Drug with New Target for Schizophrenia

Background

• • • Development of compound with new target for schizophrenia as stand-alone
    • Target was weakly affected by few antipsychotics
    • No PET tracer available for drug exposure in humans
    • Development for augmentation therapy?

Proposed Quantitative Systems Pharmacology Solution

• • • Implementation of new target process in basal ganglia
    • Use calibrated and well equilibrated existing model for PANSS
    • Simulation of full dose-response in PANSS Model as stand-alone or for augmentation therapy

Outcome: Liu (2014)

• • Calibrated QSP PANSS Total model suggested relatively modest effect as stand-alone
  • Dose-response was very dependent upon nature and dose of antipsyhotic co-med

New Cognition Enhancer for Alzheimer’s Disease

Background

• • • Development of compound with new target for symptomatic treatment in Alzheimer’s disease
    • Candidate drug improved cognitive performance in animal studies
    • Different pharmacology for rodent versus human target; concerned about impact in human patients
    • PET tracer available for drug exposure

Proposed Quantitative Systems Pharmacology Solution

• • • Calibration of neurotransmitter system using rodent fast cyclic voltammetry data combined with human imaging studies
    • Implementation of functional pharmacological effect on human receptors of candidate drug
    • Simulation of full dose-response in QSP model for cognitive readout

Outcome: Nicholas (2013)

• • QSP model correctly predicted Phase I trial outcome
  • QSP model provided biological hypothesis for translational disconnect
  • Identification of new patient population for drug

Drug with New Pharmacology for Schizophrenia

Background

• • • Development of compound with new pharmacology (part of clozapine) for schizophrenia as stand-alone
    • Candidate drug was effective in animal studies of schizophrenia
    • Candidate drug had no side-effect liability in animal studies of EPS
    • PET tracer available for drug exposure in humans

Proposed Quantitative Systems Pharmacology Solution

• • • Simulate competition with neurotransmitter on key receptors with PET imaging data
    • Simulation of full dose-response in PANSS Model and EPS liability as stand-alone

Outcome: Geerts (2012)

• • Calibrated QSP PANSS Total model suggested similar effect as comparator olanzapine
  • Calibrated QSP EPS model suggested much higher liability than with olanzapine
  • QSP model provided explanation of the observed translational disconnect

Recently Launched Antipsychotic Drug

The concept of targeted therapies remains a holy grail for the pharmaceutical drug industry for identifying responder populations or new drug targets. Here we provide quantitative systems pharmacology as an alternative to the more traditional approach of retrospective responder pharmacogenomics analysis and applied this to the case of iloperidone in schizophrenia.

Background

• Challenge to increase uptake of new antipsychotic in market
• Identifying responder population by traditional PGX
• Understanding the biology of identified SNP

Proposed Quantitative Systems Pharmacology Solution

• Keep drug pharmacology model, allow biological coupling parameters to vary and identify processes that drive difference between placebo and experimental drug
• Rank-order processes using Pareto-plots

Outcome: Geerts (2015)

• QSP platform identified one of the five SNP as driving the model outcome for new investigative drug
• QSP model provided biological explanationwe provide quantitative systems pharmacology as an alternative to the more traditional approach of retrospective responder pharmacogenomics analysis and applied this to the case of iloperidone in schizophrenia.  of the Responder SNP