The Atriva Approach
Atriva Therapeutics is changing the philosophy and strategy of antiviral drug development with its unique portfolio of broadly active and efficacious antiviral drugs based on MEK inhibitors in areas of a high unmet medical need, such as COVID-19 and influenza.
The Company’s lead drug candidate ATR-002 targets 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.
Figure: Antiviral activity of ATR-002: intracellular MEK inhibition.
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.
Figure: Viral multiplication and cytokine storm. ATR-002 addresses these effects, which often lead to severe progression of respiratory viral infections.
Research & Development
The Company’s lead drug candidate is the MEK inhibitor ATR-002. The small molecule, which can be administered orally, is under advanced clinical development in two severe respiratory viral infections: the newly discovered COVID-19 and influenza, two disease areas with an urgent need for effective therapeutics.
Preclinical studies have proved the antiviral efficacy of ATR-002 against various strains of influenza virus, Hantavirus and respiratory syncytial virus (RSV). These promising data led to a Phase I clinical study with 70 healthy volunteers, which was successfully concluded in 2019 and demonstrated excellent safety and tolerability of ATR-002 (NCT04385420). In addition, pharmacokinetics exposure and determination of MEK inhibition were verified and confirmed the maintenance of clinically relevant blood levels. This supports the intended once-daily regime for the further Phase II clinical development.
As a first-in-class concept for severe respiratory viral infections, including COVID-19 and influenza, that use the Raf/MEK/ERK signaling pathway, ATR-002 is also studied in hemorrhagic viral infections, such as hantavirus, and provides a strong platform portfolio.
For detail and further readings:
PHaasbach et al 2017; The MEK-inhibitor CI-1040 displays a broad anti-influenza virus activity in vitro and provides a prolonged treatment window compared to standard of care in vivo. Antiviral Research 142:178-184.