(W0930-10-57) Orforglipron Weight Loss and Nausea Accurately Simulated with OBESITYsym

Purpose: The recent availability of effective, GLP-1R agonist (GLP-1RA) based treatments of obesity has provided great benefit to patients. Oral GLP-1RA treatments may prove to be even more desirable than the injectables due to the ease of administration. Understanding the balance between body weight (BW) loss and nausea is paramount in predicting the effectiveness of oral GLP-1RA based medications. Quantitative systems pharmacology (QSP) modeling can aid in predicting both efficacy and adverse events of compounds, particularly when clinical data are available.

Methods: OBESITYsym, a QSP model, has been developed to enable simultaneous prediction of BW and nausea due to pharmacologic treatments. This mechanistic, mathematical model includes components of energy balance: caloric intake, energy expenditure, body composition, adaptation, as described by Hall 2010 (1). OBESITYsym also includes a novel submodel of nausea sensitivity and tolerance, a pharmacology submodel that establishes the link between compound exposure, energy balance, and nausea with pharmacokinetic models and compound potency. The model has been calibrated with clinical data from compounds administered both subcutaneously and orally including semaglutide (sema, 2.4 mg QW  for 68 weeks (2)), liraglutide (lira, 3 mg QD for 56 weeks (3)), tirzepatide (tirze, 5, 10, or 15 mg QW for 72 weeks (4)), and orforglipron (orfo, 12 and 45 mg QD for 36 weeks (5)) via simulations of phase 2 or 3 clinical trial protocols in a simulated obese population (SimPops) with mean BW of 106.2 kg +/- 14.6 kg.  Orfo 24 and 36mg (5) doses (QD for 36 weeks) were used to validate the optimization. Simulated dosing included uptitration in accordance with the protocols. Systemic exposure of each compound was simulated within OBESITYsym, providing pharmacokinetic profiles that were consistent with reported data.  Moreover, in vitro measured potency values (EC50) from the literature were employed for each treatment.

Results: The simulated clinical responses for all treatments in the SimPops aligned with reported clinical data and were within reported error bounds regardless of the route of administration. The measured average maximum % decline in BW (simulated average maximum % decline in parenthesis) were 12.5 (11.91) and 13.4 (13.06) for orfo 24 mg and 36 mg, respectively (the orfo validation data sets, Figure 1 left column) and 9.39 (10.02) and 14.6 (13.78) for orfo 12 mg and 45 mg, respectively (the orfo calibration data sets, Figure 2 left column).  The reported nausea % incidence (with simulated nausea % incidence in parenthesis) were 58 (51.8) and 41 (50.01) for orfo 24 mg and 36 mg, respectively (Figure 1 right column) and 50 (52.45) and 42 (51.8) for orfo 12 mg and 45 mg, respectively (Figure 2 right column). The subcutaneously administered compounds were also in agreement with reported clinical data in terms of both BW change (15.8 (15.1) for sema and 9.39 (9.2) for lira, Figure 3 left column) as well as reported nausea incidence (44.2 (37.56) for sema and 40.2 (40.2) for lira, Figure 3 right column). Moreover, the placebo responses (both BW and reported nausea) were accurately simulated across trials, reflecting the ability for the model to capture both treatment and lifestyle modifications on BW.

Conclusion: >There was excellent alignment between the clinical data and the predicted body weight reductions and nausea incidence for 24 mg and 36 mg orfo.  This indicates that OBESITYsym is capable of predicting the responses to both oral and injected GLP-1RA (6,7). OBESITYsym can be used to evaluate the efficacy and nausea potential for novel treatments, including oral GLP-1RA and compounds that utilize additional mechanisms to adjust energy balance.

References: 1. Hall. Am J Physiol Endocrinol Metab. 2010; 298(3): E449-66.
2. Wilding. N Engl J Med. 2021; 384(11): 989-1002.
3. Pi-Sunyer. N Engl J Med. 2015; 373(1): 11-22.
4. FDA Clinical Pharmacology Review 215866Orig1s000.
5. Wharton. N Engl J Med. 2023; 389(10): 877-888.
6. Siler. Obesity Week. 2024.
7. Kenz. ACoP. 2024.

Figure 1: Orforglipron oral (24 and 36mg) comparison of data vs simulations for % change in body weight (BW) and overall incidence of nausea, used for validation.

Figure 2: Orforglipron oral (12 and 45mg) comparison of data vs simulations for % change in body weight (BW) and overall incidence of nausea, used for calibration.

Figure 3: Subcutaneous semaglutide (2.4mg) and liraglutide (3mg) comparison of data vs simulations for % change in body weight (BW) and overall incidence of nausea, used for OBESITYsym model calibration.