Advances in Therapy最新文献

Introduction: Nipocalimab, efgartigimod, and rozanolixizumab (the last two cyclically dosed) are approved neonatal Fc receptor (FcRn) blockers for treating generalized myasthenia gravis (gMG). No trials have directly compared these therapies; hence, indirect treatment comparisons (ITCs) were conducted to evaluate their relative efficacy.

Methods: Matching-adjusted indirect comparisons (MAICs) and Bucher ITCs were used to compare nipocalimab vs. efgartigimod and rozanolixizumab for changes from baseline (CFB) in Myasthenia Gravis Activities of Daily Living (MG-ADL) total score observed in their phase 3 registration trials. Bucher ITCs used the relative treatment effect vs. placebo. As there was considerable cross-trial heterogeneity, including uncertainty in using the placebo arm as a common comparator, active treatment arms were used in unanchored MAICs. MG-ADL CFB was compared between trials (1) at multiple timepoints to evaluate onset of action and disease control over time, and (2) using area under the curve (AUC) as a measure of cumulative effect normalized per week of follow-up.

Results: In both Bucher ITCs and MAICs, nipocalimab had a comparable MG-ADL CFB at week 1 vs. the other FcRn blockers. In MAICs, MG-ADL CFB was significantly greater with nipocalimab vs. efgartigimod at week 8 sustained up to 24 weeks (p < 0.05), and vs. rozanolixizumab at week 10 sustained up to 14 weeks (p < 0.05); results numerically favored nipocalimab in corresponding Bucher ITCs. Using normalized AUC, MG-ADL CFB with nipocalimab was significantly greater in MAICs (p < 0.05) and numerically greater in Bucher ITCs vs. the other FcRn blockers.

Conclusions: Sustained disease control is an important consideration in managing chronic diseases with fluctuating symptoms such as gMG. Study results showed that nipocalimab provided a comparable onset of action and consistent and sustained disease control that was numerically or statistically significantly greater (depending on ITC method) when compared with the symptom-based cyclic FcRn blockers efgartigimod and rozanolixizumab.

Introduction: In the A DUE study, a fixed-dose combination of macitentan 10 mg and tadalafil 40 mg (M/T FDC) as a single tablet significantly improved pulmonary vascular resistance at Week 16 versus corresponding monotherapies in patients with pulmonary arterial hypertension (PAH). Safety was consistent with known profiles of macitentan and tadalafil. The open-label (OL) period of A DUE provides long-term safety/efficacy data for M/T FDC.

Methods: In A DUE (NCT03904693), patients were randomized (2:1:1) to double-blind M/T FDC, macitentan 10 mg or tadalafil 40 mg and followed for 16 weeks. They then transitioned to OL M/T FDC and were followed for up to 2 years to end of study (EOS). Efficacy analyses, including survival, changes in six-minute walk distance (6MWD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline, are reported in patients randomized to M/T FDC at start of A DUE (efficacy set). Safety is reported for all patients receiving M/T FDC at any time during the double-blind (DB) and/or OL (safety set).

Results: In A DUE, 185 patients received M/T FDC for median (range) of 105.1 (0.6, 182.6) weeks. In the efficacy set, 91% of patients were alive at EOS. Mean (SD) change in 6MWD from M/T FDC initiation to OL Week 120 was 60.5 m (84.2). For NT-proBNP, geometric mean percent of baseline was 50.2% at OL Week 120. In the safety set, adverse events (AEs) occurred in 94.1% and serious AEs in 33.5% of patients; 10.3% discontinued study treatment due to an AE. Seven on-treatment deaths occurred in those receiving M/T FDC; all were evaluated as unrelated to treatment.

Conclusions: Long-term treatment with single-tablet combination of macitentan/tadalafil was well tolerated, with no new safety findings identified. Most patients were alive at EOS. Incremental improvements in 6MWD and NT-proBNP observed in the DB with M/T FDC were sustained over 2 years.

Trial registration: ClinicalTrials.gov Identifier NCT03904693. A graphical abstract is also available for this article.

Introduction: Venetoclax plus azacitidine or decitabine is approved in the US for treatment of newly diagnosed patients with acute myeloid leukemia (AML) aged ≥ 75 years or who have comorbidities precluding use of intensive chemotherapy. As novel targeted regimens expand treatment options for AML, this study evaluated the budget impact of adopting venetoclax combinations for this population from a US third-party payer perspective to inform affordability and access at the health plan level.

Methods: The model estimated the 3-year budget impact of adopting venetoclax combinations in a hypothetical US health plan with 1 million members (60% commercial, 40% Medicare). Eligible patients were estimated using public data. Market share projections assumed venetoclax + azacitidine or decitabine captured a 53% and 15% share, respectively, from existing treatments (azacitidine, low-dose cytarabine [LDAC], decitabine, ivosidenib, gemtuzumab ozogamicin, glasdegib + LDAC, and ivosidenib + azacitidine). The model considered costs associated with drug acquisition/administration, adverse events, hospitalization, disease monitoring, blood transfusions, and subsequent AML management (2024 USD). Clinical inputs for venetoclax combinations were informed by final VIALE-A and M14-358 data, respectively. Incremental budget impact was calculated as per-member-per-month (PMPM), with one-way sensitivity analyses performed.

Results: In a 1-million-member health plan, 48 patients were eligible for venetoclax combinations. Annual costs of venetoclax + azacitidine ($258,498) or decitabine ($259,921) were lower than those of the highest-cost comparators, ivosidenib + azacitidine ($477,520) and ivosidenib ($404,869). Drug acquisition costs of adopting venetoclax combinations were offset by lower subsequent AML management costs, resulting in savings of $0.0476 PMPM in years 1-3. Results remained robust in sensitivity analyses. In a 100% Medicare scenario, 117 patients were eligible for venetoclax combinations, with savings of $0.1137 PMPM over years 1-3.

Conclusion: Inclusion of venetoclax combinations for newly diagnosed patients with AML aged ≥ 75 years or with comorbidities precluding intensive chemotherapy reduced the budget impact, providing potential financial benefits for US payers.

Introduction: For patients with autosomal dominant polycystic kidney disease (ADPKD), the only approved treatment is tolvaptan, a twice-daily medication that works to slow kidney function decline. Patients on tolvaptan report a considerable burden related to the drug's aquaretic effects which can intensify immediately following a dose of the medication.

Methods: A targeted literature review and individual concept elicitation (CE) interviews with nephrologists and adult patients with ADPKD taking tolvaptan were conducted to inform the development of a hybrid diary, programmed as a smartphone application. A sample of adults with ADPKD taking tolvaptan tested the diary for 7 days; a subset also participated in cognitive debriefing (CD) interviews. The diary was then revised and finalized.

Results: CE interviews confirmed the importance of tracking urinary frequency and urgency and timing of tolvaptan doses in real time. Results from the usability/feasibility test and CD interviews confirmed the understandability and relevance of the diary and provided critical insights to improve its content and functionality. The resulting PKD Daily includes two daily entries to report dose timing, overnight urination, and daily impacts of frequent/urgent urination; real-time entries to capture frequency/urgency of daytime urination; and reminders to encourage regular data entry.

Conclusion: Originally developed for use in a clinical trial, the PKD Daily can also provide valuable information to clinicians and patients to support treatment decisions and inform dose selection in clinical practice, becoming a valuable part of a clinician's toolbox. Further, the development of the PKD Daily can serve as a case study for the successful creation of a hybrid diary.

Introduction: Interstitial lung disease (ILD) is frequently complicated by pulmonary hypertension (PH) resulting in reduced functional capacity, diminished quality of life, and increased mortality. However, standardized screening for PH in ILD is lacking, causing delays in diagnosis and treatment. PHINDER (NCT05776225) is a prospective multicenter study that aims to identify parameters for the detection of PH in ILD.

Methods: Data were collected prospectively in patients with ILD from predefined routine testing, including clinical, physiological, and imaging assessments. Precapillary PH was defined as mean pulmonary arterial pressure > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 2 Wood units (WU). Investigators estimated probability of precapillary PH based on noninvasive evaluations before confirmation by right heart catheterization (RHC).

Results: Preliminary results included 190 participants; 105 (55%) had precapillary PH and 26 (14%) had severe PH (PVR > 5 WU). Notable parameters associated with precapillary PH included supplemental oxygen use (OR 3.6, p = 0.004), diffusing capacity of the lung for carbon monoxide ([DLCO] OR 0.9, p = 0.005), forced vital capacity % to DLCO % ratio (OR 1.1, p = 0.008), tricuspid annular plane systolic excursion to right ventricular systolic pressure ratio (OR 0.8, p = 0.020), tricuspid regurgitant velocity (OR 4.4, p = 0.006), pulmonary artery (PA) enlargement (OR 10.6, p < 0.001), PA/aorta diameter ratio (OR 1.7, p = 0.004), and right to left ventricle diameter ratio (OR 1.5, p = 0.021). There was a trend toward higher likelihood of PH with higher clinician suspicion of PH before RHC, but gestalt-based assessment showed limited accuracy relative to hemodynamic confirmation (positive predictive value, 59%; negative predictive value, 68%; accuracy, 60%).

Conclusions: Preliminary findings support the composite use of pulmonary function testing, lung imaging, and echocardiography to improve early detection of precapillary PH in ILD and guide structured screening strategies. The final data set from PHINDER will provide guidance on thresholds for continuous variables with application in diagnosing PH in ILD, facilitating the development of a validated evidence-based screening tool to aid the detection of PH in ILD.

Trail registration: NCT05776225.

Introduction: The treatment landscape for human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) in Canada is rapidly evolving. This retrospective cohort study described real-world historical treatment patterns and clinical outcomes for patients with HER2- mBC.

Methods: Adults enrolled in the pan-Canadian 'Personalize My Treatment' cancer registry and diagnosed with stage IV HER2- mBC (01/01/2015-03/01/2022) were eligible and followed until 03/01/2023. Hormone receptor-positive (HR+)/HER2- mBC and triple-negative mBC (mTNBC) were analyzed separately and further stratified by line of therapy. Main study outcomes included treatment patterns, PIK3CA/AKT1/PTEN alteration testing/positivity rates, and overall survival (OS), all analyzed descriptively.

Results: A total of 507 patients with HER2- mBC were included (HR+/HER2- mBC: 387; mTNBC: 120; median follow-up: 54.1 months). The most common HR+/HER2- mBC treatments were cyclin‑dependent kinase 4/6 inhibitors (CDK4/6is) plus endocrine therapy (ET) in first line (1L; 55.0%), targeted therapies (22.9%) and CDK4/6i + ET (22.0%) in second line (2L), and chemotherapy (CT) monotherapy (42.7%) in third line (3L). CT monotherapy was the most common mTNBC treatment in 1L (35.1%), 2L (50.6%), and 3L (54.8%). Attrition was similar for HR+/HER2- mBC and mTNBC from 1L-2L (16.9% and 16.3%, respectively) but was lower for HR+/HER2- mBC from 2L-3L (33.2% and 38.6%) and 3L-4L (48.1% and 62.1%). PIK3CA/AKT1/PTEN alteration testing was performed in 31.8% of patients with HR+/HER2- mBC and 50.0% with mTNBC, with alterations identified in 15.4% and 20.0% of patients, respectively. Median OS (65.9 and 31.4 months, respectively), OS rates (1 year: 94.8% and 79.8%; 5 years: 56.0% and 21.7%), and time to next treatment (1L-2L: 24.5 and 8.1 months; 2L-3L: 10.1 and 5.1 months) were greater for HR+/HER2- mBC than mTNBC.

Conclusions: These findings describe historical HER2- mBC treatment patterns and associated outcomes in Canada. Ongoing research is needed to optimize therapeutic strategies, expand novel treatment access, and improve patient outcomes.

Introduction: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, autosomal dominant disorder characterized by episodic yet cumulative heterotopic ossification (HO) of connective tissues. Flare-ups, i.e., sites of local soft tissue inflammation, are associated with swelling, joint stiffness, and pain are commonly associated with FOP. This study aimed to investigate the content validity of the Flares Diary by gaining an in-depth understanding of the experience of FOP flare-ups in people with FOP and by debriefing the Flares Diary to assess the relevance, comprehensiveness, and understandability of the instrument.

Methods: Adults with FOP who participated in the Phase 2 LUMINA-1 trial (NCT03188666) of garetosmab, or who were recruited by email via the International Fibrodysplasia Ossificans Progressiva Association, were enrolled in this study. Trained qualitative researchers conducted in-depth semi-structured interviews with all participants comprising concept elicitation and cognitive debriefing of the Flares Diary, with participants encouraged to describe flare-up symptoms and impacts in their own words. All interviews were conducted between March 3, 2022, and March 7, 2023. A conceptual model was developed based on participant-reported symptoms and impacts of flare-ups.

Results: Thematically analyzed interview transcripts from 20 adults with FOP identified concepts of localized and systemic symptoms, as well as impacts on participants' daily lives associated with flare-ups. Minimal issues were reported with understanding the Flares Diary, and participants found that the items were comprehensive and matched their own experience of flare-ups.

Conclusion: The results confirm the adequacy of the Flares Diary and that the symptoms assessed are important to people with FOP. Graphical abstract available for this article.

Trial registration: ClinicalTrials.gov identifier, NCT03188666.

The current standard of maintenance care for patients with moderate-to-severe asthma is the use of inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) medications; some patients may also require additional therapies including long-acting muscarinic antagonists or biologics to establish disease control. Presently, there is a striking discrepancy between the positive outcomes reported in randomised clinical trials (RCTs) of these therapies and real-world outcomes that may be independent of treatment adherence. Patients with asthma included in RCTs are selected using stringent eligibility criteria, for example they have never been heavy smokers. Because current recommendations rely on results from such exclusive RCTs, this calls into question the extent to which these recommendations are applicable in daily practice. Therefore, generalising information from RCTs can be a difficult task for a number of reasons, including differences between ICS/LABAs, varied responses to medications among patients and the limited time busy general practitioners have to bridge the care gaps that exist. Factors in choosing a desirable ICS/LABA may include (a) considerations in clinical decision-making; (b) differences in pharmacokinetic and pharmacodynamic properties of ICS/LABA molecules, therapeutic index; (c) individual patient factors which may influence or facilitate successful adherence to treatment; (d) ease of inhaler use; (e) underlying inflammation; and (f) balancing efficacy and long-term safety, including adverse events and long-term exacerbation risk, based on data from both RCTs and real-world evidence. This review article discusses factors that healthcare professionals may utilise when selecting an ICS/LABA treatment for their patients, by considering data from RCTs and real-world evidence in addition to geographical/environmental, personal, and disease factors, which may also influence the decision process, such as availability and affordability.

Over the past two decades, significant advances have been made in the characterisation of autoimmune encephalitis, its pathophysiology, and the associated autoantibodies. Given the lack of robust clinical trials, the choice of therapy is principally based on observational studies and expert consensus. Current management strategies include immunotherapy, removal of immunological triggers such as tumours when present, and symptomatic treatment of seizures and psychiatric manifestations. With an improved understanding of the underlying pathogenic mechanisms in this rapidly evolving field, the pharmacological treatment of autoimmune encephalitis has evolved over the years, now encompassing various novel therapeutic targets, particularly in the context of third-line immunotherapies. These modalities include B cell depletion, cytokine-targeted therapies, plasma cell-depleting agents, interventions aimed at intrathecal immune cells or their trafficking across the blood-brain barrier, and blockade of the neonatal Fc receptor. This article reviews both established and novel therapeutic approaches for autoimmune encephalitis, with a focus on disease associated with neural surface antibodies, covering immunotherapy and symptomatic management. Additionally, we discuss the unmet needs of patients and the burden of care within this population.