Expert Insights: Povorcitinib for Hidradenitis Suppurativa

Povorcitinib improved HiSCR50 responses in moderate-to-severe hidradenitis suppurativa, with higher dosing potentially benefiting patients with more severe disease and a generally favorable safety profile through 54 weeks.

Transcript

Hi, I’m Martina Porter. I’m a dermatologist from Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts.

What do the results from STOP-HS1 and STOP-HS2 suggest about the efficacy of povorcitinib for patients with moderate-to-severe HS?

Dr Porter: We presented the results a while ago for the primary endpoint, which was HiSCR50 at week 12. Just over 40% of patients in both dose arms—there was a 45-mg and a 75-mg dose—were able to achieve HiSCR50, compared with about 30% of patients receiving placebo. So, it was definitely positive data.

We continued to see improvements once patients crossed over and continued into the longer-term extension out to 52 weeks. Even at 6 months, they were doing much better than they were at the 12-week time point, which is a little bit early.

The other very positive news from the trial is that they looked at patients who were biologic-experienced already, meaning they’d already taken biologics for HS in the past. Those patients, despite having even more severe disease at baseline compared with the overall population, had even better efficacy outcomes. I think that’s very reassuring and probably very relevant as we move forward in the market with so many biosimilars. A lot of patients will probably have already been exposed by the time they are able to get some of these brand-name medications.

HiSCR50 response rates were similar between the 45-mg and 75-mg povorcitinib doses in both trials. How might these findings inform dose selection if povorcitinib becomes available for clinical use?

Dr Porter: I think the most important thing for clinicians and even for patients is to have some options for dosing. We see this trend a lot in HS trials now, where we test 2 doses in the phase 2 or phase 3 programs, and they end up looking very similar at a short time point, at 16 or 12 weeks, for example.

But when we get into the data more granularly, what we actually start to see is that there’s a subset of patients, particularly those with much more severe disease at baseline who are kind of masked in the averages that we show, who actually need a higher dose in order to get to the same outcomes. They often need more time, too, meaning they may not hit the endpoints until 24 weeks instead of 12 weeks, just because of the degree of severity and inflammation.

At the EADV meeting that just occurred in Vienna, they showed the povorcitinib data based on many different severity categories. There is not a consensus definition of who the most severe HS patient is. Some people look by Hurley stage; others look at the total combined count for abscesses, nodules, and draining tunnels, or the IHS4 count. Some look at those who have the highest burden of draining tunnels. They were also looking at other things, like the highest patient-reported outcome scores and highest hs-CRP, so potentially an inflammatory biomarker.

It was interesting to see because, in patients who had these very high levels of draining tunnels—more than 6—there was quite a large difference in outcome measures when they looked at the 75-mg compared with the 45-mg dose. That’s what I was talking about before: In some of these very severe patients, the higher dose is the only one that’s really probably going to get them to those efficacy endpoints.

But since they’re a smaller proportion of the overall population, we don’t see the differences in a very large data set, especially a trial like this that had over 1000 patients in it.

What are the most important takeaways from the safety findings through 54 weeks, particularly for clinicians considering long-term JAK inhibition in patients with HS?

Dr Porter: I think JAK inhibitors are very well known to dermatologists at this point in time. We have them approved for many other indications. I would say the most common side effects that we see or attribute to JAK inhibitors, which seem to occur regardless of the type of JAK inhibitor or the one that we’re actually using, are acne and herpes zoster, or shingles. Those did occur in these patients, too.

I would say the acne was actually very well characterized for this study. Again, they showed some data more granularly at the EADV meeting, but somewhere between 10% and 20% of patients by the end of 54 weeks had acne as one of the adverse events. They actually had the acne graded as part of the trial. It’s fortunate we’re dermatologists and we’re able to do this as part of our assessments, which they don’t do in rheumatology or GI trials where they also use JAK inhibitors.

Almost all the cases were mild, and there were some moderate ones, but none required discontinuation. One of the other things to note is that patients with HS aren’t allowed to take oral antibiotics or retinoids, such as isotretinoin, while they’re in a study protocol. They’re really only able to use topicals. So, it’s hard even in these trial data sets for HS to know how easy the acne is to treat because we’ve basically been taking all our tools away from us because we don’t want to impact the outcomes for the HS that we’re trying to measure.

Those things still existed. Then, I think the ones that people get more concerned about are the ones that are associated with the boxed warning, which are blood clots, cardiovascular events, and malignancies. These occurred at extremely low rates in the trial.

There were a couple of people who had thromboembolic events, but interestingly, the HS population as a whole actually has a relatively greater risk of having thromboembolic events, partially potentially because of the background disease state and inflammation, and maybe also because young females may take hormonal birth control.

Before this trial started, I would’ve thought potentially that they could have even more clots than an alopecia areata or an atopic dermatitis population, but there were almost none, and it was very close to what we would assume the baseline measures to be. Whether that’s because this is only 1200 patients or because this drug is so selective for JAK1 that it may actually not have the same risk as some of the others, I think, is yet to be seen in larger patient populations going forward. But I would say, for a JAK inhibitor in a population that’s at risk, those safety events are actually better than expected.

Given the persistent unmet needs in moderate-to-severe HS, where could an oral, selective JAK inhibitor such as povorcitinib potentially fit within the treatment landscape?

Dr Porter: For many years now, we’ve done studies about patient preferences in dermatology for systemic therapies. By and large, every survey that we’ve ever done has always shown that patients prefer oral options as opposed to injectable options. So, I think having that as an option for patients in terms of shared decision-making is very important for them.

But I think for clinicians, probably the most important thing is how well the drug works and what the side effects are—and, unfortunately, in this day and age, also how easy it is to get.

By and large, across the world, now that we have biosimilar biologics like adalimumab and, in a few years, likely biosimilar secukinumab, which are both approved for HS, I think we’re going to see a lot more patients needing to step through these therapies across the world just because of cost considerations.

I personally find that JAK inhibitors work quite well in patients with really severe disease, like I was talking about before, who have a lot of draining tunnels and have more of this Crohn’s-type phenotype. They also work really well in patients who are actually more on the moderate end of the spectrum. So, they’re not prone to getting tunnels, and they get a lot of nodules and smaller abscesses. Those patients are able to clear in a way that they really don’t achieve the same outcomes on biologics, at least.

I think when it first comes out, it’ll probably be positioned on some level behind biologics, just because that’s how it’s positioned in atopic dermatitis currently, too. But ideally, what we would see is that we’re starting to select therapies that work best for patients on the first try.

I think once people get a little bit more experience using these in their own hands and in a larger population, we’ll actually see that JAK inhibitors will be preferred for certain subsets of patients with HS. They may also be used in combination, too, because unlike some of our other biologic therapies, the mechanism of JAK inhibitors is quite different from the approved mechanisms for HS now.

I could see a world in which patients might have a partial response, for example, to an IL-17A inhibitor, and then they add a JAK inhibitor to that in some of our more severe cohorts, too. So, it’ll be exciting to see how everything turns out over the next few years, but I don’t think we’re at a state yet where we’ve gotten anywhere close to solving or treating everybody with HS. I do think in the real world we’ll be able to get much better outcomes than we do in a very contrived clinical trial setting.