Candidate Therapeutics for COVID-19: Current Scenario and Future Possibilities

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The current COVID-19 (SARS-CoV-2) pandemic has prompted unprecedented public health measures to contain the spread of the virus. While countries across the world have put in place stringent regulations to ensure physical distancing, effective therapeutics targeted towards COVID-19 are being evaluated.

Karishma Kaushik (Assistant Professor and Ramalingaswami Re-entry Fellow, Institute of Bioinformatics and Biotechnology, Savitribai Phule University) addresses five important questions about the current status of therapeutics for COVID-19 infection, and the possibilities for future therapeutic options.

Q1. Is there an effective treatment for COVID-19?

A: As of now, there are no medicines, therapeutics, drugs or other agents approved for the treatment or prevention of COVID-19. This means that there are no drugs approved for use that specifically target the virus. 

This does not mean that patients with COVID-19 cannot be treated for symptoms related to the infection or that they cannot recover from the infection. A majority of patients will recover based on the ability of their natural defense (immune) system to fight the viral infection, along with supportive treatment measures. 

Further, this is also not the first or only viral infection with no specific treatment. For example, the SARS virus outbreak of 2003 had no specific therapies that could target the virus. The SARS epidemic was subsequently contained by interrupting the chain of human-to-human transmission, using stringent surveillance, quarantine and public health measures.
 

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Natural immunity, along with supportive treatment measures, help the majority of patients recover from COVID-19 infection. 

Q2. How are COVID-19 patients currently being treated?

A: Given that there is no approved drug or medication that directly targets SARS-CoV-2, patients are currently being treated with supportive measures that are aimed at relieving their symptoms. COVID-19 causes an infection of the respiratory system, and patients commonly report symptoms of fever, cough, tiredness, and difficulty in breathing (which can be severe in certain cases). Other symptoms include sore throat, headache, and loss of sense of smell.

Supportive measures aim at ‘symptomatic treatment’, such as medication to reduce fever, anti-inflammatory drugs to alleviate bodyache, and in severe cases, the use of oxygen and ventilators to enable breathing.

Q3. Can we use antibiotics against COVID-19?

A: Antibiotics act against bacteria, and are therefore used to treat bacterial infections. Antibiotics act by interfering with or inhibiting certain structures and processes that are unique to bacteria. Notably, these features are not present in viruses. For example, critical features such as the structure of the outer coat, replication strategies, and relevant proteins and enzymes, differ in bacteria and virus. So, unfortunately, antibiotics are not effective against COVID-19. 

However, due to the damage caused by COVID-19 infection to the cells of the respiratory system, particularly the lungs, patients may be susceptible (in severe cases) to additional or superimposed bacterial infections (of the lung), which could require treatment with antibiotics.
 

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What happens to the cells of the respiratory system in a SARS-CoV-2 infected patient?

Q4. How far has scientific and medical research progressed in evaluating and developing COVID-19 treatments?

A: Novel drug development is a very long process, and can often take years, even up to decades. This is because the process involves testing efficacy, safety, dosage regimens, and side effects of the candidate therapeutic. These studies start in the laboratory, after which potential leads are taken up for animal testing, and subsequently followed up with human clinical trials. 
 

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The typical stages involved in the development of a drug.

One approach to COVID-19 treatment is to evaluate the potential of existing medications. This ‘repurposing’ of existing medications could cut short the long period of development of a completely new drug, potentially fast-tracking a medication for approval and use for COVID-19. This is because several aspects of these drugs, such as their mechanisms of action, side effects, safety profiles, and recommended dosage regimens, have already been studied, albeit in the context of other applications. This would still require that the range of potential drugs be systematically evaluated against COVID-19. This has to be done via highly regulated clinical trials on groups of COVID-19 patients. 

Broadly, selection of candidate drugs starts with an analysis of the proteins and targets of SARS-CoV-2, and then finding known therapeutic agents that target these viral components, or by evaluating agents shown to be effective against the virus in the laboratory. It is also important at this stage to make sure that the selected drugs are available, accessible, and approved for use. Multiple clinical trials are underway to evaluate drug regimens for COVID-19. They include the use of an experimental antiviral drug remdesivir, the antimalarial drug chloroquine, a combination of two anti-HIV drugs, and these two aforementioned antiretroviral drugs along with interferon, a factor that modulates the immune system. 

Q5. What is the current status of these clinical trials, and how promising are they?

These clinical trials are currently underway, and this is a rapidly evolving situation. However, two agents, Remdesivir and Chloroquine, have received much attention, and this is a round-up of the key results known so far.

Remdesivir: The experimental drug Remdesivir works by blocking replication of the virus, and has shown efficacy in the lab against coronaviruses, including COVID-19. Preliminary data shows that the drug may help patients with severe forms of COVID-19; patients given the drug required less oxygen and ventilation support. However, the limited clinical study did not compare patients with control subjects (who were not given the drug) and did not provide evidence that the drug actually reduced viral loads in the patients. In a separate clinical trial in Hubei (China), Remdesivir was administered to patients across ten hospitals. The scientists report that the drug did not significantly alleviate the health of COVID-19 patients, although treated patients showed a numerically faster time to improvement. Given that the number of subjects was low (237 patients, of which 158 received remdesivir), this holds potential for further studies.  

Chloroquine: The antimalarial drug chloroquine (hydroxychloroquine) is under investigation in clinical trials for its ability to treat and prevent infection with COVID-19, before and after exposure to the virus. In a study that was published in 2005, chloroquine was shown to have antiviral effects against SARS-CoV infection in the lab, where it prevented the spread of the virus in cell culture. 
 

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Remdesivir and Chloroquine are being investigated as potential therapeutic agents for the COVID-19 disease. 

The drug has recently been evaluated in clinical trials involving humans, and there have been variable reports about the efficacy of this drug, with moderate effects of removal of the virus and reduction of fever. However, the studies were done with small groups of patients. Additionally, in a few reports, other antiviral and anti-inflammatory drugs were also given along with these antimalarial drugs, making it difficult to clearly demarcate the effects of chloroquine or hydroxychloroquine. In any case, the effects of chloroquine on SARS-CoV-2 will likely be very different from its mechanism of action against the malarial parasite (again because of inherent differences in the structures of the two types of microbes). 

It is evident that while fast-tracking research and clinical trials in the search for treatment regimens for COVID-19 is the right step, the analysis of experimental drugs so far has revealed inconclusive results. They are, at best, moderately promising. Further investigations will be needed to provide more information on the applicability and efficacy of drugs for COVID-19.

Illustrations: Samhitha Kottamasu