WHITNEY PRUITT: Welcome. On behalf of the Mayo Clinic School of Continuous Professional Development, I'd like to welcome you to the Mayo Clinic Monoclonal Antibodies and Other Novel therapeutics in COVID-19 Treatment webinar series I'm Whitney Pruitt, your host for today's webinar, on Updates on Recently Authorized Therapies for COVID-19. This webinar is accredited by the AMA for 1.5 credits. Here are the disclosures for this activity. And we'd like to thank Eli Lilly and Company for their support of this educational activity.

Before we get started, we'll cover a few points. The first is how to claim credit. If you'd like to claim credit after the webinar, please visit ce.mayo.edu/covid0428. You'll need to log into the site. And if this is your first time visiting, you will need to create an account profile. After you've done this and logged in, you'll see an access code box. You'll want to type in today's code, which is COVID0428. This will allow you to access the course, to complete a short evaluation, and then you'll have the ability to download or save your certificate. The link and code will be dropped into the chat box throughout today's webinar.

The second item is how we'll facilitate questions. You'll see at the bottom of your screen the chat and Q&A function. If you have any questions during this webinar for today's presenters, it's important that you drop them into the Q&A channel rather than the chat box. This will help to ensure that the panel can see your questions. There's also a helpful upvote button, so that you may have the questions answered that you would like to see. If you're experiencing any technical issues during this webinar, please use the chat feature to share, so that our support team can assist.

We'd like to introduce you to our panel moderator for today, Dr. Amit Ghosh. Dr. Ghosh is a consultant and professor of medicine within the Division of General Internal Medicine at Mayo Clinic in Rochester, Minnesota. And with that, I'd like to hand it over to Dr. Ghosh.

AMIT K. GHOSH: Thank you, Whitney. Welcome, ladies and gentlemen all over the world. This is an important topic we are going to discuss today where the world is challenged with COVID like we have never seen. Some of the countries are going through the worst period at the present moment. And our entire support is with them. Joining us today is a panel of highly distinguished speakers who have been with the COVID situation and been dealing with them right from day one.

I'll be introducing five members who have played an absolutely fantastic role in our understanding, our care delivery, and the knowledge that we have in the Mayo Clinic. Our first speaker is going to be Raymund. Dr. Raymund Razonable is vice chair Division of General Internal Medicine and also program director of General Medicine of Infectious Disease.

Second speaker is going to be Dr. Ravindra Ganesh, who is an assistant professor of medicine at the Division of General Internal Medicine. And he actually led the COVID frontline care team, which was the main phase of how we managed the outpatient care of COVID. The next presenter is Professor Larry Lutwick, Stanford trained infectious disease specialist whom we were fortunate to recruit. And he works for the Mayo Clinic Health System in Eau Claire, Wisconsin. He's a professor of medicine and a specialist in infectious disease.

Next slide. And then is Miss Lori Arndt. She's also worked in the infectious disease. She has been instrumental in managing a lot of outpatient logistics and delivery of these novel therapies, which we are going to talk, at the Mayo Clinic Health System at Eau Claire, Wisconsin.

Next slide. And finally, we have Mr. Richard Arndt, who's assistant professor of pharmacy. He's the senior manager for pharmacy clinical services in Mayo Clinic Health System Eau Claire. All these speakers are extremely adept at management and delivery of this complex situation that we are facing and which requires all these therapy. I will now hand over the presentation to Dr. Raymund Razonable.

RAYMUND R. RAZONABLE: Thank you so much, Dr. Ghosh. And welcome to everybody. The learning objectives of this webinar is to explain the effect of neutralizing monoclonal antibodies on SARS-CoV-2, explain how monoclonal antibodies fit in the paradigm of outpatient therapy for COVID-19. We will explain the contraindications to monoclonal antibody therapies and how to manage reactions and complications related to treatment.

We will also address logistical requirements for the administration of monoclonal antibody therapies, identify individuals at higher risk of clinical disease progression and may benefit from early treatment with monoclonal antibody treatment therapies. We will also delve and evaluate the impact of racial, ethnic, and socioeconomic disparities in disease severity and how the access optimal therapy for mild to moderate COVID, detail the logistical requirements from the perspectives of supplies, personnel, training, nurse-initiated protocols, and processes for the administration of monoclonal antibodies.

And finally, logistical requirements for healthcare administrators who may be joining us in this webinar, the needs for infrastructure, facilities management, personnel training and deployment, as well as safety protocols, because we all know this is a highly infectious pathogen. And we have to have safety protocols in place, so that we prevent transmission to other patients as well as to our personnel and staff.

I'd like to start off by presenting a typical case of patients that we see in our clinic and in our system. So a 76-year-old man, diabetic, hypertensive, with cardiovascular disease, also has a smoking history and currently has COPD, some renal dysfunction, and has a BMI of 36.

He comes in and basically calls the provider, because he's been having fevers, chills, muscle aches, headache, sore throat, and dry cough for the past two days. There is no shortness of breath. He reports an exposure history, because he attended a community party about a week ago. And he has been tested at a community testing center, found positive for SARS-CoV-2 nucleic acid by PCR.

So this brings us to this schematic diagram of the natural history of COVID-19 in patients. There is an approximately about a two week incubation period from the time of exposure. But the vast majority really becomes symptomatic if they develop disease within five to seven days. During this pre-symptomatic phase, the patients are already having viral replication in the respiratory system and are considered infectious.

While the vast majority, roughly maybe about 50% to 60%, may remain asymptomatic, there is a proportion of patients who will go on to develop symptoms just like the patient that was presented. And of those that develop symptoms, the vast majority, roughly about 80% of them, will have mild to moderate disease, fever, muscle aches, cough, sore throat. And then they improve.

But then roughly about 20% of those who have symptoms will go on to develop severe disease as manifested by dyspnea, respiratory distress, requiring admission to the hospital. And then, a proportion of that will require intensive care unit care because of progression to severe and critical illness. This is the timeline. And we will use this as basically a framework for our discussion for the next hour in terms of what treatments may be given or appropriate at various stages of the COVID illness.

So what are the factors associated with severe disease? Who are more likely to develop an illness that requires hospitalization and some going to intensive care? And this is data that is well known and well established during the past year of the pandemic. Older populations, age over 65, those with higher body mass index of 35 or higher, those with cardiovascular disease are at increased risk for severe illness.

Chronic kidney disease increases the risk of severe illness, as well as diabetes, hypertension, chronic lung disease. And a compromised immune system, whether this is from the use of immunosuppressive therapy or an underlying immunodeficiency, increases the risk for severe illness. So keep in mind this is the higher risk group.

And if you go back to our case, it basically fits almost every criteria with the exception of the last one, because he is 76. He has a body mass index of 36, cardiovascular disease, chronic kidney disease, diabetes, hypertension, as well as COPD. I'd like to ask, then, Dr. Ganesh, Ravi, if you are presented with a patient like this, what would you recommend for this patient?

RAVINDRA GANESH: Thank you, Raymund. So for patients like this who are in the early stage of illness, the therapy that's approved for this is monoclonal antibody therapies. Specifically, these are neutralizing anti-spike monoclonal antibodies. And they are proven to prevent the clinical progression of disease.

So what happens to the coronavirus is it has all these little proteins on the surface called spike proteins. And these are the proteins that allow this virus to bind to the cell. And as you can see, it internalizes, and then it releases its genetic material, which is shown here is that squiggly spaghetti line in the bottom right. This allows for replication and infection. The target of the monoclonal antibodies is this little spike protein on the outside.

And the monoclonal antibodies, which are shown in blue, attach to these green spike proteins. And they prevent the virus from binding to the cell membrane. And therefore, it can't infect the cell or replicate. Additionally, virus particles that have these monoclonal antibodies all over their surface are more attractive targets for the immune system to chew right up. We have some animal studies that show success in decreasing viral load and increasing resolution of symptoms, both in a macaque model and a mouse model.

In light of the data that Lori Arndt is going to present in a few minutes, the FDA released EUAs for three separate monoclonal antibodies for COVID-19. The criteria of all of the EUAs, or emergency use authorizations, were mild to moderate COVID-19. Patients had to be within 10 days of symptom onset. And they had to be at high risk of progressing to severe COVID-19 and/or needing hospitalization.

The first antibody to receive monoclonal antibody EUA was bamlanivimab. And that was issued on November 9, 2020. And unfortunately, this got revoked on April 16, 2021 due to emerging resistance patterns of variants. Casirivimab and imdevimab, which is the Regeneron product, got on EUA on November 21, 2020. And bamlanivimab in combination with etesevimab released by Lilly got an EUA on February 9, 2021, which is still active. So both combo forms are still active. Let's turn over to Lori Arndt to discuss the data behind these trials.

LORI ARNDT: Thank you, Ravindra. So the bamlanivimab, the BLAZE-1 trial, which was conducted by Eli Lilly and Company, was a randomized double blind placebo-controlled trial, which included 452 patients. These patients were randomized to receive either 700, 2,800, or 7,000 milligrams of bamlanivimab monotherapy versus placebo. The patients had to test positive for SARS-CoV-2 within three days and report at least one or more mild to moderate COVID-19 symptoms.

In those patients, the median age was 45, the majority of which were female and Caucasian. 44% of those patients were considered the high risk population, with 76% reporting mild symptoms. The average duration of symptoms was five days. Median viral load, which was reported in a threshold cycle of 24. The primary outcome in this study was the change from baseline in the SARS-CoV-2 viral load at day 11.

And the study found that in phase two, only patients who received the 2,800 milligram dose of bamlanivimab had a greater decrease in day 11 viral load as compared to placebo. In the secondary endpoints, they also looked at hospitalization or emergency room visits. And at day 29, those percentage of patients who were hospitalized with COVID-19 was 1.6% in the bamlanivimab group versus 6.3% in the placebo group.

In the phase three portion of the study, it compared bamlanivimab to etesevimab in high risk patients. Again, the same criteria was met, mild to moderate COVID-19 symptoms within three days of testing positive. And those patients who were included were at least 12 years in age and older with at least one risk factor for severe disease. The study outcome noted that it was able to reduce the risk of hospitalization by 70%. And these results are consistent with those seen in other data sets in other studies. In addition, it did show that the viral load reduction was also greatest in the combination therapy of bamlanivimab and etesevimab.

RAYMUND R. RAZONABLE: Thank you so much, Lori. I'd like to ask Richard to give us details of the other cocktail of casirivimab and imdevimab.

RICHARD ARNDT: Thank you, Raymund and Lori. So I'm going to be focusing on the casirivimab/imdevimab, which was from the Regeneron COV2 trial. So this is an ongoing double-blind phase I through II placebo-controlled trial involving non-hospitalized patients with COVID-19. Patients were randomized in a 1 to 1 to 1 ratio to either receive placebo, the 2.4 gram, or the 8 gram of the casirivimab/imdevimab combination product. Patients had to have a confirmed SARS-CoV-2 infection with a positive test result no more than 72 hours before randomization and as well as symptoms onset no more than seven days before randomization.

So the interim analysis described here involved the first 275 patients. And this was the initial analysis during the phase I to II portion of the trial. The median age of the patients in these trials was 44 years with 49% of those being male and 81% being Caucasian. At baseline, 123 patients, which is about 45%, were serum antibody positive while 113 patients, that being 41%, were serum antibody negative. And 39 patients, so 14%, had unknown antibody status.

So looking at the demographic risk factors at baseline, 42% were obese and 64% of these patients presented with at least one risk factor as described previously. The median number of days of reported COVID-19 related symptoms before randomization was around three days.

So the casirivimab/imdevimab antibody cocktail reduced viral load as illustrated in the graphic shown on your right. The greatest effect was seen in participants whose immune response had not been initiated yet or who had a very high viral load at baseline. Both the 2.4 gram and the 8 gram dose of casirivimab/imdevimab was associated with very few low grade adverse effects. And this was similar to placebo. The study also illustrated that the casirivimab/imdevimab treated patients at 2.8% had fewer COVID-19 related medical visits as compared to the placebo group at a percentage of 6.5%.

RAYMUND R. RAZONABLE: Thank you so much, Lori and Richard, to summarize the available data to date that has been published. We have data on bamlanivimab monotherapy. We have data on bamlanivimab combined with etesevimab, and data on casirivimab combined with imdevimab. And as you can see, it is consistent across the clinical trials. The trials did show as a primary endpoint decline in viral load.

But as clinicians, we wanted to see clinical endpoints data. And the available data to date so far has been based on the small number of patients enrolled in these studies. But as you could see, in the secondary endpoint towards the bottom of the slides, there appears to be a signal of reduced hospitalization in patients who received these monoclonal antibodies compared to those who did not receive the antibodies or who had received placebo. And the adverse effects profile appears to be mild and consistent across the three trials.

Just like what Dr. Ganesh had earlier mentioned, the emergency authorizations of bamlanivimab has been revoked just because of increased predominance of a variance in the community. And we will discuss that towards the later part of this session. With this in mind, I'd like to turn over to Dr. Lutwick. Larry, can you tell us who is eligible? Is this somebody for everybody, or is this something that is only reserved for a certain group of patients?

LARRY LUTWICK: All right. Thanks, Ray. In review, the patients that are at high risk that are eligible for the monoclonal antibody treatment include anyone over the age of 65 years, people who are 55 years old and older with any of the following risk factors in cardiovascular disease, hypertension, and COPD, or any other chronic respiratory disease, anyone over the age of 12 years with any of the following risk factors, BMI equal to or greater than 35, chronic renal disease, diabetes, and immunosuppressive disease, or condition, and those receiving immunosuppressive therapy for other diseases.

And finally, individuals between the age of 12 and 17 years with BMI is greater than or equal to the 85th percentile, individuals with sickle cell disease, individuals with congenital or acquired heart disease, those with neurodevelopmental disorders, medical related technological dependence such as patients with tracheostomies, gastrostomies, or on positive pressure ventilation, and finally, those individuals with asthma, bronchospasm, or any reactive airway or chronic respiratory disease.

RAYMUND R. RAZONABLE: Thank you so much, Larry. I'd like to move on to look and discuss some of the logistics in setting up infusion therapy centers. So we have the products given to us through emergency authorizations. The next hurdle in the implementation of this in the real world is that we have the facilities to infuse. So what we've done as an institution is basically develop a standalone dedicated COVID-19 infusion therapy centers across our sites.

For those who are not familiar with our locations, we are located in Minnesota, states of Wisconsin, Arizona, as well as Florida. And I emphasize dedicated, because these are outpatient therapy infusion centers that are only for COVID, because we don't want to mix patients that are infected with COVID as well as others who are receiving therapy for other conditions, for example. And we established about nine infusion facilities across our sites. And we started the program way back in November of 2020.

And it's really important to basically respect the virus and protect our patients. In doing this, we have to partner with your infection prevention and control personnel, just to make sure that the procedures and the processes that you are establishing and infusing these antibodies in these facilities is within the standards to prevent spread of the virus to other patients in your center as well as to your health care personnel. So they are an integral component in administration.

The other aspect is the personnel and the team. And I'd like to turn it over to Dr. Ganesh. Ravi, if you could describe how you basically developed a multidisciplinary team to facilitate the infusion of these therapies?

RAVINDRA GANESH: Thank you. So when we created the monoclonal antibody treatment team, which had a convenient acronym of MATRx, which we love, we tried to really get everybody on board that we thought we might need, and then some. So we got clinicians together from the various departments, pulled the ID specialists, and the internal medicine and family medicine docs who will be the docs on the ground.

We got docs together who had experience with managing COVID patients, both adult and pediatrics. We got a nursing experience from the infusion therapy center. And we got nurses and pharmacists on board. We also got all the people who actually make things happen, the desk operation staff, the administrators, informatics, and EHR specialists. And then we got the people on the ground, compliance, facilities, engineering, and the folks that make sure everything we do is appropriate. So we got legal and ethics involved as well.

So with a really huge team. And I have to commend this team, because we met pretty much daily for a long time to get everything up and running. Here is a snap of one of our morning meetings. These are the physicians, administrators, support staff from all across the entire Midwest. You may recognize the bottom right and second from bottom left individuals. They're both presenting with us.

And we initially had a big challenge around patient education and consenting. And when we started calling people initially, our rejection rate was north of 70%. And we asked people. They weren't really aware of the therapy. They had hesitancy, because it was brand new. And they weren't quite sure what an EUA meant. And they were all in that sweet part of the curve where they had minimal symptoms. And a lot of people were, well, I don't feel bad right now. I don't need therapy.

And we really wanted to fix that uptake. So we created an educational video. And that's not the most flattering picture of me. Thankfully, Darcy, one of our nurses did this with me. And it was much more engaging. And we've shared this video with our partners in the state level to see if we can increase uptake. By adding the video, we actually got our acceptance rate upwards. So now, we're around 60% to 70% of people who hear about the product are willing to accept it.

The other issue that we had that we had to start with rapidly was how do we provide this treatment which is potentially life saving to the wide swath of patients in or out of areas? So we had to think about people with health disparities, the underserved populations. And folks who are exceptionally high risk are not mobile in the long term care facilities. So we partnered with our community organizations. And we tried our best to get this going.

One of our major achievements, in my mind, what I'm most proud of, is getting to the skilled nursing facilities, because if these facilities do have an outbreak, it can spread like wildfire. Reported mortality is over 50%. And we put together a mobile team, and we worked closely with our local nursing facilities to identify patients at high risk and sent our mobile infusion team out to the facility.

And in doing so, we were able to infuse anywhere from two to 20 patients in a facility at one time. And I think we greatly reduced the spread of illness. Here is a picture of our Mayo infusion van along with two of our nurses speaking to a resident of a nursing facility, with her permission, of course. And this was one of the best things we did.

LORI ARNDT: Thank you, Ravi. So as both Raymund and Ravi have pointed out, we have a therapy. We have the infusion centers. We know which patients are at high risk. Now, it's actually identifying those patients. And so here at Mayo Clinic and our health systems, those patients who tested at our locations were automatically screened for eligibility to receive the monoclonal antibody therapy based on a positive SARS-CoV-2 test.

Patients who were non-Mayo Clinic patients or those who had tested outside of Mayo Clinic and the health system could also be eligible. And they were reviewed by our COVID frontline care team through an e-consultation. And those referrals were reviewed. And any pertinent information was added to the electronic medical record, including a copy of their positive test result.

Patients were determined for their clinical eligibility and drug allocation based on something called a monoclonal antibody screening score. This was essentially a score that was developed based on internal outcomes data and eligibility criteria set forth in the FDA emergency use authorization as well as the state guidance. This was a weighted score.

And as you can see here, you see in this diagram previously those patients were given a weighted number based on specific criteria. And so those patients who were 55 with, let's say, hypertension would have a lower score of one, versus those individuals who may be 65 and older with an immunosuppressive disease or chronic kidney disease would have a much higher score with at least three.

And this was certainly important, because we knew that being able to risk stratify was important, as these patients with higher rates of hospitalization had higher rates of hospitalization based on their risk factors. And so it was essential, really, to be able to weight their comorbidity score based on this MASS score.

And finally, we would have to manually review these patients for their eligibility. They were screened to ensure that they reside within their respective regions. We would verify their comorbidities by manually reviewing their electronic medical record. We would verify the eligibility based on onset of symptoms, severity of illness, and the date of testing.

And finally, ones that would be done, nurses would contact patients for education of monoclonal antibodies and obtain consent for infusion. And the consenting patients would be scheduled as soon as possible, typically it was same day or within 24 hours. And those patients who were undecided or non-consenting patients were provided 48 hours of time to reconsider their decision.

RAYMUND R. RAZONABLE: I would like to turn, take it over, and basically discuss some of the factors we have learned since the start of the program. We have observed that there is a group of patients that are more likely to accept the offer. And there are those that are more likely to decline therapy. And as you can see here, patients are more likely to accept our offer for monoclonal antibodies if they are non-Hispanic white Caucasian, if they have English as their primary language, if they have a stronger social support system as indicated by having a spouse, or a life partner, or being a member of a religious organization or affiliation.

On the contrary, patients who are considered underrepresented are more likely to decline the offer. There are potentially multiple reasons behind that. And as a result, there should be bigger efforts to reach out to those communities, particularly if they are considered high risk. And another factor that basically was associated with the decision to accept monoclonal antibody therapy is a so-called monoclonal antibody screening score.

The higher the score a patient has, the more likely that they will accept the offer for treatment, potentially because they are aware of their higher risk conditions and their higher propensity to develop severe disease and get hospitalized. With our program, we have a time to infusion of about 2.8 days from the time of testing, with the vast majority patients will get their infusion during the first three days after they have been tested positive for COVID-19. Let's turn it over to Larry. Larry, yeah?

LARRY LUTWICK: So in summary, the milestones related to the MATRx program. November 9 was the day that the MATRx program at Mayo was organized and started. 10 days later, the first monoclonal antibody infusion was given. By the end of 2020-- it's about six weeks-- the program had infused 1,700 patients.

Into the first week of January of 2021, the milestone of 2,000 patients was reached. And by the middle of January, almost 3,000 patients were infused. And by the 22 of April, an estimated 5,200 patients were infused. This slide gives you an idea of the timeline of infusions in each of the states that we have our MATRx system running. And the top saw the line being the total number of infusions given over the first 10 weeks of the program.

RAYMUND R. RAZONABLE: Thank you so much, Larry. I'd like to ask Richard to comment. One of the questions that patients have as well as providers ask us is, how safe is monoclonal antibody therapy? And what have we been observing in our program in terms of adverse reactions? And how do we manage them?

RICHARD ARNDT: Well, thank you, Raymund. Yes, that is a question that pops up pretty frequently. And we thankfully have had a lot of experience around these infusions with, like Dr. Lutwick had mentioned, 5,200 patients have been infused to date. So when we look at the number of adverse events, we see that in about 19 patients, so only about 1% of our patients.

Some of the most common ones are, similar to infusion reactions, are fevers and chills, so six patients there. Some experienced some nausea and vomiting. Those were only five patients. Lightheadedness was seen in about three. And then in the following, rash, chest pain, confusion, and weakness were seen in two each. And then diarrhea, headache, cough, facial swelling, one each in those respective categories.

We are really happy to have seen that no one had an infusion anaphylactic reaction. And really, all adverse events were mild and did not require hospitalization. And this was across the board with our infusions that were over one hour, as well as the infusions that we had cut down when the EUA changed to the shorter infusion times.

RAYMUND R. RAZONABLE: Thank you so much, Richard. Just to highlight, while the adverse reactions are mild and the vast majority are basically systemic symptoms, so fevers and chills, there's the potential for anaphylaxis. We have not observed that. But if you have an infusion center, just make sure that you have the capacity to address those in case it happens.

The other big question is clinical outcomes. If you recall back several slides ago when we were looking at the randomized controlled trials, there is a signal. But the numbers of patients in those clinical trials are not large enough to develop or to perform statistical analysis. In the real world, what are we seeing? And I'd like to turn over to Dr. Ganesh. Rav, If you could describe the outcomes of the Mayo Clinic program on the use of these monoclonal antibodies.

RAVINDRA GANESH: Yeah. So when we start to analyze our data-- and we did this initially back when we had our first 1,600 bamlanivimab patients. Currently we have over 5,000 patients we have infused. So the first analysis that we did was looking at bamlanivimab patients who are in the blue here.

And we compared them to a 1 to 5 control match, which was matched on age, comorbidities, gender, everything that would make them as close to these patients that we treated as possible. And we can see here that the bamlanivimab treated group has less hospitalization, especially earlier in the disease, in the first 20, 25 days. And this is unpublished data, which we're trying to get out there.

RAYMUND R. RAZONABLE: Sounds good. Ravi, if I may ask, can you comment on the orange line, which appears to also show not much of hospitalization compared to the reported 10% to 15% from randomized controlled trials?

RAVINDRA GANESH: Yes. So looking at the orange line, our hospitalization rate in our system for patients who were not treated was about 4%. And this is as Raymund said, drastically less, 10% to 15% deaths reported. And that may be a factor of our system, because we did reach out to people early.

And we did monitor them with these specialized telehealth teams to try and identify who was going south and getting them into the hospital early. And we proposed that early treatment and very dedicated inpatient COVID treatment team who went through and tried to get people therapies as early as possible may have contributed to better outcomes in our baseline group.

RAYMUND R. RAZONABLE: Sounds good. Thank you. And despite the low baseline hospitalization rate for the cohort or propensity-matched untreated cohort, there was still significant decline based on this graph of the association between monoclonal antibody, in this case bamlanivimab monotherapy, and, of course, hospitalization. Do you mind to comment about severity of illness as well as maybe admissions to the intensive care unit and mortality, Dr. Ganesh?

RAVINDRA GANESH: Yeah. So when we analyzed that data, we also found that people who were admitted were less likely to get admitted to the ICU or to require mechanical ventilation when compared to people who were not treated. And in our initial analysis of that 1,600 patients, only one had died at 28 days compared to seven in the untreated group. So our initial takeaway from this study was that people who are treated early have lower admission rates and if they do get admitted are less likely to progress to severe disease and death, by virtue of treatment with bamlanivimab.

RAYMUND R. RAZONABLE: Sounds good. And of course, the next question now is, there's three products now, two products out there. During the time of this study, there were bamlanivimab monotherapy, and there's the other one casirivimab/imdevimab cocktail. Is there outcomes difference between the two?

RAVINDRA GANESH: And this is what this slide is. So we start to analyze the different outcomes between our patients treated with bamlanivimab monotherapy and the casirivimab/imdevimab cocktail. The curves do separate a little here. It does not reach statistical significance. And this is an adjusted curve that looks at comorbidities. So both groups of patients treated here are equally sick and equally at risk of being admitted.

And it does seem that casirivimab may do a little better, but it doesn't reach significance. And we need bigger numbers to confirm. This data may change as we continue to get variants with emerging resistance patterns. And we will have to keep updating this as we go. As of right now, we have no data to recommend one product over another.

RAYMUND R. RAZONABLE: OK. And just to emphasize, this comparison here is a comparison of casirivimab/imdevimab combo and the bamlanivimab monotherapy, whose emergency authorizations has just been revoked because of the emergence of a variant. This did not transmit well.

RAVINDRA GANESH: It did not come out as well as we would have hoped. So what we're looking at here was hospitalization rates for the people who had accepted versus those who had declined monoclonal antibody therapy. And we will fix this slide and send it out with the CMU materials.

But what we found is that as the [INAUDIBLE] advanced, one, people were being admitted to the hospital at a higher rate, but two, the monoclonal antibodies did show a decrease across all [INAUDIBLE] scores for hospital admission, especially when compared head to head. And this difference did get larger as we increased in monoclonal antibody severity score, which is our comorbidity predictor.

RAYMUND R. RAZONABLE: Thank you so much, Ravi. Just to highlight and summarize what is supposed to be in this slide, it shows basically the higher the comorbidity, the higher is the risk for hospitalization. But that is reduced with the use of monoclonal antibody treatment.

RAVINDRA GANESH: And this is a graph just showing the relationship between patients' monoclonal antibody severity score and their likelihood of admission. And the traditional risk factors get highlighted here with older age, male gender, chronic kidney disease, chronic respiratory disease, cardiovascular disease, immunosuppression.

Hypertension does not seem to be an independent risk factor. But when you add it to other diseases, it does seem to really ramp that rate of admission up. And when you score them all together, it turns out that as you accumulate system dysfunction, your likelihood of being admitted increases. So one morbidity is not nearly as bad as two comorbidities.

RAYMUND R. RAZONABLE: Sounds good. And the graph on the right is really something that is really informative, if I may say. The patients that are going to be admitted, there's about 4% of them at least in this cohort of 3,600, almost 3,600 patients, about 4% still ended up getting admitted despite monoclonal antibody infusion. And the significant risk factor for that is the number of medical comorbidities just like shown in the purple bar on this graph.

But the key here, though, is even if they get admitted, their severity of illness appears to be not as bad. Just like what Dr. Ganesh had said, there's really low risk of mortality in these patients. OK. All right. Richard, can you tell us something about variants? This is something that's spreading in the community. How does monoclonal antibodies impact the variants in the community?

RICHARD ARNDT: Thank you. Raymund, yes, this is definitely I think one of the hot topics currently is how do we manage these variants that are circulating around the global community? And this table really illustrates some of the identified variants and the reduction in susceptibility that has come from the CDC data, as well as other organizations to these variants.

As you can see on the right hand side, the casirivimab/imdevimab product is the one that has been shown to be susceptible to the various variants from the UK, the South Africa one, California, New York, and Brazil. The bamlanivimab and etesevimab product as well as the straight bamlanivimab has no shown reduced susceptibility to the UK variant.

However, the bamlanivimab and etesevimab also shows just a slight reduction in susceptibility to the California virus. What is not detected on here or shown on this table here are the two other variants that have recently popped up. And that was the one down in Texas, the BV-1 variant, as well as the variant from India, which is the B.1.617 variant. So we do not have susceptibility information on those two variants currently that are circulating.

RAYMUND R. RAZONABLE: Thank you so much, Richard. And just to emphasize, these are basically testing done on pseudoviruses. It's on the vesicular stomatitis virus pseudovirus experiment. So these are experimental data. And we will need to know clinical outcomes as we learn more about this. But because of this, this is the reason why bam monotherapy as a EUA by itself has been revoked.

So going back to our case, so you remember we presented a 76-year-old man, diabetic, hypertensive, with cardiovascular disease, COPD, CKD, and a BMI of 36. Based on the data that we have, this patient, despite monoclonal antibody therapy, may still get hospitalized. What if he gets hospitalized? How is the management of this patient? I'll turn it over to Lori.

This is a CT scan of this patient who subsequently developed severe COVID pneumonia. And going back to the timeline of infection has been basically divided into different phases. We saw this patient when he presented with during the early part, where it's predominantly still viral response with consitutional symptoms, cough, sore throat, and headache. Got monoclonal antibody therapy. He's high risk, but he seems to have progressed to develop shortness of breath. What is the treatment for this case? Lori?

LORI ARNDT: Thank you, Raymund. Yeah. So transitioning and looking at patients who are now seeking hospital admission or emergency room presentation, the National Institute of Allergy and Infectious Disease funded the adaptive COVID-19 treatment trial, or the ACTT-1 trial. This was a double blind, randomized, placebo controlled trial of hospitalized patients or hospitalized adults with COVID-19 infection with evidence of lower respiratory tract infection.

The primary outcome in this study was time to recovery. And remdesivir did show that it hastened time to clinical recovery by four to five days. However, based on the Kaplan-Meier estimates, there was no mortality benefit. Additionally, it did show that there was a benefit of remdesivir, most apparent in those who were on low flow oxygen, so not in those on room air, or high flow, or on non-invasive mechanical ventilation.

Hence, based on these and other observed findings that led to the guidelines from the NIH as well as the IDSA. So the NIH has stated that patients requiring supplemental oxygen, or invasive mechanical ventilation, or ECMO receive remdesivir plus dexamethasone. The IDSA came to the conclusion that those patients with severe COVID-19 on supplemental oxygen but not on invasive mechanical ventilation or ECMO, they recommended treatment with five days of remdesivir. And they recommended against remdesivir for those patients who were on room air that is greater than 94%.

RAYMUND R. RAZONABLE: And the immunomodulator therapies is all something that has gained attention during the past year of the pandemic. And if I could ask Dr. Lutwick, Larry, if you could just describe some of the findings on the use of dexamethasone and then later on on tocilizumab.

LARRY LUTWICK: Thanks, Ray. Clearly, the indirect antiviral effects remdesivir has are somewhat useful. But as the disease goes on, it appears to be a hyperactive immune response. It seems relevant in causing substantial morbidity and mortality. And one of the agents that was found early on in the-- specially reported in the recovery collaborative study in The New England Journal last year was dexamethasone.

And this slide shows you graphically broke down with regards to the kind of patients what kind of effect dexamethasone had. In the upper left showing all participants, there was a decrease in mortality for dexamethasone versus usual care. In the lower left in oxygen only, in other words, people that were receiving oxygen and not mechanical ventilation, there was also some effect of dexamethasone in decreasing mortality.

But the most prominent effect, which is in the upper right, is in those patients that required invasive mechanical ventilation, where the decrease in mortality was much more prominent with dexamethasone versus invasive mechanical ventilation. And in the lower right, in those individuals who did not receive oxygen, there was no positive effects of dexamethasone in overall mortality.

The next slide shows the same data in a somewhat graphic form with regards to rate ratio, demonstrating clearly that dexamethasone was most prominently useful in those individuals who required mechanical ventilation, but was also useful in those people getting supplemental oxygen, and not useful at all, in fact, some slightly detrimental, in those individuals who are not requiring oxygen. And when you combined them all together, there was a somewhat-- there was a useful effect in decreasing mortality of dexamethasone versus usual care. And that was from the same-- the data from the same study.

This slide is the current NIH COVID-19 treatment guidelines received for treatment. And in those individuals who are hospitalized and requiring supplemental oxygen, NIH currently recommends using remdesivir. Especially in those requiring minimal supplemental oxygen, the combination of dexamethasone and remdesivir. Remember, you need to follow liver function tests in people on remdesivir. Viral infection itself can cause elevated aminotransferases. But remdesivir can increase the aminotransferases, sometimes limiting its usefulness in giving the five days. And dexamethasone alone when remdesivir can't be used or is not available.

In those individuals who were hospitalized and requiring high flow oxygen or non-invasive ventilation, dex or dex and remdesivir are recommended. And for those who are recently hospitalized or deteriorating with evidence of systemic inflammation with regard to the inflammatory markers CRP and the like, NIH currently recommends using tocilizumab to one of the options above. And for those who are hospitalized and on ventilation, dexamethasone. In those who are recently admitted, dex and toci.

Next slide. Now finally, tocilizumab is a humanized monoclonal antibody which is directed against anti-interleukin-6 receptor and when added to dexamethasone is found to improve survival among the group that are exhibiting rapid respiratory decompensation due to COVID-19. These two lines here are basically the same two lines that were on the side before, saying those who are rapidly deteriorating or recently requiring invasive mechanical ventilation that the anti-IL-6 receptor monoclonal should be added to dexamethasone.

RAYMUND R. RAZONABLE: Thank you so much, Larry. Tocilizumab has had, I guess, a course during the pandemic. It was really very popular early on and then it lost its, I guess, its following once we had the randomized controlled trials sometime performed middle of last year. And now, it's gaining back because of emerging data that it may add benefit to dexamethasone, just like what Larry had mentioned. And then, the other immunomodulator that is also given authorization is baricitinib. Richard, can you comment on this?

RICHARD ARNDT: Thank you, Raymund. Yep. So baricitinib received its FDA EUA approval based on the ACTT-2 trial, which was a phase III adaptive randomized double blind trial, which compared the regimen of remdesivir alone versus a regimen of remdesivir with baricitinib in hospitalized patients. And the results from there showed a reduced median time to recovery of seven days versus eight days. There was a 30% higher odds of improvement in clinical status at day 15. And the incidence of progression to death or invasive ventilation was 31% lower in that group, as was the 28 day mortality rate of 5.1% versus 7.8%.

Now, when we look at the NIH COVID-19 treatment guideline panel, there is insufficient data, really, to recommend either for or against the use of baricitinib in combination with remdesivir for the treatment of our COVID-19 patients who are hospitalized, especially when corticosteroids can be utilized in its place.

This is similar recommendation by the IDSA as well, stating that among hospitalized patients with severe COVID-19 who cannot receive steroids because of a contraindication, the IDSA guideline panel really suggests the use of baricitinib with remdesivir rather than remdesivir alone in those patients. So really, the recommendations is to use the corticosteroids first. And if there's contraindications to those, to incorporate the baricitinib into the treatment with remdesivir.

RAYMUND R. RAZONABLE: Thank you so much. And of course, the big question is, now there's a push towards having the vaccines to almost everybody that's eligible depending, of course, on the supply of the vaccination. One of the common questions that come to mind as well as being asked of the MATRx team is, what is the relation between monoclonal antibody infusions and vaccines? And Dr. Ganesh, if you could give us answers to two specific questions. Can I get vaccinated after monoclonal? And if I get monoclonal and I develop COVID, am I still eligible? Or if I get vaccinated and I develop COVID, am I eligible for monoclonal antibody therapy?

RAVINDRA GANESH: All right. Thanks, Raymund. So this is a hot topic as shown by the fact that four or more of the questions in the Q&A refer to vaccines. The first question-- can somebody get vaccinated after treatment with anti-spike monoclonal antibodies? The answer is yes.