Researchers test drugs to fight coronavirus

According to the WHO, to win it is necessary to attack the virus aggressively and with targeted tactics. Test all suspects, isolate them and take care of those who are contaminated. There is still no proven effective treatment

According to the research division of the World Health Organization (WHO), there are currently 41 vaccine initiatives against Covid-19 under development. However, only one is being tested in humans, representing a hope, albeit distant, for future control of the proliferation of the virus. However, if the vaccine is approved by the competent bodies, it is estimated that its development will take two years. Until an effective vaccine arrives, scientists around the world are conducting clinical tests on drugs that already exist to find out how to treat patients with COVID-19 in severe conditions. And there are some advances. Anecdotal evidence of drugs providing a positive effect in some patients exist, but results are preliminary, and well-designed controlled clinical trials are just now being conducted to test a number of promising therapies that seem to be active against the virus in laboratory experiments.  These drugs work by inhibiting a number of different pathways that are used by the virus to infect and replicate in cells. Drugs currently under investigation include but are not limited to: chloroquine, remdesivir, favipiravir, lopinavir/ritonavir and kevzara.

The drug remdesivir appears to be one of the more promising anti-viral agents being tested in the clinic. After being used successfully on the first patients in the United States, patients in Italy also seemed to improve after taking the Gilead Sciences antiviral. Doctor and researcher André Kalil, who works at the Global Center for Health Security at the University of Nebraska Medical Center, which leads a clinical trial to test the drug, explains that this nucleotide analogue with in vitro antiviral activity against various RNA viruses, including the coronavirus, has also shown in vivo activity in animal models of MERS and SARS. Therefore, this is the drug considered to be the most promising in the attempt to combat the respiratory disease COVID-19, he highlights. The drug was identified by the National Institutes of Health (NIH) as having the greatest potential in relation to other drugs. Remdesivir was also tested recently against Ebola, in which its safety profile was established.

So far, 80 patients have participated in the trial, with half receiving the drug and the other half receiving a placebo. His team should be able to examine the results of the first 100 patients in the next two or three weeks. Asked if early use can influence treatment/cure, the researcher points out that as a general principle, antivirals are more likely to work in the early period of the disease, but the exact period when antivirals will be effective against this new coronavirus still needs to be determined.

Still, according to Dr. Kalil, the lack of evidence regarding safety and efficacy against COVID-19 is the reason for the need for a randomized, controlled study. “Remdesivir is the first drug to be tested in our randomized study. Other medications will be tested after the evaluation of remdesivir”, he points out. Dr. Kalil also points out that there are no drugs that have proven to be effective against COVID-19 so far, as of March 24 2020. Randomized clinical trials are essential if new therapies against COVID-19 are to be discovered. The Brazilian doctor admits that the experimental drug has unwanted side effects and should only be used in patients at risk of death.

Rear Admiral Richard Childs, assistant surgeon general and Clinical Director at the National Heart, Lung, and Blood Institute, at the National Institutes of Health (NIH), served as commanding officer of a team of officers from the U.S. Public Health Service who deployed to Japan in February 2020. This team facilitated the administration of remdesivir to seven critically ill American and Japanese patients diagnosed with COVID-19 from the Diamond Princess cruise ship, all who were hospitalized in Japan. Details of the effectiveness of remdesivir are still unknown, as there is still insufficient data to say whether it can definitely improve the clinical outcome of an adult individual with COVID-19. According to the researcher, although anecdotal reports and observations in patients with COVID-19 who received this drug suggest that it can be effective, we will simply not be sure until the completion of controlled clinical trials.

“The effectiveness of remdesivir is still unknown, it may or may not improve the clinical outcome of an adult individual with COVID-19 under treatment. Human studies are needed to determine the drugs effectiveness. However, pre-clinical laboratory experiments, both in the laboratory and in animals, provide evidence that this drug could have activity in humans who have COVID-19, hence the desire to quickly test this drug in well-designed clinical trials in humans. If the drug is proven to be effective, the goal is to get it approved quickly, so that it is available to as many people with COVID-19 infections as possible”, emphasizes Dr. Childs. Preliminary data using this agent for compassionate use in patients infected with COVID-19 has so far demonstrated a good safety profile, similar to previous studies that established its safety and toxicity profile in healthy volunteers and in patients with Ebola.

“In my opinion, the world that is now struggling with this pandemic can learn a lot from the U.S. Public Health Service COVID-19 mission conducted Japan. There were 14 seriously ill patients, most of them elderly Americans on the Diamond Princess cruise ship with severe COVID-19 pneumonia who were treated by our Japanese brothers and sisters, and were literally pulled from the grave with their excellent, well-coordinated and aggressive care. All four patients who were on ECMO (extracorporeal membrane oxygenation) were weaned from this life support and most have been weaned off mechanical ventilators. None of the 14 patients died and only one patient remains seriously ill and is showing very good signs of improvement. These data bring hope and teach us that aggressive care using conventional equipment in ICUs can be very effective in saving the lives of even the most severely infected patients. While those who received (compassionate use) remdesivir all survived and were amongst the most critically ill, others who did not receive the drug also survived. Therefore, it is impossible to say with certainty what the role of this drug was in the recovery of critically ill patients who received this agent”, he acknowledges.

About remdesivir

• Remdesivir is an experimental antiviral agent that interferes with the ability of RNA viruses to replicate.
• It has been shown to kill a variety of different types of coronavirus in the test tube and in animals infected with different types of coronavirus, including SARS-CoV-2 that has been causing the current pandemic.
• Remdesivir is a broad-spectrum nucleotide prodrug that inhibits RNA activity in a diverse group of RNA viruses, including filoviruses (i.e., Ebola, Sudan, Marburg), paramyxoviruses (i.e., RSV, Nipah, Hendra) and pathogenic coronavirus.
• In mouse infection models, remdesivir had therapeutic efficacy against Severe Acute Respiratory Syndrome (SARS-CoV), and Middle East Respiratory Syndrome (MERS-CoV) (7,8), which are coronavirus relatives of the current pandemic SARS-CoV-2 virus causing COVID-19 infection.
• In a recent non-human primate study, therapeutic remdesivir treatment, initiated 12 hours post inoculation with the MERS-CoV coronavirus, provided clinical benefit with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions.
• These nonclinical in vitro and in vivo data suggest that remdesivir might be useful for the treatment of COVID-19 for which no medical countermeasures are currently approved.
• A multicenter RCT of placebo vs remdesivir for patients infected with COVID-19 has just been initiated in the US and internationally.
• Remdesivir has also been made available to some patients with severe COVID-19 infection through an extended access program.
• In phase I studies, Remdesivir was found to be safe to a dose of 250 mg/kg/day.  The doses being used in the randomized trial are much lower than this dose.

Side effects:

• In general, the side effect profile is very good, most side effects being mild and quickly reversible by stopping the drug. 
• The most common side effects include constipation, heartburn, itching, unusual feelings in the ear, dizziness, loss of appetite, nausea, vomiting, shaking of the leg and arm, headache, loose stool, or upset stomach.
• Transient and reversible elevations in blood liver enzymes can also occur so patients need to have these monitored when receiving the drug.
• Since the drug is cleared via the kidneys, with toxicities being increased in patients with kidney dysfunction, patients must not have severe kidney disease to receive this agent (i.e. GFR must be >30 ml/min.)

Europe has started testing on thousands of patients, including chloroquine, an antimalarial drug. In Brazil, the Ministry of Health made official, on March 25 a position authorizing doctors to use chloroquine/hydroxychloroquine to treat patients hospitalized in serious condition with Covid-19. Minister of Health, Luiz Henrique Mandetta, warned of the risks of serious side effects caused by the drug, an immunomodulator prescribed for cases of malaria and for some autoimmune diseases, such as lupus. The Ministry will distribute 3.4 million units of chloroquine, which is produced in Brazil, among hospitals in the country. Treatment should last a maximum of five days under medical supervision, as there are no conclusive data regarding the effectiveness of the drug.

The study on favipiravir, developed by Fujifilms Toyama Chemical company, was released on March 18 The drug, used for more than 5 years against Influenza, has its use only authorized in Japan, where it is sold commercially under the name of avigan. Chinese medical authorities announced that the drug was effective against the disease and had no side effects. People who had the virus had a result after 4 days of using favipiravir. Patients treated with the drug also showed an improvement in lung function. However, the study had a small sample and was not randomized.

Lopinavir and ritonavir were used in Brazil in the 1980s and 1990s to treat HIV. Lopinavir prevents the formation of Protease, an enzyme responsible for breaking down the protein, while ritonavir is a complementary drug that prevents lopinavir from being destroyed by the liver. The recently published randomized controlled placebo study showed no benefit with lopinavir-ritonavir.

Regeneron Pharmaceuticals and Sanofi announced the start of a clinical trial to evaluate Kevzara (sarilumab) in severely hospitalized patients as a result of infection with the new coronavirus COVID-19. The study will evaluate the effectiveness of adding the use of Kevzara in the usual supportive care, compared to placebo, in up to 400 patients in 16 locations in the United States. The first part of the two-phase study will assess the impact of Kevzara on fever and the patients need for supplemental oxygen. The second part will assess the improvement in long-term results, including reducing the need for mechanical ventilation, supplemental oxygen, hospitalization and death prevention.

Urgent need for effective treatment

There is an urgent need for effective treatment, but the WHO has warned countries against untested treatments. Currently, there is no proven effective treatment against COVID-19 said WHO Director-General, Dr. Tedros Adhanom Ghebreyesus, while praising the energy applied to clinical treatments. The use of drugs without clinical evidence can cause more harm than good and still lead to a shortage of drugs needed for other diseases.

The WHO launched an international test (solidarity trial) capable of generating robust and quality evidence. Small random studies will not give us the answers we need. The more countries that enroll in the study, the faster we will have the results, said the WHO leader. He recalled, however, that these are defensive measures, and recommended an aggressive fight against the pandemic that already affects more than 300 thousand people. “It is necessary to make the population aware to adopt measures such as quarantine and social isolation. To win, we need to attack the virus aggressively and with targeted tactics. Test all suspects, isolate them and take care of those contaminated, concludes the director-general.

Hope for drugs and science

Dr. Childs values the fact that there are many incredible medical scientists exploring literally dozens of different angles to kill this virus, all of which, on paper, look like they could work. He says he is impressed by how quickly we see potential new therapeutic approaches going from the drawing board to the clinic. The researcher points out that a substantial number of the world’s medical scientists and clinical researchers are participating in this fight, including scientists and research teams who do not normally work on infectious diseases, but who have brilliant ideas for targeting different parts of the coronavirus that could be its Achilles heel. “Science and medicine have united the world to fight a common enemy of all humans. Perhaps it is an illusion, but I believe that there is hope that all humanity will be more unified when this battle is over”, he celebrates.

Finally, Dr. Childs notes that in the end, the goal of most of these drugs is to reduce viral load to a level that is no longer harming the organs to buy time for the immune system to take action and eradicate the virus. If you can keep patients with the most severe coronavirus pneumonia alive long enough with supportive care measures including when necessary, ventilators, or as the Japanese demonstrated with ECMO, sooner or later the immune system will figure things out and will eradicate the virus. 

Being aggressive with supportive care alone can also work. Although we do not currently know which drugs will prove to be beneficial in the treatment of this disease, aggressive supportive care can save the lives of the sickest patients infected with the coronavirus.…