DILIsym Services, Inc. Evaluates Prospective NAFLD Treatment, Utilizing Its Flagship Technology in Collaboration with Pfizer, Inc.

Companies will present preliminary results at ASCPT on March 17 in Washington, D.C.

Research Triangle Park, N.C., March 17, 2017 – DILIsym Services, Inc. presented today results from a collaborative study with Pfizer Inc. (NYSE: PFE) at the 2017 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) conference in Washington, D.C. The study, titled “QSP Modeling of Liver AMPK Activation Using NAFLDsym™ is Predicted to Reduce Steatosis in NAFLD Patients,” is a collaborative effort between scientists at both companies to utilize a novel mathematical modeling tool to predict the improvement for patients with non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) following treatment with a new potential therapeutic being developed by Pfizer. The collaboration utilizes DILIsym Services’ quantitative systems pharmacology (QSP) modeling software, NAFLDsym™.

NAFLDsym™ can be used to evaluate novel treatments for NASH and NAFLD by utilizing NAFLD SimPops™ (simulated populations) to predict clinical efficacy. In the study, the predicted efficacy of a specific NAFLD therapeutic target was evaluated. Candidate drugs can also be evaluated by employing key laboratory and/or clinical data describing DMPK and pharmacodynamic characteristics, enabling pharmaceutical companies to prioritize compounds and targets. Additionally, NAFLDsym™ can be used to help optimize clinical trial protocols by determining favorable dosing paradigms and outcome measurement frequency (i.e., liver fat reduction). The current work is the latest success in an ongoing collaboration between DILIsym Services, Inc. and Pfizer utilizing NAFLDsym™ to evaluate specific liver enzymes as targets for effective NASH/NAFLD treatments.

NAFLDsym™ includes many of the primary components of NASH/NAFLD pathophysiology: Steatosis, regulation of liver triglyceride and fatty acids, lipotoxicity, liver injury and proliferation, hepatocellular bioenergetics, innate immune system and inflammatory mediators, dynamic body weight and its effects on lipids, and biomarkers (e.g., ALT, AST, cytokeratin cleaved K18). These mechanistic components are combined in NAFLDsym™ to generate >300 simulated NAFLD patients. Reflecting clinical patient populations, these populations of simulated NAFLD patients (SimPops™) not only have steatosis, but many also have liver injury (e.g., elevated ALT). NAFLDsym™ is an adaptation of DILIsym Services, Inc. flagship predictive liver injury software, DILIsym®.

“NAFLD is emerging as the primary cause of serious liver disease worldwide, and there are no clearly effective drug treatments for this condition as of yet.  NAFLDsym™ is showing great promise to guide and accelerate the development of new medicines to treat this condition,” said Paul Watkins, Professor of Pharmacy, Medicine, and Public Health at The University of North Carolina at Chapel Hill (UNC) and the Director of the University of North Carolina Institute for Drug Safety Science and DILIsym Services, Inc. Chairman of the Board of Directors.

“For a condition with limited treatment options, a platform like the NAFLDsym could potentially influence the way patients with NAFLD/NASH receive treatment. With the ability to evaluate and compare multiple therapeutic targets, we can potentially prioritize therapies or combination therapies that can have a more positive impact for the patient.,” said Morris Birnbaum, Senior Vice President and Chief Scientific Officer, Internal Medicine, Pfizer.



About NAFLD and NASH

Non-alcoholic steatohepatitis (NASH) is an advanced stage of non-alcoholic fatty liver disease (NAFLD), which is categorized at early stages as excessive fat accumulation in the liver, and it is mostly asymptomatic. NASH develops when excess fat accumulates in the liver (>5% liver fat) accompanied with inflammation and hepatic cellular injury. While fat accumulation in the liver alone does not correlate with increased morbidity or mortality, the progression to NASH increases the risk of cirrhosis, liver failure and liver cancer. Morbidity and mortality from liver diseases are increased in patients with NASH, and they correlate strongly with the morbidity and mortality of cardiovascular diseases.



The prevalence of NASH in the general U.S. population is estimated at 3‑5% and around 2-4% globally. NASH is mostly diagnosed in patients with obesity, diabetes, high cholesterol and triglycerides levels, and insulin resistance. With currently no approved therapies to treat NASH, this is an area of great unmet medical need.



References:
Armstrong et al, Hepatology 2014 
Chalasani et al, Hepatology 2012
LaBrecque et al, J Clin Gastroenterol 2014, & WGO Global Guideline, 2012
Lazo et al, Am J Epidemiol 2013
Sanyal et al, Clinical Liver Disease 2015
Vernon et al, Aliment Pharmacol Ther 2011
Williams et al, Gastroenterology 2011
Younossi et al, Hepatology 2011
Younossi et al, Hepatology 2016
Wree, et al, Nat Rev Gastroenterol Hepatol 2013



About DILIsym Services, Inc.

DILIsym Services, Inc. is a leader in quantitative systems toxicology (QST) and quantitative systems pharmacology (QSP), providing software and consulting to improve the safety and efficacy profiles of therapeutics reaching the market. DILIsym Services, Inc. has programs in NAFLD and drug-induced liver injury, employing the QSP platform NAFLDsym™ and the QST platform DILIsym®. Moreover, DILIsym Services, Inc. is the coordinating member of the DILI-sim Initiative, a consortium comprised of 12 pharmaceutical companies with the goals of the DILI-sim Initiative including developing the DILIsym® software and advancing the knowledge of DILI for the benefit of the scientific community and the public at-large. More information about NAFLDsym™ software can be found at www.dilisym.com (http://www.dilisym.com/Products-Services/nafldsym.html).



DILIsym Services, Inc. Contact:

Scott Q. Siler (This email address is being protected from spambots. You need JavaScript enabled to view it.)

President

510.470.3452

DILIsym Services, Inc. Utilizes Flagship Technology to Evaluate Prospective NAFLD Treatments in Collaboration with Pfizer, Inc.

Companies will present preliminary results at ACoP7 on October 25 in Bellevue, Washington


Research Triangle Park, N.C., Oct. 19, 2016 – DILIsym Services, Inc. is pleased to announce that initial results from an ongoing collaboration with Pfizer Inc. (NYSE: PFE) will be presented on October 25 at the Seventh American Conference on Pharmacometrics (ACoP7) conference in Bellevue, Washington. The abstract being presented, “Predicting the safety and efficacy of inhibition of diacylglycerol transferase 2 for the treatment of non-alcoholic fatty liver disease (NAFLD),” is a collaborative effort between scientists at both companies to create a novel mathematical modeling tool to potentially predict liver injury progression in patients by simulating non-alcoholic fatty liver disease (NAFLD) and its improvement with treatment. The collaboration utilizes DILIsym Services’ new quantitative systems pharmacology (QSP) modeling software, NAFLDsym™.

NAFLDsym™ can be used to help evaluate treatment modalities for NAFLD by utilizing the NAFLD SimPops™ to predict efficacy, as was done in the work being presented at the ACoP7 conference. Specific compounds can be simulated by utilizing key laboratory and/or clinical data describing DMPK and pharmacodynamic characteristics, enabling pharmaceutical companies to prioritize compounds and targets. Additionally, NAFLDsym™ can be used to help optimize clinical trial protocols by determining favorable dosing paradigms and outcome (i.e., liver fat reduction) measurement frequency.

NAFLDsym™ includes many of the primary components of NAFLD pathophysiology: Steatosis, regulation of liver triglyceride and fatty acids, lipotoxicity, liver injury and proliferation, hepatocellular bioenergetics, innate immune system and inflammatory mediators, dynamic body weight and its effects on lipids, and biomarkers (e.g., ALT, AST, cytokeratin cleaved K18). These mechanistic components are combined in NAFLDsym™ to generate >300 simulated NAFLD patients. Reflecting clinical patient populations, these populations of simulated NAFLD patients (SimPops™) not only have steatosis, but many also have liver injury (e.g., elevated ALT). NAFLDsym™ is an adaptation of DILIsym Services, Inc. flagship predictive liver injury software, DILIsym®.

“NAFLD is emerging as the primary reason for liver disease in many parts of the world, including the U.S., Europe and China, and we are excited about the role NAFLDsym™ can play in accelerating the development of medicines to treat this condition,” said Paul Watkins, Professor of Pharmacy, Medicine, and Public Health at The University of North Carolina at Chapel Hill (UNC) and the Director of the University of North Carolina Institute for Drug Safety Science and DILIsym Services, Inc. Chairman of the Board of Directors.

“We believe that a reliable predictive model for NAFLD could potentially become an industry-standard tool used to monitor potential treatments for patients with NAFLD/NASH, for which limited treatment options currently exist,” said Morris Birnbaum, Senior Vice President and Chief Scientific Officer, Cardiovascular and Metabolic Research Unit, Pfizer. “Our collaboration with DILIsym has been positive to date, and we look forward to the results that we can generate together.”



About NAFLD and NASH

Non-alcoholic steatohepatitis (NASH) is an advanced stage of non-alcoholic fatty liver disease (NAFLD), which is categorized at early stages as excessive fat accumulation in the liver, and it is mostly asymptomatic. NASH develops when excess fat accumulates in the liver (>5% liver fat) accompanied with inflammation and hepatic cellular injury. While fat accumulation in the liver alone does not correlate with increased morbidity or mortality, the progression to NASH increases the risk of cirrhosis, liver failure and liver cancer. Morbidity and mortality from liver diseases are increased in patients with NASH, and they correlate strongly with the morbidity and mortality of cardiovascular diseases.

The prevalence of NASH in the general U.S. population is estimated at 3‑5% and around 2-4% globally. NASH is mostly diagnosed in patients with obesity, diabetes, high cholesterol and triglycerides levels, and insulin resistance. With currently no approved therapies to treat NASH, this is an area of great unmet medical need.



References:

Armstrong et al, Hepatology 2014 
Chalasani et al, Hepatology 2012
LaBrecque et al, J Clin Gastroenterol 2014, & WGO Global Guideline, 2012
Lazo et al, Am J Epidemiol 2013
Sanyal et al, Clinical Liver Disease 2015
Vernon et al, Aliment Pharmacol Ther 2011
Williams et al, Gastroenterology 2011
Younossi et al, Hepatology 2011
Younossi et al, Hepatology 2016
Wree, et al, Nat Rev Gastroenterol Hepatol 2013



About DILIsym Services, Inc.

DILIsym Services, Inc. is a leader in quantitative systems toxicology (QST) and quantitative systems pharmacology (QSP), providing software and consulting to improve the safety and efficacy profiles of therapeutics reaching the market. DILIsym Services, Inc. has programs in NAFLD and drug-induced liver injury, employing the QSP platform NAFLDsym™ and the QST platform DILIsym®. Moreover, DILIsym Services, Inc. is the coordinating member of the DILI-sim Initiative, a consortium comprised of 12 pharmaceutical companies with the goals of the DILI-sim Initiative including developing the DILIsym® software and advancing the knowledge of DILI for the benefit of the scientific community and the public at-large. More information about NAFLDsym™ software can be found at www.dilisym.com (http://www.dilisym.com/Products-Services/nafldsym.html).



DILIsym Services, Inc. Contact:

Scott Q. Siler (This email address is being protected from spambots. You need JavaScript enabled to view it.)
President
510.470.3452

DSSI and Otsuka Joint Publication – DILIsym used to identify Mechanisms of Tolvaptan Hepatotoxicity

Tolvaptan is a promising treatment for Autosomal Dominant Polycystic Kidney Disease (ADPKD), but was not approved by the FDA because some patients in the clinical trials developed liver injury. Starting in 2014, Otsuka sponsored the Tolvaptan Initiative, a multi-project, multi-disciplinary effort to 1) provide a mechanistic understanding of tolvaptan toxicity and 2) identify genetic and non‑genetic risk factors that could be used in the clinic to identify ADPKD patients at risk for tolvaptan‑induced liver injury.  DSSI was engaged by Otsuka to apply DILIsym® software to address this challenge. In vitro data on potential mechanisms of toxicity of parent tolvaptan and its major metabolites were obtained by BioEnergetics LLC and Dr. Kim Brouwer’s laboratory at the University of North Carolina (UNC) at Chapel Hill. Clinical data to perform PBPK modeling for tolvaptan and metabolites were provided to DSSI by Otsuka. DILIsym simulations using these data accurately reproduced the incidence of liver injury observed in the clinical trials, suggesting the mechanisms of toxicity identified in vitro could have predicted the liver safety liability of tolvaptan in the ADPKD population. Further analysis of the simulations led to the identification of pre‑treatment and on‑treatment blood tests that may be useful in the clinic to identify susceptible subjects before they develop liver injury. Together, the results provide a mechanistic back-drop for the observed liver signals and support ongoing efforts to identify and qualify biomarkers to manage the risk of liver injury in tolvaptan treated patients with ADPKD. In addition, this work builds on prior publications that support the use of DILIsym® in understanding, predicting and preventing drug-induced liver injury.

Researchers at Otsuka, BioEnergetics, UNC, and DSSI collaborated on a joint manuscript describing this research. The manuscript has been published by Toxicological Sciences and is available via open access:

https://www.ncbi.nlm.nih.gov/pubmed/27655350

DILIsym at the PSTC BSEP Webinar Series

PSTC BSEP Webinar Series – Current trends in BSEP inhibition and perturbation to bile acid homeostasis as mechanisms of drug-induced liver injury

In 2016, the Predictive Safety Testing Consortium (PSTC) organized a webinar series around inhibition of the bile salt export pump (BSEP) and subsequent perturbations to bile acid homeostasis as a mechanism of drug-induced liver injury. This was a six-part series with presentations by top researchers in the field on current research and clinical examples, in vitro and in vivo tools for identifying BSEP liabilities or bile acid perturbations, and future directions.

Drs. Brett Howell and Paul Watkins were speakers in the 6th session of the series, entitled, “Future direction and next steps”. Dr. Howell’s presentation, “Combining BSEP inhibition data with mathematical modeling to impact decisions in drug development” discussed key factors regulating the functional impact of BSEP inhibition (e.g., compound exposure kinetics, type of inhibition) and provided examples of how the DILI-sim Initiative is combining experimental techniques and mathematical modeling to inform questions around drugs with BSEP inhibition liabilities. Dr. Watkins’ presentation, “The future: how BSEP inhibition investigations will aid improved DILI predictions” provided an overall perspective on the interpretation of serum bile acid profiles in bile‑acid mediated DILI, including the application of DILIsym® to predict and improve the understanding of troglitazone DILI.

The link to the video presentations in the PSTC BSEP webinar series, including those by Dr. Howell and Dr. Watkins can be found below.

https://c-path.org/current-trends-in-bsep-inhibition-and-perturbation-to-bile-acid-homeostasis-as-mechanisms-of-drug-induced-liver-injury/

DILIsym® v5A Released

RESEARCH TRIANGLE PARK, NC – DILIsym Services Inc. (www.dilisymservices.com) announces the release of DILIsym® v5A. DILIsym® software is developed and released as part of the DILI-sim Initiative (www.dilisym.com), an effort to develop a mathematical, mechanistic model of drug-induced liver injury chaired by Dr. Paul B. Watkins. DILIsym® v5A was made available to all DILI-sim Initiative industry members as of July 18, 2016.

DILIsym® v5A introduces several new validation compounds, including TAK875 (Takeda), MK0536 (Merck), CKA (AstraZeneca), and AMG853 (Amgen). A new mechanism of toxicity, mitochondrial DNA depletion has been added, with fialuridine (FIAU) as the exemplar compound. A mechanistic representation of bilirubin transport and metabolism has been added, with indinavir and CKA as exemplar compounds. DILIsym® v5A also features a non‑alcoholic fatty liver disease (NAFLD) SimPops™.


ABOUT THE DILI-SIM INITIATIVE

The DILI-sim Initiative is a pre-competitive partnership between DILIsym Services Inc. and a diverse set of stakeholders to develop a computational model that will predict whether new drug candidates will cause drug-induced liver injury (DILI) in patients. The goals of the Initiative are to improve patient safety, reduce the need for animal testing, and reduce the costs and time necessary to develop new drugs. It is the intent of the DILI-sim Initiative to make the model, in the form of DILIsym® software, broadly available so that it may be used by the pharmaceutical industry and other entities in academia, government, and industry. The Initiative is led by Dr. Paul B. Watkins, Director of the University of North Carolina Institute for Drug Safety Sciences, located in the heart of Research Triangle Park, North Carolina. For more information, please visit www.dilisym.com.



ABOUT DILISYM SERVICES INCORPORATED

DILIsym Services, Inc. was incorporated in 2015 and is operated in Research Triangle Park, North Carolina. DILIsym Services, Inc. is a startup company committed to providing the pharmaceutical industry with the tools, resources, and information to efficiently develop safer drug therapies that increase the availability of vital therapeutics for the patients who need them. DILIsym Services, Inc.applies the DILIsym® software to improve the safety profiles of therapeutics reaching the market. 

For more information, please visit www.dilisymservices.com