A Race Against Time: What we know about therapeutics for COVID-19
By Nicole Pribut, PhD. Dr. Pribut received her PhD in medicinal chemistry from Stellenbosch University in South Africa. She currently works as a post-doctoral researcher in the lab of Dr. Dennis Liotta at Emory University in Atlanta, GA, USA.
Since the SARS-CoV-2 pandemic began in December 2019 in Wuhan, China, COVID-19 has spread throughout the global community with unprecedented speed, resulting in more than 17 million cases and over 675 000 deaths. Yet, we still find ourselves without any available safe and effective vaccines or any approved SARS-CoV-2 specific antiviral treatments.
Faced with surmounting pressure, the global scientific and healthcare communities are pressed to investigate off-label or repurposed medications. However, clinical data regarding efficacy and safety of these medications for COVID-19 patients are lacking. Patients with COVID-19 may be receiving medications that have no real-life clinical benefit and that could cause appreciable harm when used incorrectly.
Figure 1. Evidence network of COVID-19 clinical trials of top 15 interventions. This diagram was developed by Thorlund et al (2020) and made available for open access distribution under the Creative Commons CC-BY license. Original figure and associated article are found here. Nodes represent interventions or intervention groups; the numbers on the lines are the number of clinical trials in which that intervention is included [1]. The associated live Global Coronavirus COVID-19 Clinical Trial Tracker is available here.
Two such drug candidates have garnered significant global media and political attention in the last few months:
chloroquine phosphate (CQ)
hydroxychloroquine sulfate (HCQ)
These drugs have historically been used for the treatment of malaria (CQ and HCQ), lupus erythematosus (HCQ) and rheumatoid arthritis (HCQ) [1]. However, based on early promising clinical evidence for both CQ [2] and HCQ [3], the U.S. Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUA) for CQ and HCQ as off-label treatment options for COVID-19 in hospitalized adults as of May 1st, 2020.
Figure 2. Chemical structures of Chloroquine and Hydroxychloroquine. These and all chemical structure images in this article were created by Dr. Pribut.
The subsequent surge in media hype and misinformation led to serious drug shortages, self-treatment [5] and even fatal overdoses due to cardiac-related adverse effects [6] of these drugs. Recent trials using HCQ for hospitalized COVID-19 patients showed no clinical benefits over a placebo with respect to mortality rate [7] or overall clinical health [8]. One study has even demonstrated increased mortality with high dose chloroquine [9].
As of June 15th, 2020, the United States FDA revoked its Emergency Use Authorizations for both chloroquine and hydroxychloroquine.
To date, a vast number of other repurposed medications are being investigated for the treatment of COVID-19. For information on many of the medications currently listed for clinical trials, please see www.clinicaltrials.gov. This post will focus on two treatment options that are acquiring attention in the scientific community as they are the only medications that have yet shown any real clinical benefit. These medications are dexamethasone and remdesivir.
Figure 3. Dexamethasone. Chemical structure and dexamethasone solution for intravenous injection. Original image of injectable dexamethasone available here by creative commons license.
Dexamethasone is a low-cost corticosteroid (steroid derivative) on the list of essential medicines of the WHO. Some scientists believe it may help minimize inflammatory responses in the lungs [10] and thereby reduce risk of acute respiratory distress syndrome. Just recently, the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial [11], supported by the United Kingdom’s National Institute for Health Research (NIHR), evaluated the effects of dexamethasone in patients hospitalized with COVID-19. In this study, patients requiring mechanical ventilatory support to breathe that received dexamethasone had a lower mortality rate than those receiving only mechanical ventilation. Interestingly, this benefit was NOT observed for COVID-19 patients who did not require mechanical ventilation.
Several countries, including South Africa, now recommend dexamethasone for the treatment of COVID-19.
Another drug garnering plenty of attention is remdesivir, a prodrug of a nucleoside inhibitor of viral RNA polymerases [12] that was originally developed by Gilead Sciences to treat Ebola, MERS and SARS. A phase II trial, ACTT-1 (Adaptive COVID-19 Treatment Trial) [13], reported that remdesivir was partially effective in reducing time-to-recovery in patients hospitalized with severe COVID-19. The reported median time of recovery was 11 days with remdesivir and 15 days with the placebo. Remdesivir had no significant effect on overall mortality, however.
Figure 4. Remdesivir. Chemical structure; original image of capsule available here by creative commons license.
Based on the results of the ACTT-1 study, the US FDA issued an EUA in May 2020 permitting remdesivir use for COVID-19 treatment.
Due to limited supplies, hospitalized patients with severe COVID-19 requiring supplemental oxygen receive priority for remdesivir treatment. Recently, Gilead signed a non-exclusive voluntary licensing agreement with Cipla Ltd and other generics manufacturing companies to allow for the manufacture and distribution of remdesivir in 127 low- and lower-middle income countries, approximately half of which are on the African continent.
We must remember that the SARS-CoV-2 therapeutic landscape is rapidly changing, with a vast number of studies and clinical trials producing sometimes promising and often conflicting results on an almost daily basis. We cannot take every exciting press release at face value but rather must realize that adequate and robust clinical trials are necessary to establish the safety and efficacy of therapeutic agents. Until proven safe and effective, we must restrict use of investigational agents to controlled settings and clinical trials.
Dr. Pribut has no financial involvement or interest in the Bio Africa Marketplace or products mentioned therein or elsewhere within the BioAfrica Innovation Hub websites. Her role in the Scientific Resource Hub does not constitute endorsement or recommendation of specific products or suppliers mentioned within the Bio Africa Innovation Hub websites.
References
Publicly available websites and news articles are linked in the text. Full references for peer-reviewed articles or other sites not publicly accessible are available below.
1. Thorlund, K., et al., A real-time dashboard of clinical trials for COVID-19. Lancet Digit Health, 2020.
2. Rainsford, K.D., et al., Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology, 2015. 23(5): p. 231-69.
3. Gao, J., Z. Tian, and X. Yang, Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends, 2020. 14(1): p. 72-73.
4. Gautret, P., et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents, 2020. 56(1): p. 105949.
5. Abena, P.M., et al., Chloroquine and Hydroxychloroquine for the Prevention or Treatment of COVID-19 in Africa: Caution for Inappropriate Off-label Use in Healthcare Settings. The American Journal of Tropical Medicine and Hygiene, 2020. 102(6): p. 1184-1188.
6. Erickson, T.B., P.R. Chai, and E.W. Boyer, Chloroquine, hydroxychloroquine and COVID-19. Toxicol Commun, 2020. 4(1): p. 40-42.
7. Geleris, J., et al., Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. 2020. 382(25): p. 2411-2418.
8. Cavalcanti, A.B., et al., Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. 2020.
9. Borba, M.G.S., et al., Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). medRxiv, 2020: p. 2020.04.07.20056424.
10. Solinas, C., et al., A critical evaluation of glucocorticoids in the management of severe COVID-19. Cytokine & Growth Factor Reviews, 2020.
11. Group, T.R.C., Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. New England Journal of Medicine, 2020.
12. Eastman, R.T., et al., Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS central science, 2020. 6(5): p. 672-683.
13. Beigel, J.H., et al., Remdesivir for the Treatment of COVID-19 — Preliminary Report. New England Journal of Medicine, 2020.