DILIsym® and the DILI-sim Initiative Highlighted at Digestive Disease Week (DDW) 2017

DILIsym® and the DILI-sim Initiative Highlighted at Digestive Disease Week (DDW) 2017

Industry Challenges and DILIsym Contributions at DDW 2017, May 5-9 in Chicago, Illinois

Research Triangle Park, N.C., May 17, 2017 – BioWorld™, The Daily Biopharmaceutical News Source, published an article on challenges faced by industry as a result of DILI and the need for predictive tools to address these challenges. The creation of the DILI‑sim Initiative, DILIsym software, and contributions to the current understanding of DILI, including recent work to differentiate drug effects on bilirubin from functional liver deficits were discussed.

Simulations Plus to Acquire DILIsym Services, Inc.

Accretive acquisition to expand Simulations Plus offerings by adding leading provider of drug-induced liver injury (DILI) software and consulting services

May 01, 2017 08:30 AM Eastern Daylight Time

LANCASTER, Calif.--(BUSINESS WIRE)--Simulations Plus, Inc. (NASDAQ: SLP), a leading provider of simulation and modeling software for pharmaceutical discovery and development, today announced that it has entered into a Stock Purchase Agreement (the “Agreement”) with DILIsym Services, Inc. of Research Triangle Park, North Carolina.

Pursuant to the Agreement, upon closing, DILIsym Services, Inc. (“DILIsym Services”) will become a wholly owned subsidiary of Simulations Plus, Inc. (“Simulations Plus”) and will continue to operate under the DILIsym Services name. This accretive acquisition will result in the total number of Simulations Plus employees increasing from 68 to 79, and is expected to add more than $3 million to the revenues of the combined company in the coming fiscal year 2018.

Walt Woltosz, chairman and chief executive officer of Simulations Plus, said, “This is an exciting step forward for both Simulations Plus and DILIsym Services. The combination will significantly strengthen our software and consulting services efforts, and bolster our management team as well. I am pleased that the existing management team of DILIsym Services will remain with the company. The officers of DILIsym Services will be Dr. Brett Howell, who will serve as president, Dr. Scott Siler, who will serve as chief scientific officer, and Dr. Bud Nelson, who will serve as director of operations. In the aggregate, these three leaders have more than 50 years of relevant experience. I will remain as Chairman and CEO of Simulations Plus, overseeing all three divisions (Simulations Plus, DILIsym Services, and Cognigen Corporation). In addition, Professor Paul Watkins, M.D., of the University of North Carolina, internationally recognized as the foremost authority on drug-induced liver injury, will continue as the director of the DILI-sim Initiative Consortium and chairman of the Initiative’s Scientific Advisory Board. This consortium is an international group of twelve pharmaceutical companies that fund the ongoing development of the DILIsym® software.”

Dr. Brett Howell added, “Drug-induced liver injury (DILI) is a rare adverse drug reaction and is the leading cause for acute liver failure in the United States. It is also the most common factor that compels regulatory actions related to drugs, such as denial of approval or restriction of indications for using a drug. It is a prime area of concern for the U.S. Food and Drug Administration and other regulatory agencies worldwide. The DILIsym® software is the most advanced mechanistic mathematical model of drug-induced liver injury, simulating the mechanistic interactions and events from drug administration through the progression of liver injury and regeneration. DILIsym Services scientists have supported our customers to present results of DILIsym simulations to several regulatory agencies. We are excited to join Simulations Plus and take advantage of the various synergies that exist between the organizations.”

John Kneisel, chief financial officer of Simulations Plus, added, “We expect this deal will be immediately accretive to both revenues and earnings, and will not affect our ability to continue to distribute dividends. Of course, the Board of Directors determines the dividend each quarter and has the option of continuing, increasing, decreasing, or eliminating it at any time to meet the cash needs of the business.”

The Agreement

The Agreement calls for the acquisition of DILIsym Services by Simulations Plus with DILIsym Services becoming a wholly owned subsidiary of Simulations Plus following the closing of the acquisition, which is subject to final due diligence and other closing conditions. The closing date of the proposed acquisition is anticipated to be June 1, 2017.

Under the terms of the Agreement, Simulations Plus will pay the shareholders of DILIsym Services cash consideration of up to $10 million, comprised of $5 million up front plus an earn-out of up to an additional $5 million over the next three years, based on the profitability of the DILIsym Services division. The Agreement provides that $1 million of the total up-front consideration will be held back for 18 months to satisfy any indemnifiable claims that may arise pursuant to the terms of the Agreement.

Excel Partners, an investment bank with offices in New York and Los Angeles, acted as exclusive financial advisor to Simulations Plus in connection with this transaction. Procopio, Cory, Hargreaves & Savitch LLP served as legal counsel to Simulations Plus in connection with this transaction.

About Simulations Plus, Inc.

Simulations Plus, Inc. is a premier developer of groundbreaking drug discovery and development simulation and modeling software that is licensed to and used in the conduct of drug research by major pharmaceutical, biotechnology, agrochemical, and food industry companies worldwide. Simulations Plus is headquartered in Southern California and trades on the NASDAQ Capital Market under the symbol “SLP.” For more information, visit our Web site at www.simulations-plus.com.

About DILIsym Services, Inc.

DILIsym Services, Inc. was founded in 2015 in Research Triangle Park, North Carolina, and is the leading provider of drug-induced liver injury simulation software and related consulting services to the pharmaceutical industry. The company spun out of the former Hamner Institutes, acquiring all of the intellectual property, software, documentation, and other materials for the DILIsym® software. The company’s other products include MITOsym® for simulating in vitro mitochondrial function, SimPops™ for evaluating the impact of patient variability, and a new product in development called NAFLDsym™ for the study of nonalcoholic fatty liver disease – a worldwide disease with few available treatment options. For calendar year 2016, its most recent fiscal year, DILIsym Services, Inc. revenues were just over $3 million with net earnings of approximately $720,000. More information is available on the company’s Web site at https://www.dilisym.com.

Safe Harbor Statement Under the Private Securities Litigation Reform Act of 1995 – With the exception of historical information, the matters discussed in this press release are forward-looking statements that involve a number of risks and uncertainties. Words like “believe,” “expect” and “anticipate” mean that these are our best estimates as of this writing, but that there can be no assurances that expected or anticipated results or events will actually take place, so our actual future results could differ significantly from those statements. Factors that could cause or contribute to such differences include, but are not limited to: our ability to maintain our competitive advantages, acceptance of new software and improved versions of our existing software by our customers, the general economics of the pharmaceutical industry, our ability to finance growth, our ability to continue to attract and retain highly qualified technical staff, our ability to properly manage the new combined company, and a sustainable market. Further information on our risk factors is contained in our quarterly and annual reports as filed with the Securities and Exchange Commission.

Contacts

Simulations Plus Investor Relations
Ms. Renée Bouché, 661-723-7723
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or
Hayden IR
Mr. Cameron Donahue, 651-653-1854
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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

Companies Supporting DILIsym® Software Development

2016 04 DILIsim Consortium 2