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The first-in-class uridine phosphorylase inhibitor TK-90 almost completely eliminated severe oral mucositis (SOM) in patients with non-metastatic squamous cell carcinoma of the head and neck who underwent radiation therapy, a small randomized study showed.

None of the 12 patients treated with TK-90 developed SOM by the end of treatment at week 7, compared with six of 12 treated with placebo (0% vs 50%, P=0.14), reported Nabil F. Saba, MD, of the Winship Cancer Institute of Emory University in Atlanta.

At week 9 follow-up after the end of dosing, just one patient treated with TK-90 had developed SOM compared with nine in the placebo group (8.3% vs 75%, P=0.003). The duration of SOM in the patient treated with TK-90 was 12 days compared with a mean duration of 35 days in patients who developed SOM in the placebo arm (P=0.026).

"Parenteral administration of TK-90 appears to be an effective strategy for preventing radiation-induced mucositis," Saba said during a session at the Multidisciplinary Head and Neck Cancers Symposium in Phoenix. "These results merit additional validation in larger trials."

Mucositis is a debilitating complication of radiotherapy or chemotherapy, leading to weight loss, mouth ulcers, abdominal pain, vomiting, diarrhea, and potentially fatal infections.

"Uridine is essential to the preservation of the health of the normal mucosa," Saba explained. "By inhibiting uridine phosphorylase, uridine levels are restored in the mucosa, basically reducing the leakage in the mitochondria and, by doing that, protecting the mucosa from the effects of radiation and chemotherapy."

As for its mechanism of action compared with other mucositis-sparing agents, Saba pointed out that superoxide dismutase "quenches one type of free radical oxygen species, but when you give TK-90 it quenches the 20 to 30 different subtypes of oxygen species.

"The premise is that you need to quench all of these subtypes in order to be successful," he said.

In the case of antibiotics, Saba observed that they act in the later stages of mucositis progression, whereas restoring uridine levels with TK-90 acts earlier.

This phase II, placebo-controlled, randomized, assessor-blind enrolled patients from four medical institutions from July 2022 to February 2023. Different modalities of radiotherapy were administered at a daily dosage of 2.0 Gy, 5 days a week, reaching cumulative dosages of 60-70 Gy.

Participants (median age 50 years, 79% male) were randomized to receive either 45 mg/kg of parenteral TK-90 or a placebo intravenously 1 hour before and 6 hours after each infusion.

Of the 12 patients in each group, nine completed 7 weeks of treatment in the TK-90 group, and 11 in the placebo group.

The primary endpoint was the incidence of grade 3/4 SOM in the two patient cohorts, with secondary endpoints including SOM duration and drug-related toxicity.

Regarding adverse events, Saba said TK-90 was "fairly well tolerated" with "few and manageable grade 1 treatment-related adverse events. These included three reported cases of grade 1 infusion reaction in the TK-90 arm versus none with placebo and six reported cases of grade 1 infusion site irritation versus five with placebo.

There were no reported TK-90 treatment-emergent serious adverse events or treatment discontinuations. One patient in the TK-90 cohort experienced an unrelated serious cardiac arrest.

Saba noted that while TK-90 is currently administered intravenously, an oral formulation is under development.

"And it has a low production cost, which means we could potentially apply this agent to a wide population across the world, which we need to do when we are talking about alleviating mucositis," he added.

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