Janssen (Germany)

Beginning in January 2025, all new active substances must undergo evaluation of relative clinical effectiveness through European Union (EU) joint clinical assessments (JCAs). In the absence of head-to-head data, indirect treatment comparisons (ITCs) become indispensable in meeting the numerous population, intervention, comparators and outcomes (PICO) criteria to support decision-making. This study examined ITCs in European Network for Health Technology Assessment (EUnetHTA) relative effectiveness assessments (REAs) to obtain valuable insights into their potential implications for future JCAs. The EUnetHTA website was hand-searched for REAs of pharmaceutical products between 2010 and 2021. Information on PICO, ITC methods, ITC limitations/critiques, and relative effectiveness conclusions were systematically extracted. On the basis of the final EUnetHTA critiques, suitability of ITC evidence was categorised by the current study authors as appropriate, unsuitable or unclear. Twenty-three REAs were identified. Twelve REAs included an ITC, of which six were in oncology indications. Across the REAs, 64 comparisons were required, with a median of four comparators per REA (range 1-18). In total, 25 comparisons were informed by indirect evidence; the suitability of ITCs was categorised as unclear in all but one of the 25 comparisons. Multiple analyses and ITCs were necessary to address multiple PICOs. Although most ITCs were categorised as unclear within the REAs, they were still considered appropriate to inform decision-making. The EU JCA process will most likely require health technology developers to use various ITC approaches to address the multiple PICOs requested, recognising the inherent limitations of these methodologies. Efforts to address potential challenges for EU JCA should focus on supporting JCA assessors/co-assessors and national HTA agencies in the evaluation and interpretation of ITCs to enable decision-making.

Pulmonary arterial hypertension (PAH) is often diagnosed in elderly patients with comorbidities. Although initial monotherapy is recommended for these patients, the value of combination therapy remains unclear. Here, we compare the efficacy of initial monotherapy and combination therapy in PAH patients with cardiovascular comorbidities. Data from adult patients with incident pre-capillary PAH and cardiovascular comorbidities from the COMPERA database (European registry for PH) were analysed. A matched-pair analysis of patients treated with monotherapy versus combination therapy based on age, sex, WHO functional class (FC) and 4-strata risk at baseline was performed. The matching strategy identified 216 pairs of PAH patients with cardiovascular comorbidities, who differed considerably from the enrolled patient population (n=1871), especially in terms of mean age (mono: matched pairs 62.9±13.5years vs. 70.6±11.4years, combination: matched pairs 62.0±13.6years vs. 60.5±14.9years). In the matched-pair analysis, the initial combination therapy group showed more pronounced improvements in WHO-FC, N-terminal pro-B-type natriuretic peptide (BNP/NT-proBNP) and risk status than patients treated with initial monotherapy, with no significant differences in 6-min walk distance (6MWD), PAH-related hospitalisations, survival and drug discontinuation. This analysis suggests that PAH patients with comorbidities may benefit more pronounced from combination therapy regarding WHO-FC, BNP/NT-pro-BNP and risk status without a significant difference in survival. Good tolerability is indicated. However, given the relatively younger patient matched subgroup, these findings may not necessarily apply to older patients with a wider range of comorbidities.

This article proposes a mathematical model for protecting helicopter turboshaft engines from surges, starting with fuel metering supply and maintaining stable compressor operation. The model includes several stages: first, fuel is supplied according to a specified program; second, an unstable compressor operation signal is determined based on the gas temperature in front of the compressor turbine and the gas generator rotor speed derivatives ratio; at the third stage, when the ratios’ threshold value is exceeded, fuel supply is stopped, and the ignition system is turned on. Then, the fuel supply is restored with reduced consumption, and the rotor speed is corrected, followed by a return to regular operation. The neural network model implementing this method consists of several layers, including derivatives calculation, comparison with the threshold, and correction of fuel consumption and rotor speed. The input data for the neural network are the gas temperature in front of the compressor turbine and the rotor speed. A compressor instability signal is generated if the temperature and rotor speed derivatives ratio exceed the threshold value, which leads to fuel consumption adjustment and rotor speed regulation by 28…32%. The backpropagation algorithm with hyperparameter optimization via Bayesian optimization was used to train the network. The computational experiments result with the TV3-117 turboshaft engine on a semi-naturalistic simulation stand showed that the proposed model effectively prevents compressor surge by stabilizing pressure, vibration, and gas temperature and reduces rotor speed by 29.7% under start-up conditions. Neural network quality metrics such as accuracy (0.995), precision (0.989), recall (1.0), and F1-score (0.995) indicate high efficiency of the proposed method.

This article presents a vibration signal analysis method to diagnose helicopter turboshaft engine defects such as bearing imbalance and wear. The scientific novelty of the article lies in the development of a comprehensive approach to diagnosing helicopter turboshaft engine defects based on the vibration signals amplitude and frequency characteristics integral analysis combined with a neural network for probabilistic defect detection. Unlike existing methods, the proposed approach uses the energy criterion for the vibration characteristics. It averages the assessment of unique signal processing algorithms, which ensures reliable defect classification under flight vibration conditions. The method is based on representing vibration signals as a sum of harmonic oscillations supplemented by noise components, which helps to identify deviations from typical values. The developed method includes a state function in which the amplitudes and frequency characteristics from nominal parameters estimate deviations. When the critical threshold is exceeded, the function signals possible malfunctions. A multilayer neural network is used to classify defect types, providing high classification accuracy (from 0.985 to 0.994). Computer experiments on the developed seminaturalistic modeling stand confirm that the method can detect increased vibration levels, which is the potential failure indicator. Comparative analysis shows the proposed method’s accuracy and noise resistance superiority, emphasizing the importance of introducing modern technologies to improve aircraft operation reliability and safety.

This research substantiates the necessity for developing and implementing structural reconfiguration methods for automatic control systems in the event of a parametric sensor failure to enhance the helicopter turboshaft engine’s overall reliability and safety. The research aim is the substantiation of the helicopter turboshaft engine’s mathematically reconfigured automatic control system in the event of the failure of a standard sensor, which will ensure the helicopter turboshaft engine’s stable operation under failure conditions, minimizing the impact on engine control and performance. A theorem was developed and proven concerning the reconfiguration of the helicopter turboshaft engine’s automatic control system structure, defining the system’s new mathematical form using nonlinear thermogas-dynamic parameters. A method was proposed to determine the values of these parameters that keep the reconfigured control system stable. This method uses numerical optimization to find the best thermogas-dynamic parameters to ensure system stability. Experimental results showed that for slow changes, using parameters from the previous step works best, while for fast changes, restarting is more effective due to significant differences in the system states. The accuracy of the proposed mathematical model for the reconfigured control system was confirmed through mean square error analysis (within 0.4% and 0.77% under white noise), regression analysis (with a determination coefficient of 0.986), and cross-validation (with a metric deviation from the maximum mean square error of 3.88%).

To assess the association between achievement of prostate-specific antigen (PSA) levels ≤0.2 ng/mL (henceforth 'ultralow') and clinical outcomes in patients in the 'Targeted Investigational Treatment Analysis of Novel Anti-androgen' (TITAN) study (ClinicalTrials.gov Identifier NCT02489318) with metastatic castration-sensitive prostate cancer (mCSPC). Patients in the TITAN study with mCSPC were randomised to 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy. This post hoc analysis assessed the achievement of a PSA level of 0.2->0.02 ng/mL ('ultralow one' [UL1]) and ≤0.02 ng/mL ('ultralow two' [UL2]) vs >0.2 ng/mL with apalutamide treatment and its association with radiographic progression-free survival (rPFS), overall survival (OS), time to castration-resistant PC (TTCRPC), and time to PSA progression (TTPP). The landmark analysis and Kaplan-Meier methods were used. By 3 months, more patients achieved UL1 and UL2 with apalutamide (38% and 23%) vs placebo (15% and 5%). In the apalutamide-treated patients, UL2 vs PSA >0.2 ng/mL at landmark 3 months was associated with significantly longer rPFS (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.14-0.54), OS (HR 0.24, 95% CI 0.13-0.43), TTCRPC (HR 0.2, 95% CI 0.11-0.38), and TTPP (HR 0.11, 95% CI 0.04-0.27; nominal P values all <0.001); this association was also observed but less pronounced for UL1. Similar findings were observed at 6 months. Early onset of decline to UL2 by 3 months was associated with improved survival vs PSA >0.2 ng/mL anytime (HR 0.12, 95% CI 0.06-0.22; P < 0.001) in apalutamide-treated patients. In this post hoc analysis of TITAN, patients with the deepest PSA decline derived the greatest benefit. These results extend our findings of apalutamide efficacy in the overall TITAN population, underscoring the clinical value of PSA kinetics as a marker for treatment efficacy. Patients with metastatic prostate cancer that is sensitive to ongoing hormonal treatment benefited significantly from the addition of apalutamide compared with placebo. Those who achieved rapid and deep PSA reduction had the greatest survival benefit.

Abstract Background Combination induction therapy with guselkumab (GUS), an interleukin (IL)-23p19 subunit antagonist, and golimumab (GOL), a tumor necrosis factor (TNFα) antagonist, induced higher rates of clinical remission, endoscopic, and histologic outcomes than either monotherapy at Week (WK)12 in patients (pts) with ulcerative colitis (VEGA NCT03662542). Data through WK38 suggested the continued benefit of combination induction even after a transition to GUS monotherapy at WK12. We explored early molecular changes in colon tissue in a subset of pts at WK4 to define mechanistic contributions of each monotherapy and combination; these parameters were evaluated again at WK38 to assess potential carry-over of efficacy. Methods Colon biopsies were obtained at baseline (n=195), WK4 (n=42 substudy), and WK38 (n=172). Transcriptional profiles were generated with RNA sequencing (RNAseq). Gene correlation network analysis was applied in conjunction with publicly available single cell RNAseq data to define biologically relevant bulk and cell type-specific transcriptional modules associated with molecular features of disease. Gene set variation analysis (GSVA) was used to quantitatively assess changes in biologic modules with treatment. Results At WK4, combination induction (n=10) showed significant (p&amp;lt;0.05) decreases in molecular features compared to GUS (n=19) and GOL (n=13), including transcriptomic modules representing the IL-23 pathway, interferon response, and inflammatory epithelial and myeloid transcriptional states associated with endoscopic improvement at WK4 (Mayo endoscopy subscore of 0 or 1) (combination 5/11, GOL 1/13; GUS 2/19). Reduction (p&amp;lt;0.05) in inflammatory modules persisted through WK38 with combination vs monotherapy induction. Module changes between treatments at WK4 indicated a stronger correlation between GUS and combination (R=0.8; p=2.2e-16) than GOL and combination (R=0.52; p=4.1e-12), with processes associated with epithelial and stromal biology, and mucosal inflammation. In contrast, the combination effect on specific neutrophil/myeloid biology at WK4 was more similar to GOL than GUS, supporting the early role of GOL in targeting innate inflammation. Conclusion Combination induction with GUS and GOL showed significant reductions in major inflammatory features of disease as early as WK4 which persisted through WK38 with GUS maintenance. Correlative analysis supports the role of GUS as the primary driver of tissue healing, with GOL further contributing to innate inflammatory activity, which demonstrate differential and complementary mechanisms of action of TNFα and IL-23p19 subunit blockade.

Abstract Background Selective inhibition of interleukin-23 (IL-23) through antagonism of the IL-23p19 subunit has demonstrated clinical efficacy in inflammatory bowel disease, but the mechanism of action (MoA) has not been fully defined. Here we provide a detailed evaluation of the cellular and molecular MoA of guselkumab (GUS), an IL-23p19 subunit antagonist, in patients (pts) with moderately to severely active ulcerative colitis (UC) from the QUASAR Phase 2b induction study (NCT04033445). Methods Serum proteins were evaluated from 302 pts treated with intravenous GUS induction therapy or placebo (PBO) who had at least one paired sample at Weeks (WK) 0 and 4 or WK12. Matched colonic biopsies at WK0 and 12 were available for 255 pts. Transcriptional profiling was performed with bulk RNA sequencing (RNAseq). Transcriptional modules derived from public UC single cell RNAseq (scRNAseq) were evaluated with differential expression in the bulk RNAseq dataset. Flow cytometry and scRNAseq were performed on a subset of matched WK0 and WK12 cryopreserved biopsies from 60 pts. Results Both GUS induction doses were effective vs PBO in achieving key endpoints including clinical remission, endoscopic and histologic outcomes. GUS reduced serum IL-22, IFNγ and IL-17A (p&amp;lt;1e-05) as early as WK4, which further declined through WK12. Unsupervised analysis of tissue transcriptomic modules (n=69) revealed 57 that were significantly changed with GUS at WK12. The top 6 downregulated modules represented Th17 cell (IL-23 pathway), neutrophil, IFNγ signaling, plasma cell and inflammatory epithelial and fibroblast cell states, while modules associated with epithelial cell populations and metabolism were upregulated (all false discovery rate [FDR]&amp;lt;0.05). Fc-γ receptor (CD64) expression was increased at baseline in all patients and reduced at WK12. Flow cytometry demonstrated reductions of CD45+ lymphocyte and CD66+ granulocyte populations (p&amp;lt;0.01). Parallel scRNAseq showed a reduction of inflammatory monocytes and fibroblasts in GUS responders at WK12 while pro-healing indicators were observed at WK12 including an increase in EpCam+ cells, BEST4+ enterocytes, and ADAMDEC1+ fibroblasts (p&amp;lt;0.01). Module analysis indicated an increase in goblet cells (FDR&amp;lt;0.05) which play a role in barrier integrity. Conclusion GUS induction restored intestinal immune homeostasis in pts with UC who achieved key endpoints at WK12, demonstrated by resolution of inflammation associated with the IL-23 pathway and inflammatory myeloid, epithelial and fibroblast transcriptional states. GUS also promoted epithelial repair as evidenced by increases in epithelial cell population, consistent with endoscopic and histologic outcomes at WK12.