Development of an LXR agonist as first in class therapy for treatment of metastatic melanoma

Abstract Metastatic melanoma remains incurable for the majority of patients Of the patients diagnosed with Stage IIB IV melanoma annually do not respond to existing treatments and for those that do resistance is a major concern Furthermore survival rates for patients with stage IIA IIIB primary tumors steadily decrease with increasing stage Prevention of metastasis itself would offer the best chance at cure Currently there is no adjuvant therapy that is effective in preventing metastatic spread To address this need Rgenix is developing RGX as a first in class orally available therapeutic for the treatment of metastatic melanoma RGX is a Liver X receptor LXR agonist which activates expression of Apolipoprotein E ApoE a recently identified tumor suppressor gene ApoE activates the anti tumor immunity by suppressing myeloid derived suppressor cells MDSCs inhibits cancer cell invasion and angiogenesis This intricate mechanism which is fundamentally different from that of existing treatments results in robust tumor growth suppression and inhibition of metastatic growth in mouse models of melanoma Strong activity was also observed using cell lines that are resistant to approved therapies vemurafenib and decarbazine Furthermore combining RGX with approved therapeutics vemurafenib anti CTLA or anti PD results in additive tumor suppressive efficacy In depth ADME pharmacodynamic and pharmacokinetic studies have demonstrated RGX to be an excellent drug candidate Rgenix has also identified ApoE as a molecular biomarker which can be measured in the blood as a read out of response in mice and monkeys Here Rgenix aims to complete pre clinical development of RGX by developing analytical methods for ApoE PD biomarker measurements of clinical samples completing GMP scale up synthesis for Phase I clinical trial and performing safety pharmacology studies The long term goal is to develop a safe and efficient therapy for both treating metastatic melanoma and preventing metastasis formation To this end Rgenix will perform bioanalytical method development for ApoE measurement in white blood cells by quantitative real time PCR and for ApoE protein and MDSC content in patient biopsies by immunohistochemistry using a training cohort of commercially available blood and tumor samples Success in this in vitro system will set the stage for testing correlation of ApoE expression with treatment outcome during Phase I This will establish ApoE expression as a surrogate endpoint during clinical development In addition routes for GMP scale up synthesis will be refined and a kg batch of RGX for human clinical trials produced Finally to test potentially harmful effects of the drug during chronic dosing safety pharmacology studies for cardiovascular function central nervous system effects and respiratory function will be conducted Successful completion of these studies will move RGX into the clinic and allow development in both the metastatic and adjuvant settings Additionally an easily measurable molecular biomarker reflecting target engagement would accelerate clinical development of RGX Project Narrative In this Direct to Phase II proposal Rgenix plans to complete the pre clinical development of RGX a novel therapeutic that is developed for metastatic melanoma as well as for post surgical adjuvant treatment as a means of preventing metastatic spread Successful completion of the proposed studies will allow RGX to enter human clinical trials This project when successful will offer a novel and highly effective therapeutic for the treatment of Stage IIb IV melanoma which is diagnosed in patients nationwide and is incurable for roughly a quarter of these patients