COVID-19 Anti-inflammatories
Synairgen announced that NIAID had discontinued the Phase II/III ACTIV-2 COVID-19 trial (NCT04518410) in March 2022, due to changes in the pandemic that necessitate a change in how COVID-19 therapies are evaluated. ACTIV-2 was evaluating several drugs in the treatment of COVID-19. Eiger BioPharmaceuticals announced that in the 28-day, 4,669 patient, Phase III TOGETHER trial (NCT04727424), 2.7% of patients treated with peginterferon lambda were hospitalized or had an ER visit compared to 5.6% with placebo in non-hospitalized adult Brazilian patients with COVID-19, who were at high risk of progressing to severe illness. COVID-19 Vaccines The Vaccines and Related Biological Products Advisory Committee (VRBPAC), CDC and NIH will meet on 4/6/2022 to discuss additional COVID-19 vaccine boosters and how to select specific SARS-CoV-2 virus strains for COVID-19 vaccines to address current and emerging variants.
Based on previously announced data in older children from the 11,700 patient, Phase II/III KidCOVE trial(NCT04796896), Moderna is requesting approval for use of its COVID-19 vaccine in children 6 to 17 years old. We’d like to thank Emily Stock, TJ Lawall and Randy Haley who helped to update the open-access Prescribe Right COVID-19 web pages as part of their Capstone Project at the University of Health Sciences and Pharmacy in St Louis. Due to the hard work of these talented students, the pages are easier to navigate and contain quick-review summary tables.
COVID-19 Anti-inflammatories In a retrospective analysis or data for 1,164 patients, who had been hospitalized for COVID-19 and received less than 10 days of dexamethasone, continuation of dexamethasone after discharge did not reduce mortality or readmission compared to discontinuing dexamethasone at discharge. COVID-19 Vaccines An analysis of COVID-19 antibodies in breast milk of vaccinated mothers found that 96% of lactating women who received the Pfizer-BioNTech vaccine and 97% of mothers that received the Moderna vaccine had detectable IgA antibodies in their milk compared to 39% who received the AstraZeneca vaccine and 48% who received the Johnson & Johnson vaccine. COVID-19 Vaccines
The CDC now recommends an 8-week interval between the first and second dose of an mRNA COVID-19 vaccine as an option in patients 12 and older, especially males ages 12–39 years to reduce the small risk of myocarditis and increase peak antibody response and vaccine effectiveness. A CDC analysis of VAERS data, from 21,335,331 patients aged 12–20 years, found the incidence of multisystem inflammatory syndrome in children (MIS-C) to be one case per million individuals receiving one or more doses of a COVID-19 vaccine. In the 138 patient, Phase IV, CoronavRheum trial (NCT04754698), pausing methotrexate administration for two weeks after each COVID-19 vaccine dose increased IgG seroconversion and neutralizing antibody titers in Brazilian patients with rheumatoid arthritis. The Chinese Sinovac-CoronaVac COVID-19 vaccine was used in the CoronavRheum trial. A preprint draft describes the New York State Department of Health’s analysis of vaccine effectiveness with two doses of the Pfizer-BioNTech COVID-19 vaccine in children 5 to11 and 12 to 17 years after emergence of the Omicron variant. From December 13, 2021 to January 30, 2022 vaccine effectiveness (VE) in adolescents 12 to 17 years decreased from 66% to 51% and effectiveness against hospitalization decreased from 85% to 73%. In children 5 to 11 years VE decreased from 68% to 12% and against hospitalization from 100% to 48%. Unlike the New York data, an analysis of data from 10 states by the CDC did not find a rapid decrease in vaccine effectiveness in children 5 to 11 and 12 to 17 years. There was a decrease in VE against the Omicron variant with VE approaching zero at 5 months. Two weeks to ten weeks after the second immunization the CDC found vaccine effectiveness against emergency department or urgent care visits, when Omicron was the predominant variant, to be 76% for adolescents 12 through 15 years, 83% for adolescents 16 to 17 years and 46% for children ages 5 through 11. After 5-months, VE was 38% among adolescents aged 12 to 15 years and 46% among 16 to 17 years. VE increased to 83% in adolescents 16 to 17 years, 7 or more days after a booster dose. Due to the late start of vaccination for the younger age group, data was not available for longer time periods. COVID-19 Anti-inflammatories In the 101 patient, Phase III, COV-BARRIER trial (NCT04421027), adding baricitinib to standard of care, including corticosteroids, reduced mortality at 28 days (39% vs 58%) and at 60 days (45% vs 62%) compared to placebo in critically ill hospitalized adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation. COVID-19 Antibodies The FDA limited the EUA for sotrovimab to be used in geographic areas where the disease is likely caused by a susceptible COVID-19 variant. The FDA increased the initial dose of tixagevimab to 300 mg and cilgavimab to 300 mg, because available data suggests the combination is less active against certain Omicron subvariants. The higher dose may be more likely to prevent infection by the COVID-19 Omicron subvariants BA.1 and BA.1.1 than the original 150mg/150mg dose. Tixagevimab and cilgavimabhave have an EUA for emergency use as pre-exposure prophylaxis (PrEP) for prevention of COVID-19 in patients 12 years of age and older weighing at least 40 kg in patients who may not mount an adequate immune response to COVID-19 vaccination or patients who are allergic or intolerant to a COVID0-19 vaccination. COVID-19 Antivirals
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. In the 28-day, 490 patient, Phase III, I-TECH trial (NCT04920942), treatment with ivermectin did not reduce the percentage of patients that progressed to severe COVID-19 in high-risk Malaysian outpatients with COVID-19. Synairgen announced that in the 623 patient, 28-day, Phase III SPRINTER trial (NCT04732949), treatment with SNG001 did not decrease time to hospital discharge compared to placebo in hospitalized patients with COVID-19. COVID-19 Vaccines A CDC analysis found that mothers who complete a two-dose vaccination series with an mRNA COVID-19 vaccine resulted in vaccine effectiveness of 61% in their infants < 6 months old. Limited data showed vaccine effectiveness to be 32% if given during the first 20 weeks of pregnancy and 80% if given from 21 weeks to 2 weeks before delivery. A review of medical records from an Israeli managed care database found that vaccine effectiveness with the Pfizer–BioNTech COVID-19 vaccine in patients who recovered from COVID-19 was 82% in patients 16 to 64 and 60% in patients 65 and older. Sanofi and GSK announced that in the 21,046 patient, Phase III, VAT08 trial (NCT04904549), vaccination with two doses of their COVID-19 vaccine resulted in vaccine efficacy of 57.9% against any symptomatic COVID-19 disease, 75% efficacy against moderate or severe COVID-19 disease and 100% against severe COVID-19 disease and hospitalizations COVID-19 Antibodies GSK and Vir announced that in the 29-day, 754 patient, open-label, Phase III, COMET-TAIL trial (NCT04913675), intramuscular (IM) administration of sotrovimab was non-inferior to intravenous (IV) administration (2.7% vs 1.3%) for the early treatment of mild-to-moderate COVID-19 in high-risk, non-hospitalized adults and adolescents (12 years of age and older). COVID-19 Antibodies
Lilly is developing the monoclonal antibody, bebtelovimab, which preliminary data suggests has activity against the Omicron variant and viruses with mutations to the Omicron variant. Bebtelovimab is being evaluated as a treatment of mild to moderate COVID-19 in high-risk patients.
The FDA postponed the Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting to discuss dosing of the Pfizer-BioNTech COVID-19 vaccine, in children 6-months to 4 years of age, until data is available on a third dose of the vaccine in young children. Data suggests that a third dose may be needed for children 2 to 5 years old. Data on a third dose is expected to be available in April. In a final analysis of the ENSEMBLE trial, efficacy for the J&J COVID-19 vaccine against moderate to severe–critical COVID-19 was 52.9%, 28 or more days after vaccination. Efficacy was 74.6% to prevent severe–critical COVID-19 Interim results after 29-days from 458 patients enrolled in the NIH sponsored, 12-month, 950 patient, Phase I/II, MixNMatch Study (NCT04889209) examined the results of using a booster dose of the same or a different U.S. authorized COVID-19 vaccine. A booster dose increased antibody titers for all combinations of vaccines received. A CDC analysis of vaccine effectiveness (VE) data from August 2021 to January 2022 found that VE was higher after the third dose than after the second dose but decreased over time. During the Omicron-predominant period, VE against COVID-19–associated urgent care visits and hospitalizations was 87% and 91%. during the 2 months after a third dose. VE decreased to 66% and 78% four months after a third dose. Protection was higher against hospitalizations than urgent care visits. COVID-19 Antibodies and Antivirals
An ICER draft review of drugs that are effective to treat the COVID-19 Omicron variant found the risk for hospitalization or death was reduced by 79% with sotrovimab, 30% with molnupiravir and 88% with Paxlovid. A per protocol analysis of fluvoxamine suggested a 66% reduction in the risk for hospitalization. Due to differences in trial population demographics, ICER did not feel the drugs could be compared based on current evidence. All four 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. COVID-19 Antivirals 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%). 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.
The CDC agreed with the FDA’s full approval of Moderna’s COVID-19 vaccine and recommend it for patients18 years and older. At the request of the FDA, Pfizer and BioNTech have submitted a request to expand their COVID-19 vaccine EUA to include children 6 months to < 5 years of age. If approved, this age group would receive two 3 mcg doses. Data to support a third dose given 8 weeks after the second dose is expected to be submitted in the next few months. The vaccine has full approval for patients 16 years and older. An EUA covers use in patients 5 to 15 years. The FDA has scheduled a meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Feb. 15 to discuss the EUA expansion. In anticipation of approval for the vaccine in the patients 6 months to < 5 years of age, the AMA announced the addition of CPT codes to cover this age group. In a 77 patient study, 57% of infants, whose mothers were vaccinated maintained COVID-19 antibody titers, at 6-months, compared to 8% of infants whose mothers had recovered from COVID-19. COVID-19 Vaccines
The FDA granted full approval for the Moderna COVID-19 vaccine for patients 18 years and older on 1/31/2022. Moderna has given the vaccine the brand name Spikevax. A CDC study of hospitalized adults, from August 2021 to December 2021, found the vaccine effectiveness to prevent COVID-19 hospitalizations was 82% in immunocompetent patients that received two doses of an mRNA vaccine and 97% with three doses. Vaccine effectiveness in immunocompromised patients was 69% with two doses and 97% with three doses. A retrospective of the VAERS database by the CDC found the incidence of myocarditis with an mRNA vaccine to be the highest in young males (12 to 24 years) after their second dose. In a 36-day, 721 patient, Phase II trial (NCT04762680), two doses of the Sanofi-GSK CPVOD-19 vaccine was well tolerated and elicited antibodies in in healthy volunteers and recovered COVID-19 patients. Novavax submitted a request for an Emergency Use Authorization (EUA) for NVX-CoV2373, its COVID-19 vaccine candidate, for individuals 18 years of age and older. NVX-CoV2373 is a protein vaccine that delivers nanoparticles of the SARS-2 spike protein to elicit antibodies. COVID-19 Antibodies A meta-analysis (COMPILE study) of eight COVID-19 convalescent plasma studies enrolling 2,341 patients did not find any clinical improvement with convalescent plasma, but data did support use of real-time individual patient data pooling and meta-analysis during a pandemic. Using data from the COMPILE meta-analysis, researchers identified the characteristics of COVID-19 patients most likely to benefit from treatment with convalescent plasma. This data, called the treatment benefit index (TBI), was used to create a prediction tool, called the Convalescent Plasma Benefit Index Calculator. The TBI divides patients into three groups: substantial benefit from convalescent plasma, moderate benefit, and no expected benefit. The TBI was validated with four external data sets. COVID-19 Antibodies and Antivirals A Japanese in vitro study of the Omicron variant found it to be susceptible to the monoclonal antibodies tixagevimab and cilgavimab (AstraZeneca’s combination), sotrovimab (Vir), and the antivirals remdesivir, molnupiravir and nirmatrelvir plus ritonavir. Omicron was resistant to the monoclonal antibody combinations of casirivimab plus imdevimab (Regeneron) and bamlanivimab plus etesevimab (Lilly). The Department of Health and Human Services (HHS) has created a summary table of outpatient treatments of mild-to-moderate COVID-19. The table includes Paxlovid, Molnupiravir, Sotrovimab, Bamlanivimab/Etesevimab and Casirivimab/Imdevimab.
COVID-19 Antivirals 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.
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.
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. To make administration easier, Gilead is developing GS-5245, an oral prodrug for remdesivir. COVID-19 Vaccines A retrospective CDC study found that patients who received a booster dose of an mRNA vaccine were less likely to develop symptomatic COVID-19 with the Delta or Omicron variants compared to patients that received two vaccine doses or were unvaccinated. Vaccination was slightly less protective against infection for the Omicron variant. A second CDC study found mRNA vaccine effectiveness after a third mRNA vaccine was 94% for Delta variant cases and 82% for Omicron variant in preventing COVID-19–associated emergency department and urgent care encounters and 94% for Delta variant cases and 90% for Omicron variant cases in preventing COVID-19–associated hospitalization. A third CDC study found the largest impact of receiving a booster dose to decrease the risk of COVID-19 infection and death were seen in 50 years and older. COVID-19 Antibodies The FDA limited the EUA for monoclonal antibody combinations from Lilly (bamlanivimab plus etesevimab) and Regeneron (casirivimab plus imdevimab) to only be used when the patients are likely to have been infected with or exposed to a variant that is susceptible to these treatments. This excludes use for Omicron, which is the current dominant COVID-19 variant. The FDA did not discontinue either EUA, because of the potential for use in the future. As a follow-up to the FDA’s update and last week’s restriction of the two combinations in the NIH guidelines, HHS will stop distributing bamlanivimab plus etesevimab and casirivimab plus imdevimab. COVID-19 Anti-Inflammatories In an 11-day, 200 patient, open-label, Phase III trial ( NCT04726098), 31.4% of patients treated with dexamethasone 6 mg once daily for 10 days had clinical worsening compared to 16.3% with dexamethasone 20 mg once daily for 5 days, followed by 10 mg once daily for additional 5 days in hospitalized Spanish patients with confirmed COVID-19 pneumonia requiring oxygen therapy. COVID-19 Vaccines
The CDC conducted a retrospective review of data from 40,627 pregnant women and found that COVID-19 vaccination during pregnancy did not increase the risk of preterm birth or small-for-gestational-age at birth overall, stratified by trimester of vaccination, or number of vaccine doses received during pregnancy, compared with unvaccinated pregnant women. A CDC retrospective analysis of 1,228,664 patients who completed the two-dose primary vaccination from December 2020–October 2021, found the incidence of developing severe COVID-19 was 0.015%. All patients who developed severe COVID-19 had at least one risk factor for developing a severe infection. A week after restating the six-month interval for a booster with the Moderna COVID-19 vaccine, the FDA shortened time period to five-months to match the recommendation for the Pfizer-BioNTech vaccine. In a French case series of 92 kidney-transplant patients, a fourth dose of an mRNA vaccine produced a satisfactory antibody response in about half of the patients who had not responded to three doses. Antibody levels were measured a median of 29-days after the dose. In October the CDC recommended an additional booster dose, given six-months after the first booster dose, in moderately and severely immunocompromised patients. COVID-19 Antibodies NIH recommends AstraZeneca’s monoclonal antibody combination of tixagevimab and cilgavimab for COVID-19 prophylaxis in patients who are moderately to severely immunocompromised with an inadequate immune response to COVID-19 vaccination or not fully vaccinated due to a documented history of severe adverse reactions to a COVID-19 vaccine NIH recommend that nonhospitalized patients with mild to moderate COVID-19 who are at high risk of disease progression, be treated with (in order of preference):
The FDA expanded the EUA for the Pfizer-BioNTech COVID-19 Vaccine to allow for a single booster dose for patients 12 through 15 years of age. Boosters for all patients 12 years and older can now be given as soon as five months after completion of primary series. Patients who are 5 through 11 years, who have undergone solid organ transplantation or are immunocompromised to an equivalent level are also now eligible for a booster dose. The interval between the primary series and a booster dose remains unchanged at six months for the Moderna COVID-19 vaccine and two months for the J&J vaccine. South African researchers examined the results of 133,437 COVID-19 PCR tests and found the effectiveness of the Pfizer-BioNTech COVID-19 vaccine to be 70% after two doses in preventing hospitalizations for COVID-19 during a period when Omicron variant was the dominant strain compared to 93% when the Delta variant was the dominant strain. In a second study, South African researchers compared the COVID-19 neutralization ability for the Beta, Delta, and Omicron variants with serum from 20 patents that had received two vaccinations with the Pfizer-BioNTech COVID-19 vaccine to a group of 20 patients that had received three injections. The researchers found that a third dose of the vaccine increased neutralization efficiency by a factor of 100 against the Omicron variant, but neutralization was lower by a factor of four against the omicron variant compared to the delta variant. Rockefeller University researchers tested plasma from a variety of patients and found that recovered COVID-19 patients and patients that had received a third (booster) vaccination had enhanced protection against the Omicron variant. CDC researchers reviewed data from VAERS and V-Safe voluntarily surveillance systems for children ages 5 to 11 years from 11/3/2021 to 12/19/2021. The researchers found the most common adverse reactions were injection site pain, fatigue and headache. ADR were mostly mild, and few cases of myocarditis were reported. It was estimated that 8.7 million doses were given during this time period to children 5 to 11 years. A retrospective analysis of maternal and umbilical cord blood samples from 1,359 vaccinated pregnant women found that COVID-19 immunization before and throughout pregnancy resulted in detectable antibodies at delivery. The highest maternal and umbilical cord antibody levels were found in mothers who had received a complete vaccination course, had a prior history of COVID-19, or received a third-trimester booster dose. COVID-19 Antibodies The FDA issued an emergency use authorization (EUA) for convalescent plasma, on 8/23/2020, for the treatment of hospitalized patients with COVID-19. The original EUA was granted for any convalescent plasma product collected at FDA registered blood establishments. In February 2021, the FDA narrowed the EUA to high-antibody-titer convalescent plasma. The FDA no longer authorizes the use of plasma with low SARS-CoV-2 antibody titers. In December 2021, the FDA narrowed the EUA to treatment of COVID-19 in inpatients or outpatients who have an immunosuppressive disease or who are receiving immunosuppressive treatment. Fact sheets have been created for health care providers and patients. The Fact Sheet for HCPs has been revised to reflect the changes in the EUA. The documents include dosing instructions and potential adverse effects, such as allergic reactions, transfusion-associated circulatory overload, and transfusion associated lung injury, as well as the potential for transfusion-transmitted infections. COVID-19 Anti-Inflammatories Kiniksa Pharmaceuticals announced that in a 29-day, 582 patient, Phase II/III trial (NCT0444746), treatment with mavrilimumab did not decrease the percentage of patients that required mechanical ventilation or died compared to placebo in patients with severe COVID-19 pneumonia and systemic hyperinflammation. |
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