CyNRGY Platform (RRx-001)
A new class of anti-cancer therapies with the potential to covert “treatment-resistant” tumors into “treatment sensitive” tumors
EpicentRx’s lead CyNRGY platform program, RRx-001, is among a portfolio of immunotherapeutic compounds that normalize the tumor microenvironment, activate the tumor associated macrophages (TAMs) of the innate immune system, and sensitize solid tumors to standard therapies in small cell lung cancer (SCLC), glioblastoma, colorectal cancer and additional cancers.
RRx-001 is a next generation, small molecule anticancer immunotherapeutic that downregulates the CD47/SIRPα axis and repolarizes TAMs and other immunosuppressive cells in the tumor microenvironment to an immunostimulatory phenotype. RRx-001 is designed to be used either as a monotherapy or in combination with chemotherapy, radiation therapy or immunotherapy.
RRx-001 has Orphan Drug designation from FDA for SCLC, neuroendocrine cancer and glioblastoma, and from EMA for SCLC.
CD47 and SIRPa as guideposts of RRx-001-mediated innate checkpoint activity in solid tumors
The search for immune-related biomarkers to prospectively identify responders to RRx-001 is ongoing. Based on tumor biopsies from RRx-001-treated patients enrolled in Phase II clinical trials, response appears to correlate with increased infiltration of TAMs, usually a poor prognostic indicator due to strong immunosuppression. However, in the case of RRx-001, an extensive macrophage infiltrate in biopsied preclinical and clinical lesions is suggestive of better clinical outcomes. Since the main underlying mechanism of RRx-001 activity is dual downregulation of the antiphagocytic, “do not eat” CD47/SIRPα checkpoint axis, high CD47/SIRPα expressing tumors are thought to serve as guideposts for the prediction and monitoring of antitumor activity. Correlation of RRx-001-mediated outcomes and response with a combination CD47 and SIRPα biomarker is under preclinical evaluation as well as clinical investigation in the Phase III REPLATINUM trial in SCLC.
RRx-001 Inflammasome inhibition: chronic disease indications linked to uncontrolled or dysfunctional inflammation
The inflammasome is a group of large protein complexes that sense bacteria, fungi, viruses, cancer cells or tissue damage and, in response, like a match, ignites the fire of inflammation to clean up debris and infections, heal wounds and repair damaged tissues and organs. Hence, under well-controlled conditions, this fire, which leads to redness, heat, swelling, and pain serves a protective and beneficial function, stoking the cells of the body to fight against infection and to regenerate destroyed tissue. Inflammation is tightly linked to the action of immune cells and to the secretion of stimulatory factors called cytokines and chemokines.
However, when the inflammatory fire burns rampant and unchecked, which is an ever-present risk with any fire, no matter how controlled it is at the outset, the tissue destruction that occurs outpaces the regeneration of damaged tissues, leading to the death of cells and to their replacement with scar tissue. Eventually, over time, the normal function of these tissues is reduced or lost. In chronically inflamed tissues, which may result from unresolved sources of foreign bodies, irritants or infections, the inflammasome “match” is persistently lit for weeks to months or even years, resulting in a range of metabolic, neurological, autoimmune disorders as well as in the initiation of cancer. This leads to the continuous and simultaneous presence of tissue repair and injury, sustaining the inflammatory response. Damage and repair are two sides of the same inflammatory coin and so closely linked that to separate them is difficult.
In this case, the goal is to extinguish the source of inflammation or to turn it OFF with an inflammasome inhibitor like RRx-001, the lead compound of the CyNRGY platform.
Textbooks of medicine describe a huge number of diseases and it is common medical practice to treat them as separate entities with different causes, pathologies, and management. However, one mechanism that underlies all of them is inflammation. No matter how varied the cause, whether from trauma, injury, infection, autoimmunity, or stress, the development and progression of many chronic diseases are linked to uncontrolled or dysfunctional inflammation.
Potential disease indications in the inflammasome arena include Alzheimer’s, Crohn’s, gout, congestive heart failure, macular degeneration, glomerulonephritis, ALS, Parkinson’s, diabetes, allergic asthma and multiple sclerosis with the small molecule inflammasome inhibitor, RRx-001.