Abstract
Abstract Purpose: KSHN001034, a Fulvestrant (FLV) prodrug, was developed to enhance solubility and achieve higher FLV plasma exposures. Currently, Faslodex® (500 mg) intramuscular depot achieves a steady-state plasma concentration of 24-28 ng/mL in humans translating to efficacy. However, it achieves insufficient estrogen receptor (ER) blockade due to suboptimal pharmacokinetic (PK) exposures. KSHN001034 was studied in the MCF-7 xenograft model to evaluate the pharmacodynamic impact of increased FLV exposure. Methods: Higher strength formulations of KSHN001034 were prepared and 150 mg/mL FLV equivalent (eq.) strength was selected based on PK studies of KSHN001034 and Faslodex® in beagle dogs and cynomolgus monkeys. The MCF-7 xenograft study was executed in comparison with FLV where treatment was initiated with an average tumor volume (TV) of ~160 mm3 or ~450 mm3. KSHN001034 or Faslodex® were dosed at 1mg/mouse, and 5mg/mouse either alone or in combination with oral Palbociclib 50mg/kg, QD for 28 days. The plasma as well as brain concentrations (KSHN001034, FLV) and ER expression in tumor tissue were assessed at the end of the study. The toxicity studies were conducted on rats (50, 100, 250 mg/kg) and dogs (15, 30, 75 mg/kg), respectively, using 1x, 2x, and 5x eq. clinical dose of FLV. Results: Single dose PK in dogs and monkeys generated ~2.5-fold higher FLV AUC from KSHN001034 compared to Faslodex®. In the xenograft study, Faslodex® 1mg/mouse treatment in low tumor burden resulted in inhibition of tumor progression (Day 0: 160.8 vs. Day 28: 180.6 mm3) whereas KSHN001034 displayed regression (Day 0: 160.8 vs. Day 28: 143.5 mm3) due to improved FLV exposures. The brain FLV concentration (~60ng/g) post KSHN001034 dosing was observed versus BLQ after Faslodex®. The xenograft study with high tumor burden emphasized the impact of higher FLV release from KSHN001034. The results showed a >30% decrease in initial TV with KSHN001034 in 2-5 days which was not observed even after 28 days of Faslodex® treatment. Also, KSHN001034 showed significantly higher tumor regression in all treated animals compared to Faslodex® (100% vs. 62.5% animals). The safety studies established a rat dose of 250 mg/kg (2.5 g human eq.) and a dog dose of 30 mg/kg (1.0 g human eq.) as the maximum tolerated dose of FLV eq. KSHN001034. Repeat-dose 28 days toxicity studies currently underway in rodent and non-rodent species. Conclusion: Higher FLV exposures with KSHN001034 resulted in improved tumor control, addressing a significant unmet need to slow disease progression as well as its potential in window-of-opportunity trials. Citation Format: Parva Purohit, Heta Pandya, Vishal Unadkat, Sandip Mehta, Ketan Variya, Sonam Sinha, Mahesh Barmade, Vamsi Krishna, Ganesh Sangle. Pharmacological profiling of KSHN001034 - A novel prodrug of Fulvestrant with improved efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3077.
Published Version
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