Virus World

The FDA halted the use of two monoclonal antibody treatments for COVID-19 because they are not effective against the omicron variant of SARS-CoV-2, which now accounts for almost all U.S. cases. The FDA revised the emergency use authorizations for the two treatments bamlanivimab and etesevimab administered together, and the cocktail of casirivimab and imdevimab. Their use will now be limited to infections that are likely to have been caused by a variant that is susceptible to the treatments. “Because data show these treatments are highly unlikely to be active against the omicron variant, which is circulating at a very high frequency throughout the United States, these treatments are not authorized for use in any U.S. states, territories, and jurisdictions at this time,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press release. Cavazzoni said this will avoid exposing patients to side effects from treatments “that are not expected to provide benefit to patients who have been infected with or exposed to the omicron variant.” She said the treatments may be reauthorized in regions where patients are likely to be infected or exposed to a susceptible variant, or if they are proven affective against future variants. The FDA noted that there are several other therapies that are expected to work against omicron, including Paxlovid, sotrovimab, remdesivir and molnupiravir.

Regeneron said that a single dose of its antibody cocktail REGEN-COV reduced the risk for COVID-19 by nearly 82% up to 8 months after administration in a phase 3 trial. REGEN-COV, which contains 600 mg each of the monoclonal antibodies casirivimab and imdevimab, was authorized for emergency use by the FDA in November 2020 for the treatment of mild to moderate COVID-19 in high-risk patients. The FDA expanded the emergency use authorization in July to include post-exposure prophylaxis.  Trial results announced Monday by Regeneron showed that, compared with placebo, people who received a single dose of REGEN-COV had an 81.6% reduced risk for developing COVID-19 during a 2-to-8-month follow-up period (95% CI, 59.8%-91.6%) and an 81.5% reduced risk for developing COVID-19 at any time during the 8 months after receiving REGEN-COV (95% CI, 70.6%-88.4%). Myron S. Cohen, MD, who leads the monoclonal antibody efforts for the NIH-sponsored COVID Prevention Network and is director of the Institute for Global Health & Infectious Diseases at the University of North Carolina at Chapel Hill, said the findings “demonstrate how a single dose of REGEN-COV can help protect people from COVID-19 for many months after administration.” "These results demonstrate that REGEN-COV has the potential to provide long-lasting immunity from SARS-CoV-2 infection, a result particularly important to those who do not respond to COVID-19 vaccines, including people who are immunocompromised,” Cohen said.

Regeneron said the data build on previously published findings in The New England Journal of Medicine, which reported a risk reduction of 81.4% in the first month. The newly announced findings were from an 8-month follow-up that continued to compare outcomes from more than 1,600 people assigned to receive a single dose of the cocktail or placebo. In all, seven people in the treatment arm and 38 in the placebo arm developed COVID-19 within 2 to 8 months. George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron, said the data “add to the increasing body of evidence supporting the use of REGEN-COV to prevent COVID-19 in uninfected individuals.” “With infections still occurring despite widespread vaccination, the immunocompromised face an ongoing risk of encountering the virus during their daily lives,” Yancopoulos said in a statement. “We intend to rapidly share these additional data with regulatory authorities to help those in most need of protection from COVID-19.”

Regeneron cocktail reduces mortality by 20% in those who don’t produce antibodies themselves, RECOVERY trial shows. The world’s largest trial of COVID-19 therapeutics has for the first time produced convincing evidence that a therapy that directly attacks the virus can save hospitalized patients from death. A combination of antibodies called casirivimab and imdevimab, produced by Regeneron, did not lower mortality when all patients in the study were taken together, investigators of the United Kingdom’s Recovery trial announced today—but it reduced deaths by one-fifth among those who did not produce antibodies themselves. A paper with the results will be made available on the medRxiv preprint server later today, the researchers say. “Here you have really the first direct SARS-CoV-2 drug,” says Eric Topol, director of the Scripps Research Translational Institute. Two drugs previously shown to reduce mortality from COVID-19 were developed for other diseases and work by dampening an overactive immune response, which is “kind of an indirect strategy,” Topol says. But Regeneron’s antibodies, which attach to the receptor-binding domain of the spike protein and prevent the virus from entering cells, are expensive and not widely available, and quickly identifying patients that benefit from it may be a challenge.

Researchers have developed several monoclonal antibodies against SARS-CoV-2, with mixed results. Some, including Regeneron’s, have shown some positive effects on disease progression in outpatients, but none was demonstrated to save the lives of severely ill patients in the hospital. The Recovery trial started to evaluate Regeneron’s cocktail in mid-September 2020. By late May, 9785 patients had been randomly allocated to receive either the usual care in the United Kingdom or the usual care plus a one-time infusion of the two antibodies, a procedure that takes roughly 1 hour.  About one-third of the patients were seronegative when they entered the trial, meaning they did not produce antibodies themselves. That includes people with underlying health conditions that weaken their immune system, but also people who, for unclear reasons, are unable to produce antibodies early on. In this group, 30% of patients given standard care died, versus 24% of those who received the antibody cocktail. That translates to six lives saved for every 100 such patients treated with the drug. The Regeneron cocktail received a lot of attention when former U.S. President Donald Trump received it during his bout with COVID-19 in October 2020. Although it’s not clear whether Trump’s immune system produced antibodies, the new results suggest the treatment may have helped save his life, Topol says: “Who knows what might have happened at his age, with his morbid obesity and all the other risk factors that he had.”

Although it received an emergency use authorization from the U.S. Food and Drug Administration in November 2020—and the U.S. government bought 1.5 million doses— Regeneron’s therapy has not been widely used in the United States, Topol says. “This is just sitting on shelves,” he says. “I think [the Recovery trial] is going to wake people up as to the benefit.” But doctors will have to determine which patients fail to produce antibodies. “I think this isn’t a complicated test to run, it just needs to be done,” says Martin Landray of the University of Oxford, one of Recovery’s principal investigators. A bigger challenge may be cost. “We anticipate, but we don’t know this, that they may be around £1000 or £2000 per treatment,” Recovery co-investigator Peter Horby said at a press conference on Tuesday. That might put the therapy and many similar ones in the pipeline out of reach for most people living in developing countries, which also have far fewer COVID-19 vaccine doses than rich countries. Access to antibody drugs in general has been particularly unequal across the globe, says Lindsay Keir, a pediatrician who co-authored a Wellcome Trust report on global access to such treatments released last year. “Antibodies that we have benefited from in high-income countries for 20, 30 years, still aren’t available in many countries,” Keir says. The inequity is a “scandal,” Horby says. “There really must be an initiative to make these drugs accessible, and that requires two things: They have to be available, which means we have to scale up manufacturing, and they have to be affordable, which means we have to reduce the prices.”

Original findings available as preprint in medRxiV (June 16, 2021):

https://doi.org/10.1101/2021.06.15.21258542 

See Recovery trial press release (June 16, 2021):

https://www.recoverytrial.net/news/recovery-trial-finds-regeneron2019s-monoclonal-antibody-combination-reduces-deaths-for-hospitalised-covid-19-patients-who-have-not-mounted-their-own-immune-response-1 

New late-stage trial data show Regeneron and Roche's antibody cocktail against COVID-19 cut hospitalisation or death by 70% versus a placebo in non-hospitalised patients, the Swiss drugmaker said on Tuesday. The shot, consisting of casirivimab and imdevimab antibodies developed by Regeneron with financial help from the U.S. government, also met all key secondary endpoints in the phase III trial with 4,567 participants, including reducing symptom duration to 10 days from 14, Roche said.  Roche, which is making the drug at plants in California and which is responsible for sales outside the United States, and Regeneron are expecting hundreds of millions in sales in 2021 from the drug, including $260 million alone to the U.S. government in the first quarter. 

“New infections continue to rise globally with over three million reported cases last week, so this investigational antibody cocktail may offer hope as a potential new therapy to high-risk patients - particularly in light of recent evidence showing that casirivimab and imdevimab together retain activity against key emerging variants,” Roche Chief Medical Officer Levi Garraway said.  Roche has said that it and Regeneron can produce more than 2 million doses annually. The cocktail, which data previously showed has been effective against variants, has emergency approval in the United States, and has been authorized in Europe for use in non-hospitalised patients. Former U.S. President Donald Trump got the treatment when he was infected with COVID-19.

Roche's Press Release (March 23, 2021):

https://www.roche.com/media/releases/med-cor-2021-03-23.htm

Regeneron's therapy is part of a class of treatments known as monoclonal antibodies, which are made to act as immune cells that scientists hope can fight infections. The Food and Drug Administration on Saturday granted an emergency use authorization for Regeneron’s Covid-19 antibody treatment, the experimental therapy given to President Donald Trump when he contracted the coronavirus in October. Regeneron submitted an emergency use application that month after preclinical studies showed that the therapy, called REGN-COV2, reduced the amount of virus and associated damage in the lungs of non-human primates. The company said trial data also shows the drug reduces medical visits in patients with mild-to-moderate Covid-19. “The FDA remains committed to advancing the nation’s public health during this unprecedented pandemic. Authorizing these monoclonal antibody therapies may help outpatients avoid hospitalization and alleviate the burden on our health care system,” said FDA Commissioner Stephen M. Hahn. Regeneron’s therapy is part of a class of treatments known as monoclonal antibodies, which are made to act as immune cells that scientists hope can fight infections. Monoclonal antibody treatments gained widespread attention after news that Trump received Regeneron’s antibody cocktail. As Trump’s health improved, he touted it as a “cure.” But Regeneron’s CEO, Dr. Leonard Schleifer, has stressed that more testing is required.

“Some people don’t know how to define therapeutic. I view it different. It’s a cure,” Trump said in a video posted Oct. 7 on Twitter. “For me, I walked in. I didn’t feel good. A short 24 hours later, I was feeling great. I wanted to get out of the hospital. And that’s what I want for everybody. I want everybody to be given the same treatment as your president because I feel great.” Regeneron’s authorization comes after the FDA announced on Nov. 9 that it had authorized Eli Lilly’s antibody treatment – called bamlanivimab –for people newly infected with Covid and are at risk of developing a severe form of the disease. Officials said the treatment shouldn’t be used for hospitalized patients because there is no data to show the drug is helpful at that stage of the disease. The authorization will expand the number of drugs at doctors’ disposal to fight the virus, which continues to rapidly spread across the United States and other parts of the world. Before the authorization, people could only get the drug as part of an FDA program that gives some patients limited access to investigational medical products. Gilead Sciences’ antiviral drug remdesivir is the first and only fully approved treatment in the U.S. for Covid.

FDA Authorization Letter (Nov. 21, 2020):

https://www.fda.gov/media/143891/download

Clinical setbacks reported this past week by Regeneron Pharmaceuticals and Eli Lilly have raised questions about the effectiveness of antibody therapies in patients with severe COVID-19 compared to patients with mild-to-moderate forms of the virus. Regeneron said Friday it agreed to hold off on further enrollment of patients requiring high-flow oxygen or mechanical ventilation in the Phase II/III portion (NCT04426695) of an adaptive Phase I/II/III trial assessing its two-antibody “cocktail” REGN-COV2 in hospitalized adult patients with COVID-19. In pausing enrollment of the sickest patients, Regeneron said it is following the recommendation of the trial’s independent data monitoring committee (IDMC) “based on a potential safety signal and an unfavorable risk/benefit profile at this time.” Regeneron did not disclose the potential safety signal that triggered the pause in patient enrollment—but did say it would inform the FDA of its findings, since the agency is evaluating the company’s request for an emergency use authorization (EUA) of REGN-COV2 for in mild-to-moderate outpatients at high risk for poor outcomes. Regeneron is the second developer of a leading antibody candidate against COVID-19 to suffer a clinical setback this past week. On October 26, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) halted the up-to-10,000 patient Phase III ACTIV-3 trial (NCT04501978) it was conducting to assess the safety and effectiveness of Lilly’s LY-CoV555, recently renamed bamlanivimab, compared with Gilead Sciences’ Veklury™ (remdesivir) and placebo in people who have been hospitalized with COVID-19.

“Disappointing replication”

“A disappointing replication: monoclonal antibodies to #SARSCoV2 don’t provide benefit to hospitalized patients w/ moderate-severe illness,” tweeted Eric Topol, MD, founder and director of the Scripps Translational Research Institute, on Friday.  Topol, who is also professor, molecular medicine and executive vice president of Scripps Research, added that the Regeneron and Lilly disappointments reflected “the need to treat #COVID19 early or preventatively.” Florian Krammer, PhD, professor at the department of microbiology, Icahn School of Medicine at Mount Sinai, also noted in a Twitter thread that early in COVID-19, monoclonal antibodies and other antivirals are likely to help infected patients.  “Late in infection, our own immune system does the damage, and immunomodulatory drugs likely help at this stage (like dexamethasone),” Krammer said. “Using mAbs late (like in the trials stopped by Eli Lilly and Regeneron) was unlikely to work. But using them early is very promising.” Reflecting that promise, the IDMC in Regeneron’s hospitalized patient trial of REGN-COV2 also recommended continuing enrollment of the less severely injured hospitalized patients—namely those requiring either no or low-flow oxygen, “as the risk/benefit remains acceptable in these cohorts.” The trial has an estimated enrollment of 2,970 participants....

Regeneron Pharmaceuticals Inc said on Wednesday its coronavirus antibody cocktail - the experimental treatment that U.S. President Donald Trump received - significantly reduced medical visits in a trial of nearly 800 patients with mild-to-moderate COVID-19.  Regeneron said patients given the treatment, REGN-COV2, made around 57% fewer COVID-19 related medical visits than those given a placebo over a 29 day period. The drop was around 72% in patients with one or more risk factors such as being over age 50, obesity, cardiovascular, metabolic, lung, liver or kidney disease, or an immunocompromised status. Last month, the company released early data from the trial showing the treatment reduced viral levels and improved symptoms in non-hospitalized COVID-19 patients. The new data confirm the initial findings, the company said. 

Regeneron’s drug is a cocktail of two monoclonal antibodies - manufactured copies of antibodies that are one of the main weapons the immune system generates to fight infections.  Trump has credited the Regeneron therapy for his recovery from COVID-19 and said he would push for emergency use authorization (EUA) of that treatment and others like it. He also said he wanted it to be provided at no cost to Americans. The company earlier this month filed with the U.S. Food and Drug Administration seeking an EUA for the dual-antibody therapy. It said it has shared the new data with the regulator as part of the review of its request.  Eli Lilly and Co makes a similar drug and also filed for an EUA. The company signed a $375 million contract to provide 300,000 doses of its treatment to the U.S. government on Wednesday. Regeneron said earlier this month it had around 50,000 doses of its treatment ready for distribution. The U.S. government agreed in June to buy up to 300,000 doses of the antibody cocktail for $450 million.

U.S. President Donald Trump has received a promising but experimental COVID-19 drug still in clinical trials, according to a White House statement released Friday afternoon, following his diagnosis with the disease. Sean Conley, the President’s personal physician, wrote in a memo that he treated Trump with an eight-gram dose of Regeneron’s experimental antibody cocktail. Trump has also received zinc, vitamin D, aspirin, melatonin and a heartburn drug thought to help fight COVID-19. Regeneron on Tuesday announced promising results related to its monoclonal antibodies—drugs that mimic the human body’s natural immune response. When the body detects an infection, it deploys proteins called antibodies to help fight it off. Monoclonal antibodies essentially kickstart that process with synthetic proteins. In preliminary results from a trial of 275 non-hospitalized COVID-19 patients who were treated with either the antibody cocktail or a placebo, Regeneron’s cocktail reduced the amount of virus in patients’ systems and helped alleviate their symptoms, the company says. The therapy worked particularly well for patients whose immune systems failed to mount a natural response to SARS-CoV-2, the virus that causes COVID-19, according to Regeneron’s results.

While those are promising results, they have yet to be peer-reviewed, and Regeneron’s therapy has not yet been cleared by the U.S. Food and Drug Administration. After the trial’s findings were released, executives said they planned to “rapidly” discuss them with the FDA, CNBC reports. Regeneron has enrolled participants for a larger study to confirm and build upon the results of its first trial. Trump is “fatigued but in good spirits” following his diagnosis with COVID-19, Conley wrote in his memo. He has reportedly experienced mild symptoms so far. First Lady Melania Trump, who also tested positive for the coronavirus, has a headache and mild cough, according to the memo. Trump is being taken to Walter Reed National Military Medical Center for a “few days,” the Associated Press reported late Friday afternoon.

The world's largest randomised trial of potential medicines for COVID-19 is to add Regeneron's experimental antiviral antibody cocktail REGN-COV2 to the drugs it is testing in patients hospitalised with the disease. The UK RECOVERY trial, which has been testing a range of potential COVID-19 treatments since it began in April, will compare the effects of adding REGN-COV2 - a lab-manufactured monoclonal antibody - to standard care. “This is the first drug actually designed for this disease,” said Martin Landray, a professor of medicine & epidemiology at Oxford University who is co-leading the trial. “There are lots of good reasons for thinking this might be really quite a powerful treatment,” he told Reuters in an interview. The addition of Regeneron’s drug to the RECOVERY trial comes amid growing hopes that monoclonal antibodies may emerge as effective ways to treat COVID-19.  Until now, the RECOVERY trial had mostly been studying whether existing drugs could be re-purposed to tackle the new disease, and it has already found answers on a number of them.

In June and September, trial results showed that widely used steroids such as dexamethasone and hydrocortisone were able to reduce death rates among severely-ill COVID-19 patients.  Also in June, RECOVERY trial results showed that the anti-malarial drug hydroxychloroquine, once touted by U.S. President Donald Trump as a potential “game changer” in the pandemic, was of no benefit in treating COVID-19 patients.  Regeneron’s REGN-COV2 cocktail, which the company is already testing in late-stage clinical trials in people, combines one Regeneron-made antibody and a second antibody isolated from people who have recovered after being infected with COVID-19.  The combination is designed to bind to the spike protein used by the new coronavirus to gain access to human cells, limiting the virus’s ability to escape.  Regeneron developed the biological drug before linking up with Roche ROG.S to expand its manufacturing capacity in hopes of meeting global demand, should the medicine prove effective. Regeneron would handle U.S. sales, with Roche selling the medicine around the world.

Landray said his team had secured enough supply of the drug so that up to “several thousand” patients could be given it in the trial and compared with several thousand controls. “Given that the second phase (of COVID-19 infections in the UK) seems to be coming now, it is a really good time to be starting this,” he said. The United States already has a $450 million deal for the cocktail in place, under the terms of which Regeneron will sell it around 70,000 to 300,000 potential treatment doses or 420,000 to 1.3 million prevention doses of REGN-COV2. Data is due later this month, Regeneron has said.  Alongside Regeneron, Eli Lilly LLY.N, working with biotech firm AbCellera, is seen as a leading contender in the antibody race. In August it started testing whether its antibody can prevent COVID-19 infections in nursing homes. A separate trial testing the compound on recently diagnosed COVID patients may yield initial data in September or shortly after. GlaxoSmithKline GSK.L and partner Vir Biotechnology VIR.O also began testing an experimental antibody on newly diagnosed COVID-19 patients late last month. AstraZeneca AZN.L is for now testing its antibody-based cocktail on healthy volunteers for tolerability.

Glaxo (GSK) and Vir Biotechnology announce promising pre-clinical data from the study of their antibody candidate, sotrovimab, against mutations found in the Omicron variant. The antibody candidate has shown activity against several deadly mutants of coronavirus including Delta, Delta plus and Mu in clinical studies. Amid rising concerns of an Omicron outbreak, the encouraging pre-clinical data against the variant supports its strong potential as an enduring COVID-19 treatment option going forward.  Pre-clinical data included results of testing of sotrovimab against pseudo-viruses with each containing a specific individual mutation found in the Omicron variant. Glaxo and Vir Biotechnology are currently conducting an in-vitro test of their antibody drug against all mutations found in the Omicron variant in a single pseudo-virus. Data from this test will demonstrate the neutralizing ability of sotrovimab against a combination of the Omicron mutations. An update on the data from this in-vitro study is expected by the end of 2021. The companies stated that sotrovimab targets a specific portion of the coronavirus, which makes it more difficult for the variants to develop resistance against the candidate. We note that Glaxo and Vir Biotechnology’s sotrovimab, as an intravenous administration, was granted emergency use authorization (“EUA”) for treating mild-to-moderate COVID-19 in adult and pediatric patients in May. The intravenous drug is available under the tradename of Xevudy.

The approval was based on data from a late-stage study that demonstrated that treatment with sotrovimab achieved 79% reduction in risk of hospitalization or death. Glaxo’s shares have gained 12.7% so far this year compared with the industry’s 12.6% increase. In a separate press release, the companies announced that sotrovimab was granted conditional marketing authorization in the United Kingdom for the treatment of symptomatic adults and adolescents. The drug is authorized for use in patients with acute COVID-19 infection without any requirement of oxygen supplementation with increased risk of progressing to severe infection. The drug needs to be administered within five days of the onset of COVID-19 infection symptoms.  Glaxo and Vir Biotechnology already have a supply agreement in place with the government of the United Kingdom for the supply of sotrovimab. The investigational therapy is also authorized for temporary/conditional use in several other countries including Japan and Canada. It is also under review in Europe. Glaxo and Vir Biotechnology have agreements with several entities across the globe in place for supply of more than 750,000 doses of sotrovimab. The companies also have an agreement with the European Commission for additional doses.

A report released by another COVID-19 drugmaker, Regeneron REGN earlier this week stated that vaccine-induced and monoclonal antibody-conveyed neutralization activity will reduce against the Omicron variant, implying lower effectiveness of available COVID-19 solutions against the new variant of concern, including Regeneron’s antibody cocktail, REGEN-COV. Further tests are being conducted to understand the impact using the actual Omicron variant sequence.  Regeneron’s REGEN-COV comprises two monoclonal antibodies, casirivimab and imdevimab., which have demonstrated strong effectiveness against previous coronavirus strains. Regeneron added $3.5 billion to its top line from sales of REGEN-COV, leading to more than 100% increase in total revenues in the first nine months of 2021...

Vir Biotechnology press release (December 2, 2021):

https://investors.vir.bio/news-releases/news-release-details/preclinical-data-demonstrate-sotrovimab-retains-activity-against 

See also preprint here (Dec. 1, 2021):

https://doi.org/10.1101/2021.03.09.434607

The FDA has expanded its EUA for Regeneron's COVID-19 drug as a preventative therapy for those who have been exposed to the disease and who are at high risk to progress to a severe case.  With its rapid mutations, the evolutionary process of the coronavirus makes it a moving target. And so it is with treatments for the disease, which can quickly become in vogue or obsolete.  Case in point for the former: Regeneron’s antibody cocktail REGEN-COV. Over the last few months, nearly every development in the COVID-19 antibody market has broken in favor of the treatment, a combination of casirivimab and imdevimab. On Friday, the FDA granted emergency use authorization to REGEN-COV as a preventative measure for those who have been exposed to COVID-19 and who are at high risk to progress to a severe case because they are not fully vaccinated or are not expected to mount an adequate antibody response to vaccination.  About 3% of the U.S. population won't respond fully to COVID-19 vaccines, including patients on chemotherapy, people with hematologic cancers and others, Regeneron says.

The FDA based its decision on a phase 3 trial, run jointly with the National Institutes of Health, which showed that REGEN-COV cut the risk of developing symptomatic COVID by 81% among healthy individuals who lived with an infected person. The study tested the med in 1,505 people who lived with an infected person within the prior four days. Those who received an infusion of REGEN-COV showed 72% efficacy against symptomatic COVID over the first week and 93% beyond the first week. Additionally, among those who developed symptoms, REGEN-COV recipients cleared the virus faster than those in the placebo group.  While vaccine recipients need time to build an effective antibody response, especially with a two-shot regimen, a direct injection of antibodies can offer more immediate protection.   The FDA granted REGEN-COV its initial EUA in November for patients with newly diagnosed COVID-19 who are at a high risk of progressing to severe disease. Since then, the drug Regeneron’s therapy has gained FDA nods for a subcutaneous injection and at a smaller dose. Regeneron's antibody trailed Eli Lilly's antibody onto the market, but it has since proven more resilient against mutations than its rival. Another antibody drug gained FDA approval two months ago. But sotrovimab, a joint effort from GlaxoSmithKline and Vir Biotechnology, has yet to secure a supply deal from the United States.

Regeneron Pharmaceuticals is planning to ask the Food and Drug Administration (FDA) to allow its antibody cocktail to be used as a preventive treatment for COVID-19, the company said Monday.  New results from a clinical trial conducted with the National Institute of Allergy and Infectious Diseases found the drug reduced the risk of symptomatic infection by 81 percent in people who were not infected at the start of the trial, Regeneron said. The company has already received emergency use authorization from the FDA to use its antibody drugs to treat adults with mild to moderate COVID-19 and pediatric patients at least 12 years old who have tested positive for the virus and are at high risk of severe disease but are not yet hospitalized. The trial enrolled 1,505 people who were not infected with the virus but lived in the same household as someone who recently tested positive. The patients were randomized to receive either one dose of the antibody therapy or a placebo administered as injections. After 29 days, 11 people out of the 753 who received a single 1,200 mg dose of the treatment developed symptomatic COVID-19; 59 people who received a placebo out of 752 participants developed symptomatic COVID-19. 

The drug provided 72 percent protection against symptomatic infections in the first week and 93 percent protection in subsequent weeks, Regeneron said. The data has not yet been peer reviewed or published. Regeneron also said the trial found individuals treated with the therapy who experienced a symptomatic infection resolved their symptoms in one week, compared to three weeks with placebo.  Infected individuals also cleared the virus faster with the therapy, the company said. Adverse events occurred in 20 percent of patients who received the antibody drug and 29 percent of those who received a placebo, Regeneron said, but nobody withdrew from the trial because of them.  None of the participants who received the therapy were hospitalized or went to the ER because of COVID-19 over the course of 29 days; four in the placebo group did so.  There were four deaths in the trial — two in the therapy group and two in the placebo group — but none were reported due to COVID-19 or the drug. "With more than 60,000 Americans continuing to be diagnosed with COVID-19 every day, the REGEN-COV antibody cocktail may help provide immediate protection to unvaccinated people who are exposed to the virus, and we are also working to understand its potential to provide ongoing protection for immunocompromised patients who may not respond well to vaccines," George Yancopoulos, president and chief scientific officer at Regeneron, said in a statement.

Regeneron's Press Release (April 12, 2021):

https://investor.regeneron.com/news-releases/news-release-details/phase-3-prevention-trial-showed-81-reduced-risk-symptomatic-sars

The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. However, recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa) and B.1.1.248 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of UK, South Africa and Brazil variant into human cells is susceptible to blockade by entry inhibitors. In contrast, entry of the South Africa and Brazil variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment and was less efficiently inhibited by serum/plasma from convalescent or BNT162b2 vaccinated individuals. These results suggest that SARS-CoV-2 may escape antibody responses, which has important implications for efforts to contain the pandemic.

Preprint available (Feb. 11. 2021):

https://doi.org/10.1101/2021.02.11.430787 

SARS-CoV-2 can mutate to evade immunity, with consequences for the efficacy of emerging vaccines and antibody therapeutics. Herein we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is the most divergent region of S, and provide epidemiological, clinical, and molecular characterization of a prevalent RBM variant, N439K. We demonstrate that N439K S protein has enhanced binding affinity to the hACE2 receptor, and that N439K virus has similar clinical outcomes and in vitro replication fitness as compared to wild-type.

We observed that the N439K mutation resulted in immune escape from a panel of neutralizing monoclonal antibodies, including one in clinical trials, as well as from polyclonal sera from a sizeable fraction of persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.

Preprint available in bioRxiv (Nov. 5, 2020):

https://doi.org/10.1101/2020.11.04.355842

The saga of COVID-19 antibody R&D continues as the REGN-COV2 antibody cocktail used by President Donald Trump and touted as a cure has been hit by safety worries as it continues to push for an FDA emergency authorization. The cocktail, which has been erroneously called “Regeneron,” is currently in a series of tests including for patients with COVID-19 that are currently hospitalized. But Friday morning, the independent data monitoring committee (IDMC) told Regeneron safety concerns will need to see it roll back the sickest patients on the test.  It said: “Based on a potential safety signal and an unfavorable risk/benefit profile at this time, the IDMC recommends further enrollment of patients requiring high-flow oxygen or mechanical ventilation be placed on hold pending collection and analysis of further data on patients already enrolled.

It did not give details on what the safety signal was. The news hit shares, which were in the red by 2.6% premarket when the news first hit The IDMC did, however, say that the biopharma can continue enrollment of hospitalized patients who need either no or low-flow oxygen as the “risk/benefit remains acceptable in these cohorts.” It can also continue work of the outpatient trial “without modification.”  The FDA is currently assessing the cocktails for a speedy emergency use authorization nod, specifically in mild to moderate outpatients at high risk for poor outcomes. It’s not clear how this news will impact this process. This comes only a few days after the therapy showed it reduced COVID-19 related medical visits by 57% in early data.

The company said that doses of the unproven treatment would be available for 50,000 patients. It’s impossible to know whether it helped the president. The drugmaker Regeneron said on Wednesday that it had submitted an application to the Food and Drug Administration for emergency approval of the experimental antibody cocktail that President Trump had praised just hours earlier without evidence as a “cure” for the coronavirus. The company said access to the treatment would be extremely limited at first, with only enough doses for 50,000 patients, a far cry from the “hundreds of thousands” of doses that Mr. Trump, in a video released on Wednesday, said he would soon be making available to Americans free of charge. In the five-minute video, Mr. Trump said that it was a “blessing from God” that he had been infected with the coronavirus and that the Regeneron cocktail had suddenly made him feel better. “I felt unbelievable,” he said. “I felt good immediately.”  There is no evidence that the treatment is the reason he was feeling better, and his doctors have said he has taken other drugs as well. 

Mr. Trump gave the impression that he would push the F.D.A. to approve Regeneron’s treatment, even though the agency’s scientists are supposed to make independent decisions about approvals. “I have emergency-use authorization all set, and we’ve got to get it signed now,” Mr. Trump said. A spokeswoman for the F.D.A. declined to comment on Wednesday, saying the agency does not confirm or deny product applications. The news of Regeneron’s application on the same day that Mr. Trump effusively praised the unproven drug is likely to intensify fears that the president is pressuring federal health agencies to make decisions aimed at benefiting him politically. In the video, Mr. Trump repeated his desire to get a vaccine approved before the election on Nov. 3, even though the vaccine makers themselves have said that is highly unlikely...

Experts caution more data from larger trials will be needed to know how potentially beneficial monoclonal antibodies are. New data from the biotechnology firm Regeneron seem likely to add to the excitement about drugs called monoclonal antibodies as treatments for Covid-19, but experts caution more data will be needed to know how potentially beneficial the medicines are.  A high dose of the company’s antibody cocktail, REGN-COV2, led levels of the virus to decrease more quickly in infected, non-hospitalized patients, potentially indicating the treatment may help them get better, Regeneron reported Tuesday via press release. Full results will be published at a later date.  “There’s nothing bad about these results, you just can’t say much about how transformative this is going to be,” said Eric Topol, director of the Scripps Research Translational Institute. As with data from a similar antibody, developed by Eli Lilly, he warned that the data so far should not be enough for the Food and Drug Administration to grant an emergency use authorization.   “This doesn’t cut it, but it’s moving in the right direction, that’s for sure,” Topol said. In a notable finding, the data seem to show that the antibody had a bigger effect in patients who tested positive for SARS-CoV-2 but had not created high levels of their own antibodies against the virus. In this group, even a lower dose of the Regeneron antibodies seemed to result in patients getting better faster.

The data add to the early results from Eli Lilly, which showed a reduction in virus levels for patients at some doses and a tantalizing hint that the treatment might help keep patients out of the hospital.  Monoclonal antibodies are synthetic versions of one of the immune system’s own weapons against invaders. From the start of the pandemic, some experts have been most hopeful about this technology to create new medicines to fight SARS-CoV-2, the virus that causes Covid-19. But that potential could be limited by the ability to manufacture large quantities of the treatments. Regeneron has reached an agreement with Roche, the Swiss drug giant, to increase its production capacity. Experts said longer studies, which are ongoing, will be needed to really know if the antibody treatments make patients better. “We are highly encouraged by the robust and consistent nature of these initial data, as well as the emerging well-tolerated safety profile, and we have begun discussing our findings with regulatory authorities while continuing our ongoing trials,” said George Yancopoulos, Regeneron’s chief scientific officer. 

The data are from a 275-patient portion of Regeneron’s study testing REGN-COV2 in patients who have tested positive for Covid-19 but who are not in the hospital. Patients received either placebo, 2.4 grams of REGN-COV2, or 8 grams of REGN-COV2. (The antibody cocktail is delivered intravenously.) Those who received the high dose saw viral levels decrease by 0.60 log10 copies of the virus per milliliter compared to placebo after seven days, a result that was statistically significant. In the lower dose, there was a 0.23 log10 reduction, which was not statistically significant. Regeneron did not give the total amount of virus detected in its press release. At the beginning of the study, Regeneron tested patients not only to see if they had SARS-CoV-2, but also to see if they created their own antibodies against the virus. The company found that 45% of patients had created antibodies, 41% had not, and 14% had unclear results. Those without antibodies had higher levels of virus in swabs from their noses from the start. And those who had created their own antibodies got better much faster. Patients with their own antibodies in the placebo group saw symptoms disappear in seven days, while in those whom antibodies were not detected, it took 13 days for symptoms to go away. Giving the patients Regeneron’s synthetic antibody had a far greater effect on the amount of virus detected in those who did not have an antibody response before treatment. There was a reduction of 0.6 log10 copies/mL in the patients who received the high dose, and 0.51 in those who received the low dose, both of them statistically significant. The reductions were also greater in patients who had higher levels of virus. And in those patients who did not have detectable antibodies at the study’s outset, Regeneron’s antibody cocktail improved symptoms. In this group, symptoms were alleviated in 13 days on placebo, eight days in the high-dose group, and six days in the low-dose group.  Among the 275 patients for whom data are being reported, 50% were Hispanic, 14% were African American, and the rest of the racial breakdown was not disclosed. On average, they were 45 years old. Forty-nine percent of participants were male and 51% were female...

Regeneron's Press Release:

https://investor.regeneron.com/news-releases/news-release-details/regenerons-regn-cov2-antibody-cocktail-reduced-viral-levels-and 

The studies were run on a total of 36 rhesus macaques and 50 hamsters. The company is careful to caution that positive animal studies do not guarantee success in humans. In early July, Regeneron Pharmaceuticals, with the U.S. National Institute of Allergy and Infectious Diseases (NIAID), announced they were launching Phase III trials of REGN-COV-2, the company’s two-antibody cocktail to treat and prevent COVID-19. Although those results of those trials are still pending, the company issued a scientific article, not yet peer-reviewed, that shows the cocktail was able to “almost completely block establishment of virus infection,” in rhesus macaques and hamsters. Using its proprietary VelocImmune mice, Regeneron screened thousands of fully-human antibodies. The mice have been genetically modified to have a human immune system. They also evaluated antibodies isolated from people who have recovered from COVID-19. They then chose the two most potent, non-competing antibodies that were most effective at neutralizing SARS-CoV-2, the virus that causes COVID-19. They then scaled up the dual-antibody cocktail for clinical use with the company’s own VelociMab and manufacturing capabilities. The two antibodies bind non-competitively to the receptor binding domain of the virus’s spike (S) protein. This decreases the ability of mutant viruses to avoid treatment and protects against spike variants that have evolved in the human population. On June 11, the company announced the publication of two scientific articles describing the effectiveness of REGN-COV-2 in the journal Science. The first paper was, “Studies in humanized mice and convalescent humans yield a SARS-COV-2 antibody cocktail.”

In the latest animal study paper, the authors said the cocktail in monkeys and hamsters demonstrated “that REGEN-COV-2 can greatly reduce virus load in lower and upper airway and decrease virus-induced pathological sequelae when administered prophylactically or therapeutically. Our results provide evidence of the therapeutic potential of this antibody cocktail.” Essentially, the study took two approaches. One was to infect animals with the virus, then dose them with the antibody cocktail to see if it could halt the infection. It appeared to do this successfully. 

The second approach was to dose the animals with the antibody cocktail, then infect them with the virus. This also appeared to prevent infection. It’s important to note that the antibody cocktail is not a vaccine. Therapeutic antibodies such as these do not have long-range effects, although they may last several months. The studies were run on a total of 36 rhesus macaques and 50 hamsters. The company is careful to caution that positive animal studies do not guarantee success in humans. The human trials have already started. There are specifically two trials. A Phase III trial will study if REGN-COV-2 can prevent infection in uninfected people who have had close exposure to a COVID-19 patient. The drug has also been advanced into the Phase II/III portion of two adaptive Phase I/II/III trials evaluating the cocktail in treating hospitalized and non-hospitalized patients with COVID-19....

Preprint available at bioRxiv (August 3, 2020):

https://doi.org/10.1101/2020.08.02.233320