ILDSYM®, A Quantitative Systems Pharmacology (QSP) Platform, Successfully Simulates Efficacy of Key Treatments for Systemic Sclerosis-Interstitial Lung Disease

Conference: ACoP
Software: ILDsym™
Division: DILIsym Services


Systemic sclerosis (SSc) is a rare connective tissue and autoimmune disease associated with inflammation of the skin and internal organs. Interstitial lung disease (ILD), a frequent complication of SSc with highly variable course, is associated with increased morbidity and mortality risk¹. Two FDA-approved treatments, anti-inflammatory tocilizumab (TCZ) and anti-fibrotic nintedanib (NIN), demonstrate efficacy in slowing disease progression but do not reverse disease². Anti-inflammatory/anti-fibrotic mycophenolate mofetil (MMF) demonstrates efficacy and may reverse disease³. Modeling treatment responses is critical to ensuring model dynamics properly capture physiological responses, lending confidence in the potential to predict novel treatments.


ILDsym is a QSP model of SSc-ILD pathophysiology based on publicly available literature with over 700 simulated patients at various stages of disease⁴. Simulations combine predicted lung drug exposure with drug mechanisms-of-action (MoA) to modulate SSc-ILD pathophysiology and predict efficacy. Treatment MoA were defined based on available data. For MMF and NIN, treatment responses were optimized to SSc-ILD forced vital capacity (FVC) clinical data³,⁵. TCZ response was optimized to C-reactive protein (CRP) data (downstream of MoA) from rheumatoid arthritis patients⁶; treatment response in SSc-ILD was subsequently validated against clinical FVC data⁷. Simulated patients were selected (i.e., SimCohorts™ generation) to match the baseline FVC and progression rates of placebo groups for clinical trials with NIN, MMF, and TCZ.


ILDsym Model Calibation Treatments

Mycophenolate Mofetil

  • MMF is a prodrug of mycophenolic acid (MPA) which preferentially inhibits de novo guanine synthesis in activated T and B cells, reducing DNA synthesis and proliferation
    • Additional anti-proliferative and anti-inflammatory effects identified
  • Utilized off-label for SSc-ILD treatment²
  • Simulated change in FVC with MMF treatment was comparable to clinical data³
    • Clinical untreated (n=79) and MMF (n=69) SSc-ILD groups
    • ILDsym SimCohorts (n=71), matched to inclusion/exclusion criteria of clinical SSc-ILD patients, and clinical ILD patients were treated with 1500 mg BID MMF for 52 weeks


  • NIN is a small molecule receptor tyrosine kinase inhibitor targeting growth factor receptors (PDGFR, FGFR, and VEGFR*), with anti-fibrotic effects
  • FDA approved NIN for SSc-ILD treatment in 2019²
  • Simulated change in FVC with NIN treatment was comparable to clinical data⁵
    • Clinical untreated and NIN groups each composed of n=288 SSc-ILD patients
    • ILDsym SimCohorts (n=444), matched to inclusion/exclusion criteria of clinical SSc-ILD patients, and clinical ILD patients were treated with 150 mg BID NIN for 52 weeks

ILDsym Model Validation Treatment


  • TCZ is a biologic therapy that recognizes the IL-6 binding site of the human IL-6 receptor (IL-6R), inhibiting IL-6 signaling through competitive blockade of IL-6 binding
  • FDA approved TCZ for SSc-ILD treatment in 2021²
  • TCZ simulations used as ILDsym model validation
    –No further calibration of MoA in SSc-ILD to reproduce FVC in ILD patients
  • Obtained reasonable simulated fit to relative CRP response data, optimizing IC₅₀ for TCZIL-6 effects with QW and Q2W dosing paradigms
    • CRP response simulations performed in N=12 simulated ILD patients, with CRP levels similar to thoseof RA patients in the study⁶
  • Calibration simulations reproduced observed dose-response, providing increased confidencein parameterization of TCZ-mediated inhibition of IL-6 signaling
    • Increases confidence in TCZ role as validation compound in ILDsym
  • Validation simulated change in FVC with TCZ treatment was comparable to clinical data⁷
    • Clinical intent-to-treat data composed of placebo group (n=106) and TCZ group (n=104)
    • ILDsym SimCohorts (n=114), matched to inclusion/exclusion criteria of clinical SSc-ILD patients,and clinical ILD patients were treated with 162 mg SC QW for 48 weeks


ILDsym is well-positioned to support SSc-ILD drug development by providing a dynamic representation of variable SSc-ILD pathophysiology and disease progression with demonstrated success in representing treatment responses. The flexible framework of ILDsym enables its use in exploring novel targets, optimizing protocols, exploring mechanistic hypotheses, and evaluating monotherapies and combination therapies.

By Zackary R Kenz, Kyunghee Yang, Christina Battista, Lisl KM Shoda, Scott Q Siler

American Conference of Pharmacometrics (ACoP14), November 5-8, 2023, Oxon Hill, MD