James Wilson, MD, a professor and director of the Penn Gene Therapy Program and the Penn Orphan Disease Center
PHILADELPHIA—A new University of Pennsylvania (Penn) research collaboration with Regeneron Pharmaceuticals, Inc. will investigate whether Regeneron’s casirivimab and imdevimab investigational antibody cocktail can prevent COVID-19 infection when delivered intranasally via Adeno-Associated Virus (AAV) vectors. Regeneron’s antibody cocktail (casirivimab and imdevimab administered together) is being studied in clinical trials for the treatment and prevention of COVID-19 and was recently granted an Emergency Use Authorization by the U.S. Food and Drug Administration (FDA) in certain high-risk patients with mild to moderate COVID-19.
Gene therapy pioneer James Wilson, MD, PhD, professor of Medicine and director of the Gene Therapy Program and the Orphan Disease Center at Penn’s Perelman School of Medicine, and his team will work with Regeneron to study the safety and effectiveness of using AAV vectors to introduce the sequence of the cocktail’s virus-neutralizing antibodies directly to nasal epithelial cells. This new collaboration will introduce the application of AAVs, which have traditionally been used for gene therapies against deadly genetic diseases, to the fight against a virus that has infected more than 50 million people across the globe and taken the lives of 1.25 million to date.
“The fight against COVID-19 requires the most creative approaches for the prevention, testing, and treatment of this disease,” Wilson said. “Early clinical data from Regeneron show that their investigational antibody combination may play a role in helping treat the disease and reduce severity in those who are infected. We hope to leverage the virus-neutralizing ability of this antibody cocktail for prevention of COVID-19 using a novel delivery mechanism, as well.
“The advantage of AAV in this application is that can achieve sustained expression of the antibodies in the nasal mucosa, which is the site of infection, following a single administration,” he said. “In contrast to traditional vaccines, AAV delivery of antibodies provides a rapid onset of response and no reliance on the need for the recipient to mount an immune system response over time. This latter feature may be particularly attractive in people with weakened immune systems, like the elderly, or people who need rapid protection, like frontline healthcare workers.”
One of Wilson’s major goals throughout his career has been to develop new methods for delivering genes to cells. He led his lab at the GTP to discover the AAV family of viruses, found in primate tissues, that can be engineered to ferry healthy DNA into the correct cells. AAV vectors — the most commonly used viral vectors today — were developed by Wilson’s laboratory at Penn largely to treat rare and orphan diseases. In 2019, the Wilson lab celebrated the FDA approval of Zolgensma, the first approved drug for the treatment of spinal muscular atrophy. The early development of this drug was enabled by the discovery of an AAV isolate in Wilson’s lab. In the biopharma industry, at least 90 preclinical programs and 40 clinical programs use Wilson’s AAV vectors.
“Regeneron scientists specifically selected casirivimab and imdevimab to block infectivity of SARS-CoV-2, the virus that causes COVID-19, and we have been encouraged by the promising clinical data thus far,” said Christos Kyratsous, PhD, Vice President of Research, Infectious Diseases and Viral Vector Technologies at Regeneron. “In the quest to use cutting-edge science to help end this disruptive and often very devastating disease, we are excited to explore alternate delivery mechanisms such as AAV that may extend the potential benefits of this investigational therapy to even more people around the world.”
To date, AAV has been shown to be a particularly durable method of introducing antibodies into the body, because the AAV genome that codes for the therapeutic antibody remains stable in the nucleus of transduced cells. In clinical trials thus far, casirivimab and imdevimab are delivered together by intravenous or subcutaneous injection, with data showing antibody levels lasting a month or more. Based on data from Regeneron’s preclinical studies showing that the antibody cocktail can prevent infection in animal models, Wilson’s team is hopeful that introducing the therapy via single dose of AAV will be able to produce similar protection for potentially a longer duration.
To develop their investigational antibody cocktail, Regeneron scientists selected two potent, virus-neutralizing antibodies that bind non-competitively to the critical receptor binding domain of the virus's spike protein, as detailed in Science.
The casirivimab and imdevimab antibody cocktail is an investigational therapy that has not been fully evaluated by the FDA and is not yet known to be safe and effective for the treatment of COVID-19. It is being studied in four ongoing late-stage clinical trials: two Phase 2/3 trials for the treatment of certain hospitalized and non-hospitalized (“ambulatory”) COVID-19 patients, the open-label, Phase 3 RECOVERY trial of hospitalized COVID-19 patients in the UK, and a Phase 3 trial for the prevention of COVID-19 in uninfected people who are at high-risk of exposure to a COVID-19 patient (such as the patient’s housemate). Regeneron recently announced positive results from an ongoing Phase 2/3 trial of the medicine in non-hospitalized COVID-19 patients, showing significant impact on viral load and patient medical visits, like hospitalization or medical office visits.
The collaboration between Wilson and Penn’s GTP and Regeneron will have two phases. The first phase will include the validation of the effectiveness of the antibodies delivered via AAV in a large animal model challenge study, where animals will be given the antibody cocktail via AAV and exposed to the novel coronavirus. If that study is successful, the research team will complete studies to support filing of an investigational new drug (IND) application with the FDA, which is a necessary step before clinical trials in humans can begin.
Editor’s note: The University of Pennsylvania and James Wilson may benefit from licensing any intellectual property related to any inventions produced. Penn is also receiving support from Regeneron to conduct this work in the Wilson lab and Gene Therapy Program.
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