Phase II, randomized, double-blind, placebo-controlled studies of ruprintrivir nasal spray 2-percent suspension for prevention and treatment of experimentally induced rhinovirus colds in healthy volunteers

Abstract

Human rhinovirus (HRV) infections are usually self-limited but may be associated with serious consequences, particularly in those with asthma and chronic respiratory disease. Effective antiviral agents are needed for preventing and treating HRV illnesses. Ruprintrivir (Agouron Pharmaceuticals, Inc., San Diego, Calif.) selectively inhibits HRV 3C protease and shows potent, broad-spectrum anti-HRV activity in vitro. We conducted three double-blind, placebo-controlled clinical trials in 202 healthy volunteers to assess the activity of ruprintrivir in experimental HRV infection. Subjects were randomized to receive intranasal ruprintrivir (8 mg) or placebo sprays as prophylaxis (two or five times daily [2x/day or 5x/day] for 5 days) starting 6 h before infection or as treatment (5x/day for 4 days) starting 24 h after infection. Ruprintrivir prophylaxis reduced the proportion of subjects with positive viral cultures (for 5x/day dosing groups, 44% for ruprintrivir treatment group versus 70% for placebo treatment group [P=0.03]; for 2x/day dosing groups, 60% for ruprintrivir group versus 92% for placebo group [P=0.004]) and viral titers but did not decrease the frequency of colds. Ruprintrivir treatment reduced the mean total daily symptom score (2.2 for ruprintrivir treatment group and 3.3 for the placebo treatment group [P=0.014]) by 33%. Secondary endpoints, including viral titers, individual symptom scores, and nasal discharge weights, were also reduced by ruprintrivir treatment. Overall, ruprintrivir was well tolerated; blood-tinged mucus and nasal passage irritation were the most common adverse effects reported. Pharmacokinetic analysis of plasma and nasal ruprintrivir concentrations revealed intranasal drug residence with minimal systemic absorption. Results from these studies in experimental rhinoviral infection support continued investigation of intranasal ruprintrivir in the setting of natural HRV infection.

FIG. 1.

Mean log₁₀ viral titer in nasal lavage fluid over time for subjects for whom efficacy could be evaluated (5×/day [5x/d] prophylaxis, 2×/day prophylaxis, and 5×/day treatment groups). Values are given as means ± standard errors (error bars) by the least-square method. Values for the ruprintrivir-treated subjects that were significantly different (one-sided P values of <0.05) from the values for the placebo-treated subjects by ANOVA with effects for treatment (all groups), site (5x/d treatment group), and challenge virus strain (5x/d prophylaxis and treatment groups) and by ANCOVA with effects for treatment, study site, and challenge virus strain adjusted for baseline values (days 2 to 5 of 5x/d treatment group) are indicated by asterisks.

FIG. 2.

Mean log₁₀ viral RNA/ml in nasal lavage fluid over time for subjects for whom efficacy could be evaluated (5×/day [5x/d] prophylaxis, 2×/day prophylaxis, and 5×/day treatment groups). Values are given as means ± standard errors (error bars) by the least-square method. Values for the ruprintrivir-treated subjects that were significantly different (one-sided P values of <0.05) from the values for the placebo-treated subjects by ANOVA with effects for treatment (all groups), site (5x/d treatment group), and challenge virus strain (5x/d prophylaxis and treatment groups) and by ANCOVA with effects for treatment, study site, and challenge virus strain adjusted for baseline values (days 2 to 5 of 5x/d treatment group) are indicated by asterisks.

FIG. 3.

Mean total symptom score over time for subjects for whom efficacy could be evaluated (5×/day [5x/d] prophylaxis, 2×/day prophylaxis, and 5×/day treatment groups). For both treatment and prophylaxis groups, baseline values were virtually 0. Values are given as means ± standard errors (error bars) by the least-square method. Values for the ruprintrivir-treated subjects that were significantly different (one-sided P values of <0.05) from the values for the placebo-treated subjects by ANOVA for treatment (5×/day prophylaxis and 2×/day prophylaxis groups) and challenge virus strain (5×/day prophylaxis group) and by ANCOVA with effects for treatment, study site, challenge virus strain adjusted for baseline values are indicated by asterisks.

FIG. 4.

Mean nasal discharge weight over time for subjects in whom efficacy could be evaluated (5×/day [5x/d] prophylaxis, 2×/day prophylaxis, and 5×/day treatment groups). Values are given as means ± standard errors (error bars) by the least-square method. Values for the ruprintrivir-treated subjects that were significantly different (one-sided P values of <0.05) from the values for the placebo-treated subjects by ANOVA with effects for treatment (all treatment groups), study site (5x/d treatment group), and challenge virus strain (5x/d prophylaxis and treatment groups) are indicated by asterisks.

FIG. 5.

Mean scores for individual symptoms (sneezing, cough, rhinorrhea, malaise, nasal congestion or obstruction, headache, sore throat, and chilliness) over time for subjects in whom efficacy could be evaluated (5×/day treatment group). Symptom scores before challenge were 0 for all subjects, except for one subject who had a baseline rhinorrhea score of 1. Values are given as means ± standard errors (error bars) by the least-square method. Values for the ruprintrivir-treated subjects that were significantly different (one-sided P values of <0.05) from the values for the placebo-treated subjects by ANCOVA with effects for treatment, study site, and challenge virus strain adjusted for baseline values are indicated by asterisks.