3/21/2020 Coronavirus Disease 2019 (COVID-19) Treatment & Management: Investigational Drugs and Biologics

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Coronavirus Disease 2019

(COVID-19) Treatment &
Management
Updated: Mar 20, 2020
Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; Chief Editor: Michael Stuart Bronze, MD
more...

TREATMENT

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. 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. [48]

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. [49]

Lopinavir/ritonavir

A combination of lopinavir/ritonavir plus IFNb treatment improved clinical parameters in marmosets

and mice infected with MERS-CoV. [48]

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,
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mechanical ventilation, extracorporeal membrane oxygenation [ECMO]). These patients were

randomized to receive ritonavir/lopinavir 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. [50] 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. [51]

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. [52] It is a broad-spectrum antiviral
agent. [53]

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. [54]

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. [55] 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 enroll 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. [56]

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. [57]

An anti-interleukin-6 receptor monoclonal antibody (TZLS-501; Tiziana Life Sciences and

Novimmune) is currently being developed. [58]

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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. [59, 60]

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. [46] Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in
vitro. [47]

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. [59]

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 clinical improvement in patients treated with
methylprednisolone IV. [61]

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. [62]

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. [63]

Other immunomodulators and investigational therapies

Table 1. Additional Immunomodulators and Other Investigational Therapies (Open Table in a new
window)

Therapy Proposed Use Description/Comments

N-methyl-d-aspartate (NDMA) receptor glutamate

Ifenprodil (NP-
receptor antagonist. NMDA is linked to inflammation
120; Algernon ARDS/lung
and lung injury. An injectable and long-acting oral
Pharmaceuticals) injury
[64]
product are under production to begin clinical trials for
COVID-19 and acute lung injury.

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Therapy Proposed Use Description/Comments

Remestemcel-L Allogeneic mesenchymal stem cell (MSC) product

ARDS/lung
(Mesoblast Ltd) candidate being investigated as a treatment for ARDS
injury
[65] associated with COVID-19.

Inhaled therapy
(MannKind and ARDS/lung Dry powder inhaled formulation with potential to treat
injury ARDS caused by COVID-19.
Immix) [66]

TJM2 is a neutralizing antibody against human

TJM2 (I-MAB granulocyte-macrophage colony stimulating factor
Cytokine storm
Biopharma) [67] (GM-CSF), an important cytokine that plays a critical
role in acute and chronic inflammation.

Gimsilumab Monoclonal antibody that targets GM-CSF, a

Cytokine storm proinflammatory cytokine that is up-regulated in
(Roivant) [68] patients with COVID-19.

Anti-SARS-CoV-
2 polyclonal
hyperimmune Immunoglobulin Under development to treat high-risk patients.
globulin [69]

Preferentially directed immunotherapy using ligand

CEL-SCI antigen epitope presentation system (LEAPS) peptide
Immunotherapy
Corporation [70] technology to reduce COVID-19 viral load and
consequent lung damage.

Defensin-mimetic that mimics the immune system and

Brilacidin
disrupts the pathogen membrane, leading to cell
(Innovation
Immunotherapy death. It is undergoing clinical-stage testing at a US
Pharmaceuticals)
[71]
regional biocontainment laboratory. Also see Table 2
for potential use as a vaccine adjuvant.

Monoclonal Antibody-
antibodies Mab cocktail slated by mid-April, with the goal of
directed
initiating human trials by early summer.
(Regeneron) [72] therapy

Vir Antibody-
Biotechnology Human monoclonal antibodies against coronaviruses,
directed
including COVID-19.
and NIH [73] therapy

Antibodies (Eli Antibody- Antibody treatment from more than 500 unique
Lilly and directed antibodies isolated from one of the first US patients to
AbCellera) [74] therapy recover from COVID-19.

Vascular leakage Reduction of

Targets the angiopoietin-Tie2 signaling pathway to
endothelial
therapy [75] dysfunction
reduce endothelial dysfunction.

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Vaccines

Table 2. Investigational Vaccines (Open Table in a new window)

Vaccine Comments

Phase 1 human clinical trials are expected to begin in April 2020. In

INO-4800 (Inovio
addition, Inovio has received a grant from the Bill and Melinda Gates
Pharmaceuticals)
[76]
Foundation to accelerate testing and scale up a smart device
(Cellectra 3PSP) for large-scale intradermal vaccine delivery.

mRNA-1273 A phase 1 study has been initiated in 45 healthy volunteers as of

March 16, 2020 at Kaiser Permanente Washington Health Research
(Moderna Inc) [77] Instituted in Seattle.

mRNA vaccine Vaccine is in development and not yet ready for human testing as of
(CureVac) [78] March 16, 2020.

mRNA vaccine
BNT162 (BioNTech Joint development of BioNTech’s mRNA-based vaccine candidate
initiated.
and Pfizer) [79]

COVID-19 S-Trimer
(GlaxoSmithKline Preclinical development is underway using GSK’s adjuvants
[GSK] and Clover (compounds that enhance vaccine efficacy) and Clover’s proprietary
Biopharmaceuticals) proteins, which stimulate an immune response.
[80]

SARS-CoV-2 Partnering with the Biomedical advanced Research and Development

vaccine (Johnson & Authority (BARDA) to utilize Janssen’s AdVac and PER.C6
technologies, which provide rapid upscale production of an optimal
Johnson [J&J]) [81] vaccine candidate.

rDNA vaccine Collaborating with BARDA to develop a vaccine using their

(Sanofi) [82] recombinant DNA platform.

Saponin-based
Stimulates the entry of antigen-presenting cell into the injection site
Matrix-M adjuvant
and enhances antigen presentation in local lymph nodes to boost the
vaccine (Novavax)
[83]
immune response.

Live-attenuated Codagenix, a clinical-stage biotechnology company, is collaborating

vaccine with the Serum Institute of India to co-develop a live-attenuated
(Codagenix) [84] vaccine.

PCR-based DNA
vaccine (Applied The collaboration has designed four COVID-19 vaccine candidates
DNA Sciences and utilizing PCR-based DNA manufacturing systems for preclinical testing
in animals.
Takis Biotech) [85]

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Vaccine Comments

Intranasal COVID-
19 vaccine Design and synthesis has been completed and is advancing toward
animal testing.
(Altimmune, Inc) [86]

Brilacidin adjuvant Material Transfer Agreement (MTA) signed with a leading public
vaccine (Innovation health-focused US university and top coronavirus expert to evaluate
Pharmaceuticals) the potential antiviral properties as a defensing adjuvant. Also see
[87] Table 1.

Guidelines

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