From the moment Covid-19 emerged as a threat, one approach to making drugs to treat or prevent the disease seemed to hold the most promise: They’re known as monoclonal antibodies.
Now, scientists are on the brink of getting important data that may indicate whether these desperately needed therapies could be safe and effective. Clinical trials involving a pair of antibodies developed by Regeneron Pharmaceuticals will read out early results in September. A separate effort from Eli Lilly could yield data later in the fall.
Despite experts’ eagerness to see the data, however, there remains a debate over just how significant a role any antibody treatment might play in changing the course of the pandemic.
“A lot of smart people who understand immunology and virology think antibodies will work,” said Robert Nelsen, an investor at ARCH Venture Partners who is invested in Vir Biotechnology, which will start tests of its own Covid-19 antibody study this month.
Scott Gottlieb, the former commissioner of the Food and Drug Administration, is less sure antibody treatments will be significant factors in bringing the pandemic under control. Even though the development efforts have been proceeding extraordinarily fast by normal standards, the U.S. has spent billions of dollars purchasing vaccines in advance, but has not done far less to shore up capacity for antibody drugs.
“We may have missed a window to scale the manufacturing of antibody drugs that could have been an important bridge to a vaccine and a hedge in the event vaccines are delayed or don’t work,” Gottlieb, a fellow at the American Enterprise Institute and board member for Pfizer and other health care companies, told STAT. “These drugs had the ability to perhaps meaningfully change the contours of this epidemic, and we just won’t have enough doses to realize that goal.”
Monoclonal antibodies are antibodies — the kind that the body produces to neutralize invading viruses — that have been genetically engineered into new medicines.
In 1975, two researchers, Georges J.F. Köhler and César Milstein, developed the method for mass-producing them by fusing antibody-producing cells from mice with cancer cells. They shared the Nobel Prize in physiology or medicine in 1984. The first monoclonal antibody drug, for kidney transplant patients, was approved in 1986. Today, Humira, an antibody from AbbVie that treats a host of immune-related diseases, is the pharmaceutical industry’s top-selling product, generating $15 billion in sales last year.
Regeneron has produced several monoclonal antibodies since being founded in 1988, including Praluent for high cholesterol, Libtayo for a type of cancer, and Dupixent for severe eczema. In 2014, the technology was also used to develop an effective treatment for Ebola.
As the Covid pandemic hit, Regeneron’s chief scientific officer, George Yancopoulos, assigned Christos Kyratsous, a confident, Porsche-driving scientist with a dry sense of humor, to lead a team that would search for an antibody. In early February, a non-infectious fragment of genetic code of the novel coronavirus arrived at the company’s research laboratories in Tarrytown, N.Y., from China, and the company has used this starting material to produce hundreds of virus-neutralizing antibodies using genetically engineered mice, along with blood taken from survivors of Covid-19.
But getting antibodies into people has taken time. “I tragically right now have a 91-year-old aunt who’s trapped in a nursing home where right now there’s a coronavirus outbreak,” Yancopoulos said in April. “And I just wish I could get them our [drug] today. It’s just not ready.”
Other companies are advancing their own efforts. For years, AbCellera, a Vancouver-based biotech, had been working with the National Institutes of Health and the U.S. Department of Defense to game out the response to future pandemics. In February, the NIH’s National Institute of Allergy and Infectious Diseases sent the company a sample of blood from a patient who had recovered from Covid-19. AbCellera inserted the sample into a credit-card-sized device that isolates the B cells that make antibodies, and used it to find more than 550 antibodies that might work against the virus.
Regeneron’s antibodies — REGN10933 and REGN10987 — both target the “spike” protein on the virus’ surface that helps it invade cells, but individually, each drug binds to the protein at a different, non-overlapping location. This “cocktail” approach aims to increase the chance that the virus can be neutralized without escaping. It’s the same multidrug strategy used successfully to treat other viral diseases such as HIV and hepatitis C. Regeneron refers to the dual antibody regimen as REGN-COV2.
The first look at Regeneron’s data will provide results on the ability of REGN-COV2 to reduce the amount of SARS-CoV-2 virus in patients compared to placebo. Safety and other data will also be announced.
Outcomes data will come later. For the study of hospitalized Covid-19 patients, Regeneron hopes to show that the treatment can improve clinical status based on a seven-point scale ranging from hospital discharge to death. In between, the scoring system measures changes in the use of supplemental oxygen or mechanical ventilation. In the study of ambulatory Covid-19 patients, REGN-COV2 is designed to speed recovery and prevent the disease from getting worse. Unlike Regeneron, Eli Lilly and AbCellera have chosen not to use a cocktail approach, starting instead by testing a single antibody. Data from its study, however, being conducted with the NIH, aren’t expected to be released until October or November.
“Reducing the theoretical risk of escape mutations has a real cost, and the real cost is manufacturing, meaning you will have less doses available, meaning fewer people will be treated in this critical time period,” Lilly Chief Scientific Officer Daniel Skovronsky told STAT during a recent event. “So my view is we go for a single antibody, which means that we can treat twice as many people if it works.”
The Lilly antibody, called LY-CoV555, will be investigated in a placebo-controlled clinical trial of approximately 300 patients hospitalized with mild to moderate Covid-19. An initial efficacy assessment based on symptoms improvement, including the need for supplemental oxygen, will be conducted five days following the injections of LY-CoV555 or placebo. If these initial results show a benefit for the Lilly antibody, the study will be expanded to enroll another 700 patients, including people with severe cases of Covid-19.
Recently published animal data suggest these antibody treatments may work in humans. Monkeys exposed to SARS-CoV-2 followed one day later with injections of the Regeneron cocktail cleared the virus faster than monkeys treated with a placebo. Damage to the lungs, including cases of pneumonia, was reduced but not eliminated in the monkeys treated with the cocktail compared to the placebo group. The monkey study was released via a preprint server, meaning the data had not yet been peer-reviewed or published in a journal.
In a research note, SVB Leerink analyst Geoff Porges called the monkey data “quite encouraging,” but he also cautioned it may not be curative in humans on its own, citing the inconclusive pneumonia results and the challenge of treating patients early, before they might have symptoms.
“If clinical development for the antibody cocktails is successful, we believe it would be most likely to complement the existing standard of care and antiviral therapies such as remdesivir, rather than displacing antivirals,” said Porges.
Nelsen, the investor at ARCH Venture Partners, said: “If you treat people who are very sick, you may not see anything. If you treat people earlier, you will probably see what you saw in the monkeys: a significant reduction in virus, which doesn’t necessarily mean a reduction in morbidity and mortality, but it should. What you really want to do is prevent the progression of the disease.”
Vir, the biotech firm that Nelsen backed, will start a clinical trial of its lead antibody candidate VIR-7831 later this month, seeking to show that it can prevent hospitalization due to Covid-19. A second antibody candidate, VIR-7832, will advance into a clinical trial later this year. Both drugs are designed to bind to a location on the spike protein that creates a high barrier to resistance. In preclinical studies, the antibodies also recruit immune cells to help kill other cells already infected by the virus, Vir said.
Similar to vaccines, antibody treatments are also being developed to prevent Covid-19 infection, particularly in people who are at high risk and who might have been exposed to the virus through close contact with an already infected person.
“Once someone has come into contact with some of the disease, it’s too late for an active vaccine,” Lilly’s Skovronsky said. “But a passive immunization like our antibody could be valuable. When you think about the populations that are suffering the most, it’s the elderly, it’s the immunocompromised, it’s patients in nursing homes and long-term care facilities.”
Lilly and NIAID are conducting a 2,400-patient Phase 3 study to test whether its treatment can keep nursing home patients from developing Covid-19. The antibody will be given to patients and staff at places where there has been an infection to see if it can stop them from developing the disease. To conduct the study, Lilly is deploying a fleet of recreational vehicles that can be used prepare study drug and do lab work, as well as pull trailers that can be used as on-site infusion clinics.
Regeneron and NIAID are also conducting a prevention study in 2,000 healthy adults who are household contacts with an individual with a positive Covid-19 test. Will it be possible to manufacture enough antibody? Regeneron said it is “in active discussions with other parties” that can add additional manufacturing capacity.
The big determinant of how fast answers will emerge will be the speed at which doctors can enroll patients in these studies, said Anita Kohli, the director of clinical research at Arizona Clinical Trials and an investigator for both Regeneron and Eli Lilly. This, she said, is harder than it sounds, especially for patients who are not so sick that they are in the hospital. “I think some of the recruitment is more difficult, because you’re recruiting sick people,” she said. “Sick people want to eat chicken soup and stay at home and not go to the clinical trials center.”
One problem is that diagnostic tests are taking a long time to come back. Doctors are supposed to enroll patients in the studies within five or six days of the onset of symptoms. If testing takes two weeks to come back, patients often recover before they are enrolled. Kohli’s center has begun to test patients for Covid in the hopes that some will volunteer to be in studies.
“Vaccines are not going to work for everybody,” she said. “People are still going to get sick, there’s no two ways about it. And we’ve got to have a treatment.”
The problem, she said, is that patients are not being made aware of clinical trials for therapeutics soon enough.
“People have not been directed toward clinical trials, or are not thinking about them,” she said.” I think that’s what we need to change here. It’s not that they aren’t very exciting, they are very exciting. They just aren’t talked about enough.”