Advances in Therapy最新文献

Introduction: Pharmacological inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a well-established strategy for achieving substantial reductions in low-density lipoprotein cholesterol (LDL-C). Recently, novel oral PCSK9 inhibitors have emerged, providing new evidence regarding their lipid-lowering efficacy and safety.

Methods: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. Randomized clinical trials evaluating oral PCSK9 inhibitors and reporting percentage changes in lipid parameters and/or adverse events were included. A qualitative synthesis was performed for all studies meeting predefined eligibility criteria, followed by a quantitative synthesis of studies with sufficient data for statistical pooling.

Results: Seven randomized clinical trials were included in the qualitative analysis, of which four were eligible for meta-analysis. Five oral PCSK9 inhibitors were identified. Three agents (MK-0616, AZD0780, and NNC0385-0434) contributed to the quantitative analysis, while two (DC371739 and CVI-LM001) were assessed descriptively. Compared with placebo, oral PCSK9 inhibitors significantly reduced LDL-C [mean difference (MD) - 55.7; 95% confidence interval (CI) - 59.3 to - 52.1; I² = 14%)] and apolipoprotein B (MD - 46.9; 95% CI - 54.6 to - 39.2; I² = 72.9%). They also lowered non-high-density lipoprotein cholestero (MD - 49.4; 95% CI - 57.4 to - 41.5; I² = 50.3%), triglycerides (MD - 13.2; 95% CI - 21.4 to - 5.0; I² = 0%), and lipoprotein(a) (MD - 24.9; 95% CI - 34.9 to - 15.0; I² = 77.6%). Across trials, no differences in safety outcomes were observed between oral PCSK9 inhibitors and placebo.

Conclusion: Oral PCSK9 inhibitors demonstrate lipid-lowering efficacy and safety comparable to that of currently approved injectable PCSK9 therapies. These findings support their potential as a convenient and effective alternative, although current evidence remains limited to early-phase studies.

Introduction: Urgent endoscopy should be performed in patients with cirrhosis and acute gastrointestinal bleeding (AGIB), but this approach is resource-intensive and associated with procedural risks. Therefore, its necessity has been questioned in low-risk patients. This study aims to identify low-risk patients with cirrhosis and AGIB for whom endoscopy may be unnecessary during hospitalization.

Methods: Patients with cirrhosis and AGIB who presented with melena alone were retrospectively screened from an international multicenter cohort. They were further classified according to the use of endoscopy. Logistic regression analyses were performed to explore the relationship of Child-Pugh score and hepatocellular carcinoma (HCC) with in-hospital death.

Results: Overall, 673 patients were included, of whom 202 (30.0%) did not undergo endoscopy. Child-Pugh score and HCC were significantly associated with in-hospital mortality. There was no death during hospitalization among the 304 patients with Child-Pugh score ≤ 7 and without HCC, who were stratified as a low-risk population. Among them, neither in-hospital mortality (0.0% vs. 0.0%) nor rate of 5-day failure to control bleeding (1.3% vs. 4.7%, P = 0.110) was significantly different between patients who underwent endoscopy and those who did not.

Conclusions: Patients with cirrhosis and AGIB, who present with melena alone, and have Child-Pugh score ≤ 7, but without HCC, may not require urgent endoscopy.

Trial registration: This study is a secondary analysis based on the data from our previously registered study (ClinicalTrials.gov identifier NCT04662918).

Introduction: Sickle cell disease (SCD) is characterized by vaso-occlusive crises (VOCs) that can lead to clinical complications, higher mortality, and healthcare resource use (HCRU). Lack of Canadian data poses challenges to health system planning, a gap this study intends to close. We analyzed clinical complications, mortality, and HCRU in patients with SCD with recurrent VOCs in Canada.

Methods: This retrospective cohort study identified patients with SCD with recurrent VOCs from the Institute for Clinical Evaluative Sciences (ICES) databases in Ontario, Canada from January 1, 2010, to December 31, 2021. VOCs were defined as SCD with crisis, priapism, or acute chest syndrome. Patients were matched (1:3) by age, sex, and geographic area with non-SCD individuals in the general population. Clinical complications, mortality, and HCRU were analyzed.

Results: Eight hundred fifty-nine patients with SCD with recurrent VOCs were identified and matched to 2577 controls. Mean (standard deviation [SD]) age was 22.1 (14.4) years; 50.9% were female. Mean (SD) rate of VOCs per person per year was 3.2 (4.4) in patients with recurrent VOCs. Acute and chronic complication rates were higher in patients than controls. Compared with controls, mortality was substantially higher for patients with recurrent VOCs. Mean (SD) age at death for patients with recurrent VOCs was 39.2 (17.2) years. There was significantly higher HCRU than matched controls (P < 0.0001).

Conclusion: Patients with SCD with recurrent VOCs had substantially higher rates of complications, mortality, and HCRU than controls, further highlighting the need for novel therapies to reduce VOCs and the associated burden.

Delayed union and nonunion of long bone fractures are common clinical complications, especially among patients suffering from chronic diseases like osteoporosis and diabetes. Although traditional surgical procedures are commonly applied, they are characterized by numerous problems, such as the need for secondary surgical procedures and the increased risk of complications. On the other hand, non-surgical therapy presents an attractive option since it can avoid the hazards of surgery, prevent complications, and help lower medical expenses. This practice has been gaining interest in recent times. This article will summarize the most recent developments in the non-surgical treatment field for delayed union and nonunion of long bone fractures, which will help improve clinical practice and the discipline of regenerative medicine.

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.