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CPD

Implementing Monoclonal Antibodies for COVID-19 in Clinical Practice

  • Authors: Alexandra Calmy, MD, PhD, FMH
  • CPD Released: 1/3/2022
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 1/3/2023
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Target Audience and Goal Statement

This activity is intended for physicians, nurses, nurse practitioners (NPs), physician assistants (PAs) involved in the care of high-risk patients with mild to moderate COVID-19 disease who are interested in setting up an infusion center for monoclonal antibodies (mAbs).

The goal of this activity is to provide physicians and healthcare practitioners (HCPs) with expert guidance on best practices based on the latest clinical and real-world use of mAb infusions, and to foster their appropriate use in the treatment of patients with mild to moderate COVID-19.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Identification of patients who are candidates for mAbs
    • Monitoring patients for reactions during mAb infusion
    • Appropriate follow-up for patients after mAb infusion


Disclosures

WebMD Global requires each individual who is in a position to control the content of one of its educational activities to disclose any relevant financial relationships occurring within the past 12 months that could create a conflict of interest.


Faculty

  • Alexandra Calmy, MD, PhD, FMH

    Professor
    HIV/AIDS Unit Director,
    Division of Infectious Diseases
    Geneva University Hospitals
    Geneva, Switzerland

    Disclosures

    Disclosure: Alexandra Calmy, MD, PhD, FMH, has the following relevant financial relationships: 
    Grants for clinical research from: Merck Sharp & Dohme 
    Other: Unrestricted educational grants from AbbVie; Gilead SA, Merck Sharp & Dohme; ViiV Healthcare 

Editors

  • Shanthi Voorn, PhD

    Medical Education Director, WebMD Global, LLC

    Disclosures

    Disclosure: Shanthi Voorn, PhD, has disclosed no relevant financial relationships.

Content Reviewer

  • Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance

    Disclosures

    Disclosure: Leigh Schmidt, MSN, RN, CMSRN, CNE, CHCP, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.


Accreditation Statements

    For Physicians

  • The Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the United Kingdom (FPM) has reviewed and approved the content of this educational activity and allocated it 0.5 continuing professional development credits (CPD).

    Contact WebMD Global

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]


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Follow these steps to claim a credit certificate for completing this activity:

  1. Read the information provided on the title page regarding the target audience, learning objectives, and author disclosures, read and study the activity content and then complete the post-test questions. If you earn a passing score on the post-test and we have determined based on your registration profile that you may be eligible to claim CPD credit for completing this activity, we will issue you a CPD credit certificate.
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CPD

Implementing Monoclonal Antibodies for COVID-19 in Clinical Practice

Authors: Alexandra Calmy, MD, PhD, FMHFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CPD Released: 1/3/2022

Valid for credit through: 1/3/2023

processing....

Activity Transcript

Alexandra Calmy, MD, PhD, FMH: My name is Alexandra Calmy. I am the HIV/AIDS Unit Director in the division of infectious diseases in Geneva University Hospitals. I am the clinician infectiologist and I have been taking care of COVID-19 patients, mostly the one who were hospitalized.

I think the main reason why we here today, that we don't want to oppose prevention and treatment. We have a very efficient vaccination campaign, but we still have patients who do not respond to vaccines. We have patients who become infected with, for example, Delta variants despite having been vaccinated and some of them belong to the high-risk groups. And also we have to think about the future because we are always a little bit behind the virus and we have to think about new virus in the future that escape the protection of the current vaccines.

So the mechanism of the action of the monoclonal antibodies are very diverse. They can directly interfere with the viral pathogenesis in multiple ways. First, by neutralization. Binding of a neutralizing antibody to the variant can prevent target cell binding and/or fusion. And furthermore, antibody binding opsonizes the virus or infected cells for phagocytic uptake.

So if the viral protein are intercalated into target cell membranes during viral release, then monoclonal antibodies can facilitate target cell deaths via complement fixation, or antibody dependent cytotoxicity. And these mechanisms may result in a apoptosis or necrosis of the infected cell. So let's have a look now to the different types of mAb therapies for the treatment of COVID-19.

So here are the WHO recommendations for the monoclonal antibodies. These recommendations were based on the living meta-analysis informed by 4 trials that having enrolled more than 4000 patients with non-severe illness. So WHO has first issued this recommendation only regarding casirivimab and imdevimab and what they suggest is that this combination can be used in 2 different patient groups, patients with non-severe COVID-19.

And this treatment is for those who are at higher risk of hospitalization, and also can be used for severe or critical COVID-19 hospitalized patients for those who have a zero negative status. So several antibody therapies that are available or registered in Europe for outpatient use had agents who did not require supplemental oxygen and are at risk of disease progression. We have the casirivimab and imdevimab. It's the only combination for which we do have WHO recommendation. Bamlanivimab and etesevimab as a combination, and regdanvimab, sotrovimab. These first 2 monoclonal antibodies have had very good phase 3 trials that have been published in higher impact journals where the regdanvimab sotrovimab.

Let's see now the mAb activity against the SARS-CoV-2 variance. It is here very interesting because as we said before, we are sometimes lagging behind the virus and not all antibodies have the same activity against all viruses. And for this reason, we really try to use mostly combinations therapy, for example Bamlanivimab alone as a single antibody is no longer used.

We use bamlanivimab and etesevimab. We use casirivimab and imdevimab. And we do think that maybe sotrovimab is effective also against the Delta variance. But it is important that we know what variants or the strains of SARS-CoV-2 that you have in your region, to be sure you can adapt and use the most effective mAb combination.

So this slide's picture the monoclonal antibody in trials for pre and post exposure prophylaxis. But this is quite interesting to note that contrary to many other viral diseases, including HIV and AIDS, for example, large trials to assess the efficacy of mAb where when given before the disease occur.

So what we would call mostly post-exposure prophylaxis have been conducted. In post-exposure prophylaxis, let's start on the right hand side of this slide. This is trial with exposed people, but who do not report... These people do not report any symptoms. But we would include people who would be at higher risk of getting a severe disease.

Try outs of post-exposure prophylaxis using monoclonal antibodies have reported reductions in infection, but also in disease progression. And in those getting the disease, the duration of high viral load was shorter. When used in pre-exposure prophylaxis, for example, in nursing homes, monoclonal antibody administration have shown lower viral load and faster clearance of SARS-CoV-2 among recipient of mAb, who then therefore become infected despite the treatment.

But this is interesting in that sense that it could even reduce the onward transmission. And therefore, it is easy to conceive situations in which SARS-CoV-2 mAb might be used to abort outbreaks for COVID-19 in some residential facilities, such as the nursing homes, but also jails, or we can really think about other residential issues.

So this is really interesting to know that we have something that is effective in pre-exposure prophylaxis, post-exposure prophylaxis, and even can have a sort of public health interest in containing an outbreak in this COVID-19 pandemic. So we've talked already about many challenges that we need to overcome.

These challenges are from the large scale production of not an easy product to manufacture, the route of administration. Most of the monoclonal antibodies that are available right now are still I.V. administration. We will have probably, IM. We will have also subcutaneous monoclonal antibodies, but all of these requires some health service to provide this monoclonal antibodies.

Cost of course, is an issue. There may be some unwanted effects related to the potential of the dependent activity of the antibody. And of course, as I said before, we need to ensure that the monoclonal antibody combination that you choose in your setting is effective against the variants that you have in your setting.

So a lot of things that you have to take into account when you want to effectively provide, effectively and safely provide COVID-19 monoclonal antibodies.

For the clinical trial data, quite compelling if you think that maybe a year ago we did not think that we would have specific biological therapy targeting SARS-CoV-2. I mean, it's really something amazing. We don't have so many of these monoclonal antibody in infectious disease field that have been developed in less than a year. So the clinical data, we will review first the results from the post exposure prophylaxis.

And so the combination of casirivimab and imdevimab reduced by 81% the occurrence of a SARS-CoV-2 infection among healthy subjects who were enrolled within 96 hours after a household contact using an interesting subcutaneous single administration of a total dose of 1,200 milligrams.

This is for the first part of the post exposure prophylaxis clinical trials. We already discussed very quickly before about the nursing home issue. And this is the BLAZE-2 trial using a single administration of a single monoclonal antibody, the bamlanivimab. So the preventive potential of a single dose of bamlanivimab was assessed in resident and staff of nursing and living facilities in the United States.

The index case was tested SARS-CoV-2 positive within the last 7 days, then residents and staff of this facility were all eligible regardless of their own health status. And the overall prevention population, which means those who tested SARS-CoV-2 negative at baseline, bamlanivimab alone as a single monoclonal antibody significantly reduced the incidence of mild or worst disease compared with placebo.

Which is really very interesting, but we have to keep in mind today bamlanivimab monotherapy is not recommended for the treatment of COVID-19 mostly based on the new variant for which by bamlanivimab alone would not have sufficient activity. Let's move on now to the results for clinical trial, assessing the treatment in outpatient.

We have here several trial that have been done in phase 3. The first 2 rows here report data that have been published in very good journals, New England Journal of Medicine. So this is the BLAZE-1 study and the REGN-COV2 study.

Overall, I mean, what I think is quite surprising and interesting in all of these trial, that overall the phase 3 trials of all of these monoclonal antibodies have shown relatively similar reduction of around 70, 80% in hospitalization rate when monoclonal antibodies were provided early enough after symptom onset.

And all eligible patients in those trials have risk factors for disease progression. And we will see that not everyone had the same risk factors, but overall, what is important to say that it is not a universal treatment. It's really a treatment for those who need, and for those who are at risk of disease progression.

With really similar results, and so you see the first 2 ones were published already in the New England, the COMET-ICE phase 3 trial has not been published yet, and we have 3 other monoclonal antibodies. So we don't have peer reviewed report or not even manuscript that are able to inform us a little bit more about the eligibility criteria, et cetera.

But here again, what you see is similar, 70% or so reduction versus placebo in hospitalization and deaths. Mostly I would say the primary endpoint is reached because of the reduction of hospitalization rather than reduction of deaths. Because there were very few deaths, and we're happy for that, in most of these phase 3 trials.

So interesting data with very similar endpoint, very similar design across all of this mAb. And we have now 6 combinations that have reached the phase 3 showing meaningful reduction on hospitalization rates. And this is the results of the recovery trial.

This is the platform from the UK, the recovery trial platform that has tested a very high dose of monoclonal antibody, casirivimab, imdevimab, in patients who were hospitalized with several negative status. Meaning that either they came in the hospital relatively early in their disease course, despite the fact they were hospitalized and there were several negative.

Or there were several negative because they had other conditions that prevent them to elicit antibodies. But in this study, the seronegative versus seropositive status was not known at baseline. So it's only in a prespecified endpoint. And at the end of the trial, what we see on the right is if you take all participants, the one seropositive and the ones seronegative, you see no effect whatsoever of the casirivimab, imdevimab combination compared with the use of care in this hospitalized patients.

However, if you now look at the seronegative patients versus the seropositive patients, then you see a very significant effect in favor to receive monoclonal antibodies in those who were seronegative at baseline at steady entry.

We have clinical trial for outpatients, trial that have consistently shown that there is a reduction in mortality and in hospitalization rate.

With that in mind, we can ask ourselves whether we can transpose to the real-world data what we have seen in clinical trial data. Of course, we know that RCT patients are not always the same as the patient from the real-world. Well, the efficacy results support efficacy observed in randomized control trial with administration relatively early at both 7 to 10 days post symptom onset.

So it is quite interesting to see that we can transpose the data from clinical trial to the real life. In addition, I think there were really... It's a bit of a pity that none of these RCT really included at-risk patients that were immunocompromised. We have very limited data on the use of monoclonal antibody in immunocompromised transplant patients.

We have here one study on a limited number of patients, 9 patients who were receiving casirivimab, imdevimab and finally they had the clinical outcome that was favorable in all patients with not only the relief of initial COVID-19 related symptoms within 2, 3 days, but also a rapid drop in viral RNA in 5 out of 9 of these patients.

But still, I would say that this data in immunocompromised transplant patients or immunocompromised even nosocomial patients, whatever the reason, are really important because it is one of the main target patients.

These are really our at-risk patients, and we need to know whether those patients, we're really capable of decreasing sufficiently the viral load to avoid also a viral escape on those patients due to the monoclonal antibody viral pressure.

The importance now is to define what is a high-risk patient. We can say that there are different definitions of what is a high-risk patients, first based on the country where you're living. So these are here, the definition of high-risk patients with COVID-19 in the US. But even more importantly, the high-risk patient depend also on what was high-risk definition in the clinical trials.

And this is where the real life differ very much from RCT. For example, in our practice here in Switzerland, what we define as a high-risk patient was not at all the same as what I can see here on the slides. For example, patient of any age with a BMI more than 25 BMI. I mean, it's probably half of the population, so it's not a very discriminant risk factor.

So certainly diabetes, chronic kidney disease, immunosuppressive disease, or current immunosuppressive therapy are very important high-risk factors that are probably part of many of the high-risk definition across different countries. Patients age more than 65 years. Well, for example, in Switzerland, we set the age at 80 as the sole risk factors.

Here also we can see differences, and you can see another set of high-risk definitions here with patients age more than 55 years. We schedule vascular disease or hypertension or chronic respiratory condition. Well, this is also a large number of patients. So indeed you may want to select your risk factor a little bit different.

On the right hand side of the slide, you can see the patients, the younger patient, the adolescent patient, either with a high BMI or sickle cell disease, congenital acquired heart disease, neurodevelopmental disorders, or asthma, reactive airway.

Well, for asthma, for example, we didn't define asthma as being a risk factor sufficient to receive mAb in our country, and also with the next slide that, yes, the definition of high-risk varies in Europe, varies in the US, varies across different country. But what is really constant is obesity, advanced age, whatever, how you decide to define advanced age, diabetes and immunosuppressant. So immunosuppressed patients are really important, as I said just before.

First, very rarely those patients were included in trials. So we have few data on those patients, but it is really the bulk of patients we see. University hospital, you may have a lot of patients on chemotherapy, rheumatology patients.

Unfortunately, you don't have so many data to support your choice and treat them with monoclonal antibodies. So this is maybe the main difference between the patients that you include in clinical trials and the patient that you have in your real life, in your university hospitals. So in summary, the monoclonal antibody do reduce the risk of disease progression in the hospitalization.

Their effectiveness is dependent on administration very early in the disease course, and as soon as possible after symptom onset. And in general, no later as 5 days. There may be some exceptions for immunosuppressed patients, for example, for which we can accept to provide monoclonal antibodies even after those 5 days. We expect that those patients will not do any antibody or any defense by themselves to protect themselves against COVID-19 course.

It is therefore important that not only patient, but also provide family doctors, gynecologists. Gynecologist are generally excluded of all of these training sessions, but they also need to be aware of how in your region, you can get mAb therapy quickly so that you can provide and inform your patients to get this therapy.

And of course, the attention must be paid to the patterns of emergence of variants of concern when selecting monoclonal antibody therapy. In addition to this, there are some logistical consideration for the mAb therapy infusion.

In the discussion before we previously reviewed some of this logistical consideration, but I would like here to summarize some of them. So we said that there was a chain and here, this is a cycle, but clearly it's the same. The physician, nurse practitioner, the trained nurse, the clinic, the pharmacist to prepare the administration, public health facilities who need to be aware that SARS-CoV-2 positive patient will go out of his house and come to a health facilities to receive the mAb.

And these health facilities cannot be the oncology cancer center for obvious reasons. So you have to think about where those patients will be directed, who will prescribe, who will prepare. And all the pharmacies will be able to prepare or only the university hospital, pharmacy, et cetera, et cetera. All of this has to be clear, and the algorithm will really vary from region to region, from hospital to hospital.

But the most important is to know and identify where exactly all these points have to be decided. Whatever, it is really a collaboration among a large inter-professional team. It is something that has to be taken very seriously that cannot be organized in 2 minutes in a corner Friday night. So the administration, we already talked about the administration.

Well, most of the time it is an IV administration that needs 30 to 60 minutes infusion for some of these antibodies. There is even a 90-minute infusion time. And in addition of that, you need to have a surveillance of around 30 or 60 minutes, depending on the patients.

So clearly you need time, and depending on your setting, you may not be able to provide monoclonal antibody to 15 patients per day, because you may not have sufficient space, sufficient nurses, et cetera. So hence the discussion on whether you need to decentralize or not, or all of this has to be taken into account.

But you need probably 2, 3 hours to have your patient in front of you when you decide that this patient is eligible to receive monoclonal antibody therapy. And this is not trivial. That is the reason why we're really happy if we can see newer mode of administration, including IM or subcutaneous administration of this mAb.

Even inhaled monoclonal antibodies are in development, which also is very interesting. So all of this will make the administration of this kind of therapy much easier over time. So this is a little bit of the same. I don't want to go back to all of these.

What I can say is that overall with the 100 or so patients to whom we have provided monoclonal antibody therapy, nearly 150, by the way, we haven't seen one anaphylaxis or one severe adverse events. Really, really it is extremely well tolerated. And this is the good news.

So the treatment facilities have to be organized.

They should allow rapid and safe administration to infected patients, but logistical considerations should be factored in one setting facilities to mAb therapies. We also need to employ strategies to optimize care in patients with COVID-19 while ensuring safety of non-infected patients, clinician, and staff.

So once again, you have to decide where you want to provide this therapy. It is really important, and conduct the appropriate follow for patient after the mAb infusion. And for some situation, for example, for patient with immunosuppression, you may want to control the PCR to see the SARS-CoV-2 viral load, even some days after the infusion.

There is the need for some patient, at least to have a follow-up by phone by the family doctor, even after the administration of the monoclonal antibody. So, what are the key take home messages here? What I would say is we have, for very little therapy, we have so much compelling important information from randomized clinical trials. The trial data suggest that this therapy is safe and can be used to prevent a worse course of the disease. So we do have really the evidence. It is not so easy to use. It really needs a large inter-professional participation.

And for that, I think it needs time and proper organization in each of the settings to be able to organize and to provide this monoclonal antibody therapy. So it is our responsibility probably to be sure we can give this monoclonal antibody. And also we have to think also in terms of costs and some people would not think that all the risk factors that are defined by the regulatory authorities are really the one that you can use in real life.

So this is a discussion to have with your colleagues and also with the scientific societies in your country or in your setting to know what is an at-risk patients for whom we would dedicate space, time and organization to safely receive monoclonal antibodies. And that will be my take home message.

We have to be organized. It works, but it has to be tailored to the needs according of your setting, your university hospitals, not university hospitals, and of course your region and country. Thank you very much.

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