Treatment Breakthrough Changes Cystic Fibrosis Landscape

Cystic fibrosis (CF) is an inherited, progressive condition with historically high morbidity, mortality, and medical costs, including recurrent hospitalization.¹ The introduction of a novel class of therapies called cystic fibrosis transmembrane conductance regulator (CFTR) modulators and subsequent patient expansion in FDA approvals provide hope and tangible improvements in outcomes for a substantial portion of the population with CF.^2,3 This article explores the significant impact of elexacaftor/tezacaftor/ivacaftor and ivacaftor (ETI) combination therapy (Trikafta; Vertex Pharmaceuticals), a breakthrough CFTR modulator, on patients, healthcare systems, and the future implications of managing this complex disease.

CF results from 1 of >2000 identified mutation variants of the CFTR gene.² Mutations can lead to defective, reduced, or missing CFTR proteins, ultimately altering the composition and production of mucus, sweat, and digestive fluids.⁴ The disease can affect any organ with a mucosal lining, such as the lungs, pancreas, and intestines,⁵ and can lead to blockages, inflammation, and infections.^5,6 Patients with CF also have increased risks for diabetes, cirrhosis, arthritis, hypersplenism, and other comorbidities.^6,7 Nearly 40,000 children and adults are currently living with CF in the United States. Although the incidence of CF is decreasing, prevalence continues to rise as a result of earlier screening, advances in treatment, and improved life expectancy in patients with CF.⁸ CF has had devastating survival statistics: the median age at death in 2008 was 26 years, but with advancements in treatment, the median age at death has increased significantly to 66 years in 2022.⁹

The F508del-CFTR mutation is the most common CF-causing mutation, with up to 90% of patients with CF carrying >1 F508del copy.¹⁰ ETI, which is composed of fixed-dose elexacaftor/tezacaftor/ivacaftor and ivacaftor, is an oral CFTR modulator that improves difficulties in CFTR protein processing and function, including those attributed to F508del-CFTR.¹¹ ETI was granted breakthrough therapy and priority review designations by the FDA before approval, and it demonstrated substantial benefits on patients during clinical trials and after its release to market; thus, it has been heralded as a breakthrough treatment for CF.

ETI was initially approved in October 2019 for patients aged ≥12 years with ≥1 copies of the F508del-CFRT mutation based on 2 randomized, double-blind, multicenter phase 3 trials, one conducted in patients with heterozygous F508del-CFTR mutations (NCT03525444) and the other in patients with homozygous F508del-CFTR mutations (NCT03525548).^2,10,12,13 To demonstrate the safety and efficacy of ETI in patients with heterozygous mutations, Middleton and researchers randomly assigned 403 patients to receive ETI (n=200) or placebo (n=203) for 24 weeks.¹⁰ In the trial of patients with homozygous mutations and stable disease, Heijerman and colleagues randomly assigned 107 patients to receive ETI (n=55) or tezacaftor plus ivacaftor (n=52) for 4 weeks.¹³ In both studies, the ETI groups demonstrated significant improvement in the primary endpoint—an overall 10% to 14% absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (ppFEV₁)^10,13 at week 4,¹³ with continued improvement observed out to week 24 in the heterozygous mutations study.¹⁰ In addition, patients receiving ETI in both studies demonstrated improvements in infective pulmonary exacerbation rates, sweat chloride concentrations, Cystic Fibrosis Questionnaire–Revised respiratory domain scores, and body mass index (BMI).^10,13

ETI treatment was well-tolerated and considered reasonably safe. Few patients discontinued treatment, and there were no deaths as a result of adverse events (AEs) in either study.^10,13 AEs were mostly mild to moderate and generally consistent with patterns in CF itself. Severe AEs of any kind in the ETI cohorts occurred in 4% to 9.4% of patients.^10,13 The efficacy and safety of ETI in this age-group have since been demonstrated in a postmarket observational study commitment (NCT04038047).¹⁴ Overall, real-world patients receiving ETI demonstrated notable improvements in lung function, CF-associated symptoms, and BMI.¹⁴

Since its initial approval in 2019, ETI has undergone several indication expansions.¹¹ In 2021, approval was granted for its use in children aged 6 to 11 years and in patients with additional genotypes of the CFTR mutation that are responsive to ETI based on in vitro data.¹⁵ Most recently, the FDA granted approval in 2023 for the use of ETI in children aged ≥2 years, further broadening its reach within the CF population.^11,16 Although the indication was updated using data from new clinical trials, the safety profile remained similar to that observed in the trial led by Middleton and colleagues¹⁰ and did not undergo substantial revisions.¹¹ Currently, ETI is indicated for patients aged ≥2 years who have ≥1 F508del or a mutation in the CFTR gene that is responsive based on in vitro data. If the genotype is unclear, an FDA-approved CF mutation test may be needed.¹¹

The approval of ETI has led to substantial improvements in patient outcomes. According to the 2022 Cystic Fibrosis Foundation Patient Registry (CFFPR) report, overall CFTR modulator use in patients aged ≥12 years has increased from 40.1% in 2017 to 86% in 2022. The report notes outcomes improvements since ETI’s first approval: increased median predicted survival, decreased pulmonary exacerbations treated with intravenous antibiotics, and fewer lung transplants. The report also notes that the number of pregnancies in patients with CF had gradually increased through 2019 but dramatically increased in 2020 after ETI’s approval.¹⁷ Furthermore, ETI received the highest grade possible of “A” for effectiveness and value of treatment for CF from the Institute for Clinical and Economic Review (ICER).¹⁸

Despite the leap forward that ETI therapy represents, the impact on and the current unmet need of cost of care is considerable. Marshall and colleagues explored the financial implications of ETI treatment in commercially insured patients in the United States, demonstrating a potential 3-fold increase in total care costs with ETI treatment between April 2019 (pre-ETI) and June 2022 (post-ETI) from $58,180 to $198,815; P<.001).¹⁹ Medical benefit costs decreased from $28,764 to $12,484 (P<.001), but pharmacy benefit costs increased from $29,416 to $186,331 (P<.001).¹⁹ Although pharmacy costs may increase, the potential of ETI to reduce medical care and costs has broader implications. The 2022 CFFPR report showed a decrease in the annual number of days of hospitalization for pulmonary exacerbations since ETI was approved.¹⁷

In potentially anticipating such financial considerations, the SIMPLIFY trials (NCT04378153) assessed the ability of ETI to reduce the burden of CF treatment.²⁰ These 2 parallel, large, multicenter, open-label, randomized, controlled, noninferiority trials explored discontinuation versus continuation of either hypertonic saline (HS) or dornase alfa (DA) in patients with CF aged ≥12 years who were simultaneously receiving treatment with ETI.²⁰ The results showed that discontinuing either treatment for 6 weeks did not result in clinically meaningful differences in pulmonary function compared with continuing HS or DA treatment, and that it may be possible to reduce the number of concurrent therapies while receiving ETI.

Following these findings, the potential cost benefits of discontinuing HS or DA were explored using data from the Merative MarketScan Commercial Claims and Encounters Database and the ICD-10 code for CF in the inpatient and outpatient settings from January 1, 2020, to December 31, 2021, overlapping with the years of the SIMPLIFY studies. Researchers found that if patients discontinued the use of DA except for intermittent use, the collective annual savings would be $1.21 billion, and the cost-savings of discontinuing HS, except for rescue situations, was estimated at $10.2 million annually.²¹ The study demonstrated that although older therapies such as DA and HS are less costly than ETI, avenues are available to simultaneously ease the burden of outpatient prescriptions costs and reduce the complexity of treatment, while preserving the clinical and quality-of-life improvements demonstrated by ETI therapy.

ETI represents a transformative milestone in the management of CF, offering hope and tangible improvements in patient outcomes. However, ongoing research, cost considerations, and a commitment to addressing remaining challenges are paramount as we strive toward bettering the lives of those with this complex condition. When considering the cost findings, it is important to consider that almost 50% of patients are reported to participate in patient assistance programs, pointing to limitations of access without financial assistance.¹⁷ The interplay of accumulator or maximizer adjustments with assistance program monthly limits are currently of concern for maintaining access and has the potential to limit the reach of patient assistance programs.²²

References

1. Mayo Clinic. Cystic fibrosis—symptoms and causes. November 23, 2021. Accessed April 3, 2024. www.mayoclinic.org/diseases-conditions/cystic-fibrosis/symptoms-causes/syc-20353700
2. US Food and Drug Administration. FDA approves new breakthrough therapy for cystic fibrosis. October 21, 2019. Accessed April 3, 2024. www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis
3. Trikafta (elexacaftor/tezacaftor/ivacaftor). Cystic-fibrosis.com. November 17, 2019. Accessed April 3, 2024. https://cystic-fibrosis.com/treatment/trikafta
4. Farinha CM, Callebaut I. Molecular mechanisms of cystic fibrosis—how mutations lead to misfunction and guide therapy. Biosci Rep. 2022;42(7):BSR20212006.
5. Cystic fibrosis—what is cystic fibrosis? Johns Hopkins Medicine. Accessed April 3, 2024. www.hopkinsmedicine.org/health/conditions-and-diseases/cystic-fibrosis
6. National Heart, Lung, and Blood Institute. Cystic fibrosis—what is cystic fibrosis? Updated November 21, 2023. Accessed April 3, 2024. www.nhlbi.nih.gov/health/cystic-fibrosis
7. Centers for Disease Control and Prevention. Genomics & precision health—cystic fibrosis. Updated May 9, 2022. Accessed April 3, 2024. www.cdc.gov/genomics/disease/cystic_fibrosis.htm
8. Cystic Fibrosis Foundation. CF foundation estimates increase in CF population. July 28, 2022. Accessed April 3, 2024. www.cff.org/news/2022-07/cf-foundation-estimates-increase-cf-population
9. Epic Research. Cystic fibrosis patients living much longer in 2022 than in 2008. August 2, 2023. Accessed April 3, 2024. www.epicresearch.org/articles/cystic-fibrosis-patients-living-much-longer-in-2022-than-in-2008
10. Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single phe508del allele. N Engl J Med. 2019;381:1809-1819.
11. Trikafta (elexacaftor, tezacaftor, and ivacaftor; ivacaftor) granules for oral use [prescribing information]. Vertex Pharmaceuticals; August 2023. Accessed April 3, 2024. www.accessdata.fda.gov/drugsatfda_docs/label/2023/217660s000lbl.pdf
12. Trikafta (elexacaftor, tezacaftor, and ivacaftor; ivacaftor) tablets for oral use [prescribing information]. Vertex Pharmaceuticals; October 2019. Accessed April 3, 2024. www.accessdata.fda.gov/drugsatfda_docs/label/2019/212273s000lbl.pdf
13. Heijerman HG, McKone EF, Downey DG, 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.
14. Nichols DP, Paynter AC, Heltshe SL, et al. Clinical effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: a clinical trial. Am J Respir Crit Care Med. 2022;205:529-539.
15. Trikafta (elexacaftor, tezacaftor, and ivacaftor) tablets for oral use [prescribing information]. Vertex Pharmaceuticals; June 2021. Accessed April 3, 2024. www.accessdata.fda.gov/drugsatfda_docs/label/2021/212273s004lbl.pdf
16. Goralski JL, Hoppe JE, Mall MA, 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.
17. Cystic Fibrosis Foundation. 2022 Patient Registry Annual Data Report. Accessed April 3, 2024. www.cff.org/medical-professionals/patient-registry
18. Institute for Clinical and Economic Review. Modulator treatments for cystic fibrosis: effectiveness and value—final evidence report and meeting summary. September 23, 2020. Accessed April 3, 2024. www.icer.org/wp-content/uploads/2020/08/ICER_CF_Final_Report_092320.pdf
19. Marshall LZ, Espinosa R, Starner CI, et al. Real-world outcomes and direct care cost before and after elexacaftor/tezacaftor/ivacaftor initiation in commercially insured members with cystic fibrosis. J Manag Care Spec Pharm. 2023;29:599-606.
20. Mayer-Hamblett N, Ratjen F, Russell R, et al. Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials. Lancet Respir Med. 2023;11:329-340.
21. Gold LS, Hansen RN, Mayer-Hamblett N, et al. The cost of simplifying treatments for cystic fibrosis: implications of the SIMPLIFY trial. J Manag Care Spec Pharm. 2024;30:26-33.
22. Vertex copay assistance: tips from a CF pharmacist. Cystic Fibrosis Foundation. November 7, 2022. Accessed April 3, 2024. www.cff.org/community-posts/2022-11/vertex-copay-assistance-tips-cf-pharmacist