Independent report

RAPID C-19 Oversight Group report: review of Evusheld – summary

Published 6 October 2022

About the RAPID C-19 Oversight Group

The research to access pathway for investigational drugs for COVID-19 (RAPID C-19) is a multi-agency initiative set up in response to the coronavirus (COVID-19) pandemic that aims to get treatments for COVID-19 to NHS patients quickly and safely. 

Its membership includes the UK’s main healthcare agencies including:

• Medicines and Healthcare products Regulatory Agency (MHRA)
• National Institute for Health and Care Excellence (NICE)
• NHS England (NHSE)
• National Institute for Health and Care Research (NIHR)
• the devolved governments

RAPID C-19 has considered the evidence base for Evusheld (tixagevimab plus cilgavimab), starting in February 2021, and is keeping it under active review, including through monitoring the emerging data.

RAPID C-19 Oversight Group meeting: 24 August 2022

This report summarises the recommendations made by RAPID C-19 to the Chief Medical Officer (CMO) following a review of Evusheld in pre-exposure prophylaxis. Senior members of RAPID C-19 gave input into the report, and include:

• James Palmer, national medical director of specialised services, NHSE
• Helen Knight, acting interim director of medicines evaluation, Centre for Health Technology Evaluation, NICE
• Daniel McAuley, director of the NIHR Efficacy and Mechanisms Evaluation Programme
• Krishna Prasad, deputy director of innovative medicines, MHRA, and principal assessor to the Commission on Human Medicines

Context of current and past reports

In December 2021, RAPID C-19 advised the CMO of a strong signal from the PROVENT trial of the efficacy of Evusheld in pre-exposure prophylaxis.

Pre-exposure prophylaxis is when therapeutic drugs are taken before exposure to COVID-19 to help build up protection against the virus.

RAPID C-19 proposed considerations of preparations for patient access subject to marketing authorisation being granted – this was subsequently granted on 17 March 2022 – and confirmation of Evusheld’s neutralising activity against Omicron.

In May 2022, RAPID C-19 considered non-clinical data from the UK Health Security Agency and others on the efficacy of Evusheld against Omicron variants and advised the CMO this data did not warrant action to progress toward patient access.

In response to the significant unmet need in the vulnerable population who would potentially be eligible for treatment, RAPID C-19 has also reviewed real-world evidence, which is summarised in this report.

New evidence reviewed

RAPID C-19 reviewed a broad span of real-world evidence including:

Reference	Population	Methods	Outcomes
Young-Xu Y and others. ‘Tixagevimab/Cilgavimab for Prevention of COVID-19 during the Omicron Surge: Retrospective Analysis of National VA Electronic Data.’ 2022, pre-print. 300mg total dose, increased to 600mg dose in line with EUA. Up to 30 April 2022. US.	Veterans receiving veteran affairs healthcare as per emergency use authorisation (EUA) (immunocompromised or for whom vaccination is not recommended). 95% had received ≥1 vaccine dose. n=1,733	Propensity matching. Control – immunocompromised or high-risk patients. Analysed health records.	Patients who received Evusheld had a lower incidence of the composite outcome (COVID-19 infection, hospitalisation or mortality; 17 out of 1,733 (1.0%) vs 206 out of 6,354 (3.2%); hazard ratio 0.31; 95% confidence interval, 0.18–0.53.
Jurdi AA and others. ‘Tixagevimab/cilgavimab pre-exposure prophylaxis is associated with lower breakthrough infection risk in vaccinated solid organ transplant recipients during the omicron wave.’ American Journal of Transplantation 2022, early view. Brief communication. 40.5% received 300mg total dose, 59% 600mg dose and 0.5% 900mg dose. December 2021 to April 2022. US.	Solid organ transplant recipients. 99% received ≥1 dose of vaccine. n=222	Patient data registry to identify controls – vaccine-matched solid organ transplant recipients.	Breakthrough infections occurred in 11 (5%) of patients who received Evusheld vs 32 (14%) in the control group (p<0.001). Patients who had 300mg total dose had a higher incidence of breakthrough infections compared with those who received the 600mg dose (p=0.025).
Kertes J and others. ‘Association Between AZD7442 (Tixagevimab-Cilgavimab) Administration and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection, Hospitalization, and Mortality.’ Clinical Infectious Diseases 2022: ciac625, online ahead of print. 300mg total dose. December 2021 to April 2022. Israel.	Immunocompromised adults and adolescents invited to receive Evusheld. 98.8% had received ≥1 vaccine. n=825	Control – immunocompromised individuals who did not come forward for Evusheld. Analysed health records.	29 (3.5%) of Evusheld group infected with COVID-19 vs 308 out of 4,299 (7.2%) of people who did not have Evusheld (p<0.001; adjusted odds ratio 0.51).
Nguyen Y and others. ‘Pre-exposure prophylaxis with tixagevimab and cilgavimab (Evusheld) for COVID-19 among 1112 severely immunocompromised patients.’ European Society of Clinical Microbiology and Infectious Diseases 2022, in press journal pre-proof. 300mg total dose. December 2021 to March 2022. France.	Immunocompromised and impaired response to vaccine (≥3 doses). n=1,112	Non-comparative.	49 out of 1,112 (4.4%) had confirmed COVID-19 ≥5 days after treatment (median 21 days), 43 (88%) had a mild form and 6 (12%) had a moderate to severe form; 2 died. 29 out of 49 (59%) were infected with Omicron.
Ordaya EE and others. ‘Characterization of Early-Onset Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Immunocompromised Patients Who Received Tixagevimab-Cilgavimab Prophylaxis.’ Open Forum Infectious Diseases 2022: volume 9, issue 7, ofac283. 300mg total dose. US.	Immunocompromised, in line with EUA. n=674	Health records data of all patients who received Evusheld during the first 2 months of the programme at a clinic in the US.	8 out of 674 (1.2%) developed COVID-19 3 to 12 days after treatment: 7 had received ≥2 doses of vaccine. Genomic data available for 1: Omicron BA.1.
Benotmane I and others. ‘Breakthrough COVID-19 cases despite prophylaxis with 150 mg of tixagevimab and 150 mg of cilgavimab in kidney transplant recipients.’ American Journal of Transplantation 2022, early view. Brief communication. 300mg total dose. December 2021 to March 2022. France.	Kidney transplant patients with a weak serological response to COVID-19 vaccine. n=416	Non-comparative.	39 out of 416 (9.4%) developed COVID-19 (BA.1 n=5; BA.1.1 n=9; BA.2 n=1).
Goulenok T and others. ‘Pre-exposure anti-SARS-CoV-2 monoclonal antibodies in severely immunocompromised patients with immune-mediated inflammatory diseases.’ The Lancet 2022: volume 4, issue 7. E458–E461. Dose not reported. France.	Outpatients with immune-mediated inflammatory disease with inadequate humoral response to COVID-19 vaccination. n=17 eligible but only 10 received Evusheld.	Not available.	8 out of 17 patients developed COVID-19; 7 out of 8 infections were due to Omicron; 1 out of 8 received Evusheld.
Benotmane I and others. ‘Pre-exposure prophylaxis with Evusheld™ elicits limited neutralizing activity against the omicron variant in kidney transplant patients.’ 2022, pre-print. Research letter. 300mg total dose. France.	Adult kidney transplant patients. n=63	Serum samples collected to measure neutralising activity.	After a median interval from injection of 29 days, only 9.5% (6 out of 63) of patients who received Evusheld were able to neutralise Omicron BA.1 variant compared with 71% (10 out of 14) of patients who were infected with SARS-CoV-2 (positive control) and 2.6% (1 out of 39) of those who received prophylactic Ronapreve (negative control).

Recommendations

Following the review of real-world evidence by RAPID C-19, the conclusion was that the quality of data is insufficient to warrant action to progress to patient access before the completion of NICE’s technology appraisal, which will determine the drug’s clinical and cost-effectiveness.

RAPID C-19 considered that there remained uncertainty that Evusheld would prevent symptomatic COVID-19 caused by current Omicron variants in the vulnerable population who would potentially be eligible.