Relationship of Pleconaril Susceptibility and Clinical Outcomes in Treatment of Common Colds Caused by Rhinoviruses

Abstract

Pleconaril, a specific inhibitor of human picornaviruses, showed therapeutic efficacy against communityacquired colds caused by rhinoviruses in two placebo-controlled trials. Virological assessments were conducted during these trails, including virus culture and drug susceptibility testing. Nasal mucus samples collected from the enrolled patients were tested for the presence of picornavirus by reverse transcriptase PCR and culture. In total, 827 baseline nasal mucus samples were positive by virus culture (420 in the placebo group and 407 in the pleconaril group). Pleconaril treatment was associated with a more rapid loss of culturable virus. By study day 3, the number of samples positive by culture fell to 282 for the placebo-treated subjects and 202 for the pleconaril-treated subjects (P < 0.0001); and by day 6, the number of samples in the two groups positive by culture fell to 196 and 165, respectively (P ‫؍‬ 0.07). The clinical benefit correlated strongly with the pleconaril susceptibility of the baseline virus isolate. Pleconaril-treated subjects infected with the more highly susceptible viruses (50% effective concentration < 0.38 g/ml) experienced a median 1.9-to 3.9-day reduction in symptom duration compared with that for the placebo-treated subjects. By contrast, subjects whose baseline virus isolate susceptibility was >0.38 g/ml did not benefit from pleconaril treatment. These results indicate that the magnitude of symptomatic improvement in pleconaril-treated subjects with community-acquired colds is related to the drug susceptibility of the infecting virus, clearly linking the antiviral effects of the drug to clinical efficacy. Postbaseline virus isolates with reduced susceptibility or full resistance to pleconaril were recovered from 10.7% and 2.7% of drug-treated subjects, respectively. These patients shed low levels of virus and had no unusual clinical outcomes. Nevertheless, studies on the biologic properties and transmissibility of these variant viruses are warranted.

In Vitro Resistance Study of Rupintrivir, a Novel Inhibitor of Human Rhinovirus 3C Protease

“…The clinical relevance for these findings was recently demonstrated, whereby patients with baseline isolates that had greater susceptibility to pleconaril experienced lower rates of recovery of virus posttreatment and a greater reduction in the number of days to symptom resolution than patients with baseline isolates that were less susceptible to pleconaril. The latter patients experienced no benefit from drug treatment (25). In the same study, Pevear et al (25) describe the emergence of HRV variants with a Ͼ10-fold reduction in susceptibility in 10.7% of patients during 3 to 5 days of treatment with pleconaril.…”

“…Fourteen of the 23 amino acid residues of the 3C protease involved in rupintrivir binding interact via their side chains (including 25,40,71,125,127,128,130,142,147,161,163,164,165, and 170). Presumably, amino acid substitutions at these residues would be predicted to have a greater potential impact on 3C protease-rupintrivir binding.…”

Childhood asthma and infection: virus-induced exacerbations as determinants and modifiers

“…Pleconaril is an agent with broadspectrum activity against RVs, which has been developed as an oral preparation to be taken twice daily. Although modest efficacy against natural colds has been verified in phase-II clinical trials, concerns have been raised about the development of resistant RV mutants [106,107]. At this stage, there are no clinical data regarding the efficacy of pleconaril in acute asthma exacerbations.…”

Genetic and antigenic structural characterization for resistance of echovirus 11 to pleconaril in an immunocompromised patient

“…Results on the clinical outcome varied considerably from complete recovery to fatalities. Data on resistance occurrence and development have only been provided in pleconaril trials against HRV (Ledford et al, 2004(Ledford et al, , 2005Pevear et al, 2005). Remarkably, the reason for these differences in responses was never investigated by means of typing and testing the in vitro susceptibility of isolated virus strains.…”