PHILADELPHIA (FRONTLINE MEDICAL NEWS) – ALS-008176, an oral prodrug of the novel cytidine nucleoside analog, rapidly reduced respiratory syncitial virus load and clinical disease severity in healthy adult volunteers infected with a clinical strain of the virus as part of a double-blind, placebo-controlled phase IIa study.
Of 62 adults aged 18-45 years with preexisting RSV-A specific antibody titers who were inoculated with RSV-A Memphis 37b virus and randomized to receive placebo or one of three ALS-008176 dosing regimens, 35 met the criteria for infection. The viral load area under the curve (AUC) was significantly and rapidly reduced in all volunteers who received ALS-008176, compared with those who received placebo; the reduction in AUC, compared with placebo, ranged from 73% to 88% for the treatment groups at day 12 , Dr. John DeVincenzo of the University of Tennessee Health Science Center, Memphis, reported at an annual scientific meeting on infectious diseases.
Further, the AUC for symptom scores and mucous quantity as measured by weight were also reduced for all treatment groups, compared with placebo, and no subjects exhibited viral load rebound at days 16 or 28 after dosing, Dr. DeVincenzo said at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
The study subjects, who had RSV-A specific antibody titers in the lowest 25th percentile of the population, were inoculated at baseline and monitored for RSV infection in nasal wash every 12 hours. At either 12 hours after infection was detected or 6 days following inoculation – whichever came first – they were randomized to receive either placebo or ALS-008176 given as a loading dose of 750 mg followed by 500-mg maintenance doses, a loading dose of 750 mg followed by 150-mg maintenance doses, or 375 mg every 12 hours for 5 days. The treatment and placebo groups were well balanced with respect to age, body mass index, sex, and viral load. Assessment of viral load, RSV symptom scores, and mucous weight were evaluated multiple times daily for 12 days, then again on days 16 and 28.
A decrease in viral load in the treatment groups occurred as early as day 0.5 after the initial dose, whereas the viral load in the placebo group increased to more than 4 logs, peaking at day 3.5 and then dropping. The most dramatic decrease in viral load was seen in the highest-dose group and was better in both groups that received a loading dose than in the treatment group that did not.
Viral load in the treatment groups became undetectable very quickly, Dr. DeVincenzo said, noting that levels remained undetectable at days 16 and 28, indicating there was no rebound after dosing was stopped.
No viral resistance mutations were noted.
Treatment with ALS-008176, which is a potent and selective inhibitor of RSV RNA-dependent RNA polymerase that is active against multiple A and B strains of RSV, was well tolerated; no clinically significant laboratory abnormalities occurred, and adverse events all were mild or moderate and were generally balanced between the placebo and treatment groups. None of the volunteers discontinued the study because of adverse events, Dr. DeVincenzo said.
The findings are encouraging given the lack of an effective treatment or vaccine for RSV, which is an important cause of morbidity and mortality worldwide – particularly in infants.
“Further studies of ALS-008176 in natural infections are warranted,” he said, noting that such studies are currently ongoing, including one in otherwise healthy infants hospitalized with RSV.
Dr. DeVincenzo is a consultant for, and/or has received research support from, Abbvie, Alios Biopharma, Alnylam, Ark Pharma, Astra Zeneca, Biota, Crucell, the Genomics Institute of the Novartis Research Foundation, Gilead Sciences, Janssen, MedImmune, Retroscreen Virology, Teva, and Novartis.
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