A COVID-19 antibody cocktail developed by the US-based company, Regeneron, dramatically reduced the risk of mortality and shortened hospital stays in patients who didn’t naturally produce antibodies against SARS-CoV2 in a recent large-scale trial. 

Meanwhile, the US government announced that it would invest some US$3.2 billion in developing new forms of antiviral COVID-19 treatments to reduce COVID-related hospitalizations and deaths.

The Regeneron trial, published as a pre-print on medrxiv on Wednesday, is the first to demonstrate that an antibody treatment improved survival in patients hospitalised with COVID-19. The randomized controlled trial of the therapy was conducted by researchers at the University of Oxford.

Regeneron’s monoclonal treatment, dubbed REGEN-COV™, uses a combination of two antibodies that bind to the SARS-CoV2 spike protein, neutralizing the ability of the virus to infect human cells. 

Between September 2020 and May 2021, 9,785 hospitalised patients were selected to receive usual care in addition to the antibody treatment or standard care alone. 

The standard care treatment for patients was dexamethasone, a steroid treatment, which cuts death risks up to a third for seriously ill patients by reducing dangerous over-reactions of the immune system.

Significantly, however, one-third of hospitalised participants didn’t have a natural antibody response – as compared to some 54% of patients who had a strong natural antibodies response.

And those patients whose bodies lacked a natural antibody response had a greater risk of mortality. 

“Among all patients randomized, there was no significant difference in the primary outcome of 28-day mortality between the two randomized groups,” said the authors. 

Some 20% of patients in the treatment group died, compared to 21% in the usual care group. The primary efficacy of the drug was seen when comparing those without a natural antibody response in the Regeneron group to those lacking an antibody response in the control group. 

Among those without natural antibody responses, some 24% of hospitalised patients receiving the antibody combination died, in contrast to 30% of patients in the usual care group. 

The antibody combination reduced the 28-day mortality in patients lacking an antibody response by one-fifth – as compared to those receiving usual care alone. 

Among those lacking an antibody response, the treatment also shortened the duration of the hospital stay by an average of four days and reduced the risk of needing to use invasive mechanical ventilation

For every 100 patients treated, there would be six fewer deaths, calculated the study authors. 

Our investigational antibody cocktail improved overall survival in hospitalized #COVID19 patients who had not mounted their own immune response, in the @UniofOxford RECOVERY trial. We’ll be discussing the data with regulatory authorities.

— Regeneron (@Regeneron) June 16, 2021

“It’s the first time that any viral treatment has been shown to save lives in hospitalised COVID-19 patients,” said Martin Landray, Professor of Medicine and Epidemiology at the University of Oxford and Joint Chief Investigator of the trial, in a press release. 

‘Groundbreaking’ New COVID Therapy

“It is wonderful to learn that even in advanced COVID-19 disease, targeting the virus can reduce mortality in patients who have failed to mount an antibody response of their own,” said Peter Horby, Professor of Emerging Infectious Diseases at the University of Oxford and Joint Chief Investigator of the trial. 

“These results provide hope to patients who have a poor immune response to either the vaccine or natural infection, as well as those who are exposed to variants for whom their existing antibodies might be sub-optimal,” David Weinreich, the Executive Vice President of Global Clinical Development at Regeneron, said in a press release. 

The trial also provides an important indicator that hospitalised patients who made their own antibodies likely will not benefit from the treatment. 

“Patients who have made their own antibodies to the virus do not benefit from the new treatment, which is also important information given the cost of drugs,” said Fiona Watt, Executive Chair of the UK Medical Research Council, which helped fund the study. 

“If you already have antibodies, giving you more may not make much difference,” said Horby.

This is useful for guidance on use of the treatment given its high cost, which is between £1,000 and £2,000.

The cost may render the drug only available to those in wealthy countries; in addition, the drug cocktail needs to be administered by infusions. As a result, monoclonal drugs are typically best adapted to use in  high-resource health systems, and only a few monoclonals are available in low- and middle-income countries.

The result is hugely important.

But monoclonal antibodies are expensive.

“There really must be initiatives to make these drugs accessible … you have to scale up manufacturing, and they have to be affordable” 💬 ⁦@PeterHorbyhttps://t.co/pIospHChPn pic.twitter.com/SGHPrBGHid

— Wellcome (@wellcometrust) June 16, 2021

“There really must be initiatives to make these drugs accessible…you have to scale up manufacturing, and they have to be affordable,” Horby told the Guardian. 

Regeneron to Request Expanded Authorization

The therapy was first granted a United States Food and Drug Administration (FDA)  emergency use authorization (EUA) in December. That  EUA was updated in early June to permit a lower 1,200 mg dose of the REGEN-COV™ treatment, based on the recent trial results (600 mg casirivimab and 600 mg imdevimab) – half the dose originally authorised. The treatment is authorised by the FDA for adults and pediatric patients with mild to moderate COVID-19 who are at a high risk of developing severe illness. 

Previous clinical trials have shown that Regeneron’s treatment reduced viral levels, shortened the duration of symptoms, and reduced the risk of hospitalisation and death in non-hospitalised patients. 

“Definitive Phase 3 trials have now demonstrated that REGEN-COV can alter the course of COVID-19 infection from prevention, to very early infection, all the way through to when patients are on a ventilator in the hospital,” said George Yancopoulos, the Chief Scientific Officer at Regeneron.

“We intend to rapidly discuss these results with regulatory authorities, including in the US, where we will ask for our EUA to be expanded to include appropriate hospitalised patients,” Yancopoulos added. 

The trial data suggests that Regeneron’s antibody cocktail could be a valuable tool for tackling severe COVID-19 cases and reducing the worst manifestations of the virus. 

“It is fantastic news that the RECOVERY trial has provided evidence to establish another lifesaving treatment against COVID-19 through this monoclonal antiviral antibody combination,” said Nick Lemoine, Medical Director at the National Institute for Health Research, which supported the trial. 

Commitment to Invest in COVID Treatments

Investment in COVID-19 research has primarily focused on the development of vaccines instead of therapeutics. The new influx of money from the US government will fund clinical trials of drug candidates, with the aim of making COVID treatment pills available within the year.

Experts are concerned that the SARS-CoV2 virus will become a perennial threat. In addition, the current inequitable distribution of vaccines likely means that herd immunity is in the distant future for much of the world. A treatment in pill form could keep people out of hospitals and save lives over the years to come.

“There will always be a threat,” said Dr Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases. “I think there’s going to be a long-range need for drugs.”

The hope “is that we can get an antiviral by the end of the fall that can help us close out this chapter of the epidemic,” Dr David Kessler, Chief Science Officer of President Biden’s COVID-19 response team, told the New York Times.

Ideally, antiviral pills would be available at pharmacies for those who test positive or develop COVID-19 symptoms.

“I wake up in the morning, I don’t feel very well, my sense of smell and taste go away, I get a sore throat,” said Fauci. “I call up my doctor and I say, ‘I have COVID and I need a prescription.'”

Investment in further research on drugs to prevent and treat SARS-CoV2 infection “could help with this pandemic and potentially provide a first line of defense for the next one,” said Mark Namchuk, Director of Therapeutics Translation at Harvard Medical School.

Image Credits: Flickr – US Navy, Regeneron.