DGAP-News: Publication in PNAS unveils molecular pathway required for influenza virus replication with large potential as an antiviral drug target

Publication in PNAS unveils molecular pathway required for influenza virus replication with large potential as an antiviral drug target

- For the first time, research explains the cascade of events linking influenza virus-induced activation of the Raf/MEK/ERK pathway to the nuclear export of viral ribonucleoprotein (vRNP) via the host protein RSK

- Raf/MEK/ERK/RSK pathway represents an Achilles heel of virus replication and is a target of the ongoing antiviral development by Atriva Therapeutics

- MEK inhibitor ATR-002 is a potential broad-spectrum antiviral against respiratory RNA viruses dependent on Raf/MEK/ERK, such as influenza virus and SARS-CoV-2

Tübingen (Germany), June 30, 2020 - Atriva Therapeutics GmbH, a biopharmaceutical company pioneering the development of host-targeting antiviral therapies, today announced the publication of in vitro results by Atriva Co-founder Prof. Stephan Ludwig in The Proceedings of the National Academy of Sciences of the United States of America (PNAS) that show the mechanism of influenza virus-induced export of viral ribonucleoprotein (vRNP) complexes.^{[1], [2]} The research identifies and confirms the full molecular chain of events connecting the virus-activated Raf/MEK/ERK signalling pathway via its downstream target RSK to the final export of vRNPs during an influenza virus infection.

The peer-reviewed paper illustrates how influenza viruses control, to their advantage, the cellular Raf/MEK/ERK/RSK pathway to accomplish a crucial step in the virus life cycle: the export of the viral genome from the cell nucleus to the cytoplasm where it will be assembled into new progeny influenza particles. As the virus is unable to perform this function by itself, this represents an Achilles heel of virus replication. This is where ATR-002 intervenes: the MEK inhibitor medicinal product candidate was specifically developed by Atriva Therapeutics to treat respiratory infections caused by RNA viruses, such as the influenza virus and the novel SARS-CoV-2, reflecting the need for an effective antiviral to respond to public health threats emerging from seasonal flu and virus outbreaks.^[3]

"By targeting the enzyme MEK, an essential component of the signalling cascade, ATR-002 inhibits this pathway and, thus, leads to a blockade of viral replication. Our discovery of the full mechanism including the role of the downstream effector RSK finally closes a gap in our knowledge around the export process of vRNPs from the nucleus and how exactly the cellular machinery is hijacked to this end," said Stephan Ludwig, Professor, Director of the Institute of Virology, Muenster, Germany, Chair of the Supervisory Board of Atriva Therapeutics, and corresponding author of the paper. "In addition, our findings also support the strategy to advance ATR-002 as a treatment for severe respiratory viral infections that depend on this pathway, such as influenza."

"ATR-002 is an oral small molecule that has already undergone pharmacokinetic studies, as well as a very successful Phase I clinical study.^[4] In particular, the dose escalation study demonstrated the excellent safety and tolerability of ATR-002, and the observed pharmacokinetic profile supports the intended once-daily regime for the upcoming Phase II clinical development," added Dr. Rainer Lichtenberger, co-founder and CEO of Atriva. "Potential advantages of our host-targeting approach are the prolonged treatment window and the reduced probability of viral resistance compared to therapies that directly target viral structures."

On May 28, 2020, Atriva announced plans to develop ATR-002 in a Phase II clinical trial to treat COVID-19 patients.^[5] The multinational, double-blind, randomized Phase II clinical study, which is set to start in July 2020 and will include 200 patients, aims to demonstrate the efficacy of the oral small molecule ATR-002 against moderate COVID-19, compared to placebo, in hospitalized patients.

The Company program for ATR-002 in severe influenza is planned to continue in winter 2020/2021 with a Phase II clinical study.

About ATR-002's mode of action with dual benefit

Atriva's lead product ATR-002, developed specifically to treat RNA virus diseases such as influenza and coronaviruses, including SARS-CoV-2, is a clinical stage MEK inhibitor drug candidate targeting the intracellular Raf/MEK/ERK signaling pathway. This pathway is central for replication of many RNA viruses, such as the influenza virus, hantavirus or respiratory syncytial virus (RSV) and also SARS-CoV-2, the virus that causes COVID-19. In influenza virus infected cells, the interaction of ATR-002 with MEK (MAPK/ERK kinase) prevents export of the viral genome protein complexes (ribonucleoprotein, RNP) from the nucleus to the cytoplasm, thus blocking the formation of functional new viral particles. This ultimately reduces the viral load in the body.^[6]

In addition, ATR-002 has the potential to modulate the pro-inflammatory cytokine response of the body, avoiding overshooting cytokine response that can be caused by such viral infections. MEK inhibition can reduce the gene expression of some of the cytokines involved, like TNF-α, IL-1ß, IP-10, IL-8, MCP-1 and MIP-1a, and thus mitigate the overactive inflammatory response in the lungs of patients who are severely ill with influenza or COVID-19.^[7]

About Atriva Therapeutics GmbH

Atriva Therapeutics, founded in 2015, is a biopharmaceutical company specifically pioneering the development of host-targeting antiviral therapies set up by a team of leading scientists in viral research and seasoned industry experts. The Company aims to develop new antiviral therapies against different severe respiratory viral infections with a high unmet medical need, such as influenza and COVID-19. Atriva's lead product ATR-002 is a first-in-class host-targeting agent which inhibits viral replication in influenza and favorably modulates the body's immune response. ATR-002 is under clinical development and has successfully completed a Phase I trial to demonstrate safety and tolerability in healthy subjects. A Phase II study to evaluate efficacy in hospitalized COVID-19 patients is in preparation; a Phase II study in influenza is planned to start in early 2021. The Company owns eleven patent families with broad international coverage related to the use of MEK inhibitors and other kinase inhibitors for anti-viral therapies. The patent life runs through 2041. Atriva Therapeutics is located in Tübingen and Frankfurt, Germany.

For further information, please visit www.atriva-therapeutics.com and follow us on LinkedIn and Twitter.

^[1] Schreiber A et al. Dissecting the mechanism of signaling-triggered nuclear export of newly synthesized influenza virus ribonucleoprotein complexes. PNAS, June 2020.

^[2] The Proceedings of the National Academy of Sciences of the United States of America is the official journal of the National Academy of Sciences (NAS), an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.

^[3] Pleschka S, Planz O, Ludwig S. Enduring research: The constant threat of influenza virus outbreaks, Open Access Government, June 2020.

^[4] NCT04385420.

^[5] https://www.atriva-therapeutics.com/news/14-news/96-news-phase2-2020.

^[6] Pleschka S et al. Nat Cell Biol 2001 Feb 3:301-5; Planz O Antiviral Res 2013 Jun 98(3):457-68; Haasbach E et al. Antiviral Res 2017 Jun 142:178-4; Laure M et al. Antiviral Res 2020 Jun 178:104806.

^[7] Pinto R et al. Antiviral Res 2011 Oct 92(1):45-56; Planz O Antiviral Res 2013 Jun 98(3):457-68; Schräder T et al. Antiviral Res 2018 Sep 157:80-92.