AstraZeneca's Evusheld Receives EU Approval for Pre-Exposure Prophylaxis Against COVID-19 in Broad Population

AstraZeneca's Evusheld (tixagevimab and cilgavimab combination) is a long-acting antibody combination approved for marketing in the EU, intended for pre-exposure prophylaxis of COVID-19 in a broad population of adults and adolescents (aged 12 years and above and weighing 40 kg and above).

Based on the results obtained from the Evusheld clinical development program, the European Commission has approved Evusheld for marketing in Europe. The Evusheld clinical study results include data from the Phase III PROVENT pre-exposure prophylaxis trial, where the preliminary analysis showed a 77% reduction in the relative risk of symptomatic COVID-19 infection compared to placebo; the median 6-month follow-up analysis demonstrated an 83% reduction in the relative risk of symptomatic COVID-19 infection, with protection lasting at least six months. [1 2 3] Evusheld showed good tolerability in clinical trials. [1 2 3]

Christoph D. Spinner, MD, Part-time Lecturer at the Technical University of Munich, Germany, and Consultant Physician for Infectious Diseases and Epidemiology at Isar University Hospital, stated: "The number of highly contagious BA.2 subvariant cases continues to rise, but many public health prevention and control measures have been lifted, making it crucial to protect vulnerable populations, such as those with weakened immune systems, from COVID-19 infection. The approval of Evusheld for broad use will allow health authorities in EU countries to identify high-risk groups in need of additional priority protection."

Mene Pangalos, Executive Vice President of AstraZeneca and Head of Biopharmaceuticals R&D, said: "The approval of Evusheld in the EU is an important milestone in our efforts to prevent COVID-19 infections, and we will continue to work with governments across Europe to bring Evusheld to market as soon as possible. Evusheld can provide long-lasting protection for a broad population who are not adequately protected by COVID-19 vaccines, such as those who cannot be sufficiently protected by the vaccines and those at higher risk of virus exposure."

The recommended dose of Evusheld in Europe is 150 mg tixagevimab + 150 mg cilgavimab, with the two antibodies administered separately as consecutive intramuscular injections.

An increasing number of independent in vitro and in vivo (animal model) studies provide evidence supporting that Evusheld is effective in preventing the globally circulating BA.1, BA.1.1, and BA.2 Omicron subvariants of SARS-CoV-2. [4 5 6] Recently, the latest data from the Washington University School of Medicine indicates that Evusheld has potent neutralizing activity against BA.2, a highly contagious subvariant that is the most prevalent strain in many European countries, currently accounting for nearly 60% of all COVID-19 cases in Europe. [6 7] The data also shows that Evusheld has neutralizing activity against the BA.1 and BA.1.1 sub-lineages of the Omicron variant. [6]

In addition, in vivo data from mice infected with Omicron BA.1, BA.1.1, and BA.2 showed that Evusheld reduced the viral load of all Omicron variants and alleviated lung inflammation (in vivo study).[6] The SARS-CoV-2 viral load is positively correlated with disease severity, mortality, and post-COVID conditions (long COVID).[8 9]

Additional data from a "live" virus study by Aix-Marseilles University and pseudovirus data from the U.S. Food and Drug Administration also showed that Evusheld could neutralize the BA.2 sublineage [10 11].

At the end of last year, Evusheld received Emergency Use Authorization (EUA) in the United States and was recently granted a conditional marketing authorization by the UK Medicines and Healthcare products Regulatory Agency (MHRA), approving Evusheld for pre-exposure prophylaxis of COVID-19. In addition, AstraZeneca has reached agreements with many European countries to supply them with Evusheld.

In immunocompromised or immunosuppressed populations, nearly 40% exhibit a lower or undetectable immune response after vaccination, and approximately 11% fail to produce any antibodies [12]. Individuals who cannot be adequately protected by COVID-19 vaccines may particularly benefit from pre-exposure prophylaxis provided by Evusheld [13-17]. This group includes around 3 million immunocompromised individuals in the EU, such as cancer patients, transplant recipients, or those taking immunosuppressive medications [18]. Populations at higher risk of SARS-CoV-2 exposure may also benefit from the protection offered by Evusheld [19].

Evusheld is the only long-acting antibody combination proven effective in Phase III clinical trials for both prevention and treatment of COVID-19 infection. [13 14] AstraZeneca is applying for emergency use authorization or marketing approval for Evusheld globally for the prevention and treatment of COVID-19.

About Evusheld

Evusheld, formerly known as AZD7442, is a combination drug of tixagevimab (AZD8895) and cilgavimab (AZD1061), two monoclonal antibodies derived from B cells donated by convalescent patients after SARS-CoV-2 virus infection. These human monoclonal antibodies were discovered by Vanderbilt University Medical Center and licensed to AstraZeneca in June 2020. They have the ability to bind to different sites on the SARS-CoV-2 spike protein [10] and were optimized by AstraZeneca to extend half-life and reduce Fc effector function. Compared with conventional antibodies, the extended half-life increases their duration of action by more than three times [11-13]. Data from the Phase III PROVENT trial showed that the protective effect lasts for at least six months [2, 4]. The purpose of reducing Fc effector function is to minimize the risk of antibody-dependent disease enhancement (a phenomenon where virus-specific antibodies promote rather than inhibit viral infection and related symptoms) [14].

Evusheld has been granted marketing authorization in the European Union and the United Kingdom for pre-exposure prophylaxis of COVID-19. In the United States, Evusheld has received Emergency Use Authorization for pre-exposure prophylaxis of COVID-19, applicable to individuals with moderate to severe immune compromise due to disease or use of immunosuppressive medications, those who may not mount an adequate immune response to COVID-19 vaccination, and individuals with a history of severe adverse reactions to vaccines for whom vaccination is not recommended. The eligible population includes patients with hematologic malignancies or other tumors undergoing chemotherapy, organ transplant recipients taking immunosuppressive drugs, and patients with multiple sclerosis or rheumatoid arthritis who are on immunosuppressive therapy. [1] Evusheld has also received usage and marketing approval in several other countries worldwide.

The primary data supporting the authorization of Evusheld come from the ongoing PROVENT Phase III pre-exposure prophylaxis trial. The trial demonstrated that compared with placebo, the risk of symptomatic COVID-19 infection in subjects receiving Evusheld was significantly reduced, with protective effects lasting at least six months. Preliminary analysis showed a 77% reduction in risk [Evusheld group: 8/3441 (0.2%), placebo group: 17/1731 (1.0%)], and the median six-month follow-up analysis indicated an 83% reduction in risk [Evusheld group: 11/3441 (0.3%), placebo group: 31/1731 (1.8%)][1 2 3]. Further follow-up is ongoing to investigate the full duration of protection.

In October 2021, AstraZeneca announced the initial positive results of the TACKLE Phase III outpatient treatment trial, which showed that a 600 mg intramuscular injection of Evusheld was well tolerated. AstraZeneca is in discussions with health authorities regarding the treatment data for mild to moderate COVID-19 infections from the TACKLE trial.

Evusheld was generally well-tolerated in clinical trials.

The development of Evusheld was supported by the U.S. government, with federal funding from the Department of Health and Human Services, the Office of the Assistant Secretary for Preparedness and Response, the Biomedical Advanced Research and Development Authority (in collaboration with the Department of Defense), and the Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense, under Contract No. W911QY-21-9-0001.

Under the terms of a licensing agreement with Vanderbilt University, AstraZeneca will pay single-digit royalties on future net sales.

References:

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[2]. AstraZeneca news release. AZD7442 PROVENT Phase III prophylaxis trial met primary endpoint in preventing COVID-19. Available at: www.astrazeneca.com/media-centre/press-releases/2021/azd7442-prophylaxis-trial-met-primary-endpoint.html [Last accessed: March 2022].

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