Slide 1: NAFLDsym v2A Release Webinar
6” 9 DiLisymServices g'g Or g A SIMULATIONS PLUS COMPANY NANeLDSwrin WAN Release Webinat April 9, 2019 Scott Q Siler, Chief Scientific Officer DILIsym Services Division Simulations Plus
Slide 2: Disclaimer
Disclaimer: DILIsym® Services are developed and provided as an educational tool based on assessment of the current scientific and clinical information, and accepted approaches for drug safety and efficacy. The resultant data, suggestions, and conclusions (“Guidelines”) should not be considered inclu
Slide 3: NAFLDsym Is Designed to Support Drug Development with Efficacy Predictions
NAFLDsym Is Designed to Support Drug Development with Efficacy Predictions • NAFLD is a progressive disease of the liver • Incidence is growing worldwide with few treatment options – Substantial opportunity to improve health for many patients by developing treatments • NAFLDsym is a QSP model of NAF
Slide 4: DILIsym Services, Inc.
DILIsym Services, Inc. “Our vision is safer, effective, more affordable medicines for patients through modeling and simulation.” • DILIsym Services, Inc. offers comprehensive program services: – DILIsym software licensing, training, development (DILI-sim Initiative) – NAFLDsym software licensing, tr
Slide 5: Your "End-to-End" Software Provider
Simulations Plus Inc. (NASDAQ: SLP): Your “End-to-End” Software Provider HO Discovery Preclinical Clinical CH3 N H O CH3 H3C O ADMET Predictor® GastroPlus® MedChem Studio™ DDDPlus™ PKPlus™ KIWI™ MedChem Designer™ MembranePlus™ DILIsym® NAFLDsym® Consulting Services and Collaborations 5
Slide 6: Outline
Outline • Introduction to NAFLDsym Modeling Software • Demonstration of NAFLDsym v2A Software • Example NAFLDsym Application • NAFLDsym Licensing and Services Projects 6
Slide 7: NAFLDsym Predicts Efficacy via Pathophysiology, Exposure, and PD
NAFLDsym Predicts Efficacy via the Intersection Between Pathophysiology Mechanisms, Compound Exposure, and PD Exposure Pharmacodynamics Efficacy Pathophysiology 7
Slide 8: NAFLDsym v2A Overview
NAFLDsym v2A Overview Multiple interacting sub-models, including Clinical data from • Steatosis literature used to • Lipotoxicity establish quantitative • Inflammation relationships for • Fibrosis underlying biochemistry • Biomarkers • Weight gain/loss Numerous simulated Provides ability to patients
Slide 9: Pathophysiologic Variability Represented in NAFLDsym with NAFLD/NASH SimPops
Pathophysiologic Variability Represented in NAFLDsym with NAFLD/NASH SimPops • SimPops are population samples with variability across key areas of NAFLD/NASH pathophysiology • Multiple parameters are varied to produce diverse possible simulated patients • Simulated patients are compared with a multi
Slide 10: NAFLDsym v2A Overview: Steatosis-Lipotoxicity
NAFLDsym v2A Overview: Steatosis-Lipotoxicity 10
Slide 11: Simulated Patients with Steatosis, DNL, and Liver Injury Consistent with Clinical Data
NAFLDsym v2A Includes Simulated Patients with Steatosis, DNL, and Liver Injury Consistent with Clinical Data • Simulated patients have wide range of contributions to steatosis from DNL – Consistent with Lambert 2014 observation that frequency of elevated DNL higher in patients with extensive steatos
Slide 12: NAFLDsym v2A Overview: Inflammation
NAFLDsym v2A Overview: Inflammation 12
Slide 13: Lobular Macrophage and Neutrophil Numbers Consistent with Clinical Data
NAFLDsym v2A Includes Lobular Macrophage and Neutrophil Numbers Consistent with Clinical Data • Multiple papers indicate that lobular inflammatory cell numbers do not appear to change with NAFLD disease severity (Krenkel 2017, Tajiri 2009, Rensen 2009, Leicester 2006) • Lobular macrophages and neutr
Slide 14: Mediators Consistent with Majority of Data: TGF-β, PDGF
NAFLDsym v2A Include Mediators Consistent with the Majority of Data: TGF-β, PDGF • Simulation results demonstrate modest increases in TGF-β consistent with the reported range (Das 2011) – Other data show no change or modest increases with disease severity • Simulation results demonstrate modest incr
Slide 15: NAFLDsym v2A Overview: Fibrosis
NAFLDsym v2A Overview: Fibrosis 15
Slide 16: Activated HSC Consistent with Clinical Data
NAFLDsym v2A Includes Activated HSC Consistent with Clinical Data Increasing Km of HSC activation • Simulated patients have increasing CL number of activated hepatic stellate cells (aHSC) with increasing fibrosis stage – Consistent with clinical data showing increased HSC activation with more extens
Slide 17: Collagen Synthesis Rates Consistent with Clinical Data
NAFLDsym v2A Has a Range of Collagen Synthesis Rates Consistent with Clinical Data • Rates of collagen I synthesis are greater Simulation results Clinical data in higher fibrosis stages – Consistent with clinical data showing increased collagen synthesis rates in NASH patients (Decaris 2017) – Rates
Slide 18: Hepatic Collagen Levels Consistent with Clinical Data
NAFLDsym v2A Has a Range of Hepatic Collagen Levels Consistent with Clinical Data • Hepatic collagen I and III levels are Simulation results Clinical data comparable in fibrosis stages 0, 1, 2 – Consistent with clinical data showing collagen levels in NASH patients (Masugi 2018) – Histologic assessm
Slide 19: SimPops Patients Include Common Measurements of Treatment Efficacy
NAFLDsym v2A SimPops Patients Include Common Measurements of Treatment Efficacy Plasma Histology Imaging Biomarkers Measurements measurements Liver fat percentage Plasma TG Steatosis score (MRI) Liver stiffness Plasma ALT Ballooning score (MRE) Plasma cytokeratin Inflammation score cleaved 18 (cK18)
Slide 20: SimPops Simulated ProC3 is Consistent with Reported Clinical Data
NAFLDsym SimPops Simulated ProC3 is Consistent with Reported Clinical Data • ProC3 is a biomarker of collagen synthesis Levin 2017 – Proteolytic fragment of procollagen 3 that SimPops enters the circulation – Production rate of ProC3 is based on the synthesis rate of collagen 3 • Simulated ProC3 ali
Slide 21: SimPops Simulated Liver Stiffness (MRE) is Consistent with Clinical Data
NAFLDsym SimPops Simulated Liver Stiffness (MRE) is Consistent with Reported Clinical Data • Liver stiffness is an imaging biomarker of hepatic collagen levels – Magnetic resonance elastography (MRE) • NAFLDsym includes liver stiffness as an output – Liver stiffness levels correspond with amount of
Slide 22: Pathophysiologic Variability Represented in NAFLDsym with NAFLD/NASH SimPops
Pathophysiologic Variability Represented in NAFLDsym with NAFLD/NASH SimPops • SimPops are population samples with variability across key areas of NAFLD/NASH pathophysiology • Multiple parameters are varied to produce diverse possible simulated patients • Simulated patients are compared with a multi
Slide 23: SimPops Predicted Response to Weight Loss Consistent with Clinical Data: NAS
NAFLDsym v2A SimPops Predicted Response to Weight Loss is Consistent with Clinical Data: NAS • Weight loss has been shown to improve NASH and fibrosis Emergent – Current standard of care behavior – Greater efficacy with greater weight loss • Simulated ≈5% weight loss over 1 year – Comparable to data
Slide 24: SimPops and SimCohorts
NAFLDsym v2A SimPops and SimCohorts Validation filtering Interim General SimPops NAS ≤3 NAS ≥4 SimCohorts SimCohorts Trx Validation: SimCohorts for Weight loss F0 F3 prospective clinical SimCohorts SimCohorts studies can be selected NAFLD/NASH SimPops from SimPops F1 F4 SimCohorts SimCohorts Prospec
Slide 25: Outline
Outline • Introduction to NAFLDsym Modeling Software • Demonstration of NAFLDsym v2A Software • Example NAFLDsym Application • NAFLDsym Licensing and Services Projects 25
Slide 26: Outline
Outline • Introduction to NAFLDsym Modeling Software • Demonstration of NAFLDsym v2A Software • Example NAFLDsym Application • NAFLDsym Licensing and Services Projects 26
Slide 27: NAFLDsym Was Used to Support the Clinical Development of the ACCi GS-0976
NAFLDsym Was Used to Support the Clinical Development of the ACCi GS-0976 • Early clinical results indicated GS-0976 MoA may be more complex than initially believed • NAFLDsym employed to evaluate MoA hypotheses – Developed PBPK model of GS-0976 (exposure) – Utilized existing preclinical and clinica
Slide 28: ACC Inhibitor GS-0976 Has Demonstrated Ability to Reduce Liver Fat
ACC Inhibitor GS-0976 Has Demonstrated Ability to Reduce Liver Fat • GS-0976: Liver-targeted ACC inhibition – Direct pharmacological effects on de novo lipogenesis and fatty acid oxidation • Single dose clinical study revealed rapid, potent ability to inhibit hepatic DNL – Oral fructose challenge; S
Slide 29: GS-0976 Direct and Downstream PD Effects Included in NAFLDsym
GS-0976 Direct and Downstream PD Effects Included in NAFLDsym • ACC inhibitor directly reduces Malonyl CoA levels – Increases potential for increased fatty acid oxidation (ACC2) FA oxidation Mito ATP production – Decreases de novo lipogenesis (ACC1) Cleaved Cytokeratin 18 RNS/ROS Apoptosis + product
Slide 30: Good Agreement between GS-0976 Phase 2 Data and NAFLDsym Results Validates MoA
Good Agreement between GS-0976 Phase 2 Clinical Data and NAFLDsym Simulation Results Validates MoA Hypotheses Measure Dose Sampling Clinical Simulation time data results Liver fat (%) 20 mg Baseline 16.3 16.5 Liver fat (%) 20 mg Week 12 11.6 11.0 Liver fat (%) 5 mg Baseline 16.4 16.5 Liver fat (%) 5
Slide 31: Co-administration of Fibrates with GS-0976 Can Ameliorate Plasma TG Increases
Co-administration of Fibrates with GS-0976 Can Ameliorate Plasma TG Increases • Preclinical and clinical data suggest that co- administration of ACCi with a PPAR-a agonist can ameliorate hypertriglyceridemia induced by ACCi • Preclinical studies have shown ACCi can lead to increased plasma TG Goedek
Slide 32: Outline
Outline • Introduction to NAFLDsym Modeling Software • Demonstration of NAFLDsym v2A Software • Example NAFLDsym Application • NAFLDsym Licensing and Services Projects 32
Slide 33: General Project Timeline and Deliverables
General Project Timeline and Deliverables Stage I Project Activities Stage II Project Activities Stage III Project Activities • Updates to NAFLDsym to represent NAFLD therapeutic • Simulations of Compound A prior • Simulations of Compound A future clinical trial strategies studies in representative
Slide 34: NAFLDsym v2A License Provides Opportunity to Actively Utilize QSP Model
NAFLDsym v2A License Provides Opportunity to Actively Utilize QSP Model • A license to NAFLDsym v2A is $67,500 per year for 1 instance – Includes capabilities of predicting effects of treatments on steatosis, lipotoxicity, inflammation, and fibrosis in NAFLD/NASH patients – Includes 10 hours of trai
Slide 35: 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 36: NAFLDsym Is Designed to Support Drug Development with Efficacy Predictions
NAFLDsym Is Designed to Support Drug Development with Efficacy Predictions • NAFLD is a progressive disease of the liver • Incidence is growing worldwide with few treatment options – Substantial opportunity to improve health for many patients by developing treatments • NAFLDsym is a QSP model of NAF