And then there were 3.
3 companies, that is.
Or maybe 3, if Galera Therapeutics has not dropped out of the running.
At one point only a few short years ago several more were in the race to be approved for severe oral mucositis (SOM), which refers to sores or ulcers that develop in the mouth and throat. SOM is the most serious and common complication from the management of head and neck cancer, a highly curable cancer if detected early and treated fully.
Some level of oral mucositis occurs in about 40% of all patients treated with chemotherapy. This percentage rises to about 90% for head and neck cancer patients treated with both chemo- and radiotherapy. For the patients that develop severe oral mucositis, hospitalizations, feeding tube placements, and dose reductions and treatment delay or withdrawal are the norm, all of which negatively impact not only quality of life and financial well-being but also disease prognosis, and survival. .
Patients have described the agonizing pain of oral mucositis as “worse than the cancer” and compared it to “swallowing ground glass” or “biting on a hornet’s nest.” Such intense pain makes it hard to swallow, eat, drink, and sometimes even speak not only in the short term but also in the long term. Not surprisingly, dehydration, malnutrition, tube feeding, infections, depression, and failure to thrive can result.
For the estimated 66,920 people per year who undergo treatment with chemotherapy and radiation for head and neck cancer—and the incidence is on the rise because of widespread infection with human papillomavirus (HPV) from oral sex—the occurrence of oral mucositis is nearly 100%. 60-70% of these patients will develop oral mucositis that is severe enough to require emergency room visits, weeklong hospitalizations, or treatment delays and treatment discontinuations that predispose to the recurrence of the cancer. Because no therapies are currently approved for SOM in head and neck cancer, narcotics are the mainstay of treatment as other analgesics like aspirin, ibuprofen, acetaminophen, and corticosteroids do not effectively manage the pain.  Several topical coatings that are approved as medical devices, not “drugs,” like MuGard, Gelclair, Mucotrol, and Caphosol, offer limited benefit because they treat the symptoms of oral mucositis but not the underlying cause, which is complex and dependent on several factors and causes. Amgen’s palifermin (Kepivance), a growth factor, is approved to treat oral mucositis in blood cancer patients that undergo a bone marrow transplant, but it is not indicated for solid tumors because of concerns that it protects them (as well as healthy tissues) from the effects of chemotherapy and radiation.
The economic cost of oral mucositis is enormous, ranging from $12,000 to $500,000 per patient. All of this makes SOM a huge unmet need and a major blue-sky opportunity—the bigger the opportunity, the bluer the sky—for the company or companies that manage to fill it.
However, in a discouraging litany of failed clinical trials, several once-promising novel therapies including Dusquetide, AG013, laser light, cryotherapy, Brilacidin, and Validive that reached for the SOM brass ring have fallen by the wayside.
The remaining major players now include avasopasem manganese (GC4419) from Galera Therapeutics, nibrozetone (RRx-001) from EpicentRx, EC-18 from Enzychem, with ST-617 from Supportive Therapeutics, MIT-001 from MitoImmune Therapeutics, and Tempol from Matrix Biomed also in the running.
- Galera Therapeutics’ Avasopasem Manganese (US)
Maybe still be out in front—and maybe not—is Galera Therapeutics. Despite positive results from its Phase 3 ROMAN trial, the FDA rejected the NDA for avasopasem in August, stating their requirement for a second Phase 3 trial.  It is unclear at this point whether Galera Therapeutics, which laid off 70% of its workforce following the news, plans to continue with avasopasem or to pivot to another easier-to-dose analog called rucosopasem.
The issue with avasopasem, a superoxide dismutase mimetic, is the inconvenience associated with the frequency and timing of administration; avasopasem must be given 1 hour before radiation therapy 5 days a week for seven weeks. For context, radiation therapy centers are often located at some distance from the infusion centers where avasopasem is given, so a 1-hour dosing window may turn out to be too tight once the drug, as expected, is approved, and made available under real-world conditions . This regimen of 35 administrations before each radiation treatment presumably places an additional burden and psychological stress on mostly older patients because of morbidities, financial hardship, and possible dependence on caregivers.
Ahead of the Game
- EpicentRx’s nibrozetone (RRx-001) (US) and Enzychem’s EC-18 (S. Korea)
Tied for second place is EC-18, an orally administered small molecule immunomodulator made from a compound found in Sika deer antlers, and nibrozetone (RRx-001), an intravenously administered small molecule Nrf2 associated antioxidant inducer and anti-NRLP3 inflammasome inhibitor. Both have been awarded FDA Fast Track designation, which shortens long development and regulatory review times, on the back of positive Phase 2 randomized clinical trial results, and both are superior to Avasopasem in terms of convenience of administration, so the door of opportunity is wide open for them to step through. For example, nibrozetone (RRx-001) is only given 4 times in the two weeks before treatment with chemotherapy and radiation, so the convenience factor of a ‘four-and-no-more’ administration schedule looms large. In addition, neither is associated with any toxicity concerns and because nibrozetone (RRx-001) has been given to well over 350 cancer patients with several other chronic conditions like heart disease, diabetes, and emphysema, its safety track record is extensive and well-characterized .
In the Running
- Supportive Therapeutics’ ST-617 (US), MitoImmune’s MIT-001 (S. Korea), and Matrix Biomed’s Tempol (US)
Behind EC-18 and nibrozetone (RRx-001) is ST-617, an antioxidant that recently completed a Phase 1 trial, and MIT-001, an anti-inflammatory that prevents cell death, which started a Phase 2 trial in 2021. Honorable mention goes to the free radical scavenger, Tempol, only because it has been around since 1991. Matrix Biomed developed a topical formulation of Tempol, which is dosed daily during treatment with chemotherapy and radiation, and which started a Phase 2b clinical trial in 2019.
The potential problem with normal tissue protection is interference with tumor rejection. This is especially the case with antioxidants which scavenge the free radicals that chemotherapy and radiation use to damage cancer cells. Avasopasem, EC-18, and nibrozetone (RRx-001) are not associated with tumor protection, and nibrozetone (RRx-001) is under investigation in a Phase 3 clinical trial for the treatment of small cell lung cancer (SCLC), a hard-to-treat tumor type seen almost always in heavy smokers, which makes it attractive as a potential treatment for head and neck cancer.  It is unknown if and to what extent ST-617, MIT-001, and Tempol may protect tumors since they possess antioxidant properties.
So, first and foremost, an ironclad requirement for any new oral mucositis therapy is that it must not interfere with the anticancer treatment. The importance of no tumor protection is impossible to overstate since the risk to patients from interference with the anticancer activity of radiation and chemotherapy is recurrence and death. A second requirement is that the therapy is tolerable and safe in agreement with the medical motto “first do no harm” and “never make the treatment worse than the disease.” For the best chance of commercial success, as Avasopasem is likely to demonstrate, the therapy also should aim to maximize the convenience of administration and cost-effectiveness, so physicians adopt it, patients remain compliant, and insurance companies offer full reimbursement because, in the end, they save money from reduced hospitalizations, emergency room visits, and feeding tube placements.
The ‘Big Three’, Galera Therapeutics, Enzychem, and EpicentRx, have put their money where their mouth is and bet big on their therapies, avasopasem, EC-18, and nibrozetone (RRx-001), respectively, as the ones to best fill the huge unmet oral mucositis need.
Within potentially easy striking distance of severe oral mucositis (SOM), should any of these therapies ever receive approval in it, are the so-called “halo or satellite indications” like intestinal mucositis, esophagitis, radiation-associated dermatitis, pneumonitis, and proctitis; these are also huge unmet needs which share common features with SOM and find themselves within the same orbit, as illustrated in the figure below.
This makes SOM the key and the gateway to a much, much larger market.
And so, to conclude, how is one to learn when and which of these therapies, if any, are approved for the treatment of severe oral mucositis or these other halo/satellite indications?
If they perform as expected, then word of mouth, undoubtedly.
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Featured image: Natalia Blauth on Unsplash. Used with permission
How to Cite
Bryan Oronsky MD, Ph.D, 1 Babak Alizadeh, Ph.D. 1
Severe Oral Mucositis: Companies Put Their Money where the Mouth is and Vie for a Marketshare – Onco Zine – The International Oncology Network, August 1, 2023.