Abstract: PO0688
Development and Benchmarking of a Non-Human Primate Model of Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Camacho, Raul, Janssen Pharmaceutical Companies of Johnson and Johnson, Spring House, Pennsylvania, United States
- De Villa, Flordeliza Pontioso, Kunming Biomed International, Kunming, Yunnan, China
- Zhu, Zhenghua, Kunming Biomed International, Kunming, Yunnan, China
- Yang, Yong, Kunming Biomed International, Kunming, Yunnan, China
- Perez, Rosario Manocom, Kunming Biomed International, Kunming, Yunnan, China
- Xu, Jialin, Janssen Pharmaceutical Companies of Johnson and Johnson, Spring House, Pennsylvania, United States
- Polidori, David, Janssen Pharmaceutical Companies of Johnson and Johnson, Spring House, Pennsylvania, United States
- Nawrocki, Andrea R., Janssen Pharmaceutical Companies of Johnson and Johnson, Spring House, Pennsylvania, United States
Background
Diabetic Kidney Disease (DKD) is the largest cause of end stage renal disease and is responsible for 40% of new patients that require dialysis. To test novel therapies for DKD, we sought to develop a non-human primate (NHP) model of DKD that would be more representative of the etiology of human disease than genetically modified mouse models and support human dose prediction and biomarker development.
Methods
Cynomologus monkeys were fed a high fat/cholesterol diet for 5.1±2.5 (mean±SD) years and became obese (9.1±1.6 kg), hyperglycemic (267±78 mg/dL), hypertensive (systolic blood pressure [SBP] 141±11 mmHg), and macroalbuminuric (urine albumin/creatinine ratio [UACR] 562±346 mg/g). The responsiveness of the monkeys to pharmacological intervention was benchmarked using irbesartan, an angiotensin II receptor blocker (ARB), which is clinically used to treat DKD. Animals were orally dosed daily for 8 weeks with either vehicle (n=8) or irbesartan (n=14, 3 mg/kg).
Results
Exposures 24-hours after dosing were 165±111 ng/mL, similar to exposure in humans with therapeutic doses. Treatment effects on SBP (-23±8 vs. +2±15 mmHg, irbesartan vs. vehicle), urinary albumin excretion (UAE; -23% vs. +55%, irbesartan vs. vehicle) and UACR (-42% vs. +43%, irbesartan vs. vehicle) were consistent with effects seen in humans with DKD treated with irbesartan for 12 weeks. Pharmacokinetic/pharmacodynamic modeling of the observed NHP UAE response at 8 weeks suggested a similar exposure-response relationship in the NHP model as in human DKD with the magnitude of reductions being somewhat larger in the monkeys than in humans.
Conclusion
Together, these data demonstrate that we have developed and benchmarked a novel NHP model for DKD that has characteristics similar to human pathology and responds to a treatment known to improve DKD in clinical trials. This model is expected to be a valuable translational model for testing novel interventions for DKD.
Funding
- Commercial Support –