RRx-001 and FDA Fast Track

Apr 4, 2023

The big news at EpicentRx last week is that its lead small molecule, RRx-001, received Fast Track designation for the prevention/amelioration of severe oral mucositis (SOM). What is oral mucositis, how does RRx-001 prevent/ameliorate it, and why is this big news?

Firstly, oral mucositis refers to inflammation of the oral mucosa, which commonly develops during treatment of newly diagnosed head and neck cancer. The oral mucosa refers to the mucous membrane that lines the oral cavity, and since “itis” means inflammation, the term for an inflamed oral mucosa is “oral mucositis”. In over 50% of all treated patients, the oral mucosa is severely inflamed, and severely painful as a result; because the pain of SOM compels dose reduction or premature discontinuation of treatment, it puts patients at risk for recurrence, which betokens a poor prognosis. Click here to read this EpicentRx-authored review on oral mucositis.

A bleaker-than-bleak poem, which the above review cites, from writer and artist, Anita Hart Balter, who died in 1991, one year after she wrote this poem, paints an absolutely nightmarish picture of severe oral mucositis that is every bit as harrowing, as surreal, and as unnerving as the pain-distorted masterpiece of Norwegian painter, Edvard Munch, entitled The Scream. The reader vicariously experiences the hell that Balter endured through the vivid imagery that she uses, imagery which is made even more real and immediate by the knowledge that this was a first-hand account of what SOM viscerally feels like. Both Balter’s poem and Munch’s, The Scream, are shown below.

A fish hook lodges in my throat.
Spittle, kindergarten paste, thickens everything – even vision.
Mouth, pocked with sores & blisters, swollen ulcerated tongue.
Topside, sandpapered with number 7 coarsest grade.
Taste buds, saliva glands, seared.
Cool water, corrosive acid now.
The tongue rests; teeth become enemies.
Coiled steel razored wire atop dentate prison walls.
Only moans escape my lips. I cannot eat or speak.
Inside a howl festers.
Pain lengthens time.

Anita Hart Balter (NEJM 1990)

Edvard Munch, The Scream | Image source

Secondly, RRx-001 is a direct NLRP3 inflammasome inhibitor, which prevents the activation of the NLRP3 inflammasome in response to chemotherapy and radiation. Overactivation of the NLRP3 inflammasome leads to inflammation, which underlies the development of oral mucositis, and through its inhibition RRx-001 is a potent anti-inflammatory. RRx-001 also upregulates the master antioxidant protein, Nrf2, which protects cells from free radical stress and, hence, contributes to the prevention/amelioration of oral mucositis from chemotherapy and radiation.

In the randomized Phase 2 trial called PREVLAR (click here to read the PREVLAR publication), RRx-001, as a dual NLRP3 inhibitor and an Nrf2 upregulator, dramatically delayed the onset of severe oral mucositis and reduced the overall incidence, which meets the criteria for FDA Fast Track status. These criteria include the potential to address an “unmet medical need” in a “life-threatening or serious” condition with few to no treatment options. The hellish torment that Anita Balter underwent, as she so vividly describes in her poem leaves no doubt that severe oral mucositis (SOM) is a very serious condition indeed, one that impacts survival and activities of daily living, and, to date, no treatments are approved for it, which makes SOM an urgently unmet medical need.

Finally, the importance of FDA Fast Track status is that it makes RRx-001 eligible for (1) more frequent interactions with the FDA; (2) accelerated approval or priority review; and (3) rolling review, in which sections of the new drug application (NDA) are submitted in pieces and reviewed prior receipt of the full NDA.

EpicentRx has received the green light to proceed with the follow-up clinical trial to PREVLAR called KEVLARx in first line head and neck cancer. The KEVLARx clinical trial is currently in start-up and enrollment will begin shortly.