Modeling long-term health outcomes of patients with cystic fibrosis homozygous for F508del-CFTR treated with lumacaftor/ivacaftor

Abstract

Background:Lumacaftor/ivacaftor combination therapy is efficacious and generally safe for patients with cystic fibrosis (CF) homozygous for the F508del-CF transmembrane conductance regulator (CFTR) mutation. However, long-term survival benefits of lumacaftor/ivacaftor (LUM/IVA) cannot yet be quantified. Simulation models can provide predictions about long-term health outcomes. In this study, we aimed to project long-term health outcomes of LUM/IVA plus standard care (SC) in patients with CF homozygous for F508del-CFTR.Methods:This modeling study was an individual patient simulation in US patients aged ⩾6 years with CF, homozygous for F508del-CFTR. The primary outcome was projected survival among (a) a cohort of patients who ever initiated LUM/IVA, accounting for treatment discontinuations, and (b) a cohort of patients who remain on continuous LUM/IVA. Patient characteristics and model parameters were derived from clinical trials: VX14-809-109, VX13-809-011B, TRAFFIC/TRANSPORT, and PROGRESS; published literature; and the US CF Foundation Patient Registry.Results:Lumacaftor/ivacaftor + SC is expected to increase median survival by 6.1 years versus SC alone, accounting for treatment discontinuations. The incremental median predicted survival versus SC assuming initiation of LUM/IVA at ages 6, 12, 18, and 25 years was 17.7, 12.6, 8.0, and 3.8 years, respectively. Assuming lifetime treatment with LUM/IVA, incremental median survival was predicted to be 7.8 years longer in the LUM/IVA + SC cohort. Initiating LUM/IVA at ages 6, 12, 18, and 25 years and assuming lifetime treatment resulted in incremental median predicted survival of 23.4, 18.2, 11.0, and 4.8 years, respectively.Conclusions:Lumacaftor/ivacaftor is projected to increase survival for patients with CF. Initiation at an early age and treatment persistence result in further increments in projected survival.

Evaluation of a five-year predicted survival model for cystic fibrosis in later time periods

“…1). These findings suggest that the original unmodified 5-year predicted survival model remains useful for stratifying individuals into expected survival groups for observational or interventional studies of CF 29 . Worksheets allow comparisons of survival predictions using original and modified models (Table S7).…”

“…Currently recommended [10][11][12][13] beneficial treatments include pancreatic enzymes 10,14 , airway clearance 15,16 , mucolysis [17][18][19] , inhaled antibiotics [20][21][22] , anti-inflammatory agents 23,24 , and CF transmembrane regulator protein (CFTR) modulators [25][26][27] . Although gains have been tremendous, CF survival continues to fall short of the approximately 80 year expectation of life for the average newborn in the United States 28,29 , providing continued motivation to improve treatments 2 .…”

The Changing Epidemiology of Cystic Fibrosis: Incidence, Survival and Impact of the CFTR Gene Discovery

“…As these molecules have only been marketed since 2012, it is too early to assess their impact on patient survival. This is why an American team has recently sought to model, through simulations based on data from the US CF Registry, the long-term health outcomes of CF patients treated with the lumacaftor/ivacaftor combination [ 95 ]. This treatment is predicted to increase the estimated median age of survival of p.Phe508del homozygous patients by 6.1 years.…”

How Clinically Efficient Are Lumacaftor/Ivacaftor for Cystic Fibrosis Patients: An Updated Literature Review

“…They compared the treatment effects in patients with LUM/IVA with SOC and those with SOC only. They displayed that average life expectancy (LE) and additional survival years were promising in LUM/IVA compared with the SOC group [ 6 ].…”

“…The importance of early initiation of CFTR modulators in patients can be measurable with the overall first benefits of treatment on sufferers. These modulators will be a miracle drug, lessen their agony, improve their quality of life, decrease mortality, morbidity [ 5 , 6 ], and repeat hospitalization [ 7 ]. Adherence to therapy has additional beneficial effects as compared to non-adherence patients.…”