Recommended antivirals for the treatment of COVID-19	Approved drugs being evaluated for the treatment of COVID-19	Investigational Drugs being evaluated for the treatment of COVID-19	Drugs not shown to be effective ​for the treatment of COVID-19
Nirmatrelvir/ritonavir – EUA Remdesivir – FDA approved ​Molnupiravir – EUA ​	Aviptadil - EAP for COVID-19 ​G-CSF ​Risankizumab ​ ​	AT-527                    Galidesivir CPI-006.                Leronlimab CYNK-001             Opaganib ​Ensovibep.             Plitidepsin ​ ​	Azithromycin                 Ivermectin ​Favipiravir.                      Vidofludimus Lopinavir/ritonavir        Vitamin D Hydroxychloroquine/Chloroquine ​

ICER provided a review of drugs for outpatient treatment of COVID-19. ICER found that compared to symptomatic treatment:

1. Nirmatrelvir/ritonavir (Paxlovid) - evidence was adequate to support a health benefit (13-0 to support a benefit).
2. Molnupiravir - evidence was inadequate to support a health benefit (11-2 for no benefit).
3. Fluvoxamine - evidence was inadequate to support a health benefit, but the vote was 7-6 in favor of a benefit. However, NIH has determined there is not enough evidence to recommend for or against the use of fluvoxamine to treat COVID-19.​ The FDA also did not find sufficient evidence to support use of the drug to treat COVID-19.

Due to differences in trial population demographics, ICER did not feel the drugs could be compared based on current evidence. 
 
All three drugs were found to be cost effective, with a quality-of-life year gained (QALY) < $100,000. The cost of an averted hospitalization was also < $100,000.

1. Paxlovid was found to have high long-term value.
2. Molnupiravir, was found to low-to-intermediate long-term value.
3. Fluvoxamine was found to have intermediate-to-high long-term value.

​
Nirmatrelvir in combination with ritonavir (Paxlovid, Pfizer) is being evaluated for the treatment of COVID-19. Nirmatrelvir is a protease inhibitor. It is administered with ritonavir to slow the metabolism of nirmatrelvir and increase its half-life. 

• The FDA granted an emergency use authorization (EUA) for the combination of nirmatrelvir and ritonavir (Paxlovid, Pfizer), on 12/22/21, for the treatment of mild-to-moderate COVID-19 in patients 12 years of age and older weighing at least 88 pounds who are at high risk for progression to severe COVID-19. The treatment is dosed as two tablets of nirmatrelvir and one tablet of ritonavir taken together orally twice daily for five days. Please see the Fact Sheet for Healthcare Providers and Fact Sheet for Patients and Caregivers for additional information. NIH has provided a reference page to describe drug interactions and their management for Paxvolid (ritonavir-boosted nirmatrelvir).
• The FDA has provided additional information about use of Paxlovid in a 5/4/2022 posting. The FDA addresses reports of rare infection recurrences after completing a course of the drug combination. A re-analysis of Paxlovid data found that while 1-2% of patients may test positive after treatment, it was unclear whether this was a drug effect, because the same results were seen in placebo patients (tested negative, then tested positive). Based on limited information, the CDC found that COVID-19 rebound usually occurs 2 to 8 days after initial recovery and include COVID-19 symptoms or a new positive viral test after having tested negative. The natural course of COVID-19 may include a brief return of symptoms, regardless of treatment or vaccine status. Current cases of rebound COVID-19 rebound after Paxlovid have been mild. There is no evidence to support use of the Paxlovid beyond five days, but the CDC recommends following Guidance on Quarantine and Isolation. 
• ​In the 28-day, 1,379 patient, Phase II/III, EPIC-HR trial (NCT04960202), where 0.72% of patients treated with the combination of nirmatrelvir and ritonavir were hospitalized with no deaths compared to 6.45% who were hospitalized or died with placebo in unvaccinated patients with mild-to-moderate COVID-19 at risk to progress to severe illness.
• Pfizer announced that in the 14-day, 2,597 patient, Phase II/III, EPIC-PEP trial (NCT05047601), prophylactic treatment with nirmatrelvir plus ritonavir did not reduce the risk of developing symptomatic COVID-19 compared to placebo in healthy patients exposed to a patient that developed COVID-19.
• Pfizer announced that in the 28-day, 1,153 patient, Phase II/III, EPIC-SR trial (NCT05011513), treatment with nirmatrelvir plus ritonavir did not increase resolution of symptoms compared to placebo in patients with COVID-19, who were at standard risk for developing severe COVID-19.
• A 47 patient case series from the Johns Hopkins Health System, found that treatment with nirmatrelvir and ritonavir was well tolerated in pregnant patients with COVID-19. Two patients had to discontinue treatment due to adverse effects. Data was available from 25 patients that delivered after receiving nirmatrelvir and ritonavir with no adverse effects, but almost half underwent cesarean delivery.

Remdesivir – Nucleotide analogue RNA polymerase inhibitor

• The FDA approved remdesivir (Veklury, Gilead), on 10/22/2020, for the treatment of hospitalized COVID-19 patients that are 12 and up and weigh at least 40 kg (88.2 lbs).
• The FDA expanded approval for remdesivir, on 4/25/2022, for children 28 days and older, who weigh at least 3 kg (7 lbs), if they are hospitalized or outpatients at high risk for progression to severe COVID-19. 
• The FDA expanded the EUA for remdesivir to include a three-day outpatient course in non-hospitalized patients with mild-to-moderate COVID-19 at high risk to progress to severe disease.
• Use of remdesivir is based on data from the Phase III, Adaptive COVID-19 Treatment Trial (ACTT-1) trial (NCT04280705) and the  Phase III, SIMPLE trial (NCT04292899). The  SOLIDARITY trial, found an a decease in mortality in hospitalized COVID-19 patients not on a ventilator, but there was no improvement in patients already on a ventilator.
• We have a dedicated page to provide more details on remdesivir

Molnupiravir (MK-4482) is a ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2. Molnupiravir is being developed by Merck after licensing the drug from Ridgeback Biotherapeutics. Ridgeback Biotherapeutics began developing molnupiravir while the deal with Merck was begin reviewed. 

• The FDA granted an emergency use authorization (EUA) for molnupiravir (Lagevrio, Merck), on 12/23/21, for the treatment of mild-to-moderate COVID-19 in patients 18 years of age and older who are at high risk for progression to severe COVID-19 and alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate. The treatment is dosed as four tablets twice daily for five days. Molnupiravir is not recommended for use during pregnancy. Please see the Fact Sheet for Healthcare Providers and Fact Sheet for Patients and Caregivers for additional information. Merck will begin shipping 3.1 million doses of molnupiravir to the U.S. government as soon as a final label is approved by the FDA.
• The FDA granted an emergency use authorization (EUA) for molnupiravir (Lagevrio, Merck), on 12/23/21, for the treatment of mild-to-moderate COVID-19 in patients 18 years of age and older who are at high risk for progression to severe COVID-19 and alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate. The treatment is dosed as four tablets twice daily for five days. Molnupiravir is not recommended for use during pregnancy. Please see the Fact Sheet for Healthcare Providers and Fact Sheet for Patients and Caregivers for additional information. Merck will begin shipping 3.1 million doses of molnupiravir to the U.S. government as soon as a final label is approved by the FDA.
• The United Kingdom Medicines and Healthcare products Regulatory Agency approved molnupiravir for the treatment of mild-to-moderate COVID-19 in adults at risk to develop severe illness. 
• Ridgeback Biopharmaceuticals classified the drug as EIDD-2801
  • Ridgeback announced that in a 15-day, 122 patient, Phase I trial (NCT04392219), administration of molnupiravir produced no safety issues at serum levels estimated to reduce pulmonary virus levels.
  • Ridgeback initiated a 28-day, 60 patient Phase II trial (NCT04405739) in June 2020 that is evaluating the effect of molnupiravir on clearing SARS-CoV-2 in hospitalized patients with COVID-19 pneumonia.
  • Ridgeback initiated a 28-day, 44 patient Phase II trial (NCT04405570) in June 2020 that is evaluating the effect of molnupiravir on clearing SARS-CoV-2 in non-hospitalized patients with COVID-19 pneumonia.
• Merck took over development of molnupiravir in July 2020 and changed the research code from EIDD-2801 to MK-4482. The drug then was given the generic name, molnupiravir. The FDA’s Antimicrobial Drugs Advisory Committee (AMDAC) will review molnupiravir for the treatment of mild-to-moderate COVID-19 in adults at high risk for progression to severe COVID-19, including hospitalization or death on 11/30/2021.Merck announced results from a secondary endpoint in a preliminary report from 182 patients enrolled in a Phase IIa trial (NCT04405570), where 24% of patients treated with molnupiravir achieved a negative cell culture on day five compared to none that received placebo in adult outpatients with symptomatic COVID-19. Merck plans a full presentation of trial results at a future meeting.
  • Merck announced interim results from the 304 patients enrolled in the 29-day, 1,300 patient, Phase II/III, MOVe-IN trial (NCT04575584), where molnupiravir did not improve the percentage of patients that achieved sustained recovery compared to placebo in hospitalized patients with COVID-19. Merck discontinued the MOVe-IN trial, because the interim results did not demonstrate a clinical benefit with molnupiravir. 
  • In the 29-day, 304 patients, Phase II, MOVe-IN trial (NCT04575584), molnupiravir did not improve the percentage of patients that achieved sustained recovery compared to placebo in hospitalized patients with COVID-19. Merck discontinued the Phase III portion of MOVe-IN trial because the Phase II results did not demonstrate a clinical benefit with molnupiravir.
  • In the 29-day, 1,443 patient, Phase II/III, MOVe-OUT trial (NCT04575597), 6.8% of patients treated with a five-day course of molnupiravir were hospitalized or died compared to 9.7% with placebo in unvaccinated outpatients with mild-to-moderate COVID-19 with at least one risk factor to progress to severe disease. An interim analysis from 775 patients had suggested that 7.3% of patients treated with molnupiravir were hospitalized or died compared to 14.1% with placebo.
  • In the 28-day, 26,411 patient, open-label, PANORAMIC trial, adding molnupiravir to usual care did not decrease hospitalization or mortality compared to placebo in vaccinated UK outpatients with mild-to-moderate COVID-19 at risk to progress to severe disease.
  • Merck has entered an agreement with the U.S. government that if molnupiravir receives an EUA or is approved for the treatment of COVID-19, Merck will supply the U.S. with 1.7 million doses of molnupiravir for $1.2 billion.
  • Merck initiated a trial to evaluate molnupiravir in the prevention of COVID-19 in the 14-day, 1,332 Phase III, MOVe-AHEAD trial (NCT04939428), in adults who live with a symptomatic patient with a confirmed coronavirus infection.

AT-527 is an antiviral being developed by Atea Pharmaceuticals to treat Hepatitis C. AT-527 is a purine nucleotide prodrug that inhibits viral replication by interfering with viral RNA polymerase. The drug has demonstrated in vitro and in vivo antiviral activity against enveloped single-stranded RNA viruses, such as human flaviviruses and coronaviruses. Due to activity on coronaviruses, Atea began developing the drug as a treatment for COVID-19. Roche licensed development and marketing rights for AT-527 outside the U.S.

• AT-527 is an oral drug given once on day one, then twice a day for a total of 5-days
• Roche and Atea Pharmaceuticals announced that in the seven-day, 100 patient, Phase II, MOONSONG Trial (NCT04709835), treatment with AT-527 did not reduce viral load compared to placebo in non-hospitalized patients with mild to moderate COVID-19. MOONSONG included vaccinated patients, which could have affected the outcome.
• Atea is evaluating AT-527 in a 190 patient, Phase II trial (NCT04396106) in hospitalized patients 45 to 80 with moderate COVID-19.
• Roche and Atea Pharmaceuticals will evaluate AT-527 for the treatment of COVID-19 in the 1,400 non-hospitalized patient, Phase III MORNINGSKY trial.

Aviptadil (RLF-100) is a synthetic human Vasoactive Intestinal Polypeptide. Aviptadil blocks the replication of the SARS coronavirus in human lung cells and monocytes. The drug has been in clinical trials since 2001 and was unsuccessfully evaluated for Acute Respiratory Distress Syndrome and Pulmonary Arterial Hypertension.

• Aviptadil is available under an Expanded Access Protocol (NCT04453839) for the treatment of patients with COVID-19 and Respiratory Failure.
• The FDA rejected a request for an EUA for aviptadil to treat critical COVID-19 with respiratory failure and to treat COVID-19 patients, in November 2021.
• In June 2022, the FDA rejected a request for an EUA for aviptadil to treat COVID-19 respiratory failure patients who continue to worsen, despite treatment with remdesivir.
• NeuroRx is evaluating inhaled aviptadil for the treatment of moderate and severe COVID-19 patients who have not yet developed respiratory failure in a 288 patient, Phase II/III trial (NCT04360096)
• NeuroRx is evaluating intravenous aviptadil for the treatment of hospitalized patients with a Critical COVID-19 infection and respiratory failure in a 144 patient, Phase II trial (NCT04311697)
• An unpublished case study describes a double lung transplant patient that developed a COVID-19 infection with respiratory failure. The patient received three intravenous infusions of aviptadil and saw improvement within 24 hours of the third infusion. The patient was discharged home on room air one week later.
• NeuroRx  has said that similar results to the case study have been seen in 15 additional patients treated with aviptadil under the Expanded Access Protocol.

Azithromycin: In vitro evidence suggested potential activity of azithromycin against SARS-CoV-2, but clinical trials have not found a benefit. NIH recommends against the use of azithromycin with or without chloroquine or hydroxychloroquine in the treatment COVID-19.

• The 14-day, 263 patient, Phase III, ACTION trial (NCT04332107) was terminated early after an interim analysis failed to find an increase in symptom free days or hospitalizations at 21 days with azithromycin compared to placebo in outpatients with COVID-19
• In the 28-day, 292 patient, Phase III, ATOMIC2 trial (NCT04381962), treatment with azithromycin did not decrease hospitalization or mortality compared to placebo (10% vs 12%) in outpatients with COVID-19.
• In the 28-day, 1,323 patient, Phase III, PRINCIPLE trial, treatment with azithromycin did not decrease the percentage of patients recovered (80% vs 77%), hospitalized (3% each) or who died (0% each) compared to placebo in outpatients with COVID-19 at high risk to progress to more severe disease.

CPI-006 is a monoclonal antibody for CD73 that activates lymphocytes, induces the production of antigen-specific immunoglobulin from B cells and increases levels of CD4+ and CD8+ cells. CPI-006 is being developed by Corvus Pharmaceuticals as a cancer treatment.

• Corvus is evaluating a single dose of CPI-006 as a treatment of mild to moderate COVID-19, in a 30 patient, Phase I, dose-ranging trial (NCT03454451).
• An unpublished report describes how CPI-006 induced a rise in anti-SARS-CoV-2 antibodies at 7-days that continued to increase through day 56. ​
• Corvus announced data from 15 patients in the study that supported an increase in anti-SARS-CoV-2 antibodies through day 56 and an increase in B cell activation.

CYNK-001 is an allogeneic, natural killer cell therapy derived from placental hematopoietic stem cells. Natural killer cells limit virus replication by killing virus infected cells. CYNK-001 is being developed by Celularity as a chemotherapy agent. Celularity has an agreement with Sorrento Therapeutics for rapid scale up of manufacturing if clinical trials demonstrate a benefit.

• Celularity is evaluating CYNK-001 as a treatment for COVID-19 in an 86 patient, Phase I/II trial (NCT04365101).

Ensovibep – a DARPin (Designed Ankyrin Repeat Protein) antiviral is being developed by Novartis and Molecular Partners as a treatment for COVID-19. DARPins are mono or multi-specific protein-based therapies. Ensovibep has three individual DARPin domains that block receptor-binding in the SARS-CoV-2 virus causing strong neutralization of the virus.

• Ensovibep is administered as a single dose IV infusion.
• In vitro testing has demonstrated high neutralization activity against all known SARS-CoV-2 variants, including the variants of concern: Alpha, Beta, Gamma, Delta and Omicron
• Novartis, with Molecular Partners announced data from 407 patients enrolled in the dose-ranging Part A of the 2,100 patient, Phase II/III, EMPATHY trial (NCT04828161), where 1.3% of patients were hospitalized or required an ER visit with ensovibep compared to 6% with placebo in vaccinated and unvaccinated, non-hospitalized symptomatic COVID-19 patients. All doses lowered viral load over eight days compared to placebo.
• Novartis, with Molecular Partners are evaluating a single dose of ensovibep 75 mg on the occurrence of hospitalizations, emergency room visits or death in COVID-19 patients enrolled in the 29-day, 1,700 patient, Part B of the Phase II/III, EMPATHY trial (NCT04828161).

Favipiravir - inhibits RNA-dependent RNA polymerase (RdRp). The drug was approved in Japan in 2014 as an influenza treatment when other influenza treatments failed. Favipiravir is not available in the U.S. or Europe. 

• There are currently no well-designed trials evaluating favipiravir in the treatment of COVID-19.
• Fujita Health University researchers announced that in an 89 patient trial, treatment with favipiravir did not improve COVID-19 symptoms compared to placebo in patients with early-stage COVID-19.
• Glenmark Pharmaceuticals announced that in a 150 patient, open-label, Indian Phase III trial, treatment with favipiravir added to supportive care resulted in 28.6% faster viral clearance and a 40% faster attainment of clinical cure compared to supportive care alone in patients with mild to moderate COVID-19. Patients were initiated on favipiravir within 48-hours of a positive test. Glenmark did not specify whether other antivirals were included in standard supportive care in India.
• Interim results from 60 patients enrolled in a Russian COVID-19 trial, suggested that on day 5, treatment with favipiravir cleared SARS-CoV-2 in 62.5% of patients compared to 30% of patients on standard of care. There was no difference in clearance by day 10 (92.5% vs 80%). Most patients in the standard of care group received hydroxychloroquine, chloroquine or lopinavir/ritonavir. Standard of care treatment was not described, but included antibiotics, anticoagulants and/or immunosuppressants, as well as symptomatic treatment. Body temperature normalized 2 days earlier with favipiravir (2 days vs 4 days), but there was no difference in chest CT scan.
• Toyama announced that 156 patient, Phase III trial, patients treated with favipiravir cleared SARS-CoV 2 viral RNA in 11.9 days compared to 14.7 days with placebo in Japanese patients with COVID-19 and non-severe pneumonia.
• In an 89 patient trial in Oman, favipiravir and nebulized interferon beta-1b did not improve time to recovery, decrease in inflammatory markers nor improvement in oxygenations compared to hydroxychloroquine in hospitalized patients with moderate to severe COVID-19 pneumonia. Almost all patients also received antibiotics, one-third received tocilizumab, two-thirds received a corticosteroid and over half received convalescent plasma.​

Galidesivir is an adenosine nucleoside analog that blocks viral RNA polymerase. The drug was originally being developed as a treatment for yellow fever. A computer model suggested that galidesivir would bind to the RNA-dependent RNA polymerase of SARS-CoV-2 and potentially be a treatment for COVID-19. BARDA and NIAID are providing funds for the development of galidesivir.

• BioCryst is evaluating galidesivir (NCT03891420) in the treatment of COVID-19 and Yellow Fever in a 132 patient, Phase I, placebo-controlled, Brazilian trial that began in April 2020.

Granulocyte colony-stimulating factor (G-CSF) was evaluated as a treatment for COVID-19 in a Chinese trial. G-CSF increases peripheral blood leukocyte and lymphocyte and was theorized to be beneficial in COVID-19 patients with lymphopenia. Filgrastim (Neupogen, Amgen) is a G-CSF. Lenograstim is a G-CSF developed by Chugai and available in some countries as Granocyte.

• In a 21-day. 200 patient, Chinese trial, treatment with G-CSF improved a 7-category disease severity score by at least 1 point in 12 days vs 13 days with usual care in patients with COVID-19 with lymphopenia but no comorbidities. A small number of patients used interferon (9%), lopinavir/ritonavir (15%) or arbidol (18%) before enrollment.​

Hydroxychloroquine and chloroquine - As of July 8, 2021, Per the recommendation of the National Institute of Health (NIH), neither chloroquine nor hydroxychloroquine are recommended for the outpatient treatment of COVID 19.

​Argument against using drugs

• Per the Recovery Trial, Hydroxychloroquine was not found to decrease the mortality rate compared to the standard of care. This was due to the mortality rate being similar for both patients with standard of care (25%) and hydroxychloroquine (27%). The death rate was higher for hydroxychloroquine, but this could be due to the usual care having a higher number of patients and thus the results could be diluted.
• Per WHO, hydroxychloroquine and chloroquine are not recommended for the treatment of COVID 19 due to studies not showing any evidence of the drug having a lower mortality rate compared to the standard care.

Arguments for using hydroxychloroquine and chloroquine

• Early in the Pandemic, hydroxychloroquine and chloroquine were recommended as a treatment of COVID by the health guidelines from the following countries: China, South Korea, Italy, France, and the Netherlands. In addition, the United States gave hydroxychloroquine emergency use authorization for the use of treatment of COVID 19, but later rescinded the EUA.

Neither the FDA nor the NIH recommend Ivermectin for the treatment of COVID 19 due to lack of empirical evidence.  Per the FDA, clinical studies are currently ongoing. Thus, the FDA won’t grant approval until studies provide evidence suggesting that ivermectin treats COVID 19 efficiently. Additional details on ivermectin studies can be found here.

Leronlimab is a monoclonal antibody that blocks the CCR5 chemokine receptor, which results in an inhibition of a virus’ ability to enter leukocytes. Leronlimab was originally developed by CytoDyn as a treatment for HIV-1 infection.

• Among 23 hospitalized severe or critical COVID-19 patients that were treated with leronlimab through a compassionate use protocol, 17 had recovered by day 30, two were still hospitalized and four died. Most patients also received or had received convalescent plasma, hydroxychloroquine, steroids, tocilizumab, remdesivir, sarilumab and/or selinexor. 
• CytoDyn is evaluating leronlimab, as a treatment for mild-to-moderate COVID-19 in a 14-day, 86 patient, Phase II trial (NCT04343651).
• CytoDyn announced that in a 28-day, 390 patient, Phase IIb/III trial (NCT04347239), treatment with leronlimab did not decrease mortality compared to placebo in patients with severe or critical COVID-19. However, leronlimab did decrease mortality and hospital duration in a subset of patients receiving mechanical ventilation. An age adjusted analysis also found a mortality decease in the subset of patients under 65.
• Due to the volume of press releases from CytoDyn, the FDA provided a “Statement on Leronlimab” stating that neither an 86 patient trial in mild-to-moderate COVID-19 infection, nor a 394 patient trial in patients with severe disease provided evidence to support a benefit in using leronlimab in the treatment of COVID-19. The FDA does not feel that a positive finding in a sub-group supports use of the drug, rather it suggests design parameters for a new trial.
• The FDA placed a partial hold on leronlimab HIV trials and a full hold on leronlimab COVID-19 trials in the United States. At the same time, CytoDyn decided to place a hold on its leronlimab COVID-19 Brazilian trial pending review of two cardiac events by the data safety monitoring board.

The combination of lopinavir and ritonavir inhibits protease, which prevents viral replication and is FDA approved as an HIV treatment. Both drugs are available as generics). Initial case studies and case reports from China, Korea and Singapore suggested activity against COVID-19. 

• NIH recommends against using lopinavir/ritonavir or other HIV protease inhibitors for the treatment of COVID-19, except as part of a clinical trial.
• A Chinese trial did not find a benefit with lopinavir and ritonavir, but an editorial questioned if the late start of treatment may have decreased the combination’s activity.
• Interim results from the WHO sponsored, 11,330 patient, Phase II/III SOLIDARITY trial (NCT04315948), did not find an improvement in hospitalized COVID-19 patients treated with remdesivir, hydroxychloroquine, lopinavir or interferon compared to no drug in mortality, initiation of ventilation or duration of hospital stay. But some analysts did not agree with the study’s findings. A physician reviewer speculated that remdesivir may be more effective when given early in the infection to patients at high risk for progression. An editorialist highlighted the benefit of remdesivir“to change the course of hospitalization in some patients”. A second editorialist pointed out that SOLIDARITY was not designed to measure time to recovery or clinical improvement. The WHO discontinued the lopinavir/ritonavir arm of the Solidarity Trial in July 2020.
• French researchers prospectively monitored the heart rhythms of 41 hospitalized COVID-19 patients being treated with lopinavir and ritonavir and found that 22% (nine patients) experienced bradycardia at least 48 hours after initiating the drugs.
• In the 90-day, 685 patient, Phase III, TOGETHER trial (NCT04403100), neither hydroxychloroquine nor lopinavir-ritonavir reduced hospitalization or death in high-risk, Brazilian outpatients with early symptomatic COVID-19.

Metformin - NIH recommends against the use of metformin to treat COVID-19 except in a clinical trial, due to the lack of evidence to support use in the TOGETHER and COVID-OUT trials.

Opaganib is being evaluated by Redhill Biopharm as a treatment for COVID-19. Opaganib is an orally administered, sphingosine kinase-2 (SK2) selective inhibitor. The drug has both anti-inflammatory and antiviral activity, which targets viral replication, potentially minimizing the likelihood of viral resistance. Opaganib is being developed for the treatment of cholangiocarcinoma and prostate cancer. Opaganib demonstrated antiviral activity against SARS-CoV-2 in-vitro.

• 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 announced that in a 14-day, 40 patient, Phase IIa U.S. trial (NCT04414618), 50% of patients treated with opaganib did not require oxygen compared to 22% with placebo in hospitalized patients with severe COVID-19 pneumonia requiring supplemental oxygen. 86.4% in the opaganib group were discharged by Day 14 compared to 55.6% with placebo. Most patients received dexamethasone and/or remdesivir
• Redhill is evaluating the effect of opaganib on the need for mechanical ventilation in a 475 patient, Phase II/III trial (NCT04467840).
• Redhill announced that in a 437 patient, Phase II/III trial (NCT04467840), treatment with opaganib decreased time to viral RNA clearance by at least 4 days compared to placebo in hospitalized patients with severe COVID-19 pneumonia. A subset analysis of 251 patients with an FiO2 of up to 60% found a 62% reduction in mortality. Another subset analysis of 90 patients who were also treated with remdesivir, and corticosteroids found a 70.2% decrease in mortality with the addition of opaganib (6.98% vs 23.4%).

Plitidepsin is an eEF1A2 Inhibitor being developed by PharmaMar to treat multiple myeloma. Plitidepsin demonstrated in-vitro antiviral activity against a coronavirus similar to SARS-CoV-2.

• Plitidepsin is administered as an intravenous infusion and given once per day for a total of 3-days.
• An in vitro study that tested the antiviral effects of plitidepsin on wild-type SARS-CoV-2 and the Alpha, Beta, Delta, Mu and Omicron variants found good activity with all variants. 
• In a 46 patient, Phase I, APLICOV-PC trial (NCT04382066), a three-day treatment with plitidepsin reduced SARS-CoV-2 viral load with a mean time to undetectable levels of 13 days in hospitalized COVID-19 patients.
• Plitidepsin is being evaluated as a treatment for COVID-19 in the 8-day, 609 patient, Phase III, NEPTUNO trial (NCT04784559).

Risankizumab (Skyrizi, Boehringer Ingelheim and AbbVie) is a monoclonal antibody approved for the treatment of severe plaque psoriasis.

• NIAID is comparing risankizumab plus remdesivir to remdesivir alone in the treatment of hospitalized patients with COVID-19 in the 200 patient, Phase II, BET-A trial (NCT04583956).

S-217622 is a 3CL protease inhibitor, which blocks replication of SARS-CoV-2. Shionogi is evaluating an oral five-day course of S-217622 for the treatment of COVID-19.

• Shionogi announced that in the Phase IIa portion of a Phase II/III trial, S-217622 decreased viral titers by 60-80% compared to placebo by day four and decreased the time to viral clearance by two days in Japanese patients with mild, moderate, or asymptomatic COVID-19.

Vitamin D has been suggested as having immunomodulatory and anti-inflammatory properties, so Brazilian researchers evaluated, whether a single dose would have a beneficial effect on patients with COVID-19. 

• In a 237 patient Brazilian trial (NCT04449718), treatment with a single dose of vitamin D3 200 000 IU did not reduce length of stay, mortality, ICU admission or mechanical ventilation compared to placebo in patients with COVID-19.

Vidofludimus (IMU-838) is a dihydroorotate dehydrogenase (DHODH) inhibitor being developed by Immunic Therapeutics for the treatment of multiple sclerosis, inflammatory bowel disease and sclerosing cholangitis. DHODH inhibitors have host-based antiviral effects that are independent to specific virus proteins and their structure. Since the anti-viral properties may be applicable to many viruses, Immunics is evaluating vidofludimus as a treatment for COVID-19.

• Immunic announced interim data from 204 patients enrolled in the 28-day, 204 patient, Phase II CALVID-1 trial (NCT04379271), where treatment with vidofludimus did not reduce the need for invasive ventilation compared to placebo in hospitalized patients with moderate COVID-19. Investigators report the rate of ventilation was only 1%, which was lower than seen earlier in the pandemic. Clinical recovery and time to clinical improvement were improved with vidofludimus. Immics plans to announce the full results of the CALVID-1 trial in 2Q21.

Upamostat (RHB-107), a human serine protease inhibitor, is being developed by RedHill Biopharma as a treatment for COVID-19. 

• Upamostat  is being evaluated in a 57-day, 310 patient, Phase II/III trial (NCT04723527) for treatment of patients with symptomatic COVID-19 who do not require inpatient care. 
• In the 61 patient, Phase II portion of the Phase II/III trial, 0/41 patients who were treated with RHB-107 were hospitalized compared to 3/20 with placebo in in non-hospitalized patients with symptomatic COVID-19. New severe symptoms were experienced by 1/41 patients treated with upamostat and 4/20 who received placebo.
• The Phase III portion of the Phase II/III trial will examine the effect of upamostat on time to sustained recovery from symptomatic illness.