Advances in Therapy最新文献

Menopause is more than simply the end of menstrual cycles or having hot flushes-it marks a time of profound hormonal change which can cause a range of symptoms from poor sleep to anxiety, low mood, cognitive decline and difficulties with memory. These effects can be life-altering and can lead to social withdrawal, relationship strain and reduced capacity to work. With key neurotransmitter systems including serotonin, allopregnanolone and gamma-aminobutyric acid (GABA) being modulated by fluctuating levels of oestradiol, progesterone and testosterone, some women experience severe hormonally related depression and suicidality, as evidenced by the peak of women's suicide rates in midlife. Despite National Institute of Clinical Excellence (NICE) guidance recommending hormone replacement therapy (HRT) as a first-line treatment for perimenopausal mood disturbance, inconsistencies in clinical knowledge and lack of clinician awareness and confidence in prescribing HRT leave many women feeling unsupported and struggling to improve. By providing individualised menopause management through a biopsychosocial lens, supported by improved clinician training and further research, and offering treatment such as HRT alongside lifestyle and psychological support, there is potential not only to transform the lives of affected women but also to safeguard their long-term health. With nearly 40% of women's lives spent post-menopause, combined with the extensive amount of time women sometimes spend in perimenopause (up to 12%), when mental health challenges are noted to be most acute, effective menopause management should be an urgent public health priority.

Gene therapies are emerging as a promising strategy for the treatment of rare genetic diseases, for which treatment options are often limited and do not address the underlying disease mechanisms. However, there are significant challenges for gene therapy programs, including defining a suitable first-in-human cohort and selecting endpoints with appropriate variability, sensitivity, reliability, and clinical meaningfulness; a systematic framework for the assessment and approval of these treatments is lacking. In this review, we share insights from 12 clinical development programs that culminated in recent approvals of gene therapies for rare genetic diseases (2016-2023). These approvals highlight useful strategies for navigating the unique challenges of gene therapy trials, including early and frequent engagement with regulatory bodies, incorporating the patient voice, selecting meaningful clinical outcome assessments and suitable controls, and leveraging well-matched real-world data to understand long-term efficacy, durability, and safety. By systematically documenting and analyzing detailed examples in this review, it becomes possible to derive data-driven solutions that can inform the design of future studies. Such solutions may diverge from prior assumptions or preconceptions but can provide a more evidence-based foundation for improving trial efficiency, and ultimately accelerate the development of urgently needed therapies for patients with rare genetic diseases.

Introduction: Patients with active psoriatic arthritis (PsA) initiating guselkumab are nearly two times more likely to remain persistent with on-label therapy at 12 months compared to those initiating subcutaneous (SC) interleukin-17A inhibitors (IL-17Ai). In this real-world study, on-label treatment persistence at 24 months was compared between patients with active PsA initiating guselkumab versus SC IL-17Ai, overall and among biologic-naïve and biologic-experienced subgroups.

Methods: Adult patients with active PsA initiated on guselkumab or SC IL-17Ai (secukinumab, ixekizumab) between July 14 2020 and December 31 2022 were identified from the IQVIA PharMetrics^® Plus database. The first claim defined the index date, and results were stratified based on previous biologic (bDMARD) use. Treatment cohorts were balanced using propensity score overlap weighting. On-label treatment persistence (no treatment discontinuation or dose modification) through 24 months was assessed using weighted Kaplan-Meier curves and compared between cohorts using Cox proportional hazards models.

Results: Overall, 849 patients initiating guselkumab (biologic-naïve: 362, biologic-experienced: 487) and 2601 patients initiating SC IL-17Ai (biologic-naïve: 845, biologic-experienced: 1756) were included. On-label treatment persistence rates at 24 months were 44.9% and 35.0% for patients initiating guselkumab or SC IL-17Ai, respectively, with patients initiating guselkumab being 1.49 times more likely to be persistent with on-label therapy (hazard ratio [95% confidence interval]: 1.49 [1.29, 1.72]; P < 0.001). Results were consistent among biologic-naïve (1.70 [1.32, 2.20]; P < 0.001) and biologic-experienced (1.33 [1.11, 1.59]; P = 0.002) subgroups.

Conclusion: This real-world study identified greater on-label treatment persistence rates at 24 months in patients with active PsA initiating guselkumab versus SC IL-17Ai, overall and among biologic-naïve and biologic-experienced subgroups.

Pediatric blepharokeratoconjunctivitis (PBKC) is a chronic inflammatory condition of the ocular surface that affects the eyelids, conjunctiva, and cornea that can lead to corneal scarring and permanent vision loss if untreated. The condition presents with diverse clinical features, necessitating a broad range of therapeutic approaches. Current management strategies include eyelid hygiene practices, topical and systemic antibiotics, and anti-inflammatory agents, often in combination for optimal outcomes. Given the expanding spectrum of medical options and the emergence of new therapeutic avenues, staying current with available treatments can be challenging. This review, based on a PubMed search using the terms pediatric blepharokeratoconjunctivitis, pediatric ocular rosacea, pediatric phlyctenular disease, pediatric phlyctenular keratoconjunctivitis, and pediatric blepharokeratitis, aims to provide ophthalmologists with a comprehensive overview of the current medical strategies. Early and multimodal therapeutic strategies that target multiple facets of eyelid margin and ocular surface inflammation, coupled with timely amblyopia treatment, is required to prevent vision loss due to PBKC.

Introduction: Racial and ethnic minorities are underrepresented in most pulmonary arterial hypertension (PAH) studies. The OPsumit® Users (OPUS) and Opsumit® Historical Users cohort (OrPHeUS) studies captured real-world data for US patients newly initiating macitentan. Patient characteristics, treatment patterns, and outcomes in the combined OPUS/OrPHeUS dataset are described by race (Black/African American or White) and by ethnicity (Hispanic/Latino or not Hispanic/Latino).

Methods: OPUS was a prospective, observational drug registry (Apr 2014-Jun 2020; NCT02126943). OrPHeUS was a medical chart review (Oct 2013-Mar 2017; NCT03197688). All analyses are descriptive.

Results: The OPUS/OrPHeUS PAH follow-up set comprised 4626 patients: 752/4589 (16.4%) Black/African American, 3484/4589 (75.9%) White; 517/4609 (11.2%) Hispanic/Latino, 3907/4609 (84.8%) not Hispanic/Latino. Black/African American versus White patients were slightly younger at diagnosis (median [Q1,Q3] 57 [47,66]/61 [48,71] years), with more connective tissue disease-associated PAH (33.0%/25.1%). Treatment patterns between races were similar. For Black/African American versus White patients, 1-year Kaplan-Meier estimates (95% confidence limit [CL]) for survival were 89.6% (86.8,91.8)/90.3% (89.1,91.4); freedom from all-cause hospitalization was 52.5% (48.4,56.4)/61.2% (59.4,63.0). Hispanic/Latino versus not Hispanic/Latino patients were younger at diagnosis (median [Q1,Q3] 53 [39,63]/60 [48,70] years) with more congenital heart disease-associated PAH (12.8%/5.3%) and longer median (95% CL) time from diagnosis to first, double, and triple combination PAH therapy (2.8 [2.3,3.7]/1.9 [1.7,2.2], 35.6 [29.9,46.9]/17.9 [16.3,19.9], and 213.6 [127.5,372.7]/140.4 [127.5,152.3] months, respectively). For Hispanic/Latino versus not Hispanic/Latino patients, survival estimates were 93.8% (91.0,95.8)/89.9% (88.8,90.9); freedom from all-cause hospitalization was 62.5% (57.6,67.0)/59.2% (57.4,60.9). Overall, safety profiles were similar between the groups and consistent with the known profile of macitentan.

Conclusions: OPUS/OrPHeUS provides real-world insights into racial/ethnic minority groups receiving macitentan and other PAH-specific treatments in the USA. These data on treatment patterns and outcomes could help inform treatment decisions in the reported minority groups.

Trial registration: OPsumit® Users Registry (OPUS), NCT02126943; Opsumit® Historical Users cohort (OrPHeUS), NCT03197688; www.

Clinicaltrials: gov .

Introduction: Tislelizumab + chemotherapy has shown promising results as first-line treatment for advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC). We present long-term safety and efficacy outcomes from the RATIONALE-305 trial after 3 years of follow-up, focusing on the intent-to-treat (ITT) population and subgroups based on programmed death ligand-1 (PD-L1) expression.

Methods: RATIONALE-305, a randomized, double-blind, placebo-controlled, phase 3 trial conducted across 146 centers in Asia, Europe, and North America (December 2018-February 2024), enrolled 997 adults with human epidermal growth factor receptor 2-negative advanced GC/GEJC, randomized 1:1 to receive tislelizumab + chemotherapy or placebo + chemotherapy. The primary endpoint was overall survival (OS) in patients with PD-L1 Tumor Area Positivity (TAP) score ≥ 5% and the ITT population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and tolerability. At 3-year follow-up, 959 (96.2%) patients had discontinued or completed treatment. The minimum follow-up duration was 36.6 months.

Results: In all randomized patients (n = 997), 69.4% male and 30.6% female, tislelizumab + chemotherapy improved OS versus placebo + chemotherapy [15.0 months (95% CI 13.6-16.5) vs. 12.9 months (95% CI 12.1-14.1); stratified hazard ratio (HR) 0.79]. Investigator-assessed PFS was also improved [6.9 months (95% CI 5.7-7.2) vs. 6.2 months (95% CI 5.6-6.9); stratified HR 0.79]. The ORR was higher with tislelizumab + chemotherapy. In patients with a PD-L1 TAP score ≥ 5% [n = 546 (54.8%)], similar OS and PFS benefits were observed compared to the ITT population. OS was 16.4 (95% CI 13.6-19.1) months versus 12.8 (95% CI 12.0-14.5) months, stratified HR 0.71 for tislelizumab + chemotherapy versus placebo + chemotherapy, respectively. PFS was 7.2 (95% CI 5.8-8.4) months versus 5.9 (95% CI, 5.6-7.0) months, stratified HR 0.69. No new safety signals were identified.

Conclusion: Results from RATIONALE-305 continued to show durable and improved efficacy outcomes with tislelizumab + chemotherapy versus placebo + chemotherapy at 3 years in advanced GC/GEJC, supporting PD-L1 as a potential prognostic biomarker.

Trial registration: ClinicalTrials.gov Identifier: NCT03777657.

The introduction of biosimilars into global markets has increased utilisation and reduced costs of biological therapies. However, the uptake varies by country because of differences in biosimilar knowledge and concerns about their safety and efficacy. This review examines clinical and real-world data on the effects of switching between reference and biosimilar (SDZ-ETN, SB4, LBEC0101, YLB113) etanercept on treatment efficacy and safety in patients with inflammatory rheumatic and musculoskeletal diseases. To date, all controlled clinical trials and real-world studies indicate that switching between reference and biosimilar etanercept does not affect treatment efficacy and safety. These findings support broader biosimilar adoption to improve patient access and reduce healthcare costs. However, published data on multiple biosimilar switches and patient-reported outcomes remain limited, warranting further research efforts in these areas.

Introduction: Immunoglobulin A (IgA) nephropathy is a rare renal condition associated with a high risk of kidney failure. However, conducting phase 3 clinical trials with kidney failure as a primary endpoint is generally not feasible because of sample size and protracted follow-up requirements. Hence, surrogate outcomes are necessary when assessing new treatments in randomized controlled trials. Previous meta-analyses have assessed the validity of early change in proteinuria as a surrogate endpoint, and the present research updates the analysis with additional patient-level data.

Methods: The same methodology as two previously published individual patient-level meta-analyses was used, with additional data from the PROTECT study included. Early change in proteinuria was defined as change from baseline at 9 months, and the clinical endpoint was defined as the composite of doubling of serum creatinine level, kidney failure or death. The association of treatment effects was ascertained using individual patient data via a Bayesian mixed-effect regression model to relate treatment effects on the clinical outcome to treatment effects on proteinuria with study as the unit of analysis.

Results: The updated individual patient-level meta-analysis including data from PROTECT resulted in an overall slope of 1.03 (95% Bayesian credible interval - 0.40 to 2.34) between treatment effects on early change in proteinuria versus longer-term treatment effects on the clinical outcome, with an R² of 0.80 (95% Bayesian credible interval 0.07 to1.00). This corroborates the use of early proteinuria as a valid surrogate endpoint for a treatment's effect on progression to kidney failure in studies of IgA nephropathy.

Conclusions: The FDA and EMA have accepted proteinuria as a valid surrogate outcome for use in clinical trials of new interventions for the treatment of IgA nephropathy, and the present analysis provides further indications that interventions that reduce proteinuria in a short-term trial are likely to improve kidney outcomes over the long term.

Introduction: Although patients with extensive-stage small cell lung cancer (ES-SCLC) typically respond well to first-line (1L) platinum-based chemotherapy (PBC)-containing regimens, disease recurrence is common, and survival is short. Treatment options beyond 1L are limited, leaving an urgent need for more effective treatment options. Understanding patient characteristics, treatment patterns, and clinical outcomes in this setting may inform clinical development of novel therapies for ES-SCLC.

Methods: This study is a retrospective, observational analysis of real-world data from a US nationwide electronic health record-derived de-identified database. Patients with ES-SCLC who received 1L PBC between January 1, 2018, and June 30, 2023, were included. Treatment patterns were analyzed in all patients, and clinical outcomes from third-line (3L) therapy initiation were assessed in those who also received 3L treatment. The study period (January 1, 2018, through December 31, 2023) allowed for ≥ 6 months' potential follow-up.

Results: Of 2573 patients (50.5% female; 49.5% male) included in the overall population, 992 (38.6%), 344 (13.4%), and 114 (4.4%) received ≥ 1, ≥ 2, and ≥ 3 subsequent treatment lines, respectively. Treatment patterns beyond 1L were fragmented: the most common second-line treatments were lurbinectedin-containing regimens (26.5%), and in 3L were lurbinectedin-containing regimens (21.8%) or topoisomerase inhibitors (21.8%). From 3L therapy initiation, median real-world overall survival (rwOS) was 4.53 months (95% confidence interval [CI] 3.71-5.39), median real-world time to treatment discontinuation or death (rwTTD/D) was 2.56 months (95% CI, 2.27-2.79), median real-world time to next treatment or death (rwTTNT/D) was 2.92 months (95% CI, 2.69-3.12), and real-world response rate among 77 evaluable patients was 11.7% (95% CI, 5.5-21.0).

Conclusions: This study demonstrated the heterogeneity of treatments after 1L PBC-containing therapy for patients with ES-SCLC, with no clear standard of care identified. In 3L, rwTTD/D, rwTTNT/D, and rwOS were short, demonstrating the substantial unmet need for novel treatments in this setting.

Introduction: A post-marketing surveillance study of EX-PRESS™ Glaucoma Filtration Device was conducted to confirm the safety and efficacy of the product in clinical settings.

Methods: Patients with glaucoma with insufficient intraocular pressure (IOP) reduction despite glaucoma medication, laser therapy or prior glaucoma surgery underwent EX-PRESS™ filtration surgery and were followed for 3 years.

Results: The study was conducted from July 2012 to December 2017 and included 890 eyes of 835 patients from 52 medical institutions across Japan. The efficacy analysis of 821 eyes showed that the mean ± SD IOP changed from 25.0 ± 9.1 mmHg at baseline to postoperative 14.0 ± 5.4, 14.2 ± 5.8, and 14.5 ± 5.8 mmHg at 12, 24, and 36 months, respectively. The mean ± SD number of glaucoma medications used reduced from 3.5 ± 1.4 at baseline to postoperative 1.0 ± 1.5, 1.4 ± 1.7, and 1.7 ± 1.7 at 12, 24, and 36 months, respectively. The survival analysis showed that the rate of success, defined as IOP ≤ 21 mmHg and a percent reduction of ≥ 20% with or without glaucoma medication, was 64.6% at 3 years postoperatively. In the safety analysis of 824 eyes, the incidence of malfunctions was 31.9% and the incidence of adverse events (AEs) for which a causal relationship could not be ruled out was 22.2%. There were no reports of infection. The most common malfunctions were device-iris touch (26.9%), device malfunction (2.9%), device-cornea touch (2.7%), and device obstruction (1.7%). The most common AEs were IOP increased (11.9%), corneal endothelial cell loss (5.7%), glaucoma filtration surgery (5.0%), device removal (5.0%), hypotony (3.2%), and bleb reconstruction (2.4%). Five cases of reduced visual acuity and one case of visual field defect aggravation were reported as adverse events related to vision. The mean endothelial cell density (ECD) decreased after surgery but remained above 2000 cells/mm² at 36 months postoperatively. Percent change of ECD at 36 months from baseline was - 8.2 ± 22.5%.

Conclusion: The current study confirmed the efficacy and safety of the EX-PRESS™ Glaucoma Filtration Device.