Investigational Drugs, Pipeline Vaccines Are Evolving

Editor's Note: The FDA revoked Emergency Use Authorization for chloroquine and hydroxychloroquine on June 15, 2020, and no longer recommends related dosing regimens for treatment of COVID-19. This article was printed in Pharmacy Times prior to the revocation.

Although there are no FDA-approved medications for treating coronavirus disease 2019 (COVID-19), more than 405clinical studies are underway to evaluate potential treatments, according to a search of ClinicalTrials.gov.¹

In April, the National Institutes of Health (NIH) published treatment guidelines for managing patients with COVID-19 based on disease severity, and recommendations will be updated as new evidence becomes available.² Pharmacists practicing in community and hospital settings play a vital role as part of the frontline health care team in managing patients with COVID-19 by staying up-to-date with the latest drug information.

COVID-19 Treatment Guidelines

There is insufficient evidence to recommend for or against antiviral or immunomodulatory therapies in patients with mild, moderate, or severe COVID-19, according to the NIH guidelines.²

Patients with mild COVID-19 symptoms without shortness of breath can be managed in an ambulatory setting or at home through telemedicine consults.

Those with mild symptoms and other health conditions should be monitored closely, as symptoms can progress. Patients with moderate COVID-19 should be admitted to the hospital because pulmonary disease can progress quickly. Individuals who may have bacterial pneumonia or sepsis should receive empiric antibiotic treatment for community-acquired pneumonia and be reassessed daily. Patients with severe COVID-19 symptoms should be hospitalized and receive oxygen therapy and empiric antibiotics if bacterial pneumonia or sepsis are suspected. Outside of clinical trials, the guideline panel recommends against using lopinavir/ritonavir or other protease inhibitors for COVID-19 treatment, because of negative study results.²

Chloroquine and hydroxychloroquine (Plaquenil) have gained much media attention and controversy for the treatment of COVID-19, especially because of the risks of heart-related adverse effects (AEs).³

Insufficient evidence is available to recommend for or against their use, according to the NIH guidelines.²

Additionally, the FDA recently issued a drug safety communication emphasizing the importance of using chloroquine or hydroxychloroquine (whether alone or in combination with azithromycin) for COVID-19 only in a clinical trial setting or for treating certain hospitalized patients, because of the risk of heart rhythm problems, such as QT prolongation.³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society recently released guidance regarding possible serious health risks associated with azithromycin and hydroxychloroquine and recommended baseline evaluations, drug interaction assessments, and monitoring.⁴ The NIH also does not recommend using the combination of hydroxychloroquine and azithromycin, because of potential toxicities, unless it is part of a clinical trial.²

The FDA issued an emergency use authorization (EUA) for the use of chloroquine and hydroxychloroquine for the treatment of hospitalized adolescent and adult patients with COVID-19 who weigh 50 kg or more and who are unable to participate in a clinical trial.⁵ The dosage of hydroxychloroquine recommended by the EUA is 800 mg on the first day of treatment, followed by 400 mg daily for 4 to 7 days of total therapy based on clinical evaluation.⁶ Chloroquine’s EUA recommends 1 gram on day 1, followed by 500 mg daily for 4 to 7 days of total treatment based on clinical evaluation.⁷

Evidence suggests that patients with COVID19 may have an increased risk of venous thromboembolism (VTE) characterized by elevated D-dimer and fibrinogen levels, which is being studied further.⁸ All hospitalized patients with COVID-19 should receive VTE prophylaxis with low-molecular-weight heparin or fondaparinux (Arixtra). Patients with severe COVID-19 may require higher doses.⁸

Investigational DrugsRemdesivir

Remdesivir is an intravenous (IV) drug with broad antiviral activity that Gilead Sciences is studying for the treatment of COVID-19. The manufacturer has been providing emergency access to the drug for qualifying patients with severe COVID-19 who are unable to enroll in ongoing clinical trials, as part of individual compassionate-use protocols.⁹ Results of a cohort study were published that examined compassionate use, in which patients received a 10-day treatment of remdesivir: 200 mg IV on day 1, followed by 100 mg for the remaining 9 days of therapy. Fifty-three patients had data analyzed (7 lacked posttreatment data, and 1 had a dosing error), and clinical improvement was seen in 68% of patients.⁹ The most common AEs were diarrhea, hypotension, increased hepatic enzymes, rash, and renal impairment. Twelve patients (23%) experienced serious AEs, which included acute kidney injury, hypotension, multiple-organ-dysfunction syndrome, and septic shock. The results are promising, but study limitations include short follow-up duration, that it lacked a control and was not randomized.⁹

Results from a double-blind, placebo-controlled, randomized trial in China showed that remdesivir was not associated with statistically significant clinical benefits.¹⁰ Preliminary results from the first trial launched in the United States by NIH have been released; it evaluated remdesivir in a controlled, randomized trial involving 1063 patients. Study participants who received remdesivir had a 31% faster recovery than those who received placebo (P <.001).¹¹ Additionally, Gilead announced topline results from the open-label phase 3 SIMPLE trial, which showed similar efficacy for 5- and 10-day treatment courses of remdesivir for patients with severe COVID-19.¹² Based on positive results from the NIH and SIMPLE studies, the FDA issued an EUA for remdesivir for the treatment of suspected or laboratory-confirmed severe COVID-19 in hospitalized adults and pediatric patients.¹³ Results from the second SIMPLE trial evaluating remdesivir in patients with moderate COVID-19 are expected in May 2020.¹²

Azithromycin, Chloroquine, and Hydroxychloroquine

The combination of azithromycin and hydroxychloroquine for the treatment of COVID-19 was examined in an observational, nonrandomized study in France that received a lot of attention, but data were limited; the study included a relatively small number of patients, with many of those considered to be at low risk.¹⁴ The efficacy and safety of hydroxychloroquine for the treatment of COVID-19 will be further evaluated in the phase 3, multicenter, placebo-controlled, randomized ORCHID study.¹⁵ The results of a new retrospective study published in medRxiv showed that hydroxychloroquine increased overall mortality in hospitalized patients with COVID-19.¹⁶

Chloroquine studies are also underway in China and other countries, as there is limited evidence regarding its effectiveness for COVID-19. One phase 2b randomized clinical trial compared high-dose with low-dose chloroquine in 81 patients with severe COVID-19 in Brazil.¹⁷ The preliminary analysis showed that the higher-dose group had more AEs and fatalities, leading to the recommendation that the higher dose should be avoided in patients.¹⁸

Other investigational drugs are also being studied for COVID-19 (Table).

Vaccine Candidates on the Horizon

Vaccine clinical trials have begun, but none will likely be available for at least another 12 to 18 months.¹⁹ The biotechnology company Moderna Inc is evaluating their vaccine mRNA-1273 in a phase 1 trial, which is the first investigational vaccine study for COVID-19.²⁰ The second round of injections in healthy volunteers has begun, and Moderna Inc said that it submitted an investigational new drug application for a phase 2 study.^21,22 A variety of other potential vaccines are in various stages of development. The NIH recently announced the planned Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership.²³ Goals of ACTIV include prioritizing treatment and vaccine candidates, rapidly responding to COVID-19 and future pandemics, and streamlining clinical trials.²⁴

Jennifer Gershman, PharmD, CPh, is a drug information pharmacist and Pharmacy Times contributor who resides in South Florida.

REFERENCES

• National Institutes of Health; US National Library of Medicine. COVID-19 treatment. ClinicalTrials.gov. Accessed April 29, 2020. http:// clinicaltrials.gov/ct2/results?recrs=&cond=COVID-19+treatment&term=&cntry=&state=&city=&dist=
• COVID-19 treatment guidelines. National Institutes of Health. Updated May 12, 2020. Accessed May 15, 2020. https://www.covid19treatmentguidelines.nih.gov/introduction/
• FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. FDA. Published April 24, 2020. Updated April 30, 2020. Accessed May 12, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-orchloroquine-covid-19-outside-hospital-setting-or
• Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for drug interactions on QTc in exploratory COVID-19 (coronavirus disease 2019) treatment. Circulation. Published online April 8, 2020. doi:10.1161/ CIRCULATIONAHA.120.047521
• Re: request for Emergency Use Authorization for use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of 2019 coronavirus disease. FDA. Published March 28, 2020. Accessed April 26, 2020. https://www.fda.gov/ media/136534/download
• Fact sheet for health care providers: emergency use authorization (EUA) of hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of COVID-19 in certain hospitalized patients. FDA. Published April 27, 2020. Accessed May 12, 2020. https://www.fda. gov/media/136537/download
• Fact sheet for health care providers: emergency use authorization (EUA) of chloroquine phosphate supplied from the strategic national stockpile for treatment of COVID-19 in certain hospitalized patients. FDA. Published April 27, 2020. Accessed May 12, 2020. https://www.fda. gov/media/136535/download
• COVID-19 and VTE/anticoagulation: frequently asked questions. American Society of Hematology. Updated April 17, 2020. Accessed April 27, 2020. http://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation
• Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. Published online April 10, 2020. doi:10.1056/NEJMoa2007016
• Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. Published online April 29, 2020. doi:10.1016/S0140- 6736(20)31022-9
• NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19 News release. National Institutes of Health. Published April 29, 2020. Accessed April 29, 2020. https://www.nih.gov/ news-events/news-releases/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19
• Gilead announces results from phase 3 trial of investigational antiviral remdesivir in patients with severe COVID-19. News release. Gilead. Published April 29, 2020. Accessed April 29, 2020. https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19
• Coronavirus (COVID-19) update: FDA issues emergency use authorization for potential COVID-19 treatment. News release. FDA. Published May 1, 2020. Accessed May 4, 2020. https://www.fda.gov/news-events/ press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment
• Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949. doi:10.1016/j. ijantimicag.2020.105949
• NIH clinical trial of hydroxychloroquine, a potential therapy for COVID-19, begins. News release. National Institutes of Health. April 9, 2020. Accessed April 28, 2020. https://www.nih.gov/news-events/ news-releases/nih-clinical-trial-hydroxychloroquine-potential-therapy-covid-19-begins
• Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. medRxiv. Published online April 23, 2020. doi: 10.1101/2020.04.16.20065920
• Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease (ORCHID). ClinicalTrials. gov. Updated April 24, 2020. Accessed April 28, 2020. https://clinicaltrials.gov/ct2/show/NCT04332991
• Borba MGS, Val FFA, Sampaio VS, et al; CloroCovid-19 Team. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857. doi:10.1001/jamanetworkopen.2020.8857
• WHO Director-General’s opening remarks at the media briefing on COVID-19 — 27 March 2020. World Health Organization. Published March 27, 2020. Accessed April 28, 2020. https://www.who.int/dg/speeches/ detail/who-director-general-s-opening-remarks-at-the-media-briefingon-covid-19---27-march-2020
• NIH clinical trial of investigational vaccine for COVID-19 begins. News release. National Institutes of Health. March 16, 2020. Accessed April 28, 2020. https://www.nih.gov/news-events/news-releases/ nih-clinical-trial-investigational-vaccine-covid-19-begins
• Weise E. Doctors start giving second round of shots to volunteers in Seattle COVID-19 vaccine trial. USA Today. April 22, 2020. Accessed April 28, 2020. usatoday.com/story/news/2020/04/22/second-round-shotsfirst-coronavirus-vaccine-test-start/3008506001/
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• Borrell B. New York clinical trial quietly tests heartburn remedy against coronavirus. Science. April 26, 2020. Accessed May 13, 2020. https://www.sciencemag.org/news/2020/04/new-york-clinical-trial-quietly-tests-heartburn-remedy-against-coronavirus