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Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. Gates Foundation.

Rocatinlimab is a T cell rebalancing therapy that inhibits and reduces the number of pathogenic T cells by targeting the OX40 receptor expressed on the surface of activated T cells. Two global phase 3 studies were performed to assess the efficacy and safety of rocatinlimab for the treatment of moderate-to-severe atopic dermatitis in adults. ROCKET-IGNITE (IGNITE) and ROCKET-HORIZON (HORIZON) were 24-week randomised, double-blind, placebo-controlled phase 3 trials conducted in 19 countries each. Eligible patients were 18 years and older with confirmed atopic dermatitis (American Academy of Dermatology Consensus Criteria) diagnosed 1 year or longer before study entry with moderate-to-severe disease activity, defined by an Eczema Area and Severity Index (EASI) score of 16 and over, validated Investigator's Global Assessment for Atopic Dermatitis (vIGA-AD) score of 3 (moderate) or 4 (severe), and affected body surface area of 10% and above. In IGNITE, patients were randomly allocated in a 3:2:2 ratio to receive subcutaneous 300 mg rocatinlimab, 150 mg rocatinlimab, or placebo; in HORIZON, patients were randomised 3:1 to receive subcutaneous 300 mg rocatinlimab or placebo. Randomisation was stratified by baseline disease severity (vIGA-AD score of 3 vs 4) and geographical region (Japan vs non-Japan Asian countries vs rest of world). Across both trials, 24-week treatment was administered at weeks 0, 2, and 4 and then every 4 weeks thereafter with the last dose at week 20. The coprimary endpoints for both trials were EASI-75 response (&#x2265;75% improvement in EASI score from baseline) at week 24 and vIGA-AD score of 0 or 1 (defined as a score of 0 [clear skin] or 1 [almost clear skin], representing a &#x2265;2-point improvement from baseline) at week 24. Rescue therapy use, including topical therapy, phototherapy, and systemic therapy, was permitted from day 1; all patients who received rescue therapy were considered non-responders for all visits after the first use of rescue therapy but could generally continue study treatment unless prohibited per protocol. Efficacy analyses were conducted in all randomised patients; safety analyses were conducted in all patients who received one or more dose of study treatment, with patients grouped according to actual treatment received. The trials were registered at ClinicalTrials.gov: ROCKET-IGNITE (NCT05398445) and ROCKET-HORIZON (NCT05651711). Between May 31, 2022, and June 12, 2024, 769 patients were randomised in IGNITE (two patients were enrolled under an earlier protocol before study re-design and excluded from the analysis; after the protocol update, 328 were included in the 300 mg rocatinlimab group; 217 in the 150 mg rocatinlimab group; and 222 in the placebo group) and between Dec 14, 2022, and Dec 12, 2023, 726 patients were randomised in HORIZON (543 in 300 mg rocatinlimab and 183 in placebo). Both trials met their coprimary endpoints. Rocatinlimab treatment resulted in statistically significant improvements in EASI-75 response in comparison with placebo at week 24 in IGNITE (138 [42%] of 326 patients on 300 mg rocatinlimab; 78 [36%] of 215 on 150 mg rocatinlimab; and 28 [13%] of 219 on placebo; percentage difference vs placebo: 300 mg rocatinlimab 29&#xb7;5% [95% CI 22&#xb7;3-36&#xb7;1], p<0&#xb7;001 and 150 mg rocatinlimab 23&#xb7;4% [15&#xb7;4-30&#xb7;9], p<0&#xb7;001) and HORIZON (rocatinlimab, 178 [33%] of 543 vs placebo, 25 [14%] of 183; percentage difference 19&#xb7;1% [95% CI 12&#xb7;4-25&#xb7;2], p<0&#xb7;001). Statistically significant improvements with rocatinlimab treatment in comparison with placebo were also observed at week 24 for vIGA-AD score of 0 or 1 response in IGNITE (77 [24%] of 326 patients on&#x2009;300 mg rocatinlimab; 41 [19%] of 215 patients on 150 mg rocatinlimab; and 19 [9%] of 219 patients on placebo; percentage difference vs placebo 14&#xb7;9% [95% CI 8&#xb7;8-20&#xb7;6], p<0&#xb7;001 for 300 mg rocatinlimab and 10&#xb7;3% [3&#xb7;8-16&#xb7;6], p=0&#xb7;002 for 150 mg rocatinlimab) and HORIZON (105 [19%] of 543 for 300 mg rocatinlimab vs 12 [7%] of 183 for placebo; percentage difference 12&#xb7;8% [95% CI 7&#xb7;6-17&#xb7;3], p<0&#xb7;001). The incidences of treatment-emergent adverse events were generally similar across rocatinlimab and placebo treatment groups in IGNITE and HORIZON. The most frequently reported adverse events in patients receiving rocatinlimab (defined as occurring in &#x2265;4% of patients in any rocatinlimab treatment group and at a rate &#x2265;2 times that of placebo) included pyrexia (105 [12%] of 870 for 300 mg rocatinlimab and 26 [12%] of 214 for 150 mg rocatinlimab), chills (48 [6%] of 870 and five [2%] of 214 for the 300 mg and 150 mg doses, respectively), and aphthous ulcers (38 [4%] of 870 and six [3%] of 214, respectively). Most events of pyrexia and chills were considered injection-related reactions; events were generally mild or moderate in severity and primarily occurred after the first dose. Serious adverse events were reported in 2% to 5% of patients in the rocatinlimab groups and 4% to 6% of patients in the placebo groups. No deaths were reported. Rocatinlimab treatment resulted in statistically significant and clinically meaningful improvements across clinical endpoints, including the coprimary endpoints of EASI-75 response and vIGA-AD score of 0 or 1, in comparison with placebo and had a clinically acceptable safety profile in adult patients with moderate-to-severe atopic dermatitis. Amgen and Kyowa Kirin.

Comprehensive, comparable, and timely estimates of demographic metrics-including life expectancy and age-specific mortality-are essential for evaluating, understanding, and addressing trends in population health. The COVID-19 pandemic highlighted the importance of timely and all-cause mortality estimates for being able to respond to changing trends in health outcomes, showing a strong need for demographic analysis tools that can produce all-cause mortality estimates more rapidly with more readily available all-age vital registration (VR) data. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is an ongoing research effort that quantifies human health by estimating a range of epidemiological quantities of interest across time, age, sex, location, cause, and risk. This study-part of the latest GBD release, GBD 2023-aims to provide new and updated estimates of all-cause mortality and life expectancy for 1950 to 2023 using a novel statistical model that accounts for complex correlation structures in demographic data across age and time. We used 24&#x2008;025 data sources from VR, sample registration, surveys, censuses, and other sources to estimate all-cause mortality for males, females, and all sexes combined across 25 age groups in 204 countries and territories as well as 660 subnational units in 20 countries and territories, for the years 1950-2023. For the first time, we used complete birth history data for ages 5-14 years, age-specific sibling history data for ages 15-49 years, and age-specific mortality data from Health and Demographic Surveillance Systems. We developed a single statistical model that incorporates both parametric and non-parametric methods, referred to as OneMod, to produce estimates of all-cause mortality for each age-sex-location group. OneMod includes two main steps: a detailed regression analysis with a generalised linear modelling tool that accounts for age-specific covariate effects such as the Socio-demographic Index (SDI) and a population attributable fraction (PAF) for all risk factors combined; and a non-parametric analysis of residuals using a multivariate kernel regression model that smooths across age and time to adaptably follow trends in the data without overfitting. We calibrated asymptotic uncertainty estimates using Pearson residuals to produce 95% uncertainty intervals (UIs) and corresponding 1000 draws. Life expectancy was calculated from age-specific mortality rates with standard demographic methods. For each measure, 95% UIs were calculated with the 25th and 975th ordered values from a 1000-draw posterior distribution. In 2023, 60&#xb7;1 million (95% UI 59&#xb7;0-61&#xb7;1) deaths occurred globally, of which 4&#xb7;67 million (4&#xb7;59-4&#xb7;75) were in children younger than 5 years. Due to considerable population growth and ageing since 1950, the number of annual deaths globally increased by 35&#xb7;2% (32&#xb7;2-38&#xb7;4) over the 1950-2023 study period, during which the global age-standardised all-cause mortality rate declined by 66&#xb7;6% (65&#xb7;8-67&#xb7;3). Trends in age-specific mortality rates between 2011 and 2023 varied by age group and location, with the largest decline in under-5 mortality occurring in east Asia (67&#xb7;7% decrease); the largest increases in mortality for those aged 5-14 years, 25-29 years, and 30-39 years occurring in high-income North America (11&#xb7;5%, 31&#xb7;7%, and 49&#xb7;9%, respectively); and the largest increases in mortality for those aged 15-19 years and 20-24 years occurring in Eastern Europe (53&#xb7;9% and 40&#xb7;1%, respectively). We also identified higher than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 5-14 years (87&#xb7;3% higher in GBD 2023 than GBD 2021 on average across countries and territories over the 1950-2021 period) and for females aged 15-29 years (61&#xb7;2% higher), as well as lower than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 50 years and older (13&#xb7;2% lower), reflecting advances in our modelling approach. Global life expectancy followed three distinct trends over the study period. First, between 1950 and 2019, there were considerable improvements, from 51&#xb7;2 (50&#xb7;6-51&#xb7;7) years for females and 47&#xb7;9 (47&#xb7;4-48&#xb7;4) years for males in 1950 to 76&#xb7;3 (76&#xb7;2-76&#xb7;4) years for females and 71&#xb7;4 (71&#xb7;3-71&#xb7;5) years for males in 2019. Second, this period was followed by a decrease in life expectancy during the COVID-19 pandemic, to 74&#xb7;7 (74&#xb7;6-74&#xb7;8) years for females and 69&#xb7;3 (69&#xb7;2-69&#xb7;4) years for males in 2021. Finally, the world experienced a period of post-pandemic recovery in 2022 and 2023, wherein life expectancy generally returned to pre-pandemic (2019) levels in 2023 (76&#xb7;3 [76&#xb7;0-76&#xb7;6] years for females and 71&#xb7;5 [71&#xb7;2-71&#xb7;8] years for males). 194 (95&#xb7;1%) of 204 countries and territories experienced at least partial post-pandemic recovery in age-standardised mortality rates by 2023, with 61&#xb7;8% (126 of 204) recovering to or falling below pre-pandemic levels. There were several mortality trajectories during and following the pandemic across countries and territories. Long-term mortality trends also varied considerably between age groups and locations, demonstrating the diverse landscape of health outcomes globally. This analysis identified several key differences in mortality trends from previous estimates, including higher rates of adolescent mortality, higher rates of young adult mortality in females, and lower rates of mortality in older age groups in much of sub-Saharan Africa. The findings also highlight stark differences across countries and territories in the timing and scale of changes in all-cause mortality trends during and following the COVID-19 pandemic (2020-23). Our estimates of evolving trends in mortality and life expectancy across locations, ages, sexes, and SDI levels in recent years as well as over the entire 1950-2023 study period provide crucial information for governments, policy makers, and the public to ensure that health-care systems, economies, and societies are prepared to address the world's health needs, particularly in populations with higher rates of mortality than previously known. The estimates from this study provide a robust framework for GBD and a valuable foundation for policy development, implementation, and evaluation around the world. Gates Foundation.

Fractures related to osteoporosis and low bone mineral density lead to substantial morbidity, mortality, and cost to individuals and health systems. Here we present the most up-to-date global, regional, and national estimates of the contribution of low bone mineral density to the burden of fractures from falls and additional categories of injuries from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021. The burden of low bone mineral density was estimated from 1990 to 2020 in terms of years lived with disability (YLDs), disability-adjusted life years (DALYs), and deaths, for individuals aged 40 years and older, using data from population-based studies from 48 countries or territories (169 unique sources). Mean standardised femoral neck bone mineral density values were estimated by GBD location, age, and sex by meta-regression. Based on a separate meta-analysis of population-based studies from nine countries (12 unique sources), we also estimated the pooled relative risk of fractures per unit decrease in bone mineral density (g/cm2). The population-attributable fraction for low bone mineral density was calculated by comparing the observed distributions of standardised femoral neck bone mineral density to an age-specific and sex-specific counterfactual distribution, defined as the 99th percentile of five rounds of the National Health and Nutrition Examination Survey in the USA, by 5-year age group and sex. Hospital and emergency department data were used to derive the incidence of fractures for six categories of injury (road injuries, other transport injuries, falls, non-venomous animal contact, exposure to mechanical forces, and physical interpersonal violence) using ICD codes. Deaths due to fractures were estimated as the proportion of in-hospital deaths due to the specified injury causes for which a fracture (nature of injury code) was more severe than the cause of injury code. YLDs and DALYs attributable to low bone mineral density by cause of injury were also determined according to previous GBD methods. In 2020, 8&#xb7;32 million (95% UI 5&#xb7;58-10&#xb7;84) YLDs, 17&#xb7;2 million (14&#xb7;1-20&#xb7;2) DALYs, and 477&#x2009;000 (411&#x2009;000-536&#x2009;000) deaths were attributable to low bone mineral density globally in individuals aged 40 years and older. Between 1990 and 2020, global YLDs, DALYs, and deaths attributable to low bone mineral density increased by 91&#xb7;8% (88&#xb7;5-95&#xb7;1), 89&#xb7;8% (81&#xb7;5-99&#xb7;0), and 127&#xb7;1% (108&#xb7;5-144&#xb7;5), respectively. Over this period, the age-standardised global rates of YLDs, DALYs, and deaths attributable to low bone mineral density showed modest decreases. In 2020, falls accounted for 76&#xb7;2% (95% UI 74&#xb7;2-78&#xb7;3) of YLDs, 65&#xb7;2% (62&#xb7;9-67&#xb7;6) of DALYs, and 71&#xb7;0% (67&#xb7;4-72&#xb7;8) of deaths attributable to low bone mineral density, and road injuries largely accounted for the remaining amount: 12&#xb7;4% (11&#xb7;1-13&#xb7;6) of YLDs, 24&#xb7;6% (22&#xb7;5-27&#xb7;1) of DALYs, and 23&#xb7;1% (21&#xb7;6-26&#xb7;2) of deaths. As a proportion of all fall-related burden, low bone mineral density accounted for 26&#xb7;6% (23&#xb7;2-28&#xb7;7) of YLDs, 25&#xb7;6% (22&#xb7;1-27&#xb7;4) of DALYs, and 40&#xb7;6% (35&#xb7;4-44&#xb7;0) of deaths in 2020. Of all road injury-related burden, 12&#xb7;6% (10&#xb7;8-13&#xb7;5) of YLDs, 6&#xb7;3% (5&#xb7;4-6&#xb7;9) of DALYs, and 8&#xb7;9% (7&#xb7;6-9&#xb7;6) of deaths were attributable to low bone mineral density. In men, road injuries accounted for the largest proportion of DALYs attributable to low bone mineral density in those aged 40-59 years and the largest proportion of deaths in those aged 40-64 years. In women, road injuries were the leading cause of DALYs attributable to low bone mineral density in those aged 40-44 years and the leading cause of deaths attributable to low bone mineral density in those aged 40-54 years. In older age groups among both men and women, falls were the leading cause of the burden attributable to low bone mineral density. Low bone mineral density is a crucial modifiable risk factor for fractures, which are an important cause of morbidity and mortality particularly in ageing populations. This analysis highlights low bone mineral density as a cause of health loss not just from falls, but also from road injuries. Gates Foundation.

The U-ACTIVATE long-term extension study aims to evaluate the long-term efficacy and safety of upadacitinib in patients with moderately to severely active ulcerative colitis. Here, we report interim results after 3 years of total treatment. U-ACTIVATE is an ongoing, 288-week, phase 3, long-term extension study done at 307 centres across 43 countries (active sites on Dec 31, 2021, are presented as part of this interim analysis) and began on Jan 31, 2017. In brief, patients aged 16-75 years with a confirmed diagnosis of moderately to severely active ulcerative colitis for 90 days or more, an adapted Mayo score of 5-9, and an endoscopic subscore of 2 or 3 were eligible for the upadacitinib induction studies; patients who had a clinical response in the induction studies were eligible to enter the U-ACHIEVE maintenance study. Individuals who completed the U-ACHIEVE maintenance study were subsequently eligible for inclusion in the efficacy population of this long-term extension study. Patients in clinical remission per adapted Mayo score at week 52 of the maintenance study could continue their double-masked treatment upon entering the long-term extension study. Patients not in clinical remission originally randomly assigned to upadacitinib 15 mg were eligible to escalate to upadacitinib 30 mg, those originally randomly assigned to upadacitinib 30 mg continued on upadacitinib 30 mg, and those originally assigned to placebo were eligible to escalate to upadacitinib 15 mg in a masked way. We present data from weeks 48 and 96 of the long-term extension period. Key efficacy outcomes were clinical remission (per adapted Mayo score), endoscopic remission, maintenance of clinical remission, and maintenance of endoscopic remission, and are presented for those patients who had a clinical response after 8 weeks of upadacitinib 45 mg induction, completed 52 weeks of maintenance (U-ACHIEVE maintenance), and subsequently entered the long-term extension. Safety outcomes were treatment-emergent adverse events and adverse events of special interest, which were prespecified and were recorded in two populations: one comprising patients who received at least one dose of study drug in the long-term extension study and the other comprising all patients in the maintenance or long-term extension studies. Our primary approach for efficacy analysis was as-observed (ie, all observed data were used without imputation for missing data until patients switched to a different dose during the long-term extension study). This study is registered with ClinicalTrials.gov (NCT03006068). 414 patients from the phase 3 upadacitinib U-ACHIEVE maintenance study were eligible to enter this long-term extension study for assessment of efficacy endpoints following treatment with upadacitinib. Of these individuals, 369 patients (231 [63%] male individuals and 138 [37%] female individuals) were treated with upadacitinib in the long-term extension study: 142 patients with upadacitinib 15 mg and 227 with upadacitinib 30 mg. In the as-observed population, 84 (71%) of 118 patients receiving upadacitinib 15 mg were in clinical remission at week 48, as were 130 (67%) of 193 receiving upadacitinib 30 mg; by week 96, 69 (76%) of 91 patients receiving upadacitinib 15 mg and 104 (74%) of 141 of those receiving upadacitinib 30 mg were in clinical remission. Most patients who entered the long-term extension in clinical remission maintained it in the as-observed analysis (week 48 upadacitinib 15 mg 62 [81%] of 77 and upadacitinib 30 mg 90 [81%] of 111; week 96 upadacitinib 15 mg 50 [78%] of 64 and upadacitinib 30 mg 69 [84%] of 82). In the as-observed population, 60 (49%) of 123 patients receiving upadacitinib 15 mg and 93 (46%) of 202 receiving upadacitinib 30 mg were in endoscopic remission at week 48; by week 96, 45 (47%) of 95 patients receiving upadacitinib 15 mg and 69 (45%) of 153 receiving upadacitinib 30 mg were in endoscopic remission. Most patients who entered the long-term extension in endoscopic remission maintained it in the as-observed analysis (week 48 upadacitinib 15 mg 28 [70%] of 40 and upadacitinib 30 mg 51 [76%] of 67; week 96 upadacitinib 15 mg 20 [65%] of 31 and upadacitinib 30 mg 37 [73%] of 51). In the long-term extension-only safety analysis, we assessed data from 467 patients, representing 1027&#xb7;9 patient-years of continuous long-term extension exposure on a consistent upadacitinib dose. Treatment-emergent adverse events were recorded at 238&#xb7;5 events per 100 patient-years for upadacitinib 15 mg and 233&#xb7;4 events per 100 patient-years for upadacitinib 30 mg. Event rates of serious treatment-emergent adverse events were 11&#xb7;7 events per 100 patient-years for upadacitinib 15 mg and 12&#xb7;4 events per 100 patient-years for upadacitinib 30 mg. The most common adverse events of special interest were hepatic disorder, lymphopenia, creatine phosphokinase elevation, serious infection, neutropenia, and herpes zoster. Three treatment-emergent adverse events leading to death were reported in the long-term extension-only safety population. This interim analysis supports the positive long-term risk-benefit profile for upadacitinib 15 mg and 30 mg among patients with moderately to severely active ulcerative colitis. AbbVie.

Current topical treatments for scalp psoriasis are limited by formulation, efficacy, and/or safety. To assess safety and efficacy of roflumilast foam, 0.3%, in patients with psoriasis of the scalp and body. This was a phase 3 double-blinded, vehicle-controlled randomized clinical trial conducted between August 24, 2021, and June 3, 2022, at 49 sites in Canada and the US. Eligible participants were 12 years and older with plaque psoriasis affecting up to 25% of the scalp and body, at least 10% of the scalp, and up to 20% of nonscalp areas, with a minimum Scalp-Investigator Global Assessment (S-IGA) score of 3 (moderate), and minimum Body-IGA (B-IGA) score of 2 (mild). Data analyses were performed from September 9 to December 30, 2022. Once-daily roflumilast foam, 0.3%, or vehicle for 8 weeks. Coprimary end points were S-IGA and B-IGA success (clear [0] or almost clear [1] plus &#x2265;2-grade improvement) at week 8. Secondary end points included S-IGA success at weeks 2 and 4, change in Scalp Itch-Numeric Rating Scale (SI-NRS), and SI-NRS and Worst Itch-NRS (WI-NRS) success (&#x2265;4-point improvement in patients with baseline score of &#x2265;4). Safety and tolerability were also assessed. A total of 432 patients (mean [SD] age, 47.3 [14.8] years; 243 women [56.3%]) were randomized to roflumilast foam (n&#x2009;=&#x2009;281) or vehicle (n&#x2009;=&#x2009;151). At week 8, 66.4% of the roflumilast group achieved S-IGA success vs 27.8% of the vehicle group (P&#x2009;<&#x2009;.001); and 45.5% of the roflumilast group achieved B-IGA success compared with 20.1% of the vehicle group (P&#x2009;<&#x2009;.001). Rates for S-IGA success at week 2 and SI-NRS and WI-NRS success at weeks 2, 4, and 8 were significantly higher for roflumilast vs vehicle. Improvements in SI-NRS were greater for the roflumilast vs the vehicle group as early as the first assessment (24 hours after the first application). Both study groups had low rates of adverse events and favorable tolerability profiles. This randomized clinical trial found that roflumilast foam, 0.3%, improved signs and symptoms of psoriasis on the scalp and body, including pruritus, with low rates of adverse events in patients 12 years and older. These results demonstrate the potential of roflumilast foam, 0.3%, as monotherapy for patients with psoriasis of the scalp and body. ClinicalTrials.gov Identifier: NCT05028582.

The global burden of sepsis, a life-threatening dysregulated host response to infection leading to organ dysfunction, remains challenging to quantify. We aimed to comprehensively estimate the global, regional, and national burden of sepsis, including the impact of the COVID-19 pandemic and underlying causes of sepsis-related deaths with co-occurring infectious syndromes. We used multiple cause-of-death, hospital, minimally invasive tissue sampling, and linked death certificate and hospital record data representing 149 million deaths, covering 4290 location-years with mortality estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 to capture explicit and implicit sepsis cases and deaths. We estimated age-location-sex-specific fractions of sepsis-related deaths from 195 underlying causes of death and 22 infectious syndromes from 1990 to 2021 using binomial logistic regression models, and estimated sepsis-related deaths using GBD cause-specific mortality estimates. Using 250 million hospital admissions and 7&#xb7;82 million deaths from hospital data, representing 1310 location-years, we modelled case fatality rates by use of binomial logistic regression, applied to sepsis death estimates to estimate sepsis incidence by age, location, and year. In 2021, we estimated 166 million (95% uncertainty interval 135-201) sepsis cases and 21&#xb7;4 million (20&#xb7;3-22&#xb7;5) all-cause sepsis-related deaths globally, representing 31&#xb7;5% of total global deaths. Sepsis-related deaths decreased between 1990 and 2019, followed by a surge in 2020 and 2021. As of 2021, individuals aged 15 years and older experienced increases across incidence (230%) and mortality (26&#xb7;3%) since 1990. Those aged 70 years and older had the highest sepsis-related mortality in 2021 (9&#xb7;28 million [8&#xb7;74-9&#xb7;86] deaths). Sepsis-related deaths from infectious underlying causes decreased from 11&#xb7;8 million (11&#xb7;1-12&#xb7;5) in 1990 to 8&#xb7;34 million (7&#xb7;72-9&#xb7;01) in 2019, then increased by 86&#xb7;4% to 15&#xb7;5 million (14&#xb7;7-16&#xb7;4) in 2021. Sepsis-related mortality due to non-infectious underlying causes of death increased from 4&#xb7;69 million (4&#xb7;35-5&#xb7;05) in 1990 to 5&#xb7;81 million (5&#xb7;40-6&#xb7;25) in 2021; the leading non-infectious underlying causes of death with sepsis were stroke, chronic obstructive pulmonary disease, and cirrhosis. In 2021, bloodstream infections inclusive of HIV and malaria (3&#xb7;08 million [2&#xb7;83-3&#xb7;35]) and lower respiratory infections inclusive of COVID-19 (11&#xb7;33 million [1&#xb7;20-1&#xb7;47]) were the most prominent infectious syndromes complicating sepsis-related deaths from non-infectious underlying causes, representing a consistent trend since 1990. The global burden of sepsis increased in 2020 and 2021, reversing progress from 1990. Sepsis incidence and mortality increased in people aged 15 years and older, especially those aged 70 years and older, and as a complication of non-infectious underlying causes of death such as stroke, primarily through bloodstream infections and lower respiratory infections. The global burden of sepsis is substantial, and sepsis is increasingly a complication of non-infectious causes of death. Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.

Monoclonal antibodies targeting interleukin-23 and interleukin-12 are efficacious in treating plaque psoriasis but must be delivered via intravenous or subcutaneous injection. Here, we aimed to evaluate the efficacy and safety of icotrokinra (JNJ-77242113), a targeted oral peptide that selectively binds the interleukin-23 receptor, compared with both placebo and deucravacitinib in adults with moderate-to-severe plaque psoriasis. The phase 3, randomised, double-blind, placebo-controlled and active-comparator-controlled ICONIC-ADVANCE 1 and ICONIC-ADVANCE 2 trials, which are being done at 149 sites across 13 countries and 114 sites across 11 countries, respectively, randomly assigned (2:1:2 and 4:1:4, respectively) adults with moderate-to-severe plaque psoriasis diagnosed for at least 26 weeks (body-surface-area involvement &#x2264;10%, Psoriasis Area and Severity Index [PASI] &#x2264;12, and Investigator's Global Assessment [IGA] &#x2264;3) to once-daily oral icotrokinra 200 mg, placebo, or deucravacitinib 6 mg; participants randomly assigned to placebo or deucravacitinib transitioned to icotrokinra at week 16 or week 24, respectively. Coprimary endpoints were proportions of participants achieving IGA 0 or 1 (clear or almost clear skin) with at least a two-grade improvement and at least 90% improvement in PASI (PASI 90) at week 16 with icotrokinra versus placebo. These studies are registered with ClinicalTrials.gov, NCT06143878 (ADVANCE 1) and NCT06220604 (ADVANCE 2), and are ongoing. ICONIC-ADVANCE 1 enrolled participants from Jan 17, 2024, to May 24, 2024, and ICONIC-ADVANCE 2 enrolled participants from March 9, 2024, to June 13, 2024. Participants (ADVANCE 1: 774 of 988 patients screened; ADVANCE 2: 731 of 917 patients screened) were randomly assigned to icotrokinra (n=311 and 322), placebo (n=156 and 82), or deucravacitinib (n=307 and 327). All coprimary endpoints were met in both trials. Higher proportions of icotrokinra-treated versus placebo-treated participants achieved IGA 0 or 1 (ADVANCE 1: 213 [68%] of 311 vs 17 [11%] of 156, treatment difference 95% CI 58% [50-64]; ADVANCE 2: 227 [70%] of 322 vs seven [9%] of 82, 62% [53-69]; both p<0&#xb7;0001) and PASI 90 (ADVANCE 1: 171 [55%] of 311 vs six [4%] of 156, treatment difference 95% CI 51% [44-57]; ADVANCE 2: 184 [57%] of 322 vs one [1%] of 82, 56% [48-62]; both p<0&#xb7;0001) at week 16. Across studies, adverse event rates to week 16 were 303 (48%) of 632 and 136 (57%) of 237 with icotrokinra and placebo, respectively; the most common adverse events were nasopharyngitis (37 [6%] of 632 and 13 [5%] of 237) and upper respiratory tract infection (23 [4%] of 632 and eight [3%] of 237). To week 24, adverse event rates were lower than with icotrokinra (359 [57%] of 632) than deucravacitinib (411 [65%] of 634). Icotrokinra showed superior clinical response rates versus placebo and deucravacitinib in phase 3 moderate-to-severe plaque psoriasis trials, with similar adverse event rates to placebo. These findings suggest the potential of once-daily oral icotrokinra to provide robust efficacy and a favourable safety profile. Johnson & Johnson.

Zanidatamab, a dual human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody, previously demonstrated encouraging antitumour activity and a manageable safety profile in patients with treatment-refractory HER2-expressing gastro-oesophageal adenocarcinoma. Here, we evaluated the antitumour activity and safety of zanidatamab plus chemotherapy in first-line HER2-positive advanced gastro-oesophageal adenocarcinoma. This phase 2 trial enrolled patients in Canada, South Korea, and the USA who were aged 18 years and older with untreated, metastatic, or advanced HER2-positive gastro-oesophageal adenocarcinoma (HER2 IHC 3+ or 2+ by local or central assessment [part 1]; HER2 IHC 3+ or 2+ with FISH+ by central assessment [part 2]). Eligible patients, with an Eastern Cooperative Oncology Group performance status of 0 or 1 received zanidatamab intravenously plus standard chemotherapy (CAPOX [capecitabine plus oxaliplatin], FP [5-fluorouracil [5-FU] plus cisplatin], or modified FOLFOX6 [mFOLFOX6; leucovorin, 5-FU, and oxaliplatin]). In our study, part 1 aimed to characterise the safety and tolerability of zanidatamab and find the recommended dose when administered with combination chemotherapy and part 2 aimed to evaluate the antitumour activity of zanidatamab administered with combination chemotherapy in patients receiving first-line treatment for HER2-expressing advanced gastro-oesophageal adenocarcinoma. Two dosing schemes for zanidatamab were used in this study: a weight-based regimen and a two-tiered flat dosing regimen. In the CAPOX and FP groups, patients received either 30 mg/kg zanidatamab or 1800 mg or 2400 mg (patients weighing <70 kg and &#x2265;70 kg, respectively) every 3 weeks. In the CAPOX group, patients also received 1000 mg/m2 capecitabine orally twice daily on days 1-14 every 3 weeks, plus 130 mg/m2 oxaliplatin intravenously every 3 weeks. In the FP cohort, patients also received 80 mg/m2 cisplatin intravenously every 3 weeks, plus 800 mg/m2 5-FU per day continuous intravenous infusion on days 1-5 every 3 weeks. In the mFOLFOX6 group, patients received either 20 mg/kg zanidatamab or 1200 mg or 1600 mg for patients weighing under 70 kg or 70 kg and above, respectively, every 2 weeks, plus 400 mg/m2 intravenous leucovorin every 2 weeks, 85 mg/m2 intravenous oxaliplatin every 2 weeks, and 1200 mg/m2 5-FU per day as a continuous intravenous infusion for 48 h every 2 weeks. mFOLFOX6-1 included the administration of a 400 mg/m2 5-FU intravenous bolus on days 1 and 15; mFOLFOX6-2 omitted this 5-FU bolus. The primary endpoints of part 1 were safety and tolerability, which included frequencies of dose-limiting toxicities and dose reductions of zanidatamab and chemotherapy. The primary antitumour activity endpoint of part 2 was confirmed objective response rate assessed in the response-evaluable analysis set. Secondary endpoints included objective response rate, duration of response, disease control rate, clinical benefit rate, progression-free survival, and overall survival. Safety outcomes were assessed in all treated patients. We report the results from an interim analysis. This trial is registered at ClinicalTrials.gov (NCT03929666) and is complete for enrolment. Between Aug 29, 2019, and Feb 18, 2022, 46 patients were enrolled (39 [85%] were male; seven [15%] were female; 28 [61%] were white, 17 [37%] were Asian, and 43 [93%] were not Hispanic or Latino). Median follow-up was 47&#xb7;9 months (IQR 39&#xb7;2-53&#xb7;7); eight (17%) patients were on treatment and 19 (41%) were in survival follow-up. The confirmed objective response rate was 76&#xb7;2% (95% CI 60&#xb7;5-87&#xb7;9) with a median duration of response of 18&#xb7;7 months (95% CI 10&#xb7;4-44&#xb7;1). The median progression-free survival was 12&#xb7;5 months (95% CI 8&#xb7;2-21&#xb7;8) and median overall survival was 36&#xb7;5 months (23&#xb7;6-not estimable). The disease control rate was 88&#xb7;1% (95% CI 74&#xb7;4-96&#xb7;0) and clinical benefit rate was 78&#xb7;6% (95% CI 63&#xb7;2-89&#xb7;7). In part 1, there were no dose-limiting toxicities in six patients treated with zanidatamab plus CAPOX. One (50%) of two patients treated with zanidatamab plus FP had dose-limiting toxicities of diarrhoea and acute kidney injury (both grade 3). Two dose-limiting toxicities of diarrhoea (both grade 3) occurred in 2 (15%) of 13 patients receiving 5-FU 400 mg/m2 bolus on day 1 and 15 as part of the zanidatamab plus mFOLFOX6-1 regimen. 30 (65%) patients had treatment-related grade 3 or 4 adverse events. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (18 [39%]; five [24%] in the 21 patients after implementing mandatory antidiarrhoeal prophylaxis) and hypokalaemia (ten [22%]). Six (13%) patients discontinued zanidatamab due to adverse events. No treatment-related deaths occurred. Zanidatamab plus chemotherapy as first-line treatment of HER2-positive advanced gastro-oesophageal adenocarcinoma demonstrated clinically meaningful and durable antitumour activity, with a manageable safety profile. Jazz Pharmaceuticals, Zymeworks.

Long-acting injectable antipsychotic (LAI) treatment is associated with improved adherence and reduced relapse and hospitalization rates, compared with oral antipsychotics, in patients with schizophrenia. TV-46000, an LAI formulation of risperidone, is approved for the treatment of schizophrenia in adults. TV-46000 administered once monthly (q1m) and once every 2&#xa0;months (q2m) has previously been shown to be effective and safe in patients with schizophrenia in the phase 3 studies, RISE and SHINE. Here, the effect of long-term treatment with TV-46000 on psychopathological symptoms and severity of illness was evaluated. In RISE, patients were stabilized on oral risperidone for 12 weeks before randomization to subcutaneous treatment with TV-46000 q1m, q2m, or placebo (1:1:1) until study endpoint. Patients who successfully completed RISE (placebo and TV-46000 rollover cohorts) and newly recruited patients (de novo cohort) were eligible to enroll in SHINE to receive TV-46000 q1m or q2m for up to 56 weeks. Symptom severity was evaluated with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions-Severity (CGI-S) scale, and the Clinical Global Impressions-Improvement (CGI-I) scale, as prespecified exploratory endpoints from the RISE and SHINE studies. Overall, 543 adult patients were enrolled in RISE (TV-46000 q1m, n = 183; q2m, n = 179; placebo, n = 181) and 333 in SHINE (TV-46000 q1m, n = 173 and q2m, n = 160; source groups: de novo, n = 106; placebo rollover, n = 55; TV-46000 rollover, n = 172). In RISE, PANSS total scores decreased after randomization to end of treatment (EoT) for TV-46000 (least squares mean [LSM] change [SE], q1m: -3.5 [0.69]; q2m, -4.9 [0.73]), but increased for placebo (1.1 [0.86]; P < 0.0001 for both TV-46000 q1m and q2m versus placebo). Corresponding changes from baseline to last assessment (LA) were -0.9 (0.97)&#xa0;for&#xa0;q1m, -0.2 (0.99)&#xa0;for&#xa0;q2m, and 7.4 (0.99)&#xa0;for&#xa0;placebo; P < 0.0001 for both versus placebo. Similar results were seen for the PANSS positive and general psychopathology subscales (P < 0.001 for both TV-46000 q1m and q2m versus placebo). These symptom improvements were maintained or improved in the TV-46000 q1m and q2m groups in SHINE, with notable improvements observed in patients without prior TV-46000 exposure. Similar results were observed in RISE and SHINE when PANSS scores were categorized by Marder factors of schizophrenia symptoms. CGI-I scores at EoT and LA were significantly better with TV-46000 than with placebo in RISE (LSM&#xa0;at EoT and LA: 3.3 and 3.6&#xa0;for&#xa0;TV-46000 q1m, 3.2 and 3.6&#xa0;for&#xa0;q2m; 3.9 and 4.4 for&#xa0;placebo, respectively&#xa0;[P < 0.0001 versus placebo]). These scores were maintained in the TV-46000 groups in SHINE, with larger improvements seen in the de novo cohort than in the placebo rollover and TV-46000 rollover cohorts. Treatment with TV-46000 provided sustained overall symptom improvement in the RISE and SHINE studies in patients with schizophrenia who were stabilized on oral risperidone. RISE (ClinicalTrials.gov identifier: NCT03503318) and SHINE (ClinicalTrials.gov identifier: NCT03893825). TV-46000 is an antipsychotic medicine to treat schizophrenia in adults. It is injected under the skin once monthly or once every 2 months. TV-46000 was previously tested in two clinical trials, RISE and SHINE. In RISE, patients first took pills and then received TV-46000 or inactive treatment (placebo). Patients treated with TV-46000 had a longer period without schizophrenia symptoms returning than those who took placebo treatment. New patients and patients who finished RISE were allowed to participate in the SHINE study. In SHINE, patients were regrouped to receive TV-46000. Results showed that long-term treatment with TV-46000 was safe. This report used existing data from the RISE and SHINE studies to see if TV-46000 improved schizophrenia symptoms and disease severity. In RISE, schizophrenia symptoms improved with TV-46000 but worsened with placebo. Symptoms were further improved in patients who continued taking TV-46000 in SHINE. The overall disease severity was also improved in RISE and SHINE.

In the aftermath of the COVID-19 pandemic, health policymakers have been reflecting upon sustainability and resilience issues in health systems worldwide. Promoting sustainability and resilience requires policy changes built upon evidence and on the views of health stakeholders and experts. This study aimed to engage health stakeholders in designing and discussing policy recommendations with a high potential to improve sustainability and resilience in the Portuguese healthcare system. As part of the Partnership for Health System Sustainability and Resilience initiative in Portugal (PHSSR-PT), this study proposes a novel policy dialogue that combines participatory methods-workshops and Web-Delphi processes-with content analysis tools-namely Dialogue Mapping-to promote agreement and help health stakeholders and experts to identify and discuss policy recommendations with high potential to improve health systems' sustainability and resilience. Departing from the COVID-19 pandemic as a critical event and drawing on evidence and data, a group of health stakeholders and experts ideated and agreed upon high-value policy recommendations across seven domains: Governance, Financing, Workforce, Medicines and Technology, Service Delivery, Population Health and Environmental Sustainability. 40 top-level Portuguese health stakeholders and experts successfully collaborated to generate and discuss the benefits, risks and implementation issues of 69 policy recommendations, out of which 43 were selected as having gathered a high level of agreement on their potential to improve system sustainability and resilience. The adopted policy dialogue promoted high convergence. Many of these 43 recommendations were shown to entail interconnectedness with other policy recommendations. This study provides actionable insights to advance discussions on sustainability and resilience in Portugal. It shows that Governance and Population Health policy recommendations are critical to improve sustainability and resilience in several domains, and there is a high level of agreement on the need to adopt many recommendations, but questions remain about their implementation. The study also shows that new ways of engaging health stakeholders and experts can be adopted to promote dialogue, consensus and transparent discussion in policy processes.

Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive neoplasm that affects otherwise healthy adults. There are few systemic treatment options, highlighting an unmet need. We report the results of part 1 of the MANEUVER trial, which aimed to evaluate the efficacy and safety of pimicotinib, a highly selective, potent, colony-stimulating factor-1 receptor inhibitor, in patients with TGCT. MANEUVER is a randomised, placebo-controlled, phase 3 study done in 40 specialised hospitals in Asia, Europe, and North America. Patients aged 18 years and older with unresectable, symptomatic TGCT (patient-reported worse stiffness or worst pain of at least 4 on a scale of 0-10) were randomly assigned (2:1, double-blind) to oral, once-daily pimicotinib 50 mg or placebo for 24 weeks (part 1). An independent statistician used a central interactive web response system to generate the randomisation schedule; stratification was by region (China vs non-China). Masking was achieved by using placebo identical in appearance to pimicotinib. In part 1, patients, all investigators, and study funders were masked to treatment assignments. All patients who completed part 1 were allowed to continue to open-label part 2: pimicotinib-treated patients could continue the same dosage and placebo-treated patients could cross over to receive pimicotinib for 24 weeks. Eligible patients who completed part 2 were allowed to continue once-daily pimicotinib long-term in part 3. The primary endpoint was objective response rate (ORR) at week 25 by blinded independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population (all randomised patients). Safety was analysed in patients who received at least one dose of study drug. Missing data were not imputed and only observed data were analysed. Trial enrolment is complete; the study is registered at ClinicalTrials.gov (NCT05804045) and is ongoing. Between April 27, 2023, and March 29, 2024, 126 patients were screened and 94 patients (China [n=45], non-China [n=49]) were randomly assigned to, and received, pimicotinib (n=63) or placebo (n=31). 30 (32%) patients were male and 64 (68%) were female. ORR at week 25 was 54% (34 of 63) in the pimicotinib group and 3% (one of 31) in the placebo group (absolute difference 51% [95% CI 33-63], p<0&#xb7;0001). Pimicotinib was associated with mainly mild treatment-emergent adverse events, including mostly manageable asymptomatic laboratory abnormalities and clinical events, such as pruritus, facial oedema, rash, periorbital oedema, and fatigue. The only grade 3 or 4 treatment-emergent adverse event occurring in more than 10% of pimicotinib-treated patients was increase in blood creatine phosphokinase, in eight (13%) of 63 patients. The most common treatment-emergent adverse events in the placebo group were fatigue and arthralgia. Dose reductions occurred in five (8%) of 63 pimicotinib-treated patients and treatment discontinuations in one (2%) of 63 pimicotinib-treated patients. There was no cholestatic hepatotoxicity, drug-induced liver injury, or hypopigmentation of skin or hair. Pimicotinib showed robust antitumour activity with clinically meaningful improvements in TGCT-related functional limitations and symptom burden, offering an effective treatment option with a manageable safety profile for this underserved condition. Abbisko Therapeutics.

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by intensely pruritic papulonodular lesions. Patients with PN frequently experience comorbid atopic conditions. Dupilumab is the first approved therapy for PN, but the efficacy of dupilumab in patients with PN with or without atopic comorbidities has not been investigated. We aimed to assess the efficacy and safety of dupilumab in patients with PN with or without a history of atopic comorbidities. Randomized, double-blind, parallel-group, placebo-controlled, 24-week, phase III trials LIBERTY-PN PRIME and PRIME2 were conducted independently in 16 countries in North and South America, Europe, and Asia. Patients were randomized 1:1 to dupilumab 300 mg every 2 weeks or matched placebo. In this pre-specified subgroup analysis of pooled data, adults with moderate-to-severe PN, inadequately controlled by topical prescription therapies, were stratified according to the presence or absence of atopic comorbidity history. Investigators assessed itch (Worst&#xa0;Itch Numeric Rating Scale), skin lesions (Investigator's Global Assessment for PN Stage), and patient-reported quality of life (evaluated using the Dermatology Life Quality Index, Skin&#xa0;Pain Numeric Rating Scale, Hospital Anxiety and Depression Scale, and a Sleep Numeric Rating Scale). Three hundred and eleven patients were randomized to dupilumab (N = 153; atopic/non-atopic n = 67/86) or placebo (N = 158; atopic/non-atopic n = 68/90). At week 24 in both the atopic and non-atopic subgroups, significantly more patients achieved clinically meaningful improvements with dupilumab treatment compared with placebo in itch (atopic: 58.2% vs 20.6%; P < 0.0001; non-atopic: 59.3% vs 17.8%; P < 0.0001), clear/almost clear skin (atopic: 52.2% vs 16.2%; P < 0.0001; non-atopic: 41.9% vs 17.8%; P = 0.0005), and concomitant itch and skin lesion improvements (atopic: 37.3% vs 7.4%; P = 0.0057; non-atopic 33.7% vs 10.0%; P = 0.007). Patients showed significant improvements in skin pain, Dermatology Life Quality Index, Hospital Anxiety and Depression Scale, and sleep, with dupilumab treatment compared with placebo, regardless of atopic history. Safety was generally consistent with the known dupilumab safety profile. Dupilumab significantly improved disease signs, symptoms, and health-related quality of life with similar onset time and response magnitude compared with placebo in adult patients with PN, irrespective of the presence or absence of atopic comorbidities. ClinicalTrials.gov Identifiers: NCT04183335 and NCT04202679.

Most myelofibrosis (MF) patients treated with ruxolitinib fail to achieve optimal response (i.e., spleen volume reduction&#x2009; &#x2265;35% [SVR35] and improvement in total symptom score&#x2009;&#x2265;50% [TSS50], and instead experience suboptimal reductions in spleen volume and constitutional symptoms. Maximizing SVR and TSS is critical for MF patients, as both are associated with improved quality of life (QoL) and overall survival (OS). Navtemadlin is a potent, selective, oral MDM2 inhibitor that restores p53 activity, inducing apoptosis of malignant TP53 wild-type (TP53WT) CD34+ MF progenitor cells. In vitro and clinical data demonstrated navtemadlin's synergy with ruxolitinib and disease-modifying potential. POIESIS is a global, randomized, double-blind phase III trial (NCT06479135) evaluating navtemadlin versus placebo as add-on to ruxolitinib in JAK inhibitor-na&#xef;ve TP53WT MF patients with suboptimal response to ruxolitinib. The study includes a ruxolitinib monotherapy run-in period, followed by randomization of suboptimal responders to add-on navtemadlin or placebo to their stable ruxolitinib dose. Study objectives are to isolate the contribution of add-on navtemadlin by assessing SVR and TSS 24-weeks after randomization from the pre-randomization baseline and to demonstrate that this contribution is clinically meaningful using established SVR and TSS endpoints from the pre-ruxolitinib treatment baseline. Secondary endpoints include progression-free survival, leukemia-free survival, and OS.Clinical Trial Registration: NCT06479135 (ClinicalTrials.gov); EUCT 2023-504724-25-00 (EUClinicalTrials.EU). Myelofibrosis (MF) is a rare blood cancer that affects the bone marrow, causing scarring (fibrosis) and impairing healthy blood cell production. This leads to symptoms, such as fatigue, pain, night-sweats, and an enlarged spleen. Ruxolitinib, a Janus kinase inhibitor (JAKi), is a standard treatment that can reduce spleen size and improve symptoms. However, many MF patients do not respond optimally to ruxolitinib alone, known as a suboptimal response, and continue to experience persistent symptoms and an enlarged spleen. In these cases, adding a new treatment may provide further clinical benefit.Navtemadlin is an investigational treatment that inhibits MDM2, a protein which is overproduced in MF cancer cells. MDM2 blocks the activity of another protein, p53, a tumor suppressor that normally helps remove abnormal cells. By blocking MDM2, navtemadlin restores the ability of p53 to eliminate MF cancer cells.The POIESIS study is a global phase III clinical trial testing whether adding navtemadlin to ruxolitinib improves outcomes in MF patients with a suboptimal response to ruxolitinib alone. POIESIS has two treatment periods. During the first period, patients receive ruxolitinib alone for 18&#x2013;24&#x2009;weeks. If their response is suboptimal, patients may be eligible to join the second period, where they are randomly assigned to receive either add-on navtemadlin (Arm 1) or placebo (Arm 2) while continuing ruxolitinib. Navtemadlin efficacy will be assessed by measuring the rates of spleen volume reduction (by MRI/CT scan) and total symptom score improvement (using a daily 7-symptom questionnaire), in each arm, 24&#x2009;weeks after randomization.

The fibroblast activation protein &#x3b1; (FAP)-directed radiotracer [68Ga]Ga-FAPI-46 for PET-CT has shown promising diagnostic accuracy in cancer staging in retrospective studies. We aim to investigate the positive predictive value (PPV) of [68Ga]Ga-FAPI-46 PET for detecting FAP-expressing tumours and the potential association between PET radiotracer uptake intensity and immunohistochemical FAP expression. This single-centre, single-arm, interventional, phase 2 trial was conducted at the University Hospital Essen, Essen, Germany. Adults aged 18 years or older undergoing initial staging or restaging were eligible if they had at least one measurable tumour lesion (>1 cm) and a confirmed or suspected diagnosis of breast cancer, colorectal cancer, endometrial cancer, oesophageal cancer, head and neck cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), prostate cancer, thyroid cancer, glioma, hepatocellular carcinoma, lymphoma, multiple myeloma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), sarcoma, seminoma, cancer of unknown primary origin, or other tumour types; had a planned or recent surgery or biopsy within 8 weeks before or after enrolment; and an ECOG performance status of 2 or less. Key exclusion criteria were previous external beam radiotherapy to the target lesion and receiving systemic cancer therapy within 1 month before enrolment. PET-CT images were acquired at a median of 11 min (IQR 10-14) after an intravenous injection of a median of 145 Megabecquerel (MBq; 124-154) of [68Ga]Ga-FAPI-46 and analysed by three independent, masked readers. The study concluded on day 30 of follow-up if histopathological confirmation and archived tumour tissue were already available, or on the day of biopsy or surgery within 8 weeks of receiving [68Ga]Ga-FAPI-46 PET-CT. Immunohistochemical FAP expression (score 0-3) was evaluated by an independent masked pathologist. The primary endpoint was the PPV of [68Ga]Ga-FAPI-46 PET for detecting immunohistochemical FAP-positive tumours (histopathologically confirmed) on a per-patient and per-region basis, with a predefined threshold of PPV of at least 75%, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05160051, and is complete. Between Dec 1, 2021, and Feb 6, 2024, 158 eligible participants were enrolled and three were excluded. 98 (63%) of 155 participants who received [68Ga]Ga-FAPI-46 PET-CT were male and 57 (37%) were female. One (1%) participant was African, two (1%) were Asian, and 152 (98%) were White. The median age of participants was 62 years (IQR 55-70). The median follow-up was 29 days (29-30). The patient-based PPV of [68Ga]Ga-FAPI-46 PET for detecting FAP-positive tumours based on immunohistochemical FAP staining was 90% (95% CI 84-95) and region-based PPV was 92% (85-96) in 127 (88%) of 144 participants with histopathological validation. Five (6%) of 90 adverse events were classified as possibly related to [68Ga]Ga-FAPI-46. Seven (8%) adverse events were serious, none related to [68Ga]Ga-FAPI-46. One participant died due to disease progression. These results confirm the safety and potential of [68Ga]Ga-FAPI-46 PET as an imaging biomarker for the detection of FAP-expressing tumours. Further studies are warranted to refine the specificity and define the role of [68Ga]Ga-FAPI-46 PET in clinical practice. SOFIE Biosciences.

Effective and well-tolerated pharmacotherapies for generalized anxiety disorder (GAD), which is one of the most common psychiatric disorders, are needed. To determine the dose-response relationship of MM120 (lysergide D-tartrate) in adults with moderate to severe GAD. This phase 2b, multicenter, randomized, double-blind, placebo-controlled study enrolled 198 adults aged 18 to 74 years with a primary GAD diagnosis who presented with moderate to severe symptoms (defined by a Hamilton Anxiety Rating Scale [HAM-A] score &#x2265;20) and was conducted at 22 outpatient psychiatric research sites in the US from August 2022 to August 2023. The anxiety and depression end point assessments were conducted by independent central raters who were blinded to the trial protocol, treatment allocation, and study visit date. The last date of follow-up was November 27, 2023. Participants were randomized to receive a single (freebase equivalent) treatment dose with 25 &#xb5;g (n&#x2009;=&#x2009;39), 50 &#xb5;g (n&#x2009;=&#x2009;40), 100 &#xb5;g (n&#x2009;=&#x2009;40), or 200 &#xb5;g (n&#x2009;=&#x2009;40) of MM120 or placebo (n&#x2009;=&#x2009;39). The primary outcome was a dose-response relationship assessed using the multiple comparison procedure modeling (MCP-Mod) method for change in HAM-A score at 4 weeks (score range, 0-56; higher scores indicate greater severity; &#x2264;7 indicates no or minimal anxiety; 8-14, mild; 15-23, moderate; and &#x2265;24, severe). The minimal clinically important difference was 2.5 points. Of the 198 participants randomized, 194 were included in the full analysis set (mean age, 41.3 [SD, 13.6] years; 56.7% were female; and 3.6% were Asian, 7.7% were Black or African American, and 83.0% were White). The dose-response relationship assessed using the MCP-Mod method for change in HAM-A score at week 4 was statistically significant for the 100-&#xb5;g and the 200-&#xb5;g dose groups vs placebo (least-squares mean difference, -5.0 points [95% CI, -9.6 to -0.4 points] with 100 &#xb5;g of MM120 and -6.0 points [95% CI, -9.8 to -2.0 points] with 200 &#xb5;g of MM120) but the 25-&#xb5;g and 50-&#xb5;g dose groups did not reach significance vs placebo (least-squares mean difference, -1.2 points [95% CI, -6.0 to 3.5 points] with 25 &#xb5;g of MM120 and -1.8 points [95% CI, -7.6 to 4.0 points] with 50 &#xb5;g of MM120). The adverse events were consistent with the expected effects of MM120. The most common adverse events were visual perceptual changes (illusion, pseudo-hallucination, and visual hallucination), which occurred in 46.2% of participants who received 25 &#xb5;g of MM120, in 75.0% who received 50 &#xb5;g, in 92.5% who received 100 &#xb5;g, in 100% who received 200 &#xb5;g, and in 10.3% who received placebo; nausea occurred in 7.7%, 27.5%, 40.0%, 60.0%, and 7.7%, respectively; and headache occurred in 12.8%, 22.5%, 35.0%, 27.5%, and 23.1%. In participants with moderate to severe GAD, a single dose of MM120 produced a dose-dependent reduction in anxiety. These results support the dose-dependent efficacy of MM120 and inform the dose selection for phase 3 pivotal trials. ClinicalTrials.gov Identifier: NCT05407064.

ABBV-368 is a humanized monoclonal antibody that targets the costimulatory receptor OX40. Here, we investigate a treatment strategy with ABBV-368 combined with the investigational toll-like receptor 9 agonist tilsotolimod, the programmed cell death 1 inhibitor budigalimab, and nab-paclitaxel in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). To our knowledge, this is the first clinical study in this setting to investigate chemotherapy combined with three immunotherapy agents, aiming to overcome failure of prior immune checkpoint inhibition and chemotherapy. This phase 1b, multicenter, open-label study (NCT04196283) enrolled adult patients with R/M HNSCC into one of three treatment arms: ABBV-368 with tilsotolimod, ABBV-368 with tilsotolimod and nab-paclitaxel, or ABBV-368 with tilsotolimod, nab-paclitaxel, and budigalimab. Patients were treated in 28-day cycles. ABBV-368, nab-paclitaxel, and budigalimab were administered intravenously and tilsotolimod via intratumoral injection. Study objectives included safety, tolerability, pharmacokinetics, and preliminary antitumor activity. In addition, biomarker analyses were performed. Overall, 30 patients were enrolled; 16 received ABBV-368 plus tilsotolimod, 7 ABBV-368 plus tilsotolimod and nab-paclitaxel, and 7 ABBV-368 plus tilsotolimod, nab-paclitaxel, and budigalimab. In total, 80% of patients experienced any-grade adverse events related to ABBV-368. ABBV-368 and tilsotolimod induced peripheral interferon-gamma pathway upregulation, Th1 cytokine production, and T-cell activation that was not negatively impacted by nab-paclitaxel. There were no responses in the ABBV-368 plus tilsotolimod arm; one partial response was demonstrated in both the ABBV-368 plus tilsotolimod and nab-paclitaxel, and ABBV-368 plus tilsotolimod, nab-paclitaxel, and budigalimab arms, corresponding to an overall response rate of 14.3%. The quadruple combination of ABBV-368, tilsotolimod, nab-paclitaxel, and budigalimab was well tolerated and demonstrated pharmacodynamic activity. Several patients had disease stabilization, but clinical responses were limited. Initial priming and T-cell immune activation were inadequate to overcome prior therapy resistance mechanisms including a hypothesized unfavorable tumor microenvironment. Future work investigating strategies to target this inhibitory tumor microenvironment with optimally scheduled immunotherapy combinations in selected patients and indications is urgently needed to improve patient outcomes. NCT04196283.

Patients with recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) have limited treatment options and a dismal prognosis, especially when their cancer is resistant to standard treatments like anti-programmed cell death protein 1 and platinum-based therapies. Petosemtamab - a human, common light chain, bispecific antibody with enhanced antibody-dependent cellular cytotoxicity targeting epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) - demonstrated antitumor activity in r/m HNSCC. In many tumor types, including HNSCC, EGFR is an oncogenic driver, while LGR5 is upregulated. LGR5 can potentiate the wingless-type integration site (WNT)/&#x3b2;-catenin signaling pathway in response to ligand binding, stimulating cancer stem cell proliferation and self-renewal. This article describes two registration-intent, open-label, randomized phase III trials evaluating efficacy and safety of petosemtamab. LiGeR-HN1 (NCT06525220) evaluates petosemtamab plus pembrolizumab versus pembrolizumab as first-line therapy for patients with programmed cell death ligand 1-positive r/m HNSCC. LiGeR-HN2 (NCT06496178) evaluates petosemtamab versus investigator's choice of monotherapy (cetuximab, methotrexate, or docetaxel) in patients with previously treated r/m HNSCC. Primary endpoints in both trials are objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review, and overall survival. Both trials are recruiting at the time of publication.Clinical Trial Registration: NCT06525220 and NCT06496178 (ClinicalTrials.gov). Head and neck squamous cell carcinoma (HNSCC) is a common cancer located in the head or neck, particularly in the mouth, throat, and nasal cavity. People living with HNSCC whose cancer has come back after treatment (recurrent) or spread to other parts of the body (metastatic) have limited treatment options, especially when their cancer does not respond to available therapies. Petosemtamab is a drug that targets receptors called epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) &#x2013; two key drivers of tumor cells that contribute to tumor growth and spread. In a phase II trial, petosemtamab showed clinically meaningful benefit with manageable side effects for patients with recurrent or metastatic HNSCC. This article describes two phase III trials studying petosemtamab&#x2019;s ability to reduce tumors and improve survival. LiGeR-HN1 will include approximately 500 patients who have not yet been treated for recurrent or metastatic HNSCC, and whose tumors have a protein called programmed cell death ligand 1 on the cell surface. Patients will be split into two groups: one group will receive petosemtamab with pembrolizumab, an immunotherapy; the other group will receive only pembrolizumab. LiGeR-HN2 will include approximately 500 patients whose disease has progressed on or after receiving anti-programmed cell death protein 1 and platinum-based treatment for recurrent or metastatic HNSCC. Patients will be split into two groups: one group will receive petosemtamab; the other group will receive either cetuximab (targeted therapy), methotrexate (chemotherapy), or docetaxel (chemotherapy). Both trials are recruiting participants at the time of publication.

Patients diagnosed with chronic myeloid leukemia (CML) are at risk of developing financial toxicity (FT) due to the high cost of tyrosine kinase inhibitor (TKI) treatment and other cancer-related costs. This theory-based study evaluated relationships between risk factors, patients' behaviors, FT experience, and health outcomes among survivors of CML. We collected cross-sectional survey data from 129 adults with CML prescribed a TKI from 10/2019 to 01/2024. Instruments included measures of FT, patients' behaviors related to FT (financial sacrifices, non-adherence, and debt or bankruptcy), and health outcomes (psychoneurological symptom cluster severity, health-related quality of life, and distress). Risk factors were collected via a sociodemographic questionnaire and researcher-abstracted medical record data. Structural equation modeling was used to test the adapted theoretical model of FT. Participants were relatively young (mean&#x2009;&#xb1;&#x2009;standard deviation 49.7&#x2009;&#xb1;&#x2009;15.5, median 51, 19-84&#xa0;years) and balanced in sex (49% female) and race (43% non-White); median time since diagnosis was 57&#xa0;months. A higher level of FT was directly associated with adverse health outcomes (standardized coefficient&#x2009;=&#x2009;0.33, P&#x2009;<&#x2009;.01), with patients' behaviors as mediators (mediating total effects&#x2009;=&#x2009;0.62, P&#x2009;<&#x2009;.001). Risk factors, including lower education, lower income, non-private insurance, and being a racial minority, were positively associated with higher levels of FT (standardized coefficient&#x2009;=&#x2009;0.51, P&#x2009;<&#x2009;.001). Our findings support hypothesized pathways and help validate the theoretical model that contributes to understanding patients' FT experience. Further investigation is needed to explicate the longitudinal nature of FT, patients' behaviors, and outcomes to guide better methods of risk assessment and inform intervention development.