Overview of COVID 19 therapies

Human Viral DiseasesEpidemic Response

Sep 11, 2020

Humanitrack's overview of the latest and coming drug therapies for COVID-19 like Dexamethasone which has reduced mortality by 1/3rd for patients on ventilators, or other therapies like the exciting artificial antibodies like mNb6-tri (AeroNabs).

It would not be an exaggeration to say that the coronavirus affected all of our lives this year, with more than 260 thousand new cases daily (on 1st of September) and over 26 million cases in total (1).  However, while the pandemic is paralyzing the world for a several months now, the ways of treatment still stay unclear, and even the most promising drugs only help the certain groups of patients or require further trials. 

At the present moment, one of the most promising therapies is the small molecule called Dexamethasone. Widely used for the treatment in the UK and Iran (2), Dexamethasone is a cheap and widely used steroid. That type of medicine mimics anti-inflammatory hormones and reduces inflammation, triggered by coronavirus (2, 3).  Dexamethasone can only be helpful with severe symptoms and already receiving oxygen or mechanical ventilation, and might only harm patients with milder symptoms- because on these stages suppressing immune system would not help (2). According to clinical trials, Dexamethasone reduced mortality by about one third for patients on ventilators and  by about one fifth for patients requiring only oxygen (4).

Another treatment that suggests effectiveness is Remdesivir, produced by brand names Veklury {remdesivir for treatment of covid} and Covifor {covifor}.It was originally tested as a medicine against Ebola and Hepatitis C (3).   Remdesivir’s mechanism of action is binding to the viral RNA-dependent RNA polymerase, which results in inhibition of viral replication (5).  Remdesivir was the first drug to get emergency authorization from the FDA for the use against COVID-19 (3) for adults and pediatric patients hospitalized in severe condition (6). The study of efficacy of Remdesivir showed that median recovery time reduced from 15 days to 11 (5), however there is not enough data to evaluate an effect on mortality (3).

Favipiravir  (also known as Avigan, Favilavir or Fabiflu) was approved for treatment of coronavirus in China already in March (7),   as well as  in Russia and India, and  was granted an approval to have phase 2 clinical trial studies in the US by FDA (8). This drug was originally designed in Japan to treat influenza (3) and works similarly to Remdesivir- it prevents replication of viral genome by inhibiting RNA polymerase (9). Clinical trial conducted by Glenmark showed that around 70 percent of the patients receiving Favipiravir recovered by the fourth day of the study, compared to 45 percent in the control group. Some scientists argue that the data on the drug is not very convincing, however with the lack of options or Covid treatment, Favipiravir definitely shows the viral clearance (10). 

Besides antiviral drugs, designed to fight the virus, there are other available therapies. Some of them work by mimicking the immune system.
One of these therapies is the infusion of convalescent plasma. That is plasma collected from the blood people that have already recovered from the disease, and then is transferred to a patient still fighting the illness (11). Basically it is a way to get antibodies to a certain virus, produced by the recovered person’s body, to help a person who has it currently. However, this type of treatment has never been used as widely as it proposed now (12), so its efficacy is still to be determined. The use of convalescent plasma has not been approved by FDA yet, and at the moment is regulated as an investigational product. According to FDA, there are several pathways available for using convalescent plasma for Covid-19, such as clinical trials, expanded access (use for patients with life-threatening coronavirus stage who are not able to participate in clinical trials) and as single patient emergency treatment (13).

As was said above, convalescent plasma is used for treatment because it contains a mix of different antibodies, and it is assumed that some of them can attack the coronavirus. Therefore researchers focused on finding the most potent antibodies against Covid-19 and producing their synthetic copies (3).
Monoclonal antibodies are used as a therapy for decades now, and since them 79 therapeutic antibodies have been approved for treatment of the various diseases (14).  IAVI estimates that over 70 antibody therapies are now under developmwnt to treat or prevent coronavirus (15). Some of the antibodies used against coronavirus are Actemra (Tocilizumab), Avastin (Bevacizumab), Camrelizumab, Gimsilumab, Kevzara (Sarilumab) and many more. A lot of them are IL-6 I inhibitors and have anti-inflammatory effect that aims to reduce lung damage and mortality rate ( Gimsilumab (16), CD24Fc (17), Siltuximab (18 ). Other antibodies are designed to attack SARS-CoV-2 (the virus that causes Covid-19 (19), like LY-CoV555, produced by Eli Lilly (20) and REGN-COV-2, produced by Regeneron Pharmaceuticals (21). 
The main downside of an antibody therapy is it’s cost, that might make it unavailable for poor countries- the median price for antibody therapy in the US is over 15 thousand dollars for a year of treatment (15). 

Hydroxychloroquine and chloroquine were recommended for the treatment of coronavirus by Brazilian authorities. However, there are a lot of doubts on it’s effectiveness, as the drug does not meet the criteria for emergency use authorization (22). Hydroxychloroquine sulfate is FDA-approved to treat lupus and rheumatoid arthritis, and both hydroxychloroquine and  chloroquine are approved for treatmwnt or prevention of malaria, however have no approval for COVID-19 treatment (23). At first it was discovered that both drugs stop replication of coronavirus in cells, but later studies did not confirm that. It neither prevented participants from getting infected nor helped them to get better. Despite unpromising results, clinical trials on chloroquine and hydroxychloroquine are still ongoing (3). 

The researchers designed an artificial coronavirus antibody against SARS-CoV-2 virus (24). The protein called mNb6-tri (“Aeronabs” for an aerosol formulation) constraints the mechanism that allows the virus to infect human cells (25). Moreover, once AeroNabs locks on the virus protein, it doesn’t come off anymore.
AeroNabs is based on nanobodies- immune proteins similar to antibodies that naturally occur in llamas and camels. Due to their small size and simple structure, nanobodies can be mass-produced cheaper than antibodies and also are easier to manipulate in the lab. Besides that they are more stable than the antibodies of other mammals. After finding nanobody the most potent against SARS, the one now called Nb6, the scientific team turned it into a trimer, containing three identical proteins (24). By doing that, the researchers made the tri-fold nanobody fit the contours of the virus precisely and this triple nanobody is 200 000 times more potent than the initial one.
After that the three-part nanobodies were exposed to a series of stress-test, such as high temperatures, being turned into a powder or an aerosol form. These processes are usually damaging to the most proteins, but because of the stability of the nanobodies, antiviral potency remained the same in the aerosol form. Consequently, Aeronabs could be used as a shelf-stable inhaler or nasal spray (25). 

  1. https://www.worldometers.info/coronavirus/#countries

  2. https://www.bbc.com/news/health-53061281

  3. https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html

  4. https://www.who.int/news-room/q-a-detail/q-a-dexamethasone-and-covid-19 

  5. https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/remdesivir/

  6. https://www.fda.gov/media/137566/download

  7. https://www.sciencetimes.com/articles/25053/20200317/favilavir-first-approve-drug-treat-coronavirus.htm

  8. https://www.contagionlive.com/news/fda-clears-favipiravir-covid19-facility-outbreak-prevention-study

  9. https://www.drugbank.ca/drugs/DB12466

  10. https://www.moneycontrol.com/news/business/companies/drug-firms-race-to-launch-favipiravir-as-antiviral-gains-traction-in-mild-moderate-covid-19-treatment-5656091.html

  11. https://www.cedars-sinai.org/blog/what-convalescent-plasma.html

  12. https://www.nytimes.com/2020/04/24/smarter-living/coronavirus-convalescent-plasma-antibodies.html?searchResultPosition=1

  13. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma

  14. https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0592-z

  15. https://www.nature.com/articles/d41586-020-02360-y

  16. https://clinicaltrials.gov/ct2/show/NCT04351243

  17. http://www.oncoimmune.com/product-development/

  18. https://www.thepharmaletter.com/article/small-covid-19-study-shows-encouraging-results-for-eusa-pharma

  19. https://www.who.int/news-room/commentaries/detail/transmission-of-sars-cov-2-implications-for-infection-prevention-precautions

  20. https://investor.lilly.com/news-releases/news-release-details/lilly-begins-worlds-first-study-potential-covid-19-antibody

  21. https://www.nih.gov/news-events/news-releases/clinical-trials-monoclonal-antibodies-prevent-covid-19-now-enrolling)

  22. https://edition.cnn.com/2020/06/16/americas/brazil-hydroxychloroquine-recommendations-fda-intl/index.html

  23. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-reiterates-importance-close-patient-supervision-label-use

  24. https://spectrum.ieee.org/the-human-os/biomedical/devices/covid19-aeronabs

  25. https://www.ucsf.edu/news/2020/08/418241/aeronabs-promise-powerful-inhalable-protection-against-covid-19

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