Atriva Therapeutics plans (Phase II) clinical development of ATR-002 for the treatment of patients with COVID-19 disease
02.06.2020 14:35
The biopharmaceutical company Atriva Therapeutics GmbH, developer of host cell-targeted antiviral therapies, has announced its strategy for the clinical development of ATR-002 in the COVID-19 indication. The goal is to treat patients with moderate to severe COVID-19 symptoms that require hospitalization but do not require ventilation. ATR-002, an orally available small molecule, has shown in preclinical studies that it can block the replication of SARS-CoV-2.
In addition, it has an immunomodulatory effect, which leads to reduced cytokine and chemokine release. This dual benefit makes the MEK inhibitor ATR-002 particularly interesting for the treatment of COVID-19.
According to the company, ATR-002 was specifically developed to treat viral respiratory infections. It therefore inhibits MEK, a factor in the human host cell that is required for the replication of various RNA viruses, including influenza viruses and SARS-CoV-2. Preclinical studies at the universities of Tübingen and Münster with virus strains from the recent German COVID-19 outbreaks have shown that MEK inhibition by ATR-002 prevents SARS-CoV-2 from multiplying. In addition to this antiviral effectiveness, ATR-002 has a second positive effect: the MEK inhibitor significantly reduces pro-inflammatory cytokine and chemokine expression in cell lines as well as in human primary cells and in an animal model of acute lung injury (acute lung injury, ALI), as occurs with COVID-19. ATR-002 could therefore prevent a cytokine storm in patients with COVID-19 and thus stop the progression of the disease to a life-threatening condition, which is often associated with this excessive reaction of the human immune system.
Its mechanism of action with a dual benefit of antiviral activity and immune modulation uniquely positions ATR-002 as a promising therapy candidate. According to its own information, the company has registered corresponding patents with the European Patent Office. In addition, ATR-002 successfully completed a Phase I clinical trial in healthy volunteers in 2019, in which it demonstrated excellent safety and tolerability.[1]
“With ATR-002, we have developed an active ingredient specifically for the treatment of severe respiratory infections caused by RNA viruses, thereby meeting the great need for an efficient antiviral therapy,” said Dr. Rainer Lichtenberger, co-founder and CEO of Atriva. “ATR-002 could play an important role in the current pandemic. The use in tablet form offers high potential as it is very patient-friendly and can fundamentally improve treatment outcomes for COVID-19.[2] In these times, the clinical development of ATR-002 for COVID-19 therefore represents a logical step that can be crucial for healthcare systems, patients and their families. Our development programs in the key indication of influenza will benefit greatly from synergies in clinical development and ramping up manufacturing of ATR-002 to commercial scale.”
Atriva plans to begin a multinational, double-blind, randomized Phase II clinical trial with the oral agent ATR-002 for the treatment of COVID-19 in July 2020. The study is designed to demonstrate the effectiveness of ATR-002 compared to placebo in hospitalized patients with moderate COVID-19.
“The preclinical results are very encouraging. “The treatment of moderately to severely ill patients aims to reduce progression to severe disease, thereby reducing the number of patients transferred to intensive care units and requiring more invasive treatment,” said Dr. Martin Bauer, Chief Medical Officer of Atriva. “From the earliest stages of development, our ambition has been to provide an effective antiviral agent for the treatment of influenza and other serious viral respiratory infections. At this point in time, the search for an effective therapy to treat severe COVID-19 diseases is crucial for health systems, as we unfortunately have to assume that pandemics will continue to be on the health policy agenda.” Atriva does not have ATR-002 not only an effective antiviral drug, but also an agent against the excessive release of cytokines.[3]
The small molecule compound can be produced through chemical synthesis and production could be rapidly scaled up to meet high demand. Evonik Industries AG, a Germany-based global leader in specialty chemicals, is – as part of its long-standing collaboration with Atriva – the development and manufacturing partner for the investigational medication in the phase II study with ATR-002. In parallel, Atriva is preparing to scale up production of ATR-002 to provide sufficient doses for advanced large-scale clinical trials and possible market entry upon completion.
Background:
According to the company, the drug candidate ATR-002 was developed specifically for the treatment of diseases caused by RNA viruses, such as influenza viruses or coronaviruses. ATR-002 is a MEK inhibitor that targets the intracellular Raf/MEK/ERK signaling pathway. This signaling pathway is crucial for the replication of many RNA viruses, including influenza viruses, hantaviruses and RS viruses (respiratory syncytial virus) as well as SARS-CoV-2, which causes COVID-19. In influenza virus-infected cells, ATR-002 prevents the export of viral genome protein complexes (ribonucleoproteins, RNPs) from the nucleus to the cytoplasm by inhibiting MEK (MAPK/ERK kinase), thereby preventing the formation of new functional virus particles. This reduces the viral load in the body.[4]
In addition, ATR-002 has the potential to modulate the immune system and could inhibit an uncontrolled excessive inflammatory response caused by cytokines, as sometimes occurs in such viral infections. In patients severely ill with influenza or COVID-19, ATR-002 can reduce gene expression of some of the cytokines involved, such as TNF-α, IL-1ß, IP-10, IL-8, MCP-1 and MIP-1a, and thus mitigate the overactive immune response in the lungs of these patients.[5]
Sources:
[1] NCT04385420.
[2] Siddiqi HK 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.