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.
In the 28-day, 464 patient, open-label, PLACID trial, treatment with convalescent plasma did not reduce progression to severe disease or all-cause mortality (19% vs 18%), despite an almost 20% greater conversion to a negative SARS-CoV-2 test on day seven in hospitalized Indian patients with moderate COVID-19. Patients in the trial were treated with antivirals (hydroxychloroquine, remdesivir, lopinavir/ritonavir, oseltamivir), broad spectrum antibiotics and immunomodulators (steroids, tocilizumab).
The FDA allowed the Phase III trial for AstraZeneca’s coronavirus vaccine, AZD1222, to resume in the US, on 10/23/2020 after an FDA review of all safety data concluded the vaccine was safe.
Johnson & Johnson will resume the Phase III ESEMBLE trial in October 2020, after a Data Safety and Monitoring Board review found no evidence that COVID-19 vaccine candidate, Ad26.COV2-S, caused a serious medical event experienced by one study participant.
COVID-19 Monoclonal Antibodies
Lilly announced that NIAID discontinued the Phase III, ACTIV-3 trial (NCT04501978), when an interim analysis did not find an improvement when bamlanivimab was added to remdesivir compared to remdesivir alone in hospitalized patients with COVID-19.
An unpublished, unreviewed report from the WHO sponsored, 11,266 patient, Phase II/III SOLIDARITY trial, did not find an improvement in hospitalized COVID-19 patients treated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. A physician reviewer speculated that remdesivir may be more effective when given early in the infection to patients at high risk for progression.
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.
NIH will evaluate the effect of three anti-inflammatories on suppressing cytokine storm in COVID-19 patients in the 2,100 Patient, Phase III ACTIV-1 IM trial. The drugs that will be used in ACTIV-1 IM include TNF blocker, infliximab (Remicade, J&J); the CTLA-4 immunoglobulin, abatacept (Orencia, BMS); and the investigational CCR2/CCR5 agonist cenicriviroc (AbbVie).
In a 126 patient, Phase II, Italian trial (NCT04346355), treatment with tocilizumab did not reduce intensive care admission with invasive mechanical ventilation, death from all causes, or clinical aggravation compared to placebo in patients with early-stage COVID-19 pneumonia.
In a 131 patient, Phase II, French trial (NCT04331808), treatment with tocilizumab did not improve clinical progression at day 4, but did reduce death or the need for high-flow oxygen or ventilation at day 14 (24% vs. 36%) compared to placebo in patients with moderate-to-severe COVID-19 pneumonia.
A 3,924 patient retrospective U.S. analysis found a lower risk for death in 433 patients that received tocilizumab compared with those not treated with tocilizumab in critically ill COVID-19 patients.
In a 243 patient, Phase III, U.S. trial (NCT04356937), treatment with tocilizumab did not reduce intubation or death compared to placebo in patients with severe COVID-19.
COVID-19 Monoclonal Antibodies
BARDA has provided a $486 million Project Warp Speed grant to AstraZeneca to evaluate the long-acting monoclonal antibody combination, AZD7442, in two Phase III trials. A 5,000 patient trial will evaluate AZD7442 to prevent COVID-19 for up to 12 months and a 1,100 patient trial will evaluate the antibody as post-exposure prophylaxis. AstraZeneca will supply up to 100,000 doses by the end of 2020 and the US can acquire an additional one million doses in 2021 under a separate agreement.
NIAID is comparing bamlanivimab plus remdesivir to remdesivir alone in the treatment of hospitalized patients with COVID-19 in the 10,000 patient, Phase III, ACTIV-3 trial (NCT04501978). The trial was initiated in August 2020, but temporarily paused in October 2020 on the recommendation of a data and safety monitoring board to allow time to review safety data. The FDA issued a violation notice to Lilly due to quality review issues, which would need to be fixed, to be in compliance with manufacturing standards for authorization of a drug.
Vaxart is developing the non-replicating adenovirus type-5 (Ad5) viral vector DNA virus, VXA-CoV2-1.
In a 195 patient, Phase I trial (NCT04368728), two vaccine candidates (BNT162b1 and BNT162b2) were tested in healthy adults. Patients that received BNT162b2 had a lower incidence and severity of systemic reactions than BNT162b1. No safety issues were identified, but most participants reported mild to moderate injection site pain. Tiredness, headaches and fever was reported after the second dose. Both vaccines elicited antibody levels one-month after a second dose of vaccine that were greater than levels seen in a group of recovered COVID-19 patients.
Risankizumab (Skyrizi, Boehringer Ingelheim and AbbVie) is a monoclonal antibody approved for the treatment of severe plaque psoriasis.
The NIH provides guidelines for the treatment of patients with COVID-19 that are continuously updated. A list of updates and recommendations by date of publication are provided to help health care practitioners stay current. The guidelines include an Overview of Therapeutic Management of Patients with COVID-19, based on disease severity. There is also a review of evidence that supports or refutes the use of therapies and a recommendation by NIH for or against use of the therapies.
Current treatment recommendations are organized by severity of disease in an easy-to-use graphic.
COVID-19 Monoclonal Antibodies
Lilly announced interim data from 268 patients enrolled in the 800 patient, Phase II, BLAZE-1 trial (NCT04427501), where treatment with the combination of bamlanivimab and etesevimab reduced viral load at day 11. Use of bamlanivimab plus etesevimab resulted in 0.9% of patients requiring hospitalization or an ER visit compared to 5.2% in the placebo group. Lilly submitted a request for an emergency use authorization (EUA) for its monoclonal antibody bamlanivimab in October and plans to request an EUA for the combination of the two monoclonal antibodies, bamlanivimab and etesevimab, in November 2020.
Regeneron submitted a request for an emergency use authorization for its monoclonal antibody combination, REGN-COV2. If granted, initial doses would be made available at no charge, because they are covered by a Warp Speed grant from BARDA.
NIAID is comparing a single dose of Anti-Coronavirus Immunoglobulin plus up to 10 days of remdesivir to remdesivir alone in the treatment of COVID-19 in the 28-day, 500 patient, Phase III ITAC trial (NCT04546581) in hospitalized patients with severe COVID-19.
Lilly announced additional details from 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.
The ACTT-1 investigators provided a final report on the NIAID sponsored study. In the 29-day, 1,062 patient, Phase III, Adaptive COVID-19 Treatment Trial (ACTT-1) (NCT04280705), patients treated with remdesivir for up to ten days had a median time of recovery (hospital discharge or returning to normal activity level) of 10 days compared to 15 days with placebo in patients with severe COVID-19. However, there was not a significant improvement for patients that required a ventilator or ECMO at study entry. At day 15, there was a significant difference in mortality with remdesivir compared to placebo (6.7% vs 11.9%), but the difference was no longer significant at 29 days (11.4% and 15.2%).
The 15,000 patient RECOVERY trial (NCT04381936) has several arms testing lopinavir-ritonavir, dexamethasone, hydroxychloroquine, azithromycin, tocilizumab, convalescent plasma, immunoglobulin (IVIG) and the monoclonal antibody combination REGN-COV2. In the hydroxychloroquine arm of the RECOVERY trial, 1,561 patients that received hydroxychloroquine were compared to 3,155 that received usual care. There was no improvement in mortality at 28-days with hydroxychloroquine compared to usual care (27% vs 25%). Due to the lack of benefit seen at an interim analysis, the researchers discontinued enrollment in the hydroxychloroquine arm of the trial.
The EMA has started a rolling review of AstraZeneca’s COVID-19 vaccine with early non-clinical data, while the FDA still has a hold in place for the U.S. Phase III trial.
The EMA has also started a rolling review of BioNTech’s and Pfizer’s COVID-19 vaccine with early non-clinical data, a few days after initiating the rolling review for AstraZeneca’s vaccine.
The National Academies of Sciences, Engineering, and Medicine have made recommendations to NIH regarding the distribution of a COVID-19 vaccine (s), when one or more are available.
VIR and GSK announced the initiation of the 1,300 patient, Phase III portion of the COMET-ICE trial to evaluate whether VIR-7831 prevents mild or moderate COVID-19 patients from worsening as indicated by an increase in hospitalizations or death.
CPI-006 is a monoclonal antibody for CD73 that activates lymphocytes, induces the production of antigen-specific immunoglobulin from B cells and increases production of CD4+ and CD8+ cells. CPI-006 is being developed by Corvus Pharmaceuticals as a cancer treatment.
The 11,000 patient RECOVERY trial has several arms testing lopinavir-ritonavir, dexamethasone, hydroxychloroquine, azithromycin, tocilizumab, REGN-COV2 and convalescent plasma. In the lopinavir-ritonavir arm of the RECOVERY trial (NCT04381936), 1,616 patients that received lopinavir-ritonavir were compared to 3,424 patients that received only usual care. Lopinavir-ritonavir did not improve mortality at 28-days compared to usual care (23% vs 22%), nor did the drugs decrease the duration of hospital stay, or the risk of progressing to invasive mechanical ventilation.
J&J initiated the 60,000 patient, Phase III, ENSEMBLE trial (NCT04505722) to evaluate a single dose of JNJ-78436735 for the prevention of COVID-19 in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa and the United States. In an unreviewed trial report, JNJ-78436735 elicited neutralizing antibodies in a 394 patient, Phase I/II trial. The most frequent adverse events were injection site pain, fatigue, headache and myalgia.
Novavax initiated a 10,000 patient, Phase III trial to evaluate two doses of NVX-CoV2373 given 21-days apart for the prevention of COVID-19 in the United Kingdom. At least 25% of trial participants will be 65 or older.
The FDA placed a hold on a Phase II/III trial evaluating Inovio’s COVID-19 vaccine, INO-4800, due to questions regarding the vaccine and the Cellectra 2000 delivery device used in the trial.
In a 40 patient, Phase I, NIAID-sponsored, open-label trial (NCT04283461), the antibody titers increased in patients > 56 that were similar to those seen in younger patients. Antibody titers further increased with a booster dose at 1-month. As with the trial of younger patients, serum-neutralizing activity was similar to the levels seen in recovered patients. Adverse events were primarily mild to moderate (e.g., chills, fatigue) and occurred more frequently after the second vaccination.
Regeneron announced data from the first 275 patients enrolled in a 1,300 patient, adaptative Phase I/II/III trial (NCT04425629), where treatment with REGN-COV2 lowered viral levels to a greater extent at increasing viral loads. The monoclonal antibody appeared to be more efficacious in patients that had not produced antibodies and/or had higher viral loads. REGN-COV2 may alleviate symptoms in a shorter time compared to placebo, but in the preliminary data, the numerical reduction (seronegative patients only) was not statistically significant.
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.