Phase 3 Clinical Trials With Dupilumab in PN

Raj Chovatiya, MD, PhD: Sarina, maybe you could tell us a little bit more in terms of the setup of the PRIME and PRIME2 studies about the study design and the patient population. What were some of the outcome measures that we were interested in understanding when it came to intervention with dupilumab?

Sarina B. Elmariah, MD, PhD: The PRIME and the PRIME2 trial ran concurrently. They each had about 150 to 160 patients. Patients were delegated to either received dupilumab or a placebo. This was in adult patients, and they had to have the worst itch score on an NRS [numeric rating scale] of 7 or higher out of 1 to 10, 10 being the worst. So, these are pretty involved patients. They had to have over 20 lesions to be included in the trial, and they received either 300 mg every 2 weeks following a loading dose or a placebo. And the trial ran for over 24 weeks. The primary end point in the PRIME2 trial was at the 12-week point, and the primary end point at the PRIME trial was at 24 weeks. And essentially, they were looking for improvement in the worst itch score and on an NRS scale, at least a four-point improvement and in the number of lesions. They had secondary end points looking at sleep and skin pain, depression, and many other aspects of the disorder.

Raj Chovatiya, MD, PhD: I can hop into some of the numbers here, just for a little context for those of you that may not be picking up the data immediately. In terms of the primary end point for the PRIME Trial, which was at 24 weeks, looking at that four-point improvement or more in the itch, about 60% of patients treated with dupilumab vs around 18% of patients on placebo as well, and when you looked at clear or almost clear skin, it’s more of a measure of lesional severity, with nearly 50% of patients compared to only about 18% of patients on placebo.

One of the cool things that were done as a key secondary end point of the study was really trying to raise that bar of making a composite measure about how we can look at and how can we look at lesional changes as well. Two things that are really important to the disease but aren’t necessarily captured by each of those measures I just gave you. And so, when you combine looking at somebody having that meaningful improvement in itch along with getting to that clear or almost clear on this investigator’s global assessment score, about 40% of patients treated with dupilumab got there, compared to maybe only about 9% on placebo in the PRIME trial at week 24. And then, the PRIME2 trial had similar numbers, well into 30% vs only about 8.5% on placebo treatment.

As far as other stuff in the trial goes, Sarina did a very nice job talking about some of these other key secondary end points. I think that I probably would just mention a little bit about the adverse event profile, largely what’s been consistent with all the other indications for dupilumab of which we have several, and a lot of real-world data, extending at least up to 5 years for the longest indication. By and large, similar overall adverse event ratio, the most common stuff that was in the trial itself with dupilumab, nasal pharyngitis, around 5% of patients with dupilumab, 4% of placebo, something we see as a background event a lot when it comes to these types of trials. Headaches were there as well. It’s pretty similar with dupilumab and placebo, but whether you look at one trial or the other, the big thing to take away is, what was the actual treatment discontinuation due to adverse events? And it tells you a lot about what people were doing in a trial if something happened. By and large, 0% in the PRIME trial compared to 4% with placebo. So immediately, that tells you that even if somebody experienced what you may define as an adverse event, they really wanted to continue onto therapy. Are there some other highlights, Shawn, about the PRIME and PRIME2 trials in terms of top-line stuff that might be of interest?

Shawn Kwatra, MD: When you’re treating PN [prurigo nodularis], the itch is the real-time, disease severity indicator, and the nodules tend to fall a little bit behind in terms of resolution because, as you can imagine, there’s a significant degree of fibrosis. And so, we see here that the itch precedes the nodule clearance, but you do see the nodules reducing significantly, especially at that 6-month time point. And so, I think an important thing to counsel folks on is that the itch relief is going to be something that happens more suddenly and quicker at onset and then the nodules take a little bit more time to resolve. That’s one of my main takeaways from the trial. Obviously, we have many years now, our safety profile being so excellent for dupilumab. And I think that in this population, it takes special importance because of all those disease comorbidities that we know we have. Not having to check labs and all of that is great, and obviously, the adverse effect profile was very consistent, as you mentioned, with what we’ve seen. So, overall, really an excellent trial, and wonderful results as well.

Sarina B. Elmariah, MD, PhD: In both the PRIME and PRIME2 trials, you have essentially upwards of 50% response at 24 weeks’ time. Certainly, in terms of the improvement in itch, and their worst itch, that’s incredible. When you’re talking about patients with moderate to severe PN, think about how many patients, what’s our success rate, before, as practitioners who acknowledge and know how to treat this disease and aren’t afraid to use potentially caustic medications like methotrexates and even cyclosporine. But you clearly have a side effect profile that may not always be viewed as favorable, and often you don’t even hit that 50% mark. So, I think with a single therapy, and that’s important to emphasize here, that these numbers are quite encouraging.

To underscore the other important part that Shawn mentioned, which is the amount of time one needs to wait. Like some of these, the impact improvement, and it started earlier than that, but the longer these patients are on therapy, the more true modulation they get, where you start to take the wind out of the sails, and things can heal. And that’s when all these other aspects of quality of life also improve, so I think it’s important to emphasize that.

And the other point I wanted to make is when you’re talking about a drug like dupilumab because it’s viewed as being just an eczema drug, even though it is approved, and will probably be approved for many other indications. But it’s the idea that these patients are also not just diathesis patients, it was only a proportion of these patients that had an atopic diathesis. And at the time they did not even have active eczema. So, we need to recognize that, modulating the TH [thyroid hormone] to access, in this case with a drug like dupilumab, but I’m sure this will also be the case with other treatments, that these patients do not have to have comorbid atopic dermatitis for this type of drug to work.

Transcript edited for clarity