Promising COVID-19 Therapeutics

SARS-CoV-2, the causative viral agent of the novel coronavirus disease COVID-19, has sparked a global effort for creating prophylactic and therapeutic interventions. The following five companies have released information on upcoming treatments or preventative measures.

1. Gilead — Remdesivir

Remdesivir (GS-5734) is a broad spectrum antiviral nucleotide analogue which has shown promising results as a therapeutic in compassionate-use cases. Currently, it is in Phase 3 clinical trials across Asia and “other countries...with high numbers of diagnosed cases”. Two Phase 3 trials are running concurrently: the first tests the use of remdesivir in severe cases, and the second in moderate cases of COVID-19.

Preliminary non-human primate data suggests that remdesivir may be able to reduce the severity of coronavirus infections, slow viral replication, and protect lung function when given as a prophylactic or after the onset of infection. A study from the NIH Laboratory of Virology found that treatment with remdesivir one day prior to inoculation prevented the onset of MERS and inhibited MERS-CoV viral replication in respiratory tissue. It was also found to be protective against virally-induced lung lesions. When given as a treatment after successful infection with MERS-CoV, researchers reported a clear reduction in clinical symptoms and disease severity.

It is worth noting that this data is from rhesus macaques and the coronavirus MERS-CoV. The data is promising, but this outcome is from a different strain of coronavirus than the novel SARS-CoV-2. All the same, the conserved structural similarity in coronaviruses makes the findings presented here quite valuable.

Remdesivir’s mechanism of action in coronaviruses has recently been elucidated by researchers at the University of Alberta. They determined that the drug targets the RNA polymerase of MERS-CoV. Thus, the efficacy of remdesivir in cases of SARS-CoV-2 is thought to be attributed to a similar method of inhibition. The full article is available from the Journal of Biological Chemistry here.

A separate study at University of North Carolina at Chapel Hill showed that remdesivir was effective and non-toxic in murine and human airway epithelial cell culture models of coronavirus infection, both as a prophylactic and therapeutic (Source).

Until strong causal links can be drawn between remdesivir and the lessening of disease severity, usage of the drug will continue to be on a compassionate-use or investigational basis. As Gilead’s second Phase 3 trial for remdesivir will compare the drug to the standard of care treatment for moderate cases of COVID-19, the results of this trial could give more conclusive evidence that the remdesivir is safe and efficacious in human cases of SARS-CoV-2 infection. Full study information is available from the NIH Clinical Trials page here.

(All studies referenced above acknowledge an affiliation with Gilead Sciences.)

2. Moderna — mRNA-1273

Fig 1. Adapted from U.S. FDA

Moderna Therapeutics is known for its creative approaches to tackling complex challenges to human health. Particularly, Moderna specialises in mRNA prophylactics and therapeutics. (Source)

mRNA-1273 is currently in Phase 1 clinical trials to assess the safety and tolerable dose range in healthy adults. The mRNA within the vaccine codes for the full-length spike (S) glycoprotein which is present on SARS-CoV-2, the causative viral agent of the novel coronavirus disease COVID-19. It is this spike protein which facilitates viral entry into susceptible host cells, making it an attractive target for a vaccine. Although spike proteins are a common feature of coronaviruses (in fact, they are the surface protein which gives the viral family its name), SARS-CoV and SARS-CoV-2 have unique spike proteins, and thus require different therapeutic interventions. These differences in spike proteins may also be a factor in the higher transmission rate of COVID-19 compared to SARS.

More information on the trial (sponsored by the U.S. National Institute of Allergy and Infectious Diseases) can be found here.

3. Regeneron — Antibodies

Previously, Regeneron has used its proprietary technology to create therapeutics for emerging viral outbreaks such as Ebola.

The technology most crucial to these discoveries is VelocImmune®, a novel method by which to create fully human monoclonal antibodies in genetically-engineered mice. These mice are inoculated with the compound of interest and create a series of targeted antibodies, all of which are potential drugs. As a result of these antibodies being fully human, there is less potential for immunogenicity in humans. (Source)

In a press conference earlier this month, Regneron CEO Leonard Schleifer said he hopes the company will have treatment ready for clinical trials by August. Regeneron has already begun collecting antibodies from their human immune system bearing mice. These anti-SARS-CoV-2 antibodies are set to be screened for affinity over the next weeks. (Source)

Having readily accessible fully-human monoclonal antibodies could help slow the spread of coronaviruses by preventing new infections. The antibodies could also potentially be used to treat COVID-19.

For the time being, all of Regeneron’s therapeutics and prophylactics are pre-clinical.

4. Vir Biotechnology — siRNA

Fig 2. Adapted from Medical News Today

Vir Biotechnology and its partners have announced they will pursue RNA interference (RNAi) therapeutics to treat the novel coronavirus COVID-19. (Source)

In conjunction with the pharmaceutical company Alnylam, Vir is developing siRNA which can be delivered directly to the lung and used to treat SARS-CoV-2. siRNA, small interfering RNA, is double stranded RNA about 20 base pairs long. It halts the expression of genes by interfering with complementary mRNA before it can be translated.

As a result of parts of the SARS-CoV-2 genome being made available early on in the outbreak, companies have been able to preemptively begin work on treatments. An in-depth look at the sequences available is here.

Vir is also investigating monoclonal antibodies that could have biological activity against SARS-CoV-2 (Source). They are moving forward with the help of Chinese Biologics company WuXi.

5. Sanofi – Vaccine

Sanofi has joined the U.S. Department of Health and Human Services to develop a novel coronavirus vaccine for the SARS-CoV-2 pandemic. The company has extensive experience in developing vaccines and has partnered the Biomedical Advanced Research and Development Authority (BARDA) in hopes of quickly advancing the vaccine. (Source)

Sanofi’s previous work on SARS vaccines has helped quicken the development of a COVID-19 vaccine. The recombinant DNA platform will be used to re-create the viral surface proteins. From there, the DNA sequence coding for the unique viral antigen will be combined with the proprietary DNA of the baculovirus expression platform. This platform is the foundation of Sanofi’s licensed recombinant influenza product, and can be rapidly scaled up to produce immunogenic compounds. However, nothing is anticipated to hit markets until 2021.

Sanofi is also investigating the potential of currently-licensed drugs for the treatment of COVID-19. At this stage, no therapeutics have progressed to clinical trials.

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COVID-19 (SARS-CoV-2) Resources

23rd May 2022 Paige Dougherty MSc.

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