Targeting intracellular signaling as an antiviral strategy: aerosolized LASAG for the treatment of influenza in hospitalized patients

Abstract

Influenza has been a long-running health problem and novel antiviral drugs are urgently needed. In pre-clinical studies, we demonstrated broad antiviral activity of D, L-lysine-acetylsalicylate glycine (LASAG) against influenza virus (IV) in cell culture and protection against lethal challenge in mice. LASAG is a compound with a new antiviral mode of action. It inhibits the NF-κB signal transduction module that is essential for IV replication. Our goal was to determine whether aerosolized LASAG would also show a therapeutic benefit in hospitalized patients suffering from severe influenza. The primary endpoint was time to alleviation of clinical influenza symptoms. The primary analysis was based on the modified intention-to-treat (MITT) population. This included all patients with confirmed influenza virus infection who received at least one treatment. The per protocol (PP) analysis set included all subjects from the MITT population who underwent at least 13 inhalations. In the MITT group, 48 (41.7%) participants (29 LASAG; 19 placebo) had severe influenza. The mean time to symptom alleviation was 56.2 h in the placebo group and 43.0 h in the LASAG group. The PP set consisted of 41 patients (24 LASAG; 17 placebo). The mean time to symptom alleviation in the LASAG group (38.3 h; P = 0.0365) was lower than that in the placebo group (56.2 h). In conclusion, LASAG improved the time to alleviation of influenza symptoms in hospitalized patients. The present phase II proof-of-concept (PoC) study demonstrates that targeting an intra-cellular signaling pathway using aerosolized LASAG improves the time to symptom alleviation compared to standard treatment.

Acknowledgements

We thank Melissa Cox for critically reading the manuscript. This work was supported and funded by Ventaleon GmbH, Gemuenden, Germany.

Conflict of interest

Declaration of interests

GS reports personal fees from Activaero/Vectura/Ventaleon GmbH, during the conduct of the study and personal fees outside the submitted work. GS, RN, SC, KN, OP, SP, SL are shareholders from Activaero/Vectura. KN, RN report personal fees from Ventaleon GmbH outside the submitted work. OP reports grants from Activaero/Vectura/Ventaleon GmbH, during the conduct of the study; also grants from Atriva Therapeutics GmbH and Activaero/Ventaleon GmbH outside the submitted work. RN, SC, OP, SL, SP are shareholders from Atriva Therapeutics GmbH outside the submitted work. TH was, at the time of the study, a consultant to Activaero/Vectura/Ventaleon GmbH. TW reports personal fees and others outside the submitted work (GSK). In addition, SL, SP, OP have a patent 8313751 and a patent EP20090701974 both issued to Ventaleon GmbH. GS has an issued patent WO 2009/089822 A2.

Electronic supplementary material

Supplementary Information accompanies this paper at (10.1038/s41426-018-0023-3).