Lack of Respiratory and Contact Sensitizing Potential of the Intranasal Antiviral Drug Candidate Rupintrivir (AG7088): A Weight-of-the-Evidence Evaluation

Abstract

Rupintrivir, also known as AG7088, is a small molecule 3C protease inhibitor designed to target human rhinovirus as a potential intranasal treatment for the common cold. The ability of rupintrivir to induce both respiratory and contact hypersensitivity responses was evaluated using a weight of the evidence approach. A local lymph node assay (LLNA) in mice evaluating concentrations of rupintrivir up to 50% in dimethylformamide showed no evidence of sensitizing capability. An irritation study conducted in rabbits was performed to assess potential dermal irritancy and provide information for worker safety guidelines. The study showed no evidence of skin irritation when the material was placed in direct contact with the skin in a semi-occluded fashion for four days. Quantitative whole body autoradiography (QWBA) following intranasal instillation of the compound into rabbits showed that the compound was retained in the nasal cavity or was swallowed. No radioactivity was observed in the pulmonary regions of these animals. Histopathologic evaluation of the nasopharyngeal tract and the lungs of both rats and dogs exposed by intranasal instillation acutely or following repeated intranasal exposures for 14 (rat) or 28 days (rat and dog) did not reveal any evidence of irritation or inflammation in these regions of the respiratory tract. These data demonstrate that rupintrivir does not cause irritation or inflammatory responses that may precede the development of sensitization of the skin or respiratory tract. It was concluded that the weight of the available toxicologic evidence indicated that rupintrivir was not likely to cause sensitization of either the skin or the respiratory tract in humans following intranasal delivery.

Inhaled anti-infective chemotherapy for respiratory tract infections: Successes, challenges and the road ahead

“…In a randomized, double-blind, placebo-controlled Phase-II study involving 202 healthy volunteers, treatment with a 2% suspension of rupintrivir via intranasal delivery produced a 33% reduction in viral titer, individual symptom score, and nasal discharge weight [228] . Rupintrivir was well tolerated in animals and by human test subjects; however, 11 of 58 subjects reported blood-tinged mucus, and 3 of 58 subjects reported nasal passage irritation [229] .…”

Treatment of respiratory viral infections through inhalation therapeutics: Challenges and opportunities

“…Rupintrivir was well tolerated with a 33% reduction in viral titre and a significant reduction in cold symptoms [ 29 ]. However, blood-tinged mucus and some nasal passage irritation were reported in test subjects [ 110 ]. Based on these results, rupintrivir progressed to large scale phase II/III trials to treat naturally occurring rhinovirus infections.…”

Immunotoxicology

“…Assessment of respiratory sensitizing potential can be made in a tiered manner using standard toxicology studies and a sensitization test with the goal of using a weight of evidence approach to identify a cause for concern (Burns-Naas et al, 2005;Maier, 2008). Adaptations of assays used to evaluate contact sensitization have been evaluated for their ability to predict respiratory sensitization.…”