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Science Blog: September Boston QSP Event

Author: Sarah Yunes

Editors: Jae Yang and Rajiv P. Shrestha

Taking a Look Around: The History of QSP and Where it Could Go Next

Quantitative Systems Pharmacology (QSP) is currently a rapidly expanding field, with its value being increasingly recognized in drug discovery and development. Despite the early examples of mathematical modeling and simulation of biological systems as early as the 1960s, the term “QSP” was officially introduced in a White Paper released by NIH in 2011. Since then, journals and special interest groups with a focus on QSP have sprung up. Pharmaceutical companies are increasingly investing in QSP as a way to inform decision making in all aspects of drug development. Due to its increased involvement, it is worth taking another look on how QSP has developed as a field, how far it has come in the pharmaceutical industry, and where the future will take it. With this in mind, Boston QSP invited Dr. Cynthia J. (C.J.) Musante, Senior Scientific Director and Head of QSP in Pfizer Early Clinical Development in Cambridge, MA. The talk’s title is The Future Is So Bright: Quantitative Systems Pharmacology in Drug Discovery and Development.

QSP in current drug discovery and development

While QSP has become established in the pharmaceutical industry as a part of model-informed drug discovery and development, attrition remains high. Of drug candidates that enter phase I clinical trials, 10-15% make it through FDA approval. Even worse, 60-70% of drug candidates that enter phase II clinical trials fail to make it to phase III. The most common reason for these failures is insufficient efficacy. The idea is that to improve the phase II success rate the pharmaceutical industry needs to focus on improving confidence in target selection and validation. This needs to go beyond the three pillars of drug development (pharmacokinetics at the site of action, binding to the target and downstream pharmacology), to look at the whole pathway being targeted and its involvement in the disease state in the whole body context.

For example, Dr. Musante’s team worked on new strategies for treating Nonalcoholic Fatty Liver Disease (NAFLD). NAFLD is when fat builds up in the liver, usually in overweight or obese individuals. The liver generally has a small amount of fat, but in people with NAFLD, liver fat accumulates and can lead to Nonalcoholic steatohepatitis (NASH) characterized by inflammation, fibrosis and potentially leading to cirrhosis, and even liver cancer. One potential target for treating NAFLD is by inhibiting the breaking down of lipids to fatty acids, called lipolysis, in the adipose tissue. The hypothesis is that this would reduce the amount of fat in the liver. An early clinical study performed by GSK showed that an agonist of a G-protein coupled receptor could reduce fatty acids in the blood, but for several dosing paradigms the effect was not sustained over the duration of the study (Dobbins et al., 2015). Dr. Musante’s team used modeling to show that if the reduction could be sustained, it would lead to a reduction in fat accumulation in the liver, leading to increased confidence in Pfizer to pursue this strategy further.

Additionally, QSP can incorporate new technologies to further improve the drug discovery pipeline. One of these recent advances utilizes simulations of patients, called virtual patients, to simulate the response of a diverse population to a specific drug treatment. The FDA has increased its focus on modeling and simulation and has highlighted the importance of using in silico tools to improve efficiency of drug production.

Message from the speaker: follow your heart to pursue your career

After her talk, we got a chance to discuss QSP and her career with Dr. Musante. She thinks that expanding the use of QSP in exploratory research and drug discovery would have a dramatic impact on the efficiency of drug development. She got her PhD in applied mathematics, making her jump to pharmaceuticals a bit unusual. For people in similar situations who want to break into QSP, she recommends following your heart, knowing what you want to do, and following through by using your network to figure out how to get where you want to go. To expand the number of people interested in QSP, including to those in less traditional paths, she recommends reaching out to faculty at universities for awareness, collaborations, and to train students for future careers in QSP. When she’s not at work or advocating the QSP field, Dr. Musante loves to cook and is an avid fan of the Food Network.

Dr. Musante’s talk was followed by a mixer event where community members discussed and socialized over food and drinks. Check out the September Event: The Photo Blog for more details and highlights.

We would like to thank Novartis for sponsoring the event and CIC for sponsoring the venue.

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