The long and winding road in drug development: Learnings from on-going development of IEPA for chemotherapy-induced myelosuppression

Autor: Michael G. Meyer, Maciej Czajkowski, Dirk Pleimes
Rok vydání: 2020
Předmět:
Zdroj: Journal of Clinical Oncology. 38:e24134-e24134
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2020.38.15_suppl.e24134
Popis: e24134 Background: An orally bioavailable small molecule IEPA (Imidazolyl Ethanamide Pentandioic Acid) is under development as treatment for chemotherapy-induced myelosuppression (CIM) since 2013. A clinical phase 2a study in epirubicin and cyclophosphamide (CP) treated breast cancer patients demonstrated efficacy of prophylactic (5d pre-CTX) IEPA (100 mg ≈ 1.7 mg/kg/d) in the first but not the second batch of the drug product. After causality due to manufacturing was systematically excluded, the R&D team reassessed the development path and reinitiated non-clinical in vivo studies for efficacy optimization investigating a) the mode of action under different challenge (chemotherapy (CTX); radiation (RX)) b) treatment starting point c) dose d) frequency and e) route of administration to improve reproducibility of efficacy. Methods: The first study assessed hematological recovery over 19 days in mice receiving CTX and treated prophylactically (5 d pre-CTX) or therapeutically (1 h pre-CTX or 24 h post-CTX) with oral IEPA (100 mg/kg, Human Equivalent Dose (HED): 8 mg/kg) either once or twice daily. The second study investigated survival (LD25/30 and 50/30) and hematology in mice exposed to RX in prophylactically (3 d pre-RX) or therapeutically (24 h post-RX) IEPA (50 mg/kg/d) once vs. twice daily, oral vs. intraperitoneal (IP). Results: In mice exposed to CTX (200 mg/kg CP), both prophylactic and therapeutic IEPA treatment accelerated recovery of neutrophils, lymphocytes, and thrombocytes. The time to recovery of white blood cells to the baseline was reduced from 16.8 days to 5.5 days after therapeutic use of IEPA. Dose, treatment start and frequency showed comparable efficacy. In mice exposed to RX (6 Gy, LD50/30), therapeutic IEPA treatment improved survival by 30% (86% IEPA vs. 56% in control). Additionally, accelerated recovery of bone marrow cellularity and reduced body weight loss was observed. Higher doses increased efficacy, while frequency and route of administration of IEPA had limited impact. Conclusions: Two in vivo studies in mice reconfirmed IEPA’s safety and efficacy against both RX-induced mortality and CTX- and RX-induced myelosuppression. While once vs. twice daily and oral vs. IP produced no or only minor improvements, higher doses and therapeutics treatment starting 24 h post-exposure demonstrated reproducible efficacy. Results indicate that increasing the dose to up to 8 mg/kg (based on HED conversion) and starting treatment 24 h post-CTX may improve efficacy in future clinical trials.
Databáze: OpenAIRE
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