SzM protein of Streptococcus equi ssp. zooepidemicus triggers the release of neutrophil extracellular traps depending on GSDMD.

Streptococcus equissp.zooepidemicus (SEZ) is a crucial pathogen and contributes to various infections in numerous animal species. Swine streptococcicosis outbreak caused by SEZ has been reported in several countries in recent years. SzM protein is a cell membrane-anchored protein, which exhibits as an important virulence factor of SEZ. Effects of SzM protein on host innate immune need further study. Here, recombinant SzM (rSzM) protein of the SEZ was obtained, and mice were intraperitoneally injected with rSzM protein. We discovered that rSzM protein can recruit neutrophils into the injected site. In further study, neutrophils were isolated and treated with rSzM protein, NETs release were triggered by rSzM protein independently, and GSDMD protein was promoted-expressed and activated. In order to investigate the role of GSDMD in NETs formation, neutrophils isolated from WT mice and GSDMD-/- mice were treated with rSzM protein. The results showed that GSDMD deficiency suppressed the NETs release. In conclusion, SzM protein of SEZ can trigger the NETs release in a GSDMD-depending manner.

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond.

On October 24, 2016, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda; Merck & Co., Inc., https://www.merck.com) for treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test, as follows: (a) first-line treatment of patients with mNSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS] ≥50%), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, and (b) treatment of patients with mNSCLC whose tumors express PD-L1 (TPS ≥1%), with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.Approval was based on two randomized, open-label, active-controlled trials demonstrating statistically significant improvements in progression-free survival (PFS) and overall survival (OS) for patients randomized to pembrolizumab compared with chemotherapy. In KEYNOTE-024, patients with previously untreated mNSCLC who received pembrolizumab (200 mg intravenously [IV] every 3 weeks) had a statistically significant improvement in OS (hazard ratio [HR] 0.60; 95% confidence interval [CI]: 0.41-0.89; p = .005), and significant improvement in PFS (HR 0.50; 95% CI: 0.37-0.68; p < .001). In KEYNOTE-010, patients with disease progression on or after platinum-containing chemotherapy received pembrolizumab IV 2 mg/kg, 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The HR and p value for OS was 0.71 (95% CI: 0.58-0.88), p < .001 comparing pembrolizumab 2 mg/kg with chemotherapy and the HR and p value for OS was 0.61 (95% CI: 0.49-0.75), p < .001 comparing pembrolizumab 10 mg/kg with chemotherapy. IMPLICATIONS FOR PRACTICE: This is the first U.S. Food and Drug Administration approval of a checkpoint inhibitor for first-line treatment of lung cancer. This approval expands the pembrolizumab indication in second-line treatment of lung cancer to include all patients with programmed death-ligand 1-expressing non-small cell lung cancer.

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy.

On August 5, 2016, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA injection, Merck Sharp & Dohme Corp., Kenilworth, NJ) for treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. Approval was based on the objective response rate (ORR) and duration of response (DoR) in a cohort of patients in a nonrandomized multi-cohort trial (KEYNOTE-012) that included 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy. Patients received either intravenous pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks. ORR was determined by independent review according to Response Evaluation Criteria in Solid Tumors 1.1. ORR was 16% (95% confidence interval 11, 22) with a complete response rate of 5%. DoR ranged from 2.4+ months to 27.7+ months. Twenty-three of 28 responding patients (82%) had response durations of ≥6 months. Safety was evaluated in 192 patients with HNSCC receiving at least one dose of pembrolizumab. Frequent (≥2%) serious adverse reactions were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus, skin toxicity, myositis, and thyroid disorders. The benefit-risk profile of pembrolizumab was considered acceptable in this patient population. As a condition of accelerated approval, Merck is required to conduct a confirmatory trial; this trial, KEYNOTE-040, is ongoing. IMPLICATIONS FOR PRACTICE: This accelerated approval expands the U.S. Food and Drug Administration-approved indications for pembrolizumab, providing health care providers with new information regarding pembrolizumab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. Pembrolizumab is the first drug to receive approval for treatment of patients with HNSCC since cetuximab was approved for this indication in 2006.

Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response.

Pembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL. Overall results indicate that CL decreases over the treatment period of a typical patient in a pattern well described by a sigmoidal function of time with three parameters: the maximum proportion change in CL from baseline (approximately Imax or exactly eImax - 1), the time to reach Imax/2 (TI50), and a Hill coefficient. Best overall response per response evaluation criteria in solid tumor category was found to be associated with the magnitude of Imax.

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling.

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.

Computational approaches to analyse and predict small molecule transport and distribution at cellular and subcellular levels.

Quantitative structure-activity relationship (QSAR) studies and mechanistic mathematical modeling approaches have been independently employed for analysing and predicting the transport and distribution of small molecule chemical agents in living organisms. Both of these computational approaches have been useful for interpreting experiments measuring the transport properties of small molecule chemical agents, in vitro and in vivo. Nevertheless, mechanistic cell-based pharmacokinetic models have been especially useful to guide the design of experiments probing the molecular pathways underlying small molecule transport phenomena. Unlike QSAR models, mechanistic models can be integrated from microscopic to macroscopic levels, to analyse the spatiotemporal dynamics of small molecule chemical agents from intracellular organelles to whole organs, well beyond the experiments and training data sets upon which the models are based. Based on differential equations, mechanistic models can also be integrated with other differential equations-based systems biology models of biochemical networks or signaling pathways. Although the origin and evolution of mathematical modeling approaches aimed at predicting drug transport and distribution has occurred independently from systems biology, we propose that the incorporation of mechanistic cell-based computational models of drug transport and distribution into a systems biology modeling framework is a logical next step for the advancement of systems pharmacology research.

Neutrophil accumulation raises defence against Streptococcus equi ssp. zooepidemicus in the absence of Gasdermin D.

Streptococcus equi ssp. zooepidemicus (SEZ) predominantly acts as a zoonotic pathogen, capable of infecting a diverse range of animal species including human. Gasdermin D (GSDMD) exhibited comprehensive functions in host against different pathogenic microorganism. This study aimed to investigate the role of GSDMD in host against SEZ. Mice were administrated with SEZ via intranasal intubation for 24 h (3 × 106CFU), GSDMD protein expression significantly increased in the lung tissue of mice infected with SEZ. For further research on the role of GSDMD during SEZ infection, GSDMD-/- mice and WT mice were treated with SEZ via intranasal intubation for 24 h (3 × 106CFU). GSDMD-/- mice showed less severe lung tissue due to fewer bacteria colonization. Numerous neutrophils were recruited into lung tissues in GSDMD-/- mice, related to the release of CXCL1 and CXCL2 regulated by p65 phosphorylation. In further study, neutrophils of WT and GSDMD-/- mice were isolated and treated with SEZ (multiplicity of infection, MOI = 10, 4 h). The absence of GSDMD alleviated the death of neutrophils, in addition, GSDMD deficiency could promote translocation of p65 from the cytoplasm into the nucleus in neutrophil, which may contribute to the release of IL-1ß and TNF-α. This study demonstrated a novel function of GSDMD in host immune response to SEZ invading, indicating that GSDMD deficiency ameliorated SEZ infection through enhancing neutrophil accumulation into infected site, and activating NF-κB pathway in neutrophil to release cytokines against SEZ. Our study suggested that inhibition of host GSDMD may be an effective method against SEZ.

Extracellular vesicles from neural stem cells safeguard neurons in intracerebral hemorrhage by suppressing reactive astrocyte neurotoxicity.

Extracellular vesicles (EVs) derived from stem cells have shown therapeutic potential in various diseases, but their use in treating neurological disorders remains limited. In this study, we observed neurotoxic activation of reactive astrocytes and lipoapoptosis pathways in both mice and patients with intracerebral hemorrhage (ICH) and found that EVs derived from neural stem cells (EVs-NSC) could suppress this activation. Using loss- and gain-of-function approaches, we identified interferon-ß (IFNß) as a key regulator in neurotoxic activation of astrocytes. In addition, we demonstrated that the microRNA (miRNA) miR-124-3p within EVs-NSC degrades IFNß mRNA and inhibits ELOVL1 expression via miRNA-coding sequence (CDS) and miRNA-3' UTR binding mechanisms, respectively. This dual action likely reduces astrocyte neurotoxicity by lowering saturated lipid secretion. These mechanisms enable EVs-NSC or miR-124-3p overexpression to inhibit astrocyte neurotoxicity, reduce neural damage, and promote recovery in ICH models, offering strategies for treating neurological disorders by targeting neurotoxic reactive astrocytes.

FDA Approval Summary: Enfortumab Vedotin plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma.

On December 15, 2023, the FDA granted traditional approval to enfortumab vedotin-ejfv plus pembrolizumab (EV + Pembro) for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Substantial evidence of effectiveness was obtained from EV-302/KEYNOTE-A39 (NCT04223856), an open-label, randomized trial evaluating EV + Pembro versus cisplatin or carboplatin plus gemcitabine (Plat + Gem) in patients with previously untreated la/mUC. A total of 886 patients were randomized (1:1) to receive EV 1.25 mg/kg intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity plus Pembro 200 mg intravenously on day 1 of each 21-day cycle for up to 35 cycles or Plat + Gem for up to 6 cycles. Dual primary endpoints were progression-free survival determined by blinded independent central review and overall survival. The median progression-free survival was 12.5 months [95% confidence interval (CI), 10.4-16.6] in the EV + Pembro arm and 6.3 months (95% CI, 6.2-6.5) in the Plat + Gem arm [HR, 0.450 (95% CI, 0.377-0.538); P value < 0.0001]. The median overall survival was 31.5 months (95% CI, 25.4-not estimable) in the EV + Pembro arm and 16.1 months (95% CI, 13.9-18.3) in the Plat + Gem arm [HR, 0.468 (95% CI, 0.376-0.582); P value < 0.0001]. The safety profile of EV + Pembro was similar to that observed in EV-103/KEYNOTE-869 in cisplatin-ineligible patients with la/mUC. This article summarizes the data and the FDA thought process supporting traditional approval of EV + Pembro, as well as additional exploratory analyses conducted by the FDA.

A cell-based computational modeling approach for developing site-directed molecular probes.

Modeling the local absorption and retention patterns of membrane-permeant small molecules in a cellular context could facilitate development of site-directed chemical agents for bioimaging or therapeutic applications. Here, we present an integrative approach to this problem, combining in silico computational models, in vitro cell based assays and in vivo biodistribution studies. To target small molecule probes to the epithelial cells of the upper airways, a multiscale computational model of the lung was first used as a screening tool, in silico. Following virtual screening, cell monolayers differentiated on microfabricated pore arrays and multilayer cultures of primary human bronchial epithelial cells differentiated in an air-liquid interface were used to test the local absorption and intracellular retention patterns of selected probes, in vitro. Lastly, experiments involving visualization of bioimaging probe distribution in the lungs after local and systemic administration were used to test the relevance of computational models and cell-based assays, in vivo. The results of in vivo experiments were consistent with the results of in silico simulations, indicating that mitochondrial accumulation of membrane permeant, hydrophilic cations can be used to maximize local exposure and retention, specifically in the upper airways after intratracheal administration.

The extracellular microenvironment explains variations in passive drug transport across different airway epithelial cell types.

PURPOSE: We sought to identify key variables in cellular architecture and physiology that might explain observed differences in the passive transport properties of small molecule drugs across different airway epithelial cell types. METHODS: Propranolol (PR) was selected as a weakly basic, model compound to compare the transport properties of primary (NHBE) vs. tumor-derived (Calu-3) cells. Differentiated on Transwell™ inserts, the architecture of pure vs. mixed cell co-cultures was studied with confocal microscopy followed by quantitative morphometric analysis. Cellular pharmacokinetic modeling was used to identify parameters that differentially affect PR uptake and transport across these two cell types. RESULTS: Pure Calu-3 and NHBE cells possessed different structural and functional properties. Nevertheless, mixed Calu-3 and NHBE cell co-cultures differentiated as stable cell monolayers. After measuring the total mass of PR, the fractional areas covered by Calu-3 and NHBE cells allowed deconvoluting the transport properties of each cell type. Based on the apparent thickness of the unstirred, cell surface aqueous layer, local differences in the extracellular microenvironment explained the measured variations in passive PR uptake and permeation between Calu-3 and NHBE cells. CONCLUSION: Mixed cell co-cultures can be used to compare the local effects of the extracellular microenvironment on drug uptake and transport across two epithelial cell types.

Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer.

The inhibitors of apoptosis proteins (IAPs) are a class of key apoptosis regulators overexpressed or dysregulated in cancer. SM-406/AT-406 is a potent and selective small molecule mimetic of Smac that antagonizes the inhibitor of apoptosis proteins (IAPs). A physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model was developed to predict the tissue concentration-time profiles of SM-406, the related onco-protein levels in tumor, and the tumor growth inhibition in a mouse model bearing human breast cancer xenograft. In the whole body physiologically based pharmacokinetic (PBPK) model for pharmacokinetics characterization, a well stirred (perfusion rate-limited) model was used to describe SM-406 pharmacokinetics in the lung, heart, kidney, intestine, liver and spleen, and a diffusion rate-limited (permeability limited) model was used for tumor. Pharmacodynamic (PD) models were developed to correlate the SM-406 concentration in tumor to the cIAP1 degradation, pro-caspase 8 decrease, CL-PARP accumulation and tumor growth inhibition. The PBPK-PD model well described the experimental pharmacokinetic data, the pharmacodynamic biomarker responses and tumor growth. This model may be helpful to predict tumor and plasma SM-406 concentrations in the clinic.

Gene Therapy Strategies Targeting Aging-Related Diseases.

Rapid advancements have taken place in gene therapy technology. However, effective methods for treating aging- or age-related chronic diseases, which are often closely related to genes or even multiple genes, are still lacking. The path to developing cures is winding, while gene therapy that targets genes related to aging represents an exciting research direction with tremendous potential. Among aging-related genes, some candidates have been studied at different levels, from cell to organismal levels (e.g., mammalian models) with different methods, from overexpression to gene editing. The TERT and APOE have even entered the stage of clinical trials. Even those displaying only a preliminary association with diseases have potential applications. This article discusses the foundations and recent breakthroughs in the field of gene therapy, providing a summary of current mainstream strategies and gene therapy products with clinical and preclinical applications. Finally, we review representative target genes and their potential for treating aging or age-related diseases.

Model-Informed Approaches to Support Drug Development for Patients With Obesity: A Regulatory Perspective.

Obesity, which is defined as having a body mass index of 30 kg/m2 or greater, has been recognized as a serious health problem that increases the risk of many comorbidities (eg, heart disease, stroke, and diabetes) and mortality. The high prevalence of individuals who are classified as obese calls for additional considerations in clinical trial design. Nevertheless, gaining a comprehensive understanding of how obesity affects the pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of drugs proves challenging, primarily as obese patients are seldom selected for enrollment at the early stages of drug development. Over the past decade, model-informed drug development (MIDD) approaches have been increasingly used in drug development programs for obesity and its related diseases as they use and integrate all available sources and knowledge to inform and facilitate clinical drug development. This review summarizes the impact of obesity on PK, PD, and the efficacy of drugs and, more importantly, provides an overview of the use of MIDD approaches in drug development and regulatory decision making for patients with obesity: estimating PK, PD, and efficacy in specific dosing scenarios, optimizing dose regimen, and providing evidence for seeking new indication(s). Recent review cases using MIDD approaches to support dose selection and provide confirmatory evidence for effectiveness for patients with obesity, including pediatric patients, are discussed. These examples demonstrate the promise of MIDD as a valuable tool in supporting clinical trial design during drug development and facilitating regulatory decision-making processes for the benefit of patients with obesity.

Engineered Extracellular Vesicle-Delivered CRISPR/CasRx as a Novel RNA Editing Tool.

Engineered extracellular vesicles (EVs) are considered excellent delivery vehicles for a variety of therapeutic agents, including nucleic acids, proteins, drugs, and nanomaterials. Recently, several studies have indicated that clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) delivered by EVs enable efficient DNA editing. However, an RNA editing tool delivered by EVs is still unavailable. Here, a signal peptide-optimized and EVs-delivered guide RNA (gRNA) and CRISPR/CasRx (Cas13d) system capable of rapidly inhibiting the expression of targeted genes with quick catabolism after performing their functions is developed. EVs with CRISPR/CasRx and tandem gRNAs targeting pivotal cytokines are further packed whose levels increase substantially over the course of acute inflammatory diseases and find that these engineered EVs inhibit macrophage activation in vitro. More importantly, this system attenuates lipopolysaccharide (LPS)-triggered acute lung injury and sepsis in the acute phase, mitigating organ damage and improving the prognosis in vivo. In summary, a potent tool is provided for short-acting RNA editing, which could be a powerful therapeutic platform for the treatment of acute diseases.

FDA Approval Summary: Mirvetuximab Soravtansine-Gynx for FRα-Positive, Platinum-Resistant Ovarian Cancer.

On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9-41.6] with a median duration of response of 6.9 months (95% CI, 5.6-9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx.

Older Adults' Access to and Satisfaction With Primary Hospitals Based on Spatial and Non-spatial Analyses.

In order to improve the health and quality of life of older adults, the Chinese government is dedicated to establishing an equilibrium level of primary healthcare services for all communities. However, little attention has been paid to measuring the accessibility of primary hospitals to older adults, nor to understanding the seniors' satisfaction with and needs for primary healthcare services. Therefore, this study sought to investigate the spatial accessibility of primary hospitals to older adults, and also to examine the impact of walking distances on the seniors' satisfaction with their healthcare services. A two-step floating catchment area method was applied to measure the spatial accessibility of primary hospitals to older adults at the level of subdistricts. In order to investigate the actual opinions of older adults and verify the results of spatial analysis, a large-scale questionnaire survey was also conducted. The analyses found that (1) primary hospitals were not equally distributed; (2) most older adults did not have access to primary hospitals within a threshold walking distance of 1,000 m, but they usually could reach a hospital in their subdistrict within a threshold distance of 2,000 m; (3) older adults' satisfaction levels with primary hospitals were significantly different among subdistricts; (4) long walking distances negatively influenced older adults' satisfaction with primary hospitals; (5) the satisfaction of older adults was highest with a threshold distance of 500 m; and (6) a piecewise regression model indicated that older adults' satisfaction with primary hospitals would decrease with an increase in walking distance to the hospital. When the walking distances exceeded 1,000 m, the slope of the linear regression model increased significantly compared with the slope for walking distances less than 1,000 m. By adopting multiple research methods and capturing older adults' behaviors and satisfaction, our results provide (1) data on the importance of accessibility of primary hospitals to older adults, and (2) insights for future planning to achieve equity in primary healthcare and enhance the spatial distribution of primary hospitals.

Preliminary study on the effect of catabolite repression gene knockout on p-nitrophenol degradation in Pseudomonas putida DLL-E4.

P-nitrophenol (PNP) is a carcinogenic, teratogenic, and mutagenic compound that can cause serious harm to the environment. A strain of Pseudomonas putida DLL-E4, can efficiently degrade PNP in a complex process that is influenced by many factors. Previous studies showed that the expression level of pnpA, a key gene involved in PNP degradation, was upregulated significantly and the degradation of PNP was obviously accelerated in the presence of glucose. In addition, the expression of crc, crcY, and crcZ, key genes involved in catabolite repression, was downregulated, upregulated, and upregulated, respectively. To investigate the effect of the carbon catabolite repression (CCR) system on PNP degradation, the crc, crcY, and crcZ genes were successfully knocked out by conjugation experiments. Our results showed that the knockout of crc accelerated PNP degradation but slowed down the cell growth. However, the knockout of crcY or crcZ alone accelerated PNP degradation when PNP as the sole carbon source, but that knockout slowed down PNP degradation when glucose was added. The results indicate that the CCR system is involved in the regulation of PNP degradation, and further work is required to determine the details of the specific regulatory mechanism.

FDA Approval Summary: Tivozanib for Relapsed or Refractory Renal Cell Carcinoma.

On March 10, 2021, the FDA granted regular approval to tivozanib for treatment of patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Approval was based on the TIVO-3 study, a randomized trial of tivozanib versus sorafenib in patients with R/R advanced RCC. In TIVO-3, patients were randomized to receive either tivozanib 1.34 mg orally once daily for 21 consecutive days of every 28-day cycle or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival (PFS) per RECIST v1.1. Tivozanib demonstrated efficacy compared with sorafenib with an improvement in PFS [HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.016]. The estimated median PFS was 5.6 months and 3.9 months in the tivozanib and sorafenib arms, respectively. There was no evidence of a detrimental effect on overall survival: HR, 0.97 (95% CI, 0.75-1.24). The most common grade 3 to 4 adverse reaction on the tivozanib arm was hypertension (24%). Compared with sorafenib, tivozanib was associated with lower rates of grade 3 to 4 diarrhea, rash, and palmar-plantar erythrodysesthesia. Patients receiving tivozanib in TIVO-3 had lower rates of dose reduction, interruption, or permanent discontinuation than those receiving sorafenib.

FDA Approval Summary: Margetuximab plus Chemotherapy for Advanced or Metastatic HER2-Positive Breast Cancer.

On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59-0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.