Drugs with mechanisms of action that reduce inflammation and cytokine storm in the lungs are being evaluated in patients with severe COVID-19 pneumonia. 
 
Corticosteroids
 
Three studies evaluating dexamethasone and hydrocortisone in the treatment of COVID-19 with acute respiratory failure were recently published in JAMA. All three studies (CAPE COVID, CoDEX, REMAP-CAP) are likely underpowered, because they were stopped early after results of the British RECOVERY trial (NCT04381936) demonstrated efficacy with dexamethasone in the treatment of hospitalized patients with COVID-19. The data from the three trials suggested a benefit with the use of corticosteroids in patients with COVID-19 and acute respiratory failure. To further examine the role of corticosteroids the World Health Organization (WHO) sponsored a meta-analysis of seven trials involving 1,700 critically ill COVID-19 patients. The analysis found the 28-day mortality rate lower with corticosteroids (32% vs. 40%) compared to not receiving corticosteroids. Based on the results of the trials and the meta-analysis, the WHO now recommends 6 mg of dexamethasone orally or intravenously daily or 50 mg of hydrocortisone intravenously every 8 hours for 7 to 10 days in severe and critical COVID-19 patients. The WHO also recommends that corticosteroids not be used in non-severe COVID-19 patients.
 
Dexamethasone
  • The 15,000 patient RECOVERY trial (NCT04381936) has several arms testing lopinavir-ritonavir, dexamethasone, hydroxychloroquine, azithromycin, tocilizumab, convalescent plasma, immunoglobulin (IVIG) and a monoclonal antibody combination REGN-COV2. A final version of the preliminary report of the dexamethasone arm of the RECOVERY trial was published in the New England Journal of Medicine. The results included 2,104 patients that received dexamethasone (6 mg for 10 days) compared to 4,321 patients that received supportive care only. Overall 28-day mortality was 22.9% with dexamethasone compared to 25.7% with placebo. The mortality rate for patients on ventilators was 29.3% with dexamethasone compared to 41.4% with supportive care only. Dexamethasone also had a lower mortality rate in patients requiring oxygen, but not on a ventilator (23.3% vs. 26.2%) but did not reduce mortality in patients not receiving respiratory support at enrollment (17.8% vs. 14.0%).
  • In a 28-day, 299 patient, Phase III, open-label, Brazilian CoDEX trial (NCT04327401), patients treated with dexamethasone had 2.6 fewer days requiring a ventilator compared to placebo in patients with COVID-19 and moderate to severe acute respiratory failure. Use of dexamethasone did not decrease mortality or ICU days. The CoDEX trial was stopped early, at the recommendation of the data and safety monitoring board (299 of the planned 350 patients), when the British RECOVERY trial (NCT04381936) demonstrated efficacy with dexamethasone. As part of standard of care, patients in CoDEX received hydroxychloroquine (24% in the dexamethasone group and 19% in the control group), azithromycin (69%, 74%), other antibiotics (88%, 86%) and oseltamivir (29%, 35%).
  • Based on the RECOVERY trial, the National Institute of Health recommends use of dexamethasone 6 mg daily for up to ten days in COVID-19 patients the require supplemental oxygen with or without mechanical ventilation. NIH recommends against using dexamethasone in patients that do not require supplemental oxygen.
  • The WHO recommends that dexamethasone only be used in patients with severe or critical disease.
  • Researchers at Montefiore Medical Center retrospectively reviewed the medical records of 1,806 hospitalized COVID-19 patients and found that glucocorticoids administered within 48 hours of admission was not associated with a decrease in mortality or mechanical ventilation. However, patients with a CRP of 20 mg/dL or greater had a reduced risk of mortality and mechanical ventilation, while use in patients with a CRP < 10 mg/dL was associated with an increased risk of mortality or mechanical ventilation.
Hydrocortisone
  • In a 21-day, 148 patient, Phase III French, CAPE COVID trial (NCT02517489), treatment with hydrocortisone did not reduce mortality or the persistent need for ventilators/high flow oxygen compared to placebo (42.1% vs 50.7%) in critically ill patients with COVID-19 and acute respiratory failure. However, the trial was stopped early, due to the recommendation of the data and safety monitoring board (DSMB), so the trial was likely underpowered (149 patients of the planned 290). The DSMB recommended stopping the trial due to slowing in patient recruitment and the British RECOVERY trial (NCT04381936) demonstrating efficacy with dexamethasone. Patients in the trial were also treated with hydroxychloroquine (58% in the dexamethasone group and 64% in the control group), hydroxychloroquine plus azithromycin (30%, 38%), ritonavir plus lopinavir (13%, 15%), eculizimab (4%, 3%), remdesivir (3%, 4%) and toclizumab (1%, 3%).
  • The 21-day, 379 patient, Phase IV, open-label, international, REMAP-CAP trial (NCT02735707), found a 93% probability that a fixed 7-day course of hydrocortisone and an 80% probability that a shock-dependent course would reduce ICU-based respiratory or cardiovascular support compared placebo in critically ill patients with COVID-19 requiring ICU-based respiratory or cardiovascular support. The trial was stopped early, due to the recommendation of the blinded international trial steering committee, so the trial was likely underpowered (379 patients of the British RECOVERY trial (NCT04381936) RECOVERY trial demonstrating efficacy with dexamethasone. Data on concomitant drugs were not included in the published description of REMAP-CAP.
Interferon-beta-1a
  • NIH currently recommends against the use of interferons for the treatment of severe and critical COVID-19, unless the patient is participating in a clinical trial. NIH does not recommend for or against the use of interferon in the treatment of mild and moderate COVID-19.
  • Subcutaneous interferon-beta-1a
    • Subcutaneous interferon beta 1a is currently being evaluated as a treatment for COVID-19 in the UK’s RECOVERY trial and the WHO-led SOLIDARITY study.
    • In a 28-day, 81 patient, Israeli trial, adding subcutaneous interferon beta 1a to hydroxychloroquine plus lopinavir/ritonavir or atazanavir/ritonavir did not decrease the time to clinical response, but did increase discharge rate on day 14 and decreased 28-day mortality, compared to not adding interferon in patients with severe COVID-19.
  • SNG001 is a nebulizer formulation of interferon-beta-1a. 
    • SNG001 is being evaluated as a potential treatment for COVID-19 because of data from two trials showing an improvement in lung function in patients with asthma and a respiratory viral infection.
    • Synairgen announced that in a 101 patient trial, treatment with nebulized interferon beta 1a (SNG001) reduced the risk of developing severe COVID-19 and increased the likelihood of recovering in patients hospitalized with COVID-19.
NIH recommends against the use of interleukin-6 (IL-6) inhibitors (tocilizumab, sarilumab, siltuximab) for the treatment of COVID-19, due to a lack of evidence to support efficacy. The panel did not exclude use of an IL-6 inhibitor as part of a clinical trial.
  • Tocilizumab (Actemra, Roche) is an interleukin 6 (IL-6) monoclonal antibody. 
  • Italian clinicians described a reduction in COVID-19 pneumonia in two patients treated with tocilizumab. BARDA ceased funding IL-6 inhibitor trials evaluating tocilizumab and sarilumab as treatments for severe COVID-19 in August 2020. Tocilizumab and sarilumab have each failed to demonstrate improvements in clinical trials.
  • Chinese researchers announced that in a 21 patient, open-label trial, patients treated with tocilizumab had a reduction in fever and 15/20 patients had a reduction in their need for supplemental oxygen in hospitalized patients with a COVID-19 infection. 
  • Italian researchers announced that in a 123 patient trial, treatment with tocilizumab did not reduce admission to intensive care (28.3% vs. 27.0%) or 30-day mortality (3.3% vs. 3.2%) compared to placebo in patients with early-stage COVID-19 pneumonia.
  • In a 544 patient, retrospective Italian study, treatment with tocilizumab reduced the risk of mechanical ventilation or death, but had a higher incidence of new infections compared to standard of care alone after the patient sample was adjusted for sex, age, recruiting center, duration of symptoms, and Sequential Organ Failure Assessment (SOFA) score. Standard of care in Italy at the time of the study (February 21 to April 30, 2020) included treatment with oxygen, hydroxychloroquine, azithromycin, lopinavir–ritonavir or darunavir–cobicistat, and low molecular weight heparin.
  • In an observational trial, University of Michigan researchers examined outcomes in 154 mechanically ventilated patients with severe COVID-19 that received tocilizumab to those not receiving tocilizumab. Around a quarter of patients in each group received hydroxychloroquine and/or a corticosteroid and 3% received remdesivir. Patients that received tocilizumab were younger (55 vs. 60), less likely to have chronic pulmonary disease (10% vs. 28%), and lower D-dimer values (2.4 vs. 6.5 mg/dL). During a 47-day follow-up, tocilizumab patients had a higher rate of superinfections (54% vs. 26%), but a lower 28-day mortality rate (18% vs. 36%).
  • Roche announced that in the BARDA sponsored 28-day, 450 patient, Phase III COVACTA trial (NCT04320615), treatment with tocilizumab did not improve clinical status ventilator-free days or mortality compared to placebo in hospitalized patients with severe COVID-19-associated pneumonia. Patients treated with tocilizumab were discharged sooner than those in the placebo group (20 vs 28 days).
  • Roche announced that in the 28-day, 389 patient, Phase III EMPACTA trial (NCT04372186), 12.2% of patients treated with tocilizumab progressed to mechanical ventilation or death compared to 19.3% of patients treated with placebo in hospitalized patients with COVID-19 who did not require noninvasive or invasive mechanical ventilation. Almost 85% of patients were non-white with the majority being Hispanic, with inclusion of Native American and Black populations.
  • BARDA ceased funding IL-6 inhibitor trials evaluating tocilizumab and sarilumab as treatments for severe COVID-19 in August 2020. Tocilizumab and sarilumab have each failed to demonstrate improvements in clinical trials.
  • Clinical Trials
    • Roche and Gilead will compare the effect of tocilizumab plus remdesivir to placebo on clinical status, mortality, mechanical ventilation use and intensive care unit variables in the 60-day, 450 patient, Phase III REMDACTA trial (NCT04409262).
    • The 11,500 patient RECOVERY trial (NCT04381936) has several arms testing lopinavir-ritonavir, dexamethasone, hydroxychloroquine, azithromycin, tocilizumab and convalescent plasma.
  • Sarilumab (Kevzara, Regeneron, Sanofi) is an interleukin 6 (IL-6) monoclonal antibody. 
    • Sanofi and Regeneron discontinued a Phase III trial, when an interim analysis of 194 patients revealed that treatment with sarilumab did not improve the percentage of patients who achieved at least a 1-point change from baseline on a 7-point scale (death to hospital discharge) compared to placebo in COVID-19 patients requiring mechanical ventilation.
    • In a 28-day, 56-patient, observational study, 28 patients that received sarilumab were compared to 28 that did not receive the drug. Treatment with sarilumab did not improve clinical status or mortality in patients with severe COVID-19 pneumonia and systemic hyperinflammation. The study suggested that sarilumab may speed recovery in patients with minor lung consolidation at baseline. This study used a subset of patients from the Italian, 1,000 patient, COVID-BioB observational study (NCT04318366).
    • Sanofi announced that in a non-U.S., 420 patient, Phase III trial (NCT04327388), treatment with sarilumab did not improve symptoms compared to placebo in hospitalized patients with severe or critical COVID-19. 
    • BARDA ceased funding IL-6 inhibitor trials evaluating tocilizumab and sarilumab as treatments for severe COVID-19 in August 2020. Tocilizumab and sarilumab have each failed to demonstrate improvements in clinical trials.
    • Sanofi and Regeneron ceased evaluation of sarilumab in the treatment of COVID-19 in September 2020.
  • Siltuximab (Sylvant, EUSA Pharma) is an interleukin 6 (IL-6) monoclonal antibody. The drug is being evaluated in the Italian SISCO trial sponsored by EUSA. 
    • Sanofi and Regeneron discontinued a Phase III trial when an interim analysis of 194 patients revealed that treatment with sarilumab did not improve the percentage of patients who achieved at least a 1-point change from baseline on a 7-point scale (death to hospital discharge) compared to placebo in COVID-19 patients requiring mechanical ventilation. 
    • As of early July 2020, a Sanofi study evaluating sarilumab in the treatment of severe and critical COVID-19 remained active after an interim analysis. 
CM4620-IE is a CRAC channel inhibitor that may prevent cytokine storm in severe COVID-19 pneumonia is being developed by CalciMedica and evaluated in a Phase II trial.
PhaseBio is evaluating PB1046 as a treatment for hospitalized COVID-19 patients at risk for clinical deterioration and acute respiratory distress syndrome (ARDS) in the 210 patient, Phase II, VANGARD trial. The trial is expected to begin at the end of June with results from the trial expected by the end of 2020. PB1046 is an investigational vasoactive intestinal peptide (VPAC2) receptor-selective agonist being developed by PhaseBio as a treatment of pulmonary arterial hypertension.
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Baricitinib (Olumiant, Lilly), a JAK1 and JAK2 inhibitor. It is theorized that JAK inhibition may reduce cytokine storm associated with COVID-19 infection and decrease viral reproduction. 
  • Lilly is evaluating the effect of baricitinib on mortality or the need for ventilation/high flow oxygen in the 28-day, 400 patient, Phase III, COV-BARRIER trial (NCT04421027).
  • Lilly announced that in the 29-day, 1,034 patient, Phase III, ACTT 2 trial (NCT04401579), baricitinib added to remdesivir reduced the time to hospital discharge by one day (7 vs 8 days) compared to remdesivir alone in hospitalized patients with COVID-19. ACTT 2 is sponsored by NIAID. The largest effect was seen in patients requiring supplemental oxygen or high-flow oxygen/non-invasive ventilation. Lilly announced additional detailsfrom the Phase III, ACTT 2 trial (NCT04401579) where the largest benefit of adding baricitinib to remdesivir was seen in patients requiring supplemental oxygen or high-flow oxygen/non-invasive ventilation.
  • Lilly is discussing an EUA with the FDA for baricitinib as a treatment for COVID-19.
Lenzilumab is a GM-CSF monoclonal antibody being developed to suppress the cytokine storm seen in graft-versus-host disease and with CAR-T cancer therapies. Because of lenzilumab effect on decreasing cytokine storm, Humanigen is evaluating the drug as a treatment for severe COVID-19 pneumonia. 
  • An unpublished, unedited article described 12 patients with severe COVID-19 pneumonia treated under an FDA emergency IND with lenzilumab. Treatment with lenzilumab resulted in at least a 2-point improvement in an 8-point scale (death to discharged) in 11/12 of patients. 
  • Humanigen is evaluating lenzilumab as a treatment for immune-mediated cytokine release syndrome in patients with severe COVID-19 pneumonia in a 238 patient, Phase III trial (NCT04351152).
  • NIAID is comparing lenzilumab plus remdesivir to remdesivir monotherapy on the need for mechanical ventilation in hospitalized patients with COVID-19, in the 28-day, 200 patient, BIG EFFECT trial (NCT04351152).
Mavrilimumab is a granulocyte macrophage colony stimulating factor antagonist and is being developed by MedImmune as a treatment for rheumatoid arthritis. By inhibiting GM-CSK, mavrilimumab is thought to prevent the activation or amplification of several pro-inflammatory cytokine pathways leading to a reduction in inflammation caused by cytokine storm in severe COVID-19 pneumonia.
  • In a 28-day, 39 patient trial, all patients treated with mavrilimumab (n=13) plus hydroxychloroquine, azithromycin and lopinavir–ritonavir improved by two or more points (7-point scale of death to discharge) compared to 65% treated with hydroxychloroquine, azithromycin and lopinavir–ritonavir without mavrilimumab (n=26) in non-ventilated patients COVID-19 pneumonia and systemic hyperinflammation.
  • Kiniksa Pharmaceuticals is evaluating mavrilimumab in the treatment of severe COVID-19 pneumonia and systemic hyperinflammation in a 15-day, 573 patient, Phase II/III trial (NCT04447469).
An article posted on an editorial server describes compassionate use of opaganib in Israel for the treatment of severe COVID-19 (NCT04435106) in five patients and compared the results to an investigator-selected matched case-control group of 18 patients. All opaganib-treated patients were discharged on room air and none required ventilation, while 33% of standard care patients required mechanical ventilation. All patients in both groups received hydroxychloroquine and most also received azithromycin. Redhill Biopharm is initiating a 40 patient, Phase IIa U.S. trial (NCT04414618) that will evaluate opaganib in treatment of patients with severe COVID-19 pneumonia requiring hospitalization and supplemental oxygen. Redhill is also planning a European, 270 patient, Phase II/III trial and a Phase II/III in Mexico.

PTC299, a dihydroorotate dehydrogenase (DHODH) inhibitor that is being developed by PTC Therapeutics as a treatment for acute myeloid leukemia. PTC299 has been shown in vitro to inhibit replication of the SARS-CoV-2 virus and modulate the immune response by attenuating the stress-induced inflammatory cytokine storm.
  • The effect of PTC299 on respiratory symptoms is being evaluated in a 40 patient Phase II trial, followed by a 340 patient Phase III trial.
Tradipitant is a neurokinin-1 receptor (NK-1R) antagonist being developed by Vanda Pharmaceuticals for the treatment of diabetic gastroparesis, motion sickness, and atopic dermatitis. By inhibiting NK-1R, tradipitant is thought to decrease inflammatory lung injury associated with severe or critical COVID-19 pneumonia.
  • Vanda Pharmaceuticals reported that interim results from 60 COVID-19 patients enrolled in the 28-day, 300 patient, Phase III, ODYSSEY trial (NCT04326426), where a 14-day treatment with tradipitant reduced the time to improvement after 7-days compared to placebo. Despite a numerical advantage, the improvement was not significant at 28 days (10 days vs 28 days), likely due to the small number of patients. There was also no statistical difference between tradipitant and placebo in the overall percentage of patients improving (57% vs 50%) or mortality (14.2% vs 16.6%).