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President Trump was treated with an infusion of Regeneron’s REGN-COV2 monoclonal antibody “cocktail” last week before he was admitted prior to Walter Reed National Military Medical Center. Here are eight things you should know about the treatment.
1. The cocktail consists of two monoclonal antibodies that “stick” to the SARS-CoV-2 spike protein.
Cocktail may conjure up the idea of some complicated mixture, but this cocktail is just two monoclonal antibodies (REGN10933 and REGN10987). As Alina Baum and other Regeneron investigators explained in a study published in Science, treatment with two monoclonal antibodies works to defeat “viral escape” that can occur when viruses mutate so they are no longer recognized and thwarted by a single monoclonal antibody.
In that June 15, 2020, Science paper, Baum and her colleagues also explain that their results show that two monoclonal antibodies are more effective when they stick to distinct “noncompeting areas” of the spike protein of the SARS-CoV-2 virus rather than overlapping ones.
2. Regeneron has shared clinical results but not in a published format.
Company scientists, such as Baum, have published preclinical findings about the monoclonal antibody treatment of COVID-19 in highly respected, peer-reviewed journals like Science, but the main source of information about clinical trial results is information that company officials (mainly George Yancopoulos, M.D., Ph.D., co-founder, president and chief scientific officer) shared with analysts and journalists on September 29. You can view see the slides shown during that presentation here and listen to an audio recording of the call here.
COVID-19 has sped up the pace of publication, and a great deal of COVID-19-related research has been posted as preprints on medRxiv. But Regeneron was criticized (fairly gently) by some for putting out its results in this way. At the very least, said some commentators, the company-reported results need to be interpreted with some caution.
3. The monoclonal antibody combination has a larger effect in people with a relatively weak immune response to SARS-CoV-2 infection, according to the Regeneron-reported results.
The results that Yancopoulos presented in the call on September 29 were for 275 of the 900 people that the company has enrolled in a study of people with COVID-19 who have not been hospitalized. The company has launched other studies of its monoclonal antibody combination among hospitalized patients (the NHS in Great Britain is helping with that research) and among the household contacts of people with COVID-19 (the household contact study is testing whether the monoclonal antibody treatment is effective at preventing infection among people who come in close contact with infected individuals).
The study that Yancopoulos described randomized COVID-19 outpatients to one of three treatment groups: a placebo (93 patients), a one-time infusion of a low dose (2.4 grams) of the monoclonal antibody combination (92 patients), or a one-time infusion of a high dose (8 grams) of the combination (90 patients). President Trump received the high dose.
A little more than half (56%) of the study volunteers were Hispanic and a little less than half (42%) met the standard definition of being obese (a BMI higher than 30).
The outcomes included the “viral load” in samples taken with the now-familiar nasopharyngeal swabs, the time to alleviation of symptoms, and the number of “medical-assisted visits” in the 29-day period after the treatment or administration of the placebo.
The results aren’t that impressive when the patients are grouped just by the intervention. Take the median time to alleviation of symptoms, which was defined as when the symptoms are mild or absent. In the placebo group, it was nine days; in the low-dose group, it was six days; and in the high-dose group it was eight days. And when the low- and high-dose groups are combined, it was eight days.
But Yancopoulos said during the call (and he came back to this idea several times) it was important to categorize patients by their antibody levels — and an indication, of course, of the strength of their body’s own immune response — and that high antibody levels and low viral loads went hand in hand. When the results are presented in that way (which is how Regeneron reported them) the positive effect of the monoclonal antibody combination is far more pronounced. Among the 113 (41%) study volunteers who were seronegative (that is, they were classified as having low antibody levels), the median time to alleviation of symptoms in the placebo group was 13 days compared with six days for the low-dose group and eight days for those in the high-dose group.
The same basic pattern holds for the patients with high viral titers compared with those with low titers.
“The treatment effect becomes accentuated in the very patients who have the highest baseline viral titers and who presumably need the enhanced immune response provided by the therapeutic cocktail,” Yancopoulos said during the call.
4. Older people, as a group, have weaker immune systems so they might be candidates for monoclonal antibody treatment.
Older people are more likely to have a severe case of COVID-19 than younger people. Although this was not spelled out in the Yancopoulos, that generalization might argue that monoclonal antibody treatment will be most effective in older people and those who have immunocompromised for other reasons.
5. If this monoclonal antibody combination were to get approved, there may be a need to test patients for viral load or antibody level.
As Yancopoulos discussed, one of the implications of the results showing that the monoclonal antibody combination makes a much larger difference among patients with low antibody levels and high viral titers is the need for testing that would identify those patients. Yancopoulos said many companies are working on developing point-of-care tests, including its partner, Roche.
6. Other companies are also working on monoclonal antibody treatments of COVID-19.
In September, Eli Lilly announced results from a randomized, placebo-controlled phase 2 study that showed reductions in viral load among patients randomized to a mid-level dose of its antibody, LY-CoV555.
7. Regeneron hinted at talks about an emergency use authorization from the FDA.
When asked about an emergency use authorization from the FDA, Yancopoulos said that Regeneron is “very excited by this dataset” and that “I think this deserves to be discussed with the regulatory authorities because of the societal implications.” The fact that Trump was treated with the monoclonal antibodies is probably not a bad sign for Regeneron and REGN-COV2.
8. Regeneron says that with Roche’s help it could make 250,000 doses a month next year.
The data that Yancopoulos discussed showed little, if any, difference between the low-and high-dose versions of the monoclonal antibody combination. That could be important if Regeneron gets an emergency use authorization from the FDA. Yancopoulos said the company could make 300,000 of the low doses “by around the end of year.” Once Roche ramped up its manufacturing capacity, it will be possible to produce 250,000 of the lower doses a month, Yancopoulos said.