Sanofi (Netherlands)

Most human invasive infections caused by extraintestinal pathogenic Escherichia coli (ExPEC) are associated with a limited number of O-serotypes and O-serogroups, including O101/O162. Here, we examined E. coli O101/O162 O-serogroup epidemiology among bacteremia isolates and performed genetic, biochemical and structural analyses. We demonstrate that the O101/O162 O-serogroup is globally widespread and highly associated with multidrug resistance (MDR). Dominant lineages belonged to clonal complex 10, including the high-risk clone ST167. Most O101/O162 ExPEC isolates contained an unusual O101 rfb locus previously identified as Onovel32, of which 30% harbored disruptions in the methyltransferase (MT) encoding gene. These disruptions resulted in alteration of the polysaccharide composition, and we identified two major O101 variants. Additionally, we found that an intact MT is a prerequisite for O-methylation of the polysaccharide, indicating terminal capping. Our data supports a model of a co-polymeric O101 O-antigen structure, which is unique for E. coli. Finally, we established that the two clinically relevant O101 O-antigen variant structures are highly immunogenic as polysaccharide-protein conjugates but differ in their ability to elicit opsonophagocytic antibodies. Altogether, our data provides important insights into O-serotype epidemiology and O-polysaccharide variation within E. coli O101/O162 isolates associated with bacteremia.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-026-45688-7.

Respiratory syncytial virus (RSV) is the leading cause of infant hospitalizations in the United States, with a significant seasonal impact on healthcare resources. Long-acting monoclonal antibodies (mAbs), nirsevimab and clesrovimab, provide protection against RSV-related lower respiratory tract disease (LRTD); however, no head-to-head comparisons are available to inform clinical decision-making. We developed a cost-effectiveness analysis framework to perform an indirect comparison of nirsevimab and clesrovimab for RSV prevention, consistent with CDC guidance for pre-season catch-up and in-season immunization for infants born outside and during the RSV season, respectively. Pharmacokinetic data were used to model the duration of cumulative efficacy over time. A 150-day duration was evaluated for nirsevimab, while three scenarios were assessed for clesrovimab (100-, 120-, and 150-day durations). A cost-utility analysis evaluated health outcomes, healthcare resource use, and associated costs. The modeled prediction suggests nirsevimab demonstrated greater clinical benefitand more favorableeconomic outcomes compared to clesrovimab across all protection duration scenarios. Nirsevimab use consistently resulted in reduced cases of RSV medically attended (MA)-LRTDs and therefore direct and indirect costs associated with RSV management. From a cost-effectiveness perspective, nirsevimab was dominant (i.e., more effective and less costly) compared to clesrovimab in all analyzed scenarios. Additional scenario analyses leveraging trial data differentiated by infant gestational age for both nirsevimab and clesrovimab and alternative RSV seasonality demonstrated that model conclusions remain stable. These analyses confirmed the robustness of our findings, with nirsevimab consistently offering greater value. Our findings predict that nirsevimab is economically dominant over clesrovimab while providing greater clinical protection against RSV-related disease in these scenarios. These results are robust to sensitivity analyses with nirsevimab consistently estimated as reducing healthcare resource utilization and total costs compared to clesrovimab across assumptions related to clesrovimab duration of cumulative efficacy as well as variation in key model parameters.

Abstract Background High-dose inactivated influenza vaccination (HD-IIV) demonstrates superior effectiveness versus standard-dose vaccination (SD-IIV) in adults aged ≥60 years. A recent meta-analysis integrated complementary evidence sources of representing over 85 million individuals across 14 influenza seasons. Methods A previously developed model was updated using life-time horizon and societal perspective. Updated parameters included demographics, costs, hospitalization rates, and relative vaccine effectiveness (rVE): RCT evidence (24% for ILI, 7% for cardiorespiratory hospitalizations) and RCT + real-world evidence (RWE) (15% for ILI, 8% for cardiorespiratory hospitalizations). Results HD-IIV resulted in incremental cost-effectiveness ratios of €7,300/QALY (RCT evidence) and €5,800/QALY (RCT+RWE evidence). Implementation would prevent 7,200 general practitioner visits, 6,300 cardiorespiratory hospitalizations, and 269 deaths, by using RCT evidence. Probabilistic sensitivity analysis demonstrated >99% probability of cost-effectiveness at €20,000/QALY threshold for both RCT and RCT+RWE evidence. Conclusions HD-IIV remains highly cost-effective for Dutch adults aged ≥60 years under updated evidence scenarios, supporting implementation in the national immunization programme. Highlights The economic analysis of high-dose inactivated influenza vaccine was updated. Relative vaccine effectiveness of HD-IIV incorporating recent evidence was used. HD-IIV remains cost-effective in Dutch adults aged ≥60.

11129 Background: IO-inducedCRS has various signs and symptoms that impact different aspects of patients’ lives. While the frequency and severity of IO-induced CRS events underscore the benefit–risk profile and tolerability of IO therapies, patients’ perceptions are critical for measuring the impact of these events on their lives. In this qualitative research study, we developed a novel PROM to track the onset, resolution, and impact of IO-induced CRS events in clinical trials. Methods: Clinician insights and patient interviews were used to identify common IO-induced CRS signs, symptoms, and impacts. Patient-reportable symptoms and impacts were prioritized to form the basis of the IO-induced CRS Patient Diary. The PROM was tested in cognitive debriefing (CD) interviews with 3 clinicians and 3 waves of CD interviews with patients on IO (5 per wave; N = 15). Changes were made to the PROM between each wave to ensure relevance and improve interpretation and usability. Results: After a literature review, qualitative research with 9 clinical experts, and concept-elicitation interviews with 14 patients on IO (3 on CAR-T, 11 on non-CAR-T therapy), 37 patient-reportable signs and symptoms and 7 clinical signs (non–patient reportable) associated with IO-induced CRS were listed. Patients’ concept descriptions and clinicians’ concept priorities were examined, and 12 symptoms and 4 impacts across 5 domains (emotional, physical, social, activities of daily living, and financial) were included in the final diary. The IO-induced CRS Patient Diary—an electronic PROM—has three versions for use at different points in a clinical trial. The “baseline” version is completed before initial IO administration; patients report the incidence and severity of 12 symptoms and their impact on overall health (recall period: the past week). The “day of treatment” version, completed the evening of the treatment day, asks the same questions, plus about symptom manageability (recall period: since receiving the study medication on that day). The “subsequent days” version is the same as the “day of treatment” version, but also asks about impact on regular daily activities, need to rest, and amount of worry caused by CRS (recall period: past 24 hours). It may be completed daily depending on the study design or set of outcomes. Conclusions: The IO-induced CRS Patient Diary, the first of its kind, was developed in line with best practices and is content-valid for the intended use: to capture patients’ experiences with IO-induced CRS events in clinical trials. Understanding these impacts will inform the benefit–risk profile and tolerability of IO therapies. This PROM may also have value in clinical practice, for which additional validation would be needed. Future work will aim to assess its psychometric performance in clinical trials.

IntroductionChronic inflammatory demyelinating polyneuropathy (CIDP) is a rare type of autoimmune neuropathy, characterized by signs of distal and proximal weakness of the upper and lower limbs, sensory dysfunction, absent or diminished tendon reflexes, and symptoms of numbness, tingling, pain, and fatigue. These signs/symptoms can lead to difficulty walking, climbing stairs, and reduced manual dexterity. Detailed qualitative exploration of the patient experience of CIDP, notably signs/symptoms, its impacts on health-related quality of life, and treatment experience is limited. Qualitative patient experience data is recommended by regulatory bodies to inform patient-focused drug development. This study aimed to qualitatively explore the experience of CIDP from the patient and clinician perspectives.MethodsQualitative concept elicitation telephone interviews were conducted with adult patients with a confirmed diagnosis of CIDP and with neurologists experienced in diagnosing and treating patients with CIDP from the USA. Interview transcripts were analyzed using thematic analysis methods, and findings informed development of a conceptual model.ResultsOverall, 15 patients with CIDP and 10 neurologists were interviewed. A total of 19 signs/symptoms were identified as important and relevant, of which weakness, fatigue, loss of balance, tingling, numbness, pain, and loss of coordination were most frequently reported by patients and neurologists. Except for loss of coordination, these signs/symptoms were also considered most salient to patients. Patients identified fatigue as the most bothersome symptom and weakness and fatigue as the most important to treat. CIDP impacted health-related quality-of-life (HRQoL), including physical functioning (e.g., walking difficulties), activities of daily living (e.g., difficulty with personal care), work (e.g., being unable to work), emotional wellbeing (e.g., depression), social wellbeing (e.g., participation in social/leisure activities), sleep (e.g., difficulty falling asleep), and cognition (e.g., brain fog). Patients reported that current CIDP treatments lacked effectiveness in treating specific symptoms, caused unwanted side effects, and impacted their independence.ConclusionsFindings contribute novel and detailed qualitative insights into the key signs/symptoms of CIDP and the profound impact of these on patients’ HRQoL from both the patient and clinician perspectives. Findings can be used to identify treatment targets and support selection of appropriate clinical outcome assessments for the evaluation of CIDP symptoms and HRQoL impacts in future CIDP clinical trials.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-025-00732-y.

ABSTRACTDespite therapeutic advances, people with hemophilia experience bleeds. These may be life‐threatening, result in permanent joint damage, chronic pain, difficulties with mobility/daily activities, and impact quality of life. In the XTEND‐1 study (NCT04161495), once‐weekly efanesoctocog alfa (50 IU/kg) prophylaxis provided highly effective bleed prevention and high‐sustained factor levels for most of the week and was well‐tolerated. We report post hoc analysis of bleeding episodes and their treatment in previously treated patients (≥ 12 years old). Participants received 50 IU/kg efanesoctocog alfa either as once‐weekly prophylaxis (Arm A) or on‐demand followed by once‐weekly prophylaxis (Arm B) in XTEND‐1. Endpoints included treatment of bleeding episodes and response to treatment. During XTEND‐1, 422 bleeding episodes were reported among 159 participants; 362 were treated. Most treated bleeding episodes (74%; n = 268) occurred during the Arm B on‐demand period, of which 197 (74%) were spontaneous. Seventy‐five participants had no bleeding episodes in Arm A; all in Arm B had ≥ 1 bleeding episode while on‐demand. Most participants (n = 107, 81%) had zero treated spontaneous bleeding episodes and rates of treated bleeding episodes in Arm A (prophylaxis) were low (median [interquartile range] overall ABR: 0.00 [0.00–1.04]). A single injection was sufficient to resolve 97% (350/362) of treated bleeding episodes, no bleeding episodes required > 3 injections, and responses to 95% of evaluable injections were rated excellent/good. Median total dose was 50.9 IU/kg per bleeding episode. Results of this analysis further demonstrated that once‐weekly efanesoctocog alfa provides highly effective bleed protection and treatment of bleeding episodes in participants with severe hemophilia A.Trial Registration: NCT04161495

Abstract Real-world studies complement randomized controlled trials (RCTs) by providing data from a more heterogeneous population treated in a normal practice environment. In several RCTs, dupilumab has demonstrated robust efficacy with acceptable safety in patients with moderate-to-severe atopic dermatitis (AD). The main objectives of the ongoing GLOBOSTAD study (NCT03992417) are characterizing the patient population treated with dupilumab, their AD treatment patterns, long-term effectiveness, and safety of dupilumab in the real world. The GLOBOSTAD 5-year, multinational, prospective, observational study enrolled patients aged ≥ 12 years with moderate-to-severe AD. Patients received dupilumab based on country-specific prescribing information, and assessments were performed at baseline, 3 months (± 1 month), 6 months (± 2 months) and 12 months (± 2 months). The data are reported as observed for the enrolment/safety (n = 955; data cutoff March 2023) and follow-up (n = 903) populations. In total, 758, 863 and 705 patients completed at least one follow-up assessment at 3, 6 and 12 months, respectively, with a mean (SD) treatment period of 11.7 (1.2) months. The mean (SD) Eczema Area and Severity Index (EASI; > 21 = severe; ≤ 7 = mild/no disease) at baseline was 25.1 (12.8). During the study, ≥ 75% (EASI 75) and ≥ 90% (EASI 90) reductions in mean EASI scores from baseline were observed in 66.2% and 35.6% of patients at 3 months, 74.6% and 42.4% at 6 months, and 81.0% and 55.8% at the end of the observation period (12 months), respectively. The patient-reported mean (SD) weekly average pruritus numerical rating scale (NRS, range 0–10) at baseline was 6.3 (2.2). A three-point and four-point improvement from baseline or a score of 0 in pruritus NRS was observed in 66.9% and 57.1% of patients at 3 months, 73.6% and 64.1% at 6 months, and 79.0% and 70.3% at 12 months, respectively. Of the follow-up population, 67.4% achieved an absolute pruritus NRS score of ≤ 3 at 3 months, 76.4% at 6 months, and 80.3% at 12 months. Adverse events considered related to dupilumab that led to permanent discontinuation occurred in 2.4% of patients. Patients enrolled in the GLOBOSTAD study achieved rapid improvements in AD signs and symptoms on initiating dupilumab treatment, which were sustained until the end of the 1-year observation period. Safety was consistent with the known dupilumab safety profile. This research was sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

Pompe disease (PD) is a rare autosomal recessive lysosomal disorder caused by loss-of-function of the α-glucosidase (GAA) gene. The deficient GAA enzyme activity may result in potential life-threatening muscle weakness, thus requiring a rapid diagnosis to initiate therapeutic interventions. In this large retrospective study, we analyzed 30.836 PD suspect samples from 57 countries using a two-step approach utilizing dried blood spots (DBSs): biochemical testing of GAA activity followed by complementary genetic sequencing of GAA in biochemically conspicuous cases. Of these 30.836 samples, 2% (n = 639) were excluded; accordingly, this study consisted of 30.193 cases. Biochemical testing of GAA enzyme activity showed normal values in 28.354 (93.90%) and enzyme activity below the cut-off in 1843 (6.10%) cases. These biochemically suspicious cases were genetically analyzed. We identified 723 Pompe cases with 283 different GAA alterations, and 98 variants have been unpublished so far. The most common variant was the splice variant c.-32-13T>G (IVS1). Looking at the IVS1-genotype, the majority was compound heterozygous (n = 169) and identified in late-onset cases (n = 162). Comparison of early- versus late-onset cases to evaluate whether certain genotypes correlate with the age of onset revealed that homozygosity was predominantly found in infantile (85.65%) and compound heterozygosity in late-onset (76.9%) cases. Analysis of homozygous cases revealed 61% nonsense variants in the early stages and 87% missense variants in the late stages. Mapping of disease-associated (homozygous) missense variants to functional GAA protein domains showed that missense variants were found throughout GAA, but we identified enrichment in the catalytic domain. A strict genotype-phenotype correlation cannot be established; nevertheless, a phenotypic implication of some GAA variants could be drawn (e.g., c.896T>C/p.L299P, c.2015G>A/p.R672Q, and c.-32-13T>G). The combined enzyme activity and genetic testing from DBS cards can reliably identify PD and significantly accelerate diagnosis. We identified new genetic variants that contribute to the spectrum of pathogenic variants of the GAA gene.