NLRP3 Inhibitor/Nrf2 Upregulator Receives FDA FTD for Severe Oral Mucositis

The FDA accepted an investigational new drug application (IND) for and granted fast track designation to RRx-001, a direct NLRP3 inhibitor and Nrf2 upregulator, for the prevention and/or reduction of radiation- and chemotherapy-associated severe oral mucositis in head and neck cancer, according to a press release from EpicentRx.¹

Investigators are evaluating RRx-001 as a treatment for oral mucositis in patients with head and neck cancer in the phase 2 PREVLAR trial.

The accepted IND allows for follow up on the phase 2b KEVLARx trial. Currently, no FDA-approved treatment is available for severe oral mucositis, an adverse effect of chemotherapy and radiation therapy. The condition has the potential to become life threatening due to the possibility of concomitant infections.

RRx-001 is a highly selective inhibitor of NLRP3 and upregulator of Nrf2 with anti-inflammatory and antioxidant properties that is under investigation as a treatment for small cell lung cancer and to provide protection vs oral mucositis in patients with first-line head and neck cancer. Moreover, it may also have efficacy as a countermeasure for nuclear and radiological emergencies and in some neurodegenerative diseases such as Parkinson’s, amyotrophic lateral sclerosis, and motor neurone disease.

Investigators are also evaluating the safety and efficacy of RRx-001 as part of the phase 2 PREVLAR trial (NCT03515538) as a preventative measure against oral mucositis in patients with head and neck cancer undergoing treatment with chemoradiotherapy.² The trial had an actual enrollment of 48 patients.

There were several treatment arms included in the study, including RRx-001 pre-treatment plus standard of care (SOC); RRx-001 pretreatment plus 2 concurrent doses and SOC, RRx-001 pre-treatment plus 6 concurrent doses and SOC, and SOC alone. SOC consisted of a 7-week course of fractionated radiation therapy concurrent with a high-dose cisplatin-based regimen.

The study’s primary end point was duration of severe oral mucositis, with key secondary outcomes including time to onset and incidence of oral mucositis, duration and incidence of ulcerative oral mucositis, and patient-reported pain.

To enroll on the study, patients needed to have a confirmed diagnosis of squamous cell carcinoma of the oral cavity and oropharynx. Patients also needed to have an ECOG performance status of 0 to 2, adequate organ and bone marrow function, and adequate renal and liver function. Additionally, human papilloma virus tumor status needed to have been determined via immunohistochemistry.

Those who had underwent previous radiation of the head and neck; had tumors of the lips, nasopharynx, hypopharynx, larynx, or salivary glands; or had simultaneous primaries or bilateral tumors were not eligible to enroll. Moreover, metastatic stage IV disease, malignant tumors beyond head and neck cancer lesions in the last 5 years, and presence of oral mucositis or other mucosal ulceration at study entry were also grounds for exclusion.

Other exclusion criteria included having grade 3/4 dysphagia or odynophagia, a need for parenteral or gastrointestinal tube-delivered nutrition, a known history of human immunodeficiency virus or hepatitis B/C, known allergies to cisplatin and similar platinum-based compounds, or any other significant medical diseases or conditions.

References

1. EpicentRx receives fast track designation from the U.S. FDA for lead asset, RRx-001, to prevent/attenuate chemotherapy and radiation treatment induced severe oral mucositis. News release. EpicentRx Inc. March 29, 2023. Accessed March 29, 2023. http://bit.ly/433zz1e
2. Bonomi M, Blakaj DM, Kabarriti R, et al. PREVLAR: phase 2a randomized trial to assess the safety and efficacy of RRx-001 in the attenuation of oral mucositis in patients receiving head and neck chemoradiotherapy. Int J Radiat Oncol Biol Phys. Published online January 14, 2023. doi:10.1016/j.ijrobp.2022.12.031