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Pharmaceutics
Volume 17
Issue 12
10.3390/pharmaceutics17121522
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Article

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

by
Maria E. Trujillo
1,*,
Yue Han
1,
Rebecca A. Baillie
2,†,
Michael C. Weis
2,‡,
Douglas Chung
2,§,
Sean Hayes
1,
Paul E. Carrington
1,‖,¶ and
Michael Reed
2,¶
1
Merck & Co., Inc., Rahway, NJ 07065, USA
2
Rosa and Co., LLC, San Carlos, CA 94070, USA
*
Author to whom correspondence should be addressed.
†
Current address: Hebare, LLC, Albuquerque, NM 87123, USA.
‡
Current address: Kymera Therapeutics, Watertown, MA 02472, USA.
§
Current address: Certara UK, Sheffield S1 2BJ, UK.
‖
Current address: Oryn Therapeutics, West Hollywood, CA 90069, USA.
These authors contributed equally to this work.
Pharmaceutics 2025, 17(12), 1522; https://doi.org/10.3390/pharmaceutics17121522 (registering DOI)
Submission received: 30 September 2025 / Revised: 28 October 2025 / Accepted: 19 November 2025 / Published: 26 November 2025
(This article belongs to the Special Issue In Silico Pharmacokinetic and Pharmacodynamic (PK-PD) Modeling)
Versions Notes

Abstract

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.
Keywords: quantitative systems pharmacology; type 2 diabetes; proinsulin; insulin; glucose quantitative systems pharmacology; type 2 diabetes; proinsulin; insulin; glucose

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MDPI and ACS Style

Trujillo, M.E.; Han, Y.; Baillie, R.A.; Weis, M.C.; Chung, D.; Hayes, S.; Carrington, P.E.; Reed, M. 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. Pharmaceutics 2025, 17, 1522. https://doi.org/10.3390/pharmaceutics17121522

AMA Style

Trujillo ME, Han Y, Baillie RA, Weis MC, Chung D, Hayes S, Carrington PE, Reed M. 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. Pharmaceutics. 2025; 17(12):1522. https://doi.org/10.3390/pharmaceutics17121522

Chicago/Turabian Style

Trujillo, Maria E., Yue Han, Rebecca A. Baillie, Michael C. Weis, Douglas Chung, Sean Hayes, Paul E. Carrington, and Michael Reed. 2025. "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" Pharmaceutics 17, no. 12: 1522. https://doi.org/10.3390/pharmaceutics17121522

APA Style

Trujillo, M. E., Han, Y., Baillie, R. A., Weis, M. C., Chung, D., Hayes, S., Carrington, P. E., & Reed, M. (2025). 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. Pharmaceutics, 17(12), 1522. https://doi.org/10.3390/pharmaceutics17121522

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