Evaluation of a non-peptidic mimic of host defense proteins, PMX30063, in an animal model of oral mucositis.

Abstract

9119 Background: Oral ulcerative mucositis (OM) is a common, painful, dose-limiting toxicity of cancer therapy. The care for OM is largely palliative and there is an urgent need for new and effective therapies. Host defense proteins (HDPs) are amphiphilic components of the innate immune system that serve as a primary response to infection. Exclusive of their direct antimicrobial activity, HDPs have been shown to possess immune modulatory and anti-inflammatory activities. We are developing non-peptidic mimics of HDPs, capturing the structural and biological properties of HDPs within a framework of smaller fully synthetic oligomers. The lead compound, PMX30063, is in Phase 2 clinical trials for iv treatment of systemic staphylococcal infections. Recently, we observed that HDP mimics attenuate anti-inflammatory pathways and reasoned that these activities could be leveraged into a mucositis intervention. Methods: In an acute radiation hamster model, PMX30063 was applied as a topical rinse, 3 times daily at 1, 3 or 10 mg/ml over a 28 day treatment regimen ( n = 10), following a single radiation dose to the buccal cheek pouch (40 Gy). In a fractionated radiation model, radiation (7.5 Gy/dose) was administered on days 0, 1, 2, 3, 6, 7, 8 and 9, targeting the left buccal pouch mucosa. PMX30063 was given topically 3 times daily at 3 mg/ml over a 35 day regimen beginning on day 0 (n = 10). OM was scored using an established blinded method. Results: In the acute model, PMX30063 reduced the number of animal days with ulceration from 43% in vehicle-treated hamsters to < 5% in all 3 PMX30063 dose groups (χ2 test; p<0.001). In the fractionated model, PMX30063 significantly reduced the daily mucositis scores prior to peak mucositis and throughout the remaining course of treatment (Mann-Whitney Rank-sum analysis; p<0.001). PMX30063 reduced the number of animal days with ulceration from 55% in vehicle-treated hamsters to 3.3% (χ2 test; p<0.001). The time courses of efficacy argue that direct antimicrobial action is not the primary driver of efficacy. Conclusions: The safe and highly efficacious activity of PMX30063 in animals supports its further development as a topical therapeutic to prevent OM in cancer patients.