LIBERTY-AD Open-Label Extension Study Design and Safety Findings

Andrew F. Alexis, MD, MPH, and Benjamin N. Lockshin, MD, review the design of the LIBERTY-AD open-label extension trial and share clinical context regarding safety findings.

Andrew F. Alexis, MD, MPH: Because we’re treating [patients with] this condition for the long term, I think this is where safety of our treatment options really becomes so important. That segues into the study that we’re discussing, which reports on the safety and efficacy of dupilumab treatment for up to 4 years in adults with moderate to severe atopic dermatitis, as well as its efficacy in a subgroup of patients who transitioned from dupilumab once a week to administration every other week. Briefly, the study design, this was the Liberty AD [atopic dermatitis] open label extension study which enrolled adult patients who previously participated in the dupilumab AD trials from phase I to phase III. A total of …2827 patients were screened. The number enrolled was 2678. You can see that more than 2600 patients were included in the safety analysis set. When we looked at the results, we see starting with withdrawals, a low rate of withdrawals from [participants], and…in particular treatment emergent adverse events that led to study drug discontinuation. We see a rate of 3.7%, which is acceptably low. When we look at serious treatment-emergent adverse events that were related…to dupilumab, also reassuringly low: 1.2%. I’m going to pause here and turn it over to you, Dr Lockshin, and ask if you have any quick thoughts on the safety data so far.

Benjamin N. Lockshin, MD: I’ll start by saying you did an excellent job summarizing this. I love open label extensions as an investigator for studies. It’s really that carrot that you dangle out in front of the patient to say, “Hey, there’s a chance you might get placebo. There’s a chance you may get drug in the double-blind placebo control phase. But once you make it past that primary end point, as long as you’re in that, we can get you on drug.” A study like this is nice because it not only captures safety, but it captures long-term efficacy. This presents, as you mentioned, some unique findings in terms of dose changes, which really help us in the real world. Not every patient lives within the constraints of the double-blind placebo control period. As we talked about, this is a chronic condition, so a long-term approach is warranted. Hopefully we’ll go over in a little bit to talk about how patients do in the long term in terms of efficacy, and to see if there’s any amplification of safety signals over time; that legacy component of these drugs is meaningful.

Andrew F. Alexis, MD, MPH: Thank you. Looking a little further into the safety data, what we are looking at here is what were the most common treatment-emergent adverse events among these patients in the open label extension. Let me see some adverse events that were familiar where there are basically no new safety signals in this longer-term study. We’re seeing adverse events that we’ve seen before in our other studies: nasopharyngitis, atopic dermatitis as an AE [adverse event], upper respiratory tract infection. But homing in on something that’s very relevant to dupilumab, that’s conjunctivitis. We see that a rate was 10.3% in this open label extension. I’d love to get your thoughts on that and any of the other AEs that you see here.

Benjamin N. Lockshin, MD: …The hot topic is probably conjunctivitis as it was one of the signals that was not anticipated in some of the early studies, like the CHRONOS and SOLOs studies….What we do know is 2 things:…Just shy of 25% of the patients who enrolled in this study had a history of allergic conjunctivitis. Moreover, the rates of conjunctivitis were seen early in the quarter. We see here in this table that the rates do decline to about 10% of the patients who had more than 1 event during this open label period as opposed to about 20% of the patients who were in the CHRONOS study, which went out to 52 weeks. We can really lean on that in terms of explaining to our patients[that] many of the patients actually had just 1 episode….But most of those were clusters at the beginning. If you didn’t get it within that first 24- to 52-week period, the likelihood of you experiencing conjunctivitis is small. I also stress to the patients that even though there are rates of keratitis and conjunctivitis that are seen in these patients, rarely did it result in discontinuation of this medication. Is there anything that you mention to patients besides that, regarding the keratitis, conjunctivitis signal, in your clinical practice? What do you ascertain from these open label extension data?

Andrew F. Alexis, MD, MPH: I completely agree with you and with your interpretation of the data. I find it reassuring that the rates appear to be lower with ongoing exposure to dupilumab. That’s really shown here in this next slide, which plots weeks of study drug exposure. You can see over time from less than 26 weeks of exposure on the left side of the graph all the way out when you get into the right side into the 100-week plus range of the study. We see this decline in the rates of conjunctivitis. I’m also reassured by the overall severity of the conjunctivitis that was reported, with 9.3% [of cases] being mild, 9.8% of the cases being moderate, and only 1% rated as severe. I’m particularly reassured by the rates of how often conjunctivitis actually led to discontinuation: only 0.5% of patients. This is very much aligned with what I see in my own practice. I don’t find it to be a frequent occurrence to have to stop the patient who gets conjunctivitis while on therapy. It’s usually something that we can manage and continue to treat. Has that been your experience too, Ben?

Benjamin N. Lockshin, MD: Absolutely. Moreover, I think that the other specialties are more aware of this, especially ophthalmology. Early on, I get pushback from the ophthalmologist who are overly cautious. Now, to tell you the truth, I rarely see patients that have complaints of conjunctivitis with the medication. I don’t know if it’s that patients are looking online and just feel less concerned and not notifying me or if truly the events are occurring less frequently. I do think there is some component that the patients that we did enroll in clinical trials had severe disease. You look at baseline EASI [Eczema Area and Severity Index] scores and BSA [Body Surface Area] scores—they tend to be significantly higher than the general community patient that I put on a biologic therapy for AD. That may account for low rates that I’m seeing in the community. Are you also appreciating this or is it maybe just a one off with me?

Andrew F. Alexis, MD, MPH: Just to be clear, whether I’m seeing a lower severity of AD in my biologic patients in the community compared with [those] in the study—was that your question?

Benjamin N. Lockshin, MD: And also, are you seeing a lower rate of conjunctivitis than you saw maybe 5 years ago or more?

Andrew F. Alexis, MD, MPH: Come to think of it, I would agree with that. I’m on the lookout for it, that’s for sure. I mention it from the outset, but how often am I really seeing it 20% of the time; let’s say 2 out of 10 of my patients get it? No, that’s not been my experience in my practice. So it does seem to be lower than some of the rates reported.

TRANSCRIPT EDITED FOR CLARITY

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