How and when did your company start, and where are you located?
EpicentRx (formerly RadioRx) was founded in 2010, as an aerospace industry spin-off, to develop a new class of minimally toxic compounds with different features (i.e., those with never-seen-before chemical scaffolds) that engage different and multiple targets in a synergistic manner. A knowledge of the precise pharmacological target was not required by the FDA and EpicentRx, eschewing the me-too mentality, which is so common in the pharmaceutical industry, prioritized target novelty and potentially additional target specificity over conventional druggable target preferences; after all, to paraphrase Einstein, “The definition of drug development is doing the same thing over and over and expecting a different result.” A few years later EpicentRx brought in the oncolytic viruses developed by gastrointestinal oncologist and businessman, Dr. Tony Reid, and made him CEO. The company is located at 11099 North Torrey Pines Road Suite 160, La Jolla, CA 92037.
How many employees do you have, and how do you find/attract them?
The company has about 15 full-time employees. Most of the employees joined because of previous positive interactions with the company. EpicentRx is a rewarding place to work.
What are the main focus and platform technology(ies) of your company?
The focus of the company is on the treatment of diseases of high unmet need. The platform technologies are proprietary oncolytic adenoviruses, which also serve as excellent gene delivery vectors and dinitroazetidine-based small molecules with anti-inflammatory/antioxidant and tumor associated macrophage stimulatory properties.
Can you provide a short overview of your product pipeline?
The two lead products are RRx-001 and AdAPT-001. RRx-001 is under development in cancer, radiation protection, mucositis, and neurodegenerative diseases like Parkinson’s and amyotrophic lateral sclerosis/motor neuron disease (ALS/MND).
AdAPT-001 is an oncolytic adenovirus, agent of the common cold, that is armed with a transforming growth factor (TGF-ß) trap, which sequesters and neutralizes the pro-fibrotic and immunosuppressive cytokine, TGF-ß. When AdAPT-001 replicates, which it does at high titer in infected cells, it also expresses its inserted TGF-ß trap that amplifies the therapeutic effect. Experimentally, it is active in cancers that are TGF- ß-driven like sarcoma, in diseases where fibrosis is a major component like cirrhosis and pulmonary fibrosis, and potentially as a vaccine adjuvant since TGF-ß, a cytokine, which orchestrates the wound healing process, suppresses, or calms down the immune system. In the company pipeline are several other transgene-enhanced adenoviruses including a COVID-19 nucleocapsid-based vaccine.
Who is your competition, and what advantage(s) does your products/technology offer?
Technically, for the oncolytic adenoviruses, competitors are any of the several companies with an oncolytic virus in clinical development. These include Oncolys BioPharma, Targovax, PsiOxus Therapeutics, SillaJen Biotherapeutics, Sorrento Therapeutics, Lokon Pharma, Genelux Corporation, Vyriad, TILT Biotherapeutics and Cold Genesys. Practically speaking, however, to best knowledge, the EpicentRx adenoviral vector is the only one designed to replicate as fast as wild type virus. This is extremely advantageous not only in terms of anticancer activity since the faster the virus replicates the greater the cell kill and the more transgene that is expressed but also in terms of its manufacturability since expensive contract manufacturing organizations (CMOs) are not needed at least for Phase 1-2 trials. Other oncolytic viruses in development or on the market are often so hamstrung by all the “bells and whistles” that are included to improve their selectivity and/or safety profile that they tend to replicate slowly and inefficiently.
The advantage of the small molecule, RRx-001, and what makes it sui generis, is its dual mechanism of action. Inside of hypoxic tumors it polarizes tumor associated macrophages from an M2 pro-tumor phenotype to an M1 antitumor phenotype. Outside of tumors it is a direct NLRP3 inhibitor and Nrf2 activator that reduces inflammatory and oxidative damage.
What were the “highlights” in your recent development of vaccines/immunotherapeutics?
In a small, uncontrolled, multi-center Phase 1 study (ClinicalTrials.gov Identifier: NCT04673942) with patients that have exhausted all standard of care therapies, AdAPT-001 showed evidence of activity particularly but not exclusively in desmoplastic/TGF-ß driven tumors like soft tissue sarcomas, eccrine carcinoma, thyroid carcinoma, melanoma, and locally advanced rectal cancer. Also, N-finity, the nucleocapsid based COVID-19 vaccine, has been tested preclinically, manufactured, and given the green light to proceed in clinical trials by the FDA. Unlike the spike protein on which the mRNA vaccines are based, nucleocapsid is more conserved, as it is essential for RNA synthesis, and may more effectively induce T cell responses.
While the mRNA vaccines have markedly reduced adverse outcomes, the thought is that N-finity may yet have a role to play in the context of long COVID and in immunosuppressed populations ranging from patients with cancer and solid-organ transplant recipients to patients with HIV and those receiving immunomodulatory therapy for autoimmune disease that are at high risk of SARS-CoV-2 morbidity and mortality.
What have been the most critical problems in developing products in your field, and how can your company’s technology help overcome these problems?
Oncolytic viruses have, for the most part, failed to live up to expectations. This failure likely arises from two root causes: 1) several viruses contain transgenes like GM-CSF with immunosuppressive properties and 2) may of the viruses are overengineered, having been encumbered or weighed down with exogenous DNA or proteins to improve selectivity and/or safety which comes at the expense of speed and efficiency. EpicentRx overcame these problems with the addition of a TGF-ß trap to neutralize the chief immunosuppressive factor in the tumor microenvironment and through deletion of only 50 base pairs in the virus, which detargets it from normal cells but not tumor cells.
The biggest problem with the dinitroazetidine-based small molecules is that they have never been seen before in medicine and, hence, there are no congeners or predecessors from which to glean key insights that inform further development and application of the biochemistry, so we’ve had to work out what to do and where to go with them more or less in real time. This has been a challenge to say the least but, ultimately, well worth it.
What is your company’s value proposition?
The value proposition with EpicentRx is that its two core technologies, the small molecules, and oncolytic viruses, are designed to be given not only as single agents but also with other therapies including immunotherapies to make them work better and with less toxicity; to date, neither RRx-001 nor AdAPT-001 are associated with any dose-limiting toxicities (DLTs) or drug-drug interactions and RRx-001, in particular, has shown preclinical and clinical evidence that it decreases the toxicity of chemotherapies, targeted therapies, radiation, and immunotherapies. The main focus of the company is in oncology, radiation protection, and neurodegenerative diseases.
What business development strategy do you pursue?
The company follows the data and the science, wherever they lead. This guides and informs how and where (i.e., in what disease conditions) we develop our therapeutic candidates and what partners with the requisite expertise and interest to seek out as a result.
How does your company attract partners?
EpicentRx writes many grants and patents, regularly speaks at scientific conferences and expert meetings, and publishes extensively on RRx-001 and AdAPT-001. These two therapies cut across several clinical and basic research disciplines, including but not limited to cancer, cardiology, geriatrics, fibrosis, neuroinflammation, otolaryngology, pediatrics, pharmacology, pulmonology, and radiation biology.
Who are your most important partners?
Current partners include SciClone Pharmaceuticals, University of Queensland in Australia, Michael J. Fox Foundation, Shake It Up Australia, Fight MND, and Northrop-Grumman.
How do you balance performing work in-house vs out-sourcing?
A significant majority of work is outsourced, which reduces operating costs, and we extensively draw on the expertise of a trusted cadre of independent consultants and collaborators with many years of experience and proven track records of success. Most research projects are translational to directly support product development.
What are your product development goals for the next 3 y?
EpicentRx has launched a pivotal Phase 3 study for RRx-001 in small cell lung cancer. RRx-001 is also in late-stage development as an anti-mucositis agent in head and neck cancer and as a medical countermeasure in case of a radiologic or nuclear emergency. We plan to seek an appropriate path to registration with AdAPT-001 possibly in sarcoma or colorectal cancer. In addition, the development of the next generation of potential small molecule therapies and oncolytic viruses is underway.