Senhwa Biosciences Inc., of Taipei, Taiwan, said casein kinase 2 (CK2) is the right target to aim at when developing a COVID-19 therapeutic treatment. The company’s silmitasertib is the only clinical-stage inhibitor of CK2, a kinase recently identified by researchers as being hijacked by SARS-CoV-2.
The Taiwanese firm is now seeking sponsorship from the U.S. Biomedical Advanced Research and Development Authority to carry out clinical trials in COVID-19 patients. The company said it believes its dual-function silmitasertib, which controls virus replication and inflammation, could be the first CK2 inhibitor for treating patients with moderate COVID-19 infection.
“As a drug developer, the key question is target validation,” Senhwa CEO Tai-Sen Soong said at the BIO Asia-Taiwan conference last week. “You have to ask yourself whether the target you choose is validated for the usefulness of the drug. Otherwise, you kind of shoot arrows blindly.”
The problem with other COVID-19 drug candidates, Soong said, is that they are very much viral-specific, which makes them only efficacious for one virus and unable to address future pandemics.
To address the issue, Senhwa said he believes adopting the host-directed antiviral approach to control virus replication is the way to go, so silmitasertib stands a chance of proving an effective treatment. “CK2 inhibitors are dual-action drugs to inhibit viral replication through the host and to reduce or remove the cytokine storm,” Soong explained.
Silmitasertib’s safety in humans has been validated in clinical trials. To date, it has undergone three phase I trials in cancer patients, and it is in an ongoing phase I and two ongoing phase II studies. It obtained orphan drug designation from the FDA for treating cholangiocarcinoma in December 2016.
The potential of silmitasertib against COVID-19 was first discovered in March, when the Quantitative Biosciences Institute at University of California San Francisco (UCSF) found that the investigational drug displayed strong antiviral activity.
Researchers found that by inhibiting CK2, COVID-19's cellular environment could potentially shift into a more antiviral state. Disrupting CK2 could also promote the formation of stress granules that would lead to inhibiting COVID-19 proliferation.
Nevan Krogan, the director of institute, said they have tested a number of those kinase inhibitors and “some are better than remdesivir,” referring to the antiviral from Gilead Sciences Inc.
The discovery of CK2’s role in fighting COVID-19 was published in Cell on June 28.
COVID-19’s Achilles heel
Using results from the UCSF-led study, Senhwa’s Soong presented more data to support silmitasertib’s potential for combating COVID-19.
CK2 is co-localized with the viral proteins at actin protrusions. Data showed that at 24 hours, infected cells showed CK2 expression along the thin filopodia protrusions, partially co-localized with SAR-CoV-2 N protein.
When the virus infects a cell, it hijacks the CK2 protein and forces the cell to modify its structure. The infected cell produces tentacle-like structures called filopodia on its surface. The growths spread out, and coronaviruses emerge from the tips to prepare to infect neighboring cells.
“In other words, CK2 is involved in the protrusion of filopodia to allow the virus, after replication in the whole cell, to go through this tube to infect neighboring cells. CK2 is actually hijacked by the COVID-19 virus,” Soong explained.
“The virus enters the cell, then cause CK2 to overexpress and allow the virus to go through. If we inhibit CK2 in the cell, the virus will be contained in the whole cell.
“This is the so-called Achilles' heel of COVID-19,” he said. “People realize this is a weakness of COVID-19, so we need to have a drug to inhibit CK2. A lot of companies have a CK2 inhibitors, but they are toxic. It’s not easy to find a nontoxic CK2 inhibitor.”
The Taiwanese drug developer said it believes that in vivo trials conducted in collaboration with various institutions and contract research laboratories will confirm the strong antiviral and anti-inflammatory efficacy of silmitasertib. Soong explained that CK2 inhibition also has the potential to reduce viral replication through stress granule disassembly and type 1 IFN response dysregulation, and to reduce cytokine storm severity by reducing the production of IL-6, IL-8, IL-17 and TNFα.
“The most important [role] in the cytokine storm is the pro-inflammatory IL-6 and TNFα. You’ve got do the whole thing and you cannot just inhibit IL-6. A recent publication shows that IL-6 inhibitor doesn’t work and failed in a recent trial. There are six cytokines involved. If you just block one, it’s not going to do the job,” he said.
The company ultimately hopes to initiate clinical trials with COVID-19 patients, though details of such plans are yet to be announced. Soong said CK2 inhibitors are intended to be the standard of care in reducing progression to critical illness in patients with moderate COVID-19 infection.
“What I’m trying to tell you is that at a moderate stage, there is no drug yet. It’s because when you have a heavy viral load, inflammation has already kicked in. So, if you control inflammation, then you could encourage virus production. If you kill the virus, then inflammation continues. So, you have to be careful,” he explained.
“The CK2 inhibitor is critical because you can have a dual function to control virus and inflammation at the [moderate] stage,” he added.