Pfizer (Germany)

Accurate estimates of the burden of vaccine-preventable community-acquired pneumonia (CAP) hospitalisations both overall and due to the most frequent and vaccine-preventable pathogens are needed to inform the use of respiratory vaccines in adults. This was a prospective, population-based CAP surveillance study at three hospitals in Germany. All patients admitted with clinically suspected CAP were tested for Streptococcus pneumoniae using urine antigen tests and for respiratory syncytial virus (RSV), influenza virus and SARS-CoV-2 using multiplex PCR from nasopharyngeal swabs. Incidence rate calculations for all-cause CAP were based on eligible patients, regardless of enrolment status. Individuals admitted to study hospitals within the surveillance period with suspected or confirmed diagnosis of pneumonia who provided informed consent. Radiologically confirmed (RAD) CAP. Active surveillance between 1 January 2021 and 30 June 2023 identified at the three study sites 4319 adults with RAD-CAP that met eligibility criteria, of which 1479 (34.2%) were enrolled and included in the analysis for pathogen distribution. The main reason for non-enrolment was the inability to provide informed consent. Incidence estimates were based on 1254 study-eligible individuals admitted at the largest study site. SARS-CoV-2, S. pneumoniae, RSV or influenza were identified in 36.5%, 9.1%, 3.7% and 1.8% of patients with RAD-CAP, respectively. Serotypes included in the 20-valent pneumococcal conjugate vaccine were detected in 6.9% of RAD-CAP and 76.0% of pneumococcal CAP. The overall adjusted annual incidence of all-cause RAD-CAP over the study period was 490/100 000 (95% CI 461 to 521). The incidence of pneumococcal and RSV-related RAD-CAP increased 8.6-fold and 10.0-fold over the study period, resulting in an incidence of 60/100 000 (95% CI 45 to 75) and 30/100 000 (95% CI 19 to 41) in 2022/2023, respectively, while SARS-CoV-2 related RAD-CAP declined by 70% to 97/100 000 (95% CI 78 to 116). Active pneumonia surveillance reported a high burden of RAD-CAP hospitalisations in Germany, especially among older adults. The resurgence of CAP due to RSV, S. pneumoniae or influenza, alongside maintained activity of SARS-CoV-2, was associated with an overall increase of RAD-CAP among adults.

Due to the multisystemic nature of sickle cell disease (SCD), complications can occur together and thus discerning costs associated with individual complications requires a methodology that can estimate the costs of a given complication while accounting for the presence of other complications. In this study, we aimed to estimate period-based incremental costs associated with specific chronic complications in patients with SCD in England while accounting for multimorbidity. All-cause primary and secondary care healthcare resource utilisation (HCRU) was obtained for a retrospective cohort of patients with SCD using Clinical Practice Research Datalink (CPRD) Aurum linked to Hospital Episode Statistics (HES) datasets. Annualised HCRU and costs were calculated, dividing patient-level events by patient-level time (in years) to obtain per person per year estimates. A series of generalised linear models were used with adjustment for demographic factors and proportion of follow-up time with each complication to estimate the costs associated with 10 chronic SCD-related complications of interest. For these costs, annual equivalent costs can be obtained by dividing by the median follow-up time of 4.74 years. Patients with a diagnosis of SCD, with or without complications, in CPRD or HES with at least 12 months follow-up. Period-based all-cause direct healthcare costs. Of the 1271 patients with SCD included in the study, 49.9% (n=634) had at least one complication and of these 41.3% (n=262) had two or more complications either at baseline or during follow-up. Patients with complications had higher all-cause healthcare costs compared with patients without complications (mean (SD) annualised cost £16 058 (£21 488) vs £4399 (£6635)). Patients with complications had four times the number of annualised inpatient admissions (6.1 vs 1.5 admissions) and more than double the number of annualised bed days in hospital (8.3 vs 3.8 days) over a median 4.74 years of follow-up. Of the complications evaluated, end-stage renal disease had the highest estimated incremental cost of £252 083 (95% CI £214 478 to £283 745) over 4.74 years; this is in addition to the £18 547 period-based cost among patients with SCD without complications. Osteonecrosis was the most common complication with an estimated incremental cost of £27 399 (95% CI £6417 to £43 319) over the same period. Estimating the cost of complications, while accounting for multimorbidity, is essential to determine the true direct cost of SCD. The modelling method presented in our study provides period-based estimates of cost and hospital admissions for individual complications in patients with SCD, accounting for multimorbidity. This approach can be used and extended to other diseases with multisystemic complications to estimate the direct HCRU and costs of individual complications.

To identify predictors of treatment changes and to evaluate the effectiveness and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) initiating tofacitinib in a real-world setting. The non-interventional study ESCALATE-RA included 1518 patients with RA from Germany. RA treatment, including all changes in therapy, was documented for 24 months starting from the initial intake of tofacitinib. All patients started with tofacitinib therapy, either as monotherapy or in combination with methotrexate (MTX). The impact of several factors of interest on the number and timing of treatment changes was assessed as primary outcome using Cox proportional hazards models. Further outcomes were tofacitinib drug survival and the use of follow-up disease-modifying antirheumatic drugs after first treatment change. We also assessed the effectiveness, concomitant glucocorticoid (GC) use, PROs (such as functional ability, patient satisfaction, pain and quality of life) and safety. Analyses were based on observed data. 'Lack of efficacy' (HR 3.30) and 'intolerance' (HR 4.43) leading to termination of tofacitinib were key factors favouring therapy changes. Higher patient satisfaction was significantly associated with a reduced likelihood of treatment changes (HR 0.82). Increasing GC doses were associated with a higher probability of step-up/switch changes (HR 1.21). The estimated tofacitinib drug survival was 48% at the end of study. Proportions of patients achieving low disease activity (both Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) Δ62%) and remission (SDAI Δ25%, CDAI Δ28%) increased from baseline under tofacitinib and were comparable between monotherapy and combination therapy with MTX. Mean concomitant GC dose decreased (2 mg/day). PROs indicated reduced pain and fatigue, while functional ability and quality of life improved. 63.9% of the patients experienced a treatment-emergent adverse event (AE), 8.8% a treatment-emergent AE of special interest and deaths occurred in 0.5%. Key factors for therapy changes in patients with RA treated with tofacitinib were lack of efficacy and intolerance. Higher patient satisfaction was associated with a reduced probability of treatment changes, while increased GC doses led to a higher likelihood of step-ups/switches. Patients demonstrated a marked reduction in disease activity for up to 24 months, along with improvements in functional ability, pain and quality of life. Observed AEs were consistent with the known safety profile of tofacitinib. NCT03387423.

Abstract Background Group B Streptococcus (GBS) is a leading cause of severe disease among pregnant individuals, neonates, and infants. Postpartum individuals with GBS are also at risk of endometritis and postoperative wound infections. In this study we describe demographics, clinical characteristics, and health care resource utilization among pregnant and postpartum women hospitalized with laboratory-confirmed invasive GBS (iGBS). Methods Individuals ≥18 years of age who had a positive GBS specimen collected from a sterile site during an inpatient admission were identified in the PINC AI™ Healthcare Database, which includes ∼1200 US hospitals, between 2016-2024 (index admission). Female patients who had a diagnosis and/or procedure code associated with pregnancy or delivery 0-42 days prior to index admission were categorized as pregnant or postpartum. We characterized maternal age, race, payor, and underlying health conditions 0-365 days before index admission. We also captured hospital length of stay, intensive care unit (ICU) admissions during index admission, and 90-day readmissions. Results We identified 150 pregnant and postpartum women hospitalized with iGBS between 2016-2024. Most women (81%) gave birth during the index admission, 8% were postpartum, and 11% were currently pregnant. Average age at admission was 29.4 years (standard deviation [SD] = 6.6 years). Half of women (53%) were White, 33% Black, 2% Asian, and 13% reported other or unknown race. Half of women (52%) were covered by commercial payors and 44% were Medicaid beneficiaries. The most common underlying health conditions were immune suppression (23%), obesity (15%), asthma (8%), and smoking (7%). The average length of the index admission was 5.2 days (SD = 5.0 days) and 13% of women were admitted to the ICU. In addition, 15% were readmitted to the same hospital < 90 days after discharge. Conclusion These analyses provide valuable information on iGBS disease during pregnancy and the post-partum period, and patient characteristics and health care utilization associated with this infection. Future analyses should focus on estimating disease incidence and assessing predictors of severe disease among women with iGBS to guide strategies for disease prevention. Disclosures Sarah Willis, PhD, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds (Public Company) Katharina Schley, Dr. rer pol., Pfizer: Employee|Pfizer: Stocks/Bonds (Private Company) Eileen M. Dunne, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds (Public Company) Kyla hayford, PhD, Pfizer: Stocks/Bonds (Public Company) Jennifer Moisi, PhD, Pfizer Vaccines: Employer|Pfizer Vaccines: Stocks/Bonds (Public Company)

We present a calibrated model to scale-up a roller compaction process using minimal experimental data at small scales. The compression properties of three API-laden blends are evaluated for various drug loadings using a laboratory-scale roller compaction simulator (Int J Pharm 269:403-15, 2004). Using the generated blend compression properties, a calibrated model combining the Reynolds roller compaction model (Comput Chem Eng 34:1049-57 2010) and ribbon solid fraction measurements is developed to predict the ribbon solid fraction as a function of the roller compaction conditions (roll force and roll gap). The predictions of this model are compared with measurements from ribbons generated on the Gerteis minipactor at various scales using appropriate methods. The predicted solid fractions achieve good agreement with measured solid fractions for the three drug products. Further, the calibrated model is extended by developing a parametrized regression model where several API properties, formulation properties, and ribbon solid fraction predictions from the Reynolds model are taken as features to generate ribbon solid fractions for partially characterized active blends. The predictions of the hybrid model agree reasonably with measurements on ribbons produced on a Gerteis 3-W-Polygran. This hybrid model can then be deployed to run digital Design of Experiments (DOEs), which is then used to define operating ranges for the roller compaction of two drug products. This method enables the application of digital tools to aid the scale-up of fast-moving drug product processes using minimal experimental data.

Fragment-based drug design (FBDD) has become a key approach in structure-based drug discovery, allowing researchers to systematically develop molecular fragments into potent ligands. Although recent generative AI models, such as diffusion-based approaches, show great potential for designing new molecules, applying them to fragment-based methods faces challenges due to mismatches between training and inference procedures, as well as computational limitations. In this work, we develop a generative model based on stochastic interpolants that unify diffusion and flow matching paradigms, learning to create fragments through conditional training on molecular substructures. Our experiments show that models trained with explicit fragment-based conditioning perform much better than unconditional models that are adapted for fragment completion tasks. We compare diffusion models with flow matching models using identical backbone architectures and find that flow matching delivers better convergence and produces higher-quality 3D molecular poses with reduced strain energies, all while needing fewer computational steps. We test our method on standard benchmark datasets and examine different fragmentation strategies, finding that the choice of fragmentation algorithm plays an important role in model performance. Through a detailed case study on an internal PLK3 inhibitor structure, we demonstrate that our approach can generate new fragments that show computationally favorable docking scores and binding energy estimates competitive with tested internal Pfizer compounds, while also exploring regions of chemical space that go beyond existing fragment libraries. These findings establish flow matching within the stochastic interpolants framework as a promising approach for fragment-based drug design, providing both improved computational efficiency and better molecular quality for structure-based optimization.

BackgroundVisceral metastasis is prevalent among patients with advanced/metastatic breast cancer (ABC) and is a prognostic indicator of poor survival. We conducted a systematic literature review of the evidence for palbociclib plus endocrine therapy (ET) in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) ABC and visceral metastasis.MethodsPubMed, EMBASE, Cochrane Library, and relevant conference proceedings were searched through September 2023. Phase 2/3 randomized clinical trials (RCTs) and real-world evidence (RWE) studies evaluating efficacy/effectiveness, safety, and health-related quality-of-life (QoL) of palbociclib plus ET were included.ResultsQualitative synthesis was conducted on 70 articles; 24 reported results from 8 RCTs; 46 were RWE studies. Data from >10,000 patients with visceral metastasis treated with palbociclib were included. All RCTs and RWE studies (5 each) that assessed palbociclib plus ET versus ET alone in patients with HR+/HER2− ABC and visceral metastasis showed significant reduction in risk of disease progression and/or death with palbociclib plus ET (34 %–50 % reduction in RCTs; 31 %–47 % in RWE studies). In RCTs, overall survival was not significantly different between the treatment groups; however, 4 of 5 RWE studies showed a significant benefit (36 %–42 % reduced risk of death) with palbociclib plus ET. Although data for other outcomes were limited, palbociclib plus ET was generally safe and well tolerated while QoL was maintained.ConclusionBoth RCTs and RWE studies consistently showed that palbociclib plus ET is efficacious/effective in patients with HR+/HER2− ABC and visceral metastasis; further research is warranted focused on safety, tolerability, and QoL in this patient group.