This article focuses on:
- Investigational Antiviral Agents
- Other early-stage investigational antivirals
- Other investigational antivirals being tested for efficacy against COVID-19
- Immunomodulators and Other Investigational Therapies
- Hydroxychloroquine and chloroquine
- Interleukin-6 inhibitors
- Convalescent plasma
- Nitric oxide
- JAK and NAK inhibitors
- Other investigational therapies
- Investigational Vaccines
- Renin Angiotensin System Blockade and COVID-19
- Diabetes and COVID-19
- QT Prolongation with Potential COVID-19 Pharmacotherapies
- Investigational Agents for Postexposure Prophylaxis
Investigational Antiviral Agents
- The broad-spectrum antiviral agent remdesivir is a nucleotide analog prodrug.
- Remdesivir inhibits replication of other human coronaviruses associated with high morbidity in tissue cultures, including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)
- Efficacy in animal models has been demonstrated for SARS-CoV and MERS-CoV.
- Preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT) was announced April 29, 2020.
- The analysis included 1,063 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients who received remdesivir recovered faster than similar patients who received placebo.
- Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (P< 0.001).
- The median time to recovery was 11 days in patients treated with remdesivir compared with 15 days in those who received placebo.
- Results also suggested a survival benefit, with a mortality rate of 8% in the remdesivir group, compared with 11.6% in the placebo group, but this was not statistically significant (P = 0.059).
- Patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less.
- The first published report with a group of patients receiving remdesivir compassionate use described clinical improvement in 36 of 53 hospitalized patients (68%) with severe COVID-19.
- At baseline, 30 patients (57%) were receiving ventilation and 4 (8%) extracorporeal membrane oxygenation (ECMO).
- Measurement of efficacy requires randomized, placebo-controlled trials.
- Observations during compassionate use follow-up (median of 18 days) included the following:
- Oxygen-support class improved in 36 patients including 17 of 30 patients receiving mechanical ventilation who were extubated.
- Twenty-five patients were discharged.
- Seven patients died.
- The mortality rate was 18% among patients receiving invasive ventilation and 5% among those not receiving invasive ventilation.
- An in vitro study showed that the antiviral activity of remdesivir plus interferon beta (IFNb) for MERS-CoV was superior to that of lopinavir/ritonavir.
- 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 in the mice.
Other early-stage investigational antivirals
- Nitazoxanide extended-release tablets inhibit replication of a broad range of respiratory viruses in cell cultures, including SARS-CoV-2.
- Two phase 3 trials for prevention of COVID-19 are being initiated in high-risk populations, including elderly residents of long-term care facilities and healthcare workers.
- Ivermectin, an antiparasitic drug, showed in vitro reduction of viral RNA in Vero-hSLAM cells 2 hours postinfection with SARSCoV-2 clinical isolate.
- According to pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are not likely attainable in humans.
- Chaccour et al believe the recent findings regarding ivermectin warrant rapid implementation of controlled clinical trials to assess efficacy against COVID-19.
- They also raise concerns regarding ivermectin-associated neurotoxicity, particularly in patients with a hyperinflammatory state possible with COVID-19.
- Drug interactions with potent CYP3A4 inhibitors (eg, ritonavir) warrant careful consideration of coadministered drugs.
- Evidence suggests that ivermectin plasma levels with meaningful activity against COVID-19 would not be achieved without potentially toxic increases in ivermectin doses in humans.
- 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
- 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 but did not reach statistical significance.
- Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group.
Other investigational antivirals being tested for efficacy against COVID-19
- Favipiravir is an oral antiviral approved for the treatment of influenza in Japan. It selectively inhibits RNA polymerase.
- Merimepodib targets RNAdependent polymerases.It can inhibit SARS-CoV-2 replication at low concentrations. The mechanism of merimepodib is inhibition of inosine-5’-monophosphate dehydrogenase (IMPDH), leading to a depletion of guanosine for use by the viral polymerase during replication.
- Niclosamide is an anthelmintic agent that has potential use as an antiviral agent. A proprietary formulation that targets the viral reservoir in the gut to decrease prolonged infection and transmission has been developed.
- Rintatolimod is a toll-like receptor 3 (TLR-3) agonist is a broad-spectrum antiviral agent.
- Beta-D-N4-hydroxycytidine is an orally bioavailable broad-spectrum antiviral. When administered both prophylactically and therapeutically to mice infected with SARS-CoV, NHC improved pulmonary function and reduced virus titer and body weight loss.
- Bemcentinib a selective oral AXL kinase inhibitor, exhibits potent antiviral activity in preclinical models against several enveloped viruses, including Ebola and Zika virus.
- Umifenovir is an antiviral drug that binds to hemagglutinin protein; it is used to treat influenza. Drug target for umifenovir is the spike glycoproteins of SARS-CoV-2, similar to that of H3N2. Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group.
Immunomodulators and Other Investigational Therapies
Hydroxychloroquine and chloroquine
- Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are therefore also used to treat autoimmune conditions.
- As inhibitors of heme polymerase, they are also believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits the pH-dependent steps of viral replication.
- 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.
- 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.
- A retrospective analysis of data from patients hospitalized with confirmed COVID-19 infection in all US Veterans Health Administration medical centers between March 9, 2020, and April 11, 2020, has been published.
- Patients who had received hydroxychloroquine (HC) alone or with azithromycin (HC + AZ) as treatment in addition to standard supportive care were identified.
- A total of 368 patients were evaluated.
- Death rates in the HC, HC + AZ, and no-HC groups were 27.8%, 22.1%, 11.4%, respectively.
- Rates of ventilation in the HC, HC + AZ, and no-HC groups were 13.3%, 6.9%, 14.1%, respectively.
- The authors concluded that they found no evidence that hydroxychloroquine, with or without azithromycin, reduced the risk of mechanical ventilation and that the overall mortality rate was increased with hydroxychloroquine treatment.
- According to a consensus statement from a multicenter collaboration group in China, chloroquine phosphate 500 mg (300 mg base) twice daily in tablet form for 10 days may be considered in patients with COVID-19 pneumonia.
- It should be noted this is 14 times the typical dose of chloroquine used per week for malaria prophylaxis and 4 times that used for treatment.
- Cardiac toxicity should temper enthusiasm for this as a widespread cure for COVID-19.
- A randomized controlled trial in Wuhan, China, enrolled 62 hospitalized patients with confirmed COVID-19.
- Inclusion criteria included age 18 years or older, chest CT scans showing pneumonia, and SaO2/SPOs ratio of more than 93%
- Patients with severe or critical illness were excluded.
- All patients enrolled in the study received standard treatment (oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin, with or without corticosteroids).
- Thirty-one patients were randomized to receive hydroxychloroquine sulfate (200 mg PO BID for 5 days) in addition to standardized treatment.
- Changes in time to clinical recovery (TTCR) was evaluated and defined as return of normal body temperature and cough relief, maintained for more than 72 hours.
- Compared with the control group, TTCR for body temperature and cough were significantly shortened in the hydroxychloroquine group.
- Four of the 62 patients progressed to severe illness, all of whom were in the control group.
- The French have embraced hydroxychloroquine as a potentially more potent therapy with an improved safety profile to treat and prevent the spread of COVID-19.
- Optimal regimen of hydroxychloroquine : 600-800 mg per day.
Hydroxychloroquine plus azithromycin
- A prospective study found no evidence of a strong antiviral activity or clinical benefit from use of hydroxychloroquine plus azithromycin.
- Molina et al assessed virologic and clinical outcomes of 11 consecutive patients hospitalized who received hydroxychloroquine (600 mg per day x10 days) and azithromycin (500 mg Day 1, then 250 mg days 2-5).
- Patient demographics were as follows: 7 men and 4 women; mean age 58.7 years (range: 20-77); 8 had significant comorbidities associated with poor outcomes (ie, obesity 2; solid cancer 3; hematological cancer 2; HIV-infection 1).
- Ten of the eleven patients had fever and received oxygen via nasal cannula. Within 5 days, 1 patient died, 2 were transferred to the ICU.
- Hydroxychloroquine and azithromycin were discontinued in 1 patient owing to prolonged QT interval.
- Nasopharyngeal swabs remained positive for SARS-CoV-2 RNA in 8/10 patients at days 5-6 after treatment initiation.
- Another study in France evaluated patients treated with hydroxychloroquine (N=26) against a control group (n=16) who received standard of care.
- After dropping 6 patients who received treatment from the analysis for having incomplete data, the 20 remaining patients receiving hydroxychloroquine (200 mg PO q8h) had improved nasopharyngeal clearance of the virus on day 6
- A study of hydroxychloroquine in France included azithromycin in 6 patients for potential bacterial superinfection (500 mg once, then 250 mg PO daily for 4 days).
- These patients were reported to have 100% clearance of SARS-CoV-2.
- The patients receiving combination therapy had initially lower viral loads, and, when compared with patients receiving hydroxychloroquine alone with similar viral burden, the results are fairly similar.
QT prolongation with hydroxychloroquine and azithromycin
- Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population.
- A Brazilian study comparing chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days) observed QT prolongation in 25% of patients in the high-dose group.
- All patients received other drugs (ie, azithromycin, oseltamivir) that may contribute to prolonged QT.
- An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine.
- The analysis compared use of hydroxychloroquine, sulfamethoxazole, or the combinations of hydroxychloroquine plus amoxicillin or hydroxychloroquine plus azithromycin.
- Interleukin-6 (IL-6) inhibitors may ameliorate severe damage to lung tissue caused by cytokine release in patients with serious COVID-19 infections.
- Several studies have indicated a “cytokine storm” with release of IL-6, IL-1, IL-12, and IL-18, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators.
- The increased pulmonary inflammatory response may result in increased alveolar-capillary gas exchange, making oxygenation difficult in patients with severe illness.
- On March 16, 2020, Sanofi and Regeneron announced initiation of a phase 2/3 trial of the IL-6 inhibitor sarilumab .
- 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.
- Based on the phase 2 trial analysis, the ongoing phase 3 design was modified to include higher-dose sarilumab (400 mg) or placebo in critical patients
- In the preliminary phase 2 analysis, sarilumab had no notable benefit on clinical outcomes when combining the severe and critical groups versus placebo.
- However, there were negative trends for most outcomes in the severe group, while there were positive trends for all outcomes in the critical group.
- Phase 2 data for critical patients in the 400-mg group (n=145) compared with placebo (n=77), respectively, included the following:
- Change from baseline C-reactive protein level: -79% versus -21%
- Died: 23% versus 27% Remained on ventilator: 9% versus 27%
- Clinical improvement: 59% versus 41%
- Off oxygenation: 58% versus 41%
- Discharged: 53% versus 41%
- An open label, non-controlled, non–peer reviewed study was conducted in China in 21 patients with severe respiratory symptoms related to COVID-19.
- All had a confirmatory diagnosis of SARS-CoV-2 infection.
- The patients in the trial had a mean age of 56.8 years.
- Although all patients met enrollment criteria of (1) respiratory rate of 30 breaths/min or more, (2) SpO2 of 93% or less, and (3) PaO2/FiO2 of 300 mm Hg or less, only two of the patients required invasive ventilation.
- The other 19 patients received various forms of oxygen delivery, including nasal canula, mask, high-flow oxygen, and noninvasive ventilation.
- All patients received standard of care, including lopinavir and methylprednisolone.
- Patients received a single dose of 400 mg tocilizumab via intravenous infusion.
- The patients improved with lower oxygen requirements, lymphocyte counts returned to normal, and 19 patients were discharged with a mean of 15.5 days after tocilizumab treatment.
- It was concluded that tocilizumab was an effective treatment in patients with severe COVID-19.
- An anti-interleukin-6 receptor monoclonal antibody is currently being developed.
- Corticosteroids are not generally recommended for treatment of COVID-19 or any viral pneumonia.
- The benefit of corticosteroids in septic shock results from tempering the host immune response to bacterial toxin release.
- The incidence of shock in patients with COVID-19 is relatively low.
- It produces cardiogenic shock from increased work of the heart needed to distribute oxygenated blood supply and thoracic pressure from ventilation.
- Corticosteroids can induce harm through immunosuppressant effects during the treatment of infection and have failed to provide a benefit in other viral epidemics, such as respiratory syncytial virus (RSV) infection, influenza infection, SARS, and MERS.
- Early guidelines for management of critically ill adults with COVID-19 specify when to use low-dose corticosteroids and when to refrain from using corticosteroids.
- The FDA is facilitating access to convalescent plasma, antibody-rich products that are collected from eligible donors who have recovered from COVID-19.
- Convalescent plasma has not yet been shown to be effective in COVID-19.
- The FDA states that it is important to determine its safety and efficacy via clinical trials before routinely administering convalescent plasma to patients with COVID-19.
- Convalescent plasma showed improvement in oxygenation, sequential organ failure assessment (SOFA) scores, and eventual ventilator weaning in some patients.
- Inhaled nitric oxide is used 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.
- The Society of Critical Care Medicine recommends against the routine use of iNO in patients with COVID-19 pneumonia.
- Instead, they suggest a trial only in mechanically ventilated patients with severe ARDS and hypoxemia despite other rescue strategies.
JAK and NAK inhibitors
- Drugs that target numb-associated kinase (NAK) may mitigate systemic and alveolar inflammation in patients with COVID-19 pneumonia by inhibiting essential cytokine signaling involved in immune-mediated inflammatory response.
- NAK inhibition reduces viral infection in vitro.
- ACE2 receptors are a point of cellular entry by COVID-19, which is then expressed in lung AT2 alveolar epithelial cells.
- A known regulator of endocytosis is the AP2-associated protein kinase-1 (AAK1).
- The ability to disrupt AAK1 may interrupt intracellular entry of the virus.
- Baricitinib , a Janus kinase (JAK) inhibitor, is also identified as a NAK inhibitor with a particularly high affinity for AAK1.
- The cytokine profile of COVID-19 is similar to that of hemophagocytic lymphohistiocytosis (sHLH).
- sHLH is characterized by increased IL-2, IL-7, GCSF, INF-gamma, monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein-1 (MIP-1) alpha, and TNF-alpha.
- JAK inhibition may be a therapeutic option.
- Other selective JAK inhibitors (ie, fedratinib, ruxolitinib) may be effective against consequences of elevated cytokines, although baricitinib has the highest affinity for AAK1.
- Baricitinib is being studied as part of the NIAID Adaptive Covid-19 Treatment Trial.
- Ruxolitinib (Jakafi; Incyte) is part of the phase 3 RUXCOVID clinical trial.
- Pacritinib is a JAK2, interleukin-1 receptor-associated kinase-1 (IRAK-1), and colony stimulating factor-1 receptor (CSF-1R) inhibitor that is pending FDA approval for myelofibrosis.
- As a JAK2/IRAK-1 inhibitor, pacritinib may ameliorate the effects of cytokine storm via inhibition of IL-6 and IL-1 signaling.
- As a CSF-1R inhibitor, pacritinib may mitigate effects of macrophage activation syndrome
- HMG-CoA reductase inhibitors (statins) also decreases the inflammatory processes of atherosclerosis.
- An important factor that Virani points out regarding COVID-19 is that no harm was associated with statin therapy in previous trials of statins and viral infections, emphasizing that patients should adhere to their statin regimen.
Other investigational therapies
- Inhaled therapy
- Thanh Le et al describe platforms based on DNA or mRNA that offer flexibility regarding antigen manipulation and speed of development.
- Recombinant protein-based development may be beneficial owing to existing large-scale production capabilities.
- Use of an adjuvant can be of particular importance in a pandemic situation.
- Adjuvants are compounds that potentiate that antigen in the vaccine, thereby reducing the amount of antigen protein required per dose.
- This method allows more people to be vaccinated and conserves antigen resources.
- Examples of vaccines under development:
- mRNA vaccine
- mRNA vaccine
- COVID-19 S-Trimer, etc..
Renin Angiotensin System Blockade and COVID-19
- SARS-CoV-2 utilises angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells.
- The speculated mechanism for detrimental effect of ACEIs and ARBs is related to ACE2.
- It was therefore hypothesized that any agent that increases expression of ACE2 could potentially increase susceptibility to severe COVID-19 by improving viral cellular entry; however, physiologically, ACE2 also converts angiotensin 2 to angiotensin, which leads to vasodilation and may protect against lung injury by lowering angiotensin 2 receptor binding.
- It is therefore uncertain whether an increased expression of ACE2 receptors would worsen or mitigate the effects of SARS-CoV-2 in human lungs.
- ACE2 acts as a counterregulatory enzyme that degrades angiotensin 2 to angiotensin 1-7.
- SARS-CoV-2 not only appears to gain initial entry through ACE2 but also down-regulates ACE2 expression, possibly mitigating the counterregulatory effects of ACE2.
- Some studies in animals have suggested that ACEIs and ARBs increase expression of ACE2, while other studies have not shown this effect.
- Cardiology societies have recommended against initiating or discontinuing these medications based solely on active SARS-CoV-2 infection.
Diabetes and COVID-19
- High plasma glucose levels and diabetes mellitus are known risk factors for pneumonia.
- Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include the following:
- Higher-affinity cellular binding and efficient virus entry
- Decreased viral clearance
- Diminished T-cell function
- Increased susceptibility to hyperinflammation and cytokine storm syndrome
- Presence of cardiovascular disease
- SARS-CoV-2 utilizes angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells.
- Insulin administration attenuates ACE2 expression, while hypoglycemic agents up-regulate ACE2.
- Dipeptidyl peptidase 4 (DPP-4) is highly involved in glucose and insulin metabolism, as well as in immune regulation.
- This protein was shown to be a functional receptor for Middle East respiratory syndrome coronavirus (MERS-CoV), and protein modeling suggests that it may play a similar role with SARS-CoV-2.
- The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker.
- Important clinical conclusions of the review include the following:
- Hospitalization is more common for acute COVID-19 among patients with diabetes and obesity.
- Diabetic medications need to be reevaluated upon admission.
- Insulin is the glucose-lowering therapy of choice, not DPP-4 inhibitors or GLP-1 receptor agonists, in patients with diabetes who are hospitalized with acute COVID-19.
QT Prolongation with Potential COVID-19 Pharmacotherapies
- Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population.
- Chloroquine and hydroxychloroquine block the potassium channel, specifically KCNH2- encoded HERG/Kv11.1.
- Additional modifiable risk factors and nonmodifiable risk factors for QT prolongation may further increase the risk.
- Some of the modifiable and nonmodifiable risk factors may be caused by or exacerbated by severe illness.
- A retrospective study was performed by reviewing 84 consecutive adult patients who were hospitalized at NYU Langone Medical Center with COVID-19 and treated with hydroxychloroquine plus azithromycin.
- QTc increased by greater than 40 ms in 30% of patients.
- In 11% of patients, QTc increased to more than 500 ms, which is considered a high risk for arrhythmia. The researcher noted that development of acute renal failure, but not baseline QTc, was a strong predictor of extreme QTc prolongation.
- A Brazilian study (n=81) compared chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days).
- A positive COVID-19 infection was confirmed by RT-PCR in 40 of 81 patients.
- All patients received ceftriaxone and azithromycin.
- Oseltamivir was also prescribed in 89% of patients.
- Prolonged QT interval (> 500 msec) was observed in 25% of the high-dose group, along with a trend toward higher lethality (17%) compared with lower dose.
- The high incidence of QT prolongation prompted the investigators to prematurely halt use of the high-dose treatment arm, noting that azithromycin and oseltamivir can also contribute to prolonged QT interval.
- The fatality rate was 13.5%.
- In 14 patients with paired samples, respiratory secretions at day 4 showed negative results in only one patient.
- Although not specific to patients with COVID-19, an increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine in a large study of administrative claims.
Investigational Agents for Postexposure Prophylaxis
- PUL-042 is a solution for nebulization with potential immunostimulating activity.
- It consists of two toll-like receptor (TLR) ligands: Pam2CSK4 acetate (Pam2), a TLR2/6 agonist, and the TLR9 agonist oligodeoxynucleotide M362.
- PUL-042 binds to and activates TLRs on lung epithelial cells.
- This induces the epithelial cells to produce peptides and reactive oxygen species (ROS) against pathogens in the lungs, including bacteria, fungi, and viruses. M362, through binding of the CpG motifs to TLR9 and subsequent TLR9-mediated signaling, initiates the innate immune system and activates macrophages, natural killer (NK) cells, B cells, and plasmacytoid dendritic cells; stimulates interferon-alpha production; and induces a T-helper 1 cells–mediated immune response.
- Pam2CSK4, through TLR2/6, activates the production of T-helper 2 cells, leading to the production of specific cytokines