A heat shock to the system
INDIANAPOLIS—Esanex Inc., a clinical-stage company developing heat shock protein inhibitors for the treatment of cancer, recently presented preclinical data from its heat shock protein 90 (Hsp90) inhibitor SNX-5422 program, showing promising antitumor effects both alone and in combination with checkpoint inhibitors.
Dr. Steven E. Hall, president and CEO of Esanex, told DDNews, “SNX-5422 is an orally active Hsp90 inhibitor. Hsp90 is required for the proper folding and stability of key proteins that drive certain types of cancer. There are multiple client proteins upregulated in different cancers that rely on Hsp90 for their proper folding. Inhibiting Hsp90 creates a blockade and induces cell death in these cells. Since Hsp90 regulates multiple client proteins, SNX-5422 modulates multiple pathways important for tumor cell survival, including tumor cell growth, DNA damage repair, oncometabolism, DNA hypomethylation (epigenetics), inflammation and immune activation.”
“Results from these two studies reaffirm our belief in the potential of SNX-5422 both as a monotherapy and in combination with immuno-oncology drugs,” noted Dr. Everardus (Eric) Orlemans, chief scientific officer and senior vice president of development for Esanex. “We are conducting further research to explore the potential of SNX-5422 in other indications as well as through our ongoing Phase 1b trial in chronic lymphocytic leukemia (CLL). The results from the combination research support further development of SNX-5422 in combination with checkpoint inhibitors for the potential treatment of a number of cancer types.”
With regard to this work, two posters were set to be presented on Oct. 29 at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. But according to Shai Biran, media representative for Esanex, “Eric, who was supposed to present the posters at the meeting was unable to get there on time, as his flight was delayed twice.”
The first poster was “Promising antitumor effects of SNX-5422 in combination with checkpoint inhibitors in an MC38 murine model,” and the results described in it indicated that SNX-5422 at either 25 mg/kg or 40 mg/kg, in combination with the immune checkpoint inhibitors anti-PD1, PD-L1 or CTLA4, demonstrated significant antitumor activity in the MC38 murine (mouse) colon cancer model. “Additionally, there was improved antitumor activity of SNX-5422 when combined with the immune checkpoint inhibitors PD-L1 as well as CTLA4. These results support further clinical development of SNX-5422 combined with checkpoint inhibitors in cancer therapy,” the poster conclusion says.
The second poster was “SNX-2112 interferes with mitochondrial metabolism in TP53 mutant tumors,” and it described in-vitro work with SNX-2112, the active derivative of SNX-5422, which demonstrated significant antitumor activity in TP53 null tumors and in rearranged MYC (8q24) hematologic and selected solid tumors (e.g., hepatocellular carcinoma, mesothelioma). This activity appears to be, in part, the result of interference with onco-metabolic pathways. According to the poster abstract, “Further research into this mechanism is ongoing to support this target in clinical trials.”
“Esanex observed multiple objective responses in its Phase 1 monotherapy trials, but our current focus is on rationally selected combinations where we have recently completed Phase 1b trials in non-small cell lung cancer (NSCLC) and neuroendocrine tumors (NET),” notes Hall. “Combination therapy can block multiple signaling pathways, resulting in improved outcomes for patients. Preclinical studies have shown that the combination of a PD-1 inhibitor with SNX-5422 was more effective in syngeneic mouse models than either agent alone.”
SNX-5422 has provided durable clinical responses in open-label trials in non-small cell lung cancer (NSCLC) and neuroendocrine tumors (NET). The potential of SNX-5422 in hematologic cancers is currently being explored in a chronic lymphocytic leukemia (CLL) open-label clinical trial. With approximately 200 patients treated to date, SNX-5422 has a well-established safety profile that supports studying it in combination with existing approved drugs in a variety of clinical settings, according to Esanex.
“SNX-5422 has been studied with the immune checkpoint inhibitors anti-PD1 (RMP1-14), anti-CTLA4 (9D9) and anti-PD-L1 (10F.9G2) in preclinical studies. We are currently conducting a Phase 1b clinical trial to treat CLL with SNX-5422, and our mechanistic knowledge suggests SNX-5422 will be active in other hematological indications. Given the response rates observed in the NSCLC and NET trials, advancement to pivotal trials in either of these indications is warranted. As we plan for these studies, we will start to reach out to potential development partners,” Hall finishes.