Clinical Drug Development Research Articles

Analytical validation of OriMIRACLE S, a personalized and tumor-informed approach to minimal residual disease surveillance.

e15013 Background: The presence of minimal residual disease (MRD) after curative-intent therapies in solid tumors is recognized as a risk factor for relapse. Glycoprotein-based tumor markers lack sensitivity and specificity for clinical application. Circulating tumor DNA (ctDNA) based MRD detection which can identify disease relapse ahead of radiological imaging has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor-informed assay for MRD detection via plasma cell-free DNA. Methods: Tumor-specific somatic single nucleotide variants (SNVs) were identified by whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected by OriSelector algorithm for patient-specific multiplex PCR-based NGS assay for MRD tracking. The limit of detection (LOD), specificity, sensitivity, repeatability, and reproducibility of this assay were determined experimentally with a series of standard references and in silico. Standard references were developed as following for assessing assay performance. The somatic variant references were two commercialized standards each containing five positive sites at variant allele frequency [VAF] of 0.1% and 1%, and a wild type sample. The single nucleotide polymorphism (SNP) references were made by blending three gDNA samples (160 sites) with gDNA samples without these SNPs to VAFs of 0%, 0.005%, 0.01%, 0.02%, 0.05% and 0.1%. And cfDNA references were made by titrating the clinical cfDNA mixture from five patients containing 31 positive sites with mononucleosomal HEK293 DNA to VAFs of 0.01-0.3% and 0.1-3%. Results: Site level sensitivity of ctDNA samples were 68.8% to 100% with 10 to 50ng input ctDNA (3,000 to 15,000 haploid genome equivalents). Site level reproducibility and repeatability were 98.0% and 97.0% using somatic variant references, respectively. The detection of three positive sites was sufficient to achieve a nearly 100% overall sample level sensitivity and specificity (6,000 haploid genome equivalents of gDNA samples) determined either by calculating a binomial probability or in silico with customized panels have 21 to 30 variants. The LOD of this assay was as low as 0.01% with the algorithm of OriCleverClover which could filter process and sequencing-related artifacts. Conclusions: OriMIRACLE S has been analytically validated as a highly sensitive and specific method to detect low quantities of ctDNA in plasma. The low limit of detection at a VAF of only 0.01% with low DNA input. OriMIRACLE S has wide-ranging potential applications in the clinical setting and drug development in a real-world scenario.

Clinical trial and translational research for cancer immunology in Asian countries: Understanding the new frontier.

e14510 Background: Among the major advances in cancer treatment is the progress in cancer immunotherapy; however, despite the strides, there is few information specific to the Asian population. It is unclear to what extent clinical trial and translational research in cancer immunology are conducted in Asian institutions. Methods: This questionnaire-based survey was conducted among researchers and healthcare professionals who are involved in cancer immunology research and therapeutics in Asia-Pacific countries. The study identified the involvement of respondents in various phases of clinical trials, and immunotherapy research. In addition, the current capabilities of the institutions to conduct translational research were surveyed. Results: We received a total of 122 responses from 20 Asia-Pacific countries. More than half (58%) of the responders are currently conducting clinical trials on cancer immunology with 25% having performed more than 10 Phase 3 trials in the last 3 years. In clinical trials and clinical practice, immune checkpoint inhibitors were performed in most countries (81.8% and 88.6%, respectively). Clinical trials and clinical practice of CAR-T and TCR-T were performed only in some countries (CAR-T; 22.7% and 15.9%, TCR-T; 2.3% and 0%, respectively). In the absence of novel therapeutics in their institution, 18% of the responders refer their patient to facilities that have ongoing clinical trials. Among the institutions that perform Hematopoietic stem cell transplant (55.1%), the most common type offered include autologous (81.3%) and allogenic (70.8%) peripheral blood stem-cell transplantation. About 51.7% of the respondents have institutions that can conduct early drug phase development studies with only 11.2% capable of utilizing their own immunotherapeutic agents. Less than half of the respondents (40.7%) belong to institutions that have conducted translational researches using patient-derived samples for the last three years. Furthermore, more than half of the respondent institutions have no personnel that is experienced to handle and/or run patient-derived fresh peripheral blood or fresh tumors. Collaboration among neighboring countries can allow send out of specimens to other institutions that have such capability, however, 56.9% of countries have regulations or restrictions in transporting lymphocytes or tumor tissues. Conclusions: Oncologists and researchers in Asia recognize the importance of cancer immunology researches for patients. There were institutional and inter-country differences particularly in the conduct of early phase clinical drug development and translational research.

Review about Powerful Combinations of Advanced and Hyphenated Sample Introduction Techniques with Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) for Elucidating Trace Element Species in Pathologic Conditions on a Molecular Level.

Element analysis in clinical or biological samples is important due to the essential role in clinical diagnostics, drug development, and drug-effect monitoring. Particularly, the specific forms of element binding, actual redox state, or their spatial distribution in tissue or in single cells are of interest in medical research. This review summarized exciting combinations of sophisticated sample delivery systems hyphenated to inductively coupled plasma-mass spectrometry (ICP-MS), enabling a broadening of information beyond the well-established outstanding detection capability. Deeper insights into pathological disease processes or intracellular distribution of active substances were provided, enabling a better understanding of biological processes and their dynamics. Examples were presented from spatial elemental mapping in tissue, cells, or spheroids, also considering elemental tagging. The use of natural or artificial tags for drug monitoring was shown. In the context of oxidative stress and ferroptosis iron, redox speciation gained importance. Quantification methods for Fe2+, Fe3+, and ferritin-bound iron were introduced. In Wilson’s disease, free and exchangeable copper play decisive roles; the respective paragraph provided information about hyphenated Cu speciation techniques, which provide their fast and reliable quantification. Finally, single cell ICP-MS provides highly valuable information on cell-to-cell variance, insights into uptake of metal-containing drugs, and their accumulation and release on the single-cell level.

Surface-tethered electrochemical biosensor for telomerase detection by integration of homogeneous extension and hybridization reactions

The general electrochemical biosensors for telomerase detection require the immobilization of primers on the electrode surface for telomeric extension and hybridization reactions. However, immobilization of primers may suffer from the challenges of hindrance effect and configuration freedom, thus reducing the extension and hybridization efficiency. Herein, we developed a sensitive electrochemical biosensor for telomerase detection by integration of homogeneous extension and hybridization reactions and surface-tethered detection. In the presence of telomerase, the biotinylated primer (bio-primer) was efficiently elongated with telomeric repeats of (TTAGGG)n at the 3’ end in solution. Then, the extension product (bio-DNA) was hybridized with the signal probe DNA modified on the surface of ferrocene (Fc)-capped gold nanoparticle (AuNP). The bio-DNA/DNA/Fc-AuNP hybrids were then tethered by streptavidin-modified electrodes through the specific avidin-biotin interactions, thus producing strong electrochemical signals from the oxidation of Fc tags. The biosensor was successfully used to determine telomerase in HeLa cells and monitor the inhibition efficiency of inhibitor. A wide linear range for the detection of telomerase extracted from HeLa cells was attained. This method has great potential in clinical diagnosis and anti-cancer drug development, and should be beneficial for the fabrication of novel biosensors by integration of homogeneous catalysis and hybridization reactions.

Model-based dose selection to inform translational clinical oncology development of WNT974, a first-in-class Porcupine inhibitor.

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. A phase I clinical trial is being conducted in patients with advanced solid tumors. During the dose‐escalation part, various dosing regimens, including once or twice daily continuous and intermittent dosing at a dose range of 5–45 mg WNT974 were studied, however, the protocol‐defined maximum tolerated dose (MTD) was not established based on dose‐limiting toxicity. To assist in the selection of the recommended dose for expansion (RDE), a model‐based approach was utilized. It integrated population pharmacokinetic (PK) modeling and exposure–response analyses of a target‐inhibition biomarker, skin AXIN2 mRNA expression, and the occurrence of the adverse event, dysgeusia. The target exposure range of WNT974 that would provide a balance between target inhibition and tolerability was estimated based on exposure–response analyses. The dose that was predicted to yield an exposure within the target exposure range was selected as RDE. This model‐based approach integrated PK, biomarker, and safety data to determine the RDE and represented an alternative as opposed to the conventional MTD approach for selecting an optimal biological dose. The strategy can be broadly applied to select doses in early oncology trials and inform translational clinical oncology drug development.

Treatment Consideration in Postmenopausal Osteoporosis Patients at Imminent Fracture Risk

Osteoporosis is the most common metabolic bone disease and constitutes a major public health problem all over the world. Most international clinical practice guidelines have conventionally positioned the class of antiresorptive drugs, the bisphosphonates, as the first-line medical therapy for the management of postmenopausal osteoporosis. With the clinical development of more potent antiresorptive drugs as well as bone-forming drugs, more therapeutic options with different mechanisms of action, therapeutic efficacies, and adverse effect profiles are currently available. Bone-forming drugs have demonstrated a faster and better protection to patients with osteoporosis such that clinical management decisions should position their prioritized use in patients with a very high fracture risk. This article provides a review on the preferential selection of bone-forming drugs for management of postmenopausal osteoporosis in patients with imminent fracture risk.

In silico Approaches for Targeting an Essential Mycobacterial Protein, PrsA

Mycobacterium tuberculosis is a leading cause of death worldwide and with increasing cases of drug-resistance, new treatments options are required. PrsA is an essential protein in mycobacteria and is necessary for arabinogalactan production and nucleotide biosynthesis. This protein is not currently targeted by any drugs in clinical development and represents a potential drug development avenue. Currently, no crystal structure of M. tuberculosis PrsA (MtPrsA) is available, hence the SWISS-MODEL structure, based on M. smegmatis (93% similarity) was utilised. Molecular Dynamic simulations were performed on the modelled structure, to gain information on the protein’s predicted flexibility. The output trajectory was clustered, and representatives of each major cluster were used in downstream analysis. Ensemble docking, molecular docking on the ensemble of MtPrsA structures, of the GSK-177 prioritised compounds was undertaken. The docking predictions were also re-evaluated using machine learning based programmes, including NNScore. This approach yielded several compounds which could be taken forward for further computational analysis. The compound rankings were also retroactively compared to experimental data studying the GSK-177 compounds’ interactions with mycobacteria. This research represents a potential workflow for future in silico drug development efforts against M. tuberculosis and further work may allow the identified compounds to be used for the treatment of TB.

Medication Rules in Herbal Medicine for Mild Cognitive Impairment: A Network Pharmacology and Data Mining Study.

Background Although traditional Chinese medicine (TCM) has good efficacy in the treatment of mild cognitive impairment (MCI), especially memory improvement and safety, its substance basis and intervention mechanism are particularly complex and unknown. Therefore, based on network pharmacology and data mining, this study aims to explore the rules, active ingredients and mechanism of TCM in the treatment of MCI. Methods By searching the GeneCard, OMIM, DisGeNET and DrugBank databases, we obtained the critical targets associated with MCI. We matched the components and herbs corresponding to the important targets in the TCMSP platform. Using Cytoscape 3.7.2 software, we constructed a target-component-herb network and conducted a network topology analysis to obtain the core components and herbs. Molecular docking was used to preliminarily analyze and predict the binding activities and main binding combinations of the core targets and components. Based on the analysis of the properties, flavor and meridian distribution of herbs, the rules of herbal therapy for MCI were summarized. Results Twenty-eight critical targets were obtained after the screening. Using the TCMSP platform, 492 components were obtained. After standardization, we obtained 387 herbs. Based on the target-composition-herb network analysis, the core targets were ADRB2, ADRA1B, DPP4, ACHE and ADRA1D. According to the screening, the core ingredients were beta-sitosterol, quercetin, kaempferol, stigmasterol and luteolin. The core herbs were matched to Danshen, Yanhusuo, Gancao, Gouteng and Jiangxiang. It was found that the herbs were mainly warm in nature, pungent in taste and liver and lung in meridian. The molecular docking results showed that most core components exhibited strong binding activity to the target combination regardless of the in or out of network combination. Conclusion The results of this study indicate that herbs have great potential in the treatment of MCI. This study provides a reference and basis for clinical application, experimental research and new drug development of herbal therapy for MCI.

Population Pharmacokinetics/PD Modelling: a Systematic Review

It is critical to administer the correct dose of medications during the treatment regimen. Dosing inappropriately might worsen the illness or possibly result in death. The first and only important approach in clinical drug development is to determine an individual's precise dose. Pharmacokinetic variability is characterized by interindividual changes in anatomical and physiological variables. Population modeling requires a strong foundation of processes to ensure accurate data, appropriate computational platforms, sufficient resources, and good communication are all required. This paper examines the various methods for developing pharmacokinetic and pharmacodynamic models. There are a variety of ways that can be used to build population modelling: Nonlinear Mixed-effects Modeling, Bayesian population pharmacokinetic (PBPK) models, Physiological covariate modeling, Visual predictive check are some of the modeling strategies that have been discussed here. The evolution of modeling software is explored in this article. The greatest way for determining the optimal treatment for a patient with a certain ailment is to optimize drugs through optimum control. Different control techniques are also explored in this article.

The Potential Role of Gut Microbial-Derived Exosomes in Metabolic-Associated Fatty Liver Disease: Implications for Treatment.

The prevalence and incidence of metabolic-associated fatty liver disease (MAFLD), a clinically heterogeneous disease whose primary clinical therapies include dietary control and exercise therapy, is increasing worldwide and constitutes a significant medical burden. Gut microbes influence the physiopathological processes of the liver through different mechanisms based on the gut-liver axis. Exosomes are essential carriers of intercellular communication. Most previous studies have focused on adipocyte- and hepatocyte-derived exosomes, while the critical role of microbial-derived exosomes and the molecular mechanisms behind them in MAFLD have received little attention. Therefore, we searched and screened the latest relevant studies in the PubMeb database to elucidate the link between microbial-derived exosomes and the pathogenesis of MAFLD, mainly in terms of insulin resistance, intestinal barrier, inflammatory response, lipid metabolism, and liver fibrosis. The aim was to provide a theoretical framework and support for clinical protocols and innovative drug development.

Clinical development of anticancer drugs can be enhanced using efficacy data of small population clinical trials.

Although there are accelerated approval pathways based on data of small populations and surrogate endpoints, the concern that these pathways authorize the use of inefficacious drugs based on limited data from earlier phase clinical trials remains. We retrospectively investigated the efficacy of anticancer drugs, which were approved or whose development was terminated in small and large clinical trials, and verified whether small clinical trials could reflect the results for efficacy in large clinical trials. All anticancer drugs approved in Japan or whose development was terminated from 2015 to 2019 were searched. The median overall survival (OS), median progression-free survival (PFS), and overall response rates (ORR) between small clinical trials (sample size ≤100) and large clinical trials (sample size >100) with identical target populations and treatment settings were compared. Simple linear regression analysis, Spearman's correlation analysis, and paired sample t-test were performed. A total of 61 comparable small and large clinical trials were identified. For all endpoints, statistically significant linear trends and correlation were detected (p < 0.001). There were no statistically significant differences in the median PFS and ORR between small and large clinical trials. The mean differences of both clinical trials were -0.102 months and -1.531%, respectively. Even when the sample size of the clinical trial was increased, the efficacy data of anticancer drugs could not be changed significantly. These results supported the accelerated approval pathway based on the promising efficacy data of small populations in anticancer drug development.

Publication bias and reporting bias with a focus on dose-escalation trials of protein kinase inhibitors developed in oncology

Publication bias and reporting bias are a serious threat to evaluate the level of evidence of new medicines and have been poorly studied for phase I trials. Such studies –whose main objective is to define the recommended dose– are however cornerstone for clinical development of oncology drugs. Our interest was therefore to evaluate publication bias and reporting bias on dose-escalation trials of protein kinase inhibitors (PKI) developed in oncology. A systematic review was conducted between March 2020 and November 2021. Eligibility criteria were (i) PKI administered as monotherapy, (ii) healthy volunteers or patients with solid or hematological tumors, (iii) dose-escalation design. For each study, publications were searched on PubMed and Google Scholar. Publication lag was calculated as the time between the start date of the trial to the date of publication. Start date of the trial was used as a proxy because the end date of the trial is frequently lacking. Trials without publication were censored at the date of review. The quality of the reporting was assessed on the following variables: description of the (i) study design, (ii) dose levels, (iii) number of patients per dose level and (iv) number of dose-limiting toxicity (DLT) per dose level. A total of 782 dose-escalation trials were identified of which 644 have a completed status. Among these trials, 413 (64%) were published with a median time of 6.49 years [6.07 – 6.84] after starting the trial. Ten years after, 29% [25% – 33%] trials are still unpublished. A post hoc analysis –not planned initially in our protocol– shows that the publication delay is shorter for trials studying a PKI with at least one marketing authorization. Ten years after, 20% [14% – 28%] trials studying a PKI marketed are still unpublished versus 32% [27% – 38%] for trials studying a PKI without marketing authorization. Among the 413 published trials, 57 (14%) does not specify the design used for the dose escalation. The dose levels are well reported in the articles, with very few missing data (n = 6 (1%)) adding that for 22 (5%) the reporting leaves some doubt about the order of these levels. The number of patients and DLT by dose level have missing data for 31 (8%) and 79 (19%) articles respectively. The publication delay associated with the rate of unpublished trials and missing data are problematic for dose-escalation trials. There is an urgent necessity to standardize the reporting quality of dose-escalation trials. Mots clés publication bias ; reporting bias ; dose escalation ; protein kinase inhibitors Déclaration de liens d'intérêts Les auteurs n'ont pas précisé leurs éventuels liens d'intérêts

Therapeutic Delivery: Industry Update Covering January 2022

This industry update covers the period from January 1 through January 31, 2022, and is based on information sourced from company press releases, scientific literature, patents andnews websites. January 2022 saw Janssen and Midatech expand their collaboration on bioresorbable polymer microsphere technology for drug delivery. Takeda announced its plans to acquire UK-based Adaptate Biotherapeutics and Gandeeva raised further investment funds to support its drug discovery and development platform focused on the evaluation of protein-drug interactions. Biogen announced that it will sell its stake in a biosimilars joint ventureand ABL Bio and Sanofi announced a collaboration around a novel treatment for Parkinson's disease. New regulatory announcements this month included USFDA approvals of a new insomnia treatment for Idorsia and a treatment for atopic dermatitis developed by Pfizer. Insulet gained FDA clearance for a closed-loop insulin pump andAscendis Pharmafollowed up its United States approval last year for a once-weekly treatment for growth hormone deficiency with European approval. Pfizer and Ionis announced the discontinuation of the clinical development of a novel cardiovascular drug. In terms of collaborations, Novartis and Alnylam announced they will work together to explore targeted therapies to restore liver function; Scorpion Therapeutics partnered with AstraZeneca to develop novel cancer treatments and Nutriband Inc. and Kindeva Drug Deliverywill work together to develop a transdermal fentanyl patch. Collaborations were also announced betweenCentury Therapeutics and Bristol Myers Squibb andLillyand Entos Pharmaceuticalsin the areas of stem cell therapies for cancer treatment and neurology, respectively. A team from the Massachusetts Institute of Technologyreported progress in developing oral mRNA treatments and West Pharmaceutical Services published a blog describing the development of a proof-of-principle system for a closed-loop feedback system targeting opioid overdose. A report on the BBC website highlighted the benefits of more sustainable inhalers.

The implementation of a data learning series focused on clinical development teams in a contract research organization

Effective management of a clinical trial requires having real time access to information that provides useful insights into trial progress and that lends itself to collaborative decision making.&amp;nbsp; Data visualizations using data from multiple source systems employed during the conduct of a clinical trial have become an essential tool in the recent past as support for collaborative decision making by project teams. Having the ability to access, analyze, read, work with, and present data to support an argument are important skills that ensure data visualizations fulfill their purpose in clinical trial management. There is an expectation that members of the clinical trial team either possess or develop the data literacy skill sets necessary to collaborate on the successful execution of a clinical drug development trial. Here we describe the development of a Data Learning Series program targeted to increase the data literacy skills within a Contract Research Organization in support of the digital evolution of the drug development industry.

Metal-Organic Frameworks-Based Immobilized Enzyme Microreactors Integrated with Capillary Electrochromatography for High-Efficiency Enzyme Assay.

Enzyme assays are important for studying enzyme-mediated biochemical reactions and for clinical diagnosis and drug development. The technique of an immobilized enzyme microreactor (IMER) integrated with capillary electrophoresis (CE) has been frequently utilized in online enzyme assays. However, the traditional approaches for IMER-CE enzyme analysis have some defects such as low loading capacity and poor stability. Herein, metal-organic frameworks (MOFs), which have enormous potential in the fields of enzyme immobilization and capillary electrochromatographic (CEC) separation, were first explored as novel support materials with good enzyme immobilization performance and stationary phases with excellent separation abilities to construct an integrated MOFs-IMER-CEC microanalysis system for a high-efficiency online enzyme assay. As a proof-of-concept demonstration, acetylcholinesterase (AChE) was immobilized on a densely packed UiO-66-NH2 nanocrystal coating on a capillary inner surface with abundant intercrystalline mesoporosity and was employed as a highly effective and robust IMER for CEC-integrated online enzyme analysis. The excellent separation performance of the UiO-66-NH2-modified capillary was verified by high-efficiency separation of three types of neutral, acidic, and basic compounds. The Michaelis-Menten constant and enzyme inhibition kinetics of UiO-66-NH2-IMER were systematically assessed, exhibiting distinct advantages such as remarkably increased enzyme loadability, superior affinity for substrates, and greatly improved stability and repeatability compared to CE-integrated IMERs prepared by the traditional covalent bonding method. Furthermore, the developed method was successfully utilized for detecting organophosphorus pesticides in leguminous vegetable samples, demonstrating its strong practicality. The study not only proposed a novel support material and construction strategy for a high-performance microchannel-based IMER but also can be widely used in bioanalysis and biosensing research.

Guide to development of compound files for PBPK modeling in the Simcyp population-based simulator.

The Simcyp Simulator is a software platform for population physiologically‐based pharmacokinetic (PBPK) modeling and simulation. It links in vitro data to in vivo absorption, distribution, metabolism, excretion and pharmacokinetic/pharmacodynamic outcomes to explore clinical scenarios and support drug development decisions, including regulatory submissions and drug labels. This tutorial describes the different input parameters required, as well as the considerations needed when developing a PBPK model within the Simulator, for a small molecule intended for oral administration. A case study showing the development and application of a PBPK model for ondansetron is herein used to aid the understanding of different PBPK model development concepts.

What can we learn from mice lacking pro-survival BCL-2 proteins to advance BH3 mimetic drugs for cancer therapy?

In many human cancers the control of apoptosis is dysregulated, for instance as a result of the overexpression of pro-survival BCL-2 proteins. This promotes tumorigenesis by protecting nascent neoplastic cells from stress and renders malignant cells resistant to anti-cancer agents. Therefore, several BH3 mimetic drugs targeting distinct pro-survival proteins have been developed. The BCL-2 inhibitor Venetoclax/ABT-199, has been approved for treatment of certain blood cancers and tens of thousands of patients have already been treated effectively with this drug. To advance the clinical development of MCL-1 and BCL-XL inhibitors, a more detailed understanding of their distinct and overlapping roles in the survival of malignant as well as non-transformed cells in healthy tissues is required. Here, we discuss similarities and differences in pro-survival BCL-2 protein structure, subcellular localisation and binding affinities to the pro-apoptotic BCL-2 family members. We summarise the findings from gene-targeting studies in mice to discuss the specific roles of distinct pro-survival BCL-2 family members during embryogenesis and the survival of non-transformed cells in healthy tissues in adults. Finally, we elaborate how these findings align with or differ from the observations from the clinical development and use of BH3 mimetic drugs targeting different pro-survival BCL-2 proteins.

The cutting edge: leveraging pre-surgical immunotherapy trials to understand therapeutic mechanisms

One of the most persistent sources of consternation in the pathway for immuno-oncology drug development today is the high failure rate of early phase trials. Promising treatments, with excellent rationale, and similarly excellent outcomes in model systems are often discarded after failing to demonstrate similar benefit in patients. The difficult translation from preclinical to clinical testing may be in part attributable to heterogeneity in human immunobiology and carcinogenesis which is not recapitulated by animal models. Nonetheless, the contemporary clinical drug development paradigm was designed for traditional cytotoxic drugs and the complexity of modern anticancer therapeutic approaches warrants a rethinking of the most efficient path to transition novel strategies from the laboratory to the clinic. Examples of the shortcomings of current clinical drug development strategies in the context of immunomodulatory therapies include dose escalation designs with drugs that exhibit non-dose dependent effects and often delayed adverse events[1], [2]. Furthermore, there is an enormous unmet need to better understand the mechanisms of action of immuno-oncology drugs, and the underlying mechanisms of resistance that can explain heterogeneity of response and identify biomarkers to help enrich clinical trials for those patients most likely to benefit. To address this need, the platforms on which trials are designed will have to evolve, more seamlessly integrating translational science into studies with clinical endpoints, and changing a traditional ‘bench to bedside’ approach to one of contemporaneous ‘bench and bedside’ interrogation.

Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss.

New appetite‐regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are important determinants of weight loss and weight‐loss maintenance beyond appetite regulation. This review discusses prior failures in clinical development of weight‐loss drugs targeting energy expenditure and explores novel strategies for targeting energy expenditure: mitochondrial proton leak, uncoupling, dynamics, and biogenesis; futile calcium and substrate cycling; leptin for weight maintenance; increased sympathetic nervous system activity; and browning of white fat. Relevant targets for preserving lean mass are also reviewed: growth hormone, activin type II receptor inhibition, and urocortin 2 and 3. We endorse moderate modulation of energy expenditure and preservation of lean mass in combination with efficient appetite reduction as a means of obtaining a significant, safe, and long‐lasting weight loss. Furthermore, we suggest that the regulatory guidelines should be revisited to focus more on the quality of weight loss and its maintenance rather than the absolute weight loss. Commitment to this research focus both from a scientific and from a regulatory point of view could signal the beginning of the next era in obesity therapies.

BuFeiXiaoJiYin ameliorates the NLRP3 inflammation response and gut microbiota in mice with lung cancer companied with Qi-yin deficiency

IntroductionNLRP3 inflammasome responses and gut microbiota have been shown an important role in lung cancer, however, the relationship between gut microbiota and NLRP3 inflammasome responses in lung cancer with Qi-yin deficiency remains elusive.MethodsTo investigate the effect of the traditional Chinese medicine BuFeiXiaoJiYin (BFXJY) on NLRP3 inflammasome responses and dysbiosis in lung cancer with Qi-yin deficiency, the female BALB/cA-nu mice were treated with LPS and ATP to induce inflammation, and were intragastrically treated with warm Chinese medicine and smoked with shavings to induce Qi-yin deficiency, as well as were injected with 1 × 107/ml A549 cells to simulate lung cancer. Then the three different doses of BuFeiXiaoJiYin (BFXJY) and positive control (CRID3) were used for intervention in mice for 27 consecutive days. Then, we estimated the protection effect of BFXJY on lung cancer mice with Qi-yin deficiency, through deterring tumor growth, NLRP3 inflammasome, PKC signaling, and homeostasis of gut microbiota.ResultsIn this study, we found that BFXJY could inhibit the tumor growth in lung cancer with Qi-yin deficiency by reducing the production of IL-1β and IL-18 and inhibiting NLRP3 inflammasome activation, which might be associated with the inhibition of PKC signaling. Furthermore, BFXJY could promote microbial diversity and balance the microbial composition changes induced by inflammation and Qi-yin deficiency in lung cancer.ConclusionBuFeiXiaoJiYin ameliorates the NLRP3 inflammation response and gut microbiota in mice with lung cancer companied with Qi-yin deficiency. Our study provides a theoretical basis for the clinical development of therapeutic drugs targeting to treat lung cancer.