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Voronova V., Sokolov V., Al-Khaifi A., Straniero S., Kumar C., Peskov K., Helmlinger G., Rudling M., Angelin B. A physiology-based model of bile acid distribution and metabolism under healthy and pathological conditions in humans. Cell Mol Gastroenterol Hepatol. 2020 Feb 26.
This collaborative work with Karolinska University group is aimed to evaluate the impact of gastrointestinal perturbations on the levels of three key bile acids within enterohepatic and systemic circulation.

Victor Sokolov made a presentation entitled “Dapagliflozin Exposure–Response in Japanese vs Non-Japanese Patients with Type 1 Diabetes” based on exposure-response analysis included in the registration dossier supporting dapagliflozin submission in PMDA.

Kirill Peskov gave a lecture: “Application of mathematical modeling and artificial intelligence in the research and development of new medicines”  for the students of the HSE (Faculty of Computer Science)

On 2 – 5 December 2019 M&S Decisions scientists gave lectures at our annual School of Mathematical Modeling, the fourth year in a row. The School Program contained an open lecture day, followed by two days of practice based on industry cases and a training day in effective scientific communications. Participation is free of charge, but applicants had to go through the competition. In 2019, the competition amounted to 7 people per place. Traditionally participants received certificates on completion.

Victor Sokolov gave a lecture on the application of mathematical modeling in the research and development process of new medicines.

Victor Sokolov and Kirill Peskov presented a research study (poster T-79) built upon previously presented at ACoP9 work on utility analysis of five different packages available for MATLAB and R by evaluating functionalities of the MATLAB SimBiology toolbox within a QSP modeling workflow framework.

Collaborative work with experimenters from AstraZeneca pharmaceutical company entitled «Using Quantitative Systems Pharmacology modeling to predict response and resistance of immune checkpoint inhibitors (ICI) in murine syngeneic tumors» (Poster B154) was presented by Kirill Peskov and Ivan Azarov. The main message of this work was that the mechanistic quantitative immuno-oncology model demonstrated its suitability for predicting tumor size dynamics in response to various immune inhibitors for several syngeneic tumors.

A collaborative work with Sechenov University entitled “Evaluation and diagnostic potential of plasma biomarkers in bladder cancer” (Poster №1868) will be presented by Veronika Voronova. The research focuses on the application of machine learning tools to develop a multi-protein biomarker for cancer screening.

Victor Sokolov, Gabriel Helmlinger, Catarina Nilsson, Kirill Zhudenkov, Stanko Skrtic, Bengt Hamrén, Kirill Peskov, Eva Hurt-Camejo, and Rasmus Jansson-Löfmark. Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia. J Lipid Res. 2019 Sep; 60(9): 1610–1621. doi: 10.1194/jlr.M092486

Our team in collaboration with AstraZeneca developed an integrative systems pharmacology model of lipoprotein homeostasis which sets the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies, and small interfering RNA, by describing in minimalistic yet mechanistic terms complex interactions between multiple plasma lipoprotein and lipid biomarkers, and by establishing a quantitative link between plasma PCSK9 and low-density lipoprotein cholesterol reduction for five different anti-PCSK9 compounds.

Varvara Ustinova gave a lecture on mathematical modeling in drug development for high school students at the International Summer Biological School Pilgrim.

The participants learned about the process of drug development and the role of mathematical modeling in research and development of new medicines, as well as basic principles of pharmacometrics and model development workflow.

Tatiana Yakovleva, Victor Sokolov, Lulu Chu, Weifeng Tang, Peter J. Greasley, Helena Peilot Sjögren, Susanne Johansson, Kirill Peskov, Gabriel Helmlinger, David W. Boulton, Robert C. Penland. Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors. Diabetes Obes Metab. 2019 Aug 18. doi: 10.1111/dom.13858.

 Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a class of oral glucose-lowering compounds used to treat type 2 diabetes mellitus (T2DM). In collaboration with AstraZeneca quantitative drug-disease systems model was developed and used to reveal mechanistic differences in renal glucose reabsorption and urinary glucose excretion (UGE) between healthy and T2DM patients and clearly showed that SGLT2 inhibition significantly increased glucose available to SGLT1 downstream in the tubule. 

Researchers from M&S Decisions LLC shared their experience in joint modeling of longitudinal biomarker and time-to-event data for mCRPC as well as presented the work on Bayesian meta-analysis for IO therapy safety at StanCon 2019 Conference, a conference devoted to the application of Bayesian methods in the data science and pharmacology.

M&S Decisions shared its experience in joint modeling of multivariate longitudinal biomarker and time-to-event data for COPD and NSCLC by presenting two scientific works at PAGE 2019 Conference.

Azarov, I., Peskov, K., Helmlinger, G., & Kosinsky, Y. (2019). Role of T Cell-To-Dendritic Cell Chemoattraction in T Cell Priming Initiation in the Lymph Node: An Agent-Based Modeling Study. Frontiers in Immunology, 10, 1289. doi: 10.3389/fimmu.2019.01289

The collaborative work of the authors from M&S Decisions and AstraZeneca is devoted to the mechanistic description of the naive T cells activation inside the lymph node’s T-zone and the immune response initiation. The study was carried out using agent-based modeling.
Current research has convincingly shown that the predominant type of motion of naive lymphocytes is random motion. On the other hand, selective chemotaxis motion of activated cognate T cells in the direction of dendritic cells is critical for reproducing the cognate clones expansion and the immune response development.

Kirill Peskov and Tatiana Yakovleva participated in the Pharma’s cool and Job Fair held at Skolkovo Biomedical Cluster in May 13-17, 2019.

Kirill and Tatiana gave a talk about application of mathematical modeling in Pharma R&D and biomedical research.

If you are interested in Pharma R&D work and was unable to attend M&S Decisions on May 17, 2019 at Job Fair in Skolkovo please be welcome on our Careers page.

In April, 2019 a modeling work by David Busse et al. investigating pharmacokinetics and the exposure-response relationship of dapagliflozin in adolescent and adult patients with type 1 diabetes mellitus was accepted for publication in British Journal of Clinical Pharmacology.

Kirill Peskov, Ivan Azarov, Lulu Chu, Veronika Voronova, Yury Kosinsky, Gabriel Helmlinger. Quantitative mechanistic modelling in support of pharmacological therapeutics development in immuno-oncology. Front. Immunol. doi: 10.3389/fimmu.2019.00924

This mini-review focuses on the evolution and state-of-the-art of quantitative systems models describing the tumor vs. immune system interplay, and their merging with quantitative pharmacology models of IO-modulating agents, as companion tools to support the addressing of the IO drug development challenges.

M&S Decisions took part in the Medicines Digital Forum. Kirill Peskov, CEO of M&S Decisions LLC, gave a talk at the section Innovations of the Pharmaceutical Marker: “Breakthrough Technologies & Innovations – Smart Drugs”.

In April, 2019 a new research article comparing urinary glucose excretion under SGLT2 inhibitor treatment between Japanese and non-Japanese patients with type 1 diabetes mellitus was published in Diabetes, Obesity and Metabolism.

Sokolov V, Yakovleva T, Ueda S, Parkinson J, Boulton D W, Penland R C, Tang W. Urinary glucose excretion after dapagliflozin treatment: An exposure-response modelling comparison between Japanese and non-Japanese patients diagnosed with type 1 diabetes mellitus. Diabetes Obes Metab. 2019; 21:829–836

M&S Decisions took part in the Annual Meeting of American Association of Cancer Research 2019 in Atlanta, US, where two works were presented:

• “Mechanistic insights and dose optimization for AZD3458, a novel selective PI3Kʏ immuno-modulator, using a quantitative systems approach”;
• “Linking tumor microenvironment properties in murine syngeneic tumors with resistance to immune checkpoint inhibitors: Insights from a quantitative systems approach”.

In December, 2018 Skolkovo Biomedical cluster, Open Skolkovo University and M&S Decisions LLC in partnership with the AstraZeneca company organized a 4-day workshop about mathematical modeling in drug development.

The goal of the workshop was to introduce participants to the basics of pharmacometrics and systems pharmacology and show how these modeling techniques can help to solve R&D questions and support decision making at different stages of drug development pipeline.

Mathematical modeling school in pharmaceuticals has become traditional for Skolkovo and was held for the third time.

The 33rd Annual Meeting of The Society for Immunotherapy of Cancer (SITC) was held on the 7-11th of November at the Walter E. Washington Convention Center  in Washington, D.C. where M&S Decisions team presented results of collaboration with AstraZeneca on the Immune Oncology modeling platform development.

Kirill Peskov, CEO of M&S Decisions LLC, give a talk at the section Bioinformatics: “Constructive biotechnologies: the power of mathematical modelling”.

Kirill Peskov, Yuri Kosinsky, Kirill Zhudenkov, Veronika Voronova and Victor Sokolov went to sunny San-Diego to prove that «Modeling without Bounds» are not just words: keep up with our latest modeling updates in oncology, metabolic diseases and industrialization.

M&S Decisions participated in the 5th annual event aimed at recruiting young biomedical technology specialists for open positions and internship at companies participating in the Biomedical Cluster and Skolkovo Foundation.

Our company has an open position of Visiting scientist, mathematical modelling. The details are available at M&S Decisions website – Career page.

A collaborative work with Karolinska university group entitled “A physiology-based model of the distribution of individual bile acids within the enterohepatic circulation under normal and pathological conditions in human” was presented by Veronika Voronova.

Researchers from M&S Decisions in collaborative work with Karolinska utilized advanced data analysis techniques to investigate kinetics of bile acid-mediated Farnesoid X receptor activation.

Researchers from M&S Decisions LLC shared their experience in mathematical modeling of bile acids enterohepatic circulation and industrialization of systems pharmacology model development by presenting two scientific works at PAGE 2018 Conference in Montreux, Switzerland, after participating in a full-day modeling workshop organized by IntiQuan company:

• A functional, integrative R environment workflow for the development and use of quantitative systems pharmacology models presented by Artem Dolgun
• Using a physiologically-based QSP model to simulate the effects of enterohepatic circulation perturbations on the distribution of bile acids presented by Veronika Voronova

A QSP model was used to show that gastric emptying inhibition by exenatide represents an important additional mechanism of postprandial glucose stabilization. The drug effect depends on the food properties, which underscores the importance of dietary counseling as an adjunct to medication.

Voronova V, Zhudenkov K, Penland RC, Boulton DW, Helmlinger G, Peskov K. Exenatide effects on gastric emptying rate and the glucose rate of appearance in plasma: A quantitative assessment using an integrative systems pharmacology model. Diabetes Obes Metab. 2018; 1–5. 

Researchers from M&S Decisions made a presentation, summarizing usage of multiple quantitative clinical pharmacology methodologies on different stages of drug development.

M&S Decisions took part in the Annual Meeting of American Association of Cancer Research 2018 where we presented the work “Quantitative modeling as a systematic approach for drug combination evaluation in Immuno-Oncology”.

A mechanistic model describing interactions among host immune cells and tumor cells was developed. The proposed model was used to explore the effects of PD-1 and CTLA-4 immune checkpoint inhibitors, OX40 agonistic ligand and CXCR2 blocking antibody, and their combinations, on tumor microenvironment and tumor growth dynamics in various experimental murine models. The types of synergistic effects which may arise from immuno-oncology drug combinations were categorized across realistic baseline conditions prevailing in the tumor microenvironment (TME).

At ASCPT 2018 Annual Meeting, one of the biggest clinical pharmacology conferences in the US, M&S Decisions LLC presented two systems pharmacology models developed in collaboration with AstraZeneca:

• Differentiation of anti-PCSK9 antibodies and synthesis inhibitors: a drug-disease modeling study presented by Victor Sokolov;
• Contribution and regulation of SGLT1 and SGLT2 in healthy and type 2 diabetes subjects: a drug-disease modeling study presented by Tatiana Yakovleva.

Also during the session on Immuno-Oncology therapeutic combinations Gabriel Helmlinger in the talk “Quantitative Systems Pharmacology Modeling to Inform Combination Strategies in Immuno-Oncology” presented the key results of collaboration between AstraZeneca company and M&S Decisions LLC.

Researchers from M&S Decisions shared their experience in usage of QSP, PBPK, pop-PK/PD modeling in optimization of clinical trial design.

New article on immuno-oncology QSP modeling was just published in the Journal of ImmunoTherapy of Cancer.

A mathematical model is presented. It integrates key mechanistic features of immuno-oncology biology, radiation and anti PD-L1 pharmacokinetics, to accurately predict optimal radiation and anti PD-L1 dose sequencing for maximal anti-tumor efficacy. Owing to its mechanistic nature, the model features mechanistic insights into the immune-suppressive vs. immuno-activating forces underlying drug regimen optimization.

Yu. Kosinsky, S. Dovedi, K. Peskov, V. Voronova, L. Chu, H. Tomkinson, N. Al-Huniti, D. Stanski, G. Helmlinger. (2018) Radiation and PD-(L)1 treatment combinations: immune response and dose optimization via a predictive systems model, Journal for ImmunoTherapy of Cancer (2018) 6:17

Yuri Kosinsky and Oleg Stepanov, researchers from M&S Decisions, gave practical training “Introduction to pharmacometrics and population analysis” for young scientists at Future Biotech Winter Retreat 2018.

The Big Data in Pharma conference overviewed the big data spectrum in pharmaceutical development and the ways of its utilization.

M&S Decisions took part in this conference and Kirill Zhudenkov gave a report on the decision making in drug development.

M&S Decisions, Skolkovo Biomedical cluster and Open Skolkovo University held a 4-day conference and workshop, devoted to the mathematical modeling in drug development. The event was targeted to PhD students, postdocs and young scientists.

The wide range of topics was presented and studied: the principles of model-based drug development, the basics of PBPK, quantitative systems pharmacology, pharmacometrics etc. The attendees of the conference collected unique experience of working in modern R&D projects for  innovative drugs.

During the XXI Russian Congress on Oncology a special session was devoted to the presentation of Skolkovo startups performing the research in oncology. Yuri Kosinsky from M&S Decisions gave a presentation on the research of IO+RT in terms of immune response and dose regimen optimization.

Pharmacokinetics UK (PKUK) was a spin out from the DMDG (Drug Metabolism Discussion Group) in early 80s. Since those times the conference is held on the regular basis in the UK.

M&S Decisions attended the PKUK Meeting 2017, where Yuri Kosinsky made a report on radiation and anti-PD-L1 treatment combinations.

The annual Open Innovations forum has been held in Moscow since 2012 under the aegis of the Government of the Russian Federation and is considered as a unique discussion platform for participants in the formation of an innovative ecosystem.

M&S Decisions attended the Open Innovations forum in Skolkovo. Kirill Peskov took part in the discussion session “To keep pace with technologies. How to regulate new medicine?”

M&S Decisions attended the ACoP 2017 conference where a set of works devoted to the investigation of modeling methodology and disease areas: metabolic, respiratory and oncology, was presented.

M&S Decisions attended the 3rd AstraZeneca-MedImmune-CRUK Cancer Symposium, Cambridge, the UK.

Kirill Peskov, CEO of M&S Decisions LLC, presented the work “Radiation and anti-PD-(L)1 treatment combinations: Immune cell responses and dose scheduling optimization using a joint experimental and systems modeling approach” made by M&S Decisions in collaboration with AstraZeneca and MedImmune.

This project is aimed at recruiting young biomedical technology staff for employment and traineeships at companies participating in the Biomedical Technologies Cluster, pharmaceutical manufacturers, and the Skolkovo Foundation.

M&S Decisions took part in this event, established new communications and selected several candidates for a new position in the company.

Our company has open positions. The details are available at HH, Molbiol, LinkedIn or M&S Decisions website – Career page.

Victor Sokolov, a researcher from M&S Decisions LLC, presented the work “Comparison of Lipid-Lowering Properties of Anti-PCSK9 Antibodies and Synthesis Inhibitors Using a Quantitative Systems Model of Lipoprotein Metabolism”  made by M&S Decisions in collaboration with AstraZeneca at Scientific Sessions of American Diabetic Association (ADA), San Diego, USA

Researchers from M&S Decisions LLC in collaboration with AstraZeneca made four scientific presentations at PAGE 2017 conference in Budapest, Hungary, one of the biggest pharmaceutical modeling conferences in Europe.

M&S Decisions researchers presented the following talks and posters:

• Joint modeling of overall survival and tumor size dynamics in non-small cell lung cancer: Clinical trial simulations and validation of predictions at study and subject levels, presented by Dmitry Onishchenko
• Radiation and anti-PD-L1 treatment combinations: Immune cell responses and dose scheduling optimization using a joint experimental and systems modeling approach, presented by Yuri Kosinsky
• Inhibition of bile acids synthesis via fibroblast growth factor 19 (FGF19) through intestinal signaling: A population analysis, presented by Dina Chernikova
• Evaluation of immediate release exenatide effects on gastric motility and intestinal glucose absorption using a systems pharmacology model, presented by Veronika Voronova

Veronika Voronova, a researcher from M&S Decisions LLC, presented the work “Systems Pharmacology Modeling of Bile Acid Distribution and Signaling”  made by M&S Decisions in collaboration with AstraZeneca and Karolinska institute, Sweden at Keystone conference: Bile Acid Receptors as Signal Integrators in Liver and Metabolism in Monterey, the USA.

M&S Decisions LLC presented the work made in collaboration with AstraZeneca “Model-based meta-analysis of safety for immune checkpoint inhibitor combinations and monotherapy” at ASCO-SITC Immuno-Oncology Symposium in Orlando, the USA.

M&S Decisions together with Skolkovo Biomedical Technologies Cluster and Skolkovo Open University organized a school on Mathematical modelling in pharmaceutics for biomedical startups and young scientists in Skolkovo Foundation.

The aim of the school was to introduce to the participants the core methods of mathematical modelling, which were widely used for decisions making process during new drugs development.

More than 200 young specialists took part in the event, including undergraduate and post-graduate students from leading Russian universities such as Moscow State University, Moscow Institute of Physics and Technology, Mendeleev University of Chemical Technology, Sechenov First Moscow State Medical University, National Research Medical University, Mechnikov North-Western University, Altai State University and others.

On the first day of the school the Skolkovo Hypercube brought together specialists from different areas of biology, chemistry and medicine where mathematical model was actively used. Young scientist had lectures on methods how mathematical modelling was used on different stages of drugs development including:

• different phases of clinical and preclinical trials
• making decisions at drug development
• special focus was made on immuno-oncological research

The second and the third days of the school were devoted to lections and practical trainings in Pharmacometrics, Systems Pharmacology and Translation modelling.

Kirill Peskov and Yuri Kosinsky, the lead scientists at M&S Decisions, participated in the scientific seminar at the FDA, a federal agency responsible for the regulation and supervision of pharmaceutical drugs in the U.S.A. The seminar was focused on innovative methods in mathematical modeling, to improve the therapeutic outcome of novel drugs in the treatment of cancer. A new quantitative methodological platform, developed in collaboration between Skolkovo resident M&S Decisions and the pharmaceutical company AstraZeneca, was presented. The platform included a combination of modeling approaches, including systems pharmacology, pharmacometrics, and meta-analyses. It was under further development and validation work to predictively assess the therapeutic potential of novel oncology drug combinations, including the prediction of key endpoints in drug development clinical trials.

This combination of modeling approaches resulted in the creation of a ‘modeling continuum’ along pharmaceutical R&D pipeline, thereby enabling constant support towards decision-making, from preclinical to first-in-human trials, and from early clinical trials to late-phase and registration trials. ‘How’ and ‘where’ in the pipeline such quantitative modeling may support transition points and decisions, and how it may help better identify patient subpopulations who respond to specific combination therapies, were debated in a lively and interactive Q&A session that followed the presentation, and during which the overall methodology platform was seen as “progressive.”

Researchers from M&S Decisions LLC made three scientific publications at ICSB 2016 conference in Barcelona, Spain, which was the biggest European conference on Systems Biology.

M&S Decisions researchers gave the presentations and two posters:

• Quantitative Systems Pharmacology model for immuno-oncology drug development: example of CTLA4 inhibition mechanism, presented by Yuri Kosinsky
• Enhancement of cytokine signaling via cytokine-neutralizing antibodies, presented by Boris Shulgin
• A quantitative systems pharmacology model to explore combination efficacy of immuno-oncology compounds: Effects of CXCR2 and PD-1 inhibitions, presented by Kirill Peskov

Researchers from M&S Decisions LLC made six scientific publications at PAGE 2016 conference in Lisboa, Portugal, which was one of the biggest pharmaceutical modeling conferences in Europe.

M&S Decisions researchers presented the following talks and posters:

• Investigation of anti-CTLA-4 immuno-oncology therapy through a quantitative systems pharmacology model, presented by Kirill Peskov
• A Markov Chain model to characterize cataract progression and disease burden in the Russian Federation, presented by Kirill Zhudenkov
• A mechanistic PKPD model relating early asthmatic response to anti-leukotriene drug PK and biomarker levels in allergen challenge studies, presented by Victor Sokolov
• A quantitative systems pharmacology model to explore combination efficacy of immuno-oncology compounds: Effects of CXCR2 and PD-1 inhibitions, presented by Oleg Stepanov
• Investigation of the diabetes-related metabolic memory phenomenon using a quantitative systems pharmacology approach, presented by Veronika Voronova
• A systems pharmacology model of SGLT2 and SGLT1 inhibition to understand mechanism and quantification of urinary glucose excretion after treatment with Dapagliflozin, Canagliflozin and Empagliflozin, presented by Tatiana Yakovleva

Researchers from Moscow Institute of Physics and Technology, M&S Decisions LLC and Yandex LLC built a computer agent based model of the interaction between different bacteria, and between bacteria and the gut wall. This led them to explain how antibiotic-resistant microbes develop and spread; details of the study were published in the journal PLOS ONE.

The human intestine contains trillions of different bacteria, which together are called the microbiome. Bacteria protect us from harmful microorganisms, produce digestive enzymes, and help the immune system to function normally. Many diseases, such as obesity, Crohn’s disease, colon cancer, and other inflammatory processes are associated with a change in the gut microbiome. The researchers built a model of the interaction between two types of bacteria and the intestine and they determined what happened when they took antibiotics that killed a large number of microorganisms.

Source: MIPT press release

Kirill Peskov, Managing Director and Senior Principal Scientist of M&S Decisions LLC presented a lecture on the topic “Pharmacometrics and model based drug development” at Pharma Cool School organised by Skolkovo foundation.  Read more