The Case for RRx-001 as a Radiation Countermeasure
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The following article is an opinion piece written by Bryan Oronsky. The views and opinions expressed in this article are those of the author and do not necessarily reflect the official position of Technology Networks.
In case of reactor accidents, nuclear warfare, or terrorist activity, a top priority is to develop radiation countermeasures and to have them at the ready; these are agents that prevent or treat the acute effects of high dose, whole-body radiation exposure. To date, the FDA has approved only four radiation countermeasures: filgrastim (Neupogen), peg-filgrastim (Neulasta), sargramostim (Leukine), and romiplostim (NPlate), which are growth factors to treat the effects of radiation on the bone marrow. However, no radiation countermeasures have been approved to prevent or treat radiation injury to other important organs like the gastrointestinal (GI) tract or the brain. Nor have any radiation countermeasures been approved to prevent the development of injury prior to radiation exposure.
Several governments have stockpiled potassium iodide (KI) as a radiation countermeasure. Nevertheless, potassium iodide is ineffective against radiation contamination since KI only protects the thyroid, not the rest of the body. A true radiation antidote or countermeasure is one which reduces damage to the cells, tissues and organs of the body before or after radiation exposure. The former given before radiation exposure is called a radioprotector, the latter given after exposure is known as a radiomitigator.
Only one radioprotector, amifostine, has received FDA and European regulatory approval (for limited use in cancer radiotherapy) but because of the difficulty and narrow window of administration, and severe toxicities including nausea, sneezing, diarrhea, sleeplessness, low blood pressure, dizziness, low calcium or hypocalcemia, and hiccups it is not a practical option at any level and certainly not at doses required for severe radiation exposure.1 The same applies to a growth factor called palifermin that has been approved for the treatment of severe oral blistering or mucositis during bone marrow transplantation, but it is not a radioprotector per se.2 This has forced an urgent search to identify/develop an effective and feasible nuclear countermeasure, which is clearly of vital importance to governments and their citizenry.
The main danger of high doses of radiation exposure from nuclear accidents, atomic bombs, dirty bombs or radiation dispersal devices from terrorists, cancer radiotherapy, or long-distance space missions is the development of acute radiation syndrome (ARS), also known as radiation sickness, which reflects severe damage to specific organs such as the bone marrow and the GI tract. According to the Centers for Disease Control (CDC), the required conditions for ARS are a large penetrating radiation dose (i.e., greater than 0.7 Gray (Gy) or 70 rads) delivered externally, rather than inside the body, in a short time, usually over a matter of minutes, to the whole body or a significant portion of it.3
The most sensitive cells to radiation exposure are those with the highest turnover rate in the bone marrow, the GI tract, and the skin; mature cells with a low turnover rate such as those in the muscle and bone are the least sensitive to radiation.4 Most critical for immediate survival is protection against the ARS subsyndromes, particularly, GI-ARS and H (for hematopoietic or bone marrow)-ARS. In the case of GI-ARS, the immediate causes of death are malnutrition, dehydration, anemia from gastrointestinal bleeding, and infection from migration of GI bacteria across the damaged intestinal lining. In the case of H-ARS, the immediate causes of death are severe bleeding from platelet loss and infection from severely suppressed white blood cell counts.
Exposure to high dose radiation is accompanied by a massive production of free radicals. These are unstable oxygen molecules that damage DNA and lead to cell death and inflammation. An ideal radioprotector or radiomitigator is one which is itself non-toxic and which specifically prevents or reduces levels of free radicals and inflammation preferably in the GI tract and bone marrow before or after radiation exposure, as shown in Figure 1 below.
Figure 1: The free radical and inflammatory based mechanism of radiation damage. Credit: EpicentRx
Approval as a radiation countermeasure (RCM) depends on use of the FDA’s established Animal Rule (21 CFR 314.600-650) pathway, which involves a series of scientifically rigorous animal challenge studies with the RCM against acute radiation exposure, since the conduct of human studies are, for obvious reasons, especially in this instance, not possible.5
This article overviews the science behind potential use of RRx-001as a “radiation buster” with anti-inflammatory and anti-free radical properties to prevent or reduce both GI-ARS and H-ARS. RRx-001 is currently in Phase 3 for treatment of small cell lung cancer (SCLC)6 and in a soon-to-start late-stage trial for protection against severe oral blistering or mucositis caused by radiation treatment in head-and-neck cancer.
As an aside, none of this is intended to raise alarm, only awareness about the need for radioprotection and the potential for RRx-001 to be used as an option, if approved, in a worst-case scenario. Hopefully such a scenario never comes to pass. In addition to the prevention of a radiologic catastrophe, further potential uses for RRx-001 are in radiotherapy-treated cancer patients and for astronauts on extended deep space missions such as to the Moon or Mars or even the International Space Station (ISS).
RRx-001 is a small molecule that made it to the clinic having come from the aerospace industry as a derivative of rocket fuel. Originally developed as an anticancer agent by the biopharmaceutical company, EpicentRx (formerly RadioRx), RRx-001 was found also to directly inhibit the NLRP3 inflammasome and to activate the transcription factor, Nrf2, which extended its applicability to autoimmune diseases, cardiopulmonary diseases like pulmonary hypertension and pulmonary fibrosis, and neurodegenerative conditions like Alzheimer’s, Parkinson’s, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).
If inflammation, which comes from the Latin word, inflammare, meaning to set alight or ignite, is like a fire, then the NLRP3 inflammasome, a protein complex found primarily in immune cells, is like the firestarter, since it both kickstarts and kicks off the inflammatory response. The inflammatory response is a double-edged sword because, on the one hand, inflammation protects from microbial threats and, therefore, its absence is incompatible with life, but, on the other hand, inflammation also inflicts collateral damage, sometimes excessively, especially in the case of high-dose radiation exposure, that is harmfully self-perpetuating. As a direct NLRP3 inflammasome inhibitor, RRx-001 decreases bone marrow and GI tract susceptibility to radiation injury and increases survival in animal models.7,8
The transcription factor, Nrf2, is the master regulator of the antioxidant response and is the first line of defense against DNA-damaging free radical exposure. Therefore, like NLRP3 inhibition, activation of Nrf2 by RRx-001 also prevents radiation-related injury.
Notably, in 12 clinical trials and over 300 patients with multiple disease conditions that have received RRx-001, no related serious adverse events or toxicities have been attributed to it nor have any medication interactions been observed. In cancer clinical trials, RRx-001 has been administered both intravenously and subcutaneously; it is also active orally in animals.9 Oral and subcutaneous administration is preferred for military personnel and first responders, who need appropriate radioprotective agents to be given “on the fly” preventively or prophylactically prior to entry into hazardous areas for search-and-rescue missions as well as for at-risk civilian populations.
In addition to the development of RRx-001 as a radiation countermeasure, its radioprotective effects were also evaluated on the oral mucosa in first-line head-and-neck cancer patients. The oral mucosa is the “skin”, which lines the inside of the mouth, including cheeks and lips that radiation damages, causing severe oral mucositis (SOM) or blistering. So debilitating and such is the severity of the pain associated with SOM that it has been compared to a fish hook injury or the ingestion of barbed wire; patients with SOM are often painfully prevented from swallowing, eating, drinking and sometimes even speaking. This, in turn, leads to dehydration, malnutrition, weight loss, social isolation, depression, hospitalizations and unplanned breaks/discontinuations of therapy that not only negatively impact quality of life but also tumor control, recurrence and survival.10
In a randomized Phase 2 trial called PREVLAR (ClinicalTrials.gov Identifier: NCT03699956) in 53 first-line head-and-neck cancer patients that were treated with standard of care chemotherapy and radiation versus RRx-001 + standard of care chemotherapy and radiation, the administration of RRx-001 dramatically improved the incidence, duration, time to onset and severity of oral mucositis. A confirmatory trial called KEVLAR is planned in a larger first-line head-and-neck cancer population.
As a corollary to radiation protection for cancer patients, astronauts on deep space missions to the Moon or Mars or the International Space Station that are exposed to radiation from galactic cosmic rays, solar wind and solar energetic particles are at risk for the development of several diseases including cancer and heart disease and, hence, require radioprotection strategies, since physical shielding alone is insufficient.11 RRx-001 is also under investigation in Low Earth Orbit. The multiple applications for RRx-001 as a radioprotector are shown below in Figure 2.
Figure 2: Radioprotective Indications for RRx-001. Credit: EpicentRx
In the face of global instability, and the erosion of the nuclear taboo, the urgent need for a radioprotector or a radiomitigator prior to or in the aftermath of a radiologic disaster is more evident than ever. To best knowledge, no such options are in development against both H-ARS and GI-ARS save one: RRx-001. The potential advantages of RRx-001 are its tolerability, the convenience of subcutaneous administration and its dual action on inflammation through inhibition of the NLRP3 inflammasome and on free radical levels through activation of the antioxidant transcription factor, Nrf2. It also has an extensive track record in cancer patients with several chronic conditions that require multiple medications to treat them, along with an apparent lack of interactions with these medications. Several other potential indications for RRx-001 under investigation include cancer radioprotection, deep space exploration and radiomitigation where RRx-001 is administered after rather than before radiation exposure.
1. Johnke RM, Sattler JA, Allison RR. Radioprotective agents for radiation therapy: future trends. Future Oncol. 2014;10:2345–57. doi: 10.2217/fon.14.175
2. Acute radiation syndrome: a fact sheet for physicians. CDC. https://www.cdc.gov/nceh/radiation/emergencies/arsphysicianfactsheet.htm. Published April 8, 2022. Accessed November 29, 2022.
3. Balter S, Hopewell JW, Miller DL, et al: Fluoroscopically guided interventional procedures: A review of radiation effects on patients' skin and hair. Radiology 254(2):326-341, 2010. doi: https://doi.org/10.1148/radiol.2542082312
4. Kiang JG, Olabisi AO. Radiation: a poly-traumatic hit leading to multi-organ injury. Cell Biosci. 2019;9:25. doi: 10.1186/s13578-019-0286-y
5. Animal rule summary. FDA. https://www.fda.gov/emergency-preparedness-and-response/mcm-regulatory-science/animal-rule-summary. Published online March 13, 2019. Accessed November 29, 2022.
6. Oronsky B, Reid TR, Larson C, et al. 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. doi:10.2217/fon-2019-0317
7. Jurgensen KJ, Skinner WKJ, Oronsky B, et al. RRx-001 radioprotection: enhancement of survival and hematopoietic recovery in gamma-irradiated mice. Front Pharmacol. 2021. doi: 10.3389/fphar.2021.676396
8. Chen Y, He H, Lin B, et al. RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor. Cell Mol Immunol. 2021;18(6):1425-1436. doi: 10.1038/s41423-021-00683-y
9. Ning S, Oronsky B, Scicinski J, Carter CA, Knox SJ. Pilot study of the antitumor efficacy and tolerability of orally administered RRx-001 in normal and tumor-bearing mice. J Cancer Res Therap Oncol. 2018. doi: 10.17303/jcrto.2018.6.102
10. Oronsky B, Goyal S, Kim MM, et al. A review of clinical radioprotection and chemoprotection for oral mucositis. Transl Oncol. 2018. doi: 10.1016/j.tranon.2018.03.014
11. Oronsky B, Abrouk N, Caroen S, Reid T. RRx-001 and the “right stuff”: protection and treatment in outer space. Life Sciences in Space Research. Available online 12 May 2022. In press corrected proof. https://doi.org/10.1016/j.lssr.2022.05.001
Bryan Oronsky, MD, PhD, is chief development officer of EpicentRx. He combines firsthand clinical experience as a physician with 17 years of pharmaceutical development experience that includes considerable time and effort spent on publishing and patenting.