Tuesday, March 31, 2020

COVID-19: Summary of drugs that are under investigation for use as potential treatment options

SARS -CoV-2 that causes the famous disease, COVID-19, has no FDA approved treatment yet. Researchers around the world are using drugs that have previously demonstrated efficacy against similar virus types clinically or based on their in-vitro activity. Many clinical trials are also underway to demonstrate the most efficacious drug which can be used against this disease. Let's go through them today.

COVID-19: Summary of drugs that are under investigation for use as potential treatment options

1. Remdesivir
- Novel nucleotide analogue
- Originally used for SARS and MERS
- Activity against SARS-CoV-2 in-vitro and against SARS and MERS-CoV both in-vitro and in animal studies
- Recommended dose: 200 mg as a single dose on day 1, followed by 100 mg once daily for a total duration of 5 to 10 days
Read more about Remdesivir

2. Chloroquine/Hydroxychloroquine (HCQ)
- Increases pH (alkalinization) of acidic intracellular vesicles that may lead to  inhibition of endosome-mediated fusion, viral entry and pH-dependent steps in viral replication.
- Originally used for malaria
- Activity against SARS-CoV-2 in-vitro
- In an open-label study of 36 patients use of HCQ (200 mg three times a day for 10 days) vs no treatment showed a higher rate of undetectable RNA in the HCQ arm (12.5 vs 70%)
-  recommended dose: 200 mg 3 times daily for 10 days. Alternative dosing: 400 mg twice daily on day 1 followed by 200 mg twice daily for 4 days or 400 mg twice daily on day 1 followed by 400 mg once daily for 5 days or 600 mg twice daily on day 1 followed by 400 mg once daily for 4 days. Source: UpToDate

3. Tocilizumab
-  Monoclonal antibody against IL-6
-  In a retrospective observational study of 21 patients, the use of tocilizumab and standard of care lead to the resolution of fever in all patients, decrease oxygen need in 16/21 patients, CT improvement, and discharge in 19/21pts
-  Recommended dose: 400 mg single dose

4. Lopinavir-Ritonavir
-  Protease inhibitor
-  Originally used for HIV
-  Activity against SARS-CoV-2 in-vitro and some activity against MERS-CoV in animal studies
-  In a randomized, controlled trial of 199 patients, use of lopinavir-ritonavir (400/100mg)  twice daily for 14 days failed to show a statistically significant difference in outcomes
-  Trial dose: 400/100mg PO q12hr for 5–14 days

Other potential therapies:

1. Azithromycin
-  macrolide antibiotic
-  In an open-label study of HCQ+Azithromycin vs HCQ, 57.1% of patients were virologically cured
2. Sarilumab: IL-6 receptor antagonist
3. Darunavir+cobicistat: Protease inhibitor
4. Emtricitabine+tenofovir: NNRTI+NRTI
5. Ruxolitinib: licensed for use in Myelofibrosis
6. Baricitinib: inhibitor of JAK, licensed for use in Rheumatoid arthritis
7. Sirolimus: mTor inhibitor, licensed for use as anti-rejection post kidney transplant
8. IFN-alpha: licensed for use in hepatitis C and B
9. IFN-beta: licensed for use in multiple sclerosis
10. IFN-gamma: licensed for use in Chronic Granulomatous disease
11. Baloxavir: antiviral-endonuclease inhibitor, licensed for use in acute uncomplicated influenza
12. Favipiravir: antiviral-RNA polymerase inhibitor, licensed for use in Influenza
13. Umifenovir (Arbidol): antiviral
14. Nitazoxanide: antiviral
15. Anakinra:  IL-1 receptor antagonist
16. Bevacizumab: monoclonal antibody against VEGF
17. Brilacidin: host defense peptide mimetic
18. Disulfiram: blocks alcohol oxidation
19: Eculizumab: monoclonal antibody against
20. Vitamin C: an ongoing trial with high dose Vitamin C
21. Sofosbuvir: Antiviral, licensed for use in hepatitis C
22. Niclosamide: Antihelminthic
23. Nelfinavir: Protease inhibitor
24. Galidesivir: Nucleoside RNA polymerase inhibitor
25. XueBiJing: Chinese Herbal medication

Written by Devi Bavishi
Illustration by Anagha Rao

References:
  1. Erin K McCreary, PharmD, BCPS, BCIDP, Jason M Pogue, PharmD, BCPS, BCIDP, on behalf of the Society of Infectious Diseases Pharmacists, COVID-19 Treatment: A Review of Early and Emerging Options, Open Forum Infectious Diseases, ofaa105 doi: 10.1093/ofid/ofaa105
  2. Landscape analysis of therapeutics as 21st March 2020. (2020). Retrieved 31 March 2020, from https://www.who.int/blueprint/priority-diseases/key-action/Table_of_therapeutics_Appendix_17022020.pdf
  3. Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020 DOI:10.1016/j.ijantimicag.2020.105949.
  4. Cao  B, Wang  Y, Wen  D,  et al.  A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19.  N Engl J Med. 2020. doi:10.1056/NEJMoa2001282
  5. Gautret, P., Lagier, J., Parola, P., Hoang, V., Meddeb, L., & Mailhe, M. et al. (2020). Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal Of Antimicrobial Agents, 105949. doi: 10.1016/j.ijantimicag.2020.105949
  6. XU X, HAN M, LI T et al.: Effective treatment of severe COVID-19 patients with tocilizumab. ChinaXiv 2020

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