Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor–positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor–positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. Significance: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Eosinophil counts in first COPD hospitalizations: a 1-year cost analysis in Quebec, Canada

Thomas G Poder1–3 Nathalie Carrier,1 Maryse Bélanger,1,4 Simon Couillard,1,4 Josiane Courteau,1 Pierre Larivée,1,4 Alain Vanasse1,3 1Research Center, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; 2Health Technology Assessment Unit, UETMIS, CIUSSS de l’Estrie – CHUS, Sherbrooke, QC, Canada; 3Department of Family Medicine and Emergency Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; 4Respirology Service Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada Background: Exacerbations explain much of the cost of COPD. Higher blood eosinophil cell counts at admission for acute exacerbation of COPD increase the risk of subsequent exacerbations and hospitalizations. However, there is no literature on the economic burden of patients with this inflammatory profile. The objective of this study is to assess the cost of health-care service utilization according to different counts of blood eosinophils.Methods: The observational retrospective cohort included all first hospitalizations for COPD exacerbation between April 2006 and March 2013. The eosinophilic group was defined by blood eosinophil counts on admission ≥200 cells/µL and/or ≥2% of the total white blood cell count. Study outcomes were: total costs (2016 Canadian dollars) (index hospitalization and 1-year follow-up), total index hospitalization costs, total 1-year costs (all-cause readmissions, ambulatory and emergency service use), and 1-year COPD-related costs (only cost for COPD after initial discharge). Sensitivity analyses were conducted to evaluate the impact of different eosinophil cut-offs on outcomes.Results: In total, 479 patients were included, 173 in the eosinophilic group (92 in the higher cut-off). The average total cost was $18,263 ($6,706 for the index hospitalization), without significant difference between groups (P=0.3). The average 1-year COPD-related cost was higher in the eosinophilic group ($3,667 vs$2,472, P=0.006), with an adjusted mean difference of 1,416. Analysis of data using the higher cut-off of ≥400 cells or ≥3% was associated with a slightly larger difference in 1-year COPD-related costs between groups (4,060 vs $2,629, P=0.003), with an adjusted mean difference of$1,640.Conclusion: A higher blood eosinophil cell count at admission for a first hospitalization is associated with an increase in total 1-year COPD-related costs. Keywords: chronic obstructive pulmonary disease, exacerbations, health-care utilization, cohort study, Canada, Quebe

Greater eosinophil counts at first COPD hospitalization are associated with more readmissions and fewer deaths

Qing Li,1 Pierre Larivée,2,3 Josiane Courteau,2 Simon Couillard,2,3 Thomas G Poder,2,4,5 Nathalie Carrier,2 Maryse Bélanger,2,3 Alain Vanasse2,5 1Center for Innovation Management Research of Xinjiang, School of Economics and Management, Xinjiang University, Urumqi, Xinjiang, China; 2Research Center, Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada; 3Respirology Service, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; 4Health Technology Assessment Unit, UETMISSS, CIUSSS de l’Estrie – CHUS, Sherbrooke, QC, Canada; 5Department of Family Medicine and Emergency Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada Purpose: The impacts of high blood eosinophil count (HBEC) at admission for COPD exacerbation on posthospitalization outcomes are still unclear. Previous studies have focused on its associations with first readmission rates; yet, its impacts on longitudinal outcomes such as subsequent readmissions still have to be explored. The main objective of this study is to investigate outcomes associated with HBEC following a first hospitalization for COPD exacerbation.Patients and methods: This is an observational cohort study design. We retrospectively analyzed data of patients with a first hospitalization within 5 years for COPD exacerbation between April 2006 and March 2013. Patients were stratified into the HBEC group if the blood eosinophil count at admission was ≥200 cells/µL and/or ≥2% of the total white blood cells. With information on exact dates of subsequent hospitalizations and death, we modeled readmissions and death as states in a multi-state Markov model and estimated transition probabilities to the next states. Sensitivity analyses were performed by varying thresholds for the definition of HBEC (≥300 cells/µL and/or ≥3%).Results: A total of 479 patients were included, of which 173 had HBEC. The transition probabilities for a first readmission was 74% (95% CI, 66%–83%) for patients with HBEC vs 70% (95% CI, 63%–77%) for patients with normal blood eosinophil count (NBEC). The transition probabilities for a second readmission were 91% (95% CI, 84%–100%) for HBEC patients in contrast with 83% (95% CI, 74%–92%) for NBEC patients. Meanwhile, transition probability for death was lower in patients with HBEC. The differences enlarged in sensitivity analyses with higher cutoff.Conclusion: Greater blood eosinophil cell counts during a first hospitalization for COPD predict increased susceptibility to up to two readmissions. These patients may however have a lower risk of death. Keywords: COPD, blood eosinophil cell count, exacerbations, readmissions, death, multi-state Markov model, transition probability, observational cohort study, clinical data, administrative dat

Eosinophil counts in first COPD hospitalizations: a comparison of health service utilization

Maryse Bélanger,1,2 Simon Couillard,1,2 Josiane Courteau,1 Pierre Larivée,1,2 Thomas G Poder,1,3,4 Nathalie Carrier,1 Kim Girard,1 Felix-Antoine Vézina,1,2 Alain Vanasse1,4 1Research Center, Centre hospitalier universitaire de Sherbrooke, Sherbrooke, QC, Canada; 2Respirology Service, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; 3Health Technology Assessment Unit, UETMIS, CIUSSS de l’Estrie – CHUS, Sherbrooke, QC, Canada; 4Department of Family Medicine and Emergency Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada Purpose: Current evidence suggests that a higher blood eosinophil cell count at admission for acute exacerbation of COPD (AECOPD) is associated with a favorable response to systemic steroids. However, the impact of blood eosinophil counts at admission on post-hospitalization outcomes is still unclear. The main objective of this study is to investigate readmission outcomes associated with blood eosinophilia following severe COPD exacerbation in patients with infrequent COPD hospitalizations. Patients and methods: This is an observational cohort study design. We retrospectively analyzed data of patients with a first hospitalization within 5 years for COPD exacerbation between April 2006 and March 2013. Patients were stratified into the eosinophilic group if the blood eosinophil count on admission was ≥200 cells/µL and/or ≥2% of the total white blood cell (WBC) count. The primary outcome was 1-year COPD-related readmission. Secondary outcomes included 1-year all-cause mortality, 1-year all-cause readmission, length of stay, time to COPD-related readmission, and number of 1-year COPD-associated emergency department (ED) and ambulatory visits. Results: A total of 479 patients were included. Of whom, 173 were stratified into the eosinophilic group. Higher blood eosinophil cell count was associated with an increased risk of 1-year COPD-related readmission (OR, 1.83 [95% CI, 1.16–2.89]; P<0.01), a shorter time to first COPD-related readmission (HR, 1.64 [95% CI, 1.14–2.36]; P<0.01), and an increased number of 1-year COPD-related ED visits (incidence rate ratio, 1.78 [95% CI, 1.21–2.61]; P<0.01). All-cause mortality, all-cause readmission, length of stay, and number of ambulatory visits did not differ between groups. Conclusion: Higher blood eosinophil cell count at admission for a COPD exacerbation is associated with increased COPD readmission rates in patients with infrequent COPD hospitalizations. Keywords: COPD, exacerbations, hospitalization, mortality, cohort stud