NAFLDsym™

Software for modeling
nonalcoholic fatty liver disease
(NAFLD)

Request an Evaluation!

The NAFLDsym modeling software is a mechanistic, mathematical model of nonalcoholic fatty liver disease (NAFLD), which can be used to predict efficacy for treatment modalities developed for NAFLD and nonalcoholic steatohepatitis (NASH).  The NAFLDsym modeling software has been utilized to evaluate a number of compounds from several large pharmaceutical companies, supporting clinical trial design optimization and clinical development decision making.  DILIsym Services, Inc. applies the NAFLDsym modeling software in proprietary services projects by performing simulations of compounds to evaluate and model their efficacy and other effects on key characteristics related to NAFLD.  NAFLDsym is also available for in-house use through corporate software licensing.

NAFLD is a prevalent, worldwide disease with few available treatment options. Accumulating lipids within the liver cause steatosis and impose lipotoxicity upon hepatocytes that can lead to declining liver function and ultimately liver transplant. Bringing effective treatments rapidly to market is paramount to improve patient health. QSP modeling has been demonstrated to accelerate clinical development, and we anticipate NAFLDsym will contribute to accelerating the clinical development of effective treatments for NAFLD patients.  NAFLDsym employs the QSP modeling practices of combining predictions of compound exposure with the pharmacodynamic characteristics of a compound and how they can produce efficacy across a range of patients with pathophysiologic variability.

 

DILIsym Services, Inc. has significant expertise in the areas of drug-induced liver injury (DILI), quantitative systems toxicology (QST) and has employed this expertise to develop and apply DILIsym to evaluate the safety risk of numerous drug candidates. DILIsym Services also has significant experience in the area of metabolic diseases and has leveraged this area of expertise to develop the quantitative systems pharmacology (QSP) modeling software, NAFLDsym v2A. DILIsym Services applies this modeling software to assist with clinical development in collaborative partnerships and offers access to the software via corporate software licenses.

 

NAFLDsym v2A includes the mechanistic underpinnings associated with steatosis and lipotoxicity, chronic inflammation, and fibrosis within the liver.  It is useful for evaluating the efficacy of potential new drug candidates to treat NAFLD/NASH in each of these areas, including the powerful capability to evaluate combination treatment approaches.  It is a powerful tool for understanding and predicting disease progression and the complications associated with clinical trial design for NASH/NAFLD studies, including predictions for weight-stable, weight-loss, and weight-gaining patients.  Weight loss and gain are dynamically represented with a state-of-the-art body weight model (Hall 2010).  4 large pharmaceutical companies have sponsored the development of version 2A.

A number of key biomarkers or endpoints are incorporated into NAFLDsym v2A, such as

  • Plasma TG, free fatty acids, and adiponectin
  • Plasma ALT and cytokeratin-cleaved 18 (cK18)
  • Phasma TNF-alpha and TNF-beta
  • Plasma Pro-C3
  • The NAFLD Activity Score (NAS)
  • Steatosis and ballooning score
  • Inflammation score
  • Fibrosis stage
  • Liver fat percentage (MRI) and stiffness (MRE)
  • and many more…..

The heterogeneity of NAFLD/NASH is a major challenge in the quest for new treatments.  To this end, NAFLDsym v2A includes well over 1,000 simulated patients with varying stages of NAFLD and NASH.  The simulated patients, or SimPops®, can be used to optimize clinical trial protocols by determining favorable measurement frequencies and dosing levels, evaluating targets using key internal laboratory or mechanistic clinical data, testing combination treatment approaches across varying patient backgrounds, and comparing efficacy in different patient groups (e.g. stratification by NAS, etc.).  The SimPops has been validated against a large backdrop of key data sets, such as those shown below for liver fat and ALT, Plasma TGF-beta and ALT, activation of stellate cells by liver zone, and mean liver stiffness versus fibrosis stage.

 

Validation of the various relationships within NAFLDsym v2A working in harmony comes from predicted efficacy when body weight is applied as a treatment.  The results below were predicted from the first principle mechanisms included (emergent behavior from the model) during 5% weight loss over the course of a year.  Several other validations have been completed and/or are on-going in the context of confidential consulting projects.

 

NAFLDsym v2A is available for in-house use through corporate software licenses.  Contact us today for more information on license terms and pricing.

Alternatively, click here to find out more about how you can take advantage of NAFLDsym through a consulting arrangement with the DILIsym Services experts.

DILIsym Services Home

What are we providing with NAFLDsym?

NAFLDsym v2A is a computational model of nonalcoholic fatty liver disease (NAFLD) and can be used to predict efficacy for treatment modalities developed for treating NAFLD and NASH. NAFLDsym v2A includes many of the primary components of NAFLD and NASH pathophysiology such as:

  • Steatosis
  • Regulation of liver triglyceride and fatty acids
  • Lipotoxicity
  • Fibrosis
  • Inflammation
  • Liver injury and proliferation
  • Hepatocellular bioenergetics
  • Dynamic body weight and its effects on lipids
  • Biomarkers (e.g., ALT, AST, cytokeratin cleaved K18, NAS, MRI, MRE, fibrosis score)
How is NAFLDsym being applied?

These mechanistic components have been combined to generate >1000 simulated NAFLD/NASH patients in NAFLDsym v2A. Reflecting the variability in clinical patient populations, these populations of simulated patients (SimPops®) have a range of liver fat levels (steatosis), mediator levels (inflammation), collagen production levels (fibrosis), body weight, and many also have liver injury (e.g., elevated ALT).  The SimPops responds diversely to simulated treatments such as weight loss.

 

NAFLDsym applications have been conducted to address important questions for Pfizer and Gilead and also several other pharmaceutical companies.

 

What's New in NAFLDsym v2A?

NAFLDsym v2A is packed with exciting new features, such as:

  • New mechanistic areas of NAFLD/NASH including inflammation and fibrosis
  • New plasma biomarkers, histological endpoints, and image-based outputs
  • A much large SimPops of NAFLD/NASH patients with well over 1,000 simulated patients
  • A licensing structure that allows users to see and modify all differential equations

For more features, check out the NAFLDsym v2A flyer.

How do I move forward from here?

Join your peers around the world and begin working with NAFLDsym to generate the insight you can’t measure to make better decisions.