Pathogenetic treatment of cystic fibrosis: expanding access to drugs

Background. Cystic fibrosis is a hereditary monogenic disease inherited in an autosomal recessive pattern, caused by a mutation in the cystic fibrosis transmembrane regulator (CFTR) gene and characterized by multisystem involvement of exocrine glands, with particularly severe res- piratory disorders. Until recently, the treatment of cystic fibrosis was mainly symptomatic. A revolutionary breakthrough in the treatment of the disease is associated with the emergence of pathogenetic therapy with CFTR modulators, which eliminate the disturbances in the functioning of the CFTR chloride channel that underlie the disease. The article provides a detailed review of the classification of CFTR mutations and the corresponding classes of modulator drugs: potentiators (ivakaftor, detivakaftor), correctors (elexacaftor, tezacaftor, lumacaftor, vanzacaftor). Particular attention is paid to the highly effective triple combination of elexacaftor/tezacaftor/ivacaftor, which has become the gold standard for the treatment of cystic fibrosis. It is emphasized that early initiation of modulator therapy can prevent the development of severe manifestations of the disease. The epidemiological indicators of cystic fibrosis in Russia are considered separately, where there is a lag in the proportion of adult patients and the availability of targeted therapy compared to Western Europe and North America. As a solution to the problem of the availability of expensive drugs, data on generic triple therapy drugs are presented. The results of Russian studies demonstrating the bioequivalence, comparable efficacy, and safety of generic targeted drugs for the treatment of cystic fibrosis compared to the original drugs are presented.

Conclusion. CFTR modulators offer a personalized approach to the treatment of cystic fibrosis. The widespread use of both original and generic CFTR modulator drugs is a key factor in improving the effectiveness and accessibility of pathogenetic therapy, which will improve the survival and quality of life of patients with cystic fibrosis.

1. Lopes-Pacheco M. Cystic fibrosis: a clinical view. Cell Mol Life Sci. 2016; 73 (11): 2201-2214.

2. Riordan J. R. CFTR function and prospects for therapy. Annu Rev Biochem. 2005; 74: 377-405.

3. Saint-Criq V., Gray M. A. Role of CFTR in epithelial physiology. Cell Mol Life Sci. 2017; 74 (1): 93-115.

4. Moore M. D., Tarran R. Beyond CFTR: New targets for cystic fibrosis drug development. Expert OpinTher Targets. 2018; 22 (5): 423-435.

5. Cheng S. H., Gregory R. J., Marshall J., et al. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell. 1990; 63 (4): 827-834.

6. Annual Report 2023, Zolin A., Adamoli A., Bakkeheim E., 2025. https://www.ecfs.eu/sites/default/files/Annual%20Report_2023_vs1.2_ECFSPR_20250721.pdf.

7. Amelina E. L. Register of patients with cystic fibrosis in the Russian Federation. 2023. Edited by E. L. Amelina, N. Yu. Kashirskaya, E. I. Kondratyeva, S. A. Krasovsky, M. A. Starinova, A. Yu. Voronkova, E. K. Ginter. Moscow: MEDPRAKTIKA-M Publishing House, 2025, 70 p. DOI: 10.61726/1981.2025.26.16.001, ISBN: 978-5-98803-469-8. (In Russ.)

8. Cohen-Cymberknoh M., Shoseyov D., Wilschanski M. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med. 2011; 183 (12): 1569-1580.

9. Athanazio R. A., de Oliveira M. C., de Souza H. F., et al. Cystic fibrosis in Brazil: a review of recent studies. J Bras Pneumol. 2017; 43 (2): 142-150.

10. Castellani C., Assael B. M. Cystic fibrosis: diagnosis and management. Front Pediatr. 2018; 6: 174.

11. Stephenson A. L., Sykes J., Stanojevic S., et al. Lung transplantation for cystic fibrosis: outcomes in the modern era. Am J Respir Crit Care Med. 2017; 196 (12): 1581-1589.

12. Ramos K. J., Dellon E. P., Murray S., et al. Lung transplantation in cystic fibrosis: a review of current practices and outcomes. Expert Rev Respir Med. 2019; 13 (1): 25-34.

13. Calabrese D. R., Golden J. A., Leard L. E., et al. Outcomes after lung transplantation for cystic fibrosis: a single-center experience. J Heart Lung Transplant. 2015; 34 (10): 1305-1312.

14. Ronan N. J., Murphy P. J., Heaney L. G. Cystic fibrosis-related diabetes: current perspectives. Diabetes Metab Syndr Obes. 2017; 10: 313-322.

15. Lopes-Pacheco M., Amaral M. D., Cutting G. R. Emerging therapies for cystic fibrosis: from precision medicine to gene editing. Expert Opin Emerg Drugs. 2019; 24 (2): 109-123.

16. Collins F. S. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992; 256 (5058): 774-779.

17. CFTR1 Database. Cystic Fibrosis Mutation Database. http://www.genet.sickkids.on.ca/Home.html. (accessed Nov 09th, 2019).

18. Pereira A. C., Veit G., Avolio J., et al. Computational prediction of CFTR variants pathogenicity using machine learning approaches. Hum Mutat. 2019; 40 (9): 1328-1339.

19. Lucarelli M., Pelo E., Colombo C., et al. Complex alleles in CFTR: implications for diagnosis and therapy. Eur J Hum Genet. 2010; 18 (10): 1133-1139.

20. Diana A., Tomaiuolo R., Castaldo G. Complex CFTR alleles: clinical relevance and therapeutic implications. Clin Chem Lab Med. 2016; 54 (10): 1565-1572.

21. Pereira A. C., Veit G., Avolio J., et al. Complex CFTR alleles and their impact on modulator therapy response. J Cyst Fibros. 2019; 18 (6): 807-815.

22. Welsh M. J., Smith A. E. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993; 73 (7): 1251-1254.

23. Wilschanski M., Famini H., Strauss-Liviatan N., et al. A pilot study of the effect of gentamicin on nasal potential difference measurements in cystic fibrosis patients carrying stop mutations. Am J Hum Genet. 1995; 56 (5): 1165-1175.

24. Haardt M., Benharouga M., Lechardeur D., et al. Partial correction of the CFTR defect in cells from cystic fibrosis patients carrying the 3849+10kb C→T mutation by AONs. Mol Ther. 1999; 1 (4): 351-358.

25. Rowe S. M., Miller S., Sorscher E. J. Cystic fibrosis. N Engl J Med. 2005; 352 (19): 1992-2001.

26. De Boeck K., Amaral M. D. Progress in therapies for cystic fibrosis. Lancet Respir Med. 2016; 4 (8): 662-674.

27. Marson F. A., Bertuzzo V. R., Ribeiro J. D. CFTR gene mutations in cystic fibrosis: a systematic review. J Cyst Fibros. 2016; 15 (5): 565-573.

28. Veit G., Avramescu R. G., Chiang A. N., et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell. 2016; 27 (3): 424-433.

29. Rapino D., Botelho H. M., Awatade N. T., et al. Rescue of class II CFTR mutants by small molecules: a systematic approach. J Cyst Fibros. 2015; 14 (6): 749-758.

30. Dekkers J. F., Berkers G., Kruisselbrink E., et al. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci Transl Med. 2016; 8 (344): 344ra84.

31. Dekkers J. F., Wiegerinck C. L., de Jonge H. R., et al. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med. 2016; 19 (7): 939-945.

32. Lopes-Pacheco M., Veit G., Amaral M. D. CFTR modulators: the changing face of cystic fibrosis in the era of precision medicine. Front Pharmacol. 2016; 7: 511.

33. Lopes-Pacheco M., Veit G., Amaral M. D. Rescue of F508del-CFTR by correctors: mechanisms and clinical implications. J Cyst Fibros. 2017; 16 (Suppl 1): S1-S8.

34. Han S. T., Veit G., Ahmadi S., et al. Rescue of F508del-CFTR by novel correctors: structure-function insights. Mol Pharmacol. 2018; 94 (1): 712-722.

35. Awatade N. T., Wong N., Rayner C. R., et al. Heterogeneity in CFTR functional rescue by modulators across genotypes. J Cyst Fibros. 2019; 18 (3): 385-394.

36. Boyle M. P., Bell S. C., Konstan M. W., et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2014; 371 (10): 905-914.

37. Donaldson S. H., Pilewski J. M., Griese M., et al. VX-659-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med. 2018; 379 (17): 1599-1611.

38. Keating D., Marigowda G., Burr L., et al. VX-445-tezacaftor-ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med. 2018; 379 (17): 1599-1611.

39. Matthes E., Billet A., Hanrahan J. W. Rescue of F508del-CFTR by novel correctors: functional and mechanistic insights. J Cyst Fibros. 2018; 17 (3): 319-327.

40. Oates E. C., Schechter M. S. Modifiers of cystic fibrosis disease severity. Pediatr Pulmonol. 2016; 51 (S44): S28-S36.

41. O’Neal W. K., Knowles M. R. Genetic modifiers of cystic fibrosis. Am J Respir Cell Mol Biol. 2018; 58 (1): 24-31.

42. Ramsey B. W., Davies J., McElvaney N. G., et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011; 365 (18): 1663-1672.

43. Kutsev S. I., Izhevskaya V. L., Kondrateva E. I. Target therapy for cystic fibrosis. Pulmonologiya. 2021; 31 (2): 226-236. DOI: 10.18093/0869-0189-2021-31-2-226-236. (In Russ.)

44. Wainwright C. E., Elborn J. S., Ramsey B. W., et al. Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015; 373 (3): 220-231.

45. Rowe S. M., Daines C., Ringshausen F. C., et al. Tezacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017; 377 (21): 2013-2023.

46. Taylor-Cousar J. L., Munck A., McKone E. F., et al. Tezacaftor-ivacaftor in patients with cystic fibrosis heterozygous for Phe508del. N Engl J Med. 2017; 377 (21): 2013-2023.

47. Heijerman H. G. M., McKone E. F., Downey D. G., et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019; 394: 1940-1948.

48. Middleton P. G., Mall M. A., Dřevínek P., et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019; 381: 1809-1819.

49. Zemanick E. T., Taylor-Cousar J. L., Davies J., et al. A phase 3 open-label study of elexacaftor/tezacaftor/ivacaftor in children 6 through 11 years of age with cystic fibrosis and at least one F508del allele. Am J Respir Crit Care Med. 2021; 203: 1522-1532.

50. Mall M. A., Brugha R., Gartner S., et al. Efficacy and safety of elexacaftor/tezacaftor/ivacaftor in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function mutation: a phase 3b, randomized, placebo-controlled study. Am J Respir Crit Care Med. 2022; 206: 1361-1369.

51. Goralski J. L., Hoppe J. E., Mall M. A., et al. Phase 3 open-label clinical trial of elexacaftor/tezacaftor/ivacaftor in children aged 2-5 years with cystic fibrosis and at least one F508del allele. Am J Respir Crit Care Med. 2023; 208: 59-67.

52. He R., Lin F., Deng Z., Yu B. Elexacaftor-tezacaftorivacaftor for cystic fibrosis with Phe508del mutation: Evidence from randomized controlled trials. SAGE Open Med. 2024; 12: 20503121231225874.

53. Bower J. K., Volkova N., Ahluwalia N., et al. Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: Interim results of a long-term registry-based study. J Cyst Fibros. 2023; 22: 730-737.

54. Lopez A., Daly C., Vega-Hernandez G., MacGregor G., Rubin J. L. Elexacaftor/tezacaftor/ivacaftor projected survival and long-term health outcomes in people with cystic fibrosis homozygous for F508del. J Cyst Fibros. 2023; 22: 607-614.

55. Heijerman H. G. M., McKone E. F., Downey D. G., et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019; 394: 1940-1948.

56. Guo J., Garratt A., Hill A. Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J Cyst Fibros. 2022; 21 (3): 456-462.

57. Kondratyeva E. I., Avdeev S. N., Kutsev S. I. New possibilities for targeted treatment of cystic fibrosis. Pulmonology. 2025; 35 (2): 167-176. DOI: 10.18093/0869-0189-2025-35-2-167-17. (In Russ.)

58. Southern K. W. What does the expanding CFTR modulator programme mean for people with cystic fibrosis? Lancet Respir Med. 2025. PMID: 39805295. Published Online January 10, 2025. https://doi.org/10.1016/S2213-2600(24)00427-2.

59. Keating C., Yonker L. M., Vermeulen F., et al. Vanzacaftor-tezacaftordeutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials. Lancet Respir Med. 2025; published online Jan 2. https://doi.org/10.1016/2213-2600(24)00411-9.

60. Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis: ran- domised, double-blind, controlled, phase 2 trials Uluer, Ahmet Zhorsley, Alexander Solomon, George M. et al. The Lancet Respiratory Medicine, Volume 11, Issue 6, 550-562.

61. 2025 Prescribing Information uspi_vanzacaftor_tezacaftor_deutivacaftor.pdf.

62. De Vuyst R., Kam C., McKinzie C., et al. Medication Utilization and Lung Function Changes after Initiation of Treatment with Elexacaftor/Tezacaftor/Ivacaftor. Authorea. April 05, 2024. DOI: 10.22541/au.171228099.99627720/v1.

63. Vanzacaftor-tezacaftor-deutivacaftor for children aged 6-11 years with cystic fibrosis RIDGELINE Trial VX21-121-105: an analysis from a singlearm, phase 3 trial Hoppe, JordanaEMcPhail, Garyetal. The Lancet Respiratory Medicine. Vol. 13, Issue 3, 244-255.

64. Bessonova L., Volkova N., Higgins M., et al. Data from the US and UK cystic fibrosis registries sup- port disease modification by CFTR modulation with ivacaftor. Thorax. 2018; 73: 731-740.

65. Sawicki G. S., Sellers D. E., Robinson W. M. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J Cyst Fibros. 2013; 12 (2): 91-96.

66. Angelis A., Tarran R., Tiddens H., et al. Adherence to treatment in cystic fibrosis: a systematic review. Eur Respir Rev. 2015; 24 (136): 219-228.

67. Quittner A. L., Abbott J., Georgiopoulos A. M., et al. International adherence recommendations for treating cystic fibrosis. J Cyst Fibros. 2016; 15 (4): 431439.

68. Narayanan V., Sawicki G. S., Goss C. H. Adherence to chronic therapies in cystic fibrosis: a systematic review. PediatrPulmonol. 2017; 52 (10): 1283-1292.

69. Shvarts G. Ya. Generic and original drugs: war and peace. Speech at the Congress "Human and Medicine", 2012. https://www.youtube.com/watch?v=_0zkX1a0H6w. (In Russ.)

70. FDA. Facts about generic drugs. https://www.fda.gov.

71. DominguezLab S.R.L. Research Center. Bioequivalence of the generic drug Trilexa® compared to the original drug Trikafta®. (In Russ.)

72. Kondratyeva E. I. Analysis of efficacy and safety when changing target therapy within a single INN. Presentation at the conference "Vladikavkaz: Achievements and Prospects in the Diagnosis and Treatment of Respiratory Diseases", September 12, 2025. (In Russ.) https://disk.yandex.ru/i/l2bzadyKpTQkWg.

73. Mukatova I., Amelina E., Kim S., Serikova A. P066 the first experience of tripletargeted the rapyinadult patients with cysticfibrosisin Kazakhstan. J. Cyst. Fibros. 2025; 24 (Suppl. 1): S86. DOI: 10.1016/j.jcf.2025.03.084.

74. Kenzhebaeva Y. Zh., Mukatova I. Yu., Amelina E. L., Rapilbekova G. K., Ivanova-Razumova T. V., Tuleutaev E. T. Pregnancy and childbirth in a patient with cystic fibrosis against the background of a reproduced CFTR modulator: the first clinical case in the Republic of Kazakhstan. Pulmonologiia. 2025; 35 (4): 561-567. DOI: 10.18093/0869-0189-2025-35-4-561-567. (In Russ.)

75. Marshalina T. V., Zhanuzakova N. T., Mukatova I. Yu., Kim S. S., Amelina E. L. First experience of targeted therapy in children with cystic fibrosis in Kazakhstan. Nauka i Zdravookhranenie. 2024; 26 (4): 7-14. DOI: 10.34689/SH.2024.26.4.001. (In Russ.)

76. Krasovsky S. A., Kagazev R. U. Experience with the use of the generic drug elexacfort/tezacfort/ivacfort + ivacfort in patients with cystic fibrosis in routine clinical practice. Pulmonologiia. 2023; 33 (6): 781-791. DOI: 10.18093/0869-0189-2023-33-6-781-791. (In Russ.)