doi: 10.1056/NEJMoa1409547

21. Konstan MW, McKone EF, Moss RB, et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017;5(2):107–118. doi: 10.1016/S2213-2600(16)30427-1

22. Ratjen F, Hug C, Marigowda G, et al. VX14-809-109 investigator group. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017;5(7):557–567. doi: 10.1016/S2213-2600(17)30215-1

23. Chilvers MA, Davies JC, Milla C, et al. Long-term safety and efficacy of lumacaftor-ivacaftor therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label, extension study. Lancet Respir Med. 2021;9(7):721–732. doi: 10.1016/S2213-2600(20)30517-8

24. McNamara JJ, McColley SA, Marigowda G, et al. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir Med. 2019;7(4):325–335. doi: 10.1016/S2213-2600(18)30460-0

25. Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2020;12(12):CD010966. doi: 10.1002/14651858.CD010966.pub3

26. Connett GJ. Lumacaftor-ivacaftor in the treatment of cystic fibrosis: design, development and place in therapy. Drug Des Devel Ther. 2019;13:2405–2412. doi: 10.2147/DDDT.S153719

27. Boyle MP, Bell SC, Konstan MW, et al. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med. 2014;2(7):527–538. doi: 10.1016/S2213-2600(14)70132-8

28. Graeber SY, Dopfer C, Naehrlich L, et al. Effects of lumacaftor ivacaftor therapy on cystic fibrosis transmembrane conductance regulator function in Phe508del homozygous patients with cystic fibrosis. Am J Respir Crit Care Med. 2018;197(11):1433–1442. doi: 10.1164/rccm.201710-1983OC

29. Aalbers BL, Hofland RW, Bronsveld I, et al. Females with cystic fibrosis have a larger decrease in sweat chloride in response to lumacaftor/ivacaftor compared to males. J Cyst Fibros. 2021; 20(1):e7–e11. doi: 10.1016/j.jcf.2020.05.004

30. Hoppe JE, Chilvers M, Ratjen F, et al. Long-term safety of lumacaftor-ivacaftor in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a multicentre, phase 3, open-label, extension study. Lancet Respir Med. 2021;9(9): 977–988. doi: 10.1016/S2213-2600(21)00069-2

31. Burgel PR, Durieu I, Chiron R, et al. French Cystic Fibrosis Reference Network study group. Clinical response to lumacaftorivacaftor in patients with cystic fibrosis according to baseline lung function. J Cyst Fibros. 2021;20(2):220–227. doi: 10.1016/j.jcf.2020.06.012

32. Gavioli EM, Guardado N, Haniff F, et al. A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators. J Clin Pharm Ther. 2021;46(2):286–294. doi: 10.1111/jcpt.13329

33. Taylor-Cousar JL, Jain M, Barto TL, et al. Lumacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR. J Cyst Fibros. 2018;17(2):228–235. doi: 10.1016/j.jcf.2017.09.012

34. Brokaar E, van Leeuwen M, Leegwater E, et al. Adverse drug reactions and discontinuation rate during the first year on orkambi — the earliest results of the STORM study. J Cyst Fibros. 2019;18(Suppl 1):S130. doi: 10.1016/S1569-1993(19)30553-3

35. Whiting P, Al M, Burgers L, et al. Ivacaftor for the treatment of patients with cystic fibrosis and the G551D mutation: a systematic review and cost-effectiveness analysis. Health Technol Assess. 2014;18(18):1–106. doi: 10.3310/hta18180

36. Talamo Guevara M, McColley SA. The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis. Expert Opin Drug Saf. 2017;16(11):1305–1311. doi: 10.1080/14740338.2017.1372419

37. McColley SA. A safety evaluation of ivacaftor for the treatment of cystic fibrosis. Expert Opin Drug Saf. 2016;15(5):709–715. doi: 10.1517/14740338.2016.1165666

38. Talwalkar JS, Koff JL, Lee HB, et al. Cystic fibrosis transmembrane regulator modulators: implications for the management of depression and anxiety in cystic fibrosis. Psychosomatics. 2017;58(4): 343–354. doi: 10.1016/j.psym.2017.04.001

39. Schneider EK, Azad MA, Han ML, et al. An unlikely pair: the antimicrobial synergy of polymyxin b in combination with the cystic fibrosis transmembrane conductance regulator drugs KALYDECO and ORKAMBI. ACS Infect Dis. 2016;2(7):478–488. doi: 10.1021/acsinfecdis.6b00082

40. Sergeev V, Chou FY, Lam GY, et al. The Extrapulmonary Effects of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Cystic Fibrosis. Ann Am Thorac Soc. 2020;17(2):147–154. doi: 10.1513/AnnalsATS.201909-671CME

41. Gifford AH, Heltshe SL, Goss CH. CFTR modulator use is associated with higher hemoglobin levels in individuals with cystic fibrosis. Ann Am Thorac Soc. 2019;16:331–340. doi: 10.1513/AnnalsATS.201807-449OC

42. Schwartz PJ, Gnecchi M, Dagradi F, et al. From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome type 2. Eur Heart J. 2019;40(23):1832–1836. doi: 10.1093/eurheartj/ehz023

43. Ebner A, Nikova D, Lange T, et al. Determination of CFTR densities in erythrocyte plasma membranes using recognition imaging. Nanotechnology. 2008;19:384017. doi: 10.1088/0957-4484/19/38/384017

44. Moheet A, Beisang D, Zhang L, et al. PROSPECT Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Lumacaftor/ivacaftor therapy fails to increase insulin secretion in F508del/F508del CF patients. J Cyst Fibros. 2021;20(2):333–338. doi: 10.1016/j.jcf.2020.09.001