On the Origin of RRx-001

Jun 14, 2023

The adage, “there is nothing new under the sun,” (or the streetlight) particularly applies to the pharmaceutical industry whose modus operandi is to recycle, repurpose and rebrand old drugs as new or “next generation” ones based on only minor modifications, which may or may not represent therapeutic improvements over the originals. (The same adage applies to this blog post, which was very loosely adapted from an EpicentRx-authored manuscript in the Journal of Medicinal Chemistry entitled Discovery of RRx-001, a Myc and CD47 Downregulating Small Molecule with Tumor Targeted Cytotoxicity and Healthy Tissue Cytoprotective Properties in Clinical Development).

The majority of supposedly “novel” or “first-in-class” pharmaceuticals follow on from previous brand name drugs, to which they are related, either distantly or closely, in terms of chemical structure and/or therapeutic activity. The most controversial example of a so-called “me too” drug, a cynical term used to describe ‘retreads’ or ‘knock offs’ of already existing brand name medications, involves the pharmaceutical giant AstraZeneca (AZ). The controversy relates to how AZ reengineered and rebranded its blockbuster heartburn medicine, Prilosec, whose patent expiry was looming, as Nexium—the “new purple pill”, as it was called—with only the slightest structural modification, which resulted in a new patent. Advertised as an improvement, the difference between 1st generation Prilosec and 2nd generation Nexium was actually negligible on the basis of 4 separate head-to-head comparison studies. This widely used patent extension tactic, also known as “evergreening”, serves to discourage generic entry and to maintain some or most of the lucrative market share of the original, all based on a relative “improvement” of efficacy, even though that improvement, like with the Prilosec-Nexium example, is minimal, at best.

Eschewing business as usual, the investor and founder of EpicentRx, himself an immunologist and pharmaceutical veteran of over 30 years, as well as another founder, Dr. Mark Bednarski, who was a radiologist and a medicinal chemist, decided to strike out in a new direction with the aerospace industry, which they viewed as a potential source for new anticancer medicines. This unconventional choice of a drug discovery starting point was based on the sheer number and diversity of small molecular mass chemical entities (so-called small molecules) that were available to screen from there but also, most importantly, access to smart, experienced, enthusiastic chemists and state-of-the-art laboratories and instrumentation.

After 30 years in pharmaceutical development, the main motivation of the founder and investor not to pursue business as usual tactics was his frustration with the status quo, which, to date, had yielded relatively few successes against several diseases including cancer, his area of expertise, especially metastatic cancer, a relentless foe that almost inevitably developed resistance to whatever was tried against it and incurable immune-mediated inflammatory diseases. On the other hand, as Einstein famously pointed out (possibly apocryphally), the definition of insanity is doing the same thing over and over again and expecting a different result, which was exactly the case here. The pharmaceutical industry prioritizes and incentivizes imitation (i.e., me-too and follow on drugs) over innovation (i.e., novel drugs), and then—hello McFly!!— expects better/different results, which meets the above definition of insanity.

On that basis, for the founder and investor of EpicentRx, a venture capitalist (VC) from InterWest Partners, who had been there and done that, business as usual was not an option. Rejecting the “streetlight effect” (see Figure below) of traditional pharmaceutical research and development (R&D) activities, which span a remarkably small number of already exploited molecular scaffolds, and tend to omit from any screening process what is unknown, he made a solo investment in a startup called RadioRx (later name changed to EpicentRx) whose purpose it was to engineer new drug candidates with interesting biological properties and novel modes of action based on aerospace-derived chemical structures.

Figure: The streetlight effect is exemplified by the classic Mutt & Jeff cartoon strip about the drunk who searches underneath a streetlamp for a coin he dropped two blocks away because, as he states, “The light is better here”

Mutt & Jeff Bud Fisher June 3, 1942.

This solo investment also went against the grain, since the norm in venture capital is to form multi-investor syndicates that spread the financial risk and bring together more expertise and support. In fact, IW Partners had invited other VC firms to the deal, but they declined to participate based on the perceived riskiness of the investment, which was altogether too new, too different and too nervy, especially since at the time EpicentRx was a company in name only with no identified drug and only one part-time employee.

However, after a time-consuming, labor-intensive search (far, far removed from the circumscribed ‘halo’ of the streetlight) and the hiring of one more full-time employee, ABDNAZ, short for 1-bromoacetyl-3,3-dinitroazetidine, a name later shortened to RRx-001 for ease of pronunciation and communication, was identified.

Among the hundreds of screened compounds, RRx-001 was prioritized for clinical advancement because of intriguing safety and activity that it demonstrated in experimental models. This safety and activity profile favorably augured for its potential to progress from preclinical testing where it was then to, hopefully, one day, FDA approval and marketed drug status.

Another factor in its favor was that the degradation products of the precursor to RRx-001, a molecule called trinitroazetidine (TNAZ), were well-known with a relatively benign toxicology profile, suggesting that dinitroazetidine containing compounds like RRx-001 posed no inherent development risks and were less likely to expose patients to harm. Since toxicology studies, which represent a significant investment of time, resources and animals, are never undertaken lightly, it was a tremendous advantage to have access to this safety information before committing resources to the development of RRx-001.

Only one drug shares a comparable backstory to RRx-001: the explosive, nitroglycerin, that was introduced as a treatment for heart-related chest pain or angina. In an ironic twist, Alfred Nobel, the inventor of dynamite, which is nitroglycerin stabilized by clay, suffered acutely from angina but against the advice of his doctor declined to be treated with nitroglycerin and later died from heart disease. In a somewhat similar twist of fate, one of the previously mentioned founders of EpicentRx, Dr. Mark Bednarski, who helped to develop RRx-001, and may have been an ideal candidate to receive it, having been diagnosed with colon cancer, died before the start of the first RRx-001 clinical trial.

Since then, RRx-001 has safely progressed through the crucible of multiple Phase 1-2 clinical trials; a Phase 3 trial, as the last step before FDA approval, is ongoing. More recently, RRx-001 has received FDA Fast Track designation for the prevention/amelioration of severe oral mucositis, that is, blistering and ulceration of the oral cavity during treatment with chemotherapy and radiation in head and neck cancer patients (See April 4th, 2023, blog post entitled RRx-001 and FDA Fast Track). Also, the Michael J. Fox Foundation/Shake It Up Australia and Fight MND have awarded generous grants to evaluate the activity of RRx-001, as an NLRP3/ NF-κB inhibitor and Nrf2 inducer, in Parkinson’s Disease and ALS/MND, respectively. In the meantime, from its humble beginnings as an early-stage startup on a shoestring budget with one part-time employee, EpicentRx has been transformed into a well-funded late-stage organization of around 15 employees, with well over $100M raised. In 2017, EpicentRx in-licensed rights to an oncolytic adenovirus platform, the lead product of which, AdAPT-001, a TGFß trap, is in a Phase 1/2 clinical trial with promising evidence of activity to report as a single agent and in combination with a checkpoint inhibitor. (See April 10, 2023, blog post entitled The AdAPT-001 “Whichdunit”).

In summary, the improbable story of how RRx-001, a derivative of rocket propellant and the lead asset of a renegade life sciences startup called EpicentRx, emerged from the unlikeliest of places, the aerospace industry, and was spun off by an iconoclastic VC and a radiologist as an anticancer and anti-inflammatory/antioxidant agent that, to date, has been administered to over 300 patients in 12 clinical trials is perhaps as close as possible to something new under the sun, at least in pharmaceutical development.