Mayo Clinic experts discuss monoclonal antibody treatment in depth, including what it is, how it works and where it fits in the current treatment of COVID-19.
mm mm. Mhm. 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 monoclonal antibody therapy for covid 19. What you need to know This webinar is accredited by the Obama and NCC 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. Mhm. Before we get started will cover a few points. The first is how to claim credit. If you'd like to claim credit after the webinar, please visit ce dot mayo dot e d u forward slash 05 to six. 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 in London. You'll see an access code box. You'll want to type in today's code which is COVID 05-6. 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. This Lincoln code will be dropped into the chat box throughout today's webinar. The second item is how will facilitate questions. You'll see at the bottom of your screen the chat and Q. And a function. If you have any questions during this webinar for today's presenters, it's important that you dropped them into the Q and A channel rather than the chat box. This will help to ensure that the panel can see your questions. There is also a helpful up vote button So be sure to upload the questions that you would like to see answered. If you're experiencing any technical issues during this webinar please use the chat feature to share. So our support team kinesis. We'd like to introduce our moderator and panelists for today. Dr claudia libertine is our moderator and a Panelist participant. Dr libertines role in our response to the covid 19. Pandemic has included hands on care team leadership, Being a principal investigator on industry and NIH research efforts in contributing to over 100 peer reviewed publications, chapters in books featured expert. Dr lee spiker, dr kate Rotman, peter Zach and dr lisa bramble. Here are today's learning objectives which will be covered throughout the webinar. Finally, please register to attend our third and final segment of the monoclonal antibody webinar series, which takes place on june 30th 2021 at 8:30 a.m. Central us. Time. With that I'd like to turn things over to dr libertine. Welcome. We are delighted that you created time for this webinar today to spend time with us. This is the second portion of a three part series on monoclonal antibodies to be used to prevent stop progression or treat covid disease. If you miss the first webinar put on by our mayo clinic Rochester colleagues, it is available online and we will post the link in the chat box. Throughout this course we will be going over SARS COv two variants. Monoclonal infusions share multidisciplinary team approaches as well as talk about monoclonal is in the future. Specifically my objectives are to discuss with you what SARS COv two variants are to update you on the B1617 strain in India describe how anti spike protein variants may affect transmissibility and immune escape and then also provide resources for you to be able to monitor the surveillance and sequencing of viruses Stars Kobe two variants are undergo classification system that is used worldwide and the three classifications are variants of interest variants of concerned and variants of high consequence. Currently the indian strain is to be 1617 where we're seeing all the havoc unfortunately, and it has been raised to be a variant of concern. The lowest level of variance and variance occur because the virus requires to take over the machinery of our host cell and in doing so, it can create tiny errors or variations of the genome. Those variations may affect how well it transmits among people may affect our diagnostics are therapeutics and even immune escape those that are being closely epidemiologically monitored under surveillance. If they become of interest, they will get tagged as a variant of interest. But if there is evidence that the transmissibility has changed that modifications of therapeutics have needed to be done or the virus is able to escape our immune own immune system or monoclonal therapy. It is raised to be a variant of concern because of the presence of evidence. What is fortunate is that no SARS Kobe two variant to date has demonstrated failure in any of these specific areas to be a variant ified consequence. Very inspired epidemiologically being monitored across the globe and that intelligence screening and scientific sources are being shared with the Europeans, with asians with the world Health Organization. And once a week they update the variant surveillance data And you could easily find it at these two links sites so that you can know what would be happening specifically in your geographic area in the United States were divided into 10 regions and you can check your region on a weekly basis. So how are variance formed? This is a schematic of actually what we all have experienced. Um COVID-19 disease in relationship to the viral genome. And if you have an unvaccinated person who acquires the virus, the virus needs to enter the host cell in order to rapidly replicate in the log phase. When it goes into a lot phase, one then is able to get ill and has mild to moderate illness. Disease of which then make progress. All the ways to require hospitalization, shortness of breath, ventilatory support. Our goal is to vaccinate people so they build immunity to block entrance into the host cell. And if we fail at doing that or if the vaccine is not effective, we then have the ability to give monoclonal antibodies early and mild to moderate disease. Hopefully to block the entrance of the virus into the host cell. That is basically what we're trying to do. And that's dramatic of this shows it very nicely. This is the uh sars-cov-2 virus with the spikes that are on it And a specific region of it called the receptor binding domain is able to attach to the host cell via Ace two receptors that are very prominent within the lungs, brain and kidney. When that he enters the law and matches perfectly. It's able to internalize and that virus then is able the messenger RNA. Is able to take over the machinery of our host cell and making more copies of that virus to shed. Yeah the Genome of the SARS Kobe two has four structures that it makes and the structure that is most important would be the part of the key that interests. That allows the virus to enter the host cell. And that's the receptor binding domain that is here in yellow. Yeah this receptor binding domain is like a copy that is made when you take your key to a hardware store and at that hardware store. If it's not perfectly made that key when it enters a lot, maybe very efficient or it may not be functional. That's also where all the variations that are important to us occur. The variations in the gene structure and proteins can be in anywhere else in despite protein. So what are we doing with vaccines as well as monoclonal antibodies? Well, the viruses goal is to have despite receptor binding domain attached to the ace two and establishing an infection in us. What we're trying to do is to vaccinate people for future protection So that we develop our own antibodies. Or if somebody developed an infection, they develop antibodies that was then subsequently block that entrance of that key into the law which is the H2 receptor monoclonal antibodies. Are this intermediate protection? If somebody does not already have passive immunity were able to give it to them. Now this is a structure of SARS COV two receptor and the purpose of this is to understand the importance of small amino acid change that really it's a key in the lock. And if you imagine an old key it must very carefully the edges must bind here from the SARS COv tube virus into certain areas and make attachments. And if it makes those attachments more efficiently, the virus can replicate more efficiently or it could transmit more efficiently or it may not, it may be a poor copy being made. The goal of the whole premise is for the spike protein to attack the ace two receptor and then make more viruses. Are immune defense. Is to match these spike receptor binding domains with antibodies whether by vaccine or monoclonal antibodies and stop so that we don't allow an infection to occur. The genomes. What copies are may errors can easily occur and those errors could just be a simple amino acid. As we see here in the B 117 U. K variant strain, which is the variance that is most prevalent in the United States, greater than 60 to 70% of the area Has to be 117 strain. Other strains exist, such as the South African variant, which is the B- 1351 strain. What is important to appreciate is that copying the virus, a lot of mutations occur. The area that's really important is that receptor binding domain. And unfortunately in the news media there's talk about double and triple mutants and one must take great care when interpreting that Because for example, if we look at the B1351, which is not the Indian strain, it does have three set are in the receptor binding domain. So talking about double and triple mutants could lead to confusion into regards to what really is being relayed and it's best to talk about the special genotype that is being referred to. Mhm. Now what is going on in India in India in october of 2020 B 1617 strain was identified by the global surveillance program and since that time it has now has three sub lineages with spike mutations that have occurred. But the ones that are key are again on the receptor binding domain. What is important is that the World Health Organization has recognized this as a variant of concern because it has increased transmissibility and there's a possibility that there is a potential reduction of monoclonal antibodies to be able to block the receptor binding domain from attaching to the ace two receptor in the United States. We also have critical emerging stars Kobe two mutants. We have the UK strain which is B 117 of South African strain B 1351 and brazil api one. Again, multiple mutations can occur on despite protein. The area that's important is that tight area on the key the receptor binding domain and alterations of those simple amino acids may affect transmissibility, the pathogenesis, the or the violence of that virus and very importantly, it may enable it to be able to escape our immune system whether that immune system is by vaccines or by monoclonal antibodies and again, these are just not in the United States. These are worldwide in africa, europe asia. Now so far the good news is we're not seeing a lot of COVID-19 vaccine breakthrough it is described. But this is a recent article pre print that came out that is showing that among variants of concern, vaccines are still lasting for months. That after a second dose of the vaccine we still get a robust Response to all variants and that the binding and functionality of the antibodies that are formed from the vaccine kill Astra 6-7 months. And again this is a pre print article Now it has to has variants already had an impact on utilization of monoclonal antibody therapy. And that answer is yes family love a map bAM. Was FDA EU emergency use authorized approved in november. But because of the rise of resistance to bam because of the monoclonal antibody not being as effective, it was revoked in april 16th 2021. And part of what we are doing now is similar to HIV therapy where we're using combination therapies so that now we have combination drugs is noted here where two monoclonal are attacking the um right was the uh receptor binding domain of despite protein. By doing that, we're off increasing our odds. That a variance will still be hit by a monoclonal antibody and give us immunity. What's important is not just for us all to get vaccines but to appreciate that we need to continue to investigate monoclonal combinations. And a program established by the NIH of which shortly Mayo clinic in florida will be activated. Is testing to accelerate COVID-19 therapeutic interventions and vaccines. We need to keep looking for more monoclonal to be ahead of the variants that exist. And if you would need to look for a place to refer a patient here is the link for the clinical trials as well as monitoring the biologics that are becoming available. So in the summary the messenger RNA must take over our host cell in order to use the machinery in the process of doing that. It makes copy errors, those copy errors or mutations. The mutations that are important are those that occur in the receptor binding domain, small amino acid variations can occur that can infect transmissibility, pathogenesis itty and even allow us the ability to escape the immune system. What we are doing globally is doing survey epidemiologic surveillance of variance to monitor what impact they may have on our vaccines are anti spike monoclonal and diagnostic testing. The person that has been quite instrumental in developing, not developing and bringing monoclonal is to our campus. Has been Dr. spyker. She is the director of the COVID-19 virtual clinic where monoclonal antibody infusions are given. She is an assistant professor of medicine. She is a consultant in the division of consultative and diagnostic medicine. She's not only boarded by the american board of internal medicine but the american board of preventive medicine in aerospace medicine. She was a U. S. Navy flight surgeon. She obtained her mph from the University of texas medical branch. We are delighted to have Dr Spyker enlighten us with her experience in her virtual clinic and monoclonal infusions. Doctor Spiker. Yeah. Yeah. Thank you so very much for that introduction. I'll hope to build on all of that wonderful information you gave about how the spike monoclonal work to neutralize COVID-19. My objectives today include providing updates on monoclonal antibody emergency use authorization or the U. S. For the USa. We'll identify patients at higher risk of progression that might benefit from these treatments. I'll talk about the mayo clinic florida experience and how we administer these infusions. And then I'll discuss a bit about variance and how we select which monoclonal therapy to use. Currently there are no FDA approved treatments in the outpatient setting. But we do have monoclonal antibodies that are available under emergency use authorization. As dr libertine noted, there have been three different treatments available, one of which was revoked. Which was gamblin of a map alone based on issues with susceptibility and variants. You can see the dates here of when CAssie River Map and Endeavour map and then bam line of a map in combination with excessive a map or both um brought to the U. S. A. Market based on the EU A. And very importantly the two remaining treatments have had those EU A Criteria updated just recently on May 14. Okay so I'll go through both inclusion and exclusion criteria. And then those new updates the EU A. Of both of the two remaining treatments are identical and this is who they should be used for mild to moderate Cases of COVID 19 and adults or kids. The Children have to be 12 years of age or older and all must weigh at least 40 kg with positive results of Covid testing and high risk for progression. So that's quite a loaded sentence. But we'll try to break that down as we discuss who would be included. So the C. D. C. Definitions for mild to moderate illness are are listed here. Mild illness would be more like flu like symptoms or upper respiratory illness. Type symptoms moderate would be to win those symptoms develop pneumonia with 02 sat being maintained at at least 94% on room air. The infusion must be administered as soon as possible after after the viral test and within 10 days of symptom onset. Therefore you must have symptoms to establish this timeline and qualify for monoclonal infusion, Auntie Gin and PCR tests are acceptable while antibody testing would not be. So we know that the blood antibody testing uh develops usually around 10 days or after. And so this wouldn't help us establish the timeline required to use. The monoclonal exclusion criteria is listed here. We would not want to give these treatments for anyone who was hospitalized for COVID-19 who requires new oxygen therapy or an increase in oxygen therapy for COVID-19. And in fact these treatments were early on found to be more detrimental in these cases. So the c. d. c. Would define these. This population is those with more severe to critical illness. And here is a list of the big updates that have recently happened to how we define the high risk criteria and I will go through these. So older age is the same. It's always been 65 years or older, but then obesity or overweight. That moved from A. B. M. I. 35 down to a B. M. I. Of 25 which can encompass much of our population in the US For kids. The Bmi should be over the 85th%ile for their age and gender. Other risk factors are pregnancy, chronic kidney disease, diabetes, having either immunosuppressive disease or being on an immunosuppressive treatment And then cardiovascular disease, even including hypertension and sound for all ages, not just 55 and above. Same with chronic lung diseases. This um has been expanded as well to be any ages with chronic lung disease. Sickle cell disease would be another risk factor and then neurodevelopmental disorders or any conditions that confirm medical complexity, um such as syndromes or congenital abnormalities. Lastly, any medical related technological dependence would count as a high risk criteria such as a trade or G tube. The EU a criteria also points to the CDC website and any other high risk categories listed there. And so here I have put some additional high high risk criteria that is listed on the C. D. C. You can see even people have formally been a smoker and substance use disorders listed. But importantly it's anyone who a health care provider feels there's a a valid risk benefit ratio to go ahead and offer it. And um very broadly this could even include racial and ethnic. My ethnic minorities. We have seen worse outcomes and some of these populations with COVID-19 outcomes and then also anyone with disabilities. As many people who are chronic health conditions could even live in a congregate setting and have additional barriers to health care. This is a graph that shows Our volume of infusions at Mayo clinic florida since we started back in November. So over the last six months time we have given 690 infusions, you can see that this increase in volume happened when we had a surge here in florida over the winter months. So this is a bit now about how we administer these infusions. We created a covid infusion center which took quite a bit of logistical planning as you need to bring in positive covid patients during their active disease. And most infectious time we developed a process where all patients who are tested positive are screened for inclusion for monoclonal antibody treatment. We also created a referral process for those who are tested elsewhere, where they can receive infusions on our at our sites and to break this down how this works is once the patient is screened if they meet criteria, the physician notifies the covid nurse line nurse. The nurse then contacts the patient to verify inclusion criteria, provide education which is a required fact sheet and a video that was created by mayo and then offer the infusion. If the patient ends up consenting, the order is placed and then signed by the physician and once this is complete, our schedule is set up an appointment in the Covid infusion center and described the process involved. This is the work flow of the process involved so we can go through what it's like for a patient. So upon arrival at a designated area in our parking lot, the patient is instructed to call our Covid infusion center number. When that occurs, a staff member comes out and escorts the patient in and also informs the pharmacy that the patient is here and ready. We decided not to mix the medication as this in times of surges has been a very let, resource limited medication and we want to make sure that we don't waste any doses. So once the patient is brought into the infusion center vitals are checked and we assure the patient is stable. If the patient is stable, the I. V. Line is placed and then as this is going on, the pharmacy will notify us when the medication is ready to retrieve we'll go get that medication and then initiate the infusion. During this time the patient is monitored one on one with our nursing staff and then after the infusion is complete. Their monitored for another hour. In our infusion center, vital signs are again taken and if stable, the ivy is removed. The patient is educated before they leave about potential signs and symptoms of a reaction, how to seek emergency care and contact us and also to be followed if they would like in our covid virtual clinic which offers telemedicine services and then at that point the patient is escorted out to their vehicle. Next we'll talk about monoclonal choice as Dr libertine outlined very well. There is a potential for treatment failure due to resistance of different viral variants. This is what happened with family. Never mad. And we have seen some resistance with a combination of gambling and the mob and excessive a math. However, thus far all variants tested are susceptible to cassie ribbon math and endeavour math. So I encourage healthcare providers to review variants in their areas using resources available such as the CDC state and local health departments to assure they're using the correct monoclonal treatment choice. This is a slide that kind of is another way to look at this discussion. It was used in the last monoclonal Rochester. I'm sorry Mayo clinic Rochester talked last month and here you can see that any in this light red color would be a sign where the medication was no longer effective against that variant. So you can see that with handling of a map and excessive um at the combination it works for the U. K. Variant, which is the most common in the U. S. And then the California variant. And then you can see the last column. The castle River map and Endeavour map currently work for most of the common variants. For all of the common vary. This is an example if you go to the CDC website and you can look up what variants are common in your area. Here is the entire United States and again you can see over time how the UK variant has become the predominant strain. You can use this website to look by your region or state and I've included my state here, which is what I follow at Mayo clinic florida. And what's interesting about our variants in florida is that we have more of the Brazilian variant and that is why we are using the cassie Endeav regimen most commonly currently. So again, I wanted to show a graphical display of the infusions that we have given over time and this follows the availability and what's happened with the band minimum of being revoked. So that was the first monoclonal treatment available under the EU A. So we definitely had more doses of that in the beginning then the cassie River map and and diplomat became available and there was a random distribution of this when we had both available then in March is when we were first able to obtain the ramblin of a map and excessive a math combination. That was more short lived in our center because of the change in the variance and the susceptibility being available. And so that's when we have moved for the last two months where we've only been giving the Castle River map and Endeavour endeavor map combination the future of monoclonal therapy. Of course there are concerned for new variants and resistance and we'll have to keep an eye on that vaccination is certainly um decreasing cases but there are issues of breakthrough infections. And so the role of monoclonal antibodies will continue. And then lastly the future may include using monoclonal antibodies as prophylaxis in preventing covid and not just treating it. So these are two um studies that have been released through the manufacturers where bam Lunev a map alone was able to reduce infections for nursing home residents exposed to covid 19. And then another trial with CAssie ribbon mob and Endeavour map that decreased covid 19 and household contacts after exposure. And very importantly this was a subcutaneous administration. So that will be a very interesting thing to look out for to in the future. In summary. Then I have discussed the criteria for monoclonal antibodies and shown the high risk criteria that has greatly expanded It through the EU a criteria patients still must have symptoms and receive the infusion within the 1st 10 days after symptom onset. And then I've discussed how variant strains can affect monoclonal choice. Thank you for your time and I will send this over to dr libertine. Please thank you very much for a wonderful talk. You very much covered what we wanted in terms of the changes that occurred from monoclonal inclusions criteria which is much broader. Making monoclonal is available to more patients and then you've provided resources for everybody regarding how they can choose monoclonal for their given regions. Next we have Dr. who is a critical care pharmacist, she's an instructor of pharmacy here and her schooling was in the, when she received her doctor of Pharmacy in 2005 from Midwest University, Chicago College of Pharmacy. She then trained as a pharmacy practice residency in 2006 and 2007, finishing at chance in Jacksonville. She became a member of valued member of our Mayo Clinic staff in 2019. She serves as a critical care pharmacist and as an instructor in our medical school. She cares for a variety of critical ill patients. We have multiple intensive care units from surgical medical cardiac transplant and neurology patients. She has a special interest in pulmonary disorders and she precepts pharmacy residents and students in the medical critical care settings. She's currently engaged in multiple research projects. We're delighted to have her join us today. Dr Rotman. Thank you for that introduction. Yeah. The learning objectives that will discuss in this section include the logistical requirement for monoclonal antibody administration including the procurement process and preparation. And we'll also review the mayo clinic experience with monoclonal antibody monitoring and adverse events. Covid 19 emergency utilization authorization otherwise known as the EU a monoclonal antibody therapies are currently available through direct order via the authorized distributor which is Amerisourcebergen Corporation. Okay. These agents include casa river Mab with endeavor mob and family. The mob with a southern mob at a seven map is available via direct order with the intention to be paired with on hand remaining family. The map each week the U. S. Department of Health and Human Services determined state and territory allocations for each monoclonal antibody using data that's collected from the Health and human Service protect platforms. The State Department of Health determines eligible facilities and the allocation each site will receive. The information is related to the distributor abc who is responsible for coordinating the shipment of these therapies to each facility. If a facility determines that they will not use all of their allocation, these courses are redistributed to facilities that request additional doses due to higher utilization sites are required to provide either a board of pharmacy license or physician letter of authorization and they must attest to the designated class of trade and that the monoclonal product will be administered in accordance with the EU. A terms utilization data must also be submitted for the monoclonal agents. Monoclonal antibody utilization reporting is required every Wednesday for hospitals. The MAb therapeutic data is included in the U. S. Health and human services protect data collection platform for the covid 19 hospital data reporting. Additional facilities such as infusion centers are required to provide the requested data through the HHS tele tracking portal and skilled nursing. Our long term care facilities are requested to provide data for the C. D. C. S. National Healthcare Safety Network Data system. At a future date guidance on this will be forthcoming. Many components of information such as staffing that availability Um at mechanical ventilators, COVID-19 emissions and deaths etc is collected in the utilization report to facilitate federal government planning monitoring and resource allocation during this public emergency. The daily reporting is the only mechanism used for the distribution calculations and daily reports from the institutions indicated. Help ensure that we have the accurate calculations. Pharmacy does assist with collecting data on previous weeks, courses of therapeutic you, a monoclonal antibody medication use and current on hand inventory and this component again is required. Every Wednesday monoclonal antibodies have specific details to be aware of. The vials do require refrigeration storage and protection from light. My abs are metabolized similar to endogenous IgG antibodies, throop rodeo ISIS, the small peptides and amino acids, Metabolism by metabolism by sea wipe for 50 enzymes is not required. Therefore, interactions with contaminant medications such as skype for 50 substrates inducers or inhibitors are unlikely. There's no recommended adjustments for weight or renal impairment. The molecular weight of these agents is around 145 killer Dalton's, which is higher than the globular filtration rate threshold, which is usually about 55 killer dalton's. Therefore, these are not expected to be eliminated in the urine casa, river, mob and Endeavour mob are specifically complicated agents. Um, Some of the violent car carton labels that we received do not include drug names and they do not identify the specific antibody that's contained within the vials, making it difficult to ensure that both Castle River map and end of amount of are added to the appropriate really want solution and correct amounts. These packages maybe clearly march with either caution new drug limited by federal or United States law for investigational use or they could be labeled with for use under the emergency use authorization. Some vile labels and carton labels maybe coated with investigational drug trial names such as Region 10933 and Region 10987. The FDA does not require the product to be repackaged given that this is a public health emergency and it's being used in accordance with the reissued february 2021 E. U. H. Terms and conditions. Also the manufacturer's bar code does not distinguish between the two agents. The pharmacy staff must look up the product code numbers and the health care provider fact shape to help identify these drugs to confuse matters even further. The labelling of Kazarian mag and of mob may also specify ivy or sub Q. Administration on the violet for injection under the current EU. A terms and conditions. Um The product may only be a minister via I. V. Infusion casa, ruby mob and Endeavour mob may also arrive in steel plastic bag packages with a sufficient number of vials to prepare one treatment dose. It is possible that this bag may contain 25 or eight vials within the dose pack. The way approved dozing of covid 19 kozyrev mob is 1200 mg with Endeavor mob 1200 mg. And for Obama live a mob it is 700 mg with edits of a mob 1400 mg. It's important to understand the differences and how these products are dose prepared and stored as they can be different Order processing time at our facility from pharmacist verification to finish compounded products about 45-60 minutes And our experience it takes about 20-30 minutes for the product to reach room temperature. Once we remove it from the refrigerator and the vial should not be exposed to direct heat or shaken. The actual compounding process takes about 10 minutes to prepare in the sterile I. V. Room sterile compounding of these agents. As complicated as both products require multiple vials to obtain the correct dosage kozyrev mob and the mob is especially confusing as those products may be available in varying product sizes. So this means sometimes in an 11.1 ml vial may be utilized to compound the product and other times eight vials may be needed Of the 2.5 ml vials. If you have both 2.5 mi of Catherine Map and Endeavour there, which just leads to increasing air potential. Each drug should be drawn up in separate syringes and then injected into a normal saline delia went at our facility we simplified the procedure by standardizing 250 ml normal sailing as our deal you want for infusion bag and the infusion time is consistently one hour. If a patient does weigh less than 50 kg and is receiving family of a mob at a seven mob, The extended infusion time should be pushed to 70 minutes to help reduce the antitoxin load. Monoclonal antibody products are proteins and should not be shaken, but rather we should be gently inverting them to mix. Infusions do require an in line 0.2 micron or an additive 0.22 micron filter attachment and after the infusion. The I. V. Line should be flushed with normal saline to ensure the total dose of monoclonal antibody was received beyond you. Stating for stability is inconsistent across these products ideally. The product should be administered immediately after compounding Kozyrev mob and the mob is stable for four hours at room temperature and 36 hours. Refrigerated Family of a mob at a seven mob is stable for seven hours at room temperature and 24 hours refrigerated. Um if the product is refrigerated after compounding um it should be removed 20-30 minutes before administrating to also allow it to reach room temperature policy should be in place for the monitoring of vital signs and infusion reactions. When I'm ministering these monoclonal antibodies Um specifically during in one hour after the completed infusion at our institution, vital signs are obtained at baseline every five minutes for 15 minutes, then at 30 minutes and at the end of the infusion are in continues to monitor the patient and the patient's titles from one hour following completion of the infusion. In addition to infusion reactions, other immune related adverse drug events include a number of dermatological gastrointestinal endocrine and other inflammatory reactions. And this is usually related to alterations in the normal immune balance between immune activity and immune tolerance. Commonly reported adverse drug events include nausea, dizziness, pure itis, fever, chills, nausea, headache, hypertension, rash, my algebra and dizziness and clinical trials infusion related reactions, although some serious that occur. Um these were rare and then infusion related reaction occurs. Consider slowing or stopping the infusion and ministering appropriate medications and supportive care if hypersensitivity or allergic reaction occurs. The infusion should be immediately discontinued as well as appropriate medications. And supportive care should be initiated because of this site. Should follow local recommendations when determining appropriate monitoring observation periods. Um One thing to think about is the number of chairs patients will occupy during this confusion time. Um As well as their monitoring for the post treatment area and planning time to account for this infusion sites, repairs should take into account the time for patient intake preparation, fusion, post infusion observation when determining their capacity as Dr Spyker mentioned earlier, at least one healthcare professionals should be able to respond to these medical emergencies that potentially can occur, such as to their infusion reactions are hyper sensitivities and medications should be available for immediate treatment. Immediate E. M. S. Should be available as well. Um Typically it's recommended that at least one health care provider be qualified in A. C. L. S. And P. L. S. Um As well as able to provide the medications in accordance with the mandatory reporting is required for all potential medication errors and serious adverse events considered to be related to these antibodies. It's important to provide detailed information at the time of reporting regarding patient and the adverse events that occurred. Um for ongoing safety evaluation of these unapproved drugs information that can be quite included as the patient demographics such as their initials or date of birth or medical history details regarding the administration and course of illness. Any contaminant meds um The timing of the adverse have been some relationship to the administration of the medication and pertinent laboratory information. Reporting of patient outcomes is not required under the way. However, you may provide that information or any additional follow up available. Um And on the right side of the screen you will see the covid infusion medications that we have available in our Covid infusion clinic for the nurses adverse This chart is going to show some adverse drug events that were reported as either code to 50 or an 80 visit after receiving the monoclonal antibody in the Covid infusion center here at Mayo Clinic florida. Um At the time of this data um 680 patients have received monoclonal antibody therapy between november and May 13th of 2021 due to a surge in the variant cases. As Dr Spyker discussed. As a March 28th male clinic florida completely switched to casa river map and devon abuse. Um 476 patients that receive family Vinet products 204 patients receive cosmetic products. Overall, the majority of adverse drug events reported for both agents was shortness of breath or hypoxia. Other reported adverse events were nausea. Seeing with family of a mob favor chest tightness, dizziness, itching and hives. This is consistent with the adverse events that are documented in the literature. Eight patients in Obama live in that group and two patients in the cast of mad group required hospitalization and one patient and each group did expire an outside facility and I will at least let you know. I do not have any further details on those patients. Clinical worsening of covid 19 after administration has occurred based on adverse drug event reporting under the EU A This could be seen as fever, hypoxia, respiratory difficulty, arrhythmias, fatigues or altered mental status. Some of these events we do know how required hospitalization. Um but it's not known at the time of these events were related to monoclonal antibody administration or the progression of the COVID-19 disease. This just highlights some resources for you that we've utilized for this presentation. There's multiple resources out there. Um useful links are how to do the direct order process guide as well as the abc distributor lee. Um The tele tracking portal is available for your reference and guidelines for how to report this. Information links are also provided here for the FDA Med watch side as they can be reported online and the adverse events and medication errors. Patient provider guidebooks are available via the manufacturer and multiple other websites. Some other useful links is the Public Health Emergency Covid 19 monoclonal antibody digital toolkit which is actually provided by the HHS department. This includes fact sheets in both english and spanish treatment locators and information for social media platforms. Um, the link for the covid 19 disease um variant state resistance tractor is included usually on this one. You'll see lineages within a two week period based on sequence collected from each HHS region as well as combat. Covid is another useful sites. Um This one is primarily excellent for patients to be referred to. It has information on prevention, vaccines, clinical treatment, option trials and the recovery process. So in summary um, COVID-19 you a monoclonal antibodies are available via direct order. Um and these amounts are allocated by the state each week. Utilization data is required to be reported weekly, including current inventory and therapy is completed and the monoclonal antibody products at this point require no dose adjustments. Um They do require some time for the vial to reach room temperature prior to compounding as well as filter upon administration other adverse reported events. And average reported in Smartwatch should be reported in seven days. Includes vital sign monitoring should be reported as well as um other adverse events for bam 11 mob one information I did want to highlight for you was primarily we did receive a 0.25% of patients that received family. The mad reported shortness of breath and 0.11% of patients receiving beyond 11 matt products experienced nausea with kozyrev mob and Endeavour mob Chest pain was reported in 0.015% of our patients. Um as well as shortness of breath was reported 0.015% of our patients. Um And at this time I will turn it back over to Dr libertine for the next introduction. Thank you DR Robin. That was quite impressive. And you clearly demonstrated the critical role that pharmacy places part of one's team and anything that one does in the hospital, but specifically with monoclonal antibodies. We've appreciate your review and we appreciate your expertise. Our next Panelist is dr broom ball. Doctor bramble is a graduate of east Carolina school of Medicine. She completed both her internal medicine and infectious disease fellowships at Vanderbilt University. She is an assistant professor in the Mayor suitable Mayo Clinic College of Medicine and Science and is a fellow of the infectious disease society of America. She is my advice chair or vice chair of the division of infectious disease Mayo clinic florida and she's the program director of infectious disease fellowship program here. She's a key transplant lay us on for us and she's been awarded many educational awards and I'm sure you'll enjoy her talk. Dr bramble. Yeah, thank you. Dr libertine for that very kind introduction. And I want to thank the organizing committee for the invitation to participate in this webinar today. The learning objectives of my talk will include what is the Mayor clinic in florida model of care of hospitalized COVID-19 positive patients. So we're moving from outpatient management to in patient management. I will um discuss how we determine what treatment regiments will be provided to our patients. I'm going to describe for you our treatment review panel and I want to discuss with you how we conduct our daily 11 a.m. Covid 19 treatment rounds which I hope will you will find helpful. I will review criteria for the use of fossil is a math and hospitalized patients. And I will review the use of non FDA approved products. Mayo clinic created a virtual clinic in order to monitor symptomatic patients and the outpatient setting with monitoring as noted in this slide. And I want to let everyone know that this has been a huge effort by uh male clinic in florida and they have been comparable efforts at the other sites. Um We use physicians from General Internal Medicine. Uh We use providers from all areas and even some of our emeritus providers to help to monitor these patients. So it's a great team effort. Now there are a couple of different ways that patients are admitted to the hospital. Covid service patients who are monitored by the virtual clinic, maybe directly admitted to the covid hospital service if their oxygen saturation are uh 90 to 92%. However, if there is concern that the patient is experiencing severe respiratory illness or is unstable, the patient will be referred to the emergency department for further evaluation after assessing the patient the emergency department staff themed and if they deem that the patient warrants hospitalization, the patient will be admitted to one of three hospital services, they may be admitted to the covid Hospitalist service. They may be admitted to a general Internal Medicine Service or if they're critically ill they'll go straight to the I would note that the I. D. Coverage service follows all of the patients regardless of their location in the hospital at the beginning of the pandemic we did not know what medications would work. We used FDA approved antiviral agents or drugs that we hope would decrease or stop viral replication. And we also use immuno modulators. These are drugs that limit the host immune response to the virus. If the medication was not FDA approved, we strongly encourage clinical trials using emergency use authorization, expanded access protocols, compassionate use programmes or agents that were off label use of approved drugs to determine what meant what therapies might work best. But importantly we would collect data as we were treating these patients. The treatment review panel was created and this comprised of a multidisciplinary group, a physicians who constantly review the evidence based therapies and they provide oversight to ensure that patients are treated according to the trials. We are practicing evidence based medicine as peer reviewed articles are emerging and I would note that several members of the multidisciplinary hospital private team are also members of the treatment review panel, which promotes the flow of information between the groups. Now this life contains a lot of information. I'm not going to go into into detail as you will have it available for your review, but this gives you information regarding our protocols for treatment and lab monitoring. That is to be followed by all providers caring for the private patients at the time of admission. We have this on our internet. So any provider caring for the patient has access to this information. This is evidence based and is standard of care. We hold multidisciplinary rounds daily at 11 a.m. This meeting typically lasts anywhere from 30 minutes to an hour in duration, depending upon the number of patients. Hospitalist with Cuban infection. Now a member of the primary hospital service caring for the patient, be it general internal medicine or the or the covid hospitalist team. They will present their patient to the to the um uh covid team as you see here and that the person presenting the patient can be an entrant. It could be an upper level resident and attending or it could be a mid level provider. Additionally, anyone in the institution can call into the meeting to learn more about the management of covid. The covid team consists of an idea consultant, human Ecologist, oncologist, a blood bank physician and a transplant pulmonologist. This is a dedicated team who discusses each patient in detail and together through joint decision making. We determine into which trial a patient may be enrolled. We make ourselves available essentially 24 hours a day, seven days a week. Whether or not we're on the curve is service to help provide optimal care for the patients. We provide oversight as to how to care for the patient. And we always provide standard of care and we adjust our additional recommendations based upon the availability of new trials in which agent we think would best serve the patient. So this is a very fluid process and by using joint decision making patients are not bombarded by different physicians who are all competing to get patients enrolled into their trials. So we we really work together to ensure that we try to provide the best possible uh treatment protocols or additional trials for each patient. And our approach requires that we can only use a product if it is under a clinical trial protocol that has been approved by our I. R. B. Now again, we provide our recommendations back to the primary team and I want you to know that the primary team attending is ultimately the patient responsible for making the final decision regarding the patient's care. Yeah. Now getting back to monoclonal therapies, the one that is used in the hospitalized setting is socialism app or Tosi. For short, there are various clinical trials regarding the use of Tosi for the treatment of covid. With varying results, we use this to agent early in the care of patients who are exhibiting rapid respiratory decompensation. But all modalities of care are considered for the treatment of Covid patients. This picture is of a patient who developed uh severe A. R. D. S. Um and required one transplantation to recover from covid and he is currently doing quite well and we are grateful for having a transplant pulmonologist on our uh Research on our multidisciplinary 11 a.m. round who could help us to to guide appropriate pulmonary management uh of all the patients. And she's great, she's very gracious and reviews all of the images with all of us. Uh So it definitely leads to uh better recommendations being made uh to the primary team. So in summary what I want you to walk away with is that the care of the hospitalized Covid patient at Mayo Clinic florida is a multidisciplinary team approach. Again we have a multidisciplinary treatment review panel. We then have a multidisciplinary 11 a.m. curve. It I'd rounds, we have multidisciplinary team approach to our research and we ensure that patients don't get bombarded with people trying to um uh enroll them in their particular studies. So it does involve a joint decision making and all modalities of care are considered including lung transplantation. I thank you very much for the opportunity to present this information with you and I would like to turn it back to dr libertine at this time. Thank you Dr broom ball you very much stress the importance of teamwork and fluidity that exists as well as dedicated members. And we appreciate your talk. I very briefly want to go over to to show these objectives that monoclonal therapy is not just against anti spike, but that monoclonal therapy can target cytokines such as the aisle six and Tosi as dr bramble mentioned, there is information regarding the role of brands like Mack, Lafarge, Colony stimulating factors, precipitating cytokine storm. And I'd like to give you some preliminary results that are in pre print for Alan selamat trial that we conducted here and at multiple centers. I've already got the question is where does run disappears fit in. I want to stress that antiviral agents and monoclonal therapy against the anti spike protein is very important to give very early in the infection. That's why it's classified mild or moderate disease to stop the virus replication. Yeah, I'll six and GM CSF are part of the cytokine storm and there are monoclonal antibodies that can be given to stop the cytokine storm or hopefully more will be coming also. And the role there is to prevent progression of the inflammatory markers that lead to acute respiratory dress distress and multi organ failure. GM CSF in this very excellent article was shown to be associated with inflammatory as well as storm biotic consequences of the immune system and that GM CSF levels are detected very high in the first four days and are associated with disease severity. In fact, there were noted to be 10 times higher levels of GM CSF in patients who died from covid 19. That's important because GM CSF is earlier upstream than I L six L eight I'll to where Monica funnels can target those agents. So the goal of our study and it, as a multi center randomized placebo controlled study was to look at blocking by a monoclonal antibody GM CSF upstream from the other side of kind pathway cytokine storms we have experienced with with other diseases such as the immune hyper stimulation. It occurs in autoimmune diseases, Lymphoma, proliferated diseases as well as specifically party therapy. But now we have also shown that the cytokine release syndrome does occur with COVID-19, causing acute renal failure and the shock picture that we've all experienced. The lens element Phase three study was an early intervention of this monoclonal against anti GM CSF to prevent and treat cytokine storm and prevent the progression to invasive mechanical ventilation. It's a multi center placebo controlled randomized double blind trial Subjects have to be 18. They had to be hospitalized, they had to have PCR positive for SARS Cov tube and radiographic evidence of pneumonia. 0 2 sats how to be less than 94. And what is unique about this trial is still other agents that could be considered standard of care at one site were permitted to be used, such as convalescent plasma steroids, friend disappear. The primary endpoint was ventilator free survival. So an individual would be 1 to 1 randomized to either get Lindsay, lem ap 600 mg every eight hours For three doses for a total of 1800 mg in one day versus that of placebo. And that in both arms, people could get whatever the standard of care of that institution would be. Yeah. What was found was the demographics and the basic characteristics. And the end is for 79 and as high as 520 is that the average age was 62 predominant males, 64 Years of age. A good demographic profile of ethnicity and race and a pretty severe disease by use of high flow at 38-42%. So it's a pretty good representation of what we see in the hospital. And then this pre print Primary endpoint. What we see is the hazard ratio for the use of land Zilla map to be 54% improved ventilator free survival compared to placebo, which includes against standard of care with remdesivir and decks a methadone. What we also see is there was a dramatic impact that would be noted between day two and three on these captain meier curves showing that Lindsay Lohan maths outcomes improved and persisted different than the placebo group. All the ways out to monitoring day 28. The purpose of showing the data is that monoclonal therapy is not just going to be against anti spike therapy but that we have monoclonal therapy that can be utilized in the hospital Lindsay Lohan map as Tosi is a safe antibiotic. What we found here was that in hypoxic patients who had not already progressed to mechanical ventilation, there was a relative likelihood that they could survive without ventilation through day 28 by 54% beyond what our standard of care would be. And we're also demonstrating the GM CSF, maybe another target for monoclonal antibodies. So what we've reviewed today are variants, the impact that variants have on monoclonal. We've learned that they're broadening of the criteria for who can get monoclonal therapy. And we heard great details as to the meticulousness of pharmacy being involved in administering and helping us in the outpatient setting. We then shifted to the hospitalized setting and we shared with you our treatment group on multiple different levels for us to give you a sense of the importance of teamwork, especially during a pandemic, when things are rapidly changing. What I'd like to do now is go to our question and answer period and we have quite a few questions that have already come up. One question I've already answered was where to antiviral medicines or remdesivir fit in the treatment of mild to moderate covid disease and that would be in the very beginning, early stages of mild to moderate symptoms pathology. The early flu like symptoms, Preferably symptoms less than 5-7 days. That's where the remdesivir would have it straight its impact to stop the replication of the virus. Yeah, dr Speicher I have a question here for you that is can monoclonal antibodies be given to pregnant or lactating women that was not touched upon and maybe you could add some comments for us. So pregnancy is one of the high risk criteria that can qualify patients for monoclonal antibodies. Uh lactation is also noted in the Eu a criteria as a special risk population where studies have not been conclusive to recommend for or against. So right now this is the level of asking um your doctor which you know likely your obstetrician and I think this is very much where it's not perfectly clear and has to be kind of risk and benefit criteria. When you decide if you would want to recommend that the patient have monoclonal antibody. Um Dr provo here's a question would patients admitted to the hospital with medical conditions such as a stroke or subsequently found to have covid positivity but have no evidence of pneumonia still be eligible in the hospital from monoclonal therapy. Thank you. Dr Liberty. Um Yes we we we do offer that to the patients. Uh And again remember I mentioned that to socialism. Mob is the primary one that has been used in the hospital. But again the patient has to be experiencing rapid respiratory decompensation and we're trying to give it to the patient within the first three days of their hospitalization. So if they did compensate. Yes, they would be eligible. Thank you. I would like to also stress that anti spike monoclonal antibodies cannot be given to patients who are hospitalized. That is an exclusion criteria. And we like dr crumble states do use anti I'll six monoclonal therapy to stop decided kind storm. Um What is the mechanism by which monaco channels have their detrimental effects to uncoated patients that you've seen in the clinic? Doctor Spyker. If you want to take that one you're not. Yes. Yes I'll take that one. I saw that one coming up. So this is not clear either. The closest I can get to this, I will refer you. There's a new England Journal of Medicine article um released on March 11th by the active Three a study group. This was the bam of them living damn line of amount of study which they they just they said they're not sure of the mechanism. But they said that perhaps it's just when someone's so sick in the hospital there may be decreased penetration of the antibody into the infected tissue, so it's not working adequately. And then also it may play a role in a developing side of kind storm where there's increased viral replication or even exaggerated inflammation. So I think it's not known. But that was a early study when gambling um, ahmad was tested. And so then I don't think that they have tested other monoclonal antibodies that I discussed here uh in the hospitalized setting and dR broom ball. Here's a question that frequently comes up for those who received monoclonal therapy for covid and then whether they're admitted or not admitted to the hospital, how long do they have to wait to receive the vaccine? That is an excellent question. We typically wait 90 days after a patient has had a covid infection before we offer them the vaccine, regardless of whether or not they have received monoclonal antibiotics now. Dr rotten. And there's a question here that is a bit tough. I don't know if we've experienced that but there's a question what stating there has been reports in which nurses need to change ivy to be multiple times even during one infusion. What is your experience and why would you think that? Maybe? And I suspect it may have to do with the volume of the infusion. So maybe you could share with us with volume you're using with our monoclonal antibodies um at Mayo Clinic florida we are using 250 mls of normal saline and we are adding instead of removing the volume of the monoclonal is to that infusion bag. So I do see that on the U. S. And the product guides. Playbook produced by each manufacturer that they do both recommend using PVC or polyethylene line. PVC as the infusion tubing. Um Some curious what to being is being used at the site where that they're seeing these issues here. We have not had any reported incidences. Um I did check with Dr Spyker because we saw this question earlier and she has not heard of any either. Um and within the pharmacy department we've not had any reports of issues with the tubing. And while you're at it Dr Rothman would you mind reviewing for us again the adverse effects of monoclonal antibodies? Um you or Dr spiker yeah sure. Um adverse effects of monoclonal antibodies. Could be worsening of covid symptoms. Um Specifically there could be some hypersensitivity reactions such as anti black sis angio oedema. Um Could be pure itis or rash developing those in the current literature have occurred but they have been rare in the occurrence. Other common side effects is headache. Um There's been hypertension, hypertension that we've had reported. We've had some chest tightness that's frequently reported shortness of breath or hypoxia. There's also been reported um dizziness and nausea and Dr Spyker. Have I left anything out that you've seen? No I think that's an excellent review. You are ready. Thank you. Dr Spyker. There is a question here does sleep apnea. Using a cPAc or biPAc qualify for increased risk for somebody who has mild or moderate covid symptoms where they qualify for a monoclonal antibody. So that hasn't been spelled out as a high risk criteria. As I listen to my slides for either the anyway high risk criteria or by the CDC. But again I think that we are now with the expanded criteria as practitioners we can decide a risk benefit ratio for our patients. And I think often I mean the majority of the time someone would qualify by their BME if they have sleep apnea or perhaps they have hypertension as well. So I think in general I would probably qualify someone who is on CPAC when they mentioned medically assisted devices. I they are meaning that they are on um by paper. CPAP 24 7, not just using it at night. And DR Spyker. Could you also um comment for us um how long you monitor the patients and the details after the monoclonal antibody infusion? I know you stated in one hour. Is there anything in particular that you look for? Can you address that? Sure. So we're just looking for hypersensitive sensitivity reactions. Perhaps a rash, swelling, difficulty swallowing. We monitor vital signs to make sure they're stable. Um Just basics that you would um you would monitor after any vaccine for example, that we are using now. Um But no, there's nothing really super subtle that we're looking for. Usually the patient, it's what they're experiencing and they tell us and we're just there to address if anything is happening with them. Now there's a question here of what is the role of convalescent plasma and the admitted patient at the present time. And I'll take that one on and shirt with you dr bramble if you want. We do use convalescent plasma. The data by Joyner at all shows that high, tighter convalescent plasma very early on is providing antibodies to block the um spike protein from entering into the host cell in order to replicate. So we're very good at within the 1st 24 to 48 hours. If an anti spike level comes back as negative, meaning the patient does not have adequate antibody levels. Has not had a vaccine. We go ahead and give the convalescent plasma month and we're a bit more assertive in that our transplant population has not had responses well to the vaccines and we're seeing them being admitted and we do give convalescent plasma, but again it's high, tighter convalescent plasma and With limited usage. 2-3 units dr grumble. There was a question here of how did you determine who would be members of your hospital? Covid 1911. AM. It was actually those people who expressed interest in participating. So we knew we had to have people from infectious diseases obviously and um uh Dr libertine and I have taken the primary role from that perspective. Then we had dr shaw uh who is of course caring for pulmonary transplant patients and she became very interested in participating and like I said, she's been instrumental because she helps us to review all the imaging for all of the patients. Uh Dr cower uh has also been involved from human because she's helped to monitor the uh hem onc patients virtually who had um or who have covid. And so so she just um offered to help participate in these rounds as well. And then Dr O'brien from the blood bank has been just terrific in trying to ensure that we have appropriate amounts of blood products uh to try to care for our patients. So it's essentially it was a voluntary team DR Spyker. There's a question here is your exertion All test for oxygen SATs a six minute walk test or something else. How how did you make that? Is that metric? How did you measure that metric? Sure. So that side from Dr Bumbles Talk was more about how we decide if a patient should be sent to the er or perhaps directly admitted. So this was one of these great teamwork efforts with our treatment review panel where we were able to really Talk to everybody on site and I hope others can do and have done this to with their institutions where we really wanted to define a few variables is kind of like framework for how we advise patients. And so in that case any resting go to above 94%, we considered pretty safe. But then if the patient was still um you know, noticing shortness of breath or just me on exertion, we would do a simple walking test where they walk for a minute most are being monitored remotely or have a home oxygen monitor. So we would just have them walk for a minute and then test them again and see how their oxygen saturation did. And that would give us an indicator we needed to seek more aggressive care than our home telemedicine services. Thank you. There's there's a question here of how do we decide which patient qualifies for convalescent plasma vs. Monoclonal antibody? Um The generic term monoclonal antibody needs to be separated out to be those that are anti spike targeted monoclonal antibodies and those are not approved by the FDA emergency use authorization to be used in hospitalized patients. The convalescent platinum or is convalescent plasma approved to be given in the outpatient setting. So there's a distinction that exists between the two the monoclonal antibody therapies that we utilize in the hospital would be Tosi and that would be anti. I'll six and that's very limited convalescent plasma. We do use in hospitalized patients who have not had a good antibody response to a vaccine. If we were fortunate enough that they took the vaccine. Mhm. DR Spyker. There's a question here that I'm sure you've dealt with. Some centers are reporting that more than half of the patients who are offered a monoclonal therapy decline. What has been Mayo clinic florida's experience And as patients accepted increased over time. So we I did pull this data and it's um it's been accepted as a letter to the editor but has not been published. But you could look for that in august addition of the Southern Medical Journal. What we saw over time was right when monoclonal those first came out, it was just the band one of a map alone because there were lower rates of acceptance. Uh as happened like later in the process, I think more people became familiar with this. It was, you know, made famous in the media at that time and then a lot more people accepted it. So I think um that there have been differences over time and with surging and you know, fear of um how many hospital beds are available. But I think some of the most common reasons that people are hesitant to accept model funnels would be that they're not that ill. Remember this is mild to moderate severity of patients. Perhaps they don't think it's warranted. They want to make sure that other people who need it have it. They're concerned that this is still investigational and that is under EU and not FDA approved the impression they don't want to be a guinea pig. They're concerned about potential side effects. Um and then maybe concern that they could feel worse after the infusion. So it's just uh there are a bunch of unknowns and there are some difficulties in answering everybody's questions as um this is a newer treatment and um studies are still forthcoming and I do want to touch on this if I can just keep the floor for a minute. Um The outcomes are very important of what we've been able to show. And so I know in the Rochester talk last month they gave some parliament and mary data about family never map. We have been able to reduce hospitalizations. Um There is another article that has been submitted on the cassie and in depth product that again showed a decrease in hospitalizations. Yeah. That's really important for people to accept first mono funnels and vaccines as we move forward in our pandemic. Um I think we're coming close to the end of our time. I want to first of all thank all the panelists and their dedication that they've given throughout this past year working way beyond. Uh We really appreciate that. And then thank you everybody else for attending this webinar. And we hope that we've shared some information that you could take and offer to your patients and extend, um, to them improved care. Thank you.