New Drug On The Horizon, Giving Hope To Many

It has been well established that chemotherapy and radiation treatments for cancer can induce toxic side effects on the body. This is an unfortunately common consequence of these therapies due to their effects on healthy cells. One toxic side effect induced by chemotherapy and/or radiation is mucositis.

Mucositis is the painful inflammation and ulceration of the mucous membranes. Mucous membranes are found in the digestive, respiratory, and urogenital tracts including the mouth, nose, eyelids, trachea, lungs, stomach, intestines, ureters, urethra, and bladder. These mucous membranes are made up of very sensitive epithelial tissue and are more susceptible to the damage caused by radiation or chemotherapy.

It has been reported that for most cancer treatments, anywhere from 5% to 15% of patients will develop it. When treated specifically with 5-fluorouracil the chances of a patient developing mucositis increase to 40%. Also, due to the high doses of chemotherapy or radiation in preparation for a bone marrow transplant, it is estimated that around 75% to 80% of these patients will develop mucositis.

The most common location for developing mucositis is in the oral cavity.

This is particularly consistent in patients with head and neck cancers. Head and neck cancers affect around 50,000 Americans per year. It has been stated that almost every patient receiving radiation or chemotherapy treatment for head and neck cancers will develop some degree of oral mucositis. The incidence of oral mucositis is especially high in patients with primary tumors in the oral cavity, oropharynx, or nasopharynx. Reports show that 100% of patients with oral tumors will develop oral mucositis from their treatment, and about 75% will develop grade 3 or 4 severity.

The world health organization has developed a grading system for oral mucositis based on clinical appearance and functional status. These grades are as follows:

• Grade 0 - none.
• Grade I - soreness and redness.
• Grade II - redness, ulcers, the patient can still swallow food.
• Grade III - extensive redness and severe pain, the patient cannot swallow solid foods.
• Grade IV - mucositis is so severe that the patient cannot eat or drink on their own and often require feeding tubes. The patient may not be able to talk due to pain, this level may be fatal due to infections or other complications.

Mucositis grades

Oral mucositis can be very painful and significantly affect a patient's eating ability and quality of life.

For patients receiving high dose radiation and for bone marrow transplant patients, it has been reported to be the single most debilitating side effect of all their cancer treatments. The pain and loss of taste associated with oral mucositis make it difficult to eat and therefore cause weight loss and nutritional deficiencies. Other symptoms include blood in the mouth, dryness in the mouth and throat, soft white patches or pus in the mouth or throat.

Oral mucositis requires that a patient perform extensive mouth care including brushing and flossing gently up to every four hours, rinsing with mouthwash, keeping the mouth and lips moisturized. It is very important to keep the mouth clean because the sores or ulcerations can act as a portal of entry for bacteria, viruses, and fungus. Infections associated with oral mucositis can lead to life-threatening systemic sepsis, especially in the case of immunosuppressed patients. Therefore, oral mucositis can be a condition that causes delays in treatment, discontinuations, or limits the optimal dose that consequently decreases their chances of survival.

Mucositis Treatment

When oral mucositis is caused by chemotherapy, it usually is related to a low white blood cell count.

However, radiation-induced oral mucositis is due to the inflammatory effects of the radiation to the sensitive oral tissues. Radiation generates a build-up of reactive oxygen species, faster than our bodies can fight against which causes this inflammation (along with many other debilitating side effects).

In the past, treatments for oral mucositis have fallen short, consisting of supportive care, including oral hygiene, pain management, and nutritional support, and leaving patients to suffer. In the past two years, with the research extending over two decades, a new drug has been developed by Galera Therapeutics Inc. that shows promise in preventing and reducing severe oral mucositis.

Excitingly, the FDA has granted “breakthrough therapy” designation (meaning they’ve put a high priority review “flag”) on this new medication. The drug is currently called GC4419 and it acts by mimicking the superoxide dismutase enzyme in our bodies. GC4419 is highly potent and selective and will convert superoxide radicals into hydrogen peroxide and molecular oxygen. This conversion helps to reduce toxic levels of superoxide caused by radiation therapy.

Not only will it reduce the buildup of reactive oxygen species but when superoxide is converted to hydrogen peroxide, it will enhance the effects of radiation because hydrogen peroxide is selectively more toxic to cancer cells.

GC4419 is still going through clinical trials and its effects need to be confirmed in a larger scale, placebo-controlled setting, however, it has successfully completed phases 1 and 2 of clinical trials (phase 3 will be completed later this year). In phase 2b of clinical trials, GC4419 was shown to decrease the duration (by 92%), the incidence (by 34%), and the severity (by 47%) of severe oral mucositis while maintaining acceptable patient safety.

In addition, in several preclinical studies, GC4419 demonstrated an increased tumor response to radiation therapy while preventing toxicity to healthy tissues. Mel Sorensen, M.D., President and CEO of Galera Therapeutics states “We look forward to working closely with the FDA on the continued development of GC4419 for the reduction of SOM [severe oral mucositis] in patients to efficiently advance the clinical program and ultimately bring GC4419 to patients in need.”

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