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STOP-HS1 and STOP-HS2 data show povorcitinib nearly doubled treatment response rates versus placebo in moderate to severe HS.
Hidradenitis suppurativa (HS) remains 1 of the most challenging inflammatory skin conditions to manage, with limited options for treatment and a significant impact on patients' quality of life.
In a new HCPLive Q&A, Martina Porter, MD, known for her work with Beth Israel Deaconess Medical Center and Harvard Medical School, speaks on why HS has historically lagged behind other dermatologic conditions in treatment development, and what makes the recently published STOP-HS1 and STOP-HS2 trials a notable shift for patients and clinicians alike.1,2
Porter walks through the mechanism behind povorcitinib, an oral therapy under investigation for HS, and explains how it may offer a meaningfully different option for patients who haven't responded to existing treatments. She also unpacks the trials' efficacy and safety findings. The full conversation highlights Porter's complete take on where povorcitinib may fit into the evolving HS treatment landscape:
Porter: I think anyone who's ever treated an HS patient knows that it's much more difficult to treat HS than a lot of our other inflammatory skin disorders. Some of this, I think, is related to the availability of treatments. It's a newer disease state, essentially, that we've started to investigate from a research perspective to find more treatments, and we still haven't quite hit the bar that we want to for efficacy. If you compare it to psoriasis or even atopic dermatitis, the disease for patients is extremely difficult to have and has a really profound impact on their quality of life.
This is a disease that has very high rates of depression, anxiety, and even suicidality. Even for milder patients, living with the condition and not knowing when it's going to flare up, or not knowing when they're going to be able to walk, or get dressed, or have relationships with other people, really impacts every aspect of their living.
Porter: As you've alluded to, we do have a couple of other medications now that are FDA-approved and also approved in the EU for use for HS. They're all for the moderate to severe population. But all of them, so far, are biologics. So we have adalimumab, which is a TNF-alpha inhibitor, and then secukinumab, which is an IL-17 inhibitor, and bimekizumab, which is an IL-17A and F inhibitor. There are even a couple of other drugs like sonelokimab and iscalimab that are also IL-17 inhibitors and have finished phase 3.
But the STOP-HS1 and STOP-HS2 trials are the very first medication that's oral…Povarcitinib is a selective JAK-1 inhibitor, and we have other JAK inhibitors in dermatology, but we actually don't have povarcitinib approved for any other disease indication now. So, we have a new drug, but not a new mechanism. But for HS specifically, we have a new drug, a new mechanism, and an oral option. For a lot of patients, especially younger patients, the idea of getting injections is off-putting. To just have another option, I think, is very good for them from that perspective as well.
Porter: I would say that there are quite a few patients for whom the idea of taking a medicine that affects their whole body is very scary for them, and then to find out that it comes as an injection is another layer of difficulty, I think, in sort of accepting that they're taking a whole new lifestyle change for this. There is a little bit less needle-phobia, in general because of GLP-1s. People have sort of gotten used to the idea that they need to take injectable medications. But I definitely think for younger patients and those who do not really feel comfortable with medications in general, having a pill option is really helpful.
Also, the idea that they can start and stop it is also helpful too when we go through the counseling and the shared decision making process of getting patients to take therapies because unlike some of our other inflammatory disorders, when we look at HS patients, there's a willingness from dermatologists and APPs to want to prescribe some of these medications for patients. But there's much more hesitancy in the moderate to severe HS population than there is in a moderate to severe psoriasis population or a moderate to severe atopic dermatitis population. Some may be related to baseline demographics that they share or don't share.
Porter: The JAK-STAT pathways have gotten a lot of press, and there are different types of JAKs: JAK1, JAK2, and JAK3. The JAK2 and JAK3, they've always thought, are involved more in hematopoiesis, and so we see different side effects with each of the different JAKs. Actually, even a selective JAK1, for example, may still hit JAK2 or JAK3. So that's why we get into these terms like highly selective, where they're really hitting almost only Jak one and very little, if any, of JAK2 or JAK3. Then we ideally like to see from a safety profile those differences. But also, I think in terms of the pathogenesis, we still don't really understand what causes HS or what the main drivers are.
I personally think that HS is probably very heterogeneous in the sense that not every patient with HS is going to have the same things driving their disease. Therefore, not every treatment is going to work for probably every single patient. The JAK1 pathway in general is a little bit broader than what we expect for a TNF alpha inhibitor and definitely for an IL-17 inhibitor, and actually interesting. JAK1 has little impact on TNF and IL-17 overall, and so it's really nice in HS, especially for patients that have been on some of these biologics before, that this new mechanism is very different. Whereas TNF and IL-17 are very similar, so it may offer an opportunity for patients who have already tried some other medications to have another option that could work for them.
But also, in general, what I've seen with Jackson, my clinical practice in HS, is that they work quite well in patients who have actually early nodular disease and not a lot of drainage, and also patients that have really severe disease, as we see in Crohn's or cutaneous Crohn's, that have a lot of tunneling and drainage. So I think it'll be interesting over time to see where all these drugs fit.
Porter: For povorcitinib in the STOP-HS1 and 2 trials, they looked at Week 12 as the primary endpoint, and they used High Score 50, which is the same endpoint that we've historically used for other HS trials, and it loosely correlates to about 50% in disease improvement, and it's a binary outcome. So patients either achieve it or they don't. So they could be at 55% improvement or 90% improvement, and they would still fall into the high score of 50. But what they found is that at Week 12, about 40% of patients in the quovositinib arm, of which there were two doses, 45 and 75 milligrams, performed about the same. They achieved a high score of 50, so about 40% compared to 30% of the placebo.
That doesn't sound like a very large difference, but it's actually almost in line with what we've seen in some other trials; it's very similar to secukinumab and a little bit less than adalimumab and bemichizimab's data. But there are a lot of caveats in how we compare some of these numbers because the placebo rates are highly different from each trial. The adalimumab trial, for example, which was PIONEER I and II, was all bio-naïve patients, which we typically consider to be easier to treat than patients who are bio-experienced, and pulvarsitinib studies had about 30% of patients who had been exposed to a biologic before, so potentially a more treatment-refractory population at baseline. Then also, the time points of the endpoint.
So Week 12 might have been a little bit early because sometimes we do trials out to Week 16, and the vast majority of these drugs at 24 weeks and definitely a year out, we're seeing a lot more continued improvement. But we just cannot do a placebo-controlled trial for six months or 12 months in patients who have moderate to severe HS, so I think the good news is that we're in the same range, and this really will be an efficacious treatment for patients.
Porter: The most common safety findings were actually not dose-dependent. So, the 45 and 75 milligram groups had about the same number of AEs, and the most common adverse event was actually acne. It was about 17 to 20 percent of the population on the study drug, and then followed by nasopharyngitis, upper respiratory tract infection, which is not that uncommon, I would say, for a medication that acts on the immune system. The acne, I think, is notable, and one of the things to also think about is in HS trials, we tend to see a younger population, so the average age is in the 30s, and the vast majority of patients are women. And the acne in this trial was all deemed to be mild, essentially.
Because of the way the trial is designed, the treatments that we usually use for acne, like topical antibiotics, topical retinoids, oral antibiotics, isotretinoin- a lot of them overlap with HS therapies, and so they're actually prohibited because they're not. They could potentially impact the efficacy of HS. So it's kind of hard to say how these patients would do overall with their acne if they had, in regular practice, been allowed to get a bunch of other therapies. I think the other key safety findings are related to what we think of the JAK stat profile so far. We know that there's a black box warning on the other JAK inhibitors for the MACE events, [or] the major adverse cardiac events. Then also for thromboembolic events and malignancy. The good news is that these were actually very, very low in this population.
There were, I think, about three thromboembolic events, maybe four in the whole trial up to the one-year mark. This is in a patient population that already has an increased background risk due to their background demographics. Half the patients in this study are smokers. Their average BMI is about 35. So again, higher risk profile, but actually not a very high number of adverse events for those. There was one death of undetermined etiology that the investigator at that site deemed unrelated to treatment. I think for a JAK inhibitor, the safety profile is quite clean, but it still sort of fits in line with JAK inhibitors overall.
Porter: Yeah, I briefly mentioned this when I talked about the primary endpoint, but the article actually has out to the Week 54 data. If we look at some of the patients who, for example, achieve high score of 50 at Week 12, three quarters of them essentially maintain that response at Week 24 and even out to week 54, so I think that is the information that we really like to see too in these trials: how do they do in the first early months, [and] really how is it going down the line? A lot of the patients, actually, saw efficacy rates improve over time.
There are more patients achieving a high score of 50 at the six-month mark and at the one-year mark. I think this is really important because when we're using other biologics in psoriasis and atopic dermatitis, usually at the three-month mark, we expect them to essentially be at their best, almost or very close to being clear. But for HS, we're really waiting six months or longer, and the three-month assessment is just to make sure that they're on track. I think it is really important to think about both the short-term and the long-term gains.
One of the other very nice things about this medication is they actually started looking at some of the effects of the medication in terms of the efficacy endpoints and the patient-reported outcomes at Week 3. And there was actually a difference even at that time point between patients who got the study drug and patients who were on placebo. So we can see some rapid improvement in symptoms. But again, they're just really not at their peak until further down the line.
Disclosures: Porter has served as a consultant for AbbVie, Almirall, Arcutis, Aristea Therapeutics, Avalo Therapeutics, Eli Lilly, Framework for Interoperable Data Exchange (FIDE), Incyte, Janssen, Merck, MoonLake Immunotherapeutics, Navigator Biosciences, Novartis, Pfizer, Prometheus, Sanofi, Sonoma Biotherapeutics, Trifecta Clinical/WCG, UCB and Zura Bio and as an investigator for AbbVie, AnaptysBio, Arcutis, Aristea Therapeutics, Avalo Therapeutics, Bayer, Bristol Myers Squibb, Eli Lilly, Incyte, Janssen, Merck, MoonLake Immunotherapeutics, Navigator Biosciences, Novartis, OASIS Pharmaceuticals, Otsuka, Pfizer, Prometheus, Propeller Biosciences, Regeneron, Sanofi, Sonoma Biotherapeutics, UCB and Zura Bio. She has received royalties from Beth Israel Deaconess Medical Center and fellowship funding to the institution from AbbVie.
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