Every day for weeks this past fall, Brian Koffman, MD, would Google “AZD7442, AZD7442, AZD7442.”
He finally hit pay dirt December 8, when he discovered that the US Food and Drug Administration had authorized AstraZeneca’s long-acting monoclonal antibody combination, AZD7442 (Evusheld), for COVID-19 preexposure prophylaxis in adults and children at least 12 years old who don’t have an adequate immune response to COVID-19 vaccination or can’t be fully vaccinated.
Although the FDA has authorized other companies’ monoclonal antibody products for COVID-19 postexposure prophylaxis and for the treatment of mild to moderate COVID-19 in patients at risk of developing more severe disease, AZD7422 is the first to receive Emergency Use Authorization (EUA) for preexposure prophylaxis, or PrEP.
“My reaction was a combination of incredible excitement, relief, and what are my next steps to make sure I can get it for myself and my community?” said the 70-year-old Koffman, a retired family physician in Chula Vista, California, who was diagnosed with chronic lymphocytic leukemia (CLL) in 2005 and cofounded the nonprofit CLL Society in 2013.
The FDA authorized AZD7442, which is administered in 2 intramuscular injections, 1 of tixagevimab and 1 of cilgavimab, for 2 groups of people:
Those whose medical condition or immunosuppressive therapy has left them with a moderate to severely compromised immune system that might not adequately respond to COVID-19 vaccination. They might be receiving treatment for solid tumor or blood cancers, immunosuppressive therapy to prevent rejection of a solid organ transplant, or chimeric antigen receptor (CAR)–T cell therapy, according to the FDA’s AZD7442 fact sheet for clinicians.
Individuals who’ve had severe reactions to a COVID-19 vaccine or its components and, therefore, can’t get fully vaccinated.
Under an EUA, a product can be used only for the indications outlined in the authorization and not off-label.
As the FDA said in its press release announcing the EUA for AZD7442, “Pre-exposure prevention with Evusheld is not a substitute for vaccination in individuals for whom COVD-19 vaccination is recommended.”
Healthy people who want AZD7442 just because they don’t want to get vaccinated shouldn’t be able to obtain it, although, Koffman said, he expects some will slip through.
Number of doses the federal government has bought from AstraZeneca:
Number of people in the US who might benefit from AZD7442:
As many as 10 million, Myron Cohen, MD, a leader of the National Institutes of Health’s COVID-19 Prevention Network, said in an interview. “You have a pretty big imbalance.” Cohen’s role with the network has been collaborating with industry in the development of monoclonal antibodies.
AstraZeneca began manufacturing AZD7442 before receiving the EUA, a company spokesperson said in an email.
Delivery of first doses: Around the first of the year.
Delivery of the last of the 700 000 doses: Spring 2022.
Delivery of any more doses? “After the initial 700,000 doses are utilized, we will coordinate with the US government to either continue to supply the federal government doses or begin distributing product via traditional commercial channels,” the spokesperson said.
“We are committed to providing [AZD7442] as quickly as possible to all markets in which we enter firm agreements,” she added, noting that AstraZeneca has also agreed to produce it for countries other than the US. “We already hold inventory of finished product that exceeds near-term forecast demand, and manufacturing capacity has been reserved with significant further quantities of product already in various stages of manufacture in the supply chain.”
She would not say how many AZD7442 doses AstraZeneca expects to produce each month.
Echoing the FDA’s news release about the product’s EUA, the AstraZeneca spokesperson said that “individuals who believe they are candidates for [AZD7442] should reach out to their health care provider.”
The problem is that “even to this day, it is hard for patients and physicians to understand who might benefit the most. It goes along with the lack of manuscripts” about the AZD7442 clinical trials, said Cohen, who has been fielding emails about COVID-19 PrEP from both patients and physicians for weeks.
The primary data supporting the AZD7442 EUA came from PROVENT (A Phase III Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study in Adults to Determine the Safety and Efficacy of AZD7442 for Pre-exposure Prophylaxis of COVID-19).
Although AstraZeneca announced topline PROVENT results in an August press release and presented updated data at IDWeek 2021 in late September, detailed findings had not yet been published when AZD7442 received an EUA.
“We would like to see published, peer-reviewed papers about the results,” said Cohen, director of the University of North Carolina Institute for Global Health and Infectious Diseases. “The studies that I’m involved with, we kill ourselves to put them in a [preprint] and then in a journal. We just don’t do press releases.”
Only 196 of the 5197 unvaccinated adults who participated in PROVENT had a compromised immune system, although more than 75% of the participants had comorbidities such as obesity or cardiac disease that can diminish the immune response to COVID-19, according to slides provided by AstraZeneca. However, under the EUA, simply having obesity or cardiac disease (or both) isn’t enough to qualify for AZD7442.
Since there won’t be nearly enough AZD7442 to go around to everyone with a compromised immune system, physicians will have to determine which patients have the most pressing need, which isn’t rocket science, Cohen said.
Zero antibodies after 3 vaccine doses, high-dose steroid treatment, and the absence of B cells, which are needed to help fight off infections, are all among factors associated with an especially poor immune response to vaccines, he said. “The NIH has several programs trying to look observationally at who responds to vaccines and who does not.”
After eligible patients get their first AZD7442 dose, another question looms: When is it time to get the second dose? The FDA indicated that the monoclonal antibody combination may be effective for PrEP for 6 months. Preliminary pharmacokinetic modeling that had not been peer-reviewed suggested protection could last up to 12 months. Or is the optimal timing somewhere in between?
Whether monoclonal antibodies can fend off Omicron remains to be seen, since clinical trials took place before the new SARS-CoV-2 variant was first reported November 24 and deemed a variant of concern by the World Health Organization and the US within a week.
In a press release December 16, AstraZeneca reported that a laboratory study conducted by FDA scientists found that the company’s monoclonal antibody combination retained neutralizing activity against the Omicron variant at levels within the range of neutralizing titers found in someone who’d previously been infected with SARS-CoV-2. The researchers tested AstraZeneca’s product against a pseudovirus made with the full Omicron variant spike protein.
A study that wasn’t peer-reviewed found that in the laboratory, Omicron resisted Regeneron’s monoclonal antibody combination of casirivimab and imdevimab (REGEN-COV), which has EUAs for treating COVID-19 and postexposure prophylaxis.
On the other hand, other laboratory research that had not been peer-reviewed found that sotrovimab, GlaxoSmithKline and Vir Biotechnology’s investigational SARS-CoV-2 monoclonal antibody, retained effectiveness against all Omicron spike protein mutations. Sotrovimab is being studied for PrEP in hematopoietic stem cell transplant recipients.
AZD7442 is likely to have competition in the COVID-19 PrEP space.
“The bottom line is the FDA opened up the door,” Cohen said.
About 2 weeks before the AstraZeneca product received an EUA for that use, Regeneron applied for one for its casirivimab and imdevimab combination, he said.
Cohen coauthored a recent study that found that compared with placebo, the Regeneron antibodies, which already have EUAs for treating COVID-19 and postexposure prophylaxis, reduced the risk of asymptomatic and symptomatic infection in infected individuals’ household members.
The published data covered 1 month after participants received shots of the Regeneron antibodies or placebo. Subsequent analyses showed that protection was maintained for up to 8 months after participants received the shots, according to a Regeneron press release.
“If Omicron becomes dominant, they’re going to have to switch out another monoclonal,” Cohen noted.
Despite all the questions that remain, “I’m really excited that an agent has received an EUA for preexposure prophylaxis for people who need it,” Cohen said.
Still, he said, “a lot of education of physicians and patients is necessary.”
Conflict of Interest Disclosures: Dr Koffman spoke at a recent press briefing about AZD7442, for which AstraZeneca made a contribution to the CLL Society.