Projecting the impact of delayed access to Trikafta for people with CF

Sources: Projecting the impact of delayed access to elexacaftor/tezacaftor/ivacaftor for people with Cystic Fibrosis
August 23, 2020. https://doi.org/10.1016/j.jcf.2020.07.017

Background
Therapies that target the underlying defect in cystic fibrosis (CF) are likely to impact the future characteristics of the CF population and health care utilization. The objectives of this study were to estimate the potential impact of elaxacaftor/tezacaftor/ivacaftor on morbidity and mortality and the consequences of delayed access to medication.

Introduction
Predicting health outcomes can promote a better understanding of the long-term needs of a given population and anticipate the demand for future health care services and resources. The development of regular cystic fibrosis transmembrane conductance (CFTR) modulatory therapies (CFTR) that address the underlying cause of cystic fibrosis (CF) for over 90% of the CF population is expected to significantly change the characteristics and health care use needs of the CF population. Phase III clinical trials of the most effective CFTR modulator combination, elexacaftor/tezacaftor/ivacaftor (TRIKAFTA®), demonstrated improved lung function and a reduction in short-term exacerbations. CFTR modulator treatment can also change disease trajectory and long-term mortality rates. As a result, an increasing number of adult CF patients are expected to live with this chronic condition, requiring careful planning and forecasting of the future needs of the CF system.
health care.

The triple drug combination elexacaftor/tezacaftor/ivacaftor was approved by the U.S. Food and Drug Administration in October 2019; however, the approval process and expected timelines for other countries are unclear. Furthermore, national approval of a treatment does not necessarily translate into the immediate availability of therapy for all patients, especially for expensive treatments, when decisions about drug prices and insurance coverage may be prolonged.

Disease-modifying therapies have the potential to transform the lives of people living with CF and change the clinical trajectory of the disease. The impact of delayed access to medication is not well understood. The objectives of this study were to estimate the potential impact of elexacaftor/ tezacaftor/ivacaftor on morbidity and mortality in the CF population, as well as the consequences of delayed access to medication.

Method
A microsimulation transition model was applied to data from the Canadian Infectious Diseases Registry to predict the severity of lung disease, lung exacerbations, deaths, and transplants up to 2030 under three scenarios:
1) no availability of elexacaftor/tezacaftor/ ivacaftor;
2) availability in 2021 (“early”);
3) availability in 2025 (“delayed”).

Published phase III data on treatment effects were used to estimate transition rates between different disease severity states.

Results
A total of 4,440 people had lung function values available in 2018 or values that could be assumed (either by carrying forward measurements from 2017 [n = 393] or by assuming a health condition in children under 6 years of age [n = 530]).

Projected results based on microsimulation modeling
Table 3 (SVB) exposes the different populations that were generated from the microsimulation model according to the key hypotheses concerning the status of the disease and the effect of the treatment.

1. Demographics and state of the lungs
In the baseline scenario, where current transition rates continue and no new modulatory therapies are introduced, the CF population is expected to increase from 4,440 to 5,415 people (ET 15) in 2030; it consists of approximately 35% children and 65% adults. Assuming that elexacaftor/tezacaftor/ivacaftor is not available, we estimated that there would be 3,185 (ET 13) (~ 60%) individuals with mild disease, 1,166 (ET 14) (~ 14) (~ 22%) moderate, and 447 (~ 8%) severe by 2030.
However, if all patients over the age of 12 with at least one F508del mutation received elexacaftor/tezacaftor/ivacaftor in 2021 (“early”) and the treatment was effective in slowing the progression of lung disease, the CF population would be larger in 2030 and there would be fewer people living with severe lung disease than if the medication were not available (Table 3; fig. 2). By 2030, the projections would result in a 60% (95% CI 55.3; 63.9%) decrease in people with severe lung disease, and an 18% (95% CI 18.2; 19.0) decrease in individuals with mild lung disease by 18% (95% CI 18.2; 19.0) in additional individuals with mild lung disease (Table 3). Postponing the availability of elexacaftor/tezacaftor/ivacaftor until 2025 (“delayed”) would also lead to a decrease in the number of people with severe lung diseases and an increase in the number of people living with mild lung disease, but the percentages of changes in these conditions would be considerably lower than if the drug were introduced “early” (Table 3).

2. Pulmonary exacerbations
Applying 2017 exacerbation rates to the baseline forecasts, i.e. 0.09/year in the “mild” disease group, 0.9/year in the “moderate” stage group, and 2.2/year in the “severe” stage group, the estimated number of pulmonary exacerbations requiring hospitalization or IV antibiotics at home in 2030 would increase from 1,988 to 2,311 (ET 36) (Table 3) (Table 3). In total, the number of exacerbations requiring hospitalization between 2019 and 2030 was estimated at 25,370 (ET 177) if triple therapy was not available. However, if the medication was available “early” and assuming that exacerbations were reduced by 63% (i.e., the rates of exacerbation would be 0.055/year in the mild disease group, 0.55/year in the moderate group, and 1.35/year in the severe stage group), the expected number of exacerbations would decrease, with approximately 4,135 (95% CI 4042; 4226) fewer between 2021 and 2030. As for the “delayed” introduction of the drug, the
Results remain 2,141 (95% CI 2043; 2239) fewer exacerbations between 2025 and 2030, but there would be many more exacerbations avoided if elexacaftor/tezacaftor/ivacaftor were introduced “early”.

3. Death or transplant
Without elexacaftor/tezacaftor/ivacaftor, the median survival age would remain stable between 2018 and 2030 (Table 3). Assuming that all eligible patients start triple therapy “early”, the total number of deaths would be reduced by 15% (95% CI 13.2; 18.4) by 2030. Based on the initial scenario, and after 10 years of therapy, the estimated median age of survival would increase by 9.2 (95% CI 7.5; 10.8) years by 2030 and there would be 74 (95% CI 62; 86) fewer deaths (Table 3; Fig. 4) and there would be 74 (95% CI 62; 86) fewer deaths (Table 3; Fig. 4). If the medication was “delayed,” the number of transplants and deaths would also be reduced, but to a lesser extent than if the medication was introduced earlier. By 2030, the “delayed” introduction of the drug would improve the median age of survival by 3.3 years (95% 1.7; 5.0), which would make 31 (95% CI 19; 44) fewer deaths between 2021 and 2030 (fig. 4).
If the drug was available “early,” 146 fewer transplants could be expected by 2030, which would be due to fewer individuals with severe lung function and 98 fewer transplants if the medication was “delayed.”

Conclusions
Delayed access to elexacaftor/tezacaftor/ivacaftor would have a negative impact on lung health and survival in the CF population.

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