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RGX-104 is an orally bioavailable agonist of the nuclear receptor liver X receptor beta (LXRbeta; NR1H2; LXR-b), with potential immunomodulating and antineoplastic activities. Upon oral administration, LXRbeta agonist RGX-104 selectively targets and binds to LXRbeta, thereby activating LXRbeta-mediated signaling, leading to the transcription of certain tumor suppressor genes and the downregulation of certain tumor promoter genes. This particularly activates the expression of apolipoprotein E (ApoE), a tumor suppressor protein, in tumor cells and certain immune cells. This activates the innate immune system, resulting in depletion of immunosuppressive myeloid-derived suppressor cells (MDSCs), tumor cells and endothelial cells in the tumor microenvironment. This reverses immune evasion, enhances anti-tumor immune responses and inhibits proliferation of tumor cells. LXRbeta, a member of the oxysterol receptor family, which is in the nuclear receptor family of transcription factors, plays a key role in cholesterol transport, glucose metabolism and the modulation of inflammatory responses; activation of LXRbeta suppresses tumor cell invasion, angiogenesis, tumor progression, and metastasis in a variety of tumor cell types. The expression of the ApoE protein becomes silenced in human cancers as they grow, become invasive, and metastasize; ApoE silencing is related to reduced survival in cancer patients. The LXR-ApoE pathway regulates the ability of cancers to evade the immune system and recruit blood vessels.Study RGX-104-001 is a Phase 1, first-in-human, dose escalation and expansion study of RGX-104, an oral small molecule targeting the liver X receptor (LXR). RGX-104 activates LXR, resulting in depletion of both myeloid-derived suppressor cells (MDSCs) as well as tumor blood vessels. MDSCs block the ability of T-cells and other cells of the immune system from attacking tumors.
During the dose escalation stage, multiple doses and schedules of orally administered RGX-104 will be evaluated in patients with advanced solid tumors and lymphoma (i.e., locally advanced and unresectable, or metastatic) who have had progressive disease (PD) on available standard systemic therapies or for which there are no standard systemic therapies of relevant impact. In the expansion stage of the study, additional patients with melanoma, non-small cell lung cancer, epithelial ovarian carcinoma, or breast cancer will be treated at the MTD (or maximum tested dose if no MTD is identified, or dose below the MTD if there is evidence suggesting a more favorable risk/benefit profile) to provide further characterization of RGX-104 safety, efficacy, PK, and pharmacodynamics, including biomarkers of immunologic activity and LXR target activation.RGX-104 depletes both myeloid-derived suppressor cells (MDSCs) as well as tumor blood vessels. MDSCs block T-cells and other cells of the immune system from attacking tumors, resulting in immune evasion. Treatment with RGX-104 reverses immune evasion, resulting in robust anti-tumor activity in established animal models of various cancer types, including drug-resistant tumors. In pre-clinical models, RGX-104 has demonstrated remarkable single-agent activity as well as synergy with approved therapies, such as immune check-point inhibitors. RGX-104 is currently being evaluated in a Phase 1 clinical study. |
