Simulations Plus, Inc. · NASDAQ:SLP
Simulations Plus — Technical Presentation (January 2026)
37 slides from Simulations Plus's technical presentation, Jan 22, 2026
Slide 1: CAR-T Clinical Pharmacology Considerations and Modeling in Monolix
CAR-T Clinical Pharmacology Considerations and Modeling in Monolix Mitali Gaurav, Nancy Lin, Pauline Traynard January 22nd 2026 External Presentation 1 © Copyright 2025, Simulations Plus, Inc. All Rights Reserved. | NASDAQ: SLP
Slide 2: Outline
Outline • Introduction to CAR-T Cell Therapy • Approved CAR-T Cell Therapies • CAR-T cell Design & Mechanism • Evolution of CAR-T Generations • Multiphasic Cellular Kinetics of CAR-T-Cells • CAR-T Toxicities • Preclinical Considerations • First-In-Human Considerations • CAR-T Modeling Strategies • C
Slide 3: Introduction to CAR-T Cell Therapy
Introduction to CAR-T Cell Therapy • CAR-T cell therapy involves genetically engineering a patient’s own T cells to attack cancer cell, which are the body’s primary killer of infection and other disease cell. • FDA approved first CAR-T cell therapy in 2017 for pediatric acute lymphoblastic leukemia
Slide 4: Approved CAR-T Cell Therapies
Approved CAR-T Cell Therapies Drug Target Indication Dose Covariates Tested Tisagenlecleucel CD-19 B-ALL (pediatric and young Peds: <50 kg: 0.2-5 106/kg cells; >50 kg: tocilizumab, steroids, sex, race, prior HSCT, (Kymriah) adult) 0.1-2.5 108 cells (non-wt based) fludarabine (U.S FDA., 2017) LBCL
Slide 5: CAR-T Cell Design & Mechanism
CAR-T Cell Design & Mechanism • Each chimeric antigen receptor on an individual T cell spans on the cell membrane, with part of the receptor sitting out of the cell and part within the cell. • CARs consist of antigen recognition (external) & signaling domains (internal) . • Common targets for extern
Slide 6: Autologous CAR-T-Cells
Autologous CAR-T-Cells Manufacturing of Autologous CAR-T-Cells Autologous CAR-T Cell Process A diagram of a person making a cell cycle Description automatically generated A diagram of a car t-cell therapy process Description automatically generated • Vector: viral (e.g., lentiviral) systems used for
Slide 7: Comparison of Autologous vs Allogenic CAR-T-Cells
Comparison of Autologous vs Allogenic CAR-T-Cells Allogenic CAR-T Cell Manufacturing Process Allogenic Autologous Off-the-shelf Patient’s own cell Easy to scale up production Difficult to scale up, challenge to harvest for heavily pre- treated patients Increased risk of rejection Minimal risk of rej
Slide 8: Evolution of CAR-T Cell Generations
Evolution of CAR-T Cell Generations Generations Main Co-stimulatory domain Drawback cytoplasmic domains 1st a single CD3 None Failure to produce adequate IL- ζ-chain 2, low cell proliferation, higher toxicities, and brief in vivo persistence 2nd CD3 ζ-chain CD28 or 4-1BB CAR-T cell exhaustion 3rd CD
Slide 9: Multiphasic Cellular Kinetics of CAR-T-Cells
Multiphasic Cellular Kinetics of CAR-T-Cells Distribution Expansion Contraction Persistence • Distribution: from central to peripheral Expansion Expansion Contraction & persistent phases phase phase • Expansion: Cmax, Tmax, AUC0-28d indicate proliferation. • Contraction: t1/2 reflect decline phase.
Slide 10: CAR-T cell Toxicities
CAR-T cell Toxicities • Cytokine release syndrome (CRS): – Release of cytokines from bystander immune and non-immune cells – Onset: variable; peaks 2-7 days after infusion and delays up to 3 weeks – Symptoms: fever, tachycardia, hypoxia, nausea, headache, rash, shortness of breath, hypotension – Man
Slide 11: CAR-T cell Toxicities (Continued)
CAR-T cell Toxicities (Continued) • Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) – A pathologic process involving CNS following any immune effector therapy that results in the activation or engagement of endogenous or infused T cell or other immune effector cells. – Symptoms: aphas
Slide 12: CAR-T cell Toxicities (Continued)
CAR-T cell Toxicities (Continued) • Hemophagocytic lymphohistiocytosis (HLH): – Histiocytes and lymphocyte build up in organs include skin, spleen and liver and destroy other blood cells. – Rare: 3.5% incidents • Other: B-cell aplasia, cytopenia, disseminated intravascular coagulation, infection • ‘
Slide 13: Concern for PK Variability from Immunogenicity
Concern for PK Variability from Immunogenicity • Data from current approved CAR-T therapies does not seem to have apparent immunogenicity impact on CK, safety, and efficacy – Cellular immune response (T cell recognize CAR-T-Cells) • Onset: ~3-6 months • Does not impact the expansion and target engag
Slide 14: Concern for PK Variability from Products, Patients and Biomarkers
Concern for PK Variability from Products, Patients and Biomarkers 14 © Copyright 2025, Simulations Plus, Inc. All Rights Reserved. | NASDAQ: SLP
Slide 15: Preclinical-to-Clinical Translation Considerations
Preclinical-to-Clinical Translation Considerations • Interspecies – difference between preclinical model and human creates translational challenges – immune system, mimicking expression, intrinsic properties of tumor antigen, tumor microenvironment – CK profile and clinical responses are dependent o
Slide 16: Empirical Starting Dose Selection for FIH
Empirical Starting Dose Selection for FIH • Relevant CAR-T products: – Learn from prior clinical experience from previous CAR-T products – Typical starting dose: million CAR + T cells/kg • Disease factor: – Disease type impacts dosing: type of malignancy, immune condition, antigen expression, and si
Slide 17: Study Design Considerations
Study Design Considerations • Body weight-based vs fixed dose – mg/kg dosing is more common in peds – Both strategies has been used in adults – Body weight /BSA are not found to impact cellular kinetics or exposure and efficacy – Recommendation: fixed dose to initiate FIH • Dose fractionation (over
Slide 18: PK/PD Analysis of CAR-T-Cells
PK/PD Analysis of CAR-T-Cells • Conventional model-based approaches translating ADME to the mammalian models such as 1- 2- or 3- compartment models are not applicable for CAR-T. • Statistical population PK models were developed to: – capture the cellular kinetics, – identify covariates and – predict
Slide 19: © Copyright 2025, Simulations Plus, Inc. All Rights Reserved. | NASDAQ: SLP
Mody H, Ogasawara K, Zhu X, et al. Best Practices and Considerations for Clinical Pharmacology and Pharmacometric Aspects for Optimal Development of CAR-T and TCR-T Cell Therapies: An Industry Perspective. Clin Pharmacol Ther. 2023;114(3):530-557. doi:10.1002/cpt.2986 19 © Copyright 2025, Simulation
Slide 20: Non Compartmental Analysis
Non Compartmental Analysis • Characterize the expansion and persistence phase – Cmax, Tmax : describe expansion – AUC0-28d : sufficient to capture cell expansion, relevant for both expansion and persistence, and can serve as an indicator for responders (high exposure) versus non-responders (low expo
Slide 21: Non Compartmental Analysis (Continued)
Non Compartmental Analysis (Continued) Core findings from Muller et al. 2017 publication on Cellular Kinetics of CTL019: 1. Tmax ~10-14 days for peak CAR-T 2. Persistence phase: CAR-T detectable up to ~780 days in blood, bone marrow and CSF 3. CAR-T expansion and persistence (Cmax and AUC) were corr
Slide 22: Population PK Modeling
Population PK Modeling • Non-Linear Mixed Effect Modeling approach • Describes cellular kinetics, evaluate the effect of covariates, using compartmental modeling • Stein Model: – Notable publication in CAR-T domain – Describes CAR-T expansion, rapid contraction, and long- term persistence characteri
Slide 23: Population PK Modeling
Population PK Modeling -Variation of Stein model were used in the pharmacometrics submissions for tisa-cel, axi-cel, liso-cel, ide-cel, and cilta-cel Stein et al, Yescarta Wu et al Ogasawara et al 23 © Copyright 2025, Simulations Plus, Inc. All Rights Reserved. | NASDAQ: SLP
Slide 24: Semi-mechanistic PK/PD Modeling
Semi-mechanistic PK/PD Modeling • Translational PK/PD , characterize BCMA targeting CAR-Ts Model structure and tumor/biomarker dynamics – Cell level PD model in an in vitro culture – PK/PD Model: PK in blood and tissues (site of action) – Biomarkers M-protein, and sBCMA are described with a turnover
Slide 25: Longitudinal Exposure
Longitudinal Exposure Adverse Event: • First-order Markov model is used to condition the probability of transition between different severity of the adverse effects between one time point and another. • Used to quantify the longitudinal relationship between CAR-T and toxicity endpoints (CRS and Neur
Slide 26: Application of Modeling Approaches in CAR-T Therapy
Application of Modeling Approaches in CAR-T Therapy Modeling Approach Application Strength Limitation Non-Compartmental Characterize cellular Simple, fast, no model No mechanistic Analysis (NCA) kinetics, in particular assumptions interpretation, limited expansion and persistence predictive value, n
Slide 27: Challenges for CAR-T Cell Therapy
Challenges for CAR-T Cell Therapy Despite the promise of CAR-T cell therapy, several challenges persist: • Safety Concerns: Risks include cytokine release syndrome (CRS), neurotoxicity, and ‘on- target, off-tumor’ effects. • Efficacy: solid tumors still an obstacle. Results can be highly patient-spe
Slide 28: Challenges for CAR-T Cell Therapy
Challenges for CAR-T Cell Therapy • Lack of preclinical model to translate to FIH study • Dose-Exposure – No apparent dose-exposure relationship; as initial dose is not determining the final exposure. – Exposure is measured by Cmax and AUC and not by dose infused • Exposure-Response – Exposure corre
Slide 29: Summary: Key Takeaways
Summary: Key Takeaways • CAR-T cell therapy shows promise in hematologic malignancies. • Unique T-cell pharmacology require tailored modeling approaches, PK/PD evaluation must consider cellular kinetics, not classical ADME. • Modeling tools such as NCA, and PopPK are vital to understand the cellular
Slide 30: Modeling of Tisagenlecleucel CAR-T cells
Modeling of Tisagenlecleucel CAR-T cells A Monolix Case Study 30 © Copyright 2025, Simulations Plus, Inc. All Rights Reserved. | NASDAQ: SLP
Slide 31: Introduction
Introduction Tisagenlecleucel: • Chimeric antigen receptor–T cell therapy that facilitates the killing of CD19+ B cells • Produces durable responses in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (r/r B- ALL) Dataset (simulated): • Published and
Slide 32: Introduction
Introduction log-transformed tisagenlecleucel 1 = received time of first 1 = received time of first levels reported as transgene comedication comedication of comedication of comedication of copies/μg of genomic DNA of tocilizumab corticosteroids corticosteroids tocilizumab 32 © Copyright 2025, Simul
Slide 33: Base structural model
Base structural model Compartmental model ODE system Parameters: Tmax, Cmax, foldx, α, β, FB 33 Figure and equations from Stein, et al. (2019) © Copyright 2025, Simulations Plus, Inc. All Rights Reserved. | NASDAQ: SLP
Slide 34: Base structural model
Base structural model Compartmental model ODE system Equivalent equations Parameters: Tmax, Cmax, foldx, α, β, FB 34 Figure and equations from Stein, et al. (2019) © Copyright 2025, Simulations Plus, Inc. All Rights Reserved. | NASDAQ: SLP
Slide 35: Extended structural model with comedication effect on expansion
Extended structural model with comedication effect on expansion Compartmental model ODE system Equivalent equations 35 Figure and equations from Stein, et al. (2019) © Copyright 2025, Simulations Plus, Inc. All Rights Reserved. | NASDAQ: SLP
Slide 36: Conclusion
Conclusion The mixed-effect cellular kinetic model used in this case study: • characterized well the expansion and persistence of tisagenlecleucel, • shows no significant impact of the comedication on the expansion, • may be used to describe other types of genetically modified cells across multiple
Slide 37: Resources and Key References
Resources and Key References • FDA: Considerations for CAR-T Cell Products; Guidance for Industry (FDA-CART-Guidance) • Mody, H., Ogasawara, K., Zhu, X., Miles, D., Shastri, P., Gokemeijer, J., Liao, M., Kasichayanula, S., Yang, T., Chemuturi, N., Gupta, S., Jawa, V., & Upreti, V. (2023). Best Pract
Simulations Plus — Technical Presentation (January 2026) on 6ix