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 demonstrated ATR-002’s mode of action with a dual benefit. The host cell factor blocks RNA-virus replication leading to antiviral & immuno-modulating effects:
- 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 clinically study ATR-002 in COVID-19. Atriva Therapeutics obtained the approval to commence the RESPIRE trial in COVID-19 patients from German authorities on December 29, 2020. RESPIRE is an acronym for “Randomized, Double-Blind, Placebo-Controlled, Multi-Centre Clinical Trial to Evaluate the Safety and Efficacy of ATR-002 in Adult Hospitalized Patients with COVID-19”.
RESPIRE - Clinical phase II in COVID-19
RESPIRE [Randomized, Double-Blind, Placebo-Controlled, Multi-Centre Clinical Trial to Evaluate the Safety and Efficacy of ATR-002 in Adult Hospitalized Patients with COVID-19] is a randomized, double-blind, placebo-controlled, international, multi-center Phase II clinical trial in 220 adult patients with moderate to severe COVID-19, requiring hospitalization, but not requiring ICU admission or ventilator support at the time of screening or randomization. On top of standard of care, half the patients will receive ATR-002 900 mg, administered as tablets once daily on day 1, followed by ATR-002 600 mg once daily on days 2 to 6. Patients in the control group will receive placebo in a matching scheme, on top of standard of care.
Figure: RESPIRE clinical trial design.
Primary endpoint of the study is to prove the efficacy of ATR-002 versus placebo in addition to standard of care; secondary endpoints include the measurement of changes in clinical signs and symptoms and other relevant clinical parameters, scores, and study events. Outcomes will be assessed based on the clinical severity status on day 15, using a 7-point ordinal scale as suggested by the WHO COVID-19 Therapeutic Trial Synopsis. All patients will be followed-up for 90 days. The study will also evaluate the pharmacokinetics of ATR-002.
Prof. Gernot Rohde, M.D., Head of Pneumology and Professor for Respiratory Medicine and Allergology at the Goethe University Hospital, Frankfurt am Main, Germany, will act as Global Coordinating Investigator. The study will be run at the Goethe University Hospital and additional German and international clinical centers.
How to get involved in the trial
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 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 for the second half of 2021.
Further potential indications
Both antiviral and immunomodulatory assets make ATR-002 effective in successfully fighting influenza viruses, SARS-CoV-2, and potentially further life-threatening respiratory RNA viruses that rely on the Raf/MEK/ERK signaling pathway, including Respiratory Syncytial Virus and Hantavirus, the latter being associated with a bio weapon risk.
ATR-002 has the potential to be uniquely effective in high-risk patients, such as elderly patients or patients with preconditions like asthma, heart disease, chronic obstructive pulmonary disease, or certain cancers. Due to its mode of action with a dual benefit, ATR-002 could attenuate cytokine storms and severe disease courses that are in parts associated with these immune overreactions. This could significantly ease the burden on health systems, particularly in pandemic environments.