On June 5, 2023 Shanghai Escugen Biotechnology Co., Ltd. ("Escugen"), a partner of Levena (Suzhou) Biopharma Co., Ltd. ("Levena"), a wholly owned subsidiary of Sorrento Therapeutics, Inc. (Sorrento), reported preliminary results from a first-in-human study of ESG401, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), in patients with locally advanced/metastatic solid tumors at the 2023 Annual Meeting of ASCO (Free ASCO Whitepaper), the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), held June 2-6 in Chicago, IL (Press release, Sorrento Therapeutics, JUN 5, 2023, View Source [SID1234632478]). ESG401 is an innovative ADC developed by Escugen and Levena. Escugen and Levena Biopharma jointly own the domestic and international patents of this ADC and share global rights for the product. ESG401 is composed of a humanized anti-Trop2 IgG1 monoclonal antibody (mAb) conjugated to a topoisomerase I inhibitor SN38 via a proprietary stable covalent linker with a drug antibody ratio (DAR) of 8. ESG401 has potential differentiated advantages over its competitors in terms of safety, effectiveness and process robustness. Using an innovative, highly stable and cleavable linker, this ADC demonstrated that it releases very little free toxin during circulation, which may reduce off target toxicity in a series of preclinical studies. Additionally, premature release of the mAb may compete for binding sites with the ADC to reduce its efficacy. The ADC highly enriches in tumor tissues and rapidly endocytoses, thereby effectively killing tumor cells and inhibiting tumor growth.
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In the Phase I study, adult ESG401 patients with locally advanced/metastatic solid tumors refractory to or relapsed from standard treatments with measurable disease (RECIST v1.1) were eligible. ESG401 was administered by IV infusion initially in an ascending dose safety study by designated dose and regimen until unacceptable toxicity or progressive disease and followed by expansion cohorts. The Bayesian Optimal Interval (BOIN) design was used to establish the maximum tolerated dose (MTD). As of February 3, 2023, 35 heavily pretreated patients with a median age of 53 years were treated with at least one dose of ESG401 during dose escalation, 2 to 20 mg/kg administered every 3 weeks (Regimen A), or 12 to 16 mg/kg on day 1, 8, and 15 in a 4-week cycle (Regimen B). Eighty percent of the patients had an ECOG status of 1. Sixty-three percent of the patients had received at least 3 lines of prior therapy and overall the number of lines of prior therapy was a median of 4 (range 2-10). A total of 94% of patients had visceral metastases (11% brain, 63% liver, 60% lung) at baseline. From the ASCO (Free ASCO Whitepaper) poster, patient demographics and baseline characteristics is shown below:
While one patient at 20 mg/kg reported a dose limiting toxicity (grade 4 neutropenia and grade 3 febrile neutropenia), the MTD was not reached. The most common treatment-related adverse events were leukopenia, neutropenia, anemia, fatigue and nausea or vomiting. The most common grade 3 events were leukopenia (29%) and neutropenia (31%) with no grade 3 thrombocytopenia, diarrhea, skin rash or oral mucositis. There was no evidence of interstitial lung disease. The frequency of TEAEs > 15% regardless of causality is shown below.
Of the 33 efficacy evaluable patients, 12 achieved partial responses and 4 achieved stable disease lasting at least 24 weeks. The dose of 16 mg/kg was identified as the therapeutically relevant dose. The overall response rate and disease control rate were 36% (4 of 11 patients) and 64% (7 of 11 patients), respectively, in patients with triple negative breast cancer, and 62% (8 of 13 patients) and 77% (10 of 13 patients), respectively, in patients who were HR+/HER2- breast cancer. Three patients have been on treatment for at least 12 months. These data demonstrate that ESG401 is well tolerated and demonstrates efficacy in heavily pretreated patients. Additional studies are ongoing with this innovative promising treatment. A waterfall plot of the data demonstrating the best % change in sum of longest dimension in target lesions from baseline is shown below for patients who received the therapeutic relevant dose (16 mg/kg).