A cocktail of long-acting antibodies, administered intramuscularly as COVID-19 prevention, cut the risk of developing symptomatic disease in a high-risk unvaccinated patient population, AstraZeneca has announced.
In top-line data from a phase III trial (PROVENT), AZD7442 (tixagevimab and cilgavimab) as pre-exposure prophylaxis, significantly reduced the risk of developing COVID-19 symptoms by 77% (95% CI 46%-90%) versus placebo, meeting the trial's primary endpoint.
Moreover, AstraZeneca noted, there were no cases of severe COVID-19 or COVID-19-related deaths in the intervention group, compared with three cases of severe COVID-19 and two deaths in the placebo group.
There were no safety concerns, as the treatment was well-tolerated and adverse events were balanced between groups, the manufacturer said.
Importantly, 75% of the trial population had comorbidities, including being "at risk of an inadequate response to active [immunisation)", such as older adults and those with immunosuppressive disease or on immunosuppressive medication.
"With these exciting results, AZD7442 could be an important tool in our arsenal to help people who may need more than a vaccine to return to their normal lives," said the trial's principal investigator, Dr Myron Levin of the University of Colorado School of Medicine, reports MedPage Today.
AZD7442 was derived from the B cells of convalescent patients. The PROVENT randomised trial was conducted at 87 sites in the US, UK, Spain, France, and Belgium. Participants were adults "who would benefit from prevention" with the long-acting antibody, were unvaccinated at the time of enrolment, and were negative for SARS-CoV- 2 via serology testing.
Overall, 5,197 were randomised 2b1 to receive a single 300mg dose of AZD7442 or placebo. AstraZeneca noted that 43% of participants were ages 60 and older. Comorbidities included diabetes, severe obesity or cardiac disease, COPD, chronic kidney disease, and chronic liver disease. About 73% were white.
The company noted that the drug is active in lab studies against emerging strains, including the Delta variant.
Primary efficacy endpoint was the first case of SARS-CoV-2 symptomatic illness confirmed via RT-PCR that occurred post-dose prior to day 183, though subjects are slated to be followed for 15 months, AstraZeneca said.
Mene Pangalos, executive vice president, BioPharmaceuticals R&D, said: “We need additional approaches for individuals who are not adequately protected by COVID-19 vaccines. We are very encouraged by these efficacy and safety data in high-risk people, showing our long-acting antibody combination has the potential to protect from symptomatic and severe disease, alongside vaccines. We look forward to sharing further data from the AZD7442 Phase III clinical trial programme later this year.”
AZD7442 was optimised using AstraZeneca’s proprietary YTE half-life extension technology, which could afford up to 12 months of protection from COVID-19, and is delivered by intramuscular injection. Preliminary ‘in vitro’ findings from investigators at Oxford University and Columbia University demonstrate that AZD7442 neutralises recent emergent SARS-CoV-2 viral variants, including the Delta variant.1-6
AstraZeneca will prepare regulatory submission of the prophylaxis (PROVENT and STORM CHASER) data to health authorities for potential emergency use authorisation or conditional approval of AZD7442.
The manufacturer plans to submit the full results for peer-reviewed publication, while trials of the antibody continue for both treatment and prevention.
Research details
ZD7442 PROVENT Phase III trial met primary endpoint in COVID prevention
Positive high-level results from the PROVENT Phase III pre-exposure prophylaxis trial showed AstraZeneca's AZD7442 achieved a statistically significant reduction in the incidence of symptomatic COVID-19, the trial's primary endpoint.
AZD7442, a combination of two long-acting antibodies (LAAB), reduced the risk of developing symptomatic COVID-19 by 77% (95% confidence interval (CI): 46, 90), compared to placebo. The trial accrued 25 cases of symptomatic COVID-19 at the primary analysis.There were no cases of severe COVID-19 or COVID-19-related deaths in those treated with AZD7442. In the placebo arm, there were three cases of severe COVID-19, which included two deaths.
AZD7442 is the first antibody combination (non-vaccine) modified to potentially provide long-lasting protection that has demonstrated prevention of COVID-19 in a clinical trial. The trial included 5,197 participants in a 2:1 randomisation AZD7442 to placebo. The primary analysis was based on 5,172 participants who did not have SARS-CoV-2 infection at baseline. More than 75% of participants had co-morbidities, which include conditions that have been reported to cause a reduced immune response to vaccination.
The LAAB was well tolerated and preliminary analyses show adverse events were balanced between the placebo and AZD7442 groups.
AZD7442 was optimised using AstraZeneca’s proprietary YTE half-life extension technology, which could afford up to 12 months of protection from COVID-19, and is delivered by intramuscular injection. Preliminary ‘in vitro’ findings from investigators at Oxford University and Columbia University demonstrate that AZD7442 neutralises recent emergent SARS-CoV-2 viral variants, including the Delta variant.
AstraZeneca will prepare regulatory submission of the prophylaxis (PROVENT and STORM CHASER) data to health authorities for potential emergency use authorisation or conditional approval of AZD7442. Full results from PROVENT will be submitted for publication in a peer-reviewed medical journal and presented at a forthcoming medical meeting.
PROVENT
PROVENT is a Phase III, randomised, double-blind, placebo-controlled, multi-centre trial assessing the safety and efficacy of a single 300mg dose of AZD7442 compared to placebo for the prevention of COVID-19. The trial was conducted in 87 sites in the US, UK, Spain, France and Belgium. 5,197 participants were randomised in a 2:1 ratio to receive a single intramuscular (IM) dose of either 300mg of AZD7442 (n = 3460) or saline placebo (n = 1,737), administered in two separate, sequential IM injections.
The primary efficacy endpoint was the first case of any SARS-CoV-2 RT-PCR positive symptomatic illness occurring post dose prior to day 183. Subjects will continue to be followed for 15 months. Participants were adults 18 and over who would benefit from prevention with the LAAB, defined as having increased risk for inadequate response to active immunisation (predicted poor responders to vaccines or intolerant of vaccine) or having increased risk for SARS-CoV-2 infection, including those whose locations or circumstances put them at appreciable risk of exposure to the SARS-CoV-2 virus. Participants at the time of screening were unvaccinated and had a negative point-of-care SARS-CoV-2 serology test.
Approximately 43% of participants were 60 years and over. In addition, more than 75% had baseline co-morbidities and other characteristics that are associated with an increased risk for severe COVID-19 should they become infected, including those with immunosuppressive disease or taking immunosuppressive medications, diabetes, severe obesity or cardiac disease, chronic obstructive pulmonary disease, chronic kidney and chronic liver disease. Approximately 73% were White/Caucasian, 17% Black/African American, and 3% Asian. Approximately 15% of participants were Hispanic.
AZD7442
AZD7442 is a combination of two LAABs – tixagevimab (AZD8895) and cilgavimab (AZD1061) – derived from B-cells donated by convalescent patients after SARS-CoV-2 virus. Discovered by Vanderbilt University Medical Center and licensed to AstraZeneca in June 2020, the human monoclonal antibodies bind to distinct sites on the SARS-CoV-2 spike protein7 and were optimised by AstraZeneca with half-life extension and reduced Fc receptor and complement C1q binding. The half-life extension more than triples the durability of its action compared to conventional antibodies and could afford up to 12 months of protection from COVID-19 following a single administration. The reduced Fc receptor binding aims to minimise the risk of antibody-dependent enhancement of disease – a phenomenon in which virus-specific antibodies promote, rather than inhibit, infection and/or disease.12
AZD7442 is being studied in a comprehensive clinical trial programme for both prevention and treatment of COVID-19 in more than 9,000 participants. Ongoing trials include TACKLE COVID-19, a Phase III treatment trial in an outpatient setting and collaborator treatment trials in outpatient and hospitalised settings. AZD7442 is being assessed in both IM and intravenous administration routes.
Medpage Today article – AstraZeneca Says Antibody Combo Can Prevent COVID
See more from MedicalBrief archives:
Storm Chaser: AstraZeneca's antibody therapy trial recruits its first participants
AstraZeneca shoots itself in the foot, again
AstraZeneca claims 79% prevention efficacy in US vaccine trial