Are You Eligible for Monoclonal Antibody Treatment?

[MUSIC PLAYING] Welcome, everyone. I'm Dr. John Whyte, Chief Medical Officer at WebMD. And you're watching Coronavirus in Context. COVID-19 is really a story about innovation in terms of the progress we've made in testing, in vaccine development, and also therapeutics, a remarkable speed in which we have brought new drugs to market, as well as looked at new indications for currently approved drugs.

And one area where we've seen tremendous research is in the area of monoclonal antibodies. So to help talk about what monoclonal antibodies are, what they should be used for, I've asked Dr. Daniel Skovronsky-- he's the Chief Scientific Officer and Senior Vice President at Lilly. Dr. Skovronsky, thanks for joining me.

Thank you. It's a pleasure to be together.

Let's review for our audience what monoclonal antibodies are.

Sure. Monoclonal antibodies are a synthetic version of something your own body makes. So in response to infection, your body makes antibodies, lots of different ones-- we call that polyclonal-- to fight the pathogen. We selected just one of those from a patient who recovered from the disease and then amplified it, engineered it and amplified it in our labs, mass-produced it in a factory so that it can be administered to other patients to fight the disease.

So we've done that now twice. So we have two different monoclonal antibodies. And they can be administered either alone on the first one or together as a combination therapy.

The FDA has actually issued, as you know, three Emergency Use Authorizations for monoclonal antibodies-- as you said, either by itself or in conjunction with others. Sometimes people refer to them, whether it's right or wrong, as a cocktail, or polyclonal antibodies. But just this month, in early February, the FDA issued a new Emergency Use Authorization for two monoclonal antibodies. Can you talk to us about what that EUA said?

Yeah, thank you. Emergency Use Authorization-- it's different than a full FDA approval. But it is a way to get medicines out to patients during a state of emergency, as we have now with COVID-19. And it was based on phase II data and phase III data that we generated looking at patients who already have the virus and are sick. So this is different than a vaccine. It's not a preventative in this situation.

People with moderate to severe disease who are at high risk.

Yes. Yeah, so they're PCR-positive. It's not exactly moderate to severe. It's mild to moderate, so it's early in the disease course. So generally, within a week of having symptoms of disease, this is the time to use monoclonal antibodies, ours or other companies'. And these are administered to patients who are still at home, who are ambulatory. This is not for hospitalized patients. And although--

They're also not on oxygen, correct?

Yeah, that's right. And so amongst these ambulatory patients who are recently diagnosed, the focus is on those who have a higher risk of going on to more severe consequences of disease. And we know that. We know that many people-- fortunately, most people-- who get infected with COVID-19 do well. They have a self-limited illness and recover uneventfully.

But we understand now some of the risk factors for having the worst outcome. So certainly, age is the most well understood. And therefore, this is certainly-- the authorization focuses on an age as an important risk factor. So patients over the age of 65, for example, are included.

We know that younger patients, for example, people over the age of 55 that have other risk factors, like cardiovascular disease or hypertension, or lung disease-- they're also at high risk. So they're included in the emergency use. And then even below the age of 55, in younger adults, there's other risk factors that are important. If you're overweight-- so body mass index over 35, chronic illnesses, like kidney disease, or diabetes, or immunosuppression.

So those are the ways that we define a high-risk population. And we focus the use there because that's where the benefit risk of an antibody could be the highest. And our studies focused on outcomes like hospitalization and death and the ability of antibodies to reduce that.

And it showed a 70% reduction in these outcome measures. Is that correct?

Yeah, that's right. We did a phase II trial, both for the single therapy of Bamlanivimab, that monoclonal antibody, as well as the Bamlanivimab and Etesevimab together. We saw about a 70% reduction in hospitalization in that phase II trial.

And then we went on and did a large phase III study, and we replicated it. And it was almost exactly the same. We saw the 70% reduction in hospitalization and all-cause death among people treated with this drug versus placebo, which was an important and exciting finding, that I think-- the first phase III study in this population.

It is an infusion therapy. The amount of time has actually been decreased significantly, correct? in terms of the time of infusion?

Yes, so for Bamlanivimab, which was originally in the authorization focused on a one-hour infusion. Subsequent to that, we generate additional data. Now, depending on the volume that different infusion center might dilute it into it, it could be as little as 16 minutes infusion time. That helps a lot, because hospitals, infusion centers are busy. And being able to get more patients infused in a short amount of time is certainly helpful.

And sometimes folks get confused with convalescent plasma. So how is this different than the use of convalescent plasma?

Yeah, it's a great question. And it's a related concept. So the idea with convalescent plasma is you take an individual who's had disease and now, presumably, has antibodies in their blood. And you can even measure the antibodies in their blood. And you give them the plasma that contains those antibodies to another patient. There's some data, for sure. And it's been widely used.

This, instead of sort of hoping that a patient has great antibodies that can help another patient, we've produced them in a factory. So they're manufactured in a uniform way. We understand the potency. And in fact, it is, for example, the antibody that we first developed-- it was from a number of patients. We looked at the single most potent antibody in their blood. So presumably, that could lead to some advantages. But the biggest advantage is the scale and the consistency of manufacture and the widespread availability, without relying on other patients to donate their blood.

So we know we still have a lot of virus out there. We have an Emergency Use Authorization for mild to moderate disease in high-risk patients who aren't hospitalized, aren't in oxygen with significant reduction in hospitalization and deaths. But they're not being utilized. There's been lots of reports that the federal government has bought a million doses. There's no cost to patients. Yet we're having trouble getting these utilized.

Is it physician education? Is it patient education? We've talked to the FDA, and they've talked about, there's been challenges with distribution in terms of how people find out about it. Does this frustrate you at all?

Yeah, of course it does. I think we've been working hard together with the federal government and the states to increase awareness in the right way for patients and doctors and also solve some of the bottlenecks. Of course, it's frustrating given the scope of the pandemic.

I estimate in the United States, for example-- and this is now authorized in various places around the world, in a couple dozen countries. But in the United States, probably, of the million or so doses we've shipped to the US, about a quarter million have been used. That's a lot. If you thought of any new medicine in the history of the pharmaceutical industry, from launching a new therapeutic for a disease to helping potentially a quarter of a million patients in just a couple of months, that would be a great trajectory.

When you think about the scale of the pandemic and the number of people dying every day, we regret that not every dose is used. And so I think there's a couple of ways this is getting better. One is patients are requesting it. So more and more, we're hearing stories from doctors. And the doctors themselves may not be fully aware of this treatment being available. But the patients are aware. They found something on the internet. The federal government has great information on their websites. And then they ask their doctor, and the doctor looks into it and figures out how to get it. [INAUDIBLE]

They want to request it early on. That's an important point. We don't want them to be thinking about it when they're feeling so sick that they have to go to the emergency room. And that's been part of the challenge. And we need to educate consumers, because for a long time, we've told patients don't come in. Stay home.

Just wait and see how you do.

Right. And this is most effective early on in the course of the disease. So you're right. People are finding out. And having worked at the FDA, I'm glad you said that the government has very good information on their site. And they do, but sometimes it's hard to find. [LAUGHS] [INAUDIBLE] So we're educating consumers.

Yeah, the federal government has combatcovid.hhs.gov, which sort of reminds people that there is now an FDA emergency use authorized. There are treatments for early disease-- and that for people who are in this high-risk category, it's not-- their only option is not just to wait and see if they get better. There is option C, seek treatment.

So that's good. I think, importantly, you also raise the limitation here. It's not for severe patients. Once you're severe, it's too late. It's not for hospitalized patients. If you get that sick, it's not for you. Probably we should also comment that, as with any medicine, there are safety risks. Some people have allergic reaction or anaphylaxis to the drug. It's rare, but it happens. Some people get the drug and still get worse or have clinical worsening after their drug. And so those are important warnings and precautions.

But I think getting the patients educated and seeking it, and then physicians-- and what we've seen from the best of the best, the top health care systems that are really implementing well, is they have treatment pathways where, every single day, they look at all of the patients in their health care system who tested positive and look at which ones match up the criteria for the Emergency Use Authorization.

And then they call each one and say, there is this antibody treatment. Is this something you're interested in? And when they do that, they're able to get many, many more patients treated in their health care system. And they're starting to see in their own hospitals a reduction in hospitalization.

So there's an activation energy to set that up for a hospital or health care system. It takes resources to do it. But I think they're seeing the payback in the longer term.

But what about for primary care physicians that aren't affiliated with the health system, those that are still kind of in that standard private practice, and they think their patient may be eligible for monoclonal antibodies? How do they go about ordering it for their patient?

Yeah, so there's a couple of possibilities. So one is some physicians, in primary care settings even, have opted to set up their own infusion. They might have a room and then a nurse that can put in an IV, and they can do the infusion there. And they can now contact the federal government and actually request doses. And they're shipped to them-- again, at no charge-- and they can directly provide it to their patients.

Others rely on infusion centers in their area. And there's a number of resources now online from the government, as well as from the National Infusion Center, as well as Lilly has a phone number, and Regeneron, who also makes antibodies, has a phone number. That can just help them say, OK, based on where your patient lives, here are the three places closest to them where they might be able to go and get an infusion.

So there has been, I think, a perception that the antibodies are unattainable, that they're reserved for politicians.

Only if you're a celebrity. Right. Right.

Yeah. That's not the case. They're out there, and everyone, every health care facility that wants them, has an adequate supply. There's not a shortage of them. They may have a shortage of nurses to put in IV lines or infusion poles, or whatever. But they have plenty of antibody. And they need to overcome that activation [INAUDIBLE] to get set up and administer.

And sometimes you have to be the squeaky wheel, both as a patient and family member, or even a physician. I wanted to ask you about the variants and how these different variants might impact the effectiveness of monoclonal antibodies. We're studying it and the effectiveness of the vaccines, many of which the studies were done before there was a high prevalence of variants, similar to monoclonal antibodies. Do we know about the impact of the variant on the effectiveness of this therapy?

Yes. Yes. I will talk about the variant in a second. Let me come back to your squeaky wheel comment. It's so important in every-- of course, many patients contact me directly and ask, or doctors. Every single patient who is persistent and every single physician who is persistent on behalf of their patient either way, to my knowledge so far, has gotten the antibody. That's not optimal. It's good to know.

No, we need to make it easier. [LAUGHS] [INAUDIBLE].

Yes, we want to make it easier, particularly for underserved communities where they may not be used to advocating for their own health care as aggressively as others. So we're trying to lower that threshold so you don't have to be the squeaky wheel.

So let me come to the variant question now. The virus is evolving. There's no question-- primarily evolving in two ways, to become more infectious so that it can spread faster and to overcome the host immune response, to pierce through immunity.

So with respect to that first point, the most common new variant now that's talked about is the so-called UK variant, or B.1.1.7, which has increased transmissibility. It seems to be on the rise in the United States, although still just a couple of percent of all cases. We've tested our antibody in the laboratory against that, and it is able to neutralize it. So it's not a threat to the efficacy of these antibodies. Similarly, people who have been vaccinated or people who have previously been sick, this new variant, their own immune system, also, can take care of it equally well as the original strain.

The more worrisome new variants are the ones that are called the South Africa variant of the Brazil variant, which in addition, perhaps, to having some of those changes seen in the UK variant, have a number of changes in the spike protein that may make them able to pierce immunity. So in other words, even a person that's been vaccinated or a person who's been sick before and is now immune could now get sick again from this variant. They also disrupt many, if not all, of the binding of different antibodies-- the synthetic antibodies, as well as the natural antibodies.

So those are a problem. And our hope and our conviction is to avoid them spreading further. And that's why, even in this era of more and more vaccination and better and better therapies, social distancing and masks are so important. We don't want the new variants to spread.

So far, the news is good there hasn't been very much spread. It's very, very rare in the United States and many other countries. And those two variants, in particular, the virus, although it's gotten-- it's evolved to evade our immune system, it may be a somewhat less fit virus. So in other words, it doesn't replicate or spread quite as well. So that's probably some good news.

So let's say you got monoclonal antibody treatment. Your ability to get vaccinated-- we still believe that patients who have received monoclonal antibody treatment should get vaccinated, correct? But is there an issue of timing? Of how soon they could get vaccination after they've received treatment of monoclonal antibodies?

We don't know if there's an issue or not. We don't have data on this one way or another. The CDC recommendation, I think, is 90 days after the monoclonal antibody. But remember, if you're getting a monoclonal antibody, it is because you have COVID-19. The antibodies are only indicated for people who have the disease right now. And we have interest in using antibody in a prophylactic way. But that isn't authorized by the FDA.

So if you've had them a monoclonal anybody, you've had COVID-19. So you have your own natural immunity, presumably. So it's not a rush to be vaccinated. And a lot of people think that people who've recently been sick with COVID-19 should wait for vaccination anyways. They're not the highest priority, whereas the immune-naive patients probably should be earlier in line for vaccination.

And you mentioned the authorization is only for treatment for those patients who have documented COVID infection by PCR. But there is some discussion around studying it and potentially using it for ultimately either pre-exposure prophylaxis or post-exposure prophylaxis. Where are you and the industry in those studies?

Yeah, and thank you for the question. This is an idea that is sometimes considered passive immunization. So instead of giving someone the pathogen or a piece of the pathogen, letting them have their own immune response, which is how most immunizations work, the idea here is just give them the antibody, which can circulate in their blood for some time and provide some protection for the pathogen.

So we did a trial to test if this works. We did it in nursing homes, a phase III trial that looked at whether giving this to residents and staff of nursing homes prior to infection could decrease the risk of infection or even death. And that was a positive result. So we were encouraged by that it.

Probably vaccines are still the best option for providing strong and long-lasting immunity. But antibodies maybe could be faster. It's shorter-lived, but the effect may be immediate. I don't know. In our study, we saw an 80% reduction in symptomatic diseases in residents that got the antibody versus placebo. Hopefully, over time, most nursing home residents, if not all of them, get vaccinated.

So it'll be important to understand how this could work together with vaccine. We just don't have that data yet.

I mentioned at the beginning about how this is a story of innovation. And there's monoclonal antibodies, but quickly, there's also a medication that has been used for rheumatoid arthritis, for which you all have received an EUA for, as well. Can you talk about that?

Yeah, this is almost the complete opposite, the flip side of the coin here.

That's right. [INAUDIBLE]

DANIEL M. SKOVRONSKY: Whereas with the antibodies--

It's interesting.

Yeah, with the antibodies, this is a custom-designed drug that we made specifically to be against the virus, and antiviral. The drug here, Baricitinib, which was already approved for rheumatoid arthritis, is a drug, obviously, made for another purpose. And instead of boosting your immune response, which an antibody sort of is-- it's a synthetic addition to your own immune response-- Baricitinib is an immune modulator that decreases your immune response.

So why would we use that in an infectious disease? Well, it turns out that, in the late stages of the disease, so when people are in the hospital, on oxygen and ventilators, there is-- a part of their disease is in overexuberant immune response. And that's what we believe, and that's why drugs like dexamethasone, a steroid, as well as Baricitinib, a JAK inhibitor, have shown efficacy in improving outcomes for those patients by modulating their own immune response. It can decrease their stay in the hospital and lead to better outcomes. So that was in a phase III trial, also, that was so successful and authorized for a completely different population, for people late in the disease course in the hospital, with a completely different mechanism, lowering your immune system instead of boosting it. So it's a complicated disease. And we need different weapons for different aspects of the disease at different times of the disease course.

And it's a great point, because even with vaccination, we still need to have therapeutic options for people that still get COVID. Dr. Skovronsky, I want to thank you for taking the time today to help explain the latest research and data around monoclonal antibodies.

Thank you, John. It was a pleasure.

And I want to thank you all for watching. If you have questions, you can email them to me at [email protected], as well as post them on Facebook, Twitter and Instagram. Thanks for watching.

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