Using Math to Save Lives: Tuberculosis Research at Gates Medical Research Institute
Author: Sarah Yunes
Editors: Jae Yang and Rajiv P. Shrestha
Dr. Karim Azer (left) and Scientific Writer Sarah Yunes (right) during the interview
The Bill and Melinda Gates Foundation established the Bill and Melinda Gates Medical Research Institute (MRI) to fight diseases that disproportionately affect the poorest citizens of the world. As a translational medicine institute that uses the number of lives saved as their only metric, the MRI focuses on developing drugs and diseases to eradicate tuberculosis, diarrheal disease, and malaria. To introduce the Boston QSP community to the Bill and Melinda Gates MRI and how they are using quantitative systems pharmacology (QSP) to treat tuberculosis, our speaker for our November event was Dr. Karim Azer, the Head of the Quantitative Systems Pharmacology (QSP) and Drug Metabolism and Pharmacokinetics (DMPK) Modeling at the Bill & Melinda Gates Medical Research Institute (BMG MRI). His talk was titled Development and Application of Systems Modeling Capabilities for Drug and Vaccine R&D in a Global Health Setting: Science and Administration.
Tuberculosis (TB) is a devastating disease characterized by severe coughing, coughing up blood, and chest pain that is incredibly complicated to treat. The disease, caused by the Mycobacterium tuberculosis bacteria, is also one of the well-established examples of antibiotic resistance and as such it is currently the leading cause of death from infectious diseases. The current recommended treatment revolves around multi-drug regimens to promote complete eradication of the disease in the patient and hopefully preventing drug resistance. The BMG MRI is bringing together development partners to accelerate the development of new drug combinations by maximizing what can be learned from any clinical trials performed. For example, there are about 20 known compounds used to treat tuberculosis and in a standard drug regimen, a patient will take four at the same time. This leads to about 5,000 possible combinations. It’s practically impossible to test each and every single one of these in detail. To narrow down this list, Dr. Azer and his team uses a filtering system. First, high throughput technology and statistical learning is used to remove regimens based on biological mechanism and potential drug interactions until there are only five to ten possibilities of regimens remaining. While developing the algorithm for this process is challenging, how to compare these combinations from a modeling perspective is actively being studied. From there, these regimens can be incorporated into a translational QSP platform that incorporates preclinical research. The QSP model will take into account the mechanisms of action of these drugs and how they affect the disease-relevant cells and organs. This includes determining endpoints that can be used in clinical studies to determine if the drug regimen is successfully treating the TB. The QSP model is also used to determine the PKPD of the drugs, which can be used to establish dosing procedures for trial simulations in later stages of development.
Of particular interest is how this QSP modeling can be used to determine biomarkers for TB. Gene regulatory models exist for varying stages of infection. This trait can be used to determine transcriptional signatures at different degrees of infection and to measure the rate of transition between these phases. Using this information will allow for determining entry criteria for clinical studies, measure how the drugs are affecting disease state, and figuring out as quickly as possible if a drug regimen is successful or not.
The modeling work at the BMG MRI described above is in an early phase. Dr. Azer provided an example of successfully using modeling to maximize clinical trial benefits while minimizing their use on vulnerable populations, such as children. In his previous work in neglected diseases, Dr Azer and his multi-disciplinary team used modeling to reduce the number of clinical trials in children by relying on the results from previous adult clinical trials. By using the data from adults and taking into account differences in disease progression, they were able to use adult data on biomarkers and mechanism of action to develop a model alleviating the need for clinical trials in children.
When talking to Dr. Azer about his career, he emphasized following his passion for mathematics and using that to make a larger impact on the world by helping people live healthier lives. The majority of his career was spent working for pharmaceutical companies. However, the nonprofit sector allows for a true focus on what the patients need with no regard for what is profitable. With the focus of the Gates MRI being on the developing world, some of the challenges involve getting approved by a variety of regulatory bodies across the developing world and improving drug distribution in areas where clinic and physician availability is quite low. When working in a nonprofit organization, Dr. Azer said that you need to have a strong drive to work towards the mission of the organization. He recommended that those looking to be in the nonprofit sector know what missions they are passionate about. In his free time, Dr. Azer likes to spend time with his family, being outdoors, running, and playing the piano.
Dr. Azer’s talk was followed by a mixer event where community members discussed and socialized over food and drinks. Check out the November 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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