Hi, my name is Alexandra Barber. I'm a medical ICU clinical pharmacy specialist at Atrium Health Wake Forest Baptist Medical Center. Today, I'll be discussing immunomodulator management for the treatment of COVID-19. I do not have any disclosures for the content of this presentation. Key objectives for this presentation include identifying opportunities to target the inflammatory response in COVID-19 patients, assess primary literature and pharmacology of immunomodulators for the treatment of COVID-19, and finally, develop therapeutic recommendations for utilizing immunomodulator therapies for the treatment of COVID-19. To start, I want to review the SARS-CoV-2 immune response kinetics. My colleagues have already gone in-depth into the specific immunophenotype of SARS-CoV-2 infections. However, I want to relate that in this final part of our presentation to direct therapeutic agents that we can offer COVID-19 patients, and this is very key to our presentation today to identify at what points of our SARS-CoV-2 immune response kinetics may it be beneficial to use some of these immunomodulators, and which specific immunomodulators may be best for SARS-CoV-2. To start, stage one is incubation. For the first five days of symptoms, the virus is infecting pneumocytes, and there will be an initial release of cytokines and chemokines. However, there won't be any large-scale inflammatory response as of yet. Some immune cells will infiltrate the lungs, but patients are largely not symptomatic at this point as they don't have that large immune response. As compared to stage two, when patients around five days after the initial exposure will have substantial symptoms, and so this is day zero to seven, at this point, they'll have those symptoms because of the increased levels of pro-inflammatory cytokines, as well as large quantities of immune cells infiltrating the lungs, especially the alveolar space, with monocytes, macrophages, and T-cells. On the later end of stage two, right around the seven-day point, some antibody titers against SARS-CoV-2 will also start to increase. At stage three, which is around beyond seven days, at this point, patients really meet the Berlin criteria for acute respiratory distress syndrome, or ARDS, as they have persistently high levels of pro-inflammatory cytokines. They have increased immune cell infiltration in the lungs with macrophages and lymphocytes. However, at this point, they're going to have an ineffective T-cell response due to the widespread lymphopenia and T-cell exhaustion. Severe alveolar damage will impair their ability to oxygenate, and this is largely due to neutrophilic and lymphocytic infiltration. At the late end of this stage, widespread lung fibrosis results, which is largely irreversible, and there aren't really any therapies in order to reduce that lung fibrosis that occurs. Really identifying and understanding each of these stages will help us further evaluate the primary literature surrounding immunomodulator therapy for COVID-19, as it can be argued that there's inflammation at some points in these stages, as well as a need to clear the virus at other points that are more important compared to dampening down the immune system. We will explore that as we go through landmark trials for immunomodulators in the treatment of COVID-19. The first immunomodulator we will discuss are steroids. The recovery trial brought steroids to the forefront of COVID-19 treatment based on the recovery trial. It was a multicenter, randomized, controlled, open-label adaptive platform trial. It included adult patients with clinically suspected or confirmed SARS-CoV-2 infection for hospitalized patients. Patients were randomized to 6 milligrams of dexamethasone for 10 days versus usual care, and the primary outcome was 28-day mortality. Looking at patients included in this trial, the average age was around 66. There was a median day since symptom onset to randomization of around 8 days in both groups, as well as a median hospitalization time of 2 days prior to randomization. Looking at respiratory support received, just around 24% of patients did not have an oxygen requirement versus the vast majority of patients did have an oxygen requirement. This grouping combines low-flow nasal cannula, high-flow nasal cannula, and any non-invasive mechanical ventilation. You can see this makes up a large proportion of the trial. Also a minority were currently requiring invasive mechanical ventilation when they were randomized. With regards to the outcomes of this trial, there was a significant reduction in 28-day mortality in the dexamethasone group. With regards to secondary outcomes, there was also a significant increase in patients being discharged from the hospital within 28 days in the dexamethasone group as compared to the usual care group. The composite of invasive mechanical ventilation or death was not significantly different between the two groups. However, you can see a slight reduction in requiring mechanical ventilation in the dexamethasone group as compared to the usual care group. The core part of our analysis today will be really looking at subgroup analyses in each of these landmark trials. This is because if you have taken care of a COVID-19 patient or you've read any literature, you will understand that a COVID-19 patient is not one size fits all. They'll come in at different points of their symptom onset with different severity and lots of different past medical history and needs. It will be evaluating these subgroup analyses that really drive us to make some key recommendations today with regards to management. Starting with this one, this is the subgroup analysis of the 28-day mortality. You can see that only patients requiring invasive mechanical ventilation or some type of oxygen support really drove the mortality benefit in the recovery trial with dexamethasone versus those patients that were not receiving oxygen, did not benefit from dexamethasone in this trial. What we can take away from this is that likely the immunosuppressant properties of the steroids outweigh the risks that we know with steroids to be neuropathies and muscle weakness and increased risk of infections, as well as delayed time to wound healing. The benefit of that immunomodulation decreasing the immune response really occurs in your patients requiring oxygen, and it may be more harmful in those patients that are not receiving oxygen. Furthermore, looking at the time from symptom onset, this is a subgroup analysis of looking at patients discharged from the hospital alive within 28 days. You can see that patients that presented seven or more days from their symptom onset also drove the benefit of dexamethasone here. This kind of falls in those three stages. These are the patients that present to the hospital, have those severe symptoms. They have had the virus for at least seven days, and their immune system has worked to clear it. Now, at this point, very likely there's a large inflammatory response that is not really clearing the virus at this point and is really just causing end organ dysfunction. This might be the key time to go ahead and initiate an immunomodulator therapy. This is demonstrated here in the recovery trial. The next landmark trial that came out was the COVID steroid 2 trial. It was an international parallel group stratified blinded randomized clinical trial with adult patients that were a little bit more severe with SARS-CoV-2. They had an oxygen flow of greater than 10 liters a minute or noninvasive ventilation or invasive mechanical ventilation. Patients were randomized to 6 milligrams of dexamethasone or 12 milligrams of dexamethasone. Patients in this trial, similar age to the recovery trial, mid-60s. They also had a median days from onset of symptoms to hospitalization of seven, and then days from hospitalization to randomization of two. With regards to respiratory at baseline, half of the patients were on some type of nasal cannula or open mask, and about 25% of patients had a noninvasive ventilation requirement and another around 20% required invasive mechanical ventilation. There was also a median of one day of duration of noninvasive or invasive mechanical ventilation in those that required that level of support. With regards to outcomes, the primary outcome of days alive without life support at 28 days was no significant difference between the 12 milligrams and the 6 milligram dose of dexamethasone. Furthermore, there was no significant difference in the number of days alive without life support at 90 days or 28 day or 90 day mortality or the number of days alive and out of the hospital at 90 days. So globally, no difference between 12 milligrams and 6 milligrams. While we usually don't look at subgroup analyses in trials where there's no difference in that initial analysis, we are in the middle of a pandemic and we need to really kind of scoot through this literature in order to really target key patient populations that may benefit from some type of intervention. And so when we look at the subgroup analysis of days alive without life support by dexamethasone dose, our primary outcome, the one that really sticks out to me is that there may be some benefit to using larger doses of steroids in patients that did not receive a IL-6 receptor antagonist, suggesting that that IL-6 receptor antagonist is providing more immunosuppression on top of the steroids. And if patients didn't receive that, they may benefit from having some other form of more immunosuppression. But globally, no difference in 6 milligrams versus 12 milligrams. So my recommendations for steroids based off of this is to go ahead and use the dexamethasone 6 milligrams, its equivalent IV or PO. Of note, it is equivalent to prednisone 40 milligrams orally, methylprednisone 32 milligrams IV, or hydrocortisone 160 milligrams. Of note, it is a pure glucocorticoid agonist. So it's going to lead to widespread anti-inflammatory effects without mineralocorticoid stimulation that leads to sodium and water retention. It also has a half-life of four hours. So there have been many trials looking at steroids in the setting of COVID-19. Dexamethasone has had that mortality benefit and ongoing hypotheses about why that might be is because it is a pure glucocorticoid and it won't lead to water retention, which is the absolute worst thing we can do for patients with any type of lung injury. The other thing is that it has a longer half-life as compared to some of our other steroids. And so when the therapy is completed, it's very likely that it's tapering itself off over a prolonged time. And of course, once someone ends a steroid regimen, it's going to take a while for the immune system to reconstitute anyway. So it might lead to a little bit more of a prolonged immunosuppression with dexamethasone as compared to other steroids. Globally, it will decrease the production of pro-inflammatory cytokines and the recruitment of immune cells to the lungs, which is beneficial for reducing that end organ dysfunction. And so my overall recommendation is that six milligrams of dexamethasone for 10 days, any longer than that, you get concerned that you're in that fibroproliferative ARDS phase at which steroids have not been demonstrated to be beneficial. They've actually demonstrated to maybe increase the risk for mortality. So I would not continue them beyond those 10 days. And while globally, I can't recommend 12 milligrams to all patients, I would consider it in a hospital at which I did not have access to another adjunct immunomodulator, which we will continue to discuss. And I would really look to use it in that setting in patients that have some type of high-flow oxygen requirement or very severe oxygen requirements, such as mechanical ventilation. I would initiate it really in patients that have an increased oxygen requirement from baseline, and I'd recommend to initiate it somewhere along the lines of seven days when patients present with very severe symptoms. The next immunomodulator we'll be discussing is tocilizumab. Many trials have evaluated tocilizumab for the treatment of COVID-19. However, not many of them have showed beneficial outcomes. The core immuno-19, BAC-BAE, and COVACTA trials did not show a difference between using tocilizumab versus usual care. However, the IMPACTA trial did show that mechanical ventilation or death by day 28 was reduced in the tocilizumab group. And this included patients that had an oxygen requirement, but it could not be non-invasive ventilation or mechanical ventilation. Versus REMAP-CAP was really designed for critically ill patients, and it found a higher organ support free days with the use of an IL-6 antagonist overall. But the landmark trial for tocilizumab is the RECOVERY trial. It randomized patients to around eight milligrams per kilogram of tocilizumab versus usual care. This could be used as an adjunct here as the RECOVERY trial with dexamethasone had come out while this was ongoing. They broke down the dosing into these weight-based, but overall it's around eight megs per kick. Patients in this trial also had an average age of around 63, days since symptom onset of around nine, and days since hospitalization around two. Looking at the baseline respiratory support, it's pretty split in half between no ventilation support and requiring non-invasive ventilation. That no ventilation support was low flow oxygen of some variety or no oxygen support, but I will say it was only around nine patients that didn't require any oxygen at all. Non-invasive ventilation included high flow nasal oxygen or CPAP or BiPAP, and of course invasive mechanical ventilation. And then you can see the vast majority of patients required or were using systemic steroids as an adjunct to tocilizumab. Looking at outcomes, tocilizumab significantly reduced 28-day mortality as compared to usual care. And then looking at some of the secondary outcomes, there was a greater proportion of patients that were discharged from the hospital within 28 days in the tocilizumab group, as well as there was less overall mechanical ventilation in the tocilizumab group as compared to the usual care group. But you'll note that successful cessation of invasive mechanical ventilation, there was no difference. So if it was given to patients that were on mechanical ventilation, getting rid of that, this did not benefit that whole time. However, it did reduce the use of hemodialysis and hemofiltration. Looking at these subgroup analyses again, you can see specifically those days and symptom onset specific for tocilizumab doesn't look like less than or equal to seven days or over seven days really swayed that tocilizumab had a benefit on mortality. I will say those patients that presented in that less than or equal to seven-day group were pretty much presenting right on the knock at seven days. And then with regards to respiratory support at baseline, globally patients that not quite were requiring invasive mechanical ventilation really had a benefit from tocilizumab. Maybe that those patients that were mechanically ventilated just a little bit too late in that inflammatory process in order to have a meaningful impact with the tocilizumab. And then those patients that received steroids, which was the vast majority of the patients in this trial, also had a benefit of tocilizumab with regards to mortality, suggesting that steroid should be combined with tocilizumab. Also looking at invasive mechanical ventilation or death for patients not on invasive mechanical ventilation at baseline, you can see that patients, again, didn't matter duration of symptom onset or baseline respiratory support. So whether it was no ventilator or non-invasive ventilation, both had a benefit. And then again, using those steroids as an adjunct seemed to be beneficial in this trial. So what do we take from this? Tocilizumab is an IL-6 receptor antagonist. It is to be administered as an intravenous infusion over one hour. It has a half-life of around 14 days. What does that mean? Once you give that dose, it's going to take a little bit for it to have its onset of action. But then after that, it's going to hang around for a long time, at least a month, where your patient will really be immunosuppressed, especially if you're using steroids as an adjunct. But it will decrease the production of pro-inflammatory cytokines. It will decrease the recruitment of neutrophils, macrophages, and T-cells. So globally bringing down that immune response, I would recommend it as an 8 mg per kg dose up to 800 mg as a one-time dose as an adjunct to dexamethasone. I would not recommend any subsequent doses. Subsequent doses were used in a minority of patients in a variety of trials. There was never any demonstrated benefit. And if you look at the pharmacokinetics with that long half-life, there really is no need to give a subsequent dose, as that one dose of Tocilizumab is going to hang out for a prolonged period of time. I would initiate this in hospitalized COVID-19 patients with elevated inflammatory biomarkers that have a newer increased oxygen requirement from baseline. And again, I would consider it right around that seven-day mark at those severe symptoms. So you're not impairing the patient's ability to clear the virus prior to that seven days, but beyond that seven days, you're really targeting that inflammatory response that is out of control. And then thinking about those subgroup analyses, there doesn't seem to be a lot of benefit from giving it to patients that are already mechanically ventilated. So if you are in a supply crunch, which we have been throughout the COVID-19 pandemic, I would consider really giving it to your patients with high flow oxygen or non-invasive ventilation as a means of not getting to mechanical ventilation and decreasing their mortality. The last immunomodulator we'll discuss today is Baricitinib. Baricitinib has been evaluated in two key trials, the ACT-2 trial and the Cove Barrier trial. Very similar trials overall that enrolled adult patients with COVID-19, but the severity of illness is a little bit different in these two trials. In the ACT-2 trial, they included patients that had a lower respiratory tract infection with a new oxygen requirement, and that could include mechanical ventilation or even ECMO. Versus the Cove Barrier trial included hospitalized COVID-19 patients with an elevated inflammatory marker, but patients with mechanical ventilation or some other type of organ support were not included in that trial. Both trials randomized patients to Baricitinib for 14 days versus placebo. The only difference here is that in the ACT-2 trial, they combined Baricitinib with remdesivir for 10 days. So the trial's really Baricitinib plus remdesivir versus remdesivir on its own. And the Cove Barrier trial just did Baricitinib versus placebo for 14 days. The other key difference here is utilization of steroids. The ACT-2 trial excluded patients that would be receiving steroids per the treatment course for COVID-19. They could be on steroids for some other type of indication, such as adrenal insufficiency, COPD, or asthma. However, the Cove Barrier trial did allow steroids for the treatment of COVID-19. Comparing patient populations in these two trials, the average age was about 50. Looking at ACT-2, there was a significant reduction in the number of patients who were on steroids. There was a significant reduction in the median time to recovery with Baricitinib versus placebo at 7 versus 8 days. And you can see with regards to the baseline oxygen requirement that the patients that very much benefited from Baricitinib were those that were hospitalized receiving non-invasive ventilation or high-flow nasal cannula versus any other type of respiratory support, and definitely not those patients that were not requiring any respiratory support. There was no difference in 28-day mortality or the duration of hospitalization. Comparing this to the Cove Barrier trial, the primary outcome of progression to high-flow non-invasive ventilation, invasive mechanical ventilation, or death by day 28 was not significantly different between the two treatment groups, and that did not matter if patients took steroids or not, no significant difference. In the secondary outcomes, there was a significant reduction in 28-day all-cause mortality. So after the Cove Barrier and the ACT-2 trial, Baricitinib became used in widespread COVID-19 management, but there was this question of, should we be using it in more high-acuity ICU-level patients, critically ill patients? So the Cove Barrier group did an extension trial evaluating this therapy in ECMO and invasive mechanical ventilation patients. In this trial, patients had their mean age was 58, 92% of them had a duration of symptoms of seven or more days, and just 3% were on ECMO at baseline, but the vast majority did receive steroids. The primary outcome of 28-day mortality was significantly reduced in the Baricitinib group as compared to placebo. However, no difference in the duration of hospitalization or ventilator-free days. So what do we take from this? Well, Baricitinib is a Janus kinase, specifically JAK1, JAK2 inhibitor to reduce immune cell proliferation and differentiation, as well as decrease the magnitude of cytokine signaling. Unlike Tocilizumab, it has a little bit of a shorter half-life at 12 hours. So what does this mean? Well, you're going to be taking Baricitinib for 14 days for that treatment course, and with that half-life of 12 hours, the duration of immunosuppression may be a little bit less as compared to Tocilizumab. However, we don't have any data specifically for Baricitinib or Tocilizumab for how long that immunosuppression really lasts and how long those patients have that increased risk of infection for. But globally, Baricitinib will decrease the production of pro-inflammatory cytokines and immune cell infiltration into the lungs. It's dosed at four milligrams daily for 14 days, unless you have a creatinine clearance of less than 60 mils a minute, in which you would reduce the dose to two milligrams. And I would recommend this as an adjunct therapy to dexamethasone. And where I would specifically use this is in hospitalized patients with a new high-flow oxygen requirement, as again, that's vastly where we're seeing the benefit. And I would consider administration to these patients who have severe symptom onset somewhere in that seven-day window again, so that they've had some time to clear the virus, and now you're really targeting that immune response again. So some final conclusions today is that we really don't have head-to-head trials comparing any of these immunomodulators. Hopefully, that is coming. So it's really unclear if one of these is superior to another. And we'll also need more data to fully elucidate the optimal timing of immunomodulator therapies for the treatment of COVID-19. But currently, my recommendation would be to target starting these therapies around that seven-day mark or beyond, not too late in the course, somewhere in that seven days, so that you can prevent the progression of that out-of-control inflammatory response in COVID-19. But you're not giving it too early, where you would be impairing the patient's ability to clear the virus. You're also not giving it too late, where you're worried about that lung fibrosis taking into effect and that increased risk of infection without any large gain in controlling that inflammatory response. So dexamethasone, I would consider initiating in patients with a new oxygen requirement. I would then consider initiation of tocilizumab or baricitinib as an adjunct to steroids at this point. I would specifically target it to your higher-risk patients with a high-flow oxygen requirement, at least evidence of ongoing inflammatory response with an elevated inflammatory biomarker and or evidence of symptomatic pneumonia with those very typical bilateral infiltrate suggestive of ARDS. Thank you today for listening to this presentation on immunomodulator management for COVID-19.

immunomodulators

COVID-19

steroids

tocilizumab

baricitinib

patient outcomes