In This Article
- On November 9, 2020, The U.S. FDA granted emergency-use authorization (EUA) for Eli Lilly's antibody treatment, named bamlanivimab, for use against mild-to-moderate COVID-19
- The decision comes on the heels of positive interim data from the BLAZE-1 clinical trial published in the New England Journal of Medicine on October 28, 2020
- Here, Dr. Dougan explains the interim results of the trial based on treating patients with the drug, what has been learned about the therapy to date and what still needs to be studied for this drug to become a standard of care to treat COVID-19
On November 9, 2020, The U.S. FDA granted emergency-use authorization (EUA) for Eli Lilly's antibody treatment, named bamlanivimab (formerly called LY-CoV555), for use against mild-to-moderate COVID-19. The decision comes on the heels of positive interim data from the BLAZE-1 clinical trial published in the New England Journal of Medicine on October 28, 2020.
Massachusetts General Hospital is one of the trial sites for the neutralizing IgG1 monoclonal antibody, which is being led by Michael Dougan, MD, PhD, physician in the Division of Gastroenterology at Mass General and director of the GI Center for Cancer Complications at Mass General Cancer Center. The trial was designed to enroll patients with recent COVID-19 disease onset to evaluate the effect of early intervention with the antibody therapy on viral-load biomarkers, symptoms and severe clinical outcomes, such as hospitalization and death.
In this Q&A, Dr. Dougan explains the interim results of the trial based on his experience with the trial, what has been learned about the therapy to date and what still needs to be studied for this drug to become a standard of care to treat COVID-19.
Q: What are the key end points of this trial and what are the preliminary results?
Dr. Dougan: I thought these were very encouraging, preliminary results. This study provided a lot of safety data. Because this is a fully human antibody from a person who fought off this infection on their own, we anticipated that this antibody would be safe to put into another person. There is always some risk when you put a large amount of protein into somebody that there could be an unexpected side effect.
There are more adverse events in people who did not get the antibody in the control group than in the antibody group. So that's very encouraging just as we start to expand the number of people treated.
The study did meet its primary endpoint that justifies continued research to determine if we should be giving this to people as standard of care. It was shown to decrease the viral load, but only in one of the dose groups.
We picked a time point that was probably too far out (11 days out). This meant that a lot of people had actually cleared the virus whether or not they got the antibody. While we are only able to show a statistically significant difference in one of the dose groups, all of the participant groups had a large drop in viral load.
If you looked back at the 3-day time point, you see that all of the antibody doses performed pretty equivalent to each other and better than placebo. That's probably the better timepoint to look at, but since it was not the primary endpoint, we are still considering this a preliminary data set. And regardless, that's not necessarily a clinical outcome. (The major clinical outcome was defined as COVID-19–related in-patient hospitalization, a visit to the emergency department or death.)
If I said to you, "You're going to be just as sick and have just as high a chance of going to the hospital and just as a high a chance of dying, but your viral load is lower—that wouldn't be great."
We don't have the data yet to justify in my mind considering bamlanivimab a standard of care. Nevertheless, the results are super-encouraging that this should be studied more.
Q: Was there an improvement in symptoms over time?
Dr. Dougan: 94% of people in the placebo group didn't go to the emergency room, they got better on their own. The improvement in symptoms, while statistically significant, is not enough to justify giving the medicine. If we can't verify, for example, this decrease in hospitalizations, it's not a reason to do something that is this difficult. It's difficult because infusions take a lot of resources and you can't do it on your own at home. You need an isolated COVID space, a nurse, an IV and it takes time.
There are tremendous infrastructure costs to giving the drug that would be there regardless of what the drug price is. And of course, the drug price is an added cost. So you have to be pretty sure that the drug has a meaningful effect.
Q: Were there any results that came as a surprise?
Dr. Dougan: Yes. Another reason for encouragement is that among the small number of study participants who did get very sick and were admitted to the hospital tended to be in the placebo group, suggesting that the study treatment was effective. We really don't know if that's going to hold up when many more people are treated.
Q: Were you surprised by the middle dose of 2,800 milligrams performing the best?
Dr. Dougan: I was surprised when I first looked at the data. I really think it is just because they picked the wrong time to look at. If you look at day three after the infusion, all the groups are dropping at about the same rate. This is why we're investigating the lowest dose in one of the trials, ACTIV-2 (this trial has since closed). ACTIV-2 used the 700-milligram dose because it looks like that's probably just as effective as the middle dose.
Q: The company received an EUA at the 700 milligrams. Why?
Dr. Dougan: We think it's going to be equally efficacious and we would have more doses than the number of doses available at 2,800 mg. If we had 5 billion doses versus 500 million doses, maybe we would do the higher dose, but we're talking about the difference between hundreds of thousands of doses.
Q: What have you learned in regard to when to start treating a patient?
Dr. Dougan: I think that so far the trial tells us that it's probably outpatients who are earlier in their disease who stand some chance of benefiting, but as you use the antibody later in the disease course, the chances of benefiting decrease. What we know about the immune system is that it takes somewhere in the range of one to two weeks to really get a mature antibody response. We probably need to be treating people earlier than that.
There are two other trials running now where patients are started on the drug at different time points after a positive test.
From basic immunology principles, my guess is that there's going to be a big difference between giving it at less than half a week versus a full week. If I were designing a trial for myself or my family, I think that earlier is probably the better bet, but obviously we don't have the data yet.
Q: What's the next step for this specific trial? Have there been any adjustments made as the trial has progressed?
Dr. Dougan: The Blaze program is moving forward, adding more patients so that we can really solidify the endpoint. A second antibody was added to the study. So the patients who are being enrolled right now may have two antibodies at the same time—they're both human antibodies to SAR-CoV-2 that bind to different parts of the virus. Patients may receive the placebo, low dose antibody, or mid-high dose of the two antibodies.
The Blaze trial has both a high-risk study and an all covered study. High-risk is people who have features that would put them at higher risk for severe infection, such as age > 65, lung disease, high blood pressure, obesity, diabetes, kidney disease, and then the all-covered study is one that nearly any adult could enroll in. Pregnant and breast-feeding women are specifically excluded from both studies.
Q: What questions do you hope will be answered in clinical trials for this antibody?
Dr. Dougan: We need a lot more numbers to know what the risk for hospitalization actually is. And it would be nice to be able to break out the numbers to figure out who are the people who do benefit most from treatment? If we give it to 94 people to prevent four people from going to the emergency room, that is helpful to a point, but it'd be great if we could focus in and give it to 20 people to prevent them all from going to the emergency room. Those are the kinds of things that we really need to be able to answer.
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