I recently decided to look at the evidence for monoclonal antibodies to treat COVID-19, in part because I provide medical surveillance to EMS companies that have started infusing them at home, and immediately a video surfaced.
“Hello, maybe you recognize me. He’s your favorite president, ”said Donald Trump, standing in front of the White House. He’s freshly recovered from COVID-19, incredibly tanned and delighted to be here.
“I returned from Walter Reed Medical Center one day ago. I spent four days there and didn’t have to! I could have stayed in the White House. … I wasn’t that hot, and in a very short time they gave me Regeneron. … It was like incredible! I felt good straight away! … I know they call them “therapeutic”, but … I call it a cure! (YouTube. October 7, 2020; https://bit.ly/3Bm804I.)
A month before a hotly contested election, he had plenty of stuff to sell, including, apparently, a remedy called Regeneron! (This is actually the company; the President was singing the praises of REGEN-COV, a cocktail of casirivimab and imdevimab).
The president had been grieved for peddling hydroxychloroquine and shocked ridicule for his surprisingly creative disinfecting ideas: “So, suppose we hit the body with a huge, uh, whether it’s ultraviolet light or just really powerful?” … Suppose we brought light inside the body? It was the same briefing where he was considering injecting disinfectant into the blood or spraying it into the lungs, adding that, of course, “You’re going to have to bring in doctors for that.” (J Med Internet Res. 2020; 22: e20044.)
But this Regeneron story was different. Trump himself had just undergone a scientific study with an n of 1, and had seen the extremely powerful ultraviolet light that was Regeneron!
Good. After a season of mostly press releases, we finally have peer reviewed scholarships, if funded by industry. It seems reasonable to consider monoclonal antibodies as a potential … therapeutic.
Thirty-six studies are underway, not counting studies on convalescent plasma, which is different. (Cochrane database. June 17, 2021; https://bit.ly/3lfgHZnMonoclonal antibodies are engineered in the lab to attack the COVID-19 spike protein, while convalescent plasma is simply blood donated by COVID survivors which is hopefully a soup of global immunological goodness.
Data for June had been reported from six randomized controlled trials of various monoclonal drugs against COVID-19, involving a total of 17,495 patients. Two of the first focused on hospital patients and found deflating results. One of 314 patients randomized to receive placebo or Eli Lilly’s monoclonal bamlanivimab was inconclusive (N English J Med. 2021; 384: 905; https://bit.ly/3uC8EZz), but as the excellent Cochrane review noted, the study saw more deaths, side effects, and symptoms with treatment. Whoops. (This spring, the FDA revoked its emergency clearance for bamlanivimab as monotherapy, citing concerns about the resistance of newer COVID-19 variants; it can still be used in multi-mab cocktails. [FDA. April 16, 2021; https://bit.ly/3l8o3O9.])
The RECOVERY trial involved 9,785 patients randomized to receive placebo or Regeneron. No, it’s the company; sorry they were randomized to receive carisivirimab-imdevimab and found no difference. (Cochrane database. June 17, 2021; https://bit.ly/3lfgHZn.)
The appropriate response to these first two inpatient studies was ugh. But apologies were made, plans changed, and one conclusion drawn: Treat out-of-hospital patients. (“The drug doesn’t work in the hospital! Let’s give it outside the hospital.”) It sounded like a sneaky loophole. It smacked of the scandals surrounding oseltamivir (Tamiflu), the flu drug that worked well to make money for Roche but not for anything else.
But there was a scientific rationale: Monoclonal antibodies are designed to prevent viral entry into cells and therefore viral replication, so they may need to be administered earlier. This was arguably the time when mAbs for COVID became a headache for emergency physicians. Suddenly, patients (along with family and friends) all wanted to be referred to Regeneron! After all, President Trump had promised it would be free: “You’re not going to pay for this! It wasn’t your fault that it happened; it was China’s fault! And China will pay!
The Regeneron team also continued to dig into subgroups of those 9,785 hospital patients as part of the RECOVERY trial. They focused on those who did not have their own COVID-19 antibody response, about a third of hospital patients. Thirty percent of the placebo patients and 24 percent of the mAb patients died in this subgroup. (STAT News. June 16, 2021; https://bit.ly/3Firo5i.) As STAT News noted, that would be a number needed to process 17 to save a life.
Eli Lilly’s bamlanivimab was back in the New England Journal of Medicine in July, as part of a cocktail party with etesevimab. (2021; 385: 1382; https://bit.ly/3ov6rhk.) A total of 1035 outpatients were treated outside the hospital, and less progression to hospitalization or death was seen among those who received the cocktail, 2.1 percent versus seven percent. About 500 patients were in each arm, and no one who received the cocktail died, but 10 deaths occurred among those who received the placebo.
Another study on the use of casirivimab-imdevimab in ambulatory patients randomized approximately 4,000 newly diagnosed patients, particularly if they had risk factors for serious disease, to placebo or increasing doses of a casirivimab cocktail. -imdevimab. (New Engl J Med. September 29, 2021. doi: 10.1056 / NEJMoa2108163; https://bit.ly/3oC0iQN.) This is a confusing read due to the design of the multidose study, but hospitalization or death was less likely in those who received a dose of this cocktail of monoclonal antibodies (25 of 2,091 administrations of the cocktail vs. 86 out of 2089 placebo administrations), and the median time to symptom resolution was shorter (10 vs. 14 days).
A related paper in the same issue reviewed a subcutaneous injection of casirivimab-imdevimab as post-exposure prophylaxis. (N English J Med. 2021; 385: 1184; https://bit.ly/3uGE8xO.) (Wouldn’t that be a gold mine! Forget Pfizer $ 600 EpiPen [April 22, 2021; https://bit.ly/2Yf3arF]; make way for the next day’s REGEN-COV shot!) This reasonably smart study recruited people within 96 hours (seems like a long time) of having family contact diagnosed with COVID-19. The enrollees received a subcutaneous injection of monoclonal or saline solution. Results? Eleven of 753 who received casirivimab-imdevimab and 59 of 752 who received placebo developed symptomatic COVID-19.
Regeneron may be the coolest name in the history of medicine, but it’s not an “amazing cure”. That said, the evidence is weak and evolving, and a small signal of advantage is detectable through all of this overwhelming marketing noise.
Dr Bivensis an emergency physician at St. Luke’s Hospital in New Bedford, UMass Memorial Medical Center in Worcester, and Beth Israel Deaconess Medical Center in Boston. Follow him on twitter@matt_bivens.