Coronavirus Disease 2019 (COVID-19) Treatment & Management

Investigational Drugs and Biologics

No drugs or biologics have been proven to be effective for the prevention or treatment of COVID-19. Numerous antiviral agents, immunotherapies, and vaccines are being investigated and developed as potential therapies. Searching for effective therapies for COVID-19 infection is a complex process. Gordon et al identified 332 high-confidence SARS-CoV-2 human protein-protein interactions. Among these, they identified 66 human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and/or preclinical compounds. As of March 22, 2020, these researchers are in the process of evaluating the potential efficacy of these drugs in live SARS-CoV-2 infection assays. [48] Examples of prospective treatments are discussed below.

Antiviral Agents

Remdesivir

The broad-spectrum antiviral agent remdesivir (GS-5734; Gilead Sciences, Inc) is a nucleotide analog prodrug. It has been shown to inhibit replication of other human coronaviruses associated with high morbidity in tissue cultures, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. Efficacy in animal models has been demonstrated for SARS-CoV and MERS-CoV. In addition, remdesivir is in clinical trials for Ebola virus infections.

Several phase 3 clinical trials are underway for testing remdesivir for use in COVID-19 in the United States, South Korea, and China.

An in vitro study showed that the antiviral activity of remdesivir plus interferon beta (IFNb) was superior to that of lopinavir/ritonavir (LPV/RTV; Kaletra, Aluvia; AbbVie Corporation). Prophylactic and therapeutic remdesivir improved pulmonary function and reduced lung viral loads and severe lung pathology in mice, whereas LPV/RTV-IFNb slightly reduced viral loads without affecting other disease parameters. Therapeutic LPV/RTV-IFNb improved pulmonary function but did not reduce virus replication or severe lung pathology.

Lopinavir/ritonavir

A combination of lopinavir/ritonavir plus IFNb treatment improved clinical parameters in marmosets and mice infected with MERS-CoV.

In a randomized, controlled, open-label trial of hospitalized adults (n=199) with confirmed SARS-CoV-2 infection, recruited patients had an oxygen saturation of 94% or less on ambient air or PaO2 of less than 300 mm Hg and were receiving a range of ventilatory support modes (eg, no support, mechanical ventilation, extracorporeal membrane oxygenation [ECMO]). These patients were randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added to standard care (n=99) or standard care alone (n=100). Results showed that time to clinical improvement did not differ between the two groups (median, 16 days). The mortality rate at 28 days was numerically lower for lopinavir/ritonavir compared with standard care (19.2% vs 25%) but did not reach statistical significance. An editorial accompanies this study that is informative in regard to the extraordinary circumstances of conducting such a study in the midst of the outbreak.

Rintatolimod

The toll-like receptor 3 (TLR-3) agonist rintatolimod (Poly I:Poly C12U; Ampligen; AIM ImmunoTech) is being tested as a potential treatment for COVID-19 by the National Institute of Infectious Diseases (NIID) in Japan and the University of Tokyo. It is a broad-spectrum antiviral agent.

Other investigational antivirals

Other investigational antivirals being tested for efficacy against COVID-19 include azvudine (nucleoside reverse transcriptase inhibitor), danoprevir (NS3/4A HCV protease inhibitor), plitidepsin (targets EF1A), and favipiravir (viral RNA polymerase inhibitor).

Plitidepsin (Aplidin; PharmaMar) is a member of the compound class known as didemnins. In vitro studies from Spain report plitidepsin potentially targets EF1A, which is key to multiplication and spread of the virus.

Preliminary results of favipiravir’s moderate antiviral effect on COVID-19 have emerged from a study in China, although the parent company of the drug (Fujifilm Pharmaceuticals, Japan) has not confirmed the drug’s efficacy. [56] Favipiravir (Avigan) is approved in Japan and China for influenza and is investigational for use in COVID-19.

Immunomodulators and Other Investigational Therapies

Interleukin-6 inhibitors

Interleukin-6 (IL-6) inhibitors may ameliorate severe damage to lung tissue caused by cytokine release in patients with serious COVID-19 infections.

On March 16, 2020, Sanofi and Regeneron announced initiation of a phase 2/3 trial of the IL-6 inhibitor sarilumab (Kevzara). The United States–based component of the trial will be initiated in New York. The multicenter, double-blind, phase 2/3 trial has an adaptive design with two parts and is anticipated to enrol up to 400 patients. The first part will recruit patients with severe COVID-19 infection across approximately 16 US sites and will evaluate the effect of sarilumab on fever and the need for supplemental oxygen. The second, larger, part of the trial will evaluate improvement in longer-term outcomes, including preventing death and reducing the need for mechanical ventilation, supplemental oxygen, and/or hospitalization.

Genentech, maker of another IL-6 inhibitor, tocilizumab (Actemra), is working with the FDA to initiate a randomized, double-blind, placebo-controlled phase III clinical trial in collaboration with BARDA to evaluate the safety and efficacy of tocilizumab plus standard of care in hospitalized adult patients with severe COVID-19 pneumonia compared to placebo plus standard of care. The goal is to begin in early April 2020, with a target of approximately 330 patients globally. The primary and secondary endpoints of the study include clinical status, mortality, mechanical ventilation, and ICU variables.

An anti-interleukin-6 receptor monoclonal antibody (TZLS-501; Tiziana Life Sciences and Novimmune) is currently being developed.

Hydroxychloroquine and chloroquine

Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are therefore also used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). Published reports stemming from the COVID-19 Chinese outbreak have evaluated the potential usefulness of these drugs in controlling cytokine release syndrome in critically ill patients.

According to a consensus statement from a multicenter collaboration group in China, chloroquine phosphate 500-mg twice daily in tablet form for 10 days may be considered in patients with COVID-19 pneumonia. Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in vitro.

The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic models (PBPK) were conducted for each drug. Hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on PBPK models, the authors recommend a loading dose of hydroxychloroquine 400 mg PO BID, followed by 200 mg BID for 4 days. [60]

Corticosteroids

A study describing clinical outcomes of patients diagnosed with COVID-19 was conducted in Wuhan China (N = 201). Eighty-four patients (41.8%) developed ARDS, and of those, 44 (52.4%) died. Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72). [43]

An open-label prospective trial is planned to study the clinical improvement in patients treated with methylprednisolone IV.

Nitric oxide

Published findings from the 2004 SARS-CoV infection suggest the potential role of inhaled nitric oxide (iNO; Mallinckrodt Pharmaceuticals, plc) as a supportive measure for treating infection in patients with pulmonary complications. Treatment with iNO reversed pulmonary hypertension, improved severe hypoxia, and shortened the length of ventilatory support compared with matched control patients with SARS.

A phase 2 study of iNO is underway in patients with COVID-19 with the goal of preventing disease progression in those with severe ARDS.