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 [2؋/day or 5؋/day] for 5 days) starting 6 h before infection or as treatment (5؋/day for 4 days) starting 24 h after infection. Ruprintrivir prophylaxis reduced the proportion of subjects with positive viral cultures (for 5؋/day dosing groups, 44% for ruprintrivir treatment group versus 70% for placebo treatment group [P ‫؍‬ 0.03]; for 2؋/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.Human rhinoviruses (HRV) account for 40 to 50% of common colds on an annual basis and up to 80% of the colds during the autumn months in the Northern Hemisphere (2, 16). In healthy individuals, these infections are generally selflimiting and mild, although acute respiratory infections may be associated with substantial morbidity, loss of productivity, excess antibiotic use, and frequent self-medication with nonprescription remedies. HRV infection may also be complicated by acute sinusitis and otitis media and may cause exacerbations of asthma, chronic bronchitis, and cystic fibrosis, requiring acute care and hospital admission (7,15,20,21,24). For both otherwise healthy and high-risk individuals, antiviral treatment or prophylaxis would be desirable.At this time, no antiviral agents are approved for the prevention or treatment of HRV infection. Several antiviral compounds with in vitro activity against HRV have been evaluated for the management of colds, including intranasal tremacamra, a soluble intercellular adhesion molecule 1 (ICAM-1); alpha interferon 2b; and the capsid binders, pirodavir a...

Infection and Propagation of Human Rhinovirus C in Human Airway Epithelial Cells

“…Although several inhibitors showed a modest antiviral effect in early clinical trials, none have been approved for treatment. In the case of pleconaril, drug resistance was observed in 24% of patients, with 13% of patients harboring pleconaril-resistant virus at baseline (11,12). The majority of the clinical compounds were developed prior to the discovery of HRV-C, and it is unclear if any of the inhibitors exhibit antiviral activity against HRV-C strains.…”

A Randomized, Double-Blind, Placebo-Controlled Pilot Clinical Study on ColdZyme<sup>®</sup> Mouth Spray against Rhinovirus-Induced Common Cold

“…The study protocol and accompanying documents were reviewed and approved by the Regional Ethics Committee in Lund, Sweden. Based on viral load parameters from Open Journal of Respiratory Diseases a similar study [6], a total sample size of 46 was calculated to be sufficient. After signing informed consent, 82 subjects were screened for serum neutralizing antibodies against rhinovirus 16, of whom 46 seronegative subjects between the ages of 20 -46 years were included.…”

Pathogen-directed Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

“…Ruprintivir is an agent that has been developed as a nasal spray. In experimentally induced HRV colds in healthy volunteers, it was able to moderate disease severity and reduce viral load (125). Unfortunately, a subsequent natural infection study was not able to reproduce these findings (126).…”