What happens if one of the promising vaccines already endorsed under emergency use authorization doesn’t work for whatever reason? What if individuals with allergic reactions are recommended not to become exposed to the vaccines. What are these people to do? What about those facing higher risks, such as the elderly in nursing homes? The U.S. government has recently expressed an imminent urgency for additional treatments targeting COVID-19. Vaccines are not enough and that’s why recently the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response, in collaboration with the U.S. DoD awarded UK-based AstraZeneca $486 million to fund two major clinical trials investigating a monoclonal antibody cocktail developed originally by some brilliant scientists at Vanderbilt Vaccine Center and thereafter enhanced and strengthened by dedicated teams working tirelessly at AstraZeneca. The two Phase 3 clinical trials represent a quest to test whether it’s possible to introduce to the market a therapy that serves as both Pre-Exposure Prophylaxis (PrEP) and/or Post-Exposure Prophylaxis (PEP) protecting people from COVID-19. After all, in months prior other physicians and researchers in other parts of the world looked to repurposed already approved U.S. Food and Drug Administration (FDA) drugs for this purpose. AstraZeneca has made a bold move here targeting either early onset COVID-19 or even before one is infected. Competitive monoclonal antibody investigational products haven’t fared as well—prescribed only in cases where the individual is deemed high risk for disease progression and/or hospitalization. They have faced delivery and administration challenges in real world clinical environments. A multi-billion dollar annual market presents to the drug maker that can deliver the safe, effective and accessible treatment for the early onset COVID-19 case. With 339,000 deaths in America alone, and over 1.7 million worldwide due to the pandemic, PrEP and PEP treatments are needed immediately. Can AstraZeneca deliver safe and effective treatments?
What is AZD7442? The Summary
Originally discovered by a brilliant team at the Vanderbilt University Vaccine Center (VVC) back in March, AZD7442 like other anti-SARS-CoV-2 antibodies in development at companies from Eli Lilly and Regeneron to GlaxoSmithKline and Vir Biotechnology, represent a potential class of biological therapy that can possibly protect individuals who don’t have the ability to mount an adequate immune response to vaccines in effort to expeditiously eliminate COVID-19 upon contact and infection.
This class of drug, if safe and effective, could be administered to people in addition to vaccines as a way to provide extra assurance of protection to the highest risk people. These drugs can potentially be used as both Pre-Exposure Prophylaxis (PrEP) and/or Post-Exposure Prophylaxis (PEP).
Vanderbilt as it turns out was collaborating with AstraZeneca to identify over 1,500 monoclonal antibodies that bind and neutralize the COVID-19 virus in a laboratory setting. The British pharmaceutical company went on to ink an exclusive license to six candidate antibodies in the portfolio established by the university. The two top candidates were of particular interest to the British pharmaceutical giant.
At least in theory, this class of antibody could be administered as injections to stop infection, as well as to treat and possibly prevent disease progression in those individuals who had been exposed or infected by SARS-Cov-2.
Why is this class of therapy potentially important?
SARS-CoV-2 is the driving pathogen of the COVID-19 pandemic that, as of December 27, 2002, has resulted in a high death toll to date (339,000 in the U.S. and 1.7+ million deaths worldwide). Unlike the majority of coronaviruses that cause mild disease in humans and animals, SARS-CoV-2 actually does replicate in the lower respiratory tract to trigger acute respiratory distress syndrome and fatal pneumonia.
Effective interventions to prevent or treat COVID-19 remain limited in number and clinical experience is limited. Clinical management is limited to supportive care in the USA and Europe, consequently overwhelming resources of healthcare systems around the world. As will be discussed below in other parts of the world additional therapies are targeted.
A handful of big pharmaceutical companies (Regeneron, Eli Lilly, GSK) have embarked down the path of developing monoclonal antibodies (mAbs) designed in a laboratory to target COVID-19. For example, AstraZeneca now has AZD7442 targeting the SARS-CoV-2 S protein thanks again to the partnership with Vanderbilt University.
The SARS-CoV-2 spike protein contains the virus’s RBD, which enables the virus to bind to receptors on human cells. By targeting this region of the virus’s spike protein, antibodies can block the virus’s attachment to human cells, and, therefore, are expected to block infection. Amino acid substitutions have been introduced into the antibodies to both extend their half-lives, which should prolong their potential prophylactic benefit, and decrease Fc effector function in order to decrease the potential risk of antibody-dependent enhancement of disease. AZD7442, a combination of 2 of these mAbs (AZD8895 and AZD1061), is being evaluated for administration to prevent and/or treat COVID-19. There is currently one ongoing Phase I study with AZD7442.
What attracted AstraZeneca to two (2) particular antibody targets discovered by Vanderbilt?
Well, it turned out that the Vanderbilt effort led to six top candidates and out of those it was two that caught the attention of AstraZeneca. It was these two antibodies that targeted a couple distinct parts of the surface “spike” protein of the novel coronavirus; that is the part of the pathogen that enables itself to bind to and fuse with the host cell membrane.
After all, AstraZeneca was in a race against other pharmaceutical companies such as Eli Lilly and Regeneron that were already well on their research path toward major clinical trials. The stakes were big: saving human life and massive multi-billion dollar markets.
In regards to the two top antibodies and their potential, the pharmaceutical company’s Executive Vice President for Biopharmaceuticals R&D, Mene Pangalos declared, “By combining two monoclonal antibodies that bind to distinct parts of the SARS-CoV-2 spike protein into what potentially could be a single preventive therapy, we hope to improve its effectiveness in neutralizing the virus.”
What was Vanderbilt’s rationale for a deal with the UK-based company?
This answer is simple and straightforward—because that’s how drug development works. The academic medical center setting is optimized for early stage discovery and preclinical research while the pharmaceutical company brings the clinical development, manufacturing, and commercialization capacity to bring the early stage discovery to the clinic. Moreover, financial transactions are involved as well—the amount AstraZeneca paid to Vanderbilt isn’t disclosed. These deals typically involve upfront payment plus milestone payments and royalties in the single digits on commercialization-based sales.
Who led the effort at the Vanderbilt Vaccine Center?
James Crow Jr., MD, VVC Director, Ann Scott Carell Chair in the Departments of Pediatrics and Pathology, Microbiology, and Immunology in the Vanderbilt University School of Medicine
Robert Carnahan, PhD, Associate Director, VVC, associate professor of Pediatrics
Other Vanderbilt co-authors were Seth Zost, PhD, Pavlo Gilchuk, PhD, Elad Binshtein, PhD, Joseph Reidy, Andrew Trivette, Rachel Nargi, Rachel Sutton, Naveen Suryadevara, PhD, Taylor Jones, Samuel Day and Luke Myers. A full list can be viewed here.
How did VVC discover the SARS-CoV-2 antibodies?
Well, VVC research teams had already developed significant techniques that not only helped them expeditiously isolate clones of white blood cells that produce antibodies targeting particular proteins. A story from VUMC Reported back in March identified some of these approaches, which involved a comprehensive “toolkit.”
Once identified by the toolkit, the monoclonal antibodies were studied extensively so that the Vanderbilt researchers could identify those rare antibodies with “laser-like focus for finding—and neutralizing—a specific virus,” reported Bill Snyder with the VUMC Reporter.
How long had the Vanderbilt team been at it?
Since at least March (3 months), the team had been working tirelessly (like major labs and pharma companies around the world); the VVC team was affiliated with an international group of academic, government and industry partners on the quest to find antibodies targeting SARS-CoV-2
What was the preclinical breakthrough that led the VVC team to believe they were on to something?
By May, the team at Vanderbilt shared preliminary results from preclinical mice experiments. They found that the neutralizing antibodies recognizing unique sites of the spike protein actually served to shield the mice from the impacts of SARS-CoV-2 infection. The scientists observed that the mice actually were spared many of the symptoms of severe COVID-19, such as severe weight loss, reduction in viral burden and lung inflammation.
Did the Vanderbilt team document their findings?
Yes. They first posted the results online utilizing the preprint server called bioRxiv and then went on to publish their findings in Nature. The monoclonal antibodies (mAbs) were shown preclinically to block the binding of the SARS-CoV-2 virus to host cells and thus protect against infection in cell and animal models of the disease.
In discussing their findings, VVC’s Dr. Carnahan reported, “We strongly believe the future of infectious disease treatment will increasingly involve rationally designed therapeutic antibody cocktails like those we have designed for our partners for SARS-CoV-2.” The Vanderbilt Vaccine Center associate director went on “It has never been more important to both rapidly provide a treatment option and to ensure that it also has future utility as the virus evolves.”
Who funded the Vanderbilt monoclonal antibody research?
VVC received funding from the following sources:
· Defense Advanced Research Projects Agency of the U.S. Department of Defense
· National Institute of Allergy and Infectious Diseases (part of the NIH)
· Dolly Parton COVID-19 Research Fund at Vanderbilt
Once licensed, how did AstraZeneca enhance the two monoclonal antibodies discovered by VVC?
The British company sought to differentiate this approach by introducing half-life extension technology in a bid to boost the drug’s impact for half a year to a year post single administration. Could it be possible to introduce to the market a therapy that served as both Pre-Exposure Prophylaxis (PrEP) and/or Post-Exposure Prophylaxis (PEP)?
Thus in June after inking the deal with Vanderbilt, AstraZeneca used what is known as a Long-Acting Antibody (LAABs); these antibodies actually mimic natural antibodies and offer the research community an opportunity to actually treat and even prevent SARS-CoV-2 progression in those individuals already infected with the pathogen. The monoclonal antibodies were optimized by the company with half-life extension and reduced Fc receptor binding targeting the two leading candidates now known as AZD8895 and AZD1061.
What was the first clinical trial in humans?
AstraZeneca commenced a Phase 1 safety clinical trial (NCT04507256) in August. Utilizing one of the world’s largest contract research organizations (CRO) Parexel, the study was conducted at a research site in Harrow, UK led by Principal Investigator Muna Albayaty, Medical Director, Early Phase Clinical Unit, for Parexel in London.
The study commenced August 18 and at least according to their disclosure in Clinicaltrials.gov, runs the study till Oct. 25 2021. With 60 participants, this first-in-human dose escalation study of AZD7442 (AZD8895 + AZD1061) evaluates the safety, tolerability, pharmacokinetics and generation of anti-drug antibodies (ADAs). The study was designed to enable future studies of AZD744s’s efficacy in preventing and treating COVID-19.
Conducted at a single site in the UK, the randomized, double-blind, placebo-controlled and dose escalation study is segmented as follows: A) the initial screening period of up to 27 days (Day 28 through Day 2); B) A treatment period during which participants will be resident at this early phase clinical unit from Day 1-, 1 day prior to administration of AZ7442 until at least 24 hours after administration of investigational drug, followed by discharge on Day 2, after all safety evaluations have been completed, and C) a Follow up period last one year (through Day 361) after the dose of AZD7442.
Has the Study Completed with peer-reviewed results?
No. The study is ongoing and no formal results have been published that TrialSite can find publicly.
How could AstraZeneca then proceed to two large Phase 3 clinical trials if Phase 1 isn’t completed nor results documented?
TrialSite cannot answer this question with certainty without an interview with AstraZeneca. We speculate that the data safety monitoring board gave the sponsor and regulators a greenlight that it was safe to proceed (e.g. the data looks good) and hence in a similar way that Regeneron progressed with a “sentinel cohort” given pandemic conditions the British sponsor received a greenlight.
How much money did the U.S. Gov. give to AstraZeneca in October?
$486 million to fund two Phase 3 clinical trials (see below). The studies serve to assess the ability of the AZ long-acting antibodies to prevent infection from SARS-CoV-2 for up to 12 months.
The funds came from the Department of Health and Human Services and it’s Biomedical Advanced Research and Development Authority (BARDA), part of the HHS Office of the Assistant Secretary for Preparedness and Response, in collaboration with the Department of Defense.
The funds also contribute to a large-scale manufacturing demonstration project and supply of AZD7442 doses in the USA.
What are the other studies now ongoing?
There are two major studies made possible by a $486 million cash injection by the U.S. Federal government (BARDA). That is the PROVENT study and the STORM CHASER. The former focuses on PrEP and the latter PEP. TrialSite describes the studies in more detail below.
What is the Provent Study?
The Phase 3 Provent (NCT04625725) study, funded by the U.S. government, involves up to 5,000 participants at 102 trial site locations across the USA, UK and Europe. Led by Myron Levin, MD, (University of Colorado) the study was reported to have commenced Nov. 21, 2020 and runs till Feb 3, 2022.
Officially titled “A Phase III Randomized, Double-blind, Placebo-controlled, Multi-center Study in Adults to Determine the Safety and Efficacy of AZD7442, a Combination Product of Two Monoclonal Antibodies for Pre-exposure Prophylaxis of COVID-19,” the study and backing clearly indicates the concern of federal research agencies that vaccines are not sufficient to protect large populations and that more is needed.
TrialSite has reported on Provent study from a trial site perspective such as at the El Paso Medical Institute.
What is the Storm Chaser Study?
A major Phase 3 clinical trial (NCT04625972) known as Storm Chaser involves a target of up to 1,125 participants at 65 trial site locations across the United States and the UK. Initiated Dec. 2, 2020, the study runs through till Jan 4., 2022. Led again by Dr. Myron Levin (University of Colorado), the study is supported by CRO IQVIA (Quintiles).
Officially titled “Phase III Double-blind, Placebo-controlled Study of AZD7442 for Post-Exposure Prophylaxis of COVID-19 in Adults,” the study is positioned in the UK press as a “new antibody treatment with the potential to give people instant immunity after being exposed to COVID—19 and prevent illness is being trialed by scientists in the UK.”
Positioned as a drug to be administered as emergency treatment to hospital inpatients, care home residents and even university students in a bid to reduce the viral spread, the market for this kind of therapy would be in the many billions of dollars per year—an immediate blockbuster.
Just recently, the Daily Mail reported that a team of investigators from University College London Hospitals NHS (UCLH) already injected 10 people with the drug as part of the study. It is hoped again that the drug would provide protection from COVID-19 for up to 6 months to a year.
Dr. Nicky Longley, heading the University College London effort in the Provent study was quoted recently, “We want to reassure anyone for whom a vaccine may not work that we can offer an alternative which is just as protective.” And Paul Hunter, a professor of medicine at the University of East Anglia and infectious disease expert, was quoted that the therapy behind the Storm Chaser trial (AZD7442) could potentially save many thousands of lives.
What is the downside of these advanced monoclonal antibody investigational therapies?
As TrialSite has chronicled, the existing mAbs’ therapies authorized under emergency use in the United States (Regeneron and Eli Lilly) have not seen the demand take off as was projected—even despite the fact that America is in the grip of a deadly second wave of the pandemic. Why? A number of reasons that TrialSite reports on here. The researchers developing drugs in labs must be mindful of how to administer in the clinic. Key issues include access, ease of distribution and administration, cost, etc. Value drives important decisioning.
What about other more economical approaches?
There are a handful of other approaches in other parts of the world. The antiviral drug favipiravir is used extensively in other parts of the world and some evidence has surfaced via studies in Russia, India, China and elsewhere. Favipiravir is approved in Russia and has been exported by Russian pharmaceutical companies to dozens of other countries ranging from Eastern Europe to the Middle East and even South America.
Remdesivir didn’t turn out to be as valuable as many thought, although the drug’s maker, Gilead, has generated $1 billion+ in sales in less than a year thanks to first the FDA EUA followed by the approval in October. Remdesivir can’t be used however at early onset for outpatient or at home care, for example. Moreover, the World Health Organization (WHO) found that remdesivir fails. Those findings are disputed by Gilead and the NIH continues to recommend the antiviral drug.
Although controversial among the research centers of power, the antiparasitic drug Ivermectin demonstrates a growing body of evidence that it inhibits SARS-CoV-2. About 50 clinical trials are ongoing and dozens of case series, observational and randomized controlled studies point to the need for immediate support by federal research agencies such as NIH and NIAID.
A group of physicians/researchers in the U.S. called Frontline COVID-19 Critical Care (FLCC) metanalysis of that antiparasitic drug.
However, to date, the world’s major research and health agencies have dismissed such findings and rather direct precious taxpayer capital toward other directions. For an accounting of U.S. federal government funding of vaccines and therapies, see TrialSite’s piece titled “NIH’s Therapeutic Management of Patients with COVID-19 & Some Unanswered Questions About Disturbing Chasm.”
Call to Action: TrialSite continues to monitor the two major clinical trials testing AZ.