George Han, MD, PhD leads a discussion on the pooled analysis of the phase 3 reSURFACE 1 and reSURFACE 2 clinical trials assessing the 5-year safety and efficacy of tildrakizumab in patients with moderate-to-severe psoriasis.
Brad Glick, DO, MPH: George, I will turn to you and ask you—as we talk a little more specifically about some of the agents—to tell us about the pooled analyses from the phase 3 reSURFACE 1 and reSURFACE 2 trials, looking at the 5-year efficacy and safety of tildrakizumab for patients with moderate to severe plaque psoriasis. Just talk about the basics of your view of the study design, outcomes, and some of the other matters related to the trial.
George Han, MD, PhD: Right. To your point, this was a study that wrapped up in 2019. Tildrakizumab is 1 of the IL-23 inhibitors. We like these long-term data. We like the 5-year data. We like this for as long as we can get access to it, because that’s the big question. Like Dr [Erin] Boh, I have a patient on her ninth biologic. The longer we can get on 1 of these, the better. Out of the study, there’s pretty similar treatment in terms of patient cohort. There are 2 parallel trials. The second 1, reSURFACE 2, had an active comparator, etanercept. Regarding the entries into the trial, the patients were pretty typical for psoriasis cohorts: predominantly men, Caucasian, with a weight around 90 kg, so these were heavier patients. Patients’ PASI [Psoriasis Area and Severity Index] was around 20, and body surface area was around a third, so these patients weren’t too different from most of our psoriasis cohorts. When you look at them after week 28, they took the patients who were responders to tildrakizumab, or those with a PESI of 75 or above, and the partial responders or nonresponders to etanercept, or patients with a PESI under 75—from 50 to 75— or nonresponders under 50, and then carried them out with tildrakizumab for up to 5 years.
A couple of things stood out to me. At the 1-year mark, the retention rate in the study was very high. Around 96% of patients stayed in the study, and that’s remarkable because if you’re conducting these trials, you know patients aren’t happy. They want something that works for them. They start dropping out. If you even look out 5 years, the retention rate was around 80%. It was a little higher than 80%. That’s around 5% dropping out each year, and that’s quite good. We’re starting to look at some of these data, those rates, and what they means. No. 1, you can trust the data a little more. That’s nice to know. Second, it’s good to know, subjectively, that patients stayed in the study and were doing well on the drug. How well were they doing? The PESI 75 maintenance was close to around 90%, so patients—even after that 5-year mark, week 260—were maintaining PESI 75 at a 90% rate. Interestingly, the PESI 90 was around two-thirds, but PESI 100 went up a little, so that was close to a third of the patients. I’m talking about the 100-mg dose, because that’s the 1 that’s approved. One-third of patients—up from around a quarter—got to PESI 100 throughout the rest of the trial, so those are very promising data in general. What’s also good is, obviously—along with the efficacy and maintenance of efficacy—the safety. There were no new safety signals in 3 to 5 years.
Of course, we’re looking for major adverse cardiovascular events and malignancies. I mentioned earlier TNF [tumor necrosis factor] alpha inhibitors of flight signals for melanoma skin cancers skewing toward squamous cell carcinoma. We’re not seeing anything from ustekinumab on. This would be in that bucket too. Mostly, we go from malignancies or infections—serious infections. There’s nothing jumping out at you that you need to be concerned about. The last point is that a really interesting analysis they did looked at metabolic syndrome, and they subcut the analysis for metabolic syndrome.
We talked a lot about comorbidities already. We know our patients with psoriasis—I mentioned before, these were all comers, with a 90-kg average—so if you divide these patients into those with metabolic syndrome or without metabolic syndrome, you’ll see that differentiates even more. The patients without metabolic syndrome, their average weight is around 80 kg; with metabolic syndrome, it was around 105 kg. We’re talking about much heavier patients with a higher burden of cardiovascular disease. Around half the patents in that metabolic syndrome cohort have cardiovascular disease, a hybrid in diabetes. There are a lot more comorbidities. What’s interesting is they showed that the effectiveness of the medication was similar between the 2 groups, so you didn’t really see a drop-off. That’s important because we know, with just a higher weight, some of our biologics work less well. We talked about the role of increased TNF alpha, adipocytes, and we’re driving more psoriasis but also more distribution and less effectiveness for biologics.
That didn’t seem to be true here. What’s also interesting is that the safety didn’t appear very different. It really raises that question. I’m not trying to imply that there was an active difference between the 2, but it raises the question. Think about it: You take a cohort of patients with metabolic syndrome, on average 25 kg heavier than another group, and you follow them out. You’d think—50% vs a much smaller number had cardiovascular disease—that maybe you’d see a slight signal in adverse events. That wasn’t true. That really is the holy grail, the next big step in psoriasis research that will tie everything together: how we are through our treatment, and how we approach these patients with psoriasis and are able to modulate different areas of their health.
Brad Glick, DO, MPH: It would be interesting to see if the other representative agents within this class will have similar responses.
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Transcript edited for clarity.