AN0025 is a small molecule prostaglandin E receptor 4 (EP4) antagonist designed to modulate the tumor microenvironment. In-licensed from Eisai in January 2018, we have exclusive rights and license to develop and commercialize AN0025 globally, excluding Japan, Korea, Taiwan and some Southeast Asian Countries. The mechanism of action and preliminary safety profile of AN0025 have been demonstrated in early clinical trials¹. Based on its mechanism of action, we believe that AN0025 has the potential to be used in combination with multiple therapies including immune checkpoint inhibitors and radiotherapy/chemoradiotherapy to treat solid tumors.

Phase Ib study of AN0025 and Pembrolizumab Combination in Advanced Solid Tumors (NCT04432857)

AN0025 is designed to block the prostaglandin E2 (PGE2)-EP4 signaling pathway thereby inhibiting PGE2-mediated immunosuppression in cancer patients. In the anti-PD-1/PD-L1 therapy resistant CT26 murine colon cancer model, AN0025 combined with an anti-PD-1 antibody treatment demonstrated stronger antitumor activity compared to  monotherapy.

AN0025 is currently in a Phase Ib clinical trial in the US and France.The intent is to modulate the tumor microenvironment in combination with pembrolizumab in advanced solid tumors. The study includes a DLT observation phase followed by an expansion phase. The pembrolizumab dose remains constant at 200 mg every 3 weeks for each dose level of AN0025 and in each cohort. The study is currently in dose expansion phase and plan to enroll approximately 10-12 patients in each of the expansion cohorts, including recurrent non-small cell lung cancer (NSCLC) and urothelial cancer (UC) after anti-PD-1/PD-L1 treatments, recurrent triple-negative breast cancer (TNBC), microsatellite stable colorectal cancer (MSS CRC) and cervical cancer (CC) after standard of care treatments.

Phase Ib study of Preoperative AN0025 and Radiotherapy/Chemoradiotherapy Combination in Rectum Cancer (NCT03152370)

AN0025 and radiotherapy (RT) combination treatment demonstrated improved antitumor activity and antitumor memory T-cell response in mice compared with RT monotherapy. As shown in the figure below, in a CT26murine colon cancer model, treatment of AN0025 plus a single 9 Gy of RT rendered nine of the 12 animals tumor free, which was significantly better than RT alone. None of the tumor free animals regrew tumors over a subsequent 2-month period that followed the cessation of treatment, and all the nine mice completely rejected tumor rechallenge. These results suggested an antitumor memory response in those nine animals cured by the combination of AN0025 and RT.

We completed a Phase Ib study to evaluate AN0025 in combination with RT/Chemoradiotherapy (CRT) for neoadjuvant treatment of rectal cancer where primary resection without RT/CRT is unlikely to achieve clear margins. We presented encouraging interim results² of this trial at the European Society for Medical Oncology (ESMO) in October 2019. In particular, the combination therapy with AN0025 and RT/CRT reported an exceptionally high clinical complete response (cCR) of 20%, indicating surgery is no longer required for these patients, as well as a high pathologic complete response (pCR) of 16%, indicating that no residual tumors were found in these patients after the surgery. The promising results from the Phase Ib study warrants further development.

Reference

1. J Immunother Cancer, 2020 8(1): e000222 (pdf).

2. A Phase 1b Study of E7046 (AN0025) in Combination With Radiotherapy/Chemoradiotherapy (RT/CRT) in Preoperative Treatment of Rectal Cancer, ESMO 2019 (pdf).