Lebrikizumab for Moderate-to-Severe Atopic Dermatitis Shows High Level of Efficacy

In this video, Jonathan Silverberg, MD, PhD, MPH, discusses his team's study, which found that lebrikizumab was highly effective in treating symptoms of moderate-to-severe atopic dermatitis in adults and adolescents.

Additional Resource:

• Silverberg JI, Guttman-Yassky E, Thaçi D, et al. Two Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis. N Engl J Med. 2023 Mar 23;388(12):1080-1091. doi: 10.1056/NEJMoa2206714.

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Jonathan I. Silverberg, MD, PhD, MPH, is an associate professor of Dermatology at The George Washington University School of Medicine and Health Sciences (Washington, DC).

TRANSCRIPTION: 

I'm Dr Jonathan Silverberg. I'm a professor of dermatology at the George Washington University School of Medicine and Health Sciences in Washington DC and I'm also the director of clinical research and patch testing there.

Consultant360: What was the impetus for this research? Why now?

Jonathan Silverberg MD, PhD, MPH: So this has been a long time in the making. Whenever a new therapy comes out, it takes many, many years from the initial phases of research when it's studied before it gets into humans all the way through phase three registration trials such as this. But lebrikizumab was previously studied in several different due studies, most recently in a phase 2B study before this one, that showed good efficacy and safety and tolerability for lebrikizumab as a treatment for moderate to severe dystopic dermatitis, and patients who already had an inadequate response to topical therapy. And so these studies are the next step or the evolution in the clinical trials, moving into phase three trials, very large clinical program, [inaudible 00:01:24] clinicals with an observation period going out to week 52, and so I know giving us important data. Not only is this the largest trial or set of trials for lebrikizumab to date, but it's also the longest trial that we have so far for lebrikizumab.

C360: How does this study fill a current gap in our knowledge?

Dr Silverberg: Well, with any new therapy that comes to market, we need to know how well it works, how safe and well tolerated it is. Are there any side effects to be on the lookout for? Are there any specific subsets of patients that do better than others? So from the medical perspective, this trial is filling all of those gaps and teaching us about how well lebrikizumab works. In addition, a drug to get approved in the United States or in Europe, there are regulatory requirements about how large a safety pool has to be, how large a clinical trial program needs to be in order to be adequately powered, to have appropriate confidence in the efficacy readouts. And so this is a very important step forward. These data will support the application to the regulatory bodies to have approval of lebrikizumab in the [inaudible 00:02:55] and abroad.

C360: The results showed lebrikizumab’s high level of effectiveness almost across the board. Did this level of efficacy surprise you?

Dr Silverberg: I wouldn't say I was surprised by the high level of efficacy. We expected that from the phase 2B study. I think what's always tricky is whenever a drug is studied in phase two and then moves into phase three, there's always a possibility, and in fact, in many circumstances we see substantial drops in efficacy between the readouts from the phase two study and the readouts from the phase three studies. And so here, we actually see very nice efficacy and reproducible across both trials consistent with observed in the phase 2B study. So no surprises, but that I guess in itself is a pleasant surprise that we didn't see any major drops in efficacy between the phase two and the phase three studies.

C360: Regarding the regulatory aspect to this, is an FDA approval on the horizon?

Dr Silverberg: That is the goal. And the application has been submitted to the regulatory authority, and we hope if all goes well that we may have approval of lebrikizumab in the United States before the end of 2023. I don't know exactly what those dates would be, but this is something that we may be able to prescribe for our patients imminently in the next few months.

C360: Are there any gaps in our knowledge that still remain, and what kinds of studies are needed to still fill those gaps?

Dr Silverberg: Sure. So the readouts from this trial that were published in New England Journal of Medicine were efficacy and safety readouts out to week 16, which has emerged as an important time point for clinical trials in the atopic dermatitis space. But of course clinically we'd love to know, well, how well does the drug work beyond week 16? What about at week 52? What does the long-term terms do look like? So we've got additional data readouts from that week 16 to week 52 period that have also recently been published in the British Journal of Dermatology that show very nice durability of response, and for many patients, again in efficacy over time with continued dosing. So those data gaps in a sense have been filled, but we want ongoing term extension studies to read out pretty much every year. We want to know are there any new safety signals that come up not just in one year, but after two years, three years, five years. And so, these are ongoing studies, but we will continue to see those data.

I think there are some in particularly important questions that come up just given the landscape of treatment options out there. And one big one is, well, how well does lebrikizumab work if somebody already was treated with dupilumab as one of the approved options out there? And of course, we could easily use lebrikizumab as a first-line systemic or biologic option once it's approved. Logically, there there's a lot of patients who would've already been treated with dupilumab, so how will those patients do? So we're starting to see now post hoc analyses from these trials that will shed light on that, but it would be really nice if we had a study that was devoted to that. And fortunately, there are plans for such a study to be done to stand exactly that, how well lebrikizumab works, so stay tuned. I think we have a ways to go till we have all those readouts, but those will be very important data to inform our understanding of how lebrikizumab works as a second-line failure. Clearly, it works very well as a first-line systemic therapy.

C360: Do these study results impact other specialists beyond dermatologists?

Dr Silverberg: Atopic dermatitis is a complex disorder that's managed by a lot of different stakeholders. So within the more severe patient population in general, the two main provider categories are going to be dermatologists and allergy immunologists, which in the United States are two different fields, but of course in other parts of the world can be one and the same. But there are certain regions of the country where you can't find a dermatologist or an allergist, and so there are family practice and other primary care providers who might actually be the ones to be the first prescriber of a systemic or biologic for tougher cases of atopic dermatitis. So it certainly has its relevance, I think across all provider types. In particular, when a patient is being managed with these medications, it's imperative for the primary care clinicians to really have a thorough understanding of, perhaps more importantly than anything, the safety, what to be on the lookout for.

Should we be thinking about laboratory monitoring? In the case of lebrikizumab, it's simple. There is no laboratory monitoring to be thinking about, but these are the kinds of things when you're out monitoring and looking for safety concerns, these patients, even if you're not the ones prescribing them as a primary care provider, they're going to be floating through your practice, and so you need to know what to be on the lookout for. So I think it is broadly applicable to many different provider types. I think what will be very interesting is, there are some preliminary hints that lebrikizumab may work very well for asthma as well. Now, it was studied a long while back for asthma and it technically just fell short of statistical significance and failed trials. But what we've learned over the years is that it was actually grossly under-dosed in those studies, and the dose that's being studied now for atopic derma is literally quadruple what was originally studied. So it rehashes that question of, well, maybe this might be a good option for asthma.

Now, of course, until it's studied, we won't know. And I'm not sure if the manufacturer wants to study it in asthma, but it raises intriguing questions because then all of a sudden the relevance to pulmonologists and other stakeholders who are managing asthma, the whole landscape changes. So I think there's a lot for us to watch over the next few years as this story evolves.