COVID-19 Frontline Therapeutic Candidates
The speed with which small molecules are being repurposed and new drugs are being tested for the treatment of COVID-19 is unprecedented. As of May 1st, 2020, the U.S. Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUA) for the following drug candidates: hydroxychloroquine/chloroquine and remdesivir. But the safety and efficacy of EUA COVID-19 therapeutics continue to be evaluated. On June 15th, 2020, the FDA pulled the EUA for hydroxychloroquine, and there are still no FDA approved treatments for COVID-19—both important reminders that data and experience cannot be outpaced. As the world continues to seek safe and effective treatments, it’s important to take inventory of our existing knowledge of frontline COVID-19 therapies, beginning with an explanation of FDA regulatory standards.
FDA Approval vs. Emergency Use Authorization (EUA)
In the United States, the FDA is responsible for determining regulatory standards for medical devices, drugs, biological products and vaccines. FDA approval requires substantial evidence that a treatment is effective for its intended use and that the benefits outweigh the risks when the medication is used according to approved labeling.
The regulatory arsenal expands in times of emergency. When action is urgently needed to diagnose, treat or prevent serious disease, Emergency Use Authorizations (EUAs) may be issued. EUAs provide quick access to medical countermeasures that have not yet received FDA approval. EUAs are based on the best available evidence at the time and remain effective until the emergency declaration ends or new evidence prompts revision or retraction of the authorization. It’s important to recognize that the EUA process and standards are not the same as FDA clearance or approval.
Hydoxychloroquine/Chloroquine
EUA
On March 28th, 2020, the FDA issued the first Emergency Use Authorization for a COVID-19 therapeutic agent. This EUA allowed the use of chloroquine phosphate, and its derivative hydroxychloroquine sulfate, for off-label treatment of COVID-19 in hospitalized adults and teens weighing more than 50 kg (110 pounds).
On June 15th, 2020, the FDA revoked this EUA, "based on new information, including clinical trial data results," that led to the conclusion that hydroxychloroquine "may not be effective to treat COVID-19 and that the drug's potential benefits for such use do not outweigh its known and potential risks."
Drug Facts
Hydroxychloroquine and chloroquine belong to the quinoline medication class. They are both FDA approved for the treatment of malaria. Hydroxychloroquine is also approved to treat rheumatoid arthritis and lupus.
These medications are effective immune modulators. They inhibit cytokine production and interfere with antigen processing and presentation by increasing lysosomal pH and blocking toll-like receptors of antigen-presenting cells. They have also been shown to exert direct antiviral effects on several viruses, including flaviviruses, retroviruses and coronaviruses by inhibiting pH-dependent steps of virus replication.
A study conducted in 2005, revealed that chloroquine prevented in vitro replication of SARS-CoV, and anti-SARS-CoV-2 activity has been observed in vitro and in vivo for both chloroquine and hydroxychloroquine.
Retinopathy, gastrointestinal issues and cardiac side effects have been well documented under approved labeling use, but hydroxychloroquine demonstrates 3x more potency in a laboratory setting and is about 40% less toxic than chloroquine, making it the more desirable treatment option.
Efficacy
As data continues to be produced, assessed and published, a growing number of independently conducted trials have reported a lack of significant COVID-19 therapeutic value.
- A randomized control trial of 150 patients in China who were hospitalized with laboratory confirmed COVID-19, and an observational study of 181 patients from French tertiary care centers who had documented SARS-CoV-2 pneumonia recently reported similar findings. The probability of viral clearing by day 28 in patients that received hydroxychloroquine treatment in the Chinese study was 85.4% and 81.3% in the control group. And the survival rate by day 21, without transfer to the intensive care unit (ICU), for patients in the French study was 76% in the treatment group and 75% in the control group. Hydroxychloroquine did not increase the likelihood of virus elimination in patients with mild to moderate COVID-19, and it did not reduce ICU admission or death in patients with more severe illness.
- Another observational study, funded by the National Institutes of Health (NIH) and published in the New England Journal of Medicine, demonstrated that hydroxychloroquine was not associated with an increased or greatly decreased risk of intubation or death in COVID-19 patients hospitalized at a large New York City medical center.
- A controlled clinical trial, conducted by the University of Minnesota and Canada and published in the New England Journal of Medicine, reported that hydroxychlorquine did not prevent COVID-19 infection. 821 patients from across the U.S. and Canada, who had moderate to high risk of exposure to someone with laboratory confirmed, symptomatic COVID-19, were randomized within 4 days of exposure. 11.8% of those treated with hydroxychloroquine and 14.3% of those taking the placebo became ill. Statistical analysis of the difference in infection rates amongst the treatment and control groups determined it was not significant. These findings were reviewed and accredited by infectious disease experts unassociated with the study.
Remdesivir
EUA
On May 1st, 2020, the FDA issued the second Emergency Use Authorization for a COVID-19 therapeutic agent. This EUA allows remdesivir to be administered intravenously for the treatment of COVID-19 in hospitalized children and adults.
Drug Facts
Remdesivir is a nucleoside analog that was originally developed to treat Ebola. It remains an investigational drug, which means there are currently no FDA approved indications for its use. However, remdesivir has been approved for COVID-19 treatment in Japan.
This broad-spectrum, small molecule antiviral drug inhibits RNA-dependent RNA polymerase (RdRp), the virus-encoded enzyme responsible for copying SARS-CoV-2’s genetic code. When remdesivir is metabolized by the host, its active nucleotide form competes with ATP for incorporation into nascent RNA strands. If this substitution occurs, RNA synthesis is prematurely terminated.
Remdesivir demonstrates activity against SARS-CoV and MERS-CoV in animal models and has been shown to significantly reduce clinical disease and lung damage in rhesus macaques infected with SARS-CoV-2. Potential side effects for remdesivir include elevated liver enzymes and infusion-related reactions such as low blood pressure, nausea, vomiting and body temperature imbalances (shivering/sweating).
Efficacy
- A randomized, double-blinded, placebo-controlled trial, recently conducted by the National Institute of Allergy and Infectious Diseases (NIAID), evaluated the efficacy of remdesivir by monitoring disease outcomes of 1,063 hospitalized patients with advanced COVID-19. The study reported that those who received remdesivir recovered 31% faster (11 days) than those who received the placebo (15 days). Additionally, remdesivir was shown to decrease mortality rate from 11.6% to 8.0%.
- A Gilead-sponsored open-label trial recently compared the efficacy of 5-day and 10-day dosing of remdesivir in hospitalized patients with advanced COVID-19. The study reported that 50% of patients receiving the 5-day dosing recovered by day 10, and 50% of patients receiving the 10-day dosing recovered by day 11. Over 50% of the patients in both groups (64.5% in the 5-day dosing and 53.8% in the 10-day dosing) achieved clinical recovery and were discharged by day 14.
Other Notable Therapeutic Candidates
EIDD-2801
EIDD-2801 is a broad-spectrum antiviral drug that inhibits viral replication and operates similarly to remdesivir. A key benefit of this medication is that it’s administered orally and can be prescribed without hospitalization. The FDA authorized EIDD-2801 as an investigational drug in April, but there are no EUAs or FDA approvals for its usage at this time.
EIDD-2801 has demonstrated activity against MERS and SARS-CoV-2 in animals, but its safety and efficacy are still under evaluation in humans. Clinical trials began in late May, and results from the studies are pending.
Favilavir/Avifavir
Favilavir, sold under the brand name Avigan, is yet another broad-spectrum antiviral that inhibits RdRp. This medication has received a significant amount of attention because, although there are currently no FDA approvals for its usage, it has been approved for the treatment of COVID-19 in Italy and China. And Avifavir, the drug’s generic form, has been approved for the treatment of COVID-19 in Russia.
A 25-day, phase 2, partially blinded, cluster randomized controlled trial to evaluate the efficacy of favilavir for the prevention of COVID-19 in 760 participants began in Canada at the end of May. Results of the study have not yet been collected or released. However, preliminary data from a few other studies have indicated a lack of benefit to favilavir (Avigan) against COVID-19.
Suramin
Suramin is an anti-parasitic drug used to treat African sleeping sickness and river blindness that also has broad-spectrum antiviral activity against human immunodeficieny virus (HIV), hepatitis C virus, herpes simplex type-1 virus, Zika virus, dengue virus and chikungunya virus.
Emerging data suggest this drug may be a good candidate for the treatment of COVID-19. A study recently reported that suramin offered full protection against SARS-CoV-2-induced cell death and reduced extracellular viral RNA levels in cell culture. It was determined that antiviral activity occurred during an early step of infection, likely viral binding and/or entry to host cells. Properly controlled clinical trials are still needed to evaluate the efficacy of sumarin for the treatment of COVID-19 in humans.
Looking Ahead
SARS-CoV-2 hit humanity with a vengeance at the end of 2019, and even though we saw it coming, we were inherently underprepared for the fight. Since that time, science has continued to progress. The virus may have had a head start, but efforts to close the gaps in knowledge have been heroic. Hundreds of therapeutic candidates are currently being moved through clinical trials, including repurposed and investigational drugs, convalescent plasma, monoclonal antibodies and other immune modulators (such as IL-6 inhibitors).
To learn more about the development of antiviral therapies, tune in to part 3 of ASM's COVID-19 webinar series titled, "From Remdesivir to Human Convalescent Plasma: Understanding COVID-19 Therapeutic Development." New info is emerging every day, and it’s only a matter of time, data and ingenuity before we find an effective treatment for COVID-19.
