Atriva Therapeutics GmbH, a biopharmaceutical company pioneering the development of host-targeting antiviral therapies, today announced a clinical strategy to treat patients with moderate to severe COVID-19 who require hospitalization. ATR-002, an oral small molecule, has been proven in preclinical trials to block viral propagation of SARS-CoV-2 and to have an immunomodulatory effect leading to a decreased cytokine and chemokine release. This dual benefit makes the MEK-inhibitor ATR-002 particularly relevant for the treatment of COVID-19.

ATR-002 has been developed specifically to treat respiratory viral infections by inhibiting MEK, a host cell factor required for the replication of various RNA viruses, including influenza virus and SARS-CoV-2. Preclinical studies, using virus strains from the recent German COVID-19 outbreaks, performed at the Universities of Tübingen and Münster have demonstrated that MEK inhibition by ATR-002 prevents SARS-CoV-2 replication. In addition to its antiviral efficacy, ATR-002 shows a second beneficial effect: The MEK-inhibitor was able to significantly decrease pro-inflammatory cytokine and chemokine expression in cell lines, primary human cells, and an animal model of acute lung injury (ALI). Thus, ATR-002 could prevent a cytokine storm and the associated disease progression to a life-threatening condition in patients with COVID-19. Its mechanism of action with a dual benefit, antiviral activity and immunomodulation, uniquely positions ATR-002 as a promising therapeutic candidate. The Company has filed respective patents with the European Patent Office. Further, ATR-002 has successfully completed a Phase I clinical trial in 2019 where it demonstrated excellent safety and tolerability in healthy volunteers.^[1]

“With ATR-002, we developed a small molecule to specifically address the major need for an efficient antiviral therapy for severe respiratory infections caused by RNA viruses,” said Dr. Rainer Lichtenberger, co-founder and CEO of Atriva. “ATR-002 could be a game changer in the current pandemic as we see high potential for a patient-friendly, oral medication that fundamentally impacts COVID-19 outcomes.^[2] To develop ATR-002 for COVID-19 is therefore a logical step in these times and possibly vital for national health systems, patients and families. Our influenza development programs will benefit strongly from synergies in clinical development and scale-up in the production of ATR-002.”

Atriva is now starting a multinational, double-blind, randomized Phase II clinical study with the oral small molecule ATR-002 to treat COVID-19 in July 2020. The trial will aim to demonstrate its efficacy against moderate COVID-19, compared to placebo, in hospitalized patients.

“The preclinical findings are very encouraging. Treating moderately to severely-sick patients aims to reduce the number of critically ill people, otherwise referred to ICUs and requiring more invasive treatment options,” said Dr. Martin Bauer, Atriva Chief Medical Officer. “From the earliest stages of development, it has been our ambition to provide a powerful antiviral to treat influenza and other severe respiratory viral infections. At this point, finding an effective therapy to treat moderate to severe cases of COVID-19 is essential for national healthcare systems as we anticipate pandemic infections to remain on the public health agenda.” With ATR-002, Atriva not only has developed an effective antiviral compound, but at the same time a defense against the overwhelming cytokine release.^[3]

The small molecule drug can be manufactured via chemical synthesis and allows for rapid scale-up of production to meet high levels of demand. Evonik Industries AG, a German-based world leader in specialty chemicals, serves as the development and manufacturing partner to produce the ATR-002 medication for the Phase II clinical study, under its long-term collaboration with Atriva. In parallel, Atriva is preparing for the ramp-up of ATR-002 production to provide enough doses for extended clinical trials and market access following trial completion.

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.^[4]

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.^[5]

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.

About Evonik

Evonik is one of the world leaders in specialty chemicals. The company is active in more than 100 countries around the world and generated sales of €13.1 billion and an operating profit (adjusted EBITDA) of €2.15 billion in 2019. Evonik goes far beyond chemistry to create innovative, profitable and sustainable solutions for customers. More than 32,000 employees work together for a common purpose: We want to improve life, day by day.

^[1] NCT04385420.
^[2] Siddiqi H K and Mehra M R. J Heart Lung Transpl 2020 May 39;405-7.
^[3] Shunqing X and Yuanyuan L. Lancet 2020 May 395(102333):1321-22.
^[4] 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.
^[5] 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.