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.
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.
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.
The death-toll which can be observed in COVID-19 patients is driven by the viral infection, the overwhelming cytokine storm in the infected tissue, and preexisting comorbidities.
Based on its mode of action, its broad-spectrum antiviral activity against many RNA viruses, and its safety profile, ATR-002 was evaluated by the Company’s scientists as a drug candidate that might be effective against the coronavirus SARS-CoV-2 – the cause of the COVID-19 pandemic – as soon as the outbreak became known.
Given the urgent need for a therapeutic approach, the Company decided to investigate ATR-002’s efficacy against this new virus and, in March and April 2020, carried out preclinical studies with SARS-CoV-2 in laboratories at the universities of Tübingen (Prof. Oliver Planz) and Münster (Prof. Stephan Ludwig). In these studies, viruses from the German COVID-19 outbreaks were used.
The tests proved ATR-002’s mode of action with a dual benefit. The host cell factor blocks SARS-CoV-2 replication and in parallel demonstrates immuno-modulating effects, which help resolving the detrimental inflammatory effects of the infection:
- Benefit 1: Inhibition of the viral propagation by interference with host cell kinase
- Benefit 2: Inhibition of overwhelming cytokine response
These observations established the working hypothesis to study ATR-002 in COVID-19 clinically and led to a pivotal Phase II study which will start in July 2020. The multicenter, double-blind, randomized, placebo-controlled trial will evaluate the efficacy of ATR-002 in hospitalized patients with moderate COVID-19.
Influenza can be treated with a variety of approved drugs. However, all currently available therapeutic agents either only treat the symptoms of the flu and/or target viral proteins. High mutation rates resulting from the rapid multiplication of the virus lead to the insurgence of resistances. In addition, the existing antiviral medications have a short therapeutic window and must be administered latest within 48 hours after the onset of symptoms.
Atriva’s ATR-002 does not target viral proteins but a cellular pathway in the host cell, which makes the development of viral drug resistance far less likely. As a matter of fact, during preclinical trials with this host-targeting approach, no resistance formation was observed. Further, the MEK-inhibitor has also proven to have a longer treatment window compared to conventional influenza medication. Therefore, ATR-002 can be considered an excellent candidate for development as an efficient antiviral agent.
A Phase II clinical trial with ATR-002 in influenza is planned to start in early 2021.
As a first-in-class concept for respiratory and hemorrhagic viral infections that use the Raf/MEK/ERK signaling pathway, ATR-002 is also studied in tropical viruses, 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.