New Influenza Antiviral Performs Well in Human Challenge for Phase 1 Trial

Oral administration of the novel oral influenza endonuclease inhibitor AL-794 has been shown to significantly reduce viral load, symptoms, and mucus weight at a dose of 150 mg in a human challenge study—and the agent’s development comes not a moment too soon.

In findings published July 26 in the Journal of Infectious Diseases (JID), investigators from the drug’s manufacturer, Janssen, described a phase I clinical trial in which 61 subjects were inoculated intranasally with influenza virus (A/Perth/16/2009 H3N2). A total of 42 of the subjects became infected, confirmed via analysis of nasopharyngeal swabs for influenza RNA, using a qualitative integrated cycler polymerase chain reaction assay on day 4 of the trial. Infected study subjects received either 50 mg of AL-794, 150 mg of AL-794, or placebo twice daily for 5 days.

After 5 days of treatment, subjects who received 150-mg doses of AL-794 had a mean peak viral load of 2.77 log₁₀ 50% tissue culture infectious doses (TCID₅₀)/mL, compared to 3.54 log₁₀ TCID₅₀/mL in those who received 50-mg doses, and 3.72 log₁₀ TCID₅₀/mL in those who received the placebo. Mean influenza viral load area under the curve (AUC) 87.5 log₁₀ TCID₅₀/mL·h, 137 log₁₀ TCID₅₀/mL·h, and 142 log₁₀ TCID₅₀/mL·h for the 150-mg dose, 50-mg dose, and placebo groups, respectively. Median time to virus nondetection was 75.3 hours in the 150-mg dose group, versus 117 hours and 108 hours in the 50-mg dose and placebo groups, respectively.

In addition, subject self-reported scores designed to assess the most commonly reported symptoms—including runny or stuffy nose, sneezing, sore throat, headache, earache, cough, shortness of breath, muscle and or joint ache, and malaise/tiredness—showed a decreasing trend from 24 to 48 hours following treatment initiation and continued to decrease until the end of treatment. The most common adverse events associated with AL-794 administration were hyperphosphatemia, increased alanine aminotransferase/aspartate aminotransferase levels, increased cholesterol level, and epistaxis; however, the investigators reported that the majority of adverse events were mild or moderate in severity.

Contagion^® contacted authors not affiliated with the study drug manufacturer to request additional comment; however, none of them replied at the time of posting. In their concluding remarks in the JID article, the authors wrote, “Overall, AL-794 was well-tolerated and showed significant antiviral activity in a human influenza challenge model. Both 50 mg and 150 mg of AL-794 administered twice daily under fasted conditions for 5 days showed a reduction in influenza viral load greater than that observed with placebo. The safety, tolerability, and ability to achieve plasma ALS-033719 concentration multiples greater than the protein-binding—adjusted EC90 of AL-794 in this study support further evaluation of AL-794.”

In a commentary published by JID in conjunction with the study, John Treanor, MD, professor of medicine, microbiology, and immunology; Chief, division of infectious diseases, University of Rochester Medical Center; and founder, New York Influenza Center of Excellence, notes that, “The 2017-2018 influenza season was a stark reminder of the public health burden of influenza, and as data accumulated suggesting a relative lack of effectiveness of that season’s vaccine, we increasingly turned to antivirals to reduce the epidemic’s impact. The development of new antiviral agents with differing mechanisms of action are urgently needed, and on the basis of these encouraging results, the investigators plan to move forward with further clinical development.”

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous health care-related publications. He is the former editor of Infectious Disease Special Edition.