In September 2019, the health watchdog the Global Preparedness Monitoring Board (GPMB) issued a first-of-its-kind warning that the world is severely unprepared for a fast-spreading pandemic. Seasonal influenza is already a serious global health threat: an estimated one billion people are infected every year, three to five million severely, with up to 650,000 dying from related respiratory complications, according to the World Health Organization.
Unfortunately, small-molecule antiviral treatments, such as the market leader Tamiflu (oseltamivir; a neuraminidase inhibitor) and Xofluza (baloxavir marboxil; an endonuclease inhibitor), must be administered soon after the onset of symptoms, typically within 48 hours. For both drugs, resistant virus strains are known, leaving the therapies partially useless. Moreover, both drugs are approved only for uncomplicated flu infections. With novel flu virus strains emerging every year, a pandemic looming and vaccines only partially effective, a safe and efficacious influenza therapy that is also suitable for severe influenza and high-risk groups is urgently required.
Leading the therapeutic charge is Atriva, a biopharmaceutical company founded in 2015 by a team of virologists and industry experts. Located in Tübingen and Frankfurt, Germany, Atriva is pioneering the development of host-targeting antiviral therapies with a novel mode of action against respiratory viral infections, including influenza.
Instead of targeting a viral protein, Atriva’s approach interferes with the machinery inside human cells that the virus requires for reproduction. Propagation of influenza virus and other RNA viruses hinges on activation of the Raf/MEK/ERK signaling cascade inside human cells. Blocking MEK (MAPK/ERK kinase), a fundamental enzyme in that pathway, impedes the propagation process (Fig. 1). “Inhibiting MEK hinders the formation of functional new viral particles by preventing export of the viral RNA/protein complexes from the nucleus to the cytoplasm,” explained Oliver Planz, Atriva’s CSO. “This ultimately reduces the viral load in the body and allows the immune system to clear the initial infection.”
Fig. 1 | ATR-002 halts viral replication. ATR-002 functions by blocking MEK, which inhibits the formation of new viral particles by preventing the export of the viral RNA/protein complexes from the nucleus to the cytoplasm. This action reduces the overall viral load in the body, allowing the immune system to clear the initial infection.
ATR-002 shows clinical promise
Atriva’s lead product, ATR-002, a first-in-class orally administered MEK inhibitor, has been shown to be safe in doses up to 900 mg/day in a phase 1 safety and tolerability trial. Proof of concept has been demonstrated successfully in animal models. Preclinical and phase 1 data show that a once-daily oral dose of ATR-002 leads to rapid and relatively long-lasting
inhibition of the Raf/MEK/ERK replication pathway and much reduced virus particle production in the body. “A further significant advantage is the extended treatment window compared with standard-of-care therapies,” said Rainer Lichtenberger, Atriva’s CEO.
Moreover, because the virus cannot replace the inhibited human cellular function, there is a much lower risk that resistance will develop. “Furthermore, inhibition of the Raf/MEK/ERK cascade modulates the overwhelming excretion of cytokines and chemokines. Generally, the severity of influenza strongly correlates with the levels of cytokine and chemokine expression,” Planz added.
With influenza hospitalizations and deaths occurring mainly among high-risk groups such as the elderly and those who are chronically ill, but no other therapy approved specifically for these groups, ATR-002 is uniquely positioned to benefit patients at risk of developing serious complications.
New path—new indications
Atriva’s MEK inhibitor has broad efficacy against RNA viruses that require the Raf/MEK/ERK pathway to propagate—many of the viruses that cause severe and potentially life-threatening respiratory diseases, including respiratory syncytial virus and hantavirus.
Among the additional indications for ATR-002 in the company’s development pipeline is hantavirus infection. Hantaviruses are usually spread by rodents and can cause pulmonary problems, hemorrhagic fever and death. Because there is no effective therapy or vaccine, the use of hantavirus as a bioweapon is a potential threat. Having already demonstrated proof of concept, and with up to 60,000 cases of hantavirus syndromes per year in China and around 9,000 in Europe, the company plans to submit an application for US Orphan Drug Development by the end of 2019.
Atriva aims to expand its running Series A/B venture round to a total of €32 million (€6 million already subscribed via a convertible loan). Atriva is very actively pursuing applications for different formats of substantial non-dilutive funding, including the InnovFin scheme of the European Investment Bank, to extend its financial reach. In addition, Atriva strives to foster relations and future partnerships with globally and regionally acting pharmaceutical companies, with a special focus on Asia.
“Atriva’s MEK inhibitor addresses the urgent need for novel, broadly active and efficacious antiviral drugs,” said Lichtenberger. “With its unique advantages over existing therapies, our first-in-class inhibitor is set to revolutionize the treatment of influenza and other severe respiratory viral infections.”