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 issued a new EUA for remdesivir for hospitalized children age 12 and older that weigh at least 3.5 kg (7.7 lbs) but less than 40 kg, and in children under age 12 that weigh at least 3.5 kg.
• 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). However, the  SOLIDARITY trial, did not find an improvement in hospitalized COVID-19 patients.
• We have a dedicated page to provide more details on remdesivir
• An unpublished and unedited invitro study that tested the antiviral effects of plitidepsin, ralimetinib and remdesivir on early SARS-CoV-2 and the B.1.1.7 variant found similar activity with both viral strains. 

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
• 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.

• The FDA has granted aviptadil Fast Track status 
• Aviptadil is available under an Expanded Access Protocol (NCT04453839) for the treatment of patients with COVID-19 and Respiratory Failure
• 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).

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..

Lenzilumab is a monoclonal antibody that neutralizes granulocyte macrophage colony stimulating factor (GM-CSF). The drug is being developed by Humanigen as a treatment for Chronic Myelomonocytic Leukemia and Large B-cell Lymphoma.

• Humanigen is investigating lenzilumab as a treatment for cytokine storm in COVID-19 patients with severe or critical COVID-19 pneumonia in a 300 patient, Phase III trial.
• NIAID is comparing lenzilumab plus remdesivir to remdesivir alone in the treatment of hospitalized patients with COVID-19 in the 200 patient, Phase II, BET-B trial (NCT04583969).

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 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.

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.

• Molnupiravir is an oral drug that is dosed twice a day for 5 days.
• ​Based on interim results from the MOVe-OUT study, Merck plans to file for an EUA and have 10 million doses available by the end of 2021.
• Ridgeback Biopharmaceuticals called the drug 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.
  • 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.
  • Merck announced interim results from 775 patients enrolled in the 29-day, 1,550 patient, Phase II/III, MOVe-OUT trial (NCT04575597), where 7.3% of patients treated with molnupiravir were hospitalized or died compared to 14.1% with placebo in outpatients with mild-to-moderate COVID-19 with at least one risk factor 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.

Redhill Biopharm is evaluating opaganib 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).

PF-07321332 in combination with ritonavir is being evaluated by Pfizer for the treatment of COVID-19. PF-07321332 is a protease inhibitor. It is administered with ritonavir to slow the metabolism of PF-07321332, to increase its half-life. 

• Pfizer initiated a trial to evaluate PF- 07321332 in combination with ritonavir in the treatment of COVID-19 in a 28-day, 1,140 Phase III trial (NCT05011513), in symptomatic patients who have not been hospitalized and aren’t at high risk of severe illness

Plitidepsin is an eEF1A2 Inhibitor being developed by PharmaMar to treat multiple myeloma. Plitidepsin demonstrated in-vitro antiviral activityagainst 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.
• PharmaMar announced that in a 45 patient, Phase I trial (NCT04382066), treatment with plitidepsin reduced viral load in hospitalized COVID-19 patients and all patients were symptom free at the 30-day trial visit.
• An unpublished and unedited invitro study that tested the antiviral effects of plitidepsin, ralimetinib and remdesivir on early SARS-CoV-2 and the B.1.1.7 variant found similar activity with both viral strains. 
• A Phase III trial is being planned.

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).

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.