AstraZeneca (Germany)

Alkali metal alkoxides have long been known to cause hydrodehalogenation of aryl halides; this conversion of aryl halides to arenes happens when the reactions are conducted in appropriate solvents (with weak C-H bonds). More recently, when aryl halides are heated with alkoxides in arene solvents, coupling to arenes occurs. Both of these reaction types are known to involve aryl radical intermediates. The consensus has been that alkali metal alkoxides undergo electron transfer to aryl halides to form radicals, but crucial evidence has been missing. We now refute this proposal and show through deuterium isotope studies that the deprotonation of the substrates leads to benzynes that initiate radical chemistry. Surprisingly, o-, m-, p- and, in appropriate cases, r- (remote) benzynes are simultaneously formed. During reactions with potassium tert-butoxide, we observed for the first time low-level methylation of arenes, resulting from methyl radicals derived from tert-butoxide. Although methyl radicals could, in principle, arise by electron transfer from tert-butoxide ions, followed by known radical fragmentation, we show that a different, previously unreported mechanism applies.

Abstract Background Non-invasive prediction of endoscopic severity in ulcerative colitis (UC) remains challenging, as current clinical indicators often fail to accurately distinguish patients with inactive/mild from moderate-to-severe endoscopic disease, an important distinction for guiding therapeutic decisions and clinical trial design. Methods In a prospective cohort of UC patients (THAMES-IBD; n = 182), peripheral blood transcriptomes were compared between moderate-to-severe (n = 89) versus inactive/mild (n = 93) endoscopic disease, revealing differentially expressed genes (DEGs) enriched for B cell-mediated humoral immunity and type 1 interferon response (Figure 1). Machine learning (ML) models (LASSO, Random Forest, Elastic Net, and XGBoost) were used for feature selection to identify DEGs predictive of endoscopic severity. Random Forest classifiers trained on these DEGs evaluated predictive performance using 10-fold cross-validation, with discriminative ability measured by area under the receiver operating characteristic curve (AUC), both alone and in combination with validated clinical symptom scores. In a subset of patients with faecal calprotectin (FC) data (n = 132), models comparing gene signatures alone, clinical symptoms plus FC, and all three in combination were evaluated. External validation was performed in a large independent cohort of UC patients1 (Mount Sinai; n = 386), using logistic regression of gene set variation analysis (GSVA) scores of the discovered peripheral blood gene signatures together with clinical symptom scores. Results In the THAMES-IBD discovery cohort, ML-derived blood gene signatures robustly discriminated moderate-severe from mild-inactive endoscopic disease activity in UC patients (AUC 0.81–0.87), outperforming symptom-based models alone (AUC 0.77). In the cohort subset with FC data, gene signatures alone (AUC 0.82-0.85) and gene signatures together with clinical symptoms + FC (AUC 0.82–0.88) exceeded the predictive performance of the clinical symptoms + FC model (AUC 0.66). External validation in the Mount Sinai cohort confirmed these findings: GSVA scores of the gene signatures achieved AUC 0.75-0.77, and combined gene signature plus clinical symptom models achieved AUC 0.80-0.81, both outperforming clinical symptoms alone (AUC 0.73) (Figure 2). Conclusion ML-derived blood gene signatures reliably predict endoscopic severity in UC and are reproducible across cohorts. Integration of blood transcriptomics with routine clinical indices enhances non-invasive assessment of endoscopic disease severity. These findings reflect peripheral blood immune responses associated with mucosal inflammation and support the development of blood-based biomarkers for precision monitoring in UC.

Background and Aim Bruton tyrosine kinase inhibitors (BTKis) are the standard of care for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib and acalabrutinib are two commonly used BTKis, though hypertension (HTN) and other cardiovascular medical events of interest (CV MEOIs) can impact treatment tolerability and long-term use. This study compared cardiovascular safety and health care resource use (HCRU) of acalabrutinib versus ibrutinib monotherapy for R/R CLL/SLL in real-world community practice. Methods This retrospective comparative study included 270 RR CLL/SLL patients (90 acalabrutinib; 180 ibrutinib) treated from January 2017 through December 2023 across the ONCare Alliance Network, comprising 30 US community hematology practices. Endpoints included new or worsening of existing HTN, development of CV MEOIs, and treatment discontinuation due to adverse events. HCRU metrics consisted of emergency department visits, hospital admissions, length of stay, specialist consultations, and related medical procedures. Propensity score weighted multivariable logistic regression was used for the comparative analysis on the tolerability endpoints. Results At a median follow-up of 33 months, patients treated with acalabrutinib had significantly fewer HTN events (OR = 0.27, 95% CI = 0.074–0.98; p = .046) and adverse events leading to treatment discontinuation (OR = 0.39, 95% CI = 0.20–0.73; p = .002) compared to those on ibrutinib. Hospital admission rates for MEOIs were lower in the acalabrutinib group (0.20 vs. 0.24 per patient), with a shorter median length of stay (3.0 vs. 6.0 days). Additionally, acalabrutinib patients had fewer specialist consultations (0.11 vs. 0.22 per patient) and associated medical procedures (0.11 vs. 0.18 per patient). Conclusions In R/R CLL/SLL, acalabrutinib demonstrated a more favorable cardiovascular safety profile than ibrutinib, with fewer HTN events and CV MEOIs. This translated into reduced hospital admissions and lower HCRU, supporting acalabrutinib as a potentially better tolerated long-term treatment option in community practice.

CKD is a global health issue exacerbated by the rising prevalence of diabetes and obesity. Renal fibrosis, characterized by the accumulation of extracellular matrix proteins, is a critical factor in CKD progression. Transforming growth factor β (TGF-β), a key profibrotic cytokine, plays a pivotal role in this process. However, systemic inhibition of TGF-β has been limited by associated toxicities. This study explores the role of αvβ8 integrin in renal fibrosis and its potential as a therapeutic target in CKD. We used various preclinical models of CKD, including humanized αvβ8 mice and the db/db uninephrectomy model, to investigate the role of αvβ8 integrin in renal fibrosis. Gene Set Variation Analysis (GSVA) was employed to assess fibrotic gene signatures in human kidney biopsies. The therapeutic potential of MEDI8367, a monoclonal antibody targeting αvβ8 integrin, was evaluated in vitro and in vivo. Our findings demonstrate that αvβ8 integrin is upregulated in the tubulointerstitium of CKD kidneys, particularly in diabetic kidney disease (DKD), and correlates with TGF-β activation and renal function decline. MEDI8367 effectively inhibited αvβ8-mediated TGF-β activation in vitro and attenuated murine unilateral ureteral obstruction (UUO)-induced renal fibrosis. Notably, inhibition of αvβ8 reduced kidney damage and improved kidney function in models of DKD and hypertensive nephropathy. Our study highlights the potential of MEDI8367 to mitigate renal fibrosis and improve kidney function, offering a novel approach to CKD treatment that complements existing therapies.

Abstract Background Heart failure (HF) is one of the leading public health issues worldwide. Current guidelines recommend HF treatment using different drug classes depending on ejection fraction (EF) and underlying cause of HF. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a drug class with a class IA recommendation in the current ESC-guidelines for HF treatment independent of EF. The SGLT2i dapagliflozin is approved for treatment of HF across the entire spectrum of EF in Germany. However, real-world data are limited. Purpose The aim of EVOLUTION-HF DEallEF is to generate data on real-world dapagliflozin use in HF patients independently of EF in Germany under the multinational umbrella EVOLUTION-HF study protocol. Methods EVOLUTION-HF DEallEF is a non-interventional, prospective, longitudinal cohort study. It is planned to enrol a total of 1000 patients with chronic HF in Germany, including 40% patients with preserved (HFpEF; EF ≥ 50%), 20% with mildly reduced (HFmrEF; EF 41-49%), and 40% with reduced EF (HFrEF; EF ≤ 40%). Patients willing to participate, aged ≥18 years, who started dapagliflozin treatment 14 to 90 days prior to enrolment according to the local product label, are eligible for participation. Among reasons for exclusion is previous SGLT2i treatment (including dapagliflozin). Data on medical history, clinical symptoms, previous and concomitant medication and patient-reported outcomes (PROs) are collected. EVOLUTION-HF DEallEF has included its first patient in 04/2024 and is currently open for enrolment. Interim analyses (IA) were planned at predefined timepoints (after 250, 500 enrolled patients and enrolment completion). The three different EF cohorts (HFpEF, HFmrEF, HFrEF) are analysed separately and as a total population. Only descriptive statistical methods are used. Results This 1st IA (data cutoff: 02/12/2024) included 249 patients in the safety set (all patients received at least one dose of dapagliflozin, one patient refused data usage) and 244 patients who fulfilled all eligibility criteria in the full analysis set (FAS). Patients were enrolled in 31 study sites, mainly in office-based cardiologic practices. In the FAS, distribution of patients to HF cohorts was 51% with HFpEF (n=125), 30% with HFmrEF (n=73), and 19% with HFrEF (n=46). Conclusions Patients’ and disease characteristics observed at the time of the first IA are in range with previously published data indicating that a representative cohort of patients newly treated with dapagliflozin for HF are enrolled in EVOLUTION-HF DEallEF. Dysbalance in expected enrolment proportion per EF cohort is mainly caused by exclusion of patients with SGLT2i-pretreatment. The study aims to provide further insights into real-world dapagliflozin treatment for HF in Germany, focussing on clinical and patients’ perspective.

Proteolysis targeting chimeras (PROTACs) enable degradation of disease-related proteins via E3 ligase recruitment. PROTACs often do not easily crystallize, and they are usually formulated in amorphous forms. Determining the key interactions that stabilize the solid drug forms is of high interest. Here, we determine the complete atomic-level structure of an amorphous Von Hippel-Lindau (VHL)-based SMARCA2 PROTAC (PROTAC 2) using nuclear magnetic resonance (NMR) crystallography. We find that PROTAC 2 is more disordered as compared to previously studied amorphous formulations, and that the three functional units of the molecule have distinct structural types. In contrast to smaller drug molecules, where intermolecular hydrogen bonding interactions were found to be the main stabilization mechanism for the amorphous solid form, for PROTAC 2 we postulate that, in analogy to glassy polymers, the main stabilization mechanism is the entropic contribution introduced by the overall flexibility, especially in the linker region of the molecule. We also note that the most populated conformations found in the amorphous form differ from those of bound PROTAC 2 in the ternary protein complex as determined via X-ray crystallography. Our results provide insight into key structural features that stabilize amorphous formulations, specifically for molecules that can target proteins previously considered undruggable.