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COVID-19, Where we are Right Now

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Everything You Always Wanted to Know About Coronavirus (but didn’t know who to ask)

(Note: companies that
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story [desktop version]. This article uses third-party references to provide a
bullish, bearish, and balanced point of view; sources are listed after the
Balanced section.)

The Coronavirus Outbreak

As of March 24th, there were 427,663 people infected with Covid-19 worldwide, and 18,605 have died from the disease. Although the epidemic started in China, the total number of cases is higher outside of China. More countries (Italy, Spain, Germany, and others) are taking extreme measures by closing borders to prevent the spread of the infection. The International Health Regulations Emergency Committee of the World Health Organization (WHO) declared the outbreak a pandemic. On March 13, the President of the United States declared the COVID-19 outbreak a national emergency. Today, there are 44,183 confirmed cases and 544 people have died from the disease (March 24h, 2020).

At present, there is no specific antiviral treatment for COVID-19, and no vaccine is currently available. The treatment is only symptomatic, oxygen therapy represents the primary intervention for patients with pneumonia due to severe infection. Mechanical ventilation may be necessary in cases of respiratory failure refractory to oxygen therapy, whereas hemodynamic support is essential for managing septic shock. 

Exhibit 1: Fact sheet for SARS-CoV-2

Source: CDC, WHO, and WSJ

Exhibit 2: Epidemiological Comparison
of Respiratory Infections

Coronaviruses are single-stranded RNA, enveloped viruses with spike glycoproteins on the envelope. That means the viral genome consists of a strand of RNA (instead of DNA) and each viral particle is wrapped in a protein called envelope. The virus’s genome consists of 30,000 genetic letters (relatively large for a virus). Four structural proteins make up a coronavirus particle: the nucleocapsid, envelope, membrane, and spike (Exhibit 3). The nucleocapsid makes the genetic core, encapsulated in a sphere formed by the envelope and membrane proteins.

Exhibit
3. Coronavirus

 

Source:
Liu C. et al. “Research and Development on Therapeutic Agents and Vaccines for
COVID-19 and Related Human Coronavirus Diseases”, ACS Cent. Sci., March 2020

The virus enters the body through the nose, mouth or eyes by attaching to cells that produce a protein called ACE2. The spike proteins bind to receptors (ACE) on host cells and invade a cell. Similar to other viruses, coronaviruses release the genetic material (RNA) after invading a host cell. The genetic material gets incorporated into the host cell, hijacking its replication machinery to make many copies, which are released infecting other cells. Millions of copies of the virus can be produced from each infected cell. Most Covid-19 infections cause a fever as the immune system fights to clear the virus from the body. In severe cases, the immune system can overreact and begin to attack lung cells. In some cases, Covid-19 infection can lead to acute respiratory dysfunction, and possibly death.

Coughing and sneezing can expel virus droplets onto nearby people and surfaces, where the virus can remain infectious for several hours to several days. Coronavirus has a long half-life on various surfaces as listed in Exhibit 4. The C.D.C. recommends that people diagnosed with Covid-19 wear masks to reduce the release of viruses.  

Exhibit
4. Stability of Coronavirus Infection

Source: This week in virology

An overview of published scientific information was gathered by ACS Cent. Sci. March 2020 (Liu C. et al. “Research and Development on Therapeutic Agents
and Vaccines for COVID-19 and Related Human Coronavirus Diseases”.
The article highlights antiviral strategies to target complex molecular interactions involved in coronavirus infection and replication. Some of agents known to be effective against other RNA viruses including SARS-CoV, MERS-CoV, influenza, HCV, and Ebola as well as anti-inflammatory drugs are or can be repurposed to target coronavirus (Exhibit 5).

Exhibit
5.
Existing Drugs with Therapeutic Potentials for COVID-19 (Drug Repurposing)

a)
Drugs under clinical trials for treating COVID-19 (repurposing). b) Drugs under
clinical trials for other virus-induced diseases. c) Ritonavir is a
pharmacokinetic profile enhancer that may potentiate the effects of other
protease inhibitors due to its ability to attenuate the degradation of those
drugs by the liver enzyme CYP3A4 and thus is used in combination with antiviral
Lopinavir.37 d) An inhibitor of viral entry to host cells. Its direct action on
S protein and ACE2 is yet to be confirmed.

Source:
Liu C. et al. “Research and Development on Therapeutic Agents and Vaccines for
COVID-19 and Related Human Coronavirus Diseases”, ACS Cent. Sci., March 2020

Chloroquine, an antimalarial drug, was shown to be effective in treating coronavirus in China. Chloroquine phosphate, which has been used for more than 70 years, was selected from tens of thousands of existing drugs after drug screening. The medicine has been under clinical trials in China. A fixed dose of the anti-HIV combination, lopinavir?ritonavir, is currently in clinical trials with Arbidol or ribavirin.

Some potential targets, their roles in viral infection, and representative existing drugs or drug candidates that act on the corresponding targets in similar viruses are also summarized in Exhibit 6.

Exhibit
6. Key Proteins and Their Roles during the Viral Infection Process

Source:
Liu C. et al. “Research and Development on Therapeutic Agents and Vaccines for
COVID-19 and Related Human Coronavirus Diseases”, ACS Cent. Sci., March 2020

Identification of potential targets is important for the development of efficacious drugs with high target specificity and/or uncovering existing drugs that could be repurposed to treat SARS-CoV-2 infection. 3CLpro and PLpro are two viral proteases responsible for the cleavage of viral peptides into functional units, this process is essential for virus replication and packaging within the host cells. Thus, drugs that target these proteases in other viruses such as HIV drugs, lopinavir and ritonavir, are currently marketed. RdRp is the RNA polymerase responsible for viral RNA synthesis (another crucial process for viral infections).  Conceivably, the interaction of viral S protein with its receptor ACE2 on host cells, and subsequent viral entry into the cells, may also be a viable drug target. The broad spectrum antiviral drug Arbidol, which functions as a virus-host cell fusion inhibitor to prevent viral entry into host cells against the influenza virus, is also being tested in a clinical trial for the treatment of SARS-CoV-2. The protease TMPRSS2 produced by the host cells plays an important role in proteolytic processing of S protein priming to the receptor ACE2 binding in human cells. Camostat mesylate, a clinically approved TMPRSS2 inhibitor, was shown to block SARS-CoV-2 entry to human cells, indicating its potential as a drug for COVID-19. ACE2 is a potent negative regulator restraining overactivation of the renin-angiotensin system (RAS) that may be involved in the elicitation of inflammatory lung disease. The notion that ACE2 mediates coronavirus invasion is largely accepted; however, it remains unclear how the levels or activities of ACE2, AT1 receptors, and AT2 receptors are altered in coronavirus-induced diseases due to the limited number of studies. It is yet to be determined whether some drugs or compounds that target any of these proteins (e.g., L-163491 as a partial antagonist of AT1 receptor and partial agonist of AT2 receptor) may alleviate coronavirus induced lung injury.

Current Clinical Activities

Rising Pharmaceuticals’s chloroquine phosphate (anti-malarial drug) had demonstrated marked efficacy and acceptable safety in treating COVID-19 associated pneumonia in multicenter clinical trials conducted in China, as stated by the State Council of China news briefing on February 17, 2020. It was claimed that the patients treated with the medicine have shown better indicators than their control groups, fever, improvement of CT images of lungs, and the percentage of patients with negative in viral nucleic acid tests.

Gilead’s
remdesivir
was the first drug to enter the clinic against coronavirus. Remdesivir was initially tested in humans with Ebola virus disease and has shown promise in animal models for MERS and SARS. Two ongoing Phase 3 studies are assessing Remdesivir (that blocks RNA polymerase) for the treatment of COVID-19 in the United States and China.  These randomized, open-label, multicenter studies will have readouts anticipated in April 2020.

Moderna became the second company to enter the clinic to combat coronavirus following Gilead. Moderna is developing an mRNA-based vaccine mRNA-1273 to protect against coronavirus infection. The mRNA codes instruct the body’s cells to synthesize certain proteins from the virus that don’t infect a person but activate an immune response. On March 16, the first patient was dosed with mRNA-1273. The open-label trial will be tested on 45 healthy volunteers between the ages of 18 and 55, according to clinicaltrials.gov over approximately six weeks. The volunteers will be divided into three groups, each of which will receive a different dosage. Results from the Phase 1 trial are expected in June.

Sanofi and Regeneron Pharmaceuticals have started a clinical program evaluating Kevzara (sarilumab) in patients hospitalized with severe COVID-19. Kevzara is an interleukin-6 (IL-6) receptor antagonist approved by the U.S. Food and Drug Administration (FDA) in 2017 to treat adults with moderately to severely active rheumatoid arthritis. The U.S.-based trial is expected to begin in New York, to assess the safety and efficacy of adding Kevzara to usual supportive care, compared to supportive care plus placebo. The multi-center, double-blind, Phase 2/3 trial has an adaptive design. The data is anticipated to readout in April 2020.

Roche and Genentech also initiated a Phase 3 trial of Actemra in hospitalized patients with severe COVID-19 pneumonia in China and Italy. The primary and secondary endpoints of the trial include clinical status, mortality, mechanical ventilation, and ICU variables. Actemra, an interleukin-6 (IL-6) receptor antagonist, was approved by the FDA in 2010 for the treatment of moderately to severely active rheumatoid arthritis (RA) patients.

 

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