Vladimir V. Rogov

Patients with non-small cell lung cancer (NSCLC) undergoing surgical treatment are at high risk of malnutrition, which increases the likelihood of complications and prolongs hospitalization. The clinical and economic effectiveness of specialized nutritional support in this population remains insufficiently studied. Objective. To assess the clinical and economic value of high-protein nutritional support (Nutridrink Compact Protein) in patients with NSCLC during preoperative preparation and postoperative care. Material and methods. This study was based on data from the multicenter comparative low-interventional clinical trial NUTRILUNC. Patients were assigned to an intervention group, which received specialized nutrition (2 × 125 ml for 14 days before and 14 days after surgery), or to a control group with standard nutrition. Outcomes included length of hospital stay, frequency of bronchoscopies, infectious complications, and quality of life (EORTC QLQ-C30). The clinical and economic analysis was performed using a cost-effectiveness model from the perspective of a healthcare organization. Calculations were based on the Russian State Healthcare Guarantee Program (Government Decree No. 2497 of 29.12.2022) and the manufacturer’s retail prices. Results. The clinical and economic analysis of nutritional support in perioperative lung cancer treatment demonstrated that its inclusion in standard patient management improves clinical and functional outcomes and reduces the need for resource-intensive procedures. High-protein nutritional support (Nutridrink Compact Protein) reduced mean hospital stay by 1.36 days, increased bed turnover by 11%, and generated additional revenue of 689.774 rubles per surgical bed per year. Additional cost savings (an average of 6.650 rubles per patient) were achieved through a significant reduction in bronchoscopy frequency: 20.0% in the intervention group versus 57.9% in the control group (a 65.5% decrease). Conclusion. Specialized nutritional support in the perioperative treatment of NSCLC patients after surgical intervention is clinically justified and economically feasible, supporting its inclusion in standard treatment protocols and strategies for optimizing inpatient care.

Budget Impact Analysis (BIA) is a key step in justifying the inclusion of new medicines in the list of vital and essential medicines (VED). It allows you to predict the financial consequences of the introduction of therapy and evaluate the effectiveness of resource allocation, which is of particular importance when using innovative antitumor drugs.The aim. Implementation of the BIA of Healthcare of the Russian Federation of the use of sonidegib to assess the feasibility of inclusion in the list of VEDs for the treatment of patients with locally advanced basal cell carcinoma (laBCCs).Materials and methods. In the pharmacoeconomic model developed for use in the Russian Federation, the BIA was conducted for healthcare in the Russian Federation based on comparative modeling of two scenarios: basic (all patients receive vismodegib) and alternative (phased introduction of sonidegib with an increase in the share to 50% by the third year). The time horizon is 3 years. Direct medical costs, price data from VED registers, government procurement, regulatory allowances, demographic and epidemiological parameters are taken into account. Additionally, a one-way sensitivity analysis was performed in the range of ±10% of key variablesResults. An analysis of the impact on the healthcare budget of the Russian Federation showed that the inclusion of sonidegib in the list of VED will lead to a 3.15% reduction in budget costs for the treatment of patients with laBCCs (-37,270,334 rubles or -387,440.81 USD) within the modeled patient population. The presented BIA results remain stable with changes in the price of comparison drugs, the total population size and the distribution of patient flow over the years, with a deviation from the baseline value of ±10%.Conclusion. Modeling shows that the inclusion of the drug sonidegib in the list of VED leads to a reduction in the costs of the healthcare system with a possible increase in the tolerability of therapy and an expansion of the therapeutic arsenal for the treatment of laBCCs, i.e. it is justified from the point of view of clinical and economic consequences. The results obtained confirm its pharmacoeconomic validity as an alternative to vismodegib in the treatment of laBCCs.

One of the key factors in ensuring the availability of modern treatments and choosing the optimal therapy for patients is the clinical and economic characteristics of new medical technologies.The aim: to assess the clinical and economic feasibility of using sonidegib in widespread clinical practice.Materials and methods. General scientific research methods were used as a methodological basis. A "decision tree" model was developed to conduct a clinical and economic assessment. The clinical and economic assessment of the use of sonidegib was carried out from the perspective of the healthcare system of the Russian Federation: the costs of systemic drug therapy for the 1-line of patients with locally advanced basal cell carcinoma (BCC) were taken into account.Results. A comparative analysis of efficacy based on the progression-free survival (PFS) criterion revealed the advantage of sonidegib over vismodegib: the odds ratio (OR) of disease progression in patients with locally advanced BCC 12 months after the start of therapy was 0.27778 (95% CI 0.125–0.618; p=0.0017; Z=3.1423). The reduction in the risk of progression when using sonidegib compared to vismodegib was 59.1% (OR= 0.409; 95% CI 0.229–0.732, p=0.0026, Z=3.013). The results of testing the hypothesis about the equality of the proportion of patients with locally advanced BCC without disease progression 12 months after the start of therapy also confirmed the presence of statistically significant differences in efficacy between the two treatments in favor of sonidegib (χ²=9.2007, df=1, p=0.002419, 95% CI 0.09312–0.432132). The use of sonidegib in the 1-line of therapy, 2.53 million rubles per year will be required per 1 patient, which is 10.86% lower than the use of vismodegib, and corresponds to an absolute saving of 308.55 thousand rubles. The "cost-effectiveness" indicator (CER) for sonidegib was 114,627 rubles versus 220,295 rubles for vismodegib. The incremental cost-effectiveness ratio (ICER) is 175,050 rubles per additional month of PFS. Sensitivity analysis showed the stability of the results when changing key parameters.Conclusion. Based on the results of the study, the hypothesis about the clinical and economic benefits of sonidegib in the treatment of locally advanced BCC was confirmed, and data were obtained on the clinical and economic feasibility of using sonidegib in widespread clinical practice.

The aim of this study was to evaluate the clinical and economic rationale for the integration of camrelizumab as a first-line treatment for non-small cell lung cancer (NSCLC) in adult patients without EGFR/ALK/ROS1 mutations and with any level of PD-L1 expression in the Russian healthcare system. Methods. Data were obtained from the randomized CameL and CameL-sq clinical trials, as well as other international RCTs evaluating PD-1/PD-L1 inhibitors, domestic epidemiological studies and real-world clinical practice. Given the comparable overall survival, progression-free survival, and objective response rates across studies, a cost-minimisation analysis was performed. A budget impact analysis was conducted over a 24-month time horizon, taking into account patient flow patterns, treatment costs, registered prices of vital and essential medicines, and various camrelizumab uptake scenarios. Results. The total cost of a full course of camrelizumab therapy was 33–200% lower than the cost of regimens utilizing other PD-1/PD-L1 inhibitors. In the budget impact analysis, the introduction of camrelizumab led to a reduction in total two-year healthcare expenditures by 7.36–7.59 billion rubles (savings of 17.8–18.0%). A one-way deterministic sensitivity analysis confirmed the robustness of the model as ±10% variations in key parameters did not alter the conclusion that camrelizumab was economically preferable. Conclusion. The use of camrelizumab as first-line treatment for NSCLC provides comparable clinical efficacy and substantial cost savings compared to alternative PD-1/PD-L1 inhibitors. These results confirm the economic rationale for camrelizumab use and highlight its potential to expand patient access to immunotherapy within the Russian Federation.

Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome. In this work, we rigorously tested the target engagement of the reported ATTECs to validate the existing LC3/GABARAP ligands. Surprisingly, we were unable to detect interaction with their designated target LC3 using a diversity of biophysical methods. Intrigued by the idea of developing ATTECs, we evaluated the ligandability of LC3/GABARAP by in silico docking and large-scale crystallographic fragment screening. Data based on approximately 1000 crystal structures revealed that most fragments bound to the HP2 but not to the HP1 pocket within the LIR docking site, suggesting a favorable ligandability of HP2. Through this study, we identified diverse validated LC3/GABARAP ligands and fragments as starting points for chemical probe and ATTEC development.

The characterization of interactions between autophagy modifiers (Atg8-family proteins) and their natural ligands (peptides and proteins) or small molecules is important for a detailed understanding of selective autophagy mechanisms and for the design of potential Atg8 inhibitors that affect the autophagy processes in cells. The fluorescence polarization (FP) assay is a rapid, cost-effective, and robust method that provides affinity and selectivity information for small molecules and peptide ligands targeting human Atg8 proteins. This chapter introduces the basic principles of FP assays. In addition, a case study on peptide interaction with human Atg8 proteins (LC3/GABARAPs) is described. Finally, data analysis and quality control of FP assays are discussed for the proper calculation of K_i values for the measured compounds.

Isothermal titration calorimetry (ITC) is a widely used technique for the characterization of protein–protein and protein–ligand interactions. It provides information on the stoichiometry, affinity, and thermodynamic driving forces of interactions. This chapter exemplifies the use of ITC to investigate interactions between human autophagy modifiers (LC3/GABARAP proteins) and their interaction partners, the LIR motif-containing sequences. The purpose of this report is to present a detailed protocol for the production of LC3/GABARAP-interacting LIR peptides using E. coli expression systems. In addition, we outline the design of ITC experiments using the LC3/GABARAP:peptide interactions as an example. Comprehensive troubleshooting notes are provided to facilitate the adaptation of these protocols to different ligand-receptor systems. The methodology outlined for studying protein–ligand interactions will help to avoid common errors and misinterpretations of experimental results.

The characterization of interactions between autophagy modifiers (Atg8-family proteins) and their natural ligands (peptides and proteins) or small molecules is important for a detailed understanding of selective autophagy mechanisms and for design of potential Atg8 inhibitors that affect the autophagy processes in cells. The fluorescence polarization (FP) assay is a rapid, cost-effective and robust method which provides affinity and selectivity information of small molecules and peptide ligands targeting human Atg8 proteins. This chapter introduces the basic principles of FP assays are introduced. In addition, a case study for FP small molecule and peptide interactions with human Atg8 proteins (LC3/GABARAPs) is described. Finally, data analysis and quality control of FP studies are discussed for the proper calculation of Ki values of the measured compounds.

Isothermal titration calorimetry (ITC) is a widely used technique for the characterization of protein-protein and protein-ligand interactions. It provides information on the stoichiometry, affinity, and the thermodynamic driving forces of interactions. This chapter exemplifies the use of ITC to investigate interactions between human autophagy modifiers (LC3/GABARAP proteins) and their interaction partners, the LIR motif containing sequences. The purpose of this report is to present a detailed protocol for the production of LC3/GABARAP-interacting LIR peptides using E. coli expression systems. In addition, we outline the design of ITC experiments using the LC3/GABARAP:peptide interactions as an example. Comprehensive troubleshooting notes are provided to facilitate the adaptation of these protocols to different ligand-receptor systems. The methodology outlined for studying protein-ligand interactions will help to avoid common errors and misinterpretations of experimental results.

Recent successes in developing small-molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the target recruitment to LC3/GABARAP, a family of membrane-bound proteins that tether autophagy receptors to the autophagosome. In order to validate the existing ligands, we rigorously tested target engagement of reported ATTEC ligands and handles. Surprisingly, using various biophysical methods, most available ligands did not interact with their designated target LC3. Intrigued by the idea of developing ATTECs, we evaluated the druggability of LC3/GABARAP by in silico docking and large scale crystallographic fragment screening. The data revealed that most fragments bound to the HP2, but not the HP1 pocket of the LC3-interacting region (LIR) docking site, suggesting favorable druggability of this binding pocket. Here, we present diverse comprehensively validated ligands for future ATTEC development.