Candidate: EVUSHELD™ (AZD7442)
Type: Long-acting antibody (LAAB) combination therapy for preventing and treating COVIED-19, consisting of two monoclonal antibodies derived from B-cells donated by convalescent patients with SARS-CoV-2 infection, tixagevimab (AZD8895; 150 mg dose) and cilgavimab (AZD1061; 150 mg dose). Both were discovered at Vanderbilt University Medical Center’s Vanderbilt Vaccine Center. The coronavirus-neutralizing antibodies were developed through the company’s program to use the Defense Advances Research Project Agency’s Pandemic Prevention Platform (P3).
AZD7442 has been optimized using AstraZeneca’s proprietary YTE half-life extension technology, which the company says could afford up to 12 months of protection from COVID-19.
2022 Status: Additional 1M Doses for U.S.—AstraZeneca said February 14 that the US Department of Health and Human Services has finalized its agreement to purchase an additional one million doses of EVUSHELDTM. The agreement included a 500,000-dose purchase announced by the US government on January 12, and followed the government’s initial agreement for the purchase of 700,000 doses of EVUSHELD, for a total of 1.7 million doses. The US government has indicated that it plans to distribute these additional doses to states and territories at no cost, according to AstraZeneca.
Additional 500,000 Doses—AstraZeneca on January 12 said it welcomed the US government purchase of an additional 500,000 doses of the antibody, now known as EVUSHELD. Delivery of the additional 500,000 doses is anticipated in the first quarter of 2022. Additional details will be released “in coming weeks,” AstraZeneca said.
2021 Status: ASTRAZENECA PURSUES EUA—AstraZeneca said October 5 that it submitted to the FDA a request for Emergency Use Authorization (EUA) for AZD7442 for prophylaxis of symptomatic COVID-19, citing positive data from the Phase III PROVENT pre-exposure prevention trial (NCT04625725), as well as from the Phase III STORM CHASER trial (NCT04625972), which yielded mixed results (See below).
The company also cited preliminary ‘in vitro’ findings showing that AZD7442 demonstrated broad anti-COVID activity, and specifically neutralized the Delta and Mu variants of SARS-CoV-2. AZD7442 offers the potential to provide protection from COVID-19 for those not expected to mount an adequate immune response following vaccination, AstraZeneca said.
Positive Phase III PROVENT Results—AstraZeneca said August 20 that AZD7442 met its primary endpoint in the Phase III PROVENT pre-exposure prevention trial (NCT04625725) by achieving a statistically significant reduction in the incidence of symptomatic COVID-19. AZD7442 reduced the risk of developing symptomatic COVID-19 by 77% compared to placebo. The trial accrued 25 cases of symptomatic COVID-19 at the primary analysis, based on 5,172 participants who did not have SARS-CoV-2 infection at baseline. The trial included 5,197 participants who were randomized 2:1 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.
While more than 75% of participants had co-morbidities, 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. The primary efficacy endpoint was the first case of any SARS-CoV-2 RT-PCR positive symptomatic illness occurring post dose before day 183. Participants will continue to be followed for 15 months.
Mixed Phase III STORM CHASER Results—AstraZeneca acknowledged June 15 that its Phase III STORM CHASER trial (NCT04625972) did not meet the primary endpoint of post-exposure prevention of symptomatic COVID-19 with AZD7442 compared to placebo. While AZD7442 reduced the risk of developing symptomatic COVID-19 by 33% compared to placebo, the difference was not deemed statistically significant.
However, in a pre-planned analysis of SARS-CoV-2 PCR positive (detectable virus) and PCR negative (no detectable virus) participants, AZD7442 was shown to reduce the risk of developing symptomatic COVID-19 by 73% compared with placebo in participants who were PCR negative at time of dosing. A post-hoc analysis showed that in participants who were PCR negative at baseline, AZD7442 reduced the risk of developing symptomatic COVID-19 by 92% versus placebo more than seven days following dosing, and by 51% up to seven days following dosing.
“We are encouraged by the protection seen in the PCR negative participants following treatment with AZD7442,” stated Mene Pangalos, AstraZeneca Executive Vice President, BioPharmaceuticals R&D. He said the company will await results from its Phase III PROVENT pre-exposure prevention trial (NCT04625725) and Phase III TACKLE treatment trial (NCT04723394) to understand the potential role of AZD7442 in protecting against COVID-19.
STORM CHASER included 1,121 participants randomized 2:1 AZD7442 to placebo, with 23 cases of symptomatic COVID-19 accrued in the AZD7442 arm (23/749) and 17 cases accrued in the placebo arm (17/372), AstraZeneca said.
The U.S. Army Contracting Command on March 30 reserved a minimum of 100,000 doses of AZD7442 through a contract modification valuled at $204.88 million, to be funded through its fiscal 2021 research, development, test and evaluation funds. The doses will be produced in Wilmington, DE, with an estimated completion date of December 31.
AstraZeneca said March 16 that it modified an existing agreement with the U.S. government to supply up to 500,000 additional doses of AZD7442. The agreement with the departments of Health and Human Services and Defense builds on an October 2020 agreement to support late-stage development of AZD7442 and the supply of an initial 100,000 doses of AZD7442, including the option to acquire additional doses in 2021. The company also has a separate agreement to supply the Defense Department with 100,000 doses, bringing potential U.S. supplies of AZD7442 to 700,000 this year.
The NIH and its National Institute of Allergy and Infectious Diseases (NIAID) said February 8 that it was evaluating AZD7442 in the international randomized, controlled Phase III ACTIV-3 trial (NCT04501978), designed to assess the safety and efficacy of AZD7442.
ACTIV-3 is part of the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership, designed to develop a coordinated research strategy for prioritizing and accelerating development of the most promising treatments and vaccines. ACTIV-3 is a master trial through which NIAID is conducting multiple different trials of experimental therapeutics simultaneously. In addition to AZD7442, ACTIV-3 includes sub-studies of VIR-7831, a Vir Biotechnology/GlaxoSmithKline partnered monoclonal antibody; and of the combination of BRII-196 and BRII-198, two neutralizing monoclonal antibodies manufactured by Brii Biosciences.
If outcomes assessed at five days, after approximately 150 volunteers have received AZD7442, indicate that AZD7442 is likely to be both safe and effective, enrollment in the trial will be expanded, NIAID said, to an additional 700 participants, some of whom may have more severe cases of COVID-19. ACTIV-3’s primary endpoint is sustained recovery as defined by patients being discharged from the hospital and living at home for 14 consecutive days.
2020 Status: AstraZeneca on October 9 was awarded $486 million toward two Phase III trials and related development activities related to AZD7442, including a large-scale manufacturing demonstration project and supply of doses in the U.S. The company estimated that 100,000 doses of AZD 7442 could be available from the project for high-risk patients unable to benefit from a vaccine by December 2020.
One Phase III trial will assess the safety and efficacy of the antibody combination to prevent infection for up to 12 months in approximately 5,000 volunteers. An additional Phase III study will evaluate if AZD7442 can help prevent infection in people who have come in contact with someone with COVID-19 in a post-exposure prophylaxis setting. That study will enroll approximately 1,100 volunteers.
The funding comes through Operation Warp Speed, the Trump administration’s program designed to accelerate the development, manufacturing, and distribution of COVID-19 diagnostics, drugs, and 300 million doses of vaccines. AstraZeneca’s Warp Speed funding comes from the Biomedical Advanced Research and Development Authority (BARDA), and the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and Army Contracting Command.
In August, AstraZeneca began human clinical testing of AZD7442 in a Phase I trial (NCT04507256). The first-in-humans dose escalation study is designed to assess the antibody combination in up to 48 healthy participants in the U.K., ages 18–55 for safety, tolerability, pharmacokinetics, and generation of anti-drug antibodies (ADAs).
After licensing the combination from VUMC in June through an agreement of undisclosed value, AstraZeneca optimized the antibodies with half-life extension and reduced Fc receptor binding. The half-life extended monoclonal antibodies should afford at least six months of protection from COVID-19, according to AstraZeneca.
The Biomedical Advanced Research and Development Authority (BARDA) said June 9 it will award AstraZeneca $23.65 million and join the Defense Advanced Research Projects Agency (DARPA) within the Department of Defense in partnering with the company to advance its monoclonal antibody combination therapy for the treatment and protection against COVID-19 into Phase I clinical development. The agencies also agreed to work with AstraZeneca to manufacture the antibodies for Phase I testing.
In April, AstraZeneca said it is exploring three potential sources for antibodies against SARS CoV-2: Patients who have recovered from COVID-19, immunized humanized mice, and lab techniques such as phage display.
AstraZeneca also disclosed collaborations with external partners: The Chinese Academy of Sciences, and VUMC have provided genetic sequences for antibodies they have discovered against SARS2-CoV-2 for further in silico and in vitro assessment, while the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) and the University of Maryland School of Medicine are conducting preclinical safety and efficacy assessments of antibody candidates discovered through internal research.
The company said March 24 it will donate 9 million face masks for healthcare workers worldwide, with Italy receiving the first shipments.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: