LXR agonist (Ocean University of China)

On November 28, 2018, Masoud Tavazoie, Co-Founder and CEO of Rgenix, made a presentation at AACR’s Tumor Immunology and Immunotherapy conference in Miami, Fl. As part of his presentation, Masoud described the LXR/ApoE pathway and its role in regulating the innate immune system in cancer. The LXR/ApoE pathway was discovered as a cancer pathway by Rgenix founding scientists utilizing an unbiased experimental approach to identify key drivers of cancer progression. This approach forms the foundation of the Rgenix target discovery platform which has yielded novel clinically relevant targets for first-in-class therapeutics currently under development at the company. This includes Rgenix’s lead drug candidate RGX-104, a novel immunotherapy agent that targets the LXR/ApoE pathway to activate anti-tumor immunity. Dr. Tavazoie provided an overview of the role of the LXR/ApoE pathway in regulating cancer progression, highlighting its potential as a therapeutic target. Research has revealed that activation of the LXR/ApoE pathway with the small molecule LXR agonist RGX-104 can generate an anti-tumor immune response by targeting the innate immune system. In many cancers, cells of the innate immune system – such as immature myeloid cells – can inhibit the anti-tumor immune response by blocking T cell activation, which is required for successful immune attack against tumors. By depleting immature myeloid cells, RGX-104 shifts the innate immune response from immune-suppressive to immune-stimulatory. This effect is associated with activation of dendritic cells and relevant T cell populations, resulting in shrinkage of tumors in animal models and in advanced cancer patients treated with the agent. Additionally, RGX-104 has also demonstrated the potential to enhance the efficacy of checkpoint blockade and T cell adoptive transfer therapy in mouse models. Pre-clinical and clinical data presented at the meeting establish the drug candidate RGX-104 as a novel immunotherapy agent with a unique mechanism of action and the capacity to shrink tumors via modulation of the LXR/ApoE pathway. Learn more

RGX-104 shown to be well-tolerated and capable of generating immunologic and anti-tumor activity in advanced cancer patients. Rgenix continues Phase Ia/b trial with a RGX-104 monotherapy expansion cohort and dose escalation/ expansion cohorts of RGX-104 in combination with nivolumab. New York, NY – June 4, 2018 – Rgenix, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, announced today it is presenting data on the safety, pharmacodynamics, and clinical activity from the dose escalation stage of the ongoing Phase Ia/b trial of RGX-104, an oral small molecule immunotherapy that targets the liver X receptor (LXR). In a poster presentation of an abstract accepted for the 2018 Annual Meeting of the American Society of Clinical Oncology, “Pharmacodynamic and clinical activity of RGX-104, a first-in-class immunotherapy targeting the liver-X nuclear hormone receptor (LXR), in patients with refractory malignancies”, Rgenix showed the first-in-class compound to be capable of generating immunologic and anti-tumor activity. RGX-104 is a small-molecule LXR agonist that modulates innate immunity by activating the ApoE gene. In murine models, the small molecule depletes myeloid derived suppressor cells (MDSCs) and stimulates dendritic cells (DCs), activating anti-tumor immunity as a single agent as well as in combination with adoptive T cell therapy or checkpoint inhibitors. The Phase 1a/b trial in progress is studying the therapy with regards to safety, efficacy, pharmacokinetics and pharmacodynamics. A total of 26 patients with a broad array of tumors have received RGX-104 at a range of dose levels and frequency as part of the dose escalation stage of the study. RGX-104 was well tolerated across dose cohorts, with hyperlipidemia – an on target effect of LXR agonism – representing the most common adverse event. Robust ApoE target gene engagement was observed in patients, along with substantial MDSC depletion and DC stimulation in 12 of 17 evaluable patients. Activation of circulating PD-1+ T cells was observed in 11 of the 12 patients that experienced MDSC depletion. One patient with a high-grade neuroendocrine malignancy with small cell features had a confirmed radiographic partial response with a 53% reduction in index hepatic metastases at the 160 mg BID dose. This response was associated with a greater than 12-fold increase in activated PD-1+ T cells. Additionally, seven patients had stable disease for durations of 8-16 weeks. The dose of 160 mg BID was chosen as the Recommended Phase 2 Dose, with robust pharmacodynamic effects on ApoE expression and relevant immune cell populations. Masoud Tavazoie, MD, PhD, and Chief Executive Officer of Rgenix, said, “Today’s presentation illustrates the promise of our lead clinical candidate RGX-104. It enables us to move forward with our plans to study the compound in expansion cohorts as a single agent as well as in combination with a PD-1 inhibitor in patients with both checkpoint-inhibitor refractory and naïve tumors.” Escalation and Expansion cohorts in the Phase 1b stage of the clinical trial are currently enrolling patients with epithelial ovarian carcinoma (EOC), melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), renal cell cancer (RCC), bladder cancer (BLC), and triple negative breast cancer (TNBC). About Rgenix Rgenix, Inc., is a privately-held clinical-stage biopharmaceutical company focused on the discovery and development of novel cancer drugs that target key pathways in cancer progression. The company is pursuing several first-in-class drug candidates to treat cancers of high unmet need. Rgenix identifies novel cancer targets using a microRNA based target discovery platform originally developed by Rgenix’s scientific co-founders at The Rockefeller University and now exclusively licensed to Rgenix. The company brings together distinguished scientific founders, a seasoned Board, and a leadership team comprised of experienced drug developers. The company is funded by leading biotechnology investors, including Novo A/S, Sofinnova Partners, and Alexandria Venture Investments. For more information, please visit www.rgenix.com. About RGX-104 RGX-104 is an orally-administered potent small molecule agonist of the Liver X Receptor (LXR) that is currently being evaluated in a clinical study. Activation of the LXR-ApoE pathway by RGX-104 stimulates the innate immune response in cancer via depletion of myeloid-derived suppressor cells and activation of dendritic cells, leading to stimulation of T cells and anti-tumor immunity. LXR activation also blocks the ability of tumors to recruit blood vessels. These combined effects result in suppression of tumor growth and metastasis in a broad array of animal tumor models. The LXR-ApoE pathway was originally identified as a cancer target using a novel microRNA-based discovery platform developed by Rgenix’s scientific co-founders at The Rockefeller University. Rgenix is conducting a Phase 1a/b clinical trial of RGX-104 in patients with advanced solid malignancies—for more information about the clinical trial, please visit: https://clinicaltrials.gov/ct2/show/NCT02922764. Media Contacts: RooneyPartners Marion Janic 212-223-4017 mjanic@rooneyco.com