Real-world assessment of LCI following lumacaftor-ivacaftor initiation in adolescents and adults with cystic fibrosis.

Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0]. At both M6 and M12, no statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV1 were observed in one-third of the patients. In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease.

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.

The effectiveness and value of novel treatments for cystic fibrosis.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Seidner, Rind, and Pearson are employed by ICER. Tice reports contracts to his institution, University of California, San Francisco, from ICER during the conduct of this study. Wherry has nothing to disclose.

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.

Cystic fibrosis 2019: Year in review.

The evidence base for modulator therapies in cystic fibrosis (CF) has continued to expand, and it is likely that up to 90% of people with CF could benefit. Worldwide there are however marked inequalities of access to basic CF care and modulator therapies. For infants and young children there is now an evidence base for inhaled hypertonic saline. There is increasing evidence that structural lung disease in CF is not due purely to infection and that mucus retention and inflammation are also key, and further evidence of the value of azithromycin in those chronically infected with Pseudomonas aeruginosa. Finally, exercise is good for you, but airway clearance is better for mucus clearance.

Adherence to lumacaftor-ivacaftor therapy in patients with cystic fibrosis in France.

BACKGROUND: Lumacaftor-ivacaftor combination is a promising treatment for cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation. Optimal adherence is essential to achieve full health outcomes benefits. METHODS: This retrospective study used pharmacy refills data to calculate proportion of days covered (PDC). Adherence was defined as a PDC ≥80%. A logistic regression analysis was conducted to examine factors associated with medication adherence. RESULTS: Ninety-six patients were included in the final cohort for analysis. The mean PDC was 96%  ± 14 at 6 months, and 91% ± 17 at 12 months. The proportion of adherent patients was 89% and 83% at 6 and 12 months respectively. Age and ppFEV1 were found to affect medication adherence. CONCLUSIONS: Considering the medico-economic impact of CFTR modulator therapy, high adherence rates to lumacaftor-ivacaftor found in this study are encouraging.

Effect of Lumacaftor/Ivacaftor on Pulmonary Exacerbation Rates in Members with Cystic Fibrosis in a Medicaid Population.

BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) is indicated for patients with cystic fibrosis (CF) homozygous for the F508del mutation in the CFTR gene. In clinical trials, LUM/IVA decreased pulmonary exacerbation rates. To our knowledge, there is no published data evaluating real-world outcomes for Medicaid patients receiving LUM/IVA. OBJECTIVE: To compare CF pulmonary exacerbation rates before and after initiation of LUM/IVA in 1 state's Medicaid program. METHODS: This pre-post claims analysis screened fee-for-service and managed Medicaid members who had ≥ 1 pharmacy claim for LUM/IVA between July 2, 2015, and September 30, 2016. Members were included if they were aged ≥ 6 years with a CF diagnosis and homozygous for the F508del mutation, consistent with the indication at study initiation. Exclusion criteria included Medicaid as a secondary payer or any break in coverage during the study. The index date was defined as the first claim for LUM/IVA. Demographics and outcomes were derived from pharmacy and medical claims. Outcomes included overall rate of pulmonary exacerbations (reported as the total events for the study population 6 months before and after the index date and average annualized rate). Pulmonary exacerbation was defined as any combination of medical claims for an emergency room (ER) visit or inpatient hospitalization with a CF pulmonary exacerbation or respiratory infection (ICD-9/10-CM codes) or pharmacy claims for an oral or intravenous antibiotic (excluding macrolides). A gap of > 7 days was considered a new pulmonary exacerbation. Paired t-test was used to test significance. RESULTS: 21 patients met inclusion criteria with an average age at treatment initiation of 20.1 years. Average proportion of days covered (SD) was 0.62 (0.29). The number of pulmonary exacerbations increased from 45 to 48 during the 6 months before and after the index date, respectively, and the annualized rate increased from 4.37 to 4.66 (P = 0.69). While the number of pulmonary exacerbations associated with antibiotics alone increased (23 to 33; P = 0.08), those associated with at least 1 ER visit or inpatient hospitalization decreased (22 to 15; P = 0.08). CONCLUSIONS: This analysis did not find a decrease in pulmonary exacerbation rate for Medicaid members receiving LUM/IVA; however, adherence was low. Further study of similar populations is needed to better understand the long-term effect of treatment. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. A poster of this project was presented at the Academy of Managed Care Pharmacy Managed Care & Specialty Pharmacy Annual Meeting 2018 in Boston, MA, on April 23-26, 2018.

Rate and predictors of prescription of lumacaftor - Ivacaftor in the 18 months following approval in the United States.

RATIONALE: Lumacaftor-ivacaftor (LUM-IVA) was approved in the US in 2015 for patients with CF aged >12 homozygous for the delF508 mutation, and patients aged 6 to 12 in 2016. OBJECTIVES: To examine the rate of initial LUM-IVA prescriptions following approval. METHODS: We compared patients eligible for LUM-IVA in the CF Foundation Patient Registry with and without prescriptions in 2015-2016. RESULTS: 5534 (53%) eligible patients had reported prescriptions. Prescription rate in children ages 6-11 was 19% and 61% among patients ≥12 years old. Individuals ≥12 with prescriptions more likely observed among those with private insurance, clinical trial participation, ages 18-30, FEV1 < 90%, more pulmonary exacerbations, and more use of chronic medications. CONCLUSIONS: LUM-IVA uptake was less rapid than what was previously observed for ivacaftor, a CFTR modulator approved for a different population. Age, insurance status, disease severity and use of other therapies differed in those prescribed LUM-IVA in the initial post-approval period.

Comparing effectiveness and outcomes in asthma and cystic fibrosis.

As technology yields new treatments, pediatric pulmonologists need determine how best to use them and how to decide which ones are best for any specific group or individual patient. Physicians have always customized therapies based upon patient response, but the new concept of "Personalized (or precision) medicine" focuses attention to a greater degree on the individual needs of patients based on their genetic, biomarker, phenotypic, or psychosocial characteristics. The newly developed biologics for treatment of asthma and CFTR modulators for treatment of cystic fibrosis (CF) highlight this newer approach. As we have more treatments available, new approaches to testing efficacy and effectiveness of these new therapies is necessary in order to efficiently bring them to market and compare their benefits in real world practice. While comparative effectiveness can be tested in pragmatic clinic trials, the most common approaches make use of observational data such as administrative databases and patient registries but their use for this is fraught with pitfalls that may or may not be methodologically surmountable. Once new therapies have been shown to be efficacious and effective, it is important to be cognizant of methods for ensuring that all patients actually receive the treatments that will be best for them. Comparisons of the effectiveness of clinical practice in the form of benchmarking is helpful for this, and consideration of costs and cost-effectiveness is essential to judging the best treatment for patients in a real-world setting.

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.

$850 Per Bowel Movement?! Hard To Justify That Cost.

Constipation can be a serious and painful problem, and we shouldn't dismiss other people's suffering. On the other hand there's a danger when new medications are compared against placebo rather than against over-the-counter products with a history of effectiveness.

Healthcare resource utilization associated with ivacaftor use in patients with cystic fibrosis.

OBJECTIVE: Ivacaftor was approved in 2012 to treat patients with cystic fibrosis (CF) with specific CFTR gene mutations. The objective of this analysis was to analyze the impact of ivacaftor on health resource utilization through analysis of claims data. METHODS: Patients diagnosed with CF aged ≥6 years prescribed ivacaftor between January 1, 2012 and July 31, 2014 with ≥12 months of continuous insurance coverage prior to and following the prescription were identified. All-cause and CF-specific healthcare resource utilization during the pre- and post-prescription periods and ivacaftor adherence levels were studied. RESULTS: The 79 identified patients had a mean age of 20.8 years, and 54% were female. The proportion of patients with inpatient admissions (all-cause and CF-related) was significantly higher in the pre index compared to post index period (p ≤ 0.05). Mean ivacaftor medication possession ratio was 0.8 (SD = 0.3), and 73% of patients had a medication possession ratio >0.80. LIMITATIONS: Only a small number of patients met the inclusion criteria. Additionally, claims data may contain errors or inconsistencies and cannot be used to determine if medications were taken as prescribed. CONCLUSIONS: Ivacaftor therapy was associated with significant reductions in hospitalizations along with high rates of adherence to treatment over 12 months.

Economic evaluation of linaclotide for the treatment of adult patients with irritable bowel syndrome with constipation in the United States.

OBJECTIVES: To use techniques of decision-analytic modeling to evaluate the effectiveness and costs of linaclotide vs lubiprostone in the treatment of adult patients with irritable bowel syndrome with constipation (IBS-C). METHODS: Using model inputs derived from published literature, linaclotide Phase III trial data and a physician survey, a decision-tree model was constructed. Response to therapy was defined as (1) a ≥ 14-point increase from baseline in IBS-Quality-of-Life (IBS-QoL) questionnaire overall score at week 12 or (2) one of the top two responses (moderately/significantly relieved) on a 7-point IBS symptom relief question in ≥ 2 of 3 months. Patients who do not respond to therapy are assumed to fail therapy and accrue costs associated with a treatment failure. Model time horizon is aligned with clinical trial duration of 12 weeks. Model outputs include number of responders, quality-adjusted life-years (QALYs), and total costs (including direct and indirect). Both one-way and probabilistic sensitivity analyses were conducted. RESULTS: Treatment for IBS-C with linaclotide produced more responders than lubiprostone for both response definitions (19.3% vs 13.0% and 61.8% vs 57.2% for IBS-QoL and symptom relief, respectively), lower per-patient costs ($803 vs $911 and $977 vs $1056), and higher QALYs (0.1921 vs 0.1917 and 0.1909 vs 0.1894) over the 12-week time horizon. Results were similar for most one-way sensitivity analyses. In probabilistic sensitivity analyses, the majority of simulations resulted in linaclotide having higher treatment response rates and lower per-patient costs. LIMITATIONS: There are no available head-to-head trials that compare linaclotide with lubiprostone; therefore, placebo-adjusted estimates of relative efficacy were derived for model inputs. The time horizon for this model is relatively short, as it was limited to the duration of available clinical trial data. CONCLUSIONS: Linaclotide was found to be a less costly option vs lubiprostone for the treatment of adult patients with IBS-C.