Cystic Fibrosis:The Modulator Era

Cystic Fibrosis (CF) is a genetic disease caused by variants in the CFTR gene. CFTR is a crucial membrane protein responsible for chloride transport in epithelial cells, impacting organ function. The Modulator Era focuses on CFTR modulators approved by the FDA for treating CF and improving outcomes. Learn about CF pathophysiology, CFTR mutations, and the importance of balanced ion gradients in managing CF. Explore the impact of CFTR dysfunction on pulmonary and extrapulmonary health.

• Cystic Fibrosis
• CFTR Protein
• CF Modulators
• Genetic Disease
• Organ Function

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1. Cystic Fibrosis: The Modulator Era Jake Brockmeyer, PharmD, BCPS, BCPPS Clinical Pharmacist Specialist, Cystic Fibrosis March 9th, 2024

2. The Eras Era The Modulator Era.. This may sound like a reference to Taylor Swift as she dominates the media during her "Eras Tour" However, the Modulator Era started well before her tour and this concept starting showing up in CF literature as early as 2015. So maybe Taylor actually got the idea from us?

3. Learning Objectives Understand the pathophysiology of CFTR protein as it relates to Cystic fibrosis Review FDA approved CFTR modulators Describe pulmonary and extrapulmonary outcomes of interest 3

4. Cystic Fibrosis (CF) CF is a genetic disease caused by variants of the CFTR gene Must get copy of the gene from both parents 1 in 2500 people born with CF 1 in 20 people are carriers of one gene www.cff.org/What-is-CF/Testing/Carrier-Testing-for-Cystic-Fibrosis/ 4

5. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) CFTR is a membrane protein belonging to the ABC transporter family CFTR transports Cl-out of epithelial cells CFTR is important to balance the ionic gradient and hydrate epithelial lining of various organs Education Steering Group. http://www.cftr.info. Accessed 2016. Zegarra-Moran O, Galietta LJV. CFTR pharmacotherapy. Cell Mol Life Sci. 2016. 5

6. CFTR - Mutation types Mechanism 4 1 premature insertion of a stop codon 6 3 2 defective protein processing and trafficking 3 altered CFTR gating and reduced CFTR opening probability 2 4* altered CFTR channel conductance 5* affecting mRNA splicing 1 5 6 increased CFTR turnover * - mild disease Schmidt BZ, Haaf JB, Leal T, et al. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. Clin Pharmacol. 2016;8:127-140 6

7. Mutations There are over 2000 mutations that lead to dysfunctional CFTR 7

8. Mutations 8

9. Outcome of F508del mutation Causes a defect in processing leading to decreased number of active proteins on the membrane For the active proteins that do make it, this mutation also disrupts channel opening Correcting CFTR activity in patients with this mutation would require a two-step approach Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor- ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-31. 9

10. Pulmonary Disease The hallmark characteristic of CF is chronic lung injury Cyclical process of airway obstruction, infection, and inflammation that leads to fatal tissue destruction Schmidt BZ, Haaf JB, Leal T, Noel S. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. Clinical Pharmacology: Advances and Applications. doi:10.2147/CPAA.S100759 10

11. Extrapulmonary Disease Other systems effected; Pancreases Liver Reproductive Sinus Renal GI Tract 11

12. Disease Progression Liou TG. The Clinical Biology of Cystic Fibrosis Transmembrane Regulator Protein: Its Role and Function in Extrapulmonary Disease. Chest. 2019 Mar 1;155(3):605 16. 12

13. General Management of CF Treatment Types Specific Therapies Airway Clearance Breathing techniques Chest physiotherapy/vests Inhaled and Oral Medications Bronchodilators Mucolytics Antibiotics Steroids Pancreatic Enzymes Pancrelipase (Creon, Pancreaze, Zenpep, etc) CFTR Modulators Potentiators: Ivacaftor Correctors: Lumacaftor, Tezacaftor, Elexacaftor Treatments and Therapies. Cystic Fibrosis Foundation. https://www.cff.org/Life-With-CF/Treatments-and-Therapies 13

14. Symptomatic Treatment Boeck KD. Cystic fibrosis in the year 2020: A disease with a new face. Acta Paediatrica. doi:10.1111/apa.15155 14

15. General Management of CF Treatment Types Specific Therapies Airway Clearance Breathing techniques Chest physiotherapy/vests Inhaled and Oral Medications Bronchodilators Mucolytics Antibiotics Steroids Pancreatic Enzymes Pancrelipase (Creon, Pancreaze, Zenpep, etc) CFTR Modulators Potentiators: Ivacaftor Correctors: Lumacaftor, Tezacaftor, Elexacaftor Treatments and Therapies. Cystic Fibrosis Foundation. https://www.cff.org/Life-With-CF/Treatments-and-Therapies 15

16. 16

17. CFTR - Mutation types Mechanism 4 1 premature insertion of a stop codon 6 3 2 defective protein processing and trafficking 3 altered CFTR gating and reduced CFTR opening probability 2 4* altered CFTR channel conductance 5* affecting mRNA splicing 1 5 6 increased CFTR turnover * - mild disease Schmidt BZ, Haaf JB, Leal T, et al. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. Clin Pharmacol. 2016;8:127-140 17

18. Corrector Potentiator Pharmacology of CFTR Education Steering Group. Helping healthcare professionals understand the role of genetic changes in CF. http://www.cftr.info. Accessed December 2016. 18

19. Pharmacology of CFTR https://www.youtube.com/watch?v=7WTjQY0V4qI 19

20. Potentiator Ivacaftor (Kalydeco) Mechanism of Action Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. KALYDECO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 20

21. Potentiator Ivacaftor (Kalydeco) 21

22. Potentiator Ivacaftor (Kalydeco) KALYDECO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 22

23. Corrector Potentiator Lumacaftor/Ivacaftor (Orkambi) Mechanism of Action Lumacaftor improves the conformational stability of F508del- CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. ORKAMBI [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 23

24. Corrector Potentiator Lumacaftor/Ivacaftor (Orkambi) ORKAMBI [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 24

25. Corrector Potentiator Lumacaftor/Ivacaftor (Orkambi) ORKAMBI [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 25

26. Corrector Potentiator Tezacaftor/Ivacaftor (Symdeko) Mechanism of Action Tezacaftor facilitates the cellular processing and trafficking of normal and select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface SYMDEKO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 26

27. Corrector Potentiator Tezacaftor/Ivacaftor (Symdeko) SYMDEKO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 27

28. Corrector Potentiator Tezacaftor/Ivacaftor (Symdeko) Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. doi:10.1056/NEJMoa1709846 28

29. Corrector Potentiator Corrector Elexacaftor/Tezacaftor/Ivacator (Trikafta) Mechanism of Action Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface TRIKAFTA [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2019. 29

30. Corrector Potentiator Corrector Elexacaftor/Tezacaftor/Ivacator (Trikafta) TRIKAFTA [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2019. 30

31. Corrector Potentiator Corrector Elexacaftor/Tezacaftor/Ivacator (Trikafta) Middleton PG, Mall MA, D ev nek P, et al. Elexacaftor Tezacaftor Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. New England Journal of Medicine. October 2019. doi:10.1056/NEJMoa1908639 31

32. Modulator Era: Outcomes of Interest 32

33. Potentiator FEV1 Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 33

34. Potentiator FEV1 Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 34

35. Potentiator Pulmonary Exacerbations Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 35

36. Potentiator Hospitalizations Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 36

37. Potentiator Hospitalizations Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 37

38. Potentiator Manifestations Bessonova L, Volkova N, Higgins M, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax. 2018;73(8):731-740. doi:10.1136/thoraxjnl-2017-210394 38

39. Corrector Potentiator OR FEV1 Meta Analysis Potentiator Habib ARR, Kajbafzadeh M, Desai S, Yang CL, Skolnik K, Quon BS. A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis. Sci Rep. 2019;9(1):7234. doi:10.1038/s41598- 019-43652-2 39

40. Extrapulmonary Outcomes Overview Sergeev V, Chou FY, Lam GY, Hamilton CM, Wilcox PG, Quon BS. The Extrapulmonary Effects of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Cystic Fibrosis. Annals ATS. 2019;17(2):147-154. doi:10.1513/AnnalsATS.201909-671CME 40

41. Potentiator Pancreatic Exocrine Function (Fecal Elastase 1) Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open- label, single-arm study. Lancet Respir Med. 2016;4(2):107-115. doi:10.1016/S2213-2600(15)00545-7 41

42. Corrector Potentiator Corrector Pancreatic Function (Fecal Elastase 1) FE-1 levels rise in pediatric CF post-modulator therapy. Indicates potential pancreatic function improvement. Underlines the importance of early CFTR modulator therapy. Stephenson KG, Lingle AJ, Baumberger KA, et al. Changes in fecal elastase-1 following initiation of CFTR modulator therapy in pediatric patients with cystic fibrosis. J Cyst Fibros. 2023;22(6):996-1001. doi:10.1016/j.jcf.2023.09.005 42

43. Corrector Potentiator BMI Burgel P-R, Munck A, Durieu I, et al. Real-Life Safety and Effectiveness of Lumacaftor Ivacaftor in Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2019;201(2):188-197. doi:10.1164/rccm.201906-1227OC 43

44. Potentiator Nutrition / Growth Followed 15 young children (2-24 months) with CF starting ivacaftor Over the first 12 weeks of therapy, significant weight gain and beneficial changes in nutritional biomarkers Supports ivacaftor's role in improving growth patterns. Comparable outcomes to non-CF children Tindall A, Bass R, Maqbool A, Stallings VA. Changes in nutrition and growth status in young children in the first 12 weeks of ivacaftor therapy. J Cyst Fibros. 2023;22(6):989-995. doi:10.1016/j.jcf.2023.04.010 44

45. Corrector Potentiator Corrector Nutrition / BMI 40 adult patients followed pre/post ELX/TEZ/IVA BMI increase but consumption decreased Suggesting increased BMI is caused mechanisms affecting metabolism and energy balance Caley LR, Jarosz-Griffiths HH, Smith L, et al. Body mass index and nutritional intake following Elexacaftor/Tezacaftor/Ivacaftor modulator therapy in adults with cystic fibrosis. J Cyst Fibros. 2023;22(6):1002-1009. 45 doi:10.1016/j.jcf.2023.06.010

46. Corrector Potentiator Corrector BMI - FFM Adult CF patients initiating ELX/TEZ/IVA. Explores the effect on BMI and body composition Results reveal significant increases in both fat mass (FM) and fat-free mass (FFM) among adults with CF, Indicating changes beyond mere BMI growth Incorporating routine body composition assessment in CF care can offer more health insights, enabling personalized management Proud D, Duckers J. Weight a minute: Exploring the effect on weight and body composition after the initiation of elexacaftor/tezacaftor/ivacaftor in adults with CF. J Cyst Fibros. 2023;22(5):847-850. doi:10.1016/j.jcf.2023.06.002 46

47. Corrector Potentiator Corrector Vitamin Levels Significant increase in vitamin A levels after ETI No significant change in vitamin D or E Highlights the need for regular vitamin monitoring Schembri L, Warraich S, Bentley S, Carr SB, Balfour-Lynn IM. Impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in children with cystic fibrosis. J Cyst Fibros. 2023;22(5):843-846. doi:10.1016/j.jcf.2023.04.019 47

48. Corrector Potentiator Corrector OR Vitamin Levels Potentiator Corrector OR CF patients various ages, impact of CFTR modulators on nutritional status and fat-soluble vitamins. ELX/TEZ/IVA therapy significantly improves nutritional status and increases levels of all fat- soluble vitamins in CF patients Ivacaftor and Lumacaftor/ivacaftor did not show the same improvements across vitamin D, A, and E Potentiator Francalanci M, Terlizzi V, Fevola C, et al. Nutritional Status and Circulating Levels of Fat-Soluble Vitamins in Cystic Fibrosis Patients: A Cohort Study and Evaluation of the Effect of CFTR Modulators. Children (Basel). 2023;10(2):252. doi:10.3390/children10020252 48

49. Potentiator CF Related Diabetes (CFRD) Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 49

50. Potentiator CF Related Diabetes (CFRD) Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 50

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