Advances in Therapy最新文献

Introduction

The clinical benefits of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) have been demonstrated in clinical trials. There is limited evidence regarding the effectiveness and economic outcomes associated with FF/UMEC/VI use in US clinical practice. This real-world study assessed asthma-related exacerbations, healthcare resource utilization (HRU), and healthcare costs among a Medicare Advantage-insured population before and after initiation of FF/UMEC/VI in patients with asthma previously treated with an inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA).

Methods

De-identified data were obtained from the Komodo Health database (01/01/2016–12/31/2023) for adults with asthma who received prior ICS/LABA treatment and had ≥ 12 months of continuous Medicare Advantage coverage both pre- and post-FF/UMEC/VI initiation (index date). Rates of asthma-related exacerbations and HRU were compared using rate ratios (RR) from Poisson regressions. Healthcare costs were calculated per patient per year (PPPY) and compared using mean cost differences from generalized linear models.

Results

In total, 2598 Medicare Advantage-insured patients who initiated FF/UMEC/VI for asthma were included. The mean ± SD age was 67.9 ± 12.3 years; 75.5% were female. The rate of overall asthma-related exacerbations was 31% lower in the post- versus pre-initiation period (RR 0.69; 95% CI 0.65, 0.73; p < 0.001) and included a 24% lower rate of inpatient/emergency department (IP/ED)-defined exacerbations (RR 0.76; 95% CI 0.68, 0.85; p < 0.001) and a 34% lower rate of systemic corticosteroid (SCS)-defined exacerbations (RR 0.66; 95% CI 0.61, 0.71; p < 0.001). Asthma-related ED visits (RR 0.69; 95% CI 0.60, 0.80; p < 0.001) and asthma-related outpatient (OP) visits (RR 0.77; 95% CI 0.71, 0.84; p < 0.001) were both lower, and the mean reduction in cost was $411 PPPY (95% CI $575, $248; p < 0.001), after FF/UMEC/VI initiation.

Conclusions

Initiation of FF/UMEC/VI after ICS/LABA treatment among Medicare Advantage-insured patients with asthma was associated with reduced rates of asthma-related exacerbations, ED and OP visits, and healthcare costs, highlighting the benefits of therapy escalation among this patient population.

The healthcare system in the United States (US) is complex and often fragmented across national and regional health plans which exhibit substantial variability in benefit design and formulary policies for accessing medications. We propose an access-focused value assessment framework for formulary decision-making for medications to manage immune-mediated inflammatory diseases (IMIDs), where patients are at the center of this framework. Formulary decision-making for IMID medications can be a challenging, even daunting, task with continuously evolving and enhanced treat-to-target goals. Given the complexity of the US healthcare system, patients and their caregivers need assurance from formulary decision-makers that rapid, predictable, and sustained access to both well-established treatments and innovative therapies will be a priority, with a particular emphasis on continuity of effective care. This access-focused patient-centric (APAC) value assessment approach encompasses three “value components”—higher therapeutic goals, better health-related quality of life, and improved work productivity—the monetization of which can be derived using data from clinical trials when real-world data are yet to become available. Measures and assessment approaches are outlined to serve as a pragmatic tool for decision-makers in the US to ensure timely delivery and sustained access of clinically indicated therapies aimed to improve patient outcomes, enhance equity, and increase efficiency.

Introduction

Weight-banded trofinetide dosing improved physician- and caregiver-rated efficacy measures and had acceptable tolerability in patients aged 2‒4 years (DAFFODIL study) and 5‒20 years (LAVENDER study) with Rett syndrome (RTT). Selection of weight-banded dosing regimens for these studies was based on population pharmacokinetic (popPK) modeling and exposure simulations. This study applied an updated popPK model to confirm steady-state trofinetide exposures achieved in DAFFODIL patients were within target range.

Methods

A popPK model was developed using data from 14 clinical studies of trofinetide in healthy volunteers and pediatric and adult patients, including the LAVENDER and DAFFODIL studies. Individual exposure measures (area under concentration–time curve over 0–12 h [AUC_0–12] were generated via integration of the predicted concentration–time profile for each DAFFODIL study participant based on the popPK model and individual empiric Bayesian pharmacokinetic parameter estimates. Distributions of steady-state AUC_0–12 values for each body-weight group were compared against target exposure (AUC_0–12 = 800‒1200 µg·h/mL).

Results

Distribution and box plots of simulated steady-state AUC_0–12 values achieved with the weight-banded DAFFODIL dosing regimen used in younger individuals aged 2–4 years with RTT (twice daily trofinetide 5 g [≥ 9 to < 12 kg] or 6 g [≥ 12 to < 20 kg]) indicated good overlap with the target exposure range. Median steady-state AUC_0–12 values for both body-weight bands fell within the target exposure range.

Conclusions

PopPK model-based simulations confirm that the weight-banded dosing regimen used in DAFFODIL is adequate to achieve target trofinetide exposure in 2- to 4-year-olds with RTT.

Graphical Abstract

Introduction

Oral trofinetide administered using a body weight-banded dosing regimen was approved in the US for the treatment of Rett syndrome (RTT) in patients aged ≥ 2 years. This approval was principally based on efficacy and safety findings of the phase 3 LAVENDER study in girls and women aged 5–20 years with RTT and extended to younger children aged 2–4 years with supporting data from the DAFFODIL study. Weight-banded dosing regimens were selected based on early clinical population pharmacokinetic (popPK) modeling and different scenario simulations. We report the development and application of an updated popPK model to confirm that steady-state trofinetide exposures achieved in individual patients in the LAVENDER study were within target exposure range.

Methods

A previously developed popPK model using data from nine clinical studies was updated based on 13 clinical studies of trofinetide in healthy volunteers and pediatric and adult patients, including the LAVENDER study. PopPK model and empiric individual Bayesian pharmacokinetic parameter estimates were used to generate trofinetide exposures. Covariate data from the pharmacokinetic dataset from LAVENDER study subjects (n = 92) were used to estimate individual steady-state trofinetide exposure (area under concentration–time curve over 0–12 h [AUC_0–12]). Steady-state exposures in individual patients in the LAVENDER study were used to confirm that the dosing regimens resulted in exposures within the target range.

Results

Among 5- to 20-year-olds receiving the LAVENDER BID dosing regimen [trofinetide 6 g (12‒20 kg), 8 g (> 20‒35 kg), 10 g (> 35‒50 kg), and 12 g (> 50 kg)], simulated AUC_0-12 values overlapped with the target exposure range; median AUC_0–12 values were within target exposure range for all weight bands.

Conclusions

PopPK model-based simulations confirm that weight-banded trofinetide dosing used in LAVENDER in girls and women aged 5–20 years with RTT achieved target exposure.

Graphical abstract available for this article.

Graphical Abstract

Introduction

Bowel urgency has recently been recognized as a Crohn’s disease (CD) symptom that substantially impacts patients’ quality of life. The Urgency NRS is a single-item patient-reported outcome measure assessing bowel urgency severity in the past 24 h (0–10 scale). We aimed to evaluate the psychometric properties of the Urgency Numeric Rating Scale (NRS) in adults with moderately to severely active CD and to estimate thresholds for meaningful improvement and bowel urgency remission.

Methods

Psychometric analyses used pooled data from the Phase 3 VIVID-1 study of mirikizumab, where participants with CD completed the Urgency NRS and other assessments. The Patient Global Rating of Severity (PGRS) and Patient Global Impression of Change (PGIC) were used as primary anchors to estimate Urgency NRS thresholds representing meaningful improvement and remission.

Results

The Urgency NRS showed good test–retest reliability in participants who were stable based on PGRS and PGIC. It was moderately correlated with similar assessments and weakly correlated with endoscopic/laboratory assessments. It differentiated between participant subgroups varying in disease severity and quality of life based on PGRS and other assessments. It was sensitive to change, as Urgency NRS improvements during the trial differed between most PGRS change and PGIC categories. A 3–5-point reduction on the Urgency NRS represented meaningful improvement and a score of ≤ 2 represented remission.

Conclusion

The Urgency NRS demonstrated strong psychometric properties in the VIVID-1 population of moderately to severely active CD. Analyses also suggested meaningful improvement and remission thresholds.

Trial Registration

Clinicaltrials.gov, NCT03926130. Registered 23 April 2019, https://clinicaltrials.gov/study/NCT03926130.

Introduction

Type 2 diabetes (T2D) is a major cause of chronic kidney disease (CKD) in Japan, and there is an increasing treatment need for first- and second-line care in these patients. The addition of finerenone to current treatment modalities lowers the risk of CKD progression and cardiovascular events in patients with CKD and T2D from the Japanese payer perspective. This study investigated the cost-effectiveness analysis of adding finerenone to standard of care (SoC) versus SoC alone for the treatment of CKD in patients with T2D.

Methods

The FINE-CKD model validated to estimate the cost-effectiveness of finerenone uses the Markov model to simulate the disease pathway of patients over a lifetime horizon. The model was adapted to reflect the Japanese payer perspective and estimated incremental costs, utilities, and incremental cost-effectiveness ratios (ICERs). Sensitivity and scenario analyses were performed to evaluate the effect of the uncertainty of each parameter using a robust model.

Results

The quality-adjusted life years (QALYs) for finerenone and SoC were estimated at 9.39 and 9.25, respectively, with an incremental QALY for finerenone for SoC of 0.14. The total cost of finerenone was estimated at ¥ 8,912,601, at an incremental cost of ¥ 274,052, leading to an ICER of ¥ 1,959,516 per QALY gained compared with SoC alone.

Conclusion

Finerenone in conjunction with SoC is a more cost-effective treatment alternative to SoC alone for adult patients with CKD and T2D from a Japanese healthcare payer perspective.

Introduction

Recent trial-level meta-analyses have established disease-free survival (DFS) as a valid surrogate for overall survival (OS) in human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC), irrespective of disease stage, and in early-stage hormone receptor-positive (HR+)/HER2− BC. To advance the understanding of the association between additional DFS endpoints and OS, this study assessed the patient-level correlations between DFS and OS, invasive DFS (IDFS) and OS, and distant DFS (DDFS) and OS in Medicare beneficiaries with early-stage HER2− BC, overall and in subgroups of patients with HR+/HER2− BC and triple-negative BC (TNBC).

Methods

Patients with stages I–III HER2− BC aged ≥ 66 years were identified from SEER-Medicare data (2010–2019). DFS, IDFS, DDFS, and OS were assessed using Kaplan–Meier analyses. Normal scores rank correlation was estimated between each DFS endpoint and OS, overall and separately in patients with HR+/HER2− BC and TNBC.

Results

Of 28,655 patients, 90.4% had HR+/HER2− BC and 9.6% had TNBC (median follow-up 4 years). Median DFS, IDFS, and DDFS were 4.5, 5.9, and 6.3 years, respectively, in HR+/HER2− BC and 3.0, 3.8, and 4.4 years, respectively, in TNBC. Median OS was not reached (5-year OS, HR+/HER2− BC 83.7%; TNBC 67.7%). A significant positive correlation was observed between each DFS endpoint and OS across cohorts, with the strongest correlation observed between DDFS and OS in HR+/HER2− BC (correlation coefficient 0.60; 95% confidence interval 0.57–0.62; p < 0.001) and in TNBC (0.69; 0.65–0.71; p < 0.001).

Conclusion

We observed significant positive patient-level correlations between DFS and OS, IDFS and OS, and DDFS and OS in early-stage HER2− BC. Our IDFS and DDFS findings advance the understanding of the role of these DFS endpoints as predictors of OS, and their potential utility as surrogate endpoints in clinical trials of early-stage HER2− BC, given additional validation in trial-level meta-analyses.

Introduction

To date, no study has compared the healthcare resource utilization (HCRU), costs, and discontinuation of the two calcitonin gene-related peptide antagonists, galcanezumab (monoclonal antibody subcutaneously injected monthly) and rimegepant (oral gepant taken every other day), for migraine prevention. This study aimed to assess all-cause and migraine-related HCRU, costs, and treatment discontinuation at 12 months following treatment initiation in commercial/Medicare beneficiaries with episodic migraine who received galcanezumab versus rimegepant as preventive migraine treatment.

Methods

This retrospective study used the Merative™ MarketScan^® Research Databases (June 2020–June 2023). Adults with episodic migraine were grouped into the galcanezumab (≥ 1 claim) or rimegepant cohort (≥ 1 claim with quantity ≥ 15 during the index period). Changes from baseline in all-cause and migraine-related HCRU and cost between the propensity score-matched cohorts were determined using Wilcoxon signed rank test and chi-square test. Treatment discontinuation was assessed using Kaplan–Meier analysis and Cox proportional hazards model.

Results

All-cause and migraine-related HCRU and costs increased over the 12-month follow-up in both cohorts. The galcanezumab cohort had a significantly lower increase in mean all-cause total medical + pharmacy costs (21% lower) and migraine-related total medical + pharmacy costs (76% lower) than the rimegepant cohort at the 12-month follow-up (p < 0.0001 for both assessments). Mean (standard deviation) number of days from initiation to discontinuation (> 60-day gap) was 244.6 (135.3) for galcanezumab cohort and 178.1 (141.1) for rimegepant cohort (p < 0.0001). Treatment discontinuation rate was 1.8 times less likely in the galcanezumab cohort than the rimegepant cohort (hazard ratio = 1.81, 95% confidence interval = 1.56–2.10). Similar trends were observed using a 30-day gap.

Conclusion

Among matched patients, both cohorts of patients with episodic migraine showed all-cause and migraine-related total cost increases over 12 months. However, the magnitude of the increases was significantly lower for the galcanezumab cohort than for the rimegepant cohort. Treatment discontinuation rate was significantly lower in the galcanezumab versus the rimegepant cohort.

Introduction

The Quality of Life-Bronchiectasis (QOL-B) questionnaire and Patient Reported Outcome Measurement Information System Short Form v1.0—Fatigue 7a (PROMIS-F SF-7a) have the potential to measure respiratory and fatigue symptoms, respectively, in patients with Mycobacterium avium complex (MAC) lung disease but have not yet been evaluated for content validity in this population.

Methods

Semi-structured qualitative interviews were conducted in United States patients with a current MAC lung disease diagnosis. Concept elicitation (CE) interviews were conducted (n = 25 participants) to identify key respiratory and fatigue symptoms expressed as important and relevant to patients with MAC lung disease and to evaluate the appropriateness of the QOL-B and PROMIS-F SF-7a to measure these symptoms. Cognitive interviews (CIs) were subsequently conducted (n = 20 participants) to evaluate the relevance, comprehensibility, and appropriateness of the QOL-B respiratory domain (QOL-B-RD) and PROMIS-F SF-7a. All interviews were recorded, transcribed, and coded for qualitative content analysis.

Results

The most important or relevant respiratory symptom concepts to CE interview participants were “cough,” “shortness of breath during activity,” and “mucus/phlegm.” The most important or relevant fatigue symptom concepts were “tiredness,” “lack of energy,” and “tire easily/low stamina.” These symptoms are covered by existing items in the QOL-B-RD and PROMIS-F SF-7a. Cognitive interview participants’ feedback confirmed the item content, response options, concept attributes, and recall period for each instrument were effective, relevant, and meaningful to most patients with MAC lung disease. Based on Wave 1 findings, the QOL-B instructions were revised for the Wave 2 interviews, where the text referencing “bronchiectasis” was replaced with “your lung condition.” Participant feedback in Wave 2 confirmed the revised instruction wording was easily understood and appropriate.

Conclusions

The study results support the content validity of the QOL-B-RD and PROMIS-F SF-7a, which were shown to be relevant and appropriate to evaluate respiratory and fatigue symptoms, respectively, in patients with MAC lung disease.