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Repurposing Host-Directed Therapeutics for COVID-1 ...
Repurposing Host-Directed Therapeutics for COVID-19
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So, these are my disclosures. As I mentioned, I'm a full-time employee of Genentech Roche, and some of the work that I'm going to be talking about today was funded in part by a grant from BARDA. Next slide, please. Okay, great. So, let's take ourselves back to December of 2019, and I realize that's probably a time that most of you are reluctant to go back to, but bear with me here for the sake of the presentation. A novel coronavirus associated with a high incidence of severe respiratory failure has been identified in China and is beginning to spread in Europe, and the rest of the world is just starting to wake up and understand kind of the potential devastation of the emerging global pandemic. So, right around this time, we begin to hear some case reports of the use of tocilizumab, an IL-6 receptor inhibitor, in severe and critical COVID-19 patients. And so, my first thought, as a good drug developer, is, well, that's pretty bold because IL-6 inhibitors, including tocilizumab, have boxed warnings because of the risk of severe infection. But the results of the case series are actually pretty remarkable, and so my second thought, like I said, as a good drug developer, is we need to do a randomized controlled trial to determine not only if this treatment is potentially effective, but is it safe? Next slide, please. So, Craig kind of covered this, so I'll go pretty quickly, but the theory, of course, was that COVID-19 is a biphasic disease, where there's an initial phase characterized by acute viral replication, and then in some patients, a second phase that's mediated by a dysregulated host response, and, of course, it was the second phase that was being targeted with tocilizumab. But, again, it was by no means clear that TOSI was going to be safe or effective in this disease. Next slide, please. And so, we initiated not just one, but three separate randomized controlled trials, Covactin, Impactin, and Aribdactin. Next slide, please. Comparing these three studies, all were placebo-controlled, double-blind RCTs, target enrollment range between 380 and 650. There were slightly different patient populations recruited in the studies and different endpoints because, honestly, we didn't know what the right endpoint was for a study of this nature. The enrollment periods were sequential, and this is really significant given the constantly evolving background standard of care for these patients with the resulting changes in the expected outcomes. Next slide, please. And you may recall the efficacy results from these studies were a bit of a mixed bag. Two of the studies, Covactin and Aribdactin, were negative, while Impactin was positive. But, of course, this is an oversimplification. Covactin did not meet its primary endpoint clinical status on the ordinal scale of day 28, but there was an eight-day improvement in time to discharge, which was actually larger than the benefits seen with remdesivir or baricitinib at the time. Impacta showed 44% relative reduction in progression to mechanical ventilation or death, but no mortality benefit was demonstrated. And then remdacta did not meet either its primary or secondary endpoints, but did demonstrate a small numerical improvement in mortality at day 28 and 60. Next slide, please. So, on the other hand, from a safety standpoint, the results were quite consistent across all three studies. In each study, the rates of serious adverse events, infections, and serious infections were lower in the tocilizumab group compared with placebo. And this is, of course, reassuring, if a bit surprising. Next slide, please. But the story probably would have ended there if it hadn't been for recovery. Next slide. So, recovery, as you're aware, is an open-label platform, randomized evaluation of COVID-19 therapy. We'll get to the next slide eventually, I think. It's being conducted through the U.K. National Health Service, and I'm speaking about it in the present tense because it's actually an ongoing study, but the tocilizumab randomization closed in January of 2021. That's a two-part factorial design, which I'll explain a little bit more in the next slide. Open-label study, and a major consequence of this is that there has been very little safety data collection. Currently, there's 188 sites active, over 48,000 patients enrolled, and the eligibility criteria for this study are very broad. It's really intended to enroll just about anyone hospitalized with COVID. Next slide. So, a little more detail on the study design. This is a very busy slide, but I'll just point out a few things. You can see that there was a first randomization with multiple sub-randomizations, and this is that factorial design that I referred to. In addition, for patients with clinically progressive disease and evidence of inflammation with an elevated CRP, at the investigator's discretion, they could undergo a second randomization to receive tocilizumab or no additional treatment. The primary endpoint was all-course mortality at day 28, with secondary endpoints of time to discharge and the need for mechanical ventilation. Next slide, please. So, 4,116 patients underwent the secondary randomization, and the study hit its primary and secondary endpoints. Providing a statistically significant improvement in 28-day mortality, as well as a 9-day improvement in time to discharge and reduced need for invasive mechanical ventilation. Next slide, please. The size of the study also allowed for a robust examination of subgroups, which showed similar benefits across categories of baseline characteristics, with the potential exception of patients who were not receiving corticosteroids at baseline who may have had less benefit. Next slide, please. So, comparing the Roche studies and recovery, recovery was obviously a much larger study. Interestingly, the enrollment period for recovery spanned the serial enrollment periods for the Roche studies almost perfectly. Recovery and Remdachta hit their primary endpoints, Covacta and Remdachta did not. However, recovery was somewhat non-informative with regard to safety, which the three Roche studies, well, the three Roche studies consistently demonstrated no safety issues. So, by the time these studies read out, there were multiple other RCTs, mostly smaller ones that had been done and really demonstrated a range of results. So, what do we do when we have discordant trial results? Of course, we do a meta-analysis, and in fact, multiple meta-analyses were done, most significantly by the World Health Organization, and that's what the results are on this slide here. Focusing on the tocilizumab results, the WHO meta-analysis demonstrated a relatively small, but clinically meaningful and statistically significant reduction in mortality with an odds ratio of 0.83. The forest plot on the right, which is a little hard to read, I realize, but it displays all 19 tocilizumab studies that were included in the meta-analysis, and I just want to point out a few things. First of all, if we look at recovery, which is the largest blue square there on the slide, the point estimate is similar to the overall point estimate for the TOSI studies combined, which is at the bottom of the figure. This is not a surprise, given that recovery contributed most of the patients in the meta-analysis. But if we look at the other studies, you can see that there are variable point estimates, but the 95% confidence intervals all contain the recovery point estimate and the overall point estimate. So, from a statistical standpoint, there's actually very little heterogeneity here. And if you put all the studies together, even without recovery, you get the same point estimate of the treatment effect. So, all of this suggests that the studies were indeed just too small to individually demonstrate the benefits seen with larger recovery study. Next slide, please. I'm going to skip this, maybe, in the interest of time. Let's just go to the next slide. So, at the end of the day, the totality of the evidence from multiple sources was required to support an eventual emergency use authorization. Evidence of efficacy came primarily from the recovery platform study. Evidence of safety came from the Roche-sponsored randomized control trials. And all of this was in the background of numerous other studies that, together, demonstrated consistent benefits. At the same time, there was increasing clinical acceptance in the form of clinical guidelines, as Craig referred to, defining the role of ectemera in severe COVID. Next slide, please. So, one interesting question that we've been asking ourselves and that I'd like to leave you with is whether we could have figured this all out sooner. All right? So, on the left-hand side, you can see that the total enrollment in all of the other studies, the smaller studies, the randomized studies, was about equal to the enrollment in recovery. Okay? And on the right-hand side, you can see that what I've plotted is, on the y-axis, the cumulative enrollment of all of the studies, and on the x-axis, the timing of the primary readout of those studies. So, what this shows is that, hypothetically, if all the smaller studies had been combined into a single larger study, efficacy could have been demonstrated a couple of months before recovery actually read out. Now, obviously, it would have taken a tremendous effort to roll out such a study during a pandemic, which makes the point that, in order to make the biggest possible impact, the study infrastructure really needs to be in place before the pandemic even begins. I think I'm going to stop there, and thank you for your attention.
Video Summary
The presentation discusses the exploration and trials involving tocilizumab, an IL-6 receptor inhibitor, for treating severe COVID-19, despite initial safety concerns. Three Roche-sponsored trials—Covactin, Impactin, and Aribdactin—produced mixed results. Impactin showed positive outcomes, reducing the progression to severe illness, albeit without impacting mortality. Notably, the larger U.K.-based Recovery trial demonstrated a significant mortality benefit with tocilizumab. Despite some safety data gaps in Recovery, subsequent meta-analyses confirmed tocilizumab's effectiveness while Roche trials assured its safety, leading to emergency use authorization. The speaker suggested pre-pandemic study infrastructure could improve response efficiency.
Asset Caption
90-Minute Session | Clinical Evidence for Host-Directed Therapeutics
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Presentation
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Year
2024
Keywords
tocilizumab
COVID-19
clinical trials
mortality benefit
emergency use authorization
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