RRx-001: Jack of all trades, master of…many

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Bryan Oronsky, Chief Development Officer at EpicentRx, discusses how one drug sourced from the defense and aerospace industry, could have many potential disese targets.

Introduction

The term “dilettante”, at least in English, connotes a sloppy bungler, a smatterer, a second rater, unskilled and unserious, lacking breadth and depth, and someone to whom the pejorative label, “jack of all trades, master of none”, is attached. The pharmaceutical equivalent of “dilettante”— predictably with no less of a negative connotation—is the term “polypharmacologic”, which refers to agents that act, usually unintentionally or serendipitously, on a plethora of molecular targets or biochemical pathways. Despite several success stories with polypharmacology including aspirin, antidepressant serotonin reuptake inhibitors (SSRIs) and the anticancer agent, Gleevec, to describe a drug as “polypharmacologic” is to stigmatise it as “dirty”, “sloppy” or “promiscuous”; such a stigma is invariably present with therapies that inhibit many targets non-specifically (master of none) and these multitargeted therapies are often deprioritised, usually due to concerns about side effects, in favour of therapies, which are specialised to inhibit one target very well (master of one). A variation on the master of none vs master of one theme is a single drug that targets several diseases (hence, master of many) but only inhibits a few targets; in the case of the small molecule known as RRx-001, those targets are subject to change depending on the local environmental conditions that are present in certain tissues or cells. 

Designed and developed by the privately held, dual platform-based biopharmaceutical company, EpicentRx, in collaboration with a major multinational American aerospace and defense contractor, RRx-001 is a Jekyll-and-Hyde small molecule, which in the manner of a Dr Jekyll benignly confers protection on normal tissues under normal oxygen conditions. However, under severely oxidative and/or severely hypoxic or low oxygen conditions that are mainly observed in cancer, RRx-001 transforms into its aggressive twin, Mr Hyde, which is highly toxic to tumours.

RRx-001 directly and irreversibly binds to a specific amino acid cysteine residue on a protein complex called the NLRP3 inflammasome, which serves as the “on switch” for inflammation. Since inflammation underlies so many diseases and conditions, RRx-001, as an NLRP3 inflammasome inhibitor1, which turns off or turns down inflammation, is broadly protective. Accordingly, RRx-001 is under development as a radioprotector, meaning it decreases radiation-related side effects on normal cells during the treatment of cancer, such as head and neck cancer, with radiotherapy or during a nuclear reactor meltdown/nuclear attack or a long-duration space mission, during which astronauts are chronically exposed to galactic cosmic rays (GCRs). A late-stage clinical trial in head and neck cancer for the treatment of severe oral blistering or oral mucositis caused by radiation therapy is planned. RRx-001 is also under development as treatment for neurodegenerative diseases like Parkinson’s, Alzheimer’s, and ALS and cardiopulmonary diseases such as heart failure and pulmonary hypertension, which are associated with inflammation.

 

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Figure 1: RRx-001 is one drug with many targets.

However, in severely hypoxic tumours, RRx-001 fragments or breaks apart, releasing Hyde-like metabolites that specifically target so-called tumour associated macrophages (TAMs) and tumour blood vessels. TAMs protect tumours, instead of the host; however, through downregulation of a “do not eat me” molecule called CD47, RRx-001 ‘rewires’ these TAMs to attack and eat tumour cells. In addition, through release of the vasodilator, nitric oxide, and inhibition of a molecule called VEGF, RRx-001 makes severely abnormal tumour blood vessels more functional so that blood flow and the efficiency of drug uptake and oxygenation increase. Accordingly, RRx-001 is currently in a phase III trial called REPLATINUM2  for the treatment of third line or beyond SCLC, a disease mainly of heavy smokers, in combination with the chemotherapy agents, carboplatin and etoposide. RRx-001 has been designated as an orphan drug both in the United States for SCLC, acute radiation syndrome, glioblastoma, and neuroendocrine cancer. 

Having been sourced from the defense and aerospace industry, RRx-001 is without precedent in the pharmaceutical industry since its closest chemical relative is a component of rocket fuel3. As the prototype or pioneer of the dinitroazetidine class that has progressed safely into late-stage testing via a ‘blast(-off) to bench to bedside’ sequence, RRx-001 paves the way not only for second and even third generation iterations of RRx-001 but also for the development of other aerospace-derived cysteine-targeted molecules, with dual Jekyll-and-Hyde-like properties in normal tissues vs. tumours, which are advancing through EpicentRx’s CyNRGY platform. The CyNRGY name is a nod to the cysteine binding properties of these molecules and their synergy with other anticancer agents such as chemotherapy and immunotherapy and other non-anticancer agents. Synergy or activity in combination is made possible by the different mechanisms of action of these CyNRGY compounds and the lack of any observed drug-drug interactions (DDIs), food-drug interactions or drug-disease interactions, which refers to how other drugs, certain foods or individual disease states may react and/or interfere with their activity and effects. Whatever the advantages of these aerospace-derived, energetic compounds, and there are several, unsurprisingly, one of their main issues, to be discussed below, is the tendency to go boom, loudly and violently during manufacture when triggered by heat, mechanical stress, light, metals, sparks etc.

The other EpicentRx platform, which complements and synergises with CyNRGY, is called AdAPT for the development of oncolytic adenovirus-based therapies that deliver transgenes or vaccine antigens to target cells and tissues. The lead AdAPT candidate, AdAPT-001, in a Phase I/II clinical trial for the treatment of cancer, carries an extra piece of DNA called a transgene that binds to, traps, and neutralises a molecule called transforming growth factor-beta (TGF-b), which tumours hijack to suppress the antitumour immune response. As a virus, AdAPT-001 selectively infects cancer cells and makes thousands and thousands of copies of itself and the TGF-b transgene that it carries, which ultimately leads to rupture of cancer cells and release of new viruses for subsequent rounds of infection. However, this overview is focused on RRx-001, not AdAPT-001 and the AdAPT platform.

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Figure 2: Evidenced activity of RRx-001 versus potential activity in other disease states, based on its mechanism of action, which free radicals (oxidative stress) and hyperinflammation underpin. The anticancer properties of RRx-001 are counterbalanced in normal tissues by protective and anti-inflammatory effects, which reduces inflammation, immune cell activation, and, ultimately, tissue damage.

Safety

To date, in over 300 patients and over 12 clinical trials, no serious and/or dose limiting toxicities have ever been attributed to RRx-001 and a maximal tolerated dose or MTD was never reached in the first-in-man (FIM) Phase I clinical trial. It is perhaps fitting for a derivative of rocket fuel that the main and, arguably, the only, side effects associated with RRx-001, are localised burning during injection or infusion and inflammation of the veins, which may be accompanied by clotting and/or infection. To minimise these side effects, RRx-001 is co-administered with about two-and-a-half teaspoons of the patients’ own blood, called autologous blood, in a user-friendly external or ex vivo device customised for RRx-001 called the eLOOP. Accordingly, the FDA has designated RRx-001 as a combination drug-device with the eLOOP. 

Patents

RRx-001 and second- and third-generation iterations of RRx-001 as well as other aerospace-derived compounds in the CyNRGY platform are wholly owned by EpicentRx with no freedom to operate issues. In addition, a robust patent portfolio supplemented by trade secrets and FDA and EMA exclusivity periods both for new molecular entities and orphan indications protects these compounds, including RRx-001 and the RRx-001 drug-device combination. RRx-001 has been categorised as a first-in-class molecule and has been assigned the non-proprietary name bromonitrozidine by USAN.

Manufacturing

As alluded to earlier, having been derived from a component of rocket fuel, RRx-001 and its intermediates are highly energetic to the point that they will decompose and massively explode during manufacture or transport if initiated by an external agent such as impact, friction, heat, and electric spark. In addition, the final form of RRx-001, a white fluffy crystalline powder, readily disperses in the air making it a potential dust explosion hazard as well as an inhalation hazard, since RRx-001 is known to cause irritation to mucous membranes.  

So extreme and so complex are the special safety and handling measures required during the manufacture of RRx-001 that only a handful of highly specialised contract manufacturing organisations (CMOs) in the world possess the necessary qualifications, expertise, and experience to make and store it. These safety measures include proper facilities with concrete barricades that are remote from populated areas and the use of personal safety equipment like masks and face shields and remote-control arms for manipulation of the drug and its intermediaries at a safe distance to protect personnel from fire and explosion hazards.

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Figure 3: The blast off to bench to bedside continuum of RRx-001, which serves as a blueprint or a road map on how to successfully advance aerospace-sourced molecules into the clinic.

Conclusion

In summary, RRx-001 (proudly) wears the label of a ‘jack of all trades’ and ‘master of a great many’, given the sheer number of pathologic conditions against which it has demonstrated activity including cancer, radiation exposure, cardiovascular, metabolic, autoimmune, neurodegenerative, and inflammatory diseases. On the one hand, the use of one drug to treat so many different disease states and conditions may (and probably does) sound too good to be true; on the other, the accumulated weight of positive preclinical and clinical data tells a different story, one which explains the diverse pharmacologic effects of RRx-001 both in and out of cancer through its dual mechanism of action. To recapitulate, in well-oxygenated tissues RRx-001 inhibits the NLRP3 inflammasome, whose abnormal activation is associated with a wide range of diseases and whose inhibition supports the resolution of inflammation. Conversely, under hypoxic, oxidative conditions common to tumours RRx-001 fragments to release highly active metabolites. These metabolites stimulate and reprogramme TAMs or tumour associated macrophages (literally “big eaters”) to engulf cancer cells, rather than to protect them. No “one-trick pony”, the effects of RRx-001, therefore, dynamically switch between inflammatory (mainly in tumours) and anti-inflammatory (mainly outside of tumours), depending on local conditions, which greatly limits side effects. 

Finally, despite its many advantages as a well-tolerated multi-disease targeted agent, RRx-001 is associated with two main drawbacks: the first is its potential explosivity, which requires EpicentRx to finance the manufacture of a remote, semi-automated, built-for-purpose and inherently safe unit that is dedicated to the contamination-free synthesis of RRx-001. The second, perhaps somewhat ironically, is exactly what disease indications—out of the enormous number available to RRx-001, given how broad its potential clinical applicability— are feasible to pursue because of cost, time, and resource considerations, which are finite even for a well-funded biopharmaceutical company like EpicentRx.  

Too much choice is perhaps a good problem to have and certainly better than the opposite in many respects, but, in the end, for RRx-001 and EpicentRx, it is still a problem.

DDW Volume 24 – Issue 1, Winter 2022/2023

References

  1. Chen Y, He H, Lin B, Chen Y, Deng X, Jiang W, Zhou R. RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor. Cell Mol Immunol. 2021 Jun;18(6):1425-1436.
  2. Oronsky B, Reid TR, Larson C, Caroen S, Quinn M, Burbano E, Varner G, Thilagar B, Brown B, Coyle A, Ferry L, Abrouk N, Oronsky A, Scribner CL. REPLATINUM Phase III randomized study: RRx-001 + platinum doublet versus platinum doublet in third-line small cell lung cancer. Future Oncol. 2019 Oct;15(30):3427-3433.
  3. Oronsky B, Scicinski J, Ning S, Peehl D, Oronsky A, Cabrales P, Bednarski M, Knox S. Rockets, radiosensitizers, and RRx-001: an origin story part I. Discov Med. 2016 Mar;21(115):173-80.

 

Bryan OronskyAbout the author:

Bryan Oronsky, MD, PhD serves as EpicentRx Chief Development Officer and combines first hand clinical experience as a physician with 17 years of pharmaceutical development experience that includes considerable time and effort spent on publishing and patenting.

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