Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: Secondary analyses by baseline pain intensity and use of rescue medication of a phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: In the randomized, phase 3, SUSA-301 trial, celecoxib-tramadol co-crystal (CTC) provided significantly greater analgesia compared with celecoxib, tramadol, or placebo in adults with acute, moderate-to-severe, postoperative pain. This post hoc, secondary analysis further evaluated the use of rescue medication and the incidence of treatment-emergent adverse events (TEAEs). METHODS: Patients (N = 637) were randomized 2:2:2:1 to receive oral CTC 200 mg twice daily (BID; n = 184), tramadol 50 mg four times daily (QID; n = 183), celecoxib 100 mg BID (n = 181), or placebo QID (n = 89). Post hoc analyses were conducted on the use of rescue medications up to 4 and 48 h post-study drug dose, stratified by baseline pain intensity (moderate/severe), and on the incidence of TEAEs, stratified by rescue medication use. RESULTS: A significantly lower proportion of patients received any rescue medication within 4 h post-study dose with CTC (49.5%) versus tramadol (61.7%, p = 0.0178), celecoxib (65.2%, p = 0.0024), and placebo (75.3%, p = 0.0001); this was also seen for oxycodone use. Fewer patients in the CTC group received ≥3 doses of rescue medication compared with the other groups, irrespective of baseline pain intensity. In patients who did not receive opioid rescue medication, CTC was associated with a lower incidence of nausea and vomiting TEAEs versus tramadol alone. In patients who received rescue oxycodone, the incidence of nausea was similar in the CTC and tramadol groups, and higher versus celecoxib and placebo. CONCLUSION: Celecoxib-tramadol co-crystal was associated with reduced rescue medication use and an acceptable tolerability profile compared with tramadol or celecoxib alone in adults with acute, moderate-to-severe, postoperative pain.

Leveraging a Longitudinally Linked Dataset to Assess Recurrence of Severe Maternal Morbidity.

OBJECTIVES: Among those with a severe maternal morbidity (SMM) event and a subsequent birth, we examined how the risk of a second SMM event varied by patient characteristics and intrapartum hospital utilization. METHODS: We used a Massachusetts population-based dataset that longitudinally linked in-state births, hospital discharge records, prior and subsequent births, and non-birth-related hospital utilizations for birthing individuals and their children from January 1, 1999, to December 31, 2018, representing 1,460,514 births by 907,530 birthing people. We restricted our study sample to 2,814 people who had their first SMM event associated with a singleton birth and gave birth a second time within the study period. Our outcome measure was recurrence of SMM in the second birth. We calculated the prevalence of SMM at second birth, compared SMM conditions between births, and estimated the adjusted risk ratios and 95% confidence intervals for having an SMM event at second birth among those who had an SMM at the first birth. We also examined overall hospital utilization including inpatient admissions, emergency room visits, and observational stays, and hospital utilization by interpregnancy intervals (IPIs) between the first and second birth. RESULTS: There were 2,814 birthing people with at least one birth after the first SMM singleton birth. Among those, 198 (7.0%) had a subsequent SMM. The percentage of people with a second SMM event varied by age, race/ethnicity, insurance, IPI, and history of hypertension at first case of SMM (all p < .05). Between births, people with a second SMM event had significantly higher proportions of inpatient admissions (60.1% vs. 33.2.0%; p < .001), emergency room visits (71.7% vs. 57.7%; p < .001), and observational stays (35.4% vs. 19.5%; p < .001) compared with those who did not experience a second SMM event. CONCLUSION: Hospital utilization after a birth with SMM might indicate an elevated risk of a second SMM event. Providers should counsel their patients about prevention and warning signs.

Efficacy of Co-Crystal of Tramadol-Celecoxib (CTC) in Patients with Acute Moderate-to-Severe Pain: A Pooled Analysis of Data from Two Phase 3 Randomized Clinical Trials.

BACKGROUND AND OBJECTIVES: New acute pain medications are needed that provide effective analgesia while minimizing side effects and opioid exposure. Clinical trials of co-crystal of tramadol-celecoxib (CTC) have demonstrated an improved benefit/risk profile versus tramadol or celecoxib alone. We pooled data from two phase 3 clinical trials to evaluate the efficacy of CTC 200 mg twice daily (BID) in acute moderate-to-severe pain. METHODS: Efficacy data were pooled from STARDOM1 [acute pain following oral surgery (NCT02982161)] and ESTEVE-SUSA-301 [acute pain following bunionectomy (NCT03108482)]. The primary efficacy outcome was sum of pain intensity difference from 0 to 48 h (SPID0-48). RESULTS: A total of 344 patients received CTC 200 mg BID, 342 received tramadol 50 or 100 mg four times a day, 181 received celecoxib 100 mg BID, and 172 received placebo. The least-squares mean difference in SPID0-48 was -21.8 (p = 0.002) for CTC versus tramadol and -72.8 (p < 0.001) for CTC versus placebo. A similar pattern of SPID0-48 was observed with CTC versus comparator whether patients had moderate or severe pain at baseline. Reduction in pain intensity was faster and reached mild intensity earlier with CTC versus comparators. Patients were significantly (p ≤ 0.005) less likely to receive rescue medication within 4 or 48 h with CTC compared with tramadol or placebo. CONCLUSIONS: This pooled analysis reinforces the efficacy profile of CTC versus tramadol and, given that CTC permits lower daily tramadol dosing and thereby reduces unnecessary opioid use, this highlights its improved benefit/risk profile and its potential for the management of moderate-to-severe pain.

Talazoparib in Patients With Solid Tumors With BRCA1/2 Mutation: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with various solid tumors with germline or somatic BRCA1/2 mutations treated with talazoparib are reported. METHODS: Eligible patients had advanced solid tumors, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Patients with germline BRCA-mutated human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer were not eligible for this study. Primary end point was disease control (DC) determined by investigator assessment of objective response (OR) or stable disease (SD) of at least 16 weeks duration (SD16+). The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = 0.82; α = .10). Secondary end points were OR, progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS: Twenty-eight patients (20 cancer types) with BRCA1/2 mutations were enrolled from December 2019 to September 2021 and collapsed into a single histology pooled cohort for analysis. All patients were evaluable for efficacy. One complete response, nine partial response, and six SD16+ were observed for DC and OR rates of 57% (one-sided 90% CI, 43 to 100) and 36% (95% CI, 19 to 56), respectively. The null hypothesis of a 15% DC rate was rejected (P < .001). Patients with OR had the following tumor types: breast (2), nonmelanoma skin, mesothelioma, stomach, uterus, non-small cell lung cancer, ovary, hepatocellular carcinoma, and pancreas. Thirteen patients had at least one grade 3-5 adverse event (AE) or serious AE at least possibly related to talazoparib. All were consistent with the drug label except bilirubin increase and hyponatremia (both grade 3 AEs). CONCLUSION: Talazoparib demonstrated antitumor activity in patients with advanced solid tumors and BRCA1/2 mutations, including cancer types for which poly ADP-ribose polymerase inhibitors are not yet US Food and Drug Administration-approved.

Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP, DSP, and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Structural characterization of strawberry pomace.

Strawberries are a nutrient dense food rich in vitamins, minerals, non-nutrient antioxidant phenolics, and fibers. Strawberry fiber bioactive structures are not well characterized and limited information is available about the interaction between strawberry fiber and phenolics. Therefore, we analyzed commercial strawberry pomace in order to provide a detailed carbohydrate structural characterization, and to associate structures with functions. The pomace fraction, which remained after strawberry commercial juice extraction, contained mostly insoluble (49.1 % vs. 5.6 % soluble dietary fiber) dietary fiber, with pectin, xyloglucan, xylan, ß-glucan and glucomannan polysaccharides; glucose, fructose, xylose, arabinose, galactose, fucose and galacturonic acid free carbohydrates; protein (15.6 %), fat (8.34 %), and pelargonidin 3-glucoside (562 µg/g). Oligosaccharides from fucogalacto-xyloglucan, methyl-esterified rhamnogalacturonan I with branched arabinogalacto-side chains, rhamnogalacturonan II, homogalacturonan and ß-glucan were detected by MALDI-TOF MS, NMR and glycosyl-linkage analysis. Previous reports suggest that these oligosaccharide and polysaccharide structures have prebiotic, bacterial pathogen anti-adhesion, and cholesterol-lowering activity, while anthocyanins are well-known antioxidants. A strawberry pomace microwave acid-extracted (10 min, 80 °C) fraction had high molar mass (2376 kDa) and viscosity (3.75 dL/g), with an extended rod shape. A random coil shape, that was reported previously to bind to phenolic compounds, was observed for other strawberry microwave-extracted fractions. These strawberry fiber structural details suggest that they can thicken foods, while the polysaccharide and polyphenol interaction indicates great potential as a multiple-function bioactive food ingredient important for gut and metabolic health.

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Pertuzumab Plus Trastuzumab in Patients With Biliary Tract Cancer With ERBB2/3 Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with biliary tract cancer (BTC) with ERBB2/3 amplification, overexpression, or mutation treated with pertuzumab plus trastuzumab are reported. METHODS: Eligible patients had advanced BTC, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with ERBB2/3 alterations, and a lack of standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16+ weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Twenty-nine patients were enrolled from February 2017 to January 2022, and all had advanced BTC with an ERBB2/3 alteration. One patient was not evaluable for efficacy. One complete response, eight partial responses, and two SD16+ were observed for DC and OR rates of 40% (90% CI, 27 to 100) and 32% (95% CI, 16 to 52), respectively. The null hypothesis of 15% DC rate was rejected (P = .0015). Four patients had at least one grade 3 adverse event (AE) or serious AE at least possibly related to treatment: anemia, diarrhea, infusion-related reaction, and fatigue. CONCLUSION: Pertuzumab plus trastuzumab met prespecified criteria to declare a signal of activity in patients with BTC and ERBB2/3 amplification, overexpression, or mutation.

Neural dynamics of robust legged robots.

Legged robot control has improved in recent years with the rise of deep reinforcement learning, however, much of the underlying neural mechanisms remain difficult to interpret. Our aim is to leverage bio-inspired methods from computational neuroscience to better understand the neural activity of robust robot locomotion controllers. Similar to past work, we observe that terrain-based curriculum learning improves agent stability. We study the biomechanical responses and neural activity within our neural network controller by simultaneously pairing physical disturbances with targeted neural ablations. We identify an agile hip reflex that enables the robot to regain its balance and recover from lateral perturbations. Model gradients are employed to quantify the relative degree that various sensory feedback channels drive this reflexive behavior. We also find recurrent dynamics are implicated in robust behavior, and utilize sampling-based ablation methods to identify these key neurons. Our framework combines model-based and sampling-based methods for drawing causal relationships between neural network activity and robust embodied robot behavior.

Asthma control in the United States: relationships between short-acting ß2-agonist and systemic corticosteroid use.

BACKGROUND: Asthma control assessment is based on impairment (current symptoms) and risk (exacerbation history). OBJECTIVE: To understand the extent of uncontrolled asthma, we assessed relationships between prescription fills for systemic corticosteroids (SCS) and short-acting ß2-agonists (SABA) as risk and impairment markers, respectively. METHODS: Annual SCS and SABA fills among US patients with asthma were evaluated by a retrospective analysis of IQVIA Longitudinal Access and Adjudication Data. Patient severity was assigned based on GINA step-therapy level. Exacerbations were evaluated by SCS fills within 12 months of a first asthma prescription fill. Uncontrolled asthma was defined as ≥2 SCS and/or ≥3 SABA fills annually. Individual patient relationships between SCS and SABA fills were assessed by Pearson's correlation coefficient. RESULTS: 4,506,527 patients were included: 15% had ≥2 SCS fills, 29% had ≥3 SABA fills, 37% fulfilled either or both criteria. If only SCS were assessed, 22% treated as mild-to-moderate and 27% as severe asthma would have been misclassified as controlled. If only SABA use was evaluated, 8% treated as mild-to-moderate and 11% as severe asthma would have been misclassified. Overall, 81% of uncontrolled asthma occurred in patients treated for mild-to-moderate disease. Among patients with ≥2 SCS fills, mean SABA fills were 2.9; the correlation between SCS and SABA fills per patient was significant but weak (r=0.18; p<0.001). CONCLUSION: High symptom burden and SCS exposures are not limited to severe asthma but are also characteristic in patients treated for mild-to-moderate disease. Both impairment and risk assessments are required to understand the full extent of uncontrolled asthma across disease severities.

Multivariate Cluster Analyses to Characterize Asthma Heterogeneity and Benralizumab Responsiveness.

BACKGROUND: An improved understanding of how severe asthma heterogeneity affects response could inform treatment decisions. OBJECTIVES: Characterize heterogeneity and benralizumab responsiveness in patients grouped by predefined Severe Asthma Research Program clusters using a multivariate approach. METHODS: In post-hoc analyses of the randomized, double-blind, placebo-controlled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) studies, patients with severe asthma who received benralizumab or placebo were assigned to clusters using an established discriminant function to analyze 11 clinical characteristics simultaneously. The annualized asthma exacerbation rate, exacerbation incidence, and lung function were analyzed across clusters. RESULTS: Patients (n = 2,281) met criteria for four of five clusters: cluster 2 (early-onset moderate asthma, n = 393), cluster 4 (early-onset severe asthma, n = 386), cluster 3 (late-onset severe asthma, n = 641), and cluster 5 (late-onset severe, obstructed asthma, n = 861); no patients met cluster 1 criteria. Exacerbation rate reductions were significant in late-onset severe asthma (-48% [95% CI, -61% to -31%]; P < .0001) and late-onset severe, obstructed asthma (-50% [95% CI, -59% to -38%]; P < .0001), with nonsignificant reductions in early-onset clusters. These differences could not be fully explained by blood eosinophil count differences. Values for improvements in FEV1 were significant in late-onset severe asthma (+133 mL [95% CI, 66-200]; P = .0001) and late-onset severe, obstructed asthma (+160 mL [95% CI, 85-235]; P < .0001) while maintaining acute bronchodilator responsiveness. CONCLUSIONS: Benralizumab reduced exacerbations and improved lung function, primarily in late-onset asthma clusters. This multivariate approach to identify subphenotypes, potentially reflecting pathobiological mechanisms, can guide therapy beyond univariate approaches.

A novel DNase assay reveals low DNase activity in severe asthma.

Secreted deoxyribonucleases (DNases), such as DNase-I and DNase-IL3, degrade extracellular DNA, and endogenous DNases have roles in resolving airway inflammation and guarding against autoimmune responses to nucleotides. Subsets of patients with asthma have high airway DNA levels, but information about DNase activity in health and in asthma is lacking. To characterize DNase activity in health and in asthma, we developed a novel kinetic assay using a Taqman probe sequence that is quickly cleaved by DNase-I to produce a large product signal. We used this kinetic assay to measure DNase activity in sputum from participants in the Severe Asthma Research Program (SARP)-3 (n = 439) and from healthy controls (n = 89). We found that DNase activity was lower than normal in asthma [78.7 relative fluorescence units (RFU)/min vs. 120.4 RFU/min, P < 0.0001]. Compared to patients with asthma with sputum DNase activity in the upper tertile activity levels, those in the lower tertile of sputum DNase activity were characterized clinically by more severe disease and pathologically by airway eosinophilia and airway mucus plugging. Carbamylation of DNase-I, a post-translational modification that can be mediated by eosinophil peroxidase, inactivated DNase-I. In summary, a Taqman probe-based DNase activity assay uncovers low DNase activity in the asthma airway that is associated with more severe disease and airway mucus plugging and may be caused, at least in part, by eosinophil-mediated carbamylation.NEW & NOTEWORTHY We developed a new DNase assay and used it to show that DNase activity is impaired in asthma airways.

Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma.

BACKGROUND: The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain. OBJECTIVE: We sought to determine the utility of EPX as a biomarker of systemic and airway eosinophilic inflammation in asthma. METHODS: EPX protein was measured by immunoassay in serum and sputum in 110 healthy controls to establish a normal reference range and in repeated samples of serum and sputum collected during 3 years of observation in 480 participants in the Severe Asthma Research Program 3. RESULTS: Over 3 years, EPX levels in patients with asthma were higher than normal in 27% to 31% of serum samples and 36% to 53% of sputum samples. Eosinophils and EPX correlated better in blood than in sputum (rs values of 0.74 and 0.43, respectively), and high sputum EPX levels occurred in 27% of participants with blood eosinophil counts less than 150 cells/µL and 42% of participants with blood eosinophil counts between 150 and 299 cells/µL. Patients with persistently high sputum EPX values for 3 years were characterized by severe airflow obstruction, frequent exacerbations, and high mucus plug scores. In 59 patients with asthma who started mepolizumab during observation, serum EPX levels normalized in 96% but sputum EPX normalized in only 49%. Lung function remained abnormal even when sputum EPX normalized. CONCLUSIONS: Serum EPX is a valid protein biomarker of systemic eosinophilic inflammation in asthma, and sputum EPX levels are a more sensitive biomarker of airway eosinophilic inflammation than sputum eosinophil counts. Eosinophil measures in blood frequently miss airway eosinophilic inflammation, and mepolizumab frequently fails to normalize airway eosinophilic inflammation even though it invariably normalizes systemic eosinophilic inflammation.

Novel Machine Learning Identifies 5 Asthma Phenotypes Using Cluster Analysis of Real-World Data.

BACKGROUND: Asthma classification into different subphenotypes is important to guide personalized therapy and improve outcomes. OBJECTIVES: To further explore asthma heterogeneity through determination of multiple patient groups by using novel machine learning (ML) approaches and large-scale real-world data. METHODS: We used electronic health records of patients with asthma followed at the Cleveland Clinic between 2010 and 2021. We used k-prototype unsupervised ML to develop a clustering model where predictors were age, sex, race, body mass index, prebronchodilator and postbronchodilator spirometry measurements, and the usage of inhaled/systemic steroids. We applied elbow and silhouette plots to select the optimal number of clusters. These clusters were then evaluated through LightGBM's supervised ML approach on their cross-validated F1 score to support their distinctiveness. RESULTS: Data from 13,498 patients with asthma with available postbronchodilator spirometry measurements were extracted to identify 5 stable clusters. Cluster 1 included a young nonsevere asthma population with normal lung function and higher frequency of acute exacerbation (0.8 /patient-year). Cluster 2 had the highest body mass index (mean ± SD, 44.44 ± 7.83 kg/m2), and the highest proportion of females (77.5%) and Blacks (28.9%). Cluster 3 comprised patients with normal lung function. Cluster 4 included patients with lower percent of predicted FEV1 of 77.03 (12.79) and poor response to bronchodilators. Cluster 5 had the lowest percent of predicted FEV1 of 68.08 (15.02), the highest postbronchodilator reversibility, and the highest proportion of severe asthma (44.9%) and blood eosinophilia (>300 cells/µL) (34.8%). CONCLUSIONS: Using real-world data and unsupervised ML, we classified asthma into 5 clinically important subphenotypes where group-specific asthma treatment and management strategies can be designed and deployed.

Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses.

Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. Results: Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed. Conclusions: Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure. Clinical trial number: NCT03780543. Impact and implications: Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir.

Sunitinib in Patients With Breast Cancer With FGFR1 or FGFR2 Amplifications or Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results from cohorts of patients with metastatic breast cancer (BC) with FGFR1 and FGFR2 alterations treated with sunitinib are reported. METHODS: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16 weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Forty patients with BC with FGFR1 (N = 30; amplification only n = 26, mutation only n = 1, both n = 3) or FGFR2 (N = 10; amplification only n = 2, mutation only n = 6, both n = 2) alterations were enrolled. Three patients in the FGFR1 cohort were not evaluable for efficacy; all patients in the FGFR2 cohort were evaluable. For the FGFR1 cohort, two patients with partial response and four with SD16+ were observed for DC and OR rates of 27% (90% CI, 13 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected (P = .169). No patients achieved DC in the FGFR2 cohort (P = 1.00). Thirteen of the 40 total patients across both cohorts had at least one grade 3-4 adverse event or serious adverse event at least possibly related to sunitinib. CONCLUSION: Sunitinib did not meet prespecified criteria to declare a signal of antitumor activity in patients with BC with either FGFR1 or FGFR2 alterations. Other treatments and clinical trials should be considered for these patient populations.