A low-cost COVID-19 treatment is in works. It is based on a generic drug with anticoagulant properties.
The low-cost COVID-19 treatment is being developed by Covistat, a biopharmaceutical company. The company is repurposing nafamostat, a short-acting anticoagulant, as a therapy for the novel disease. Lab tests showed that the drug could interfere with the life cycle of SARS-CoV-2. But the active ingredient is meant to block host cells, not the virus. An enzyme in these cells could be blocked to disrupt viral replication. The molecular mechanism of nafamostat on SARS-CoV-2 has been described in the journal bioRxiv.
Low-Cost COVID-19 Therapy Being Developed
Remdesivir, an investigational drug, is one of the few medications that demonstrated efficacy against COVID-19. Its effects on SARS-CoV-2 can improve the symptoms to patients and speed up their recovery. However, there are three main challenges in its use clinically. First, its current route of administration is intravenous. This increases the risk of systemic adverse reactions. Second, it is a very expensive drug unproven to treat COVID-19. It can cost a few hundred bucks per vial or a few thousand dollars per treatment course. Its use is due to emergency authorization in select countries. And third, not every COVID-19 patient can get the benefit from remdesivir. Only those with severe and those in critical status under supportive breathing are likely to benefit from the drug.
After acquiring the technology and intellectual property of Mucokinetica, Covistat announced the repurposing of nafamostat, a generic drug used to remedy acute kidney injury and pancreatitis. Based on lab findings, the drug could act as an inhibitor of an enzyme SARS-CoV-2 require to infect human host cells. The drug would intercept and block the enzyme before the viral spike proteins could be primed.
"The Mucokinetica team has dedicated their lives to fighting devastating diseases. Together, we can formulate the safest, most accessible treatment to reduce progression of this powerful virus and help protect against COVID-19, as well as future strains and other seasonal coronaviruses," said Dr. Lynn Kirkpatrick, CEO at Covistat, quoted PR Newswire, a US news distributor.
On March 5, 2020, a paper published in the journal Cell showed the role of an enzyme in SARS-CoV-2's life cycle. Researchers highlighted that SARS-CoV-2 and SARS-CoV require the ACE2 receptor proteins to enter host cells. Once attached to ACE2, an enzyme also found in those cells would prime both coronaviruses. The enzyme is called TMPRSS2 and has been investigated for inhibition.
On July 21, 2020, a paper submitted to bioRxiv described the molecular mechanism of two drugs on TMPRSS2. Both drugs were found with inhibitory properties against the enzyme. A modeling approach showed its potential in limiting the life cycle of the novel coronavirus. Without the required enzyme, the binding to ACE2 would not prime the virus. No priming would lead to zero execution of genetic instructions for viral replication.
TMPRSS2 and Coronaviruses
Research data on SARS-CoV-2 and SARS-CoV pinpointed the significance of spike proteins in infecting host cells. These proteins facilitate the entry to target cells but a primer must exist to enable hijacks. During an engagement with the ACE2 receptor, the cellular enzyme TMPRSS2 primes the spike proteins. Once primed, the virus could start the hijacking process and take over cellular gear.
In the Cell paper, ACE2 could be found among bats and humans, though, bats would be unaffected by coronaviruses. Both species exhibited the enzyme and antibodies to counter the viruses. A clinically-approved inhibitor could interfere with the priming process. This was identified as substantial in SARS-CoV while moderate in SARS-CoV-2. The effect was not limited to the lungs since the receptor could be found in the upper respiratory tract as well.
Furthermore, researchers detected SARS-CoV-2 neutralizing antibodies in SARS patients. Their antibodies might disrupt SARS-CoV-2 and reduce the virus' ability to enter host cells. However, the efficiency of SARS-CoV antibodies against SARS-CoV-2 appeared low. Thus, SARS-CoV resistance would require vaccination against SARS-CoV-2 to obtain maximum protection against COVID-19.
In the bioRxiv paper, in vitro assays were utilized to demonstrate inhibitors of TMPRSS2. Two candidates, camostat and nafamostat, were investigated by researchers. The molecular mechanisms of both drugs against the enzyme were determined via experiments and simulations. Through a model, researchers confirmed that both drugs could inhibit the enzyme linked to SARS-CoV-2's life cycle. But between the two, nafamostat showed better inhibitory properties than camostat.
On the official website of the company, they simplified the mechanism. Without nafamostat, the novel coronavirus binds to the receptor and fuses to the membrane of healthy cells. With nafamostat, the enzyme was prevented from activating the spike protein. From there, SARS-CoV-2 could not instruct the cell to make new copies. Theoretically, this would lower the viral load in a patient due to interfered viral replication process.
Importance of a Low-Cost COVID-19 Therapy
Africa is one of many regions with several low-income countries currently bombarded by COVID-19. In the 199th Situation Report of the World Health Organization of the United Nations, the region reported 848,053 confirmed cases and 15,252 confirmed deaths, as of August 6, 2020. South Africa had the highest confirmed cases at 529,877 and confirmed deaths at 9,298. It was followed by Nigeria with 44,890 cases and 927 deaths, Ghana with 39,075 cases and 199 deaths, Algeria with 33,055 cases and 1,261 deaths, and Kenya with 23,873 cases and 391 deaths. All these numbers confirmed community transmission.
Covistat plans to release nafamostat for COVID-19 in three forms: oral, intranasal, and inhalable. While all forms are more convenient than intramuscular or intravenous, the oral form is the best for covering a wide range of population groups. Oral medications are substantially less expensive to develop and sell in the market. It can make the drug more accessible.
Moreover, oral medicines are easier for logistics. These drugs are often stable while being transported. They also have longer shelf lives compared to other forms. So, hospitals will not have to dedicate resources for special storage.