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Cytokine-Targeted Therapy for Patients With COVID-19: From Guidelines to Latest Developments

  • Authors: Ivan O. Rosas, MD; Paolo A. Ascierto, MD; Puja Mehta, MD
  • CPD Released: 11/20/2020
  • Valid for credit through: 11/20/2021
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Target Audience and Goal Statement

This educational activity is intended for an international audience of non-US critical care specialists, rheumatologists, and ID/HIV specialists.

The goal of this activity is to educate physicians on the current guideline recommendations regarding the use of cytokine-targeted therapies for patients with coronavirus disease 2019 (COVID-19) and the most recent clinical trial outcomes data with these drugs.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Current understanding of COVID-19-associated hyperinflammation 
    • Current treatment guidelines for severe or critically ill patients with COVID-19 
    • Latest evidence from clinical trials with immunomodulatory therapies for patients with COVID-19 


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.


  • Ivan O. Rosas, MD

    Associate Professor of Medicine
    Harvard Medical School
    Boston, Massachusetts, United States


    Disclosure: Ivan O. Rosas, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb Company; Genentech, Inc.
    Received grants for clinical research from: Genentech, Inc.

  • Paolo A. Ascierto, MD

    Director, Melanoma Unit
    Cancer Immunotherapy and Innovative Therapy
    National Tumor Institute Fondazione G. Pascale
    Naples, Italy


    Disclosure: Paolo A. Ascierto, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Alkermes, Inc.; AstraZeneca Pharmaceuticals LP; Array; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb Company; Eisai Inc.; Idera; Immunocore; Incyte Corporation; Italfarmaco; MedImmune Inc.; Merck & Co., Inc.; Merck Serono; Nektar; Novartis Pharmaceuticals Corporation; Pierre Fabre; Regeneron Pharmaceuticals, Inc.; Roche-Genentech, Inc.; Sandoz; Sanofi; Sunpharma; Syndaz   
    Received grants for clinical research from: Array; Bristol Myers Squibb Company; Roche-Genentech, Inc.
    Owns stock, stock options, or bonds from: Primevax

  • Puja Mehta, MD

    Department of Rheumatology
    University College London Hospital
    London, United Kingdom


    Disclosure: Puja Mehta, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Sobi
    Received grants for clinical research from: GlaxoSmithKline


  • Shanthi Voorn, PhD

    Medical Education Director, WebMD Global, LLC


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

Content Reviewer

  • Robert Morris, PharmD

    Associate Director, Accreditation and Compliance


    Disclosure: Robert Morris, PharmD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: ViiV Healthcare
    Owns stock, stock options, or bonds from: GlaxoSmithKline

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 0.50 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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Cytokine-Targeted Therapy for Patients With COVID-19: From Guidelines to Latest Developments

Authors: Ivan O. Rosas, MD; Paolo A. Ascierto, MD; Puja Mehta, MDFaculty and Disclosures

CPD Released: 11/20/2020

Valid for credit through: 11/20/2021


Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. In order to facilitate disseminating this educational activity as quickly as possible, the associated slides and transcript will be included 1-2 weeks after the activity posting date.


Announcer (00:03):

This program is presented by Medscape Education Global.

Prof Ivan Rosas (00:08):

Hello, everyone. I want to introduce myself. My name is Ivan Rosas. I'm a professor and Section Chief at Pulmonary Critical Care Medicine, at Baylor College of Medicine in Houston. It's my pleasure to welcome everybody today. We almost have 200 folks in the audience right now.

Prof Ivan Rosas (00:26):

A great pleasure to actually introduce our panelists. First, I'm going to introduce Paolo Ascierto, who's a physician and the Director of the Melanoma Unit, Cancer Immunotherapy, and Innovative Therapy, from the National Tumor Institute of the Fondazione Pascale, which is in Naples, Italy. Welcome Paolo.

Prof Paolo Ascierto (00:45):

Thank you.

Prof Ivan Rosas (00:46):

I also have the pleasure of introducing on Puja Mehta, who's also a physician in the Department of Rheumatology at UCL, or University College London Hospital, in London. Welcome, Puja.

Dr Puja Mehta (00:58):

Hi there.

Prof Ivan Rosas (00:58):

Great. And I want to just give you a brief overview of what we're going to be talking about. Obviously this is a COVID-19 discussion, but we're really going to focus on the area of inflammation.

Prof Ivan Rosas (01:11):

We're very interested in discussing recent studies, suggesting how we treat patients with severe COVID pneumonia, and we're going to really focus on what's been proven, treatment guidelines are derived from this, but we also want to speculate a little bit about the future directions, in terms of the treatment of COVID-19.

Prof Ivan Rosas (01:27):

There's a number of questions that we've received already from the audience. We'll look forward to live questions from the audience, as well. So, in starting, let's just tackle the big question, Paolo. What is hyperinflammation?

Prof Paolo Ascierto (01:42):

So, hyperinflammation is a condition where there is an increase of immune system cells, and immune system cells can increase the production of cytokine. And for this reason, we know also that hyperinflammation is a cytokines storm, where the increase of the cytokine can give some symptoms and disease.

Prof Paolo Ascierto (02:06):

We know that there are some condition... familiar condition, like the hemophagocytosis lympho... hemophagocytic lymphohistiocytosis. We have also a secondary HLH to some condition like infection, sepsis, in some cases of malignancies. Just two, couple of weeks ago, I got HLH from a patient's on [inaudible 00:02:33] checkpoint inhibitors.

Prof Paolo Ascierto (02:35):

And looking to the cytokine storm, in COVID 19, we have a cytokine storm, and even some condition related to cancer and more familiar with these like the CAR T-cell, the bi-specific antibody, or as I told you, the immune-related adverse event from checkpoint inhibitors.

Prof Ivan Rosas (02:51):

Sure. So, it seems to me, what you just said, is that we can actually make correlations between COVID-19 and other conditions, but Puja, in terms of our present understanding of the course of the illness of patients with COVID-19, let's put that in the context of hyperinflammation.

Dr Puja Mehta (03:06):

Sure. So, fast as important to recognize that most patients with COVID 19 will recover and do well, but in some patients, it appears to be a biphasic illness. And this is a very beautiful study schematic that you may have seen a lot. It's promiscuous.

Dr Puja Mehta (03:22):

It's made its rounds in many presentations, because it so elegantly defines this biphasic initial viral response phase, with an overlapping host inflammatory response, where an overexuberant, excessive, inappropriate immune system response, results in inflammation. And it's these patients we think may benefit from immunomodulatory strategies.

Prof Ivan Rosas (03:42):

Great. So Paolo, can you to tell us some of the markers of inflammation that we've seen in this COVID-19 population?

Prof Paolo Ascierto (03:57):

Yeah, sure. There are some clinical features and also laboratory features. The fever for sure is one of the most important characteristic. We know also the fever is one of the side effects from the treatment with the IL-2 that we used years ago. And today we have also some [inaudible 00:04:16] in the field of cancer.

Prof Paolo Ascierto (04:19):

But we have also some other laboratory issue, like anemia, thrombocytopenia neutropenia, but for sure, the increase of the ferritin in the CD25, IL-6, may be also important. And if you want a definition about the hyperinflammation COVID-19, for sure, looking to the C-reactive protein, the IL-6, there is a correlation between these two molecules, because IL-6 can to affect the increase of CRP. The increase of this, and also the doubling in 24 hours, is something that is related to hyperinflammation, as well as, also, as I told you, the increase of the ferritin.

Prof Ivan Rosas (05:09):

Right. That suggest to me that there is a lot of observational studies that highlighted both clinical and molecular criteria, and actually used to define these populations, but there's so much of this data coming up. Puja, how do you think we should actually standardize this information?

Dr Puja Mehta (05:27):

Well, it's really important that we try to predict patients, who are likely to benefit from immunomodulatory strategies, and minimize harm in those who may not benefit. And therefore, it's quite important, in order to identify patients who have this hyperinflammatory phenotype, and this study recently published in the Lancet Rheumatology, is the first validated criteria for hyperinflammation in COVID-19.

Dr Puja Mehta (05:50):

Looking at clinical, as well as laboratory outcome markers, fever, ferritin, which is now a routine measurement in COVID-19 patients hospitalized, probably wasn't before, but now probably is. We have the full blood count, D-dimer, liver function tests, as well as more specialized tests, perhaps only available in specialist centers, like the IL-6 and triglycerides, and this may allow prognostic enrichment in future clinical trials.

Prof Ivan Rosas (06:19):

Right. So Paolo, I actually have this sense that at the beginning of the epidemic, when I was reading papers in March, we were all excited about this hyperinflammation. And I don't know if appropriate or not, with terming this as cytokine release syndrome.

Prof Ivan Rosas (06:33):

It seems to be a very specific condition, that we're seeing a subpopulation of patients that are treated for cancer. Tell us about your experience about the CRS and CAR T-cell therapy, which I think is actually a very well-defined?

Prof Paolo Ascierto (06:45):

Yeah. You are right, Because hematologist and oncologist knows very well the cytokine release syndrome disease, or the most frequent adverse event from the CAR T-cell treatment. And not only because I also studied some bi-specific antibody that are some side effects similar to the CAR T-cell and this is... Sometimes I like treating adverse, right?

Prof Paolo Ascierto (07:17):

And now we know that the cytokine storm, we can see in the level of patients treated with CAR T-cell, very high level of IL-6, that is one of the most important cytokine related to this syndrome. And I have to say that anti IL-6, do they change it also, the recovering from this condition, and that this condition are the most important symptoms, is the hypovolemic shock.

Prof Paolo Ascierto (07:45):

And also we have respiratory distress, similar to that we are seeing in the COVID-19. So, in this condition, this high production of cytokine from the T-cell from the CAR-T, okay? Is able to produce this life-threatening condition and anti-IL-6 are really useful, in order to recover from this.

Prof Ivan Rosas (08:12):

Thanks, Paolo. So, pulmonologists should not be talking about hyperinflammation in the presence of a rheumatologist, but let me just put myself out there. So, the way I see this, is that we really have a very broad armamentarium to treat inflammation.

Prof Ivan Rosas (08:30):

This has been developed probably over the last 20 years, and particularly monoclonal antibodies are going to allow us target-specific molecular targets. And so, I think in my mind, corticosteroids are this big hammer that affect many cell populations, that are in charge of the immune response. And also specifically, the production of the cytokines. At least that's what the observations would show, but that would be a broad approach.

Prof Ivan Rosas (08:51):

We can go to more specific approaches, in which we could target, for example, GM-CSF, that protein was described so long ago and has been targeted in other instances in different conditions, or IL-1 beta, which is also something that's been described for decades, and also have been tried to target in a specific format.

Prof Ivan Rosas (09:12):

And the big player here obviously is CNF, right? Particularly in rheumatology, it changed the life of many people, thousands of people were affected from these inflammatory disorders. But more recently, we actually saw the integration of numerous cytokines that are involved in disease. Like IL-17, IL-23, or even second messengers, like the JAK inhibitor therapies.

Prof Ivan Rosas (09:33):

And so, it seems like we have these broad approaches, or we have these more specific approaches, in order to actually be able to treat this disease. And I think in that context, I like to discuss the actual evidence that is present right now, for the use of these treatments.

Prof Ivan Rosas (09:51):

And so, Puja, tell us about this tremendously impactful study, that was developed in the UK. It was very impressive, how quickly the whole country got together, to decide to do this very impressive adaptive trial and come up with a therapy that's very inexpensive, readily accessible, and the only one that's actually shown us to impact mortality. So, we'd like to know more about the specifics of the recovery spec.

Dr Puja Mehta (10:19):

Oh, absolutely. And I hold them for [inaudible 00:10:22], very impressive, a large study. This is an unblinded adaptive trial, looking at hospitalized patients who've proven or suspected COVID, who were randomized in a two-to-one to one-to-one fashion, to no additional treatment.

Dr Puja Mehta (10:36):

So, usual care. Lopinavir-Ritonovir, dexamethasone six milligrams once daily, either orally or intravenously for 10 days. Hydroxychloroquine, which we're not going to talk about today. Azithromycin, and there's also a second randomization, the convalescent plasma, and Tocilizumab, where there's a stratification parameter of the CRP of 75, as well as hypoxia. And the Tocilizumab arm of recovery, the data is eagerly anticipated.

Dr Puja Mehta (11:03):

The primary end points was all cause mortality. And here we have the dexamethasone results, which were very important. So, dexamethasone at a dose of six milligrams per day, given for 10 days, reduced the 28 day mortality in patients with severe COVID-19.

Dr Puja Mehta (11:21):

And the effect was best demonstrated in mechanically ventilated patients, with an NNT of eight, but also apparent in patients needing oxygen therapy with an NNT of 25. So, those patients who had a requirement for supplemental oxygen, or mechanical ventilation. It's really important to note that it doesn't look to be helpful and may actually be harmful in patients not requiring mechanical ventilation or oxygen therapy, and is likely to be more helpful if started at greater than seven days after symptom onset.

Dr Puja Mehta (11:52):

So, this is really important just as you said, shows a definite improval in mortality and it's cheap as chips. So very, very important.

Prof Ivan Rosas (12:03):

Right. And actually, I think this is a real important contribution for the field. I'm very impressed again, by how it was done, but there were other groups in other places in the world, that were thinking about steroids as well, for the obvious reasons that we transpired before.

Prof Ivan Rosas (12:20):

So, what about the other steroids that are available?

Dr Puja Mehta (12:24):

So, now we're moving on to REMAP-CAP, which is a platform study, looking at patients in intensive care, who required respiratory cardiovascular support. And they used intravenous hydrocortisone.

Dr Puja Mehta (12:36):

Patients are randomized to either fixed dose, or shock dependent, or no hydrocortisone groups. And here we have an almost independent validation of the concept of using steroids. Treatment with a seven day course of hydrocortisone, resulted in 93% or 80% probabilities of superiority, with regard to the odds of improvement in organ support-free days within 21 days.

Dr Puja Mehta (12:57):

It is important to note, however, that after the recovery trial was published, the hydrocortisone arm of REMAP-CAP was rightfully stopped. It was stopped early, and that statistical significance was not reached, but this really does hit home. That steroids in selected patients, who have severe COVID-19 requiring supplemental oxygen, who are critically ill, unwell in hospital, should be treated with steroids.

Dr Puja Mehta (13:22):

I'm going to move us on to the meta-analysis of seven randomized control trials of about 1,700 patients across five continents. And you're not supposed to be able to read the details of these slides, but essentially administration of corticosteroids was associated with a lower, all caused mortality at 28 days after randomization. And based on this, the World Health Organization produced guidance for corticosteroids in COVID-19, recommending corticosteroids with the treatment of patients with severe and critical COVID-19, and discouraging corticosteroids in the treatment of patients with non-severe COVID-19.

Dr Puja Mehta (14:00):

We therefore do have a recommendation with a semi-stratification of patients by severity.

Prof Ivan Rosas (14:07):

Right. I mean, again, the importance of these findings cannot be overstated. The consensus from many organizations, including the World Health Organization, the NIH in the United States, and obviously this study was performed in the UK. So, this has been adopted, and I know in Italy we're doing the same thing.

Prof Ivan Rosas (14:24):

So, this is a worldwide approach. It's without a doubt, one of the most important contributions today. Is this the end of the story? Is this where this all ends? And so, Paolo, tell us a little bit more about, as I did in the preamble, telling you about more specific approaches, what about targeted therapy? And I want you to talk about IL-6, because there's a lot of data, but if you can make comments about other cytokine approaches, if you're interested at this point.

Prof Paolo Ascierto (14:49):

Yeah. So, we got some interesting data from the autopsy that came from the China, during the first wave in China with the COVID-19 pandemic, and in the lungs of the patients who died for the COVID-19, it was found an increase of macrophages.

Prof Paolo Ascierto (15:11):

So, [inaudible 00:15:11] immunity, even some TSS, but it was also found an increase of IL-6 that's defined the importance of the increase over the production of the cytokine, and testifying the possible cytokines storm. So, IL-6 is for sure, one of the important cytokine creating the respiratory distress. And for this reason, the usage of an anti-IL-6 at the beginning of the story was largely involved in the treatment of COVID-19 pneumonia. And we have some data here, the third controverts that data, we have some positive data and some negative data.

Prof Paolo Ascierto (15:54):

This is a retrospective analysis. We had to stop COVID-19 and evaluated about 4,000 patients, and of this 4,000 patients, 432 patients were treated with Tocilizumab. And that the patients treated with TOCI, get a lower risk of death, compared to the patients who not were treated with Tocilizumab. And of course, this study has all the limitations of a retrospective analysis.

Prof Paolo Ascierto (16:20):

There was another positive study, TOCIVID-19. It is an Italian study. A study that we did at the beginning of our first wave here in Italy in March. The study, enroll the patients on the 19th of March, and we are enrolling the 330 patients in 20 hours, just in order to give you an idea about how was real important problem at the time. The study was a phase two trial in patients with severe COVID pneumonia, and here you can see the inclusion criteria.

Prof Paolo Ascierto (16:53):

And we had also... Part of the cohort of patients we didn't enter in the inclusion criteria for the TOCIVID-19, because one of the criteria for instance was, the patient should be [inaudible 00:17:06] for less than 24 hours. For all the other patients, we use the prospective course, but here, the main point was the mortality rate at two weeks and one month. And if we look the data two weeks were not positive, but if you look at the data at one month was positive, because the study was designed to find that 10% of reduction of the mortality rate at four months. At that time, the data that we got from our nationalistic [inaudible 00:17:45] was 35%, a one month mortality rate that is higher compared to the other, but this was the rate.

Prof Paolo Ascierto (17:51):

And as you can see here in the TOCIVID-19, the one month mortality rate was 22%. So, more than 10%. For these reasons we can consider positive, but this was not a randomized trial. Looking to some randomized trial impact, there was a randomized trial in patients with treated with all the other therapy that we know, and Tocilizumab was added, was randomized in two-to-one. And the patients that enrolled were about 79, and 85% of patients had... already with patients with... from a minority racial and ethnic group. But, the patients treated with Tocilizumab, got a better outcome. And, the treatment was able to reduce the risk of mechanical ventilation or, deaths of 44%.

Prof Paolo Ascierto (18:50):

If you look at the ratio from the [cool 00:18:52] was 0.56 and also the median time to clinical failure was better than the patients treated with Tocilizumab.

Prof Paolo Ascierto (19:02):

And another phase III trial was the COVACTA. The COVACTA... the inclusion criteria of COVACTA were similar to the inclusion criteria from TOCIVID-19. The study was randomized, Tocilizumab to the classical, dose injecting, general we use in the CAR T-cell cytokine release syndrome adverse, right? Eight milligrams per kilograms. But the study was negative, because it didn't meet the primary end point. It was the difference in the clinical status between the seven category ordinal scale, and also no difference with the mortality rate at four months between the two group, placebo and tocilizumab. Just the time to hospital, this change was better, and shortened, the patients treated with Tocilizumab.

Prof Paolo Ascierto (19:51):

Another negative study was the ((BACC)) Bay Tocilizumab trial. This was a trial, still randomized, double-blind. Not in patients with similar COVID-19 pneumonia, but in patients with moderate pneumonia. And as you can see here, the trial was negative, because no improvement in patients treated with Tocilizumab. These results were similar in other Italian study with the same setting of patients. So, the patients with mild or moderate COVID-19 pneumonia, and so Tocilizumab seems to not be good [improvement 00:20:31] the cytokine storm, because in the patients with mild and moderate symptoms and pneumonia, probably there is not the cytokine storm that could be targeted by this compound.

Prof Ivan Rosas (20:47):

So Paolo, it seems like you've now confused all the 300 audience that we have, because [crosstalk 00:20:51] that in some studies it's positive, in other studies it's negative. I have the observation that when I compare it to RECOVERY, it's a very small side study. So Puja, how do we put this all together? I mean, does it work? Who does it work in? What's the answer here?

Dr Puja Mehta (21:10):

So tricky, the future's not looking bright for anti-IL-6 located in COVID-19. We still have the RECOVERY of which is eagerly anticipated, but so far it's not looking great. But before we delve into the data, which we already have, really, I just want to take a step back.

Dr Puja Mehta (21:27):

Now, IL-6 gained a lot of popularity and attention at the beginning of the pandemic, but this was more a relationship of convenience, rather than hypothesized advantage of blocking this cytokine over the others. Tocilizumab was available in China. It made its way into treatment guidelines in China, as well as Italy. IL-6 is easy to measure, whereas IL-1, for example, is not. And therefore, perhaps this gained a lot of popularity for the wrong reasons. I'm not saying that it shouldn't have been explored. Absolutely it should, but so far, the evidence is not great.

Dr Puja Mehta (22:04):

IL-6 blockade has some benefits, in terms of indirect comparisons between the different trials, because the treatment on those [inaudible 00:22:13] regimen is quite standardized. Even with sarilumab, for example, it's a one single shot which can be repeated intravenously, and therefore it's easier to compare, but there are differences between the studies that this very nice table demonstrates. Some studies were retrospective, some were prospective. Some were randomized, some observational. The participant numbers are variable between the studies, the outcome measures were different, the severity is different. But overall, as Paolo has just very nicely demonstrated... it doesn't look great.

Prof Ivan Rosas (22:47):

Okay. And so, does that actually help us anyway, in terms of interpreting broader design of studies, or how does this actually educate us on how we should be interpreting these studies?

Dr Puja Mehta (22:59):

Yes, absolutely. So, it's really complex. It's not easy just to read the headline, or the abstract, to see if the trial is positive or negative, because for example, with one of the sarilumab studies, the primary endpoint was a change in CRP, which is a mechanistic effect of the drug. So rather than just, is it positive? Is it negative? We really need to think about this deeply, which is why it's so good to have these meetings, where we can discuss amongst ourselves and amongst the audience, to determine whether this truly is a beneficial outcome or not.

Dr Puja Mehta (23:30):

Now, I think it's easiest to, again, step back, go back to basics, looking at our PICO model of population, intervention, comparison, and outcome. What is the patient population? Are the patients hypoxic? Are they hospitalized? Have we stratified for hyperinflammation, have we not? Are there any stratification parameters at all?

Dr Puja Mehta (23:50):

The intervention itself... We just talked about Tocilizumab and anti-IL-6, the dosing regimen, the dosing strategies, the route of administration, more standardized with an anti-IL-6, but less so with anakinra, which we'll come to shortly. The timing of intervention is really important. And this is a schematic that we created for a recent review, where there may be a sweet spot, a window of opportunity. Perhaps if we intervene too early in the viral phase that we saw in the earlier slide, that may be harmful. If we intervene too late, perhaps the patient's already tipped over into an unsalvageable state. We don't actually know what is the comparator.

Dr Puja Mehta (24:30):

We talk about standard of care, but is it really standard? What is standard of care now, and what was it before? We have dexamethasone and steroid availability now, as standard of care, which we didn't at the beginning of the pandemic, but also Remdesivir, which is beyond the scope of this study, or presentation, as well as ventilatory strategies, pruning our standard of care. Nursing, our ability to care for patients.

Dr Puja Mehta (24:59):

And our clinical practice really is, or are our priors, in a bayesian approach. And the outcomes, are we looking at hard outcomes of mortality? Is it changes in ventilatory support? What are the outcomes? And it's very, very difficult to interpret clinical studies, if we haven't considered all of the different factors that we just discussed.

Prof Ivan Rosas (25:19):

Oh, that's great. I mean, I think that really highlights some of the problems, or challenges, that you have moving forward. And it seems to me that what you're saying is, that there's not only probably a heterogeneity in the population that we study, but more importantly, there's a heterogeneity on the study design and limitations on interpreting, when we actually have additional intervention. So, many factors to key in.

Prof Ivan Rosas (25:42):

So, with that in mind, I'd like to ask you to speculate about the other cytokines studies, because I realize one of the problems we have with Tocilizumab, is that we went from thousands of patients, to hundreds of patients, and now we're actually talking about 20, 40 patients. So, let's talk a little bit about these other cytokines, acknowledging that limitation.

Dr Puja Mehta (26:06):

Absolutely. So, let's go to IL-1 blockade firstly. We have two cohort studies retrospective, one prospective from France and Italy, small numbers, 29 patients, 52 patients, historical controls, rather than a randomized control study, but those studies do show some efficacy signals, which is interesting, it's promising, but we do need randomized control trial data.

Dr Puja Mehta (26:28):

There are randomized control trials, and you're not supposed to be able to see this slide and it'd be very impressive if you've can, but this very nice paper from the Lancet Respiratory magazine... Lancet Rheumatology, I should say, describes the different clinical trials, using anakinra in COVID-19, and shows the disparity and heterogeneity of trials focusing particularly on the dose of anakinra use, which can be widely variable between the trials, the duration. Some studies have treated for seven days, other for up to 15 days, and the route of administration, which is such a key parameter when dealing with anakinra, we recently published a viewpoint in the Lancet Rheumatology, looking at intravenous anakinra.

Dr Puja Mehta (27:15):

And the Cmax, you can see here, is achieved far faster, using intravenous anakinra. The maximal plasma concentration, compared with subcutaneous. So, the bioavailability, the pharmacokinetics really important here, particularly with critical illness where patients may have purported poor peripheral absorption.

Dr Puja Mehta (27:34):

Let's move on to GM-CSF. Now, GM-CSF is complex. And I think GM-CSF itself very elegantly displays the complexity of COVID-19. GM-CSF is a pro-inflammatory cytokine Ivan, that you mentioned right at the beginning, has been used historically, or has been studied in clinical phase for rheumatoid arthritis, cytokine release syndrome, post CAR T-cell therapy.

Dr Puja Mehta (27:58):

And there are multiple trials, at least six different companies, looking at GM-CSF blockade in COVID-19. Pro-inflammatory cytokine involved in ARDS recruitment of neutrophils, and looking at maybe a benefit in COVID-19. However, intriguingly the flip side is, that it has a very important role in antiviral immunity and host defense homeostasis. And there is a trial administering recombinant inhaled GM-CSF to patients with COVID-19, as well.

Dr Puja Mehta (28:31):

So, this is really confusing, in terms of do we block, or do we administer? We recently published this viewpoint expressing and describing the complexity of the dilemma. And until we have randomized control trial data, we are none the wiser, that there is some suggestion of benefit, a single center prospective cohort study from Italy, De Luca and Lorenza [Daniel's 00:28:56] study, which looked at Mavrilinumab, which is an anti GM-CSF receptor monoclonal antibody, 13 patients, but a nice signal of survival benefit in the Mavrilinumab-group, compared to the control group. So again, we need to take all of these observational studies with a pinch of salt, but it's promising and we await the randomized control trials with interest.

Prof Ivan Rosas (29:20):

Yeah. So, I suggest that we actually go to... take all this information that you've given us something at first sight can purchase. And I'm very impressed by how the UK manages the healthcare system, but more impressed on how it's been leveraged, to do these very complex study design. Tell us a little bit about the UK? How are you actually managing the hospitalized patients then, and how does all the information you've provided us, help you deal with the pandemic?

Dr Puja Mehta (29:51):

So, this is a nice algorithm that's been produced for the coronavirus therapeutics advisory group, of which I'm a member. And here we have patients who are adults, hospitalized with proven or suspected COVID-19. If they have a critical or a severe illness, then dexamethasone as recommended by the World Health Organization. If they are eligible for Remdesivir, they'll be given that. And if they're eligible for a clinical trial, they'll be entered into that.

Dr Puja Mehta (30:15):

Now, it's really important to mention here, that the UK has a very fun stance. The CMO, the chief medical officer, has stipulated that all patients should be assessed for trial eligibility. And there is no use of "compassionate" in inverted commas of monoclonal antibodies outside of clinical trials. And that's really important, because we do need to accumulate data, and therefore clinical trials are absolutely of paramount importance.

Prof Ivan Rosas (30:45):

So, you agree with me that there's a bottom line today? There is actually something that we can take home today. So, what do you think that is?

Dr Puja Mehta (30:51):

So, the take home message is that right now, as we stand, dexamethasone is the standard of care for severe or critical COVID-19 patients, and targeted anti-cytokine therapies, or selective cytokine blockade, small molecules, like JAK inhibitors, should only be used in a clinical trial setting only.

Prof Ivan Rosas (31:08):

Yeah. But I think we have to actually acknowledge, that we either have to design other studies, and we have to actually be thoughtful of how about these waves are giving us an opportunity to test some of the less proven therapies. We have to think about how we better use these biomarkers that both of you have been describing.

Prof Ivan Rosas (31:29):

And then, I think one of the things that I'm very interested to hear from both of you, is what's next, in terms of including other treatments that we haven't discussed today, and may be effective, like antivirals? Well, let's start with this topic of biomarkers. So Paolo, how can that help us design and interpret the study?

Prof Paolo Ascierto (31:47):

So biomarker, I believe are crucial, like in all the other field of the medicine. We publish there is more experience with Sarilumab given Sub-Q. At the time we had some problems with the drug supply for this reason. We used it Sub-Q and we treated 15 patients up. And what we have seen in the patients who responded to sarilumab, it is another anti-IL-6, compared to patients who are not, looking to the baseline IL-6 level, the IL-6 level high in all the patients, but were not so high in the patients who responded well, like were more high than the patients who not. And probably in the last group there was already damage of the tissue. And for this reason, probably I didn't see, was not able to recover.

Prof Paolo Ascierto (32:46):

But look into [Berakah 00:32:47]. What is also important is the C-reactive protein, because in the responder, as you can see here in this slide, the blue are the patients who respond, compared to right, who not, within three, five days became normal. And also the neutrophil lymphocyte ratio was another interest in biomarker, who became normal in a few days in the responder, not in the responder, the eosinophils increased in the responder. And probably one of the key that is important to know, that to better interpret the data, is to evaluate the baseline level of IL-6 and CRP in the patients, to see if really the patients with the cytokine storm correspond to anti-IL-6.

Prof Ivan Rosas (33:37):

I think there's many examples of how try to find populations with molecular markers has led to identifying the subpopulations of benefit from one therapy to another. And I think you're telling us is that we have to get smarter about how we designed the study. The other thing that I think is really important to acknowledge, is that there is an ion... there's a virus causing this infection and potentially treating the virus, is affected. And, I acknowledge that there are some contradictory findings in recent trials, supporting the use of Remdesivir and not supporting the use of Remdesivir. I think we're already in it, meaning that we're already using these anti-virals, in combination with the anti-inflammatories there.

Prof Ivan Rosas (34:15):

So, we don't have a lot of time to get into this, but just to your point, Paolo, I think that stratifying these populations and these combination algorithms, may require some of the molecular approaches that you have kindly described to us.

Prof Ivan Rosas (34:30):

So, but this has been a very exciting discussion and we don't have more time, but I'm going to basically say that the take-home message is that right now we have a treatment option for patients who actually have severe disease, and Puja very clearly made a statement that dexamethasone is the standard of care. And this is something that we should all be very happy and you Puja, should be very proud of the results of the RECOVERY study that [inaudible 00:34:56] offering. But I think we also acknowledge that this is not the only therapy that we can have available and that we can have. We have to look more carefully at subpopulations of patients, maybe the timing of which we're giving these treatments could be really important, using some of Puja's concepts about how the timing of which some of these events occur.

Prof Ivan Rosas (35:16):

Could we time the use of IL-6 or other focused approaches, to benefit patients who are not intubated? And we could potentially prevent the intubation of the patients, as the impact that [inaudible 00:35:26] has suggested obviously more studies needed to actually survive... demonstrate this. But I think the bottom line is that, in order to be optimized as treatments, we're going to have to better understand the course of the disease, the so-called endotypes, the different markers that are probably outlining these different phenotypes, to be able to be smart about how we design the future studies. That's what I learned from with Paolo and Puja today. I really want to thank both of them for an energetic discussion. There's a lot of information here for themselves. They'll be presented in a very simple way. So, thank you both of you for joining us today.

Prof Ivan Rosas (36:02):

So, I know that the audience has questions. We still have almost 300 people on the line. So, why don't we actually think about answering some questions? I have some questions that I'd like to actually start with. So, the first one is, what about... and these were questions that we got from... obvious previously. So, are you concerned about thrombosis with JAK inhibitors and the question that we received are ruxolitinib safer than baricitinib?. So, tell us a little bit about the complications of therapies, is I think what this question refers to.

Dr Puja Mehta (36:40):

So, I might take that if that's okay? So, the JAK inhibitors have been purported as a potential strategy for COVID-19. They are oral agents with a rapid onset of action. Short half life, can be discontinued, and wash out fast. Certain JAK inhibitors, baricitinib, for example, may have a dual anti-inflammatory and antiviral activity, reducing or impairing viral endocytosis, viral entry into the cell.

Dr Puja Mehta (37:06):

And we know that severe COVID-19 is a pro-thrombotic state. Patients have microvascular thrombosis, there are thrombotic events. At autopsy, as well as on clinical screening with CDKs, and so on. And there is a worry with certain JAK inhibitors, several JAK inhibitors are licensed for rheumatoid arthritis for example, and have FDA black box warnings for venous and arterial thrombotic events, resulting in dose restrictions. But it's really important to recognize that it's not clear whether these presumed pro-thrombotic risks are dependent on JAC's activity, drugs specificity, dose, or treatment duration, or are confounded by indication.

Dr Puja Mehta (37:49):

And I stress the last point, because the question was about baricitinib and tofacitinib, but baricitinib, ruxolitinib, those JAK1, JAK2 inhibitors. Baricitinib is a drug that's been studied in rheumatoid arthritis. This BTE safety signal is airing its ugly head. Ruxolitinib in myeloproliferative neoplasms may potentially reduce thrombotic risk. However, we don't know what would happen if we took the same drug in the different populations, and in this new disease indication of COVID-19, and therefore it's actually inappropriate to extrapolate the safety signal, or the false reassurance to COVID-19. So, right now the safest thing to do is to exercise caution and hypervigilance towards potential increased pro-thrombotic risk with both JAK inhibitors in COVID-19, until we have data.

Prof Ivan Rosas (38:44):

Great. Thank you very much. And I have another great question, which is actually very, very complicated. So, it refers to the use of a ventilator and the potential relationship with this has followed with the cytokine release syndrome. So, is there any evidence that cytokine release syndrome is actually precipitated by some of the interventions that we use to treat these patients, and just as important, is the intensity of the cytokine release syndrome potentially related with long-term complications like fibrosis?

Prof Paolo Ascierto (39:15):

Yeah. This is an important topic. At the moment we have specific follow-up for these patients, because one of the main question, is if this fibrosis may be transience, or make an impact on the quality of life and maybe sometimes also poor mind. The question is interesting. At the moment, it seems that more than the cytokine storm could be the longer [inaudible 00:39:43], and the long time in the intensive care unit with the mechanical ventilation, that can have more an impact on the fibrosis, on the lung cancer. But, at the moment, as I told you, there are some study ongoing and I believe that we will have for the end of year, the six months follow-up consolidated that can give us more information about this.

Prof Ivan Rosas (40:09):

Puja, I know that a lot of your research is centered around the fibrotic responses associated through all immunity. So, what can you borrow from there, in terms of educating us, as to what's to be expected?

Dr Puja Mehta (40:24):

That's a fascinating question. At UCL Respiratory Health, we are doing researching, in both post COVID fibrosis, as well as other interstitial lung diseases. And this may be that COVID-19 is a model. We have a defined insult, a trigger, and therefore this could be a learning opportunity, in terms of pro-fibrotic or fibergenic mechanisms. But right now it's very difficult to know what the outcomes are. As Paolo said, does the fibrosis regress? Does it melt away? Why does it melt away in some patients and not in others? And there is a lot of data emerging all over the world about these patients, from [inaudible 00:41:00] studies, for example, as well.

Dr Puja Mehta (41:02):

And we're learning as we go along.

Prof Ivan Rosas (41:06):

So, I actually had... I saw a patient in clinic the other day, and the patient was a young clinician who... he was convinced he had COVID-19, and it was never demonstrated, but for discussion for another day. But what was really impressive was assuming that he's correct, if he had the infection, was the amount of complaints he had. It was a plethora of symptoms that he obviously did not previously have, because he was a healthy physician who would actually been able to describe the presence of disease, or disease manifestation facts.

Prof Ivan Rosas (41:39):

So, with this in mind, with this as a really scary example of what this disease could do, how do you think intervention at the early stages could prevent some of these long-term manifestations of disease that we are seeing, and what are these disease manifestations that we should be expecting?

Dr Puja Mehta (41:56):

So, there is a lot of accumulating data about long COVID or so-called lung COVID patients, who have considerable morbidity after COVID-19 suspected or confirmed, with a wide array of manifestations affecting nearly every organ system. Right now, we don't know enough about which patients may develop long COVID, and whether early intervention with which strategies may prevent it.

Dr Puja Mehta (42:25):

There's been a lot of talk about steroids, which we've contributed to tonight and it may not necessarily be protective for COVID-19. In rheumatology, we have a global rheumatology alliance, where rheumatologists all over the world have been inputting data into a registry. And the initial results reports have shown that patients on 10 milligrams, or more, of prednisolone may have poorer outcomes, if they acquire COVID-19. So, it's not a straightforward steroids protect. And even the recovery trial that we looked at earlier on, has shown there may be a suggestion of [inaudible 00:43:03] in patients who do not require supplemental oxygen.

Dr Puja Mehta (43:06):

And so, it's not straightforward. We don't really know right now.

Prof Ivan Rosas (43:11):

Right. And one last question, I think we have a couple of minutes to wrap up. Paolo, so, we're seeing so many divergent practices throughout the world. And so, one of the folks in the audience has asked us that there are studies, and not studies... that there is a practice of combining bevacizumab with Tocilizumab and Remdesivir. So, let's just make it more generic.

Prof Ivan Rosas (43:36):

So, what about these anecdotal data suggesting that combinations of different therapies, like monoclonal antibodies in combination with Remdesivir, is an effective way to treat the patients? And my question is directed to, should we be doing that? And second, is the data out there for us to actually evaluate it critically? And both of you did today.

Prof Paolo Ascierto (43:57):

So, I fully agree with you that combination therapy will be the key there, to improve the treatment and to increase the number of patients, who can get a benefit from this treatment. But this is the first time that I'm hearing a combination with bevacizumab, that is an anti-VEGF, which [inaudible 00:44:17] in general was... is used it in oncology, in combination with checkpoint inhibitors, in order to increase... we know the rest of the results of anti PD-L1 plus bevacizumab, inevitable cellular carcinoma.

Prof Paolo Ascierto (44:32):

So, I don't know the why and the reason of this combination, but for sure, to combine treatment, to use antiviral, to use... to target some key molecule in the pathogenesis over the respiratory distress may increase, as I already told you, the benefit of patients with a faster recovery.

Prof Ivan Rosas (44:57):

Well Paolo and Puja, it's been really a pleasure to spend these quick 45 minutes, going over a barrage of data that's available right now. We haven't even started touching the surface.

Prof Ivan Rosas (45:08):

I hope both of you agree that one of the things that we really need to be very grateful for, is a really strong commitment that the medical and scientific community have to develop therapies for this disease, and doing it in such a short time. It's really impressive to see how rapidly evolving we're seeing a discovery of mechanisms of disease and targeting specific in some of these mechanisms, as a true manifestation of where medicine rec, right?

Prof Ivan Rosas (45:32):

A lot of evidence-based, knowledge-based approaches to treating this disease. And hopefully we'll be able to make a difference, by studying and implementing these therapies. So again, I want to thank both of you for your energetic discussion, the sponsors of this presentation, and the audience that's really impressed with the 300 people that actually spec onto our conversation. So, thank you very much.

Dr Puja Mehta (45:57):

Thank you. And thank you to you too, Ivan.

Prof Paolo Ascierto (46:01):

Thank you. Bye-bye. Ciao.

Dr Puja Mehta (46:02):


Prof Ivan Rosas (46:02):


Announcer (46:06):

This program was presented by Medscape Education Global.

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