Cost-Effectiveness of Ivacaftor Therapy for Treatment of Cystic Fibrosis Patients With the G551D Gating Mutation.

OBJECTIVES: Cystic fibrosis (CF) is a rare genetic disease with no cure. Until recently, treatment has targeted symptoms of the disease and not the disease-causing genetic defect. Ivacaftor is included in a new class of breakthrough drugs targeting the genetic defects of CF. We sought to estimate the long-term cost-effectiveness of ivacaftor from a US payer perspective. METHODS: We developed an individual-level microsimulation model that followed a cohort of heterogeneous US CF patients over a lifetime. The primary outcome of interest was quality-adjusted life years (QALYs). We also compared unadjusted life years, count of acute pulmonary exacerbations, and count of lung transplants over a lifetime between patients treated with ivacaftor plus best supportive care and patients treated with best supportive care alone. We conducted one-way and probabilistic sensitivity analyses to test the impact of various model inputs and uncertainties. RESULTS: We found a substantial increase in QALYs, life years, and treatment costs over a lifetime for patients treated with ivacaftor plus best supportive care versus best supportive care alone. Discounted results for ivacaftor were 22.92 QALYs and $8 797 840 in total lifetime costs compared to 16.12 QALYs and $2 336 366 lifetime costs for best supportive care alone. The incremental cost-effectiveness ratios (ICERs) were $950 217 per QALY. Results from the probabilistic sensitivity analysis indicated a 0% chance that ivacaftor was cost-effective at a willingness-to-pay (WTP) threshold of $500 000 per QALY. CONCLUSIONS: Treatment with ivacaftor plus best supportive care versus best supportive care alone is not cost-effective at or near commonly accepted WTP thresholds.

Indacaterol/glycopyrronium is cost-effective compared to salmeterol/fluticasone in COPD: FLAME-based modelling in a Swedish population.

BACKGROUND: This study assessed the cost-effectiveness of indacaterol/glycopyrronium (IND/GLY) versus salmeterol/fluticasone (SFC) in chronic obstructive pulmonary disease (COPD) patients with moderate to very severe airflow limitation and ≥1 exacerbation in the preceding year. METHODS: A previously published and validated patient-level simulation model was adapted using clinical data from the FLAME trial and real-world cost data from the ARCTIC study. Costs (total monetary costs comprising drug, maintenance, exacerbation, and pneumonia costs) and health outcomes (life-years (LYs), quality-adjusted life-years (QALYs)) were projected over various time horizons (1, 5, 10 years, and lifetime) from the Swedish payer's perspective and were discounted at 3% annually. Uncertainty in model input values was studied through one-way and probabilistic sensitivity analyses. Subgroup analyses were also performed. RESULTS: IND/GLY was associated with lower costs and better outcomes compared with SFC over all the analysed time horizons. Use of IND/GLY resulted in additional 0.192 LYs and 0.134 QALYs with cost savings of €1211 compared with SFC over lifetime. The net monetary benefit (NMB) was estimated to be €8560 based on a willingness-to-pay threshold of €55,000/QALY. The NMB was higher in the following subgroups: severe (GOLD 3), high risk and more symptoms (GOLD D), females, and current smokers. CONCLUSION: IND/GLY is a cost-effective treatment compared with SFC in COPD patients with mMRC dyspnea grade ≥ 2, moderate to very severe airflow limitation, and ≥1 exacerbation in the preceding year.

The pharmacokinetic interaction between ivacaftor and ritonavir in healthy volunteers.

AIMS: The aim of this study was to determine the pharmacokinetic interaction between ivacaftor and ritonavir. METHODS: A liquid chromatography mass spectrometry (LC-MS) method was developed for the measurement of ivacaftor in plasma. An open-label, sequential, cross-over study was conducted with 12 healthy volunteers. Three pharmacokinetic profiles were assessed for each volunteer: ivacaftor 150 mg alone (study A), ivacaftor 150 mg plus ritonavir 50 mg daily (study B), and ivacaftor 150 mg plus ritonavir 50 mg daily after two weeks of ritonavir 50 mg daily (study C). RESULTS: Addition of ritonavir 50 mg daily to ivacaftor 150 mg resulted in significant inhibition of the metabolism of ivacaftor. Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf obv ) increased significantly in both studies B and C compared to study A (GMR [95% CI] 19.71 [13.18-31.33] and 19.77 [14.0-27.93] respectively). Elimination half-life (t1/2 ) was significantly longer in both studies B and C compared to study A (GMR [95% CI] 11.14 [8.72-13.62] and 9.72 [6.68-12.85] respectively). There was no significant difference in any of the pharmacokinetic parameters between study B and study C. CONCLUSION: Ritonavir resulted in significant inhibition of the metabolism of ivacaftor. These data suggest that ritonavir may be used to inhibit the metabolism of ivacaftor in patients with cystic fibrosis (CF). Such an approach may increase the effectiveness of ivacaftor in 'poor responders' by maintaining higher plasma concentrations. It also has the potential to significantly reduce the cost of ivacaftor therapy.

Forecasting the Long-Term Clinical and Economic Outcomes of Lumacaftor/Ivacaftor in Cystic Fibrosis Patients with Homozygous phe508del Mutation.

OBJECTIVES: To forecast lifetime outcomes and cost of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis (CF) with homozygous phe508del mutation from the US payer perspective. METHODS: A lifetime Markov model was developed from a US payer perspective. The model included five health states: 1) mild lung disease (percent predicted forced expiratory volume in 1 second [FEV1] >70%), 2) moderate lung disease (40% ≤ FEV1 ≤ 70%), 3) severe lung disease (FEV1 < 40%), 4) lung transplantation, and 5) death. All inputs were derived from published literature. We estimated lumacaftor/ivacaftor's improvement in outcomes compared with a non-CF referent population as well as CF-specific mortality estimates. RESULTS: Lumacaftor/ivacaftor was associated with additional 2.91 life-years (95% credible interval 2.55-3.56) and additional 2.42 quality-adjusted life-years (QALYs) (95% credible interval 2.10-2.98). Lumacaftor/ivacaftor was associated with improvements in survival and QALYs equivalent to 27.6% and 20.7%, respectively, for the survival and QALY gaps between CF usual care and their non-CF peers. The incremental lifetime cost was $2,632,249. CONCLUSIONS: Lumacaftor/ivacaftor increased life-years and QALYs in CF patients with the homozygous phe508del mutation and moved morbidity and mortality closer to that of their non-CF peers but it came with higher cost.

Ivacaftor for cystic fibrosis: An evaluation of real world utilisation and expenditure in the Irish Healthcare Setting.

In Ireland, Ivacaftor is reimbursed, on the High-Tech Drug Scheme, for the treatment of cystic fibrosis in patients age 6 years and older who have the G551D mutation. The aim of this study was to analyse the utilisation and expenditure of Ivacaftor on this scheme in the 12 month period post-reimbursement. All patients who had received Ivacaftor (regardless of General Medical Services Scheme eligibility/ineligibility) were included. A total of 140 individuals (male=74; 53%) received Ivacaftor over the defined 12 month study period (from January 2015 to December 2015 inclusive). The cohort ranged in age from 6 years to 61 years. The mean age was 22 years; a positive skew in age distribution indicated that a greater number of the cohort were in the younger age groups. No statistically significant difference was detected in the mean ages of the male and female subgroups. Drug acquisition expenditure by the Health Services Executive on Ivacaftor over the 12 month study period was €29.81 million.

Forecasting US ivacaftor outcomes and cost in cystic fibrosis patients with the G551D mutation.

Ivacaftor, a breakthrough treatment for cystic fibrosis (CF) patients with the G551D genetic mutation, lacks long-term clinical and cost projections. This study forecasted outcomes and cost by comparing ivacaftor plus usual care versus usual care alone.A lifetime Markov model was conducted from a US payer perspective. The model consisted of five health states: 1) forced expiratory volume in 1 s (FEV1) % pred ≥70%, 2) 40%≤ FEV1 % pred <70%, 3) FEV1 % pred <40%, 4) lung transplantation and 5) death. All inputs were extracted from published literature. Budget impact was also estimated. We estimated ivacaftor's improvement in outcomes compared with a non-CF referent population.Ivacaftor was associated with 18.25 (95% credible interval (CrI) 13.71-22.20) additional life-years and 15.03 (95% CrI 11.13-18.73) additional quality-adjusted life-years (QALYs). Ivacaftor was associated with improvements in survival and QALYs equivalent to 68% and 56%, respectively, for the survival and QALY gaps between CF usual care and their non-CF peers. The incremental lifetime cost was $3 374 584. The budget impact was $0.087 per member per month.Ivacaftor increased life-years and QALYs in CF patients with the G551D mutation, and moved morbidity and mortality closer to that of their non-CF peers. Ivacaftor costs much more than usual care, but comes at a relatively limited budget impact.

Cystic fibrosis in an era of genomically guided therapy.

Although affecting only 4-5% of those with cystic fibrosis (CF), the G551D-CFTR mutation is the target of the recently approved 'orphan drug', ivacaftor. The promise of such genomically guided therapies heralds a new era in the management of CF. A phase 3 trial demonstrated significant improvements in forced expiratory volume in 1 s (FEV(1)) from baseline, average weight gain, concentration in sweat chloride and reductions in pulmonary exacerbations [Ramsey, B.W., et al. A CFTR potentiator in patients with CF and the G551D mutation. N. Engl. J. Med., 2011. 365: 1663-1672.)]. Ivacaftor is among a group of recently approved, novel, mutation guided 'orphan drug' therapies that have established clinical benefits within their respective disease categories. They do not, however, offer a cure. Pharmaceutical and biotech companies have leveraged the incentivized benefits of the Orphan Drug Act to develop more of these drugs for orphan disorders affecting populations of <200 000 patients. With marked clinical efficacy via DNA sequence guidance, these drugs have also set a precedent in terms of the substantial annual costs and if this trend continues, such expenditures may become unsustainable. This paper explores the genomic pathophysiology of CF and how therapies such as ivacaftor provide benefit to those with the disease but at a considerably elevated price point.

Sweat chloride is not a useful marker of clinical response to Ivacaftor.

Clinical trials have revealed that Ivacaftor significantly reduces sweat chloride in patients with cystic fibrosis who carry the G551D mutation. This finding has been incorporated into the commissioning guidelines in the UK with a sweat chloride reduction of 30% or below 60 mmol/L, specified as the main criteria for continued funding of Ivacaftor for individual patients. In a cohort of 24 adults who were prescribed Ivacaftor, there was no correlation between absolute or relative reductions in sweat chloride and improvements in lung function. This questions the validity of sweat chloride as a surrogate marker of clinical efficacy.

Clinical, economic, and societal burden of cystic fibrosis and the impact of the CFTR modulator, lumacaftor/ivacaftor: an assessment using linked registry data in Sweden.

AIMS: We aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm) treatment on people with CF, caregivers, and healthcare systems. MATERIAL AND METHODS: This retrospective study used linked real-world data from Swedish national population-based registries and the Swedish CF Quality Registry to assess clinical, economic, and societal burden and CFTR impact in CF. Records from people with CF and a ten-fold control population without CF matched by sex, birth year, and location were compared during 2019. Outcomes for a subset aged >6 years initiating lumacaftor/ivacaftor (LUM/IVA) in 2018 were compared 12 months pre- and post-treatment initiation. RESULTS: People with CF (n = 743) had >10 times more inpatient and outpatient specialist visits annually vs controls (n = 7406). Those aged >18 had an additional 77·7 (95% CI: 70·3, 85·1) days of work absence, at a societal cost of €11,563 (95% CI: 10,463, 12,662), while caregivers of those aged <18 missed an additional 6.1 (5.0, 7.2) workdays. With LUM/IVA treatment, people with CF (n = 100) had significantly increased lung function (mean change in ppFEV1 [3·8 points; 95% CI: 1·1, 6·6]), on average 0·5 (95% CI: -0·8, -0·2) fewer pulmonary exacerbations and 45·2 (95% CI: 13·3, 77·2) fewer days of antibiotics. Days of work lost by caregivers of people with CF aged <18 decreased by 5·4 days (95% CI: 2·9, 7·9). CONCLUSION: CF is associated with a high clinical economic and societal burden in Sweden. Improvements in clinical status observed in people with CF treated with LUM/IVA were reflected in reduced caregiver and societal burden.

Cystic fibrosis (CF) is a disease caused by a single faulty gene called CFTR, which affects the lungs, pancreas, and other organs. Medications known as CFTR modulators help improve the function of this faulty gene and have shown benefits for people with CF. In Sweden, two such medicines, lumacaftor and ivacaftor (LUM/IVA), have been available since July 2018 for treating CF. This study looks at the impact of CF on patients, caregivers, and the healthcare system, as well as the benefits of CFTR modulators. Using data from Swedish national healthcare and social insurance registries, the study compared 743 people with CF in 2019 to about 7400 people without CF, matched by sex, birth year, and location. The findings show that people with CF had 24 times higher direct healthcare costs, including outpatient visits, hospitalizations, and CF-related medications, totaling 23,233 Euros. Indirect costs, such as work absences for those over 18 with CF anssd caregivers' absences to care for sick children, were 9,629 Euros, which is five times higher than the general population. Those over 6 years old treated with LUM/IVA showed improved lung health, reduced hospitalizations (though not significantly), and needed fewer antibiotics. Caregivers' work absences decreased, but there was no change in work absences for adults with CF. Overall, treatment with LUM/IVA improved clinical outcomes and reduced the burden on caregivers and society.

Cost-effectiveness of adjunctive therapy with atypical antipsychotics for acute treatment of major depressive disorder.

BACKGROUND: While the clinical utility of atypical antipsychotics has been established in patients with major depressive disorder (MDD) who are refractory to antidepressant therapy, their cost-effectiveness is unknown. OBJECTIVE: To examine the cost-effectiveness of aripiprazole, quetiapine, and olanzapine/fluoxetine in adults with MDD who are refractory to antidepressant therapy. METHODS: Using techniques of decision analysis, we estimated expected outcomes and costs over 6 weeks in adults with MDD receiving (1) aripiprazole 2-20 mg/day and antidepressant therapy; (2) quetiapine 150 mg/day or 300 mg/day and antidepressant therapy; (3) the fixed-dose combination of olanzapine 6, 12, or 18 mg/day with fluoxetine 50 mg/day; or (4) antidepressant therapy alone. Cost-effectiveness was assessed in terms of the cost per additional responder at 6 weeks, defined as the ratio of the difference in the cost of MDD-related care over 6 weeks versus antidepressant therapy alone to the difference in the number of patients achieving clinical response by 6 weeks. We estimated the model using data from Phase 3 clinical trials of atypical antipsychotics along with other secondary data sources. RESULTS: With antidepressant therapy alone, the estimated clinical response rate at 6 weeks was 30%. Aripiprazole, quetiapine 150 mg/day, quetiapine 300 mg/day, and olanzapine/fluoxetine were estimated to increase clinical response at 6 weeks to 49%, 34%, 38%, and 45%, respectively. Costs of MDD-related care over 6 weeks were estimated to be $192 for antidepressant therapy, $847 for aripiprazole, $541 for quetiapine 150 mg/day, $672 for quetiapine 300 mg/day plus antidepressant therapy, and $791 for olanzapine/fluoxetine. Costs per additional responder (vs antidepressant therapy) over a 6-week period were estimated to be $3447 for aripiprazole, $8725 for quetiapine 150 mg/day, $6000 for quetiapine 300 mg/day, and $3993 for olanzapine/fluoxetine. CONCLUSIONS: Atypical antipsychotics substantially increase clinical response at 6 weeks. Cost per additional responder is lower for aripiprazole than for quetiapine or olanzapine/fluoxetine.

Evaluating the impact of a novel restricted reimbursement policy for quinolone antibiotics: a time series analysis.

BACKGROUND: Publicly-funded drug plans often use prior authorization policies to limit drug prescribing. To guide physician prescribing of a class of antibiotics with broad antimicrobial activity (quinolone antibiotics) in accordance with new prescribing guidelines, Alberta's provincial health ministry implemented a new mechanism for formulary restriction entitled the optional special authorization (OSA) program. We conducted an observational study to determine the impact of this new formulary restriction policy on antimicrobial prescription rates as well as any clinical consequences. METHODS: Quinolone antibiotic use, and adherence with quinolone prescribing guidelines, was assessed before and after implementation of the OSA program in patients with common outpatient infections using an administrative data cohort and a chart review cohort, respectively. At the same time this policy was implemented to limit quinolone prescribing, two new quinolone antibiotics were added to the formulary. Using administrative data, we analysed a total of 397,534 unique index visits with regard to overall antibiotic utilization, and through chart review, we analysed 1681 charts of patients with infections of interest to determine the indications for quinolone usage. RESULTS: Using segmented regression models adjusting for age, sex and physician enrollment in the OSA program, there was no statistically significant change in the monthly rate of all quinolone use (-3.5 (95% CI -5.5, 1.4) prescriptions per 1000 index visits) following implementation of the OSA program (p = 0.74). There was a significant level change in the rate of quinolone antibiotic use for urinary tract infection (-33.6 (95% CI: -23.8, -43.4) prescriptions and upper respiratory tract infection (-16.1 (95%CI: -11.6, -20.6) prescriptions per 1000 index visits. Among quinolone prescriptions identified on chart review, 42.5% and 58.5% were consistent with formulary guidelines before and after the implementation of the OSA program, respectively (p = 0.002). There was no change in hospitalization, mortality or use of physician services after implementation of the OSA program. CONCLUSIONS: Despite the addition of two new quinolone antibiotics to the formulary, we found that there was no change in the use of quinolones after implementation of a new formulary restriction policy for outpatients with common outpatient infections.

Metabolic effects and cost-effectiveness of aripiprazole versus olanzapine in schizophrenia and bipolar disorder.

OBJECTIVE: To assess the cost-effectiveness of aripiprazole versus olanzapine in the treatment of patients with schizophrenia or bipolar disorder in Sweden with focus on the metabolic impact of the treatments. METHOD: A Markov health-state transition model was developed. The risks of developing metabolic syndrome after one year of treatment with aripiprazole or olanzapine were derived from a pooled analysis of three randomised clinical trials. The subsequent risks of developing diabetes or coronary heart disease were based on previously published risk models. A societal perspective was applied, adopting a lifetime horizon. Univariate and probabilistic sensitivity analyses were conducted. RESULTS: Treatment with aripiprazole dominates over olanzapine in both schizophrenia and bipolar disorder. In schizophrenia, quality-adjusted life-years (QALYs) gained were 0.08 and cost savings Swedish kronor (SEK) 30,570 (USD 4000); in bipolar disorder, QALYs gained were 0.09 and cost savings SEK 28,450 (USD 3720). In probabilistic sensitivity analyses, aripiprazole resulted in a dominant outcome in 84% of cases in schizophrenia and in 77% of cases in bipolar syndrome. CONCLUSION: The significantly lower risk of developing metabolic syndrome observed with aripiprazole compared with olanzapine is associated with less risk of diabetes and cardiovascular morbidity and mortality that translates into lower overall treatment cost and improved quality of life over time.

Comparison of short-acting intramuscular antipsychotic medication: impact on length of stay and cost.

A retrospective cohort study was conducted to determine if there is an association between short-acting intramuscular (SAIM) antipsychotics used for acute agitation and length of stay (LOS). Patients with a diagnosis of schizophrenia or schizoaffective disorder who were dispensed at least one dose of a SAIM antipsychotic were divided into groups based on the initial SAIM antipsychotic received once admitted to a psychiatric unit. Electronic records were used to gather demographic information, LOS, and number of injections received during an admission. Cost was calculated from the number of injections received. One-hundred and thirty-six patients were enrolled. When comparing the haloperidol group to the second generation antipsychotic group, there was no statistically significant difference, in LOS 16.98 ± 9.56 days versus 17.59 ± 11.52 days (P = 0.75), respectively. There was a statistically significant difference in both cost and number of injections between groups, favoring the haloperidol group. Ziprasidone was associated with a shorter LOS compared with olanzapine, 13.57 and 19.10 days, respectively (P = 0.026). Patient characteristics should be evaluated when determining an agent for acute agitation. However, because literature indicates second generation SAIM antipsychotics are only noninferior to haloperidol; other factors should also be evaluated; including impact on LOS and impact on hospital resources. This study indicates use of a second generation SAIM antipsychotic for acute agitation is more costly, requires more injections, and was not associated with a shorter length of stay when compared with SAIM haloperidol.

A pharmacoeconomic analysis of sertindole in the treatment of schizophrenia in Sweden.

BACKGROUND: Atypical antipsychotics have similar clinical efficacy in the treatment of schizophrenia; variability in their tolerability represents the discerning factor in treatment choices. Sertindole has a relatively good tolerability profile that favours long-term patient adherence and, therefore, is associated with lower rates of relapse and rehospitalization. AIM: A model was developed to compare the cost-effectiveness of a 5-year treatment strategy starting with sertindole versus olanzapine, risperidone, aripiprazole or the typical antipsychotic agent, haloperidol. METHODS: The model was based on published trials and local clinical practice, and considered costs from the perspective of the Swedish National Health Insurance Board. RESULTS: All atypical agents were clinically superior and more cost-effective than haloperidol with a cost per quality-adjusted life year gained of approximately 490,000 Swedish kroner. Sertindole was associated with the lowest direct and indirect medical costs, driven by its tolerability profile. CONCLUSIONS: Sertindole represents a useful alternative to the current treatment options available in Sweden. CLINICAL IMPLICATIONS: The relatively good tolerability profile of sertindole translates into lower costs of schizophrenia management, primarily driven by substantially lower direct and indirect costs. Sertindole appears to be a clinically and cost-effective alternative in the management of patients with schizophrenia in Sweden.

CFTR modulators: transformative therapies for cystic fibrosis.

DISCLOSURES: No funding contributed to the writing of this commentary. Both authors are employed by the Cystic Fibrosis Foundation. The Cystic Fibrosis Foundation has entered into therapeutic development award agreements and licensing agreements to assist with the development of CFTR modulators that may result in intellectual property rights, royalties, and other forms of consideration provided to CFF. Some of these agreements are subject to confidentiality restrictions and, thus, CFF cannot comment on them.