Atriva Development Programs
Atriva Therapeutics researches and develops first-in-class host-targeting therapies to treat severe respiratory viral infections, including influenza, COVID-19, RSV, dengue and hanta.
The COVID-19 death toll was driven by the viral infection, the derailment of the immune system such as the overwhelming cytokine storm in the infected organs, and pre-existing comorbidities.
Based on its mode of action, its broad-spectrum antiviral activity against many RNA viruses, and its safety profile, zapnometinib 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.
Given the urgent need for a therapeutic approach during the past pandemic, the company decided to investigate zapnometinib’s efficacy against the SARS-CoV-2 virus and conducted preclinical studies.
The results clearly demonstrated the dual benefit of zapnometinib’s mechanism of action: The host cell factor blocks RNA-virus replication and in parallel generates immuno-modulating effects:
- Benefit 1: inhibition of the viral propagation by interference with host-cell kinase
- Benefit 2: inhibition of cytokine response
These observations established the rationale to clinically investigate zapnometinib in COVID-19. On December 29th, 2020, Atriva Therapeutics obtained RESPIRE trial approval in COVID-19 patients from German authorities. In April 2021, the company announced the dosing of the first patient at Charité – Universitätsmedizin Berlin, Germany. The trial was ended in the third quarter of 2022 following the decreasing pandemic threat.
Clinical Phase II in COVID-19
RESPIRE [Randomized, Double-Blind, Placebo-Controlled, Multi-Center Clinical Trial to Evaluate the Safety and Efficacy of zapnometinib in Adult Hospitalized Patients with COVID-19] was a randomized, double-blind, placebo-controlled, international, multi-center Phase II clinical trial for 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 would receive zapnometinib 900 mg, administered as tablets once daily on day 1, followed by zapnometinib 600 mg once daily on days 2 to 6. Patients in the control group would receive placebo in a matching scheme, on top of standard of care.
Primary objective of the study was to prove the efficacy of zapnometinib versus placebo in addition to standard of care; secondary endpoints included the reduction of duration of hospitalization, the measurement of changes in clinical signs and symptoms and other relevant clinical parameters, scores, and study events. Outcomes were 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 enrolled patients were followed-up for 90 days. The study also evaluated the pharmacokinetics of zapnometinib and was ended with promising results in September 2022. These results now form a solid foundation for Atriva`s Phase 2 development program in the treatment of patients hospitalized with a severe influenza infection.
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 zapnometinib 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, our MEK inhibitor has also demonstrated to have a longer treatment window compared to conventional influenza treatments. Therefore, zapnometinib can be considered an excellent candidate for development as an efficient antiviral agent.
Further potential indications
Both, antiviral and immunomodulatory properties make zapnometinib effective in successfully treating influenza viruses, SARS-CoV-2, and potentially further life-threatening respiratory RNA viruses that rely on the Raf/MEK/ERK signalling pathway, including respiratory syncytial virus (RSV) and hantavirus, the latter being associated with a bioweapon risk.
Zapnometinib has the potential to be uniquely effective in high-risk patients, such as elderly 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, zapnometinib inhibits the viral replication and attenuates a potential cytokine storm which is regarded as the main cause of an immune overreaction.