Inside LEVEL UP: Lead Investigator Discusses Upadacitinib Study

A recent study produced favorable topline results regarding the efficacy and safety of upadacitinib for adults and adolescents with moderate-to-severe atopic dermatitis (AD) who had an inadequate response to systemic therapy or when use of those therapies was inadvisable suggested that treatment with the drug was effective.

Practical Dermatology^® got the inside story from the lead study investigator, Jonathan Silverberg, MD, PhD, MPH, professor of dermatology and director of clinical research at the George Washington University School of Medicine and Health Sciences.

Practical Dermatology (PD): Why was this such an important topic to study?

Jonathan Silverberg, MD, PhD, MPH: Upadacitnib was approved for treatment of moderate-to-severe atopic dermatitis with two different doses: 15 mg and 30 mg. The pivotal studies up to this point had evaluated each dose from the start of treatment to the end. Both doses were highly effective, but the 30-mg dose was more so. Both doses got approved, but the FDA added a recommendation for a strategy that had not been studied: to start with 15 mg and, if necessary, step up to the 30-mg dose. That was partly based on an arbitrary standard that has been applied to the class across many different divisions, recommending the lowest doses possible. The challenge was that we did not have data to justify this approved indication. We had a head-to-head study showing that upadacitinib at 30 mg was more effective than dupilumab, which was the first approved biologic in the US, but the FDA recommendation is not to start with 30 mg, so we had a gap between that and starting with 15 mg before stepping up to 30 mg if needed. We needed to study how that dosing strategy stacked up against the benchmark.

PD: Besides the dosing, what about the format of this study was important?

Dr. Silverberg: Obviously, the dosing was important in providing us with information to understand the efficacy of that strategy. Beyond that, however, we were fortunate to have an active comparator, because true head-to-head studies are not necessarily common in dermatology. Often, with placebo-controlled studies, we are left scratching our heads as to how something compares to the standard of care. Here, we had that active comparator.

PD: What kind of impact do you expect the results to make?

Dr. Silverberg: The impact of this study will be quite significant. It fills that important data gap for us to understand how this paradigm works, and the head-to-head nature provides a very clear comparison. We already had a clear sense that upadacitinib was more effective at the 30-mg dose. We predicted that that would be the case with the 15-mg dose, but until we had the data, we did not know it. Now, we know it demonstrably outperforms the benchmark on every one of these secondary endpoints. That will be a bit of a frame shift in the perspective for the dermatologist and how they discuss options with patients. We now have an oral option, which patients prefer, that is also the more effective option. There are specific safety considerations with the class that need to be discussed with patients, and that is the offset compared to dupilumab, which has been on the market longer. But this head-to-head study is a very important discussion point with patients when considering first-line or second-line usage of different systemic biologic therapies and trying to match the right drug to the right patient.

PD: So, was it fortuitous in the end that the FDA made that unexpected recommendation?

Dr. Silverberg: I don’t know if I would use the word fortuitous. In other regions of the world, regulators have dealt with the approval of upadacitinib differently. In some countries, they have the ability to use either 15 mg or 30 mg, on-label, immediately. Many have argued, from an academic perspective, that starting with the 30-mg dose makes more sense because it is so effective and so fast, and then we can taper down to a lower dose for maintenance. Conceptually, that makes a lot of sense. The FDA’s clinical recommendation makes that approach officially off-label and less likely to be utilized, even though there is an argument to be made that that is actually quite reasonable for a subset of patients. The data from our study informed what is now the labeled indication, but it is important for dermatologists to understand that, while it might be off-label to start with 30, there are some clinical scenarios where that might make sense.