Therapeutic frontiers: the potential of RRx-001 and AdAPT-001

What makes RRx-001 a first-in-class hypoxia-activated therapeutic, and how does its dual mechanism of action differ from traditional cancer treatments?

Most, if not all, traditional cancer treatments are single minded. Their mechanisms of action are completely consistent no matter the tissue or environment in which they find themselves. RRx-001 (nibrozetone) is different because in tissues where 3 “Hs” are present, namely hypoxia (low oxygen), hyperaemia (over-vascularisation), and high hydrogen donation, the small molecule “shape shifts”, in other words, it fragments to release metabolites such as nitric oxide and other nitrogen-centred free radicals that target diseases like cancer. However, in tissues where the 3 Hs are not present, the small molecule has anti-toxicity activity through 1) direct inhibition of the NLRP3 inflammasome, an inflammation starter and perpetuator, and 2) upregulation of the master antioxidant transcription factor, Nrf2.^1,2

What makes RRx-001 (nibrozetone) first-in-class is its unprecedented chemical structure, which has never been seen before in or out of the clinic, and the environmental shape shifts that occur because of its chemical structure.^3,4

The assignment of the international nonproprietary name (INN), nibrozetone, for RRx-001 signifies that it is unique and does not fit existing nomenclature.

Could you explain the significance of RRx-001 receiving FDA Fast Track designation for the indication of protection against oral mucositis in first-line head and neck cancer?

Fast Track designation not only validates the entire RRx-001 (nibrozetone) clinical program, which is now eligible for priority review and accelerated approval, but also recognises the medical need for new effective treatment options in oral mucositis.

In addition to its cancer indications, are there any other potential applications or therapeutic areas being explored for RRx-001 or other compounds developed by EpicentRx?

RRx-001 (nibrozetone) crosses the blood brain barrier, where it has demonstrated promising activity as an anti-neurodegenerative agent because of the anti-inflammatory and antioxidative properties described above. The Michael J Fox Foundation and Fight MND have awarded substantial, long-term grants to evaluate RRx-001 (nibrozetone) in Parkinson’s Disease and ALS/MND, respectively. Several metabolites of RRx-001 (nibrozetone) are under preclinical evaluation.

How does the chemical structure of RRx-001, being derived from aerospace origins, contribute to its unique properties as a therapeutic agent?

Because RRx-001 (nibrozetone) derives from rocket fuel, it is extremely energy-dense and prone to bond breaking reactions under certain microenvironmental conditions that include hyperaemia, hypoxia, and high hydrogen donation, that is the 3 Hs.

What are the potential benefits of using “nibrozetone” as the nonproprietary name for RRx-001, and what considerations were taken into account when selecting this name?

The World Health Organization (WHO) in collaboration with the United States Adopted Names (USAN) council selected “nibrozetone” as the international nonproprietary name (INN) for RRx-001. The name is a quasi-portmanteau of the chemical constituents of nibrozetone: nitro, bromine, and ketone.  As such, nibrozetone is not subsumable under a pre-existing drug class, which signifies that it is the first in a completely new class of drugs.

Can you provide more details about EpicentRx’s AdAPT-001 compound, including its target indications and current development status?

AdAPT-001 is an adenovirus, agent of the common cold, currently in a Phase 2 clinical trial. The virus carries a transforming growth factor- beta (TGF-β), which it expresses at high levels. We like to refer to TGF-β as the “apex predator” of the tumour microenvironment because it exerts complete dominance over other immunosuppressive factors like immune checkpoints.⁵

So, for example, immune checkpoint inhibitors such as Keytruda or Opdivo only benefit between roughly 20-40 percent of patients with susceptible tumour types like melanoma and non-small cell lung cancer (NSCLC). The presence of TGF-β is highly associated with checkpoint inhibitor resistance in the other 60-80 percent of nonresponding patients. 

The biggest knock on anticancer viral vectors is that they are locally delivered agents, which do not regress distant, noninjected tumours. Whether it is because of the TGF-β trap that AdAPT-001 carries, which neutralises the omnipresent TGF-β cytokine or whether it is because AdAPT-001 replicates faster than other viral vectors, or both, we see clear evidence of systemic or abscopal activity with single agent AdAPT-001 in the clinic. Also, unlike several other viruses, AdAPT-001 is deliverable systemically.

References

1. Oronsky B, Scribner C, Aggarwal R, Cabrales P. RRX-001 protects normal tissues but not tumors via NRF2 induction and bcl-2 inhibition. Journal of Cancer Research and Clinical Oncology. 2019;145(8):2045–50. doi:10.1007/s00432-019-02958-4
2. Chen Y, He H, Lin B, Chen Y, Deng X, Jiang W, et al. RRX-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor. Cellular & Molecular Immunology. 2021;18(6):1425–36. doi:10.1038/s41423-021-00683-y
3. Oronsky B, Takahashi L, Gordon R, Cabrales P, Caroen S, Reid T. RRX-001: A chimeric triple action NLRP3 inhibitor, NRF2 inducer, and nitric oxide superagonist. Frontiers in Oncology. 2023;13. doi:10.3389/fonc.2023.1204143
4. Jayabalan N, Oronsky B, Cabrales P, Reid T, Caroen S, Johnson AM, et al. A review of RRX-001: A late-stage multi-indication inhibitor of NLRP3 activation and chronic inflammation. Drugs. 2023;83(5):389–402. doi:10.1007/s40265-023-01838-z
5. Oronsky B, Cabrales P, Alizadeh B, Caroen S, Stirn M, Williams J, et al. TGF-β: The apex predator of immune checkpoints. Future Oncology. 2023;doi:10.2217/fon-2023-0491