Cerulean Pharma’s nanopharmaceuticals: From bench to bedside

S. Eliasof
Cerulean Pharma Inc., US

Keywords: nanopharmaceutical

Summary:

Cerulean is advancing CRLX101, a dynamically tumor-targeted nanopharmaceutical designed to penetrate tumor tissues, enter cancer cells, and provide sustained delivery of its payload, camptothecin (CPT), providing durable therapeutic effects. In various human xenograft tumor models, CRLX101 has demonstrated highly improved efficacy and PK profiles, and reduced toxicity compared to CPT. Efficacy exceeded every comparator drug tested in every model. CRLX101 is designed to provide maximum CPT tumor exposure over an extended period of time and as a direct consequence, inhibits not only topoisomerase 1 but also HIF-1α, a transcription factor that promotes tumor angiogenesis, invasion, and metastasis. HIF-1α is considered an important cancer target in part because anti-angiogenic therapy can increase HIF-1α and thereby become resistant to treatment. We have demonstrated that CRLX101 is synergistic with various anti-angiogenic treatments in mice, and we conclude that CRLX101 may overcome HIF-mediated acquired resistance to antiangiogenic drugs through inhibition of HIF-1α in addition to its inhibition of topoisomerase 1. Because dynamically tumor-targeted nanopharmaceuticals target the leaky vasculature present in most tumors, CRLX101 represents opportunities for patients with many different tumor types. Accordingly, CRLX101 is currently being evaluated in four Phase 2 clinical trials as a monotherapy for non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), ovarian cancer, and gastric cancer. The randomized Phase 2b NSCLC trial has completed enrollment, and final data from the study are expected in March. In addition, a Phase 1b/2a trial of CRLX101 plus bevacizumab is currently underway in renal cell carcinoma, to explore the clinical potential for synergy with anti-angiogenic agents.