“It’s like Avastin on steroids!”
This direct quote came courtesy of an executive at a major pharmaceutical company after he reviewed the mechanism of action of RRx-001 and learned about the results of a Phase 2 randomized trial called ROCKET of RRx-001 vs. regorafenib in 3rd/4th line colorectal cancer at the January 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco.
By way of context, the anti-angiogenic agent, bevacizumab (Avastin), is one of the most ubiquitously administered medications for the treatment of cancer, particularly colorectal cancer. Avastin decreases pressure in the tumor through improved vessel function, leading to better delivery and efficacy of systemic chemotherapy agents. Similarly, the NLRP3 inhibitor, RRx-001, also potentially decreases the leakiness of vessels in the tumor, which may lead to increased delivery, penetration, and anticancer activity of chemotherapy drugs.
However, unlike Avastin, which is associated with several severe side effects among them high blood pressure and perforation of the intestine, to date, in over 300 patients treated, no dose limiting toxicities or DLTs have been observed with RRx-001. Also, unlike Avastin, which directly binds to vascular endothelial growth factor (VEGF) to block the formation of new blood vessels or angiogenesis, RRx-001 not only inhibits VEGF in cancer and normalizes tumor vessels or makes them deliver blood more efficiently but also releases nitric oxide, inhibits epigenetic enzymes, blocks the inflammatory protein complex, NLRP3, and reprograms tumor associated macrophages or TAMs to attack tumor cells.
Presumably, this was the reason for the pharmaceutical exec to describe RRx-001 as “Avastin on steroids”, the implication being that it does what Avastin does only much better. RRx-001 is still experimental and, therefore, not approved by the FDA, which makes it impossible for us to officially confirm or deny but, in animals, at least, RRx-001 is more active than Avastin. Experiments described in a peer-reviewed, published article titled vascular priming with RRx-001 to increase the uptake and accumulation of temozolomide and irinotecan in orthotopically implanted gliomas demonstrate that administration of RRx-001 prior to the chemotherapy agents, temozolomide or irinotecan, results in significantly increased uptake of irinotecan and temozolomide in tumors consistent with ‘remodeling’ of the dysfunctional tumor vessels.
In the Phase 2 ROCKET trial, (study schema shown below), RRx-001, given for 2 months, is hypothesized to have primed or prepared the tumor to respond better to the chemotherapy agent, irinotecan, than it normally would have in 3rd/4th line colorectal cancer after patients had already received irinotecan in first or second line. It is not standard in colorectal cancer to re-administer or rechallenge patients with chemotherapy on which they previously progressed. However, if RRx-001 is successful in this regard, as a chemotherapy “resensitizer”, it may lead to a treatment loop in which patients are repeatedly shuttled between RRx-001 and chemotherapy, since each time RRx-001 is administered it potentially makes the tumor more susceptible to conventional treatments like irinotecan.
Figure 1: ROCKET Treatment Schema
To read more about the activity of RRx-001 in colorectal cancer, view the newly published, open access manuscript in the journal, Clinical Colorectal Cancer: ROCKET, a Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer,
Anyway, with the Big Pharma exec having inadvertently touched off an unofficial competition between Avastin and RRx-001 what immediately comes to mind is the show tune from the Broadway musical, Annie Get Your Gun. The most memorable line from this tune, sung by the sharpshooter, Annie Oakley, and her love interest, a man named Frank Butler, is “Anything you can do; I can do better; I can do anything better than you.” Annie and Frank each sing over each other, loudly insisting that they are better than the other at any given activity, whatever that activity is, shooting and singing included. By their own admission, however, neither can bake a pie. Here we can state with confidence that, however versatile they are, this is also true for RRx-001 and Avastin.