In Silico Hypothesis Testing in Drug Discovery: Using Quantitative Systems Pharmacology Modeling to Evaluate the Therapeutic Value of Proinsulin Conversion to Insulin Therapy for Type 2 Diabetes Mellitus.

Background/

Objectives

Proinsulin, the precursor to insulin, has limited activity on the insulin receptor. Proinsulin levels increase with increasing insulin resistance in type 2 diabetes due to incomplete processing by the β-cell. To assess whether the development of peptides that could convert circulating proinsulin to insulin in the blood would provide therapeutic value, we used a quantitative systems pharmacology (QSP) model of glucose homeostasis. In silico hypothesis testing such as this is an example of how modeling can inform decisions in drug discovery.

Methods

In silico hypothesis testing involved (1) the addition and qualification of proinsulin biology into a preexisting QSP model, (2) the creation and validation of virtual patients (VPs) for subpopulations of type 2 diabetics based on phenotypic traits, and (3) the simulation of clinical trials evaluating the therapeutic value of the conversion of circulating proinsulin to insulin in the VPs created.

Results

Proinsulin conversion led to a ~0.2% reduction in HbA1c in VPs at varying stages of diabetes, a decrease that does not hold meaningful therapeutic value. The lack of significant impact on HbA1c was likely a result of the surprisingly small effect on plasma insulin levels from proinsulin, which has a significantly slower secretion and clearance rate. Although patients with higher proinsulin/insulin ratios showed the largest reductions, clinically significant ≥ 0.5% reduction in HbA1c required ratios of proinsulin/insulin above the reported physiological range.

Conclusions

This effort demonstrates how in silico hypothesis testing using QSP modeling can provide insights on the probability of success of novel interventions with minimal time and resources. These efficiencies are a means of overcoming the pressures on the pharmaceutical industry to do more with less in providing therapies that improve the lives of patients.