Advances in Therapy最新文献

Introduction: In 2021, breast cancer affected 75,619 women in Denmark. Approximately 50% of breast cancers are considered human epidermal growth factor receptor 2 (HER2)-low. The DESTINY-Breast04 (DB-04) trial led to European Medicines Agency (EMA) approval of trastuzumab deruxtecan (T-DXd) as a treatment for patients with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Moreover, the Danish Breast Cancer Group guidelines recently included T-DXd as a treatment for HER2-low metastatic breast cancer. This economic evaluation aims to estimate the cost-effectiveness of T-DXd for the approved EMA indication in Denmark.

Methods: A three-state-progression-free, post-progression, and death-partitioned survival model was developed to estimate the cost-effectiveness of T-DXd versus treatment of physician's choice over a lifetime horizon following the Danish Medicines Council guidelines. Clinical data were gathered from the DB-04 trial, and cost and resource use data were sourced from the literature. Sensitivity and scenario analysis were conducted to explore uncertainty.

Results: T-DXd led to 0.78 incremental quality-adjusted life years (QALYs) gained and incurred DKK 621,325 in incremental costs compared to the treatment of physician's choice. This resulted in an incremental cost-effectiveness ratio of DKK 795,181 per QALY gained, which falls below the willingness-to-pay threshold. Sensitivity and scenario analyses showed the robustness of the deterministic result, with T-DXd remaining cost-effective.

Conclusion: Our study demonstrates that T-DXd is a cost-effective treatment for patients with HER2-low unresectable or metastatic breast cancer who have received prior chemotherapy in Denmark.

Introduction: Indirect treatment comparisons (ITCs) evaluate novel treatments compared to appropriate comparators when direct evidence is unavailable or infeasible. The objective of this study was to highlight the prevalence of different ITC methods in oncology drug submissions and to provide insights into how ITCs have been used in recent regulatory approval, reimbursement recommendations, or pricing decisions across various regions and diverse assessment frameworks.

Methods: A targeted literature review was conducted to identify assessment documents for oncology drug submissions that included ITCs. This included hand searches of the websites of four regulatory bodies and four health technology assessment (HTA) agencies with varying assessment frameworks across North America, Europe, and Asia-Pacific.

Results: A total of 185 documents were included for synthesis. Documents were retrieved from all four HTA agencies and the European Medicines Agency (EMA), the only regulatory body with eligible records. Within these, 188 unique submissions included a total of 306 supporting ITCs of various methods. Authorities more frequently favored anchored or population-adjusted ITC techniques for their effectiveness in data adjustment and bias mitigation. Furthermore, ITCs in orphan drug submissions more frequently led to positive decisions compared to non-orphan submissions.

Conclusions: This review highlights the crucial role and widespread use of ITCs in global healthcare decision-making, particularly when direct evidence is lacking, and in the discernment of market-specific clinical benefits. This work contributes to bolstering the credibility and recognition of ITCs across regulatory and HTA agencies of diverse regions and assessment frameworks.

Introduction: Although contrast-induced (CI) acute kidney injury (AKI) is a common complication in high-risk individuals requiring evaluation with contrast-enhanced angiography, the possible predictors of CI-AKI in patients with obesity are not fully understood. The aim of this study was to elucidate plausible factors associated with the irreversibility of CI-AKI in individuals with obesity undergoing contrast-enhanced computed tomography coronary angiography.

Methods: A total of 96 adult patients with obesity and the KDIGO criteria of CI-AKI (increase of serum levels of creatinine ≥ 25% or ≥ 500 µmol/L at 48 h after procedure) were retrospectively screened from the cohort of 1833 patients who underwent iodine contrast medium (ICM)-enhanced computed tomography coronary angiography, and were included in the study. The patients were divided into two cohorts: 96 adult patients with obesity and recovery of CI-AKI in 7 days after initiating of the event, and 57 individuals with irreversibility of CI-AKI. Serum concentrations of conventional biochemistry and urine biomarkers [i.e., hemoglobin, creatinine, high-sensitivity C-reactive protein, urinary albumin/creatinine ratio (UACR)] as well as natriuretic peptide, adropin, apelin, irisin, tumor necrosis factor-alpha (TNF-alpha), were determined at baseline. The levels of creatinine were measured at baseline, at the event, and in 7 days after the event.

Results: We identified 12 variables, which were associated with irreversibility of CI-AKI: age > 75 years [odds ratio (OR) = 1.22. P = 0.001], male gender (OR = 1.03, P = 0.042), stable coronary artery disease (OR = 1.06, P = 0.048), chronic kidney disease (CKD) 1-3 grade (OR = 1.60, P = 0.001), heart failure with preserved ejection fraction (HFpEF) (OR = 1.07, P = 0.046), baseline estimated GFR < 80 mL/min/1.73 m² (OR = 1.10, P = 0.040), UACR > 17.5 mg/g Cr (OR = 1.05, P = 0.048), TNF-alpha > 3.11 pg/mL (OR = 1.12, P = 0.001), and adropin < 2.43 ng/mL (OR = 1.18, P = 0.001). After adjustment for CKD and UACR > 17.5 mg/g Cr, only HFpEF (OR = 1.06, P = 0.042) and adropin < 2.43 ng/mL (OR = 1.11, P = 0.001) remained independent predictors of CI-AKI irreversibility. Yet, adropin < 2.43 ng/mL at baseline exerted sufficiently better predictive ability than both HFpEF and preexisting CKD 1-3 grade.

Conclusion: In a multivariate prediction model adjusted for CKD and urinary albumin/creatinine ratio > 17.5 mg/g Cr, low levels of adropin (< 2.43 ng/mL) in individuals with non-morbid obesity together with the presence of HFpEF were independent predictors of CI-AKI irreversibility after ICM-enhanced computed tomography coronary angiography.

Introduction: Chronic idiopathic constipation (CIC) is a common disorder that has a large unmet clinical need, affecting 8.0-12.0% of the US population and disproportionately affecting female individuals more than male individuals. Patients and physicians are equally dissatisfied with over-the-counter and prescription treatments. Physician dissatisfaction is at 78%. CIC has a significant negative impact on quality of life (QoL). The objective of this analysis was to compare the total cost and QoL of the Vibrant System vs. linaclotide, over 1-3 years of treatment.

Methods: Markov models were utilized to project 1-3-year US costs and health outcomes (quality adjusted life years, QALYs) comparing the Vibrant System to the current standard of care pharmacologic therapy (linaclotide). One model examined direct (D) costs plus QALYs. Direct (D) costs included list price of product and medical treatment costs due to adverse events. Costs (D) were as of 2024; derived from the medical literature. A second model examined D as well as indirect (I) costs (absenteeism, presenteeism) [D + I] and QALYs. Longitudinal 12-month persistence prescription data for linaclotide was obtained from IQVIA claims data. The Vibrant System persistence data was derived from post market collection. One-way sensitivity analyses were also performed.

Results: Years 1-3 direct costs were lower with Vibrant System with improved QALYs. Cumulative D + I data analysis for the Vibrant System at 12 months, and for years 2 and 3 show increased cost savings from $345 to $3866 with improved effectiveness.

Conclusion: On the basis of lower costs and improved QALYs, the Vibrant System should be considered a first-line therapy for CIC and should be covered by insurers.

Introduction: Phosphorodiamidate morpholino oligomers (PMOs), weight-based treatments administered weekly by intravenous infusion, are approved in the US for patients with Duchenne muscular dystrophy (DMD) amenable to certain exon skipping. Evidence regarding PMO treatment patterns in real-world settings is limited. This study used longitudinal administrative claims data to characterize PMO treatment patterns among US patients with DMD.

Methods: MarketScan^® commercial and Medicaid data (January 1, 2018-December 31, 2021) were used to identify claims for PMO treatments (eteplirsen, golodirsen, viltolarsen, casimersen). The proportion of days covered (PDC), proportion with continuous PMO claims coverage (no gaps in claims ≥ 30 days), and time to subsequent PMO claims after a ≥ 30-day gap in PMO claims were described.

Results: One hundred thirty-three patients with ≥ 1 PMO claim were identified. Multiple codes were needed to identify PMO treatment coverage. Mean age was 14.1 years; all patients were male. Mean continuous follow-up duration was 669.3 days. Median PDC was 83.4%. Seventy-four (55.6%) patients had continuous PMO claims coverage (no ≥ 30-day gaps in claims). Of the 59 patients with ≥ 1 gap in PMO claims of ≥ 30 days, 39 had ≥ 1 subsequent PMO claim. Accounting for censoring via Kaplan-Meier analysis, 75.5% had a subsequent PMO claim within 1 year after a ≥ 30-day gap, with a median time of 64 days (including the qualifying 30 days).

Conclusion: Understanding treatment patterns is important for characterizing real-world utilization of precision genetic medicines. This study observed a high PDC for PMO treatments for DMD. Most patients had continuous PMO claims coverage, and most patients with a gap in PMO claims had a subsequent PMO claim. Nonetheless, the observed persistence may have been underestimated given shortcomings of claims data and payer coverage considerations. Caution should be exercised when inferring treatment effectiveness or tolerability based on observed treatment patterns from claims data alone for weight-based, infused PMO treatments.

Introduction: The effect of neutropenia and the use of granulocyte colony-stimulating factor (G-CSF) in critically ill patients with cancer are controversial, notably in those with lung injury. Neutropenia recovery can be associated with an acute respiratory failure (ARF) requiring intensive care unit (ICU) admission, especially when G-CSF is administered.

Methods: In a single-center retrospective study, we evaluated (1) the effect of neutropenia recovery on the 90-day mortality and (2) the impact of G-CSF use on the outcome of patients with cancer and neutropenia with ARF admitted to the ICU.

Results: Among 1098 screened patients, 152 were neutropenic at ICU admission. The 90-day mortality was 44.7%. Factors independently associated with the 90-day mortality were invasive mechanical ventilation, ground-glass opacities and nodules on computed tomography scans, a disease in progression and the Simplified Acute Physiology Score (SAPS II) at ICU admission. The lack of neutropenia recovery during the ICU stay was associated with the 90-day mortality. Using G-CSF had no effect on the 90-day mortality or the neutropenia duration, but the PaO₂:FiO₂ ratio was significantly lower after neutropenia recovery in patients who received G-CSF. Thus, respiratory deterioration can occur in the neutropenia recovery period, potentially exacerbated by G-CSF.

Conclusion: Our study suggests that neutropenia recovery was associated with survival in critically ill patients with cancer and neutropenia with ARF admitted to ICU, and the G-CSF could worsen the respiratory parameters.

Introduction: Studies directly comparing the effectiveness of different biologics over long observation periods are lacking. As many treatment guidelines are formulated based on drug class, there is a particular need to compare drug classes rather than specific biologic agents.

Methods: This post hoc analysis compares the effectiveness and durability of biologics that target the interleukin (IL)-17 A ligands or the IL-17 receptor A (IL-17RA) relative to other approved drug classes in patients with moderate-to-severe plaque psoriasis, through 12 months in a real-world setting.

Results: In the Psoriasis Study of Health Outcomes (PSoHO) (N = 1981), patients treated with anti-IL-17A/RA resulted in a higher proportion of patients who achieved the primary outcome [proportion of patients who had at least a 90% improvement in Psoriasis Area and Severity Index score (PASI90) and/or a score of 0 or 1 in static Physician Global Assessment (sPGA)] compared to anti-IL-23-, anti-IL-12/23-, and tumor necrosis factor (TNF)-α-treated patients at week 12, month 6, and month 12, except versus anti-IL-23 at month 12. Similar trends were observed for a 100% improvement in PASI score (PASI100), PASI90, and Dermatology Life Quality Index score of 0 or 1 [DLQI (0,1)]. At month 12, the unadjusted response rates across the drug classes were 53.5-69.1% for the primary outcome, 27.6-40.8% for PASI100, 41.7-55.9% for PASI90, and 31.8-33.0% for DLQI (0,1). Regarding the durability of effectiveness, anti-IL-17A/RA patients had the highest response rate, and for the adjusted analysis, using Frequentist Model Averaging (FMA), patients had 1.4-2.6 times higher odds of achieving the primary durability outcome compared to patients treated with any other drug class.

Conclusion: Overall, anti-IL-17A/RA had the highest effectiveness of achieving early response to treatment and maintaining that response through 12 months compared to other drug classes.

Trial registration: The study was registered at the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCEPP24207).

Introduction: Endoscopic minimally invasive valve surgery is a promising alternative to valve surgery through median sternotomy. Our study compared the short-term outcomes of patients undergoing endoscopic minimally invasive multiple concomitant valve surgeries (MIMVS) with median sternotomy (MS).

Methods: Demographic, clinical, and procedural data of all consecutive patients who underwent multiple-valve surgeries at two institutions in Germany from March of 2017 to March of 2023 were retrospectively collected. Patients were divided into two groups: MIMVS versus MS and their outcomes were compared before and after propensity score matching. Primary endpoint was the incidence of 30-day mortality.

Results: A total of 317 patients were included in the study; 112 patients in each group were matched 1:1. MIMVS was performed on 123 patients. After propensity matching, 30-day mortality rates were 8% for MIMVS versus 12.5% for MS (p = 0.28). Median blood transfusion in the MIMVS group was 0 [0-3] vs 1 [0-4] in the MS group (p = 0.002). MIMVS was associated with similar cardiopulmonary bypass time 105.5 [79.8-124] versus 98 [68.8-130.3] mins and aortic cross clamping times 70 [53-80.3] versus 63.5 [46-90.3] mins (p values 0.9 and 0.76, respectively). Median intensive care and inhospital stays were similar between both groups (2 [1-4] vs 2 [1-5] days, p = 0.36, and 12 [8-17] vs 12.5 [9-21] days, p = 0.38). Incidences of intrathoracic bleeding, stroke, and acute kidney injury were similar in both groups.

Conclusions: In our experience, endoscopic minimally invasive multiple-valve surgeries through right anterior mini-thoracotomy is as feasible, safe, and effective as medial sternotomy in select patients.

Introduction: Sulforaphane (SFN) is a naturally occurring isothiocyanate associated with various health benefits, including reduced cancer risk, and has been extensively explored as a potential therapeutic. However, its inherent instability presents challenges in formulation, storage, and administration as a medicinal product. SFX-01 (Sulforadex^®) is a patented synthetic form of d,l-SFN stabilized within a biologically inert alpha-cyclodextrin complex.

Methods: The safety, tolerability, and pharmacokinetics of an enteric-coated tablet formulation of SFX-01 were evaluated in a randomized, double-blind, placebo-controlled, dose-escalation study [300 mg once daily (46.2 mg SFN), 300 mg twice daily or 600 mg once daily (92.4 mg SFN)] over 7 days in healthy male participants.

Results: Treatment-emergent adverse events (TEAEs) occurred in 94% of participants who received SFX-01 and were most commonly gastrointestinal events, which were mild in severity and related to treatment. Following ingestion of SFX-01 tablets, SFN was rapidly absorbed, with a timescale consistent with the enteric coating, and subsequently metabolized. The observed peak blood concentration (C_max) for the sum of SFN and metabolites (total thiol) across all treatment cohorts ranged from 0.43 to 2.12 µmol/L in 3-6 h. C_max data were considered inconclusive with respect to dose-proportionality and there was minimal evidence of accumulation of SFN and metabolites. Urinary excretion of SFN and individual metabolites ranged from < 1 to 41%, and the proportion excreted did not appear to be influenced by the dose.

Conclusion: This study demonstrated the safety and tolerability of SFX-01 over 7 days and indicated that the pharmacokinetic behavior of SFX-01 enteric-coated tablets was in line with expectations.

Trial registration: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) number: 2022-001601-43; ISRCTN Study Registration number: ISRCTN9628565.