Evusheld™ Long-Acting Monoclonal Antibody Clinical Trials, Efficacy, Side Effects
AstraZeneca's Evusheld™ (AZD7442) is a Long-Acting antibody (LAAB) combination that protects people from developing COVID-19 following exposure to the SARS-CoV-2 coronavirus. In addition, Evusheld contains infection-fighting proteins called monoclonal antibodies, which provide s (mAbs) and preexposure protection from the coronavirus entering the body's cells and causing infection. Evusheld combines tixagevimab (AZD8895) and cilgavimab (AZD1061), derived from B-cells donated by convalescent patients after SARS-CoV-2 beta coronavirus infections.
mAbs are Y-shaped molecules produced naturally by the body's immune system that recognize, bind to, and neutralize specific viruses and other pathogens. Because the mAbs bind to different parts of the protein, using them in combination has been effective. Evusheld was designed to attach to the spike protein of SARS-CoV-2 at two other sites and was optimized with half-life extension, reduced Fc receptor, and complementary C1q binding. Evusheld protects those not expected to mount an adequate immune response following vaccination.
Discovered by Vanderbilt University Medical Center and licensed to AstraZeneca on Jun. 9, 2020. Evusheld was engineered with AstraZeneca's proprietary half-life extension technology to increase the therapy's durability. AstraZeneca's LAABs mimic natural antibodies and can potentially treat and prevent disease progression in patients already infected with the virus. In addition, the LAAB extension more than triples the durability of its action compared to conventional antibodies.
On Dec. 8, 2021, the U.S. Food and Drug Administration (FDA) issued emergency authorization for Evusheld, tixagevimab co-packaged with cilgavimab. Evusheld was developed with support from the U.S. Government, including federal funds from the Department of Health and Human Services (HHS); Office of the Assistant Secretary for Preparedness and Response (ASPR); Biomedical Advanced Research and Development Authority (BARDA) in partnership with the Department of Defense; Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense, under Contract No. W911QY-21-9-0001. As of Jan. 20, 2023, about 90% of circulating SARS-CoV-2 variants in the U.S. were unlikely to be susceptible to the combined mAbs, tixagevimab and cilgavimab (Evusheld) used for preexposure prophylaxis. The FDA announced on Jan. 26, 2023, that Evusheld is no longer authorized for preexposure prophylaxis against SARS-CoV-2 infection in the U.S.
On Nov. 10, 2022, TIME named EVUSHELD on its 2022 list of the Best Inventions.
AstraZeneca (LSE/STO / Nasdaq: AZN), located in Cambridge, UK, and Delaware, operates in over 100 countries. Its innovative medicines are used by millions of patients worldwide. Visit astrazeneca.com for additional information. The Brand Institute partnered with AstraZeneca to develop the brand name EVUSHELD™.
Evesheld Availability
As of May 2023, Evusheld had been authorized for use in about 30 countries.
Sipavibart (formerly AZD3152)
Sipavibart (formerly AZD3152) is an investigational LAAB against COVID-19. Sipavibart is designed to provide broad and potent coverage across Omicron and ancestral viral SATS-CoV-2 virus variants by neutralizing spike protein interaction with the host receptor ACE2. Sipavibart was derived from B-cells donated by convalescent patients after SARS-CoV-2 infection. Sipavibart has been engineered using the same antibody scaffold as Evusheld and was optimized with the same half-life extension, reduced Fc effector function, and complemented the C1q binding platform. The reduced Fc effector function aims to minimize the risk of antibody-dependent disease enhancement, in which virus-specific antibodies promote, rather than inhibit, infection and/or disease.
AZD5156
AZD515 is an investigational, long-acting antibody combination of cilgavimab, a component of EVUSHELD, and a new long-acting mAb, AZD3152. As of Apr. 27, 2023, AstraZeneca reported AZD5156 retained in vitro neutralization activity against all SARS-CoV-2 variants known to date, including BQ.1 and BQ.1.1, in a phase 3 SUPERNOVA trial, sponsored by AstraZeneca. SUPERNOVA evaluates the safety and neutralizing activity for the prevention of COVID-19 in adults and children 12 years of age or older with conditions that cause immune impairment and separately assesses the safety and PK of AZD5156, a combination of AZD3152 and AZD1061. Last Update Posted: May 22, 2023.
Evusheld Immunocompromised COVID-19 Patients
Beginning on Apr. 14, 2023, AstraZeneca presented: Implementation of AZD7442 COVID-19 preexposure prophylaxis (PrEP) in the largest HMO in Israel: real-world uptake and sociodemographic and clinical characteristics across immunocompromised patient groups; Initial use of AZD7442 (tixagevimab/cilgavimab) for PrEP in severely immunocompromised patients in the United States: Prevention of deaths and underestimation of effectiveness due to misclassification of medically attended COVID-19; Clinical effectiveness of AZD7442 COVID-19 hospitalization among immunocompromised patients in the US Veterans Affairs health system: Overall and during periods of susceptible vs. resistant omicron variants; Efficacy and safety of a single dose of AZD7442 for prevention of COVID-19: 12-month analysis of the PROVENT phase 3 study.
Evuesheld in Europe
The European Medicines Agency (EMA) issued authorization on Mar. 24, 2022, followed by the European Union (EU) on Mar. 30, 2022: EMEA/H/C/005788. On Jun. 8, 2022, the EMA published a list of critical authorized medicines (Evusheld) for COVID-19 public health. AstraZeneca AB was granted marketing authorization in the EU. As of December 2023, the EMA authorization remained effective.
Evusheld in Canada
Evusheld received a Notice of Compliance from Health Canada on Oct. 18, 2022, for treating mild to moderate COVID-19 in adults and adolescents (≥12 years of age weighing) on Oct. 18, 2022. This approval follows AstraZeneca's announcement in April 2022 that Evusheld had been approved as a preventative treatment for COVID-19 and was available across Canada.
Evusheld Subvariants
On Feb. 15, 2024, a letter reported that in the ambulatory setting, and while ancestral strains were circulating, the administration of intramuscular T-C to treat SARS-CoV-2 infections significantly reduced the risk of hospitalization and death in patients at risk for disease progression, compared to placebo. In the hospital setting, the double-blinded, placebo-controlled ACTIV-3-TICO trial evaluating T-C in 1417 patients with COVID-19, with > 50% of participants infected with the Delta variant, demonstrated that treatment with T-C was associated with a 30% relative risk reduction in mortality (9% vs. 12%; hazard ratio [HR] 0.70 [95%CI 0.50-0.97]; p=0.032) through day 90. The EU DisCoVeRy placebo-controlled trial (NCT04315948) began enrolling on April 28, 2021, after these trials were initiated (January 28, 2021, and February 10, 2021, respectively) and aimed to confirm efficacy and safety data in hospitalized COVID-19 patients during a later stage of the pandemic when the natural evolution of SARS-CoV-2 strains had led to the emergence of variants of concern (VOC), and mass vaccination campaigns had been ramped up worldwide.
Evusheld At U.S. Pharmacy
The U.S. Administration announced on Jul. 12, 2022, that it would make effective pre-exposure prophylactics such as Evusheld more widely available through enhanced distribution to clinicians' offices and clinics. Previously, Amber Specialty Pharmacy (Hy-Vee) announced on Jun. 23, 2022, the launch of expanded EVUSHELD services at 19 locations.
Evusheld Dosage
Patients receive one dose of EVUSHELD, composed of two separate injections, given by a healthcare provider as two intramuscular injections. On Jun. 29, 2022, the FDA revised the Evusheld Fact Sheet for Healthcare Providers. In the EU, Evusheld for treatment is 300mg of tixagevimab and 300mg of cilgavimab, administered as two separate, sequential IM injections. In addition, the U.S. CDC published on Sept. 2, 2022, that Evusheld should be administered to moderately or severely immunocomised patients every six months for preexposure prophylaxis to supplement vaccine protection. Per the updated EUA, Evusheld can be given at least two weeks after COVID-19 vaccination.
Evusheld Indication
The U.S. CDC published 'People Who Are Immunocompromised' on Jun. 29, 2022: Evusheld is authorized as preexposure prophylaxis (PrEP) for preventing COVID-19. It is given before you get exposed or test positive to help prevent COVID-19 infection. Evusheld is not used to treat COVID-19 symptoms. It is also not a substitute for COVID-19 vaccination. Do not take EVUSHELD if you have had a severe allergic reaction to EVUSHELD.
Evusheld Adolescents
Australia granted Provisional Determination to Astrazenecas's Evusheld for adolescents (12+) on Jan. 4, 2022. As did Europe on Mar. 28, 2022.
Evusheld Pregnancy
There is insufficient data to evaluate a drug-associated risk of significant congenital disabilities, miscarriage, or adverse maternal or fetal outcomes. Therefore, EVUSHELD should only be used during pregnancy if the potential benefit outweighs the risk for the mother and the fetus. There are no available data on the presence of tixagevimab or cilgavimab in human milk or animal milk, the effects on breastfed infants, or the effects of the drug on milk production. Maternal IgG is known to be present in human milk.
Evusheld and Multiple Sclerosis
In a study published on May 21, 2022 - Tixagevimab and Cilgavimab boost antibody levels to SARS-CoV-2 in patients with multiple sclerosis on b-cell depleters - In this study, patients with MS who had an attenuated antibody response to COVID-19 vaccines due to exposure to b-cell depleters now had the highest antibody response possible after receiving Evusheld.
Evusheld and Cancer
A study retrospectively analyzed serologic responses to initial and booster COVID-19 vaccination and mAbs treatment in 378 patients with hematologic (blood cancer) malignancy. None of the twenty-five cancer patients given Evusheld tested positive for the coronavirus.
Evusheld Side Effects
In the PROVENT study, the most common adverse effects of tixagevimab plus cilgavimab were headache (6%) and fatigue (4%). Rates of overall and severe adverse events in the antibody and placebo groups were similar. However, in the post-hoc analysis of PROVENT, the incidence of serious cardiac adverse events (myocardial infarction, cardiac failure, arrhythmia) was higher in the antibody group than in the placAstraZeneca's6 % vs. 0.2%). All subjects with events had cardiac risk factors and/or "prior history of cardiovascular disease at baseline. A causal relationship between EVUSHELD and these events has not been established.
Evusheld News
January 26, 2023 - The U.S. FDA announced it had withdrawn the Evushels EAU.
August 15, 2022 - The BMJ reported that the UK would not buy Evusheld owing to "insufficient data" on protection. The UK's Medicines and Healthcare Products Regulatory Agency approved Evusheld on March 17, 2022, to prevent COVID-19 in people unlikely to mount an immune response from vaccination or for whom vaccination was not recommended.
July 6, 2022 - China's regulatory agency authorized Evusheld's use of AstraZeneca Plc.
July 1, 2022 - The U.S. FDA stated, 'Nonclinical data and pharmacokinetic modeling suggest that activity against the currently circulating SARS-Co" -2 variants and subvariants may be retained for six months at drug concentrations achieved following an Evusheld dose of 300 mg of tixagevimab and 300 mg cilgavimab.'
May 5, 2022 - Taylor Francis Online published: COVID-19 vaccine-associated transverse myelitis-Evusheld as an option when vaccination is not recommended due to severe adverse events. 'We report the safe administration of EvushThere'sa patient who experienced transverse myelitis 11 months previously due to receiving the Moderna mRNA vaccine. This patient has experienced no adverse events to Evusheld.'
April 21, 2022 - AstraZeneca US announced preexposure prophylaxis phase 3 clinical trial found up to 83% reduction of symptomatic COVID-19 risk, with no severe disease or COVID-19-related deaths in the EVUSHELD group.
December 23, 2021—AstraZeneca announced that EVUSHELD retained neutralization activity against the Omicron SARS-CoV-2 variant, according to new authentic 'live' virus neutralization data from the University College Oxford, UK, and Washington University School of Medicine, St. Louis, US.
December 8, 2021 - The U.S. FDA issued an EUA for tixagevimab co-packaged with cilgavimab.
November 19, 2021—The BMJ reported that AstraZeneca's AZD7442 long-lasting experimental treatment effectively prevents and reduces severe COVID-19 illness.
July 15, 2020 - Study published by Nature: Potently neutralize and protect human antibodies against SARS-CoV-2. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130, or a combination of both antibodies protected mice from weight loss. Furthermore, it reduces the viral burden and levels of inflammation in the lungs.
June 9, 2020 - Vanderbilt University Medical Center discovered the human monoclonal antibodies and licensed them to AstraZeneca. Under the terms of the licensing agreement with Vanderbilt, AstraZeneca will pay single-digit royalties on future net sales.
April 8, 2020—The Chinese Academy of Sciences and Vanderbilt University Medical Center will provide AstraZeneca with genetic sequences for antibodies discovered against SARS-CoV-2 for further in silico and in vitro assessment.
Evusheld Clinical Trials
Visit AstraZeneca for more sponsored trial information.
AstraZeneca announced on Jun. 8, 2022, that detailed results from the TACKLE Phase III outpatient treatment study showed Evusheld provided clinically and statistically significant protection against progression to severe COVID-19 or death from any cause compared to placebo. In addition, on Jul. 8, 2022, The Lancet published: Tixagevimab–cilgavimab for treatment of patients hospitalized with COVID-19: a randomized, double-masked, phase 3 trial - Interpretation: Among patients hospitalized with COVID-19 receiving remdesivir and other standard care, tixagevimab–cilgavimab was safe and led to a 30% relative risk reduction for mortality up to day 90. The absolute risk reduction was 3.6%.
ClinicalTrials.gov Identifier: NCT04723394 - Phase III Study of AZD7442 for Treatment of COVID-19 in Outpatient Adults (TACKLE) - Findings: Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab–cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab–cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6–71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1–8·0; p<0·0001). Adverse events occurred in 132 (29%) of 452 participants in the tixagevimab–cilgavimab group and 163 (36%) of 451 participants in the placebo group and were mostly of mild or moderate severity. There were three COVID-19-reported deaths in the tixagevimab–cilgavimab group and six in the placebo group.
BasAZD7442's results of PROVENT (Clinical Trial NCT04625725) - the U.S. FDA issued an Emergency Use Authorization on December 8, 2021, for the anti-SARS-CoV-2 monoclonal antibodies tixagevimab plus cilgavimab (Evusheld). Phase III Double-blind, Placebo-controlled Study of AZD7442 for Preexposure Prophylaxis of COVID-19 in Adults. (PROVENT). The PROVENT study will assess the safety and efficacy of a single dose of AZD7442(× 2 I.M. injections) compared to a placebo to prevent COVID-19. AstraZeneca presented an abstract at IDWeek that this study hit the primary endpoint in preventing COVID-19.
Clinical Trial NCT04507256: AZD7442 is a Potential Combination Therapy for the Prevention and Treatment of COVID-1This first-in-human dose-escalation study will evaluate AZD7442 (AZD8895 + AZD106ed for safety, tolerability, and pharmacokinetics generation of anti-drug antibodies (ADAs). In addition, the study is intended to enable future studies of AZD7442's efficacy in preventing and treating COVID-19. The study will consist of A Screening Period of up to 27 days (Day -28Dayrough Day -2) and a Treatment Period during which participants will be resident at the Clinical Unit from Day -1, 1 day before Investigational Medicinal Product (IMP) administration (on Day 1) until at least 24 hours after IMP administration, will be discharged on Day 2 after all safety evaluations have been completed, and a Follow-up Period lasting 360 days (through to Day 361) after the IMP dose.
Ongoing trials include TACKLE COVID-19, a Phase III mild-to-moderate COVID-19 outpatient treatment trial, and collaborator treatment trials in outpatient and hospitalized settings. TACKLE is a Phase III, randomized, double-blind, placebo-controlled, multi-center trial assessing the safety and efficacy of a single 600mg I.M. dose of AZD7442 compared to a placebo for the outpatient treatment of COVID-19. The trial was conducted in 96 sites in Brazil, Czech Republic, Germany, Hungary, Italy, Japan, Mexico, Poland, Russian Federation, Spain, Ukraine, U.K., and U.S. 903 participants were randomized (1:1) to receive either AZD7442 (n = 452) or saline placebo (n = 451), administered in two separate, sequential IM injections. Participants were adults 18 years old and over who were non-hospitalized with mild-to-moderate COVID-19 and symptomatic for seven days or less. Participants had a documented laboratory-confirmed SARS-CoV-2 infection, as determined by a molecular test (antigen or nucleic acid) from any respiratory tract specimen (e.g., oropharyngeal, nasopharyngeal, or nasal swab or saliva) collected no more than three dayDayefore day one. The primary efficacy endpoint was the composite of severe COVID-19 or death from any cause until day 29. Subjects will continue to be followed for 15 months. Approximately 13% of participants were 65 years and over. In addition, 90% had baseline co-morbidities and other characteristics that put them at high risk of progression to severe COVID-19, including cancer, diabetes, obesity, chronic lung disease or asthma, cardiovascular disease, or immunosuppression. Approximately 62% were White/Caucasian, 4% were Black/African-American, 6% were Asian, and 24% were American Indian or Alaskan Native. About 52% of participants were Hispanic/Latino.
