Study of the efficacy and safety of the generic drug ivacaftor + tezacaftor + elexacaftor/ivacaftor (trade name Trilexa^®)

Cystic fibrosis (CF) is a universal exocrine disorder that affects virtually all organs and systems containing exocrine glands. A genetic defect in the cystic fibrosis transmembrane conductance regulator gene leads to increased viscosity of exocrine gland secretions, primarily in the respiratory tract. CFTR modulators improve the synthesis, processing, and/or function of the defective CFTR protein, which is a chloride channel.

Objective. To evaluate the efficacy of the generic drug ivacaftor + tezacaftor + elexacaftor/ivacaftor (trade name Trilexa®), in a group of patients not previously receiving triple targeted therapy after 3 months of treatment in patients who have not previously received the first threecomponent CFTR modulator.

Methods. Data from the Russian CF Patient Registry, entered into the “Targeted Therapy” block, were analyzed for the period from January to August 2025 (main group) and for the period from January 2022 to August 2022 (comparison group). Two groups of patients were identified: Group 1 included 28 pediatric patients (12 boys/16 girls) with a confirmed diagnosis of cystic fibrosis, who started receiving triple targeted therapy generic drug ivacaftor + tezacaftor + elexacaftor/ivacaftor. Group 2, the comparison group, consisted of 34 pediatric patients (14 boys/20 girls) who started receiving the original triple targeted drug ivacaftor + tezacaftor + elexacaftor/ivacaftor (trade name Trikafta®).

Results. When assessing the nutritional status, a significant increase in BMI was shown in both groups of patients at the start and after 3 months; p < 0.001. Sweat test parameters (conductivity in mmol/L) differed significantly both at the start of therapy and after a month in both groups. The difference between the average sweat test values (Δ mmol/L) in both groups were comparable and did not differ from each other. The groups did not differ in the number of adverse events, which were mild and did not lead to drug discontinuation. Both drugs, the original and the generic, demonstrated safety and good tolerability. Group 1 value was 43 (35.5; 55), and Group 2 value was 42 (32; 50.3); p = 0.86. FEV1 and FVC indicators showed a tendency to increase with both drugs, but it was not significant in both groups.

Conclusion. The triple targeted therapy with the use of generic drug ivacaftor + tezacaftor + elexacaftor/ivacaftor is effective and safe in this sample of pediatric patients with cystic fibrosis. No significant differences were found between generic drug and the original drug in relation to the main efficacy criteria during 3 months of use. The frequency, spectrum, and severity of reported adverse events associated with the use of generic drug were comparable to those associated with the use of the original drug.

1. Ministry of Health of the Russian Federation. [Clinical guidelines: Cystic Fibrosis (mucoviscidosis)]. 2021. Available at: https://cr.minzdrav.gov.ru/view-cr/372_2 (in Russian).

2. Mall M.A., Mayer-Hamblett N., Rowe S.M. Cystic fibrosis: emergence of highly effective targeted therapeutics and potential clinical implications. Am. J. Respir. Crit. Care Med. 2020; 201 (10): 1193–1208. DOI: 10.1164/rccm.201910-1943SO.

3. Bell S.C., Mall M.A., Gutierrez H. et al. The future of cystic fibrosis care: a global perspective. Lancet Respir. Med. 2020; 8 (1): 65–124. DOI: 10.1016/S2213-2600(19)30337-6.

4. Drugs.com. Trikafta (elexacaftor, tezacaftor, and ivacaftor): package insert / prescribing. Last updated on February 18, 2025. Available at: https://www.drugs.com/pro/trikafta.html#s-34067-9

5. Lopez A., Daly C., Vega-Hernandez G. et al. Elexacaftor/tezacaftor/ivacaftor projected survival and long-term health outcomes in people with cystic fibrosis homozygous for F508del. J. Cyst. Fibros. 2023; 22 (4): 607–614. DOI: 10.1016/j.jcf.2023.02.004.

6. Sutharsan S., McKone E.F., Downey D.G. et al. Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial. Lancet Respir. Med. 2022; 10 (3): 267–277. DOI: 10.1016/S2213-2600(21)00454-9.

7. Daines C.L., Tullis E., Costa S. et al. Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 144-week interim results from a 192-week open-label extension study. Eur. Respir. J. 2023; 62 (6): 2202029. DOI: 10.1183/13993003.02029-2022.

8. Kondratyeva E.I., Odinaeva N.D., Pasnova E.V. et al. [Efficacy and safety of triple therapy (elexacaftor/tezacaftor/ivacaftor) in children with cystic fibrosis: 12-month follow-up]. Pul'monologiya. 2024; 34 (2): 218–224. DOI: 10.18093/0869-0189-2024-34-2-218-224 (in Russian).

9. Voronkova A.Yu., Zhekaite E.K., Fatkhullina I.R. et al. [Adverse events during long-term use of two targeted drugs in pediatric patients with cystic fibrosis in the Russian Federation]. Pul'monologiya. 2025; 35 (2): 202–212. DOI: 10.18093/0869-0189-2025-35-2-202-212 (in Russian).

10. Zyryanov S.K., Fitilev S.B., Shkrebneva I.I., Vozzhaev A.V. [Drug interchangeability: clinical efficacy and safety]. Nevrologiya, neiropsikhiatriya, psikhosomatika. 2017; 9 (1S): 4–10. DOI: 10.14412/2074-2711-2017-1S-4-10 (in Russian).

11. Zyryanov S.K., Belousov Yu.B. [Quality of generic drug products and equivalence to original drug products]. Klinicheskaya mikrobiologiya i antimikrobnaya khimioterapiya. 2010; 12 (4): 314–320. Available at: https://cmac-journal.ru/publication/2010/4/cmac-2010-t12-n4-p314/ (in Russian).

12. Plotnikova E. Yu., Sukhikh A. S., Gracheva T. Yu. [Generics: global and domestic practice]. Pharmateka. 2019; 26 (9): 87–94. DOI: 10.18565/pharmateca.2019.9.87-94 (in Russian).

13. Khoseva E. N., Morozova T. E. [Economic advantages and weaknesses of generics in the drug provision system in Russia and abroad]. Kachestvennaya klinicheskaya praktika. 2013; (2): 63–68. Available at: https://www.clinvest.ru/jour/article/view/182 (in Russian).

14. Pal A., Wu F., Walenga R. et al. Leveraging modeling and simulation to enhance the efficiency of bioequivalence approaches for generic drugs: highlights from the 2023 generic drug science and research initiatives public workshop. AAPS J. 2024; 26 (3): 45. DOI: 10.1208/s12248-024-00916-8.

15. Zhukova D.Ya., Koval'skaya G.N. [The original and generic drugs in medical therapy]. Baykal'skiy meditsinskiy zhurnal. 2011; 106 (7): 96–102. Available at: https://cyberleninka.ru/article/n/originalnye-i-dzhenericheskie-lekarstvennye-sredstva-v-terapevticheskoy-praktike (in Russian).

16. [Scientific and analytical report on the assessment of the clinical efficacy, safety, and bioequivalence of the drug “Trilexa” (ivacaftor + tezacaftor elsacaftor and ivacaftor)]. Moscow; 2025. Available at: https://www.irwin.ru/wp-content/zagruzki/2025/01/Отчет-Трилекса.pdf (in Russian)

17. Food and Drug Administration. Bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA. February 24, 2022. Available at: https://www.fda.gov/drugs/news-events-human-drugs/bioequivalence-studies-pharmacokinetic-endpoints-drugs-submitted-under-anda-02242022

18. Eurasian Economic Union. [On the rules for conducting bioequivalence studies of reproduced medicines in the field of circulation of medicines in the Eurasian Economic Union]. 2015. Available at: https://regulation.eaeunion.org/orv/2288/ (in Russian).

19. Baran E., Pereyra B., Mattos L. et al. 382 Real-world experience with bioequivalent ETI formulations in adult cystic fibrosis patients: a prospective cohort study in Argentina. J. Cyst. Fibros. 2025; 24 (Suppl. 2): S212. DOI: 10.1016/S1569-1993(25)02000-4.

20. Tupayachi Ortiz M., Pereyra B., Baran E. 665 Comparative clinical outcomes of Trikafta versus bioequivalent ETI formulations in the management of cystic fibrosis in adults: a real world experience. J. Cyst. Fibros. 2025; 24 (Suppl. 2): S397. DOI: 10.1016/S1569-1993(25)02281-7.

21. Krasovskiy S.A., Kagazezhev R.U. [Using generic drug elexacaftor/tezacaftor/ivacaftor + ivacaftor in patients with cystic fidosis in routine clinical practice]. Pul'monologiya. 2023; 33 (6): 781–791. DOI: 10.18093/0869-0189-2023-33-6-781-791 (in Russian).

22. Marshalkina T.V., Zhanuzakova N.T., Mukatova I.Y. et al. The first results 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.

23. Kenzhebayeva Y.Zh., Mukatova I.Yu., Amelina E.A. et al. [Pregnancy and childbirth in a cystic fibrosis patient receiving a generic CFTR modulator: the first clinical case in Republic of Kazakhstan]. Pul'monologiya. 2025; 35 (4): 561–567. DOI: 10.18093/0869-0189-2025-35-4-561-567 (in Russian).

24. Mukatova I., Amelina E., Kim S., Serikova A. P066 the first experience of triple targeted therapy in adult patients with cystic fibrosis in Kazakhstan. J. Cyst. Fibros. 2025; 24 (Suppl. 1): S86. DOI: 10.1016/j.jcf.2025.03.084.

25. Kameneva M.Yu., Cherniak A.V., Aisanov Z.R. et al. [Spirometry: national guidelines for the testing and interpretation of results Interregional Public Organization “Russian Respiratory Society” All-Russian Public Organization “Russian Association of Specialists in Functional Diagnostics” All-Russian Public Organization “Russian Scientific Medical Society of Therapists”]. Pul'monologiya. 2023; 33 (3): 307–340. DOI: 10.18093/08690189-2023-33-3-307-340 (in Russian).

26. Lopez A., Daly C., Vega-Hernandez G. et al. Elexacaftor/tezacaftor/ivacaftor projected survival and long-term health outcomes in people with cystic fibrosis homozygous for F508del. J. Cyst. Fibros. 2023; 22 (4): 607–614. DOI: 10.1016/j.jcf.2023.02.004.

27. Kondratyeva E.I., Odinaeva N.D., Zhekaite E.K. et al. [Efficacy of CFTR modulators in clinical practice (6-month follow-up)]. Pul'monologiya. 2023; 33 (2): 189–197. DOI: 10.18093/0869-0189-2023-33-2-189-197 (in Russian).

28. Zemanick E.T., Ramsey B., Sands D. et al. Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment. J. Cyst. Fibros. 2025; 24 (2): 246–254. DOI: 10.1016/j.jcf.2024.12.006.

29. Dagenais R.V.E., Su V.C., Quon B.S. Correction: Dagenais et al. Real-world safety of CFTR modulators in the treatment of cystic fibrosis: a systematic review. J. Clin. Med. 2021, 10, 23. J. Clin. Med. 2022; 11 (2): 318. DOI: 10.3390/jcm11020318.