Simulations Plus, Inc. · NASDAQ:SLP
Simulations Plus — Technical Presentation (January 2019)
39 slides from Simulations Plus's technical presentation, January 2019
Slide 1: DILIsym v8A Release Webinar
Please note: this presentation, including questions from the audience, is being recorded *DILIsym®, NAFLDsym®, MITOsym®, ADMET Predictor®, GastroPlus® and SimPops® are registered trademarks, and SimCohorts™ and RENAsym™ are trademarks, of DILIsym Services Inc. and/or SLP for computer modeling softwa
Slide 2: The DILIsym Services Team
The DILIsym Services Team Paul B. Watkins DILI-sim Initiative Founder and Shawn O’Connor Scientific Advisory Board Chair Scott Q Siler Brett Howell CEO, Simulations Plus Inc. RTP, NC Chief Scientific Officer President Lancaster, CA Bay Area, CA RTP, NC Lisl Shoda Grant Generaux Jeff Woodhead Kyunghe
Slide 3: DILIsym v8A Release Webinar Agenda
DILIsym v8A Release Webinar Agenda • Introduction to DILIsym Software platform • DILIsym version 8A highlights • DILIsym v8A demo • Questions 3
Slide 4: Simulations Plus (SLP) Family: Saying "I do" to the QSAR / PBPK / QST marriage
Simulations Plus (SLP) Family: Saying “I do” to the QSAR / PBPK / QST marriage… Permeability, Local & systemic solubility vs. pH, exposure, drug pKa(s), distribution, logD vs. pH, parent and Fup, metabolite blood:plasma levels, ratio, tissue Kps, patient CLint, CLfilt variability 4
Slide 5: DILIsym Services QST and QSP Models
DILIsym Services QST and QSP Models • Predicts drug-induced • Predicts acute drug- • Predicts liver disease induced kidney injury improvements in So how can DILIsym help my organization? non-alcoholic fatty liver disease with • Predict DILI liabilities beforehand and save $$$ treatment • Choose the
Slide 6: The DILI-sim Initiative is a Partnership between DILIsym Services and Pharmaceutical Companies
The DILI-sim Initiative is a Partnership between DILIsym Services and Pharmaceutical Companies to Minimize DILI • Overall Goals – Improve patient safety through QST – Reduce the need for animal testing – Reduce the costs and time necessary to develop new drugs • History – Officially started in 2011
Slide 7: DILI-sim Initiative Membership Benefits
DILI-sim Initiative Membership Benefits Access to DILIsym software, equations, and support • DILI-sim members receive access to the DILIsym software during their active membership term • DILI-sim members receive a PDF copy of all equations included in each version of the DILIsym software released du
Slide 8: DILIsym Software Licenses Are Available to Industry and Academia
DILIsym Software Licenses Are Available to Industry and Academia • DILI-sim membership not required to license the DILIsym modeling software • Training provided in various formats − Training courses and workshops DILIsym Output Table − Web-based videos − User manual − Documentation • Academic and re
Slide 9: DILI-sim Scientific Advisory Board
DILI-sim Scientific Advisory Board Dr. Neil Kaplowitz Dr. Paul B. Watkins Dr. Kevin Park Professor of Medicine DIRECTOR, INSTITUTE FOR DRUG SAFETY SCIENCES Head of Institute of Translational Medicine / USC Thomas H. Brem Chair in Medicine HOWARD Q. FERGUSON DISTINGUISHED Director, MRC Centre for Dru
Slide 10: DILIsym Overview
DILIsym Overview • Multiple species: human, rat, mouse, and dog • Over 60 detailed - Population variability representations of • The three primary acinar optimization or zones of liver represented validation compounds • Essential cellular with 80% success processes represented to multiple scales in
Slide 11: Variability and Enhanced Software Highlight Stage 3 Areas of Focus
Immunology, Cholestasis, Population Variability and Enhanced Software Highlight Stage 3 Areas of Focus • Immunology is a critical area for latent DILI and many oncology related DILI events • Cholestasis has become increasingly important from a regulatory standpoint – Phospholipids and MDR3 an import
Slide 12: DILIsym Utilizes Various Data Types to Inform Decisions
DILIsym Utilizes Various Data Types to Inform Decisions Exposure Data Modeling & PBPK Modeling Simulation • Compound Properties - Tissue partition coefficients Simulations and Assays inform: • Tissue penetration studies • Prediction of DILI risk - Liver to blood ratio • Participating DILI mechanisms
Slide 13: Known DILIsym Applications Submitted to or Intended for Regulatory Agencies
Known DILIsym Applications Submitted to or Intended for Regulatory Agencies Presented/ N Agency Context Scenario Simulation Type Submitted By Simulation results included in formal, written correspondence to Hepatocyte loss (biomarker 1 FDA agency Sponsor responding to concerns over liver safety sign
Slide 14: Refactored DILIsym and GastroPlus Will Be Integrated for More Efficient and Powerful Predictions
Refactored DILIsym and GastroPlus Will Be Integrated for More Efficient and Powerful Predictions DILIsym Stand-alone • Integration will Both DILIsym occur via an and GastroPlus X interoperability DILIsym within plugin will operate GastroPlus X independently of • During integration, each other DILIsy
Slide 15: DILIsym v8A Release Webinar Agenda
DILIsym v8A Release Webinar Agenda • Introduction to DILIsym Software platform • DILIsym version 8A highlights • DILIsym v8A demo • Questions 15
Slide 16: Highlights of DILIsym v8A (Released Jan 2019)
Highlights of DILIsym v8A (Released Jan 2019) • 10 NEW exemplar Compounds included with varying clinical presentations – Includes several GSK compounds and valproate • NEW Cholestatic liver injury mechanism • UPDATED SimPops with re-calibrated bile acid sub- including MDR3 inhibition and phospholipi
Slide 17: 10 New Compounds Included in DILIsym v8A
10 New Compounds Included in DILIsym v8A • Seven GSK compounds: Phenoxybenzamine, Zafirlukast, Fluconazole, GSK Compound A, GSK Compound B, GSK Compound C, and GSK Compound D – Represented by both GSK and DILIsym Services in parallel – DILIsym Services correctly predicted hepatotoxicity (or lack of
Slide 18: MDR3 Inhibition Can Alter Canalicular Phospholipid Levels and Increase Cholestasis Risk
MDR3 Inhibition Can Alter Canalicular Phospholipid Levels and Increase Cholestasis Risk Hepatocellular • Alterations in the canalicular ratio of BA to toxicity PL can increase risk of cholangiocyte death and cholestasis • Steps to Incorporate Cholestasis Submodel into DILIsym : Bile BA Acids 1. Repr
Slide 19: Cholestasis Sub-Model Constructed
Cholestasis Sub-Model Constructed • Cholangiocyte model consists of mature, Mature Young mitotic, young, and apoptotic cholangiocytes Cholangiocytes Cholangiocytes – Cell numbers suggested by Barros 2009, Yoo 2016, Xia 2006 • BA:PL ratio modulation will increase cellular Mitotic apoptosis (Chang 201
Slide 20: MDR3 Inhibition Can Lead to Simulated ALP Increases
MDR3 Inhibition Can Lead to Simulated ALP Increases HUMAN • Theoretical MDR3 inhibitor 2.50E+07 Number of cholangiocytes introduced to cholangiocyte- 2.00E+07 phospholipid-bile acid system 1.50E+07 1.00E+07 – Causes disruption in phospholipid transport, leading to increased BA:PL 5.00E+06 ratio 0.00
Slide 21: NRF-2 Based ROS/RNS Adaptation Framework in DILIsym v8A for Exploration
NRF-2 Based ROS/RNS Adaptation Framework in DILIsym v8A for Exploration RNS/ROS RNS/ROS • DILIsym incorporates adaptive response to Balance Clearance RNS/ROS levels in the form of NRF-2 induction of GSH synthesis, which can + decrease levels of reactive species + Enzymatic • NRF-2 drives other respo
Slide 22: DILIsym v8A ROS Sub-model is Same as DILIsym v7A by default
DILIsym v8A ROS (Oxidative Stress) Sub-model is Same as DILIsym v7A by default By default enzymatic antioxidant switch is “off” 22
Slide 23: DILIsym v8A ROS Sub-model with Exploratory Enzymatic Antioxidant Mechanism
DILIsym v8A ROS Sub-model with Exploratory Enzymatic Antioxidant Mechanism Enzymatic antioxidant switch must be turned “on” RNS/ROS NON-enzymatic Enzymatic clearance Feedback: fold increase in NRF-2 leads to increased clearance from enzymatic sources 23
Slide 24: Access of Exploratory Mechanism Using Switch and Output Panel
Access of Exploratory Mechanism Using Switch and Output Panel • 1 new parameter as switch to activate enzymatic clearance • New output panel 24
Slide 25: NRF-2 Adaptation Mechanism Reduces ROS Levels
NRF-2 Adaptation Mechanism Reduces ROS Levels 1x single 0.6x loading dose of dose followed compound by 1x dose of with compound oxidative with oxidative stress stress HUMAN HUMAN Simulation Results 25
Slide 26: NRF-2 Adaptation Mechanism Reduces ALT
NRF-2 Adaptation Mechanism Reduces ALT 1x single 0.6x loading dose of dose followed compound by 1x dose of with compound oxidative with oxidative stress stress HUMAN HUMAN Simulation Results 26
Slide 27: Bilirubin SimPops Allows Simulation of Variability in Response to Bilirubin Processing Perturbation
Bilirubin SimPops Allows Simulation of Variability in Response to Bilirubin Processing Perturbation • Bilirubin SimPops (n=285) with normal baseline serum total bilirubin (< 1 mg/dL) has been created – Variability added to several parameters related to bilirubin disposition • Bilirubin SimPops that
Slide 28: Influence of UGT1A1 Polymorphisms and Efavirenz on Serum Bilirubin Simulated
Influence of UGT1A1 Polymorphisms and Efavirenz on Serum Bilirubin Simulated HUMAN Clinical • Efavirenz monotherapy significantly reduced total, conjugated and unconjugated serum bilirubin levels TB – 600 mg/day efavirenz for 17 days – Serum bilirubin levels measured at study entry (screen) and 1 we
Slide 29: Influence of UGT1A1 Polymorphisms and Efavirenz on Serum Bilirubin Simulated
Influence of UGT1A1 Polymorphisms and Efavirenz on Serum Bilirubin Simulated HUMAN Clinical Sim: UGT induction Sim: UGT/MRP2 induction Sim: UGT/OATP induction **** **** **** TB **** **** **** **** **** **** **** **** **** UB **** **** **** **** **** **** X ** ** CB **** **** **** ***
Slide 30: GLDH to Be Included in DILIsym v8A with Similar Mathematical Structure to ALT
GLDH to Be Included in DILIsym v8A with Similar Mathematical Structure to ALT • GLDH is a mitochondrial enzyme MICE primarily found in liver • Similar to ALT, elevations of serum GLDH are a result of enzyme release due to hepatocellular necrosis and/or apoptosis • Elevations in GLDH may provide a me
Slide 31: Human GLDH Sub-model Successfully Recapitulates GLDH Clinical Data
Human GLDH Sub-model Successfully Recapitulates GLDH Clinical Data HUMAN • The time profile of simulated ALT was determined by invoking the direct necrosis model implemented in the DILIsym – The amount of hepatocellular death was optimized using clinical ALT as a target signal (McGill 2012) • Using
Slide 32: Rat GLDH Sub-model Recapitulates GLDH Preclinical Rat Data
Rat GLDH Sub-model Recapitulates GLDH Preclinical Rat Data RAT 500 mg/kg 1000 mg/kg 1500 mg/kg Thulin 2017 • Preclinical Data: Groups of male Crl:WI (Han) rats 6 – 8 weeks of Key DILIsym Parameters Value Source (comment) age received 500, 1000, or 1500 mg/kg of APAP p.o. (Thulin 2017) Thulin et al (
Slide 33: DILIsym v8A Includes Neutrophils
DILIsym v8A Includes Neutrophils Liver Neutrophils (Simulation) • Following APAP overdose, magnitude of Mouse APAP PMNs Lawson 2000 C3H 300mgperkg (Experiment) Williams 2014 C57Bl6 300mgperkg (Experiment) simulated PMN accumulation is consistent 80 Williams 2011 C57Bl6 530mgperkg (Experiment) Liu 20
Slide 34: Bile Acid Renal Clearance and ASBT-Mediated Gut Reuptake Added for v8A
Bile Acid Renal Clearance and ASBT- Mediated Gut Reuptake Added for v8A • DILIsym v8A includes the CDCA renal Serum effect of renal clearance clearance CDCA on plasma bile acids • Saturable gut uptake Portal implemented in v8A blood CDCA – Recirculation fraction used in v7A Hepatocyte • All bile aci
Slide 35: Human Plasma Bile Acids Recapitulate Literature Data Better in v8A
Human Plasma Bile Acids Recapitulate Literature Data Better in v8A • v8A_1 SimPops used to model bosentan (500 mg BID, 30 days) v4A-v7A – Bile acids at beginning and end of simulation compared to Fattinger data for individuals with 10000 ALT elevations that do not Fattinger 2001, pre-treatment Fatti
Slide 36: DILIsym v8A Release Webinar Agenda
DILIsym v8A Release Webinar Agenda • Introduction to DILIsym Software platform • DILIsym version 8A highlights • DILIsym v8A demo • Questions 36
Slide 37: Key DILIsym Dates in 2019
Key DILIsym Dates in 2019 2018 2019 Q2 Q3 Q4 March 28th TBD Q1 update Q3 DILI-sim F2F TBD Q2 Update TBD Q4 update DILIsym 1 or 3 day training course Redwood City, CA February 25th – 27th Remote or onsite attendance! 37
Slide 38: 3 Day DILIsym Workshop Will Be Offered in Redwood City, CA in February
3 Day DILIsym Workshop Will Be Offered in Redwood City, CA in February Alongside GastroPlus Training: Remote Attendance Offered • When: Feb. 25-27, 2019 (3 day workshop or mix and match days) • Where: Seaport Conference Center, Redwood City, CA or attend remotely • What: 3 day DILIsym workshop to in
Slide 39: Questions?
Questions? Contact Us Today for a Free Trial Version! www.DILIsym.com www.Simulations-Plus.com/contact/ Email: bhowell@DILIsym.com Phone: 919-558-1323 39
Simulations Plus — Technical Presentation (January 2019) on 6ix