539. GS-CA2: A Novel, Potent, and Selective First-In-class Inhibitor of HIV-1 Capsid Function Displays Nonclinical Pharmacokinetics Supporting Long-Acting Potential in Humans. (26th November 2018)

• Record Type: Journal Article
• Authors: Zheng, Jim; Yant, Stephen R; Ahmadyar, Shekeba; Chan, Tiffany Y; Chiu, Anna; Cihlar, Tomas; Link, John O; Lu, Bing; Mwangi, Judy; Rowe, William; Schroeder, Scott D; Stepan, George J; Wang, Kelly Wei; Subramanian, Raju; Tse, Winston C
• Is Part Of: Open forum infectious diseases. Volume 5(2018)Supplement 1
• Page Start: S199
• Page End: S200
• Publication Date: 2018-11-26
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofy210.548
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: Background: GS-CA2, an analog of GS-CA1, is a novel and selective inhibitor of HIV-1 capsid function. Safety and pharmacokinetics (PK) of GS-CA2 is currently being evaluated in healthy human subjects. Herein, we present the anti-HIV activity and nonclinical PK of GS-CA2, demonstrating its potential as a first-in-class long-acting antiretroviral agent. Methods: GS-CA2 antiviral activity was evaluated in MT-4 cells and in human peripheral blood mononuclear cells (PBMCs) acutely infected with HIV-1 (IIIb) and clinical HIV-1 isolates, respectively. Standard in vitro methods were used to characterize compound lipophilicity (LogD), solubility and relative binding to cell culture and plasma proteins. Metabolic stability was assessed in cryopreserved hepatocytes. GS-CA2 PK parameters following intravenous and subcutaneous (SC) administration were assessed in rat and dog. GS-CA2 plasma concentrations were determined by HPLC-MS/MS. Results: GS-CA2 showed potent and selective anti-HIV activity in MT-4 cells (EC50 = 0.1 nM; CC50 = 26.6 µM). In PBMCs, GS-CA2 displayed a mean EC50 of 0.05 nM (0.02–0.16 nM) against 23 HIV-1 clinical isolates representing all major subtypes. GS-CA2 is highly lipophilic (LogD of 3.7) with low aqueous solubility (<0.01 mg/mL) and low predicted clearance (CL) in human hepatocytes (0.01 L/h/kg). In rat and dog, GS-CA2 demonstrated low CL (<4% of liver blood flow). GS-CA2 PK in rat and dog exhibited sustained and slow drug release following a single SC administration. Factors including species, formulation, concentration, dose, volume, and number of injections were examined for the effect on systemic exposure over time. GS-CA2 plasma concentrations in dogs (Figure 1) were maintained above the human plasma protein binding-adjusted EC95 (4 nM) for the entire study duration (16 weeks). Conclusion: GS-CA2 is a selective and first-in-class HIV capsid inhibitor with picomolar potency and potential to be clinically effective against a broad range of HIV-1 strains. In animals following a single SC injection, GS-CA2 maintained therapeutically relevant concentrations for >3 months. These nonclinical data support clinical development of GS-CA2 as a novel long-acting antiretroviral agent suitable for the treatment of HIV-1 infection. Disclosures: J. Zheng, Gilead Sciences, Inc.: Employee, Salary. S. R. Yant, Gilead Sciences, Inc.: Employee, Salary. S. Ahmadyar, Gilead Sciences, Inc.: Employee, Salary. T. Y. Chan, Gilead Sciences, Inc.: Employee, Salary. A. Chiu, Gilead Sciences, Inc.: Employee, Salary. T. Cihlar, Gilead Sciences, Inc.: Employee, Salary. J. O. Link, Gilead Sciences, Inc.: Employee, Salary. B. Lu, Gilead Sciences, Inc.: Employee, Salary. J. Mwangi, Gilead Sciences, Inc.: Employee, Salary. W. Rowe, Gilead Sciences, Inc.: Employee, Salary. S. D. Schroeder, Gilead Sciences, Inc.: Employee, Salary. G. J. Stepan, Gilead Sciences, Inc.: Employee, Salary. K. W. Wang, Gilead Sciences, Inc.: Employee, Salary. R. Subramanian, Gilead Sciences, Inc.: Employee, Salary. W. C. Tse, Gilead Sciences, Inc.: Employee, Salary.