ALS-008176 shows promise in healthy adults with RSV
PHILADELPHIA — The novel compound ALS-008176 yielded significant treatment reductions in respiratory syncytial virus viral load in healthy adults experimentally infected with a clinical strain of RSV, according to findings presented at IDWeek 2014.
John DeVincenzo, MD, of the department of pediatrics at the University of Tennessee Health Science Center in Memphis, Tenn., said the current double blind, placebo-controlled phase 2 study aimed to evaluate ALS‑008176, an oral nucleoside analogue that causes nascent RNA chain-termination, thereby inhibiting RSV replication.
Eligible participants were aged 18 to 45 years and were screened to have low preexisting RSV-specific antibody titers to the Memphis-37 RSV challenge strain.
“Challenge studies are complicated but can yield important results,” DeVincenzo said. “Volunteers were quarantined on study day minus 2 and then were inoculated on study day 0 with the RSV-A Memphis-37 strain.”
The safety analysis included 62 patients in the ITT population. There were 35 volunteers who met the definition of infection and these volunteers were analyzed for efficacy in an ITT-infected analysis. Participants were randomly assigned placebo or one of three dosing regimens of the study drug administered every 12 hours for 5 days: a 750-mg loading dose followed by 500-mg maintenance doses; a 750-mg loading dose followed by 150-mg maintenance doses; or a 375-mg dose every 12 hours.
The researchers monitored patients intensively for efficacy outcomes — including nasal wash viral load, RSV symptom scores and mucus weight — while the volunteers were in quarantine (through study day 12).
“We also looked at safety signals throughout the 28 days of the study,” DeVincenzo said. “The possible development of viral resistance was also monitored throughout the study.”
Area under the curve of RSV viral load from before the first dose to day 12 served as the predetermined primary endpoint.
All dosing regimens of the study drug reached the primary endpoint compared with placebo (P<.001 for all). Also, viral clearance was accelerated in all of the treatment groups compared with placebo (P<.05).
“Compared to placebo, we saw a dramatic reduction in viral load over the first 12-hour time interval after initiation of treatment,” DeVincenzo said. “This decrease occurred most rapidly in both treatment groups that incorporated a loading dose. In the non-loading dose arm, the viral load reduction was more gradual within the first 24 hours compared to the loading dose arms, but the reductions were still significant vs. placebo, illustrating a dose-response effect of ALS-008176.”
Measures of clinical disease severity (symptom scores and mucus weights) also were significantly reduced in the active therapy arms compared with placebo, according to DeVincenzo.
“The other important thing to note is that viral load ceased to be detected shortly after dosing,” he said. “Additionally, after dosing for only 5 days, there was no viral rebound after cessation of drug. This included the evaluations at study day 16 or 28. Perhaps most importantly, there were no viral resistance mutations noted.”
Safety endpoints were generally balanced across the treatment and placebo groups, according to DeVincenzo. “No events were serious or led to discontinuation,” he said. “However, this trial was relatively small, so it is preferable to make broad safety conclusions with larger data sets.”
DeVincenzo concluded that ALS-008176 warrants further study in RSV patient populations, naturally infected with RSV, including those with severe disease. — by Rob Volansky
For more information:
DeVincenzo J. #LB-1. Presented at: IDWeek 2014; Oct. 8-12; Philadelphia.
Disclosure: DeVincenzo reports associations with companies including Alios BioPharma, Alnylam, AstraZeneca, Biota, Crucell, Gilead Sciences, Janssen, MedImmune, Novartis and Teva.