Simulations Plus, Inc. · NASDAQ:SLP

Simulations Plus — Technical Presentation (2022)

27 slides from Simulations Plus's technical presentation, Aug 30, 2022

1. Slide 1: Ophthalmic clinical PK/PD prediction using PBPK model validated against preclinical datasets

   Ophthalmic clinical PK/PD prediction using PBPK model validated against preclinical datasets Maxime Le Merdy, PharmD Senior Scientist Please note: this presentation, including questions from the audience, is being recorded and may be made available. 1 | NASDAQ: SLP

2. Slide 2: Prescription dispensed vs medicine spending

   89% 27% Prescription dispended Medicine spending 2 | NASDAQ: SLP

3. Slide 3: FDA mission to promote generic drug development; locally acting drug issues

   O n e o f F D A’s m i s s i o n i s t o promote generic drug products development Specific issues for locally acting drug (LAD) 3 | NASDAQ: SLP

4. Slide 4: LAD

   LAD  Local site of action is local: skin, lungs, eyes, the gastrointestinal tract…  Drug products not intended to be absorbed into the bloodstream  If the API is detectable in plasma, does the plasma concentration time course reflect local concentrations? 4 | NASDAQ: SLP

5. Slide 5: Bioequivalence

   Bioequivalence Test Reference 90% confidence interval of the Concentration ratio of a log-transformed Plasma exposure measure (AUC and/or Cmax) falls completely within the range 80-125% Time 5 | NASDAQ: SLP

6. Slide 6: LAD Bioequivalence

   LAD Bioequivalence Q3 Clinical Characterization and Performance studies Pk or PD endpoint Does not allow Allows Q1/Q2/Q3 Q1/Q2 differences differences In Vitro only In Vivo option 6 | NASDAQ: SLP

7. Slide 7: LAD Bioequivalence Q1 Q2 Q3

   LAD Bioequivalence Q1 Q2 Q3 Same Same Same matter components concentrations arrangement 7 | NASDAQ: SLP

8. Slide 8: LAD Bioequivalence Q1 Q2 Q3

   LAD Bioequivalence Q1 Q2 Q3 Same Same Same matter components concentrations arrangement excipients % excipients 5% rule 8 | NASDAQ: SLP

9. Slide 9: 9 | NASDAQ: SLP

   9 | NASDAQ: SLP

10. Slide 10: Ophthalmic drugs on the US market

    LAD Bioequivalence Ophthalmic drugs on the US. Market 1000 Princep N products 100 Generic 10 1 Emulsion Gel Insert Ointment Solution Suspension 10 | NASDAQ: SLP

11. Slide 11: Ophthalmic drugs on the US market

    Ophthalmic drugs on the US. Market 1000 Princep N products 100 Generic 10 1 Emulsion Gel Insert Ointment Solution Suspension 11 | NASDAQ: SLP

12. Slide 12: The issue

    The issue Site of action concentration Safety Efficacy PBPK 12 | NASDAQ: SLP

13. Slide 13: Ocular PBPK model (MIDD)

    Aqueous Humor Palpebral Conjunctiva a= Bulbar Conjunctival > MIDD:2e ‘Model informed Drug Development + 13 | NASDAQ: SLP Sagittal plane

14. Slide 14: Creation of first ocular PBPK and FDA grants

    Creation of first First FDA Second FDA ocular PBPK grant grant 2010 2014 2017 2020 2023 V1 V2 V3 14 | NASDAQ: SLP

15. Slide 15: How can PBPK modeling accelerate ophthalmic generic drug development?

    How can PBPK modeling be used to accelerate the development of ophthalmic generic drugs? 15 | NASDAQ: SLP

16. Slide 16: Model development

    Model development 16 | NASDAQ: SLP

17. Slide 17: Model Validation

    Model Validation max 17 | NASDAQ: SLP

18. Slide 18: Model Validation

    Model Validation 18 | NASDAQ: SLP

19. Slide 19: Model Application

    Model Application 19 | NASDAQ: SLP

20. Slide 20: What can we do using PBPK model?

    What can we do using PBPK model? 20 | NASDAQ: SLP

21. Slide 21: Data available in rabbit and human by formulation

    PK | PD only > | 4 | | x Ointment and | Ointment and | Ointment and o others | others others E : se] | ° | < | | 2 Suspension (2) Suspension | Suspension © S E ro} LL (1) Solution —@)— Solution Solution | Data Available in Rabbit and Human MIDD: a [4 L, SimulationsPlus ‘Mode! Informed Drug Devel 21

22. Slide 22: Clinical Ocular Exposure Extrapolation Using PBPK

    ‘@. SimulationsPlus MIDD: 22 Mode! Informed Drug Development Clinical Ocular Exposure Extrapolation Using PBPK Maxime Le Merdy!, Yujuan Zheng!, Viera Lukacova?, Ming-Liang Tan?, Andrew Babiskin? and Liang Zhao? 41: Simulations Plus, Inc. Lancaster, CA. USA 2: Office of Research and Standards, Office

23. Slide 23: Formulation complexity and data available

    PK | | Ointment and | Ointment and Ointment and others | others others | | | | | © PK&PD PD only Formulation complexity | Suspension @)- Suspension Suspension | | | 7 | (1) Solution —@)— Solution | Solution | Data Available in Rabbit and Human MIDD ‘Be p25 SimulationsPlus Informed Drug Develop 23 |

24. Slide 24: Dexamethasone aqueous humor concentrations versus time

    Mean Dexamethasone Aqueous Humor Concentrations Versus Time from Cataract Patients Following a Single Unilateral Topical Ocular Dose of Tobramycin 0.3%/Dexamethasone 0.05% or TOBRADEX Figure 2.2.3-1. (er Protocol Analysis) 60 5 50 HUMAN NDA50818 TOB 0.1% HUMAN NDAS0818 Tob ST 0.05% 2 60. of “ 55: 55

25. Slide 25: Watson 1988 dexamethasone penetration into human aqueous humor

    Watson 1988 Penetration of topically applied dexamethasone alcohol into human aqueous humor 25 | NASDAQ: SLP

26. Slide 26: Conclusion

    Conclusion • LAD bioequivalence presents challenges compare to oral drug products • PBPK model can support bioequivalence assessment of LAD • Research on PBPK models for ophthalmic formulations started more than 10 years ago and is still ongoing • Preclinical to clinical extrapolation validation is

27. Slide 27: Q&A Questions & Answers

    Q&A Questions & Answers 27 | NASDAQ: SLP

Simulations Plus — Technical Presentation (2022) on 6ix