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Researchers have been testing several drug combinations to fight off SARS-Cov-2 infection. Daniel Grizelj/Getty Images
  • There is an urgent need for effective and readily available antiviral therapies to treat COVID-19.
  • A new study has found that a drug combination involving the antivirals interferon-alpha (IFN-α) and nafamostat effectively combatted SARS-CoV-2 infection.
  • The drug combination inhibited SARS-CoV-2 replication in cell culture and animal studies at lower concentrations than the individual drugs.
  • The higher efficacy of the IFN-α-nafamostat combination at lower concentrations may help reduce side effects and improve patient outcomes.
  • The drug combination produces its antiviral effect by inhibiting a host enzyme instead of a viral protein, potentially reducing the risk of drug resistance.

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Although high-income nations have achieved high vaccination rates, the unequal distribution of COVID-19 vaccines has left low-income countries struggling to immunize their populations. This disparity in access to vaccines is highlighted by the fact that only 2.3% of individuals in low-income countries have received at least a single dose of the vaccine.

Until vaccines become available to the rest of the global population, effective antiviral treatments against COVID-19 could help reduce fatalities and even hospitalizations. Furthermore, antiviral treatments could play a pivotal role in the pandemic, especially in the event of the emergence of SARS-CoV-2 variants resistant to vaccines.

Although the Food and Drug Administrations (FDA) has approved some antiviral treatments, these treatments have several shortcomings. These limitations include the need for intravenous administration, limited availability, high costs, and therapeutic effects confined to a narrow time window.

A recent study published in the journalViruses shows that a combination of two antiviral drugs, interferon-alpha (IFN-α) and nafamostat, was effective in combating SARS-CoV-2 infection.

“Here, we demonstrated that combinations of IFN-α with nafamostat appear to be effective for the treatment of SARS-CoV-2 in cell culture and small animals. Moreover, the combinational therapies required lower drug concentrations than monotherapies, reducing side effects,” said the study’s lead author Dr. Denis Kainov, a professor at the Norwegian University of Science and Technology.

“Therefore, development of IFN-based combinations may lead to practical therapeutic options, especially for newly diagnosed SARS-CoV-2 positive [people] who have yet to develop severe disease.”

In contrast to the rapid development of COVID-19 vaccines, antiviral treatments tested against COVID-19 have shown limited success so far.

Currently available treatments, such as remdesivir and monoclonal antibodies, are effective only during the early stages of COVID-19. Furthermore, there is mixed evidence about the effectiveness of remdesivir, whereas monoclonal antibodies have shown limited efficacy against new SARS-CoV-2 variants.

The limited success of single-drug therapies, also known as monotherapies, in treating people with COVID-19 has led researchers to use a combination of these drugs.

Combination therapies have been deployed against various infectious diseases due to their similar or better efficacy against the infectious agent at lower doses than the individual drugs. In other words, using two or more drugs can produce a synergistic effect, where the effect of the drug combination is greater than the sum of the effect produced by the individual drugs.

The use of lower drug doses in combination therapies can result in milder and fewer side effects. In addition, combination therapies can also reduce the risk of the emergence of drug-resistant variants.

Previous human studies had suggested that IFN-α alone and nafamostat in combination with another antiviral could be effective in treating COVID-19.

Consequently, the researchers investigated the antiviral effects of the IFN-α-nafamostat combination against SARS-CoV-2.

Interferons, including IFN-α, belong to a class of signaling molecules called cytokines that immune cells release during a viral infection.

During a SARS-CoV-2 infection, IFN-α helps recruit immune cells to the lungs and activate them, contributing to the antiviral response. IFN-α also stimulates the secretion of other cytokines that amplify the immune response, thus limiting SARS-CoV-2 replication.

In the present study, the researchers used pegylated IFN-α, a chemically modified form of IFN-α that lasts longer in the body than the unmodified form. Pegylated IFN-α, sold under the brand name Pegasys, is used in combination with other antivirals to treat hepatitis B and C.

On the other hand, nafamostat is a drug used for the treatment of acute pancreatitis and as an anticoagulant to prevent blood clots.

“Of all drugs with potency data from laboratory studies using human cell lines against SARS-CoV-2, nafamostat appears to be the most potent and may be the only drug where blood concentrations almost always exceed levels required to stop the virus from replicating. It is also likely that nafamostat will reach high levels in the lungs where the SARS-CoV-2 virus causes so many of its problems. Nafamostat also has a favorable safety profile,” explained Dr. Kainov.

Dr. Kainov continued, “The anti-blood-clotting properties of nafamostat may be a further potential advantage of this drug as micro clots in the vascular system can be complications of COVID-19. Nafamostat has been clinically studied in small case series of patients hospitalized with COVID-19, and there are few planned randomized controlled trials.”

The researchers first compared the efficacy of the Pegasys-nafamostat combination with the drugs as monotherapies in laboratory cultures of human lung cells. They measured the ability of the drug combination and the individual drugs to inhibit SARS-CoV-2 replication and prevent the death of the cultured human lung cells due to the infection.

The Pegasys-nafamostat combination had comparable efficacy against the virus at low concentrations as the individual drugs at much higher concentrations.

The researchers then tested the combination in hamsters inoculated with SARS-CoV-2. Three days of treatment with the combination resulted in significantly lower viral RNA levels in the lungs than untreated hamsters in the control group.

The Pegasys-nafamostat combination had an additive effect on viral RNA levels. In other words, this effect of the combination treatment on viral mRNA levels was approximately close to the sum of the effect expected with the two individual drugs.

Combination therapy with Pegasys and nafamostat also resulted in increased expression of genes encoding cytokines involved in the antiviral response.

The researchers also investigated the potential mechanism for the synergistic effects of the Pegasys-nafamostat combination. Their previous research had shown that IFN-α increases the expression of the Serpin E1 gene in human cells.

Furthermore, other studies have shown that both nafamostat and Serpin E1 inhibit the expression of the enzyme transmembrane protease serine 2 (TMPRSS2), which plays a critical role in viral replication.

Hence, the researchers investigated whether the inhibition of TMPRSS2 mediated the synergistic actions of the Pegasys-nafamostat combination.

Similar to the previous experiment, the researchers treated SARS-CoV-2-inoculated hamsters with a combination of Pegasys, nafamostat, and a Serpin E1 inhibitor for 3 days. The inclusion of the Serpin E1 inhibitor eliminated the impact of Pegasys, inhibiting viral RNA levels in the lungs to a similar extent as nafamostat alone.

These results indicate that the activation of Serpin E1 plays a central role in mediating the antiviral effects of Pegasys. Moreover, these results suggest that the inhibition of TMPRSS2 possibly mediated the synergistic effects of Pegasys and nafamostat.

Identifying TMPRSS2 inhibition as the potential mechanism for synergistic effects of the Pegasys-nafamostat combination could lead to the development of other drug combinations that target this enzyme.

Significantly, SARS-CoV-2 and certain influenza viruses rely on TMPRSS2 for entry into human cells. Since the antiviral effects of the Pegasys-nafamostat combination are due to the inhibition of a host or human protein, it might reduce the likelihood of the emergence of drug-resistant variants.

This is unlike the action of other antiviral drugs that target viral proteins. Antiviral drugs that target viral proteins are more likely to result in drug resistance due to mutations in the viral protein.

Dr. Jordan Feld, a clinical scientist at Toronto General Hospital Research Institute, told Medical News Today:

“The concept is certainly attractive in that this approach would likely be effective irrespective of the viral sequence, which is quite relevant with the continuing emergence of new variants of concern. That being said, it would be helpful to confirm the mechanism somewhat more convincingly and to understand how specific the mechanism is.”

“Usually, resistance is not an issue with interferons because of the multi-pronged attack that interferon drives. However, if the antiviral effect, in this case, is very specific to TMPRSS2 activity, it is possible that resistance could emerge. Given that both drugs can be given to people, it would certainly be reasonable to consider a pilot trial of this combination,” Dr. Feld continued.

Dr. Kainov indicated that they intend to conduct clinical trials involving the drug combination in the future.

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