Remember when PASI 75 was the gold medal? Today, it barely makes the podium. In this episode of the JDD Podcast, host Dr. Adam Friedman welcomes Dr. James Song for a conversation that explores how the definition of “success” in dermatology has undergone a remarkable transformation. Like smartphones, social media, or your favorite coffee order, our expectations have evolved, and fortunately, so have our therapies. What was once considered exceptional efficacy is now often viewed as the starting line. Using psoriasis as the blueprint and hidradenitis suppurativa as the next frontier, Dr. Song unpacks how we progressed from celebrating PASI 75 to routinely discussing PASI 90 and PASI 100, and why that evolution represents far more than a numbers game. Together, they examine whether current clinical trial endpoints truly capture what patients value most, how higher efficacy benchmarks translate into meaningful improvements in quality of life, and why statistical significance doesn’t always equal clinical significance. Importantly, Drs. Friedman and Song tackle an important question: Are we finally measuring what matters, or have we simply become better at measuring what has always mattered?

Whether you’re interpreting the latest trial data, counseling patients about treatment expectations, or simply trying to keep pace with a rapidly evolving therapeutic landscape, this episode offers a practical framework for understanding where dermatology has been, where it’s headed, and why yesterday’s  outcome MVP may be today’s bench warmer.

Psoriasis Endpoints: A Decade of Change

[00:47]

Dr. Adam Friedman: Welcome to the podcast, Dr. Song.

Dr. James Song: Great to be here, Adam. Thanks for having me.

Dr. Adam Friedman: Of course. All right. So first off, this whole doctor nonsense, we’re friends here. We can assume, go by first name basis, James. Let’s maybe start by jumping in the DeLorean, revving up to 88 miles per hour and going back in time, maybe 10 years ago, and looking at clinical trial endpoints and clinical trials in psoriasis—I’d say hidradenitis suppurativa, but those were barely existent. Sadly, though that has changed, fortunately. But in the world of psoriasis clinical trials, what constituted a successful endpoint and how does that match up now 10 years into the future? Where does it match up with what our expectations are today?

Dr. James Song: And it’s funny you say 10 years ago, because that’s right around the time I graduated. So my attendings, they would make fun of me. They’re like, James, you’re so lucky. You don’t know what it used to be like back in the dark ages when we use methotrexate, where a 50% improvement was considered to be a good response. And at the time we had TNF inhibitors and we just had ustekinumab. So getting to a 75% improvement was really considered to be kind of a high bar for us. And that is really what patients expected as well. But I think naturally as our understanding of the disease gets better, so do our therapies. And we really start to understand the immune mechanisms of psoriasis at a much deeper level. And so it’s not just inflammation, but it’s really this IL-23, TH17 axis that’s driving a lot of psoriasis. And so now we’re looking at 90% better as a primary endpoint in some of our newer studies. And now we’re at a point where 100% skin clearance is an actual primary endpoint. And that tells you that this is something that’s not just a pipe dream anymore, but that this is an attainable result for a lot of our patients. And as our treatments just get better, I think the expectations just get higher. And we see the treatment guidelines kind of follow that as well, where PASI 75 was considered to be an acceptable treatment response. Then BSA of 1% or less was considered to be the goal. And now more recently, we have this definition from the NPF of on-treatment remission, which is 100% skin clearance, and you need to maintain that for at least six months. So I think psoriasis has been really just a beautiful example of how bench-to-bedside research has really led to better and better therapies, and that has translated to better and better care for our patients.

The Evolution of Expectations and Science

[04:09]

Dr. Adam Friedman: So you don’t think it’s just that we are more demanding? I mean, I know you and I are technically millennials. We can talk about the Gen Zers and beyond in dermatology, but rather it’s that the therapies are actually conferring a greater benefit than what we had 10 years ago.

Dr. James Song: Yes, 100% agree.

Dr. Adam Friedman: So what do you think is the greatest driver behind that? I mean, you started to speak a little bit about the shift in our understanding of the pathophysiology. And so with that in mind, obviously there’s been, I think, a very rapid evolution with respect to our understanding of disease. Also, I’d say understanding of how you translate severity. It’s not just about, you mentioned BSA before, and I think something that I’d love to get your insight on is there was this mindset that BSA of 10% is the cutoff for severe or not severe or warranting an advanced therapy, and I think that’s changed, especially for special and disabling sites. But what do you think has really been the greatest driver of this shift? Is it simply just science? Is it the patient voice in our experience with patient hearing? What they really define as success? Or you mentioned the NPF’s call to clearance on-treatment remission, or is it all of the above? I mean, I feel like when you see ‘all of the above’ you’re supposed to actually circle that one on every test for any residents listening. What do you think has really driven this mindset of ‘we should be getting every patient clear’ and if people didn’t know that, please know that and keep them clear?

Dr. James Song: And I’ll take your advice, all of the above. No, I think in all seriousness, the science has really driven a lot of this. We understand now that while IL-17 is a key effector cytokine in psoriasis, IL-17 could be produced by many different sources, not just these IL-23-dependent sources. And even within the IL-17 family, we’re starting to understand that there’s different members to this family that could have very similar overlap with some of each other and they can activate these receptors in a very similar fashion. So I think the science has taught us a little bit more about how we could get even deeper levels of response. But the patient voice, as you mentioned, I think we’ve heard loud and clear that if we only treat patients who have a certain body surface area, then we are going to be leaving out a very large swath of patients that are still suffering miserably from this debilitating disease. And as you mentioned, Adam, those patients include those who have high-impact sites that are affected, like your scalp, the palms, the soles, the genital skin, of patients who have high symptoms associated with psoriasis. So they have maybe limited BSA, but they have high itching, burning pain. And this idea of a systemic disorder now that we know psoriasis is, how just treating patients with a topical therapy may not be enough to address some of the underlying systemic inflammation that can lead to potentially other comorbidities down the road. So we’ve heard from patients that we should be able to treat not just this limited group of patients with what we used to consider to be severe disease, but maybe we should lower that threshold of offering patients advanced systemic therapies. And I think that’s the reason why now so many of our patients are able to benefit from these medications, partly driven by the science, partly driven by the patient voice.

Communicating Outcomes to Patients

[07:27]

Dr. Adam Friedman: I really love that you frame that about the concept of this being truly a systemic disease and we’re seeing the cutaneous manifestations and how, if you think of that perspective, a topical is not appropriate for many of these patients. I often will tell patients, you wouldn’t treat diabetes with a topical. That’s a systemic disease. Though maybe one day, as a big nanotechnology nerd, maybe there’s some way to encapsulate insulin or some peptide and get through the skin, but we’re certainly not there yet, or at least the government hasn’t let us know that we’re there yet. But along those lines, and in that communication to the patients, we have shifted. You mentioned PASI 75 was kind of a gold standard 10 years ago. Now it’s like you kind of scoff like, ‘PASI 75? Talk to me when you’re at 90 or 100.’ How has that changed the way you talk to patients about the treatments we have and expectations?

Dr. James Song: I will usually start off with telling a patient that if 100% skin clearance is your goal, which it should be for the vast majority of people, then we could do a very simple, what we call numbers needed to treat analysis. How many patients do I need to treat with a particular drug to get 100% clear? And there’s a couple that really stand out that I would say are going to give you the best chance of getting to 100% clear. So those are the ones that I usually will offer up first and explain that this will give you the best chance of having a quality of life that is not affected by your psoriasis at all. Because we even have data that patients who are almost clear, who have a pretty good quality of life, getting that incremental benefit from almost clear to completely clear can make a pretty dramatic difference in their overall quality of life. But I think it also allows us to fight this kind of treatment inertia, Adam, where you’re getting to 75% or 90% clearance, and that’s all you’re constantly doing. And you could be like, ‘You know what? We are able to maybe get you even clearer because we do have medications that can get you there.’ So let’s have a conversation. And there are some patients who might be completely fine with having a little bit of psoriasis here and there. So I’m not necessarily advocating that we over-treat every single patient, but at least they should be given the option; that conversation should start with that.

Psoriasis Patients and Treatment Goals

[09:38]

Dr. Adam Friedman: You know, it’s funny you bring up the almost clear, and I think for certain disease states, patients would absolutely bow down to that almost clear. I don’t know, I find psoriasis patients, you walk in, you don’t see—you see literally a speck, a little bit of psoriasis, and you’re celebrating, you’re doing a happy dance, hopefully on the inside, not the outside, and they’re furious. They’re like, ‘Look, don’t you see that right there?’ Is that your experience as well?

Dr. James Song: Yes, it is.

Dr. Adam Friedman: Something unique about psoriasis patients, maybe it has to do with these outcomes that are out there and they’re aware of these PASI 100s, these completely clear results that they’re expecting. It does change the way they look at how well they’re doing. Are you experiencing that also? These patients, like they have literally a 0.1 square centimeter and they’re miserable.

Dr. James Song: Yes, I 100% agree with that sentiment. I think it’s a reminder to these patients that they still have a disease, even though it’s not as bad as it was before, that this disease maybe isn’t in full remission. And even the worst part of it is when a patient gets initially clear and they start to lose a little bit of response. I think those patients really start to worry, ‘Is my body starting to fight this drug off? How many other options do I have left?’ So getting to clear certainly is important, but it’s also maintaining clear for the long term, that’s equally important.

Long-Term Durability in Psoriasis

[10:57]

Dr. Adam Friedman: Right. And that too, in thinking about clinical trial design, it is so important to have those long-term extensions to see that durability. And I also just want to pick your brain. I’ve seen this in my own practice. Of all the patients out there for whom there are advanced systemics approved or even off-label, psoriasis patients have been burned more than anyone with, ‘Hey, I got a great response two, three years in, wait a minute, what on earth is happening now?’ How does that fit in in terms of how you think about what medication you select? How important is that long-term data from that perspective of psoriasis patients?

Dr. James Song: It’s incredibly important. And I think the truth is for a lot of these open-label extension studies, you are somewhat looking at what we call a responder population, people who are generally doing well. And so all the lines are always like a hockey stick, right? They go up and they stay flat. But what we’ve seen in the real world is different. And I would say certain classes of medications certainly have better long-term durability than others. And I generally see this more in patients who are heavier, as well as those who may have been more systemically experienced, so they’ve done the other systemic therapies before. And so if a patient is doing well, and they’re like, ‘Dr. Song, could I stop this medication?’ I’m just like, ‘You know what? I know you’re doing well, but I just can’t guarantee you that if you stopped the medication and then you restart it, that you’re going to get back to where you were before.’ And so that’s part of the conversation that we have.

HS Endpoints and Challenges

[12:20]

Dr. Adam Friedman: So maybe let’s shift gears a little bit to HS. And I think hidradenitis suppurativa has historically lagged behind psoriasis in terms of available therapies and attention, no doubt, and also treatment expectations. How has the endpoint landscape evolved in HS? So, we saw PASI 75, 90, 100. How has that changed for HS in a similar fashion?

Dr. James Song: You know, with HS, the study designs are a little bit challenging because our primary endpoint, I don’t think fully captures the patient’s global experience. You know, we’re looking at reducing abscesses and nodules and not getting any new abscesses or any new fistulas. But we actually know that even in patients who get to, let’s say, a 50% improvement in this what we call HiSCR, they could still have significant pain, they could still have significant drainage and odor, they could have a tremendous impact on quality of life. So there really is, I think, a need to try to raise that bar even higher from just 50% improvement, which has been historically our primary endpoint in all HS trials, to maybe HiSCR 75, 90, 100, even looking at some of these other kind of more novel and more global measures of HS improvement. I think the challenge though is because of the waxing and waning nature of this disease and the fact that it’s hard sometimes to grade abscesses and nodules and fistulas, you see these wild placebo rates which makes it hard to interpret how much is this drug actually doing and how much of it is just a natural course of the disease. But as your endpoints get more stringent, you tend to see more separation from the placebo arm to the active treatment arm, which is why I tend to like to look at some of the higher bars to really tell me how well is this drug working.

Dr. Adam Friedman: And beyond the things that HiSCR really captures, to your point, new lesions or flares, establish things and even the formation of new tunnels or scarring, what else do you think matters most, maybe more to the HS patient than even to us? I mean, you mentioned pain, which I think we have a lot of itchy skin disease and these patients have itch too. Let’s not forget that. This is such an exquisitely painful condition. So it’s pain reduction, drainage control, quality of life, which historically wasn’t really captured so well in some early studies, flare frequency. What do you think is—when you’re looking at the clinical trial programs that have come and those that are forthcoming and evolving—what really is important to the patient and of course by default you?

Dr. James Song: You know, I think generally speaking, as you go from HiSCR 50 to 75 to 90, 100, you definitely see not just an incremental increase, but a dramatic kind of almost exponential increase in the quality of life. So I like studies that are showing us higher or more stringent HiSCR thresholds. But in addition to that, and you mentioned all the key ones, you know, pain, fatigue, a flare—however you define flare, because this is a very dynamic disease, much more so than psoriasis—the usage of pain medications, right? Whether that’s NSAIDs or narcotics, we know that this is something that’s been used a lot by our patients. And so can we reduce the amount of pain medications that they’re using? And then just a more of a global quality of life. We know there’s so many different things that go into quality of life. And historically we’ve used measures that maybe were not designed specifically for the disease that we’re trying to study, like the DLQI is kind of more of a rough and dirty quality of life measure, but using ones that are specific for a disease has been validated in HS, like the HS quality of life, or there’s the international IGA score that we use as well. So I think incorporating more and more of that into not just clinical trials, but even in our day-to-day practice, and they’re not hard to do, I think we better fully capture the entire patient experience.

Case Study: Bimekizumab

[16:13]

Dr. Adam Friedman: So maybe let’s do a kind of case study, so to speak. We’re talking about clinical trial metrics. What is meaningful to the patient? What is meaningful for us? And maybe using bimekizumab as an example, it has an indication across multiple inflammatory diseases. Maybe to start, what makes the clinical trial program—and we can divide it, psoriasis, HS—noteworthy in your eyes? Are there unique things? Because we’re talking really about the evolution of clinical trials and the evaluation of these drugs in setting metrics and evaluating things that are important for everybody. Were there things in these two programs that stood out to you?

Dr. James Song: Let’s start with psoriasis. The two things that really stood out for me was one looking at 100% clearance as a primary endpoint as early as week 16 and then doing it against a medication that is technically in the same class. And so historically we haven’t seen two drugs in the same class go against each other. It’s usually two different MOAs, but now we’re actually looking at the IL-17 inhibitors which are both effective. We’re looking at 100% clearance at week 16 and this is actually the only medication that we currently have where the majority of patients actually got to 100% clearance by the primary endpoint. We’re seeing more than six out of 10 patients are getting there. And the truth is, secukinumab, which was the comparator in that study, is also an effective medication. But the difference, the delta was quite dramatic. And the further you went out, the more of a difference that was seen between these two medications as well. And we’re doing that really at a fraction of the doses of secukinumab. And from a dosing standpoint too, I think you kind of get the best of the IL-17s, but also the IL-23s because you kind of have both of them with the dosing.

Dr. Adam Friedman: You brought up an important point that I have found keeps coming up in our resident clinic, in discussions with colleagues about the timing. You mentioned the further you go out, you see you’re capturing more and more patients hitting this metric. I think we’re getting very privileged in having drugs that work very well and could also work quickly. But I think there’s also a detriment to that in that if you’re not seeing that PASI 100 or almost clear or clear by an earlyish time point, then the drugs fail and you switch gears. And I think that’s actually a very bad move. Or for example, you mentioned the real-world chaos of ‘you’re doing really well and you flare a little bit, and oh God, you failed this medication, you gotta switch gears.’ I think that’s actually not the right move because there’s many different costs associated with switching medications. I would love your perspective on how that data gives you confidence that maybe, hey, give it more time. And I’d love to know what that timeframe looks like for you. But also, what do you do in those scenarios where someone has maybe a blip in terms of doing well and they flare a little bit? Do you abandon all hope and run to another category or do you stick with it?

Dr. James Song: That’s a great question, Adam. And I 100% agree with you in that we’re trying to limit treatment cycling; even though we have 15 FDA-approved therapies, you’re eventually going to run out. And to your earlier comment, it is more expensive every time you switch. I think it really just depends on the MOA, where certain MOAs work faster than others. And if a patient doesn’t improve at all on a particular drug by like three to six months, then I’m worried that I have the right—that I might have the wrong diagnosis. So if I don’t see anything at the time, that’s one thing, but if I see something, I think it’s reasonable to continue them on for at least six months. And in certain areas, like for example, the palms and soles and the nails, I would give it at least a year. Those areas just take longer to clear up. But I do want to see something. Now, if the patient initially improved and they lose response over time, we call that a secondary non-responder, sometimes it’s just a matter of boosting them. So you might want to repeat the induction dose, so you could kind of load them up again. Make sure you’re optimizing topicals, you could throw on a little bit of another medication just to kind of rescue them, whether it’s cyclosporine—which I know a lot of our residents aren’t using anymore, I still will use them—or even good old methotrexate. Just a little with the methotrexate is all you need to get them back to your level of before. But I don’t want to give up on the medication too quickly because of your earlier points.

21:01: 

Adam Friedman:Yeah,I love it. I’m like stuttering because I love it when you know you do things a certain way, but you’re not sure if you’re the outlier and you’re Captain Crazy. And when you hear someone who you respect and learn from as well say literally what you’re doing, I completely agree with everything you said. And it goes back to the having that clinical trial data to assure you that, hey, maybe someone hasn’t gotten to the metric you’re hoping for by certain time point. Is there still a chance? You know, I feel like, you know, you know, Jim Carrey from dumb and Dumb and Dumber, you’re telling me there’s a chance that they may still get passing 100 in a couple of weeks from now, you know?

Dr. James Song:That’s right.

Dr. Adam Friedman: So I think that’s that’s that’s that’s great.

Dr. James Song: Yes, yes.

Redesigning Clinical Trials

[21:50]

Dr. Adam Friedman: So let’s talk about the HS program. I definitely have my favorite metric, but I’d love to hear yours from looking at bimekizumab for HS.

Dr. James Song: Just the fact that HiSCR 75 was never even a pre-specified secondary endpoint. We always just fixated on HiSCR 50. But the fact that HiSCR 75 was a secondary endpoint for the first time in an HS trial, that’s one thing. But even the fact of looking at HiSCR 90 or HiSCR 100, that to me gets so exciting because it tells you how far we’ve come. And the fact that we could just show you the data really speaks to the progress that we’ve made in HS. So I like to look at the higher bars. There are other patient-reported outcomes that I think are meaningful as well, as far as pain improvement, but the HiSCR 90 and 100, I think that is really, really impressive for me.

Dr. Adam Friedman: You know, for me, it was fascinating that out of the gate, we’re talking about two-week data. We don’t talk about two weeks unless we’re going to—of course this is off-label—give someone a prednisone pulse or even an off-label JAK inhibitor, or even those sometimes don’t work quickly. So the fact that in branded programs, in the study, we can talk about the impact at two weeks is extremely meaningful because these patients, it’s usually a slow story for them. So for me, and I agree with everything you said about 5–10 years ago, talking about HiSCR 90 was unheard of. You would never go there. Or even 100, you would never talk about that. I think the early onset of activity married to reduction in pain, that kind of did it for me. I think that was a really bold time point to evaluate. Along those lines, in terms of communicating these different things to patients, do you ever incorporate—when you’re talking about a drug that has multiple indications across different diseases—does that work into the discussion with the patient? Does that also work into your thinking of, if a drug is approved for several things, does that give you more confidence? Does that maybe drive you towards a certain patient type?

Dr. James Song: Excellent point. We know that even though these diseases may not necessarily be identical, they share a lot of the same immune pathways and having one of these diseases will increase your risk for having another one as well. And so just the fact that we can have this more comprehensive coverage with some of our medications is a feather in the cap for some of them. But on the other hand, there are some medications that can worsen a certain comorbidity or medical condition as well. So it kind of cuts both ways, but certainly with HS and psoriasis, we know that they can have both. And a lot of the inflammatory arthropathies that we see with one are also seen with others and you can treat them both with an IL-17 inhibitor.

Dr. Adam Friedman: So a pivot and hopefully a fun question and not too much pressure. If you could redesign clinical trial endpoints, just burn the whole thing down and build it back up, would you rebuild what we have right now in this moment? Would you add, remove, would you prioritize certain endpoints? And we can split it between psoriasis and HS.

Dr. James Song: Maybe I’ll start with psoriasis because that’s the easier one. I actually think that our current scoring systems are pretty darn good. And there’s really good inter- and intra-observer validity that we’ve seen. And I actually think for patients who have pretty significant disease, PASI scores are actually pretty good at capturing improvement. I would love to see inclusion criteria become a little bit more permissible, not just capturing the more severe patients, but those who have more limited disease and treating them earlier. I think that’s another area of interest: Does early intervention lead to potentially better outcomes, higher chances of remission, and even potentially a cure? So if we could find groups of patients that have disease for less than let’s say one or two years and you treat them with one of these effective medications, then maybe that will answer that question. So that’s for psoriasis. For HS, there are so many things I wish we could redo or do differently. One would be to treat them earlier as well. For me, once a patient qualifies for a clinical trial, which is generally Hurley Stage two or three, the cat’s out of the bag already. You already have these draining fistulas and sinuses that are going to be very hard to undo or reverse with a medical therapy. A lot of times we have to use surgical intervention. But also grading HS severity can be very challenging, even for those who are experienced clinical trialists, because these tunnels and fistulas and abscesses and nodules, they all kind of just merge together sometimes. And so if you were to look at more objective ways of measuring HS severity, whether that’s using ultrasound—ultrasounds are a great way to do it—it just has not been validated yet. But if you could use ultrasounds to more consistently capture HS severity, then I think it makes it more of an apples-to-apples comparison when we compare across trials. But those are just my two cents. I’m curious what you think, Adam.

Dr. Adam Friedman: You know, I agree. I think that we’ve seen an incredible evolution of what is being evaluated. I know you have your primary outcomes, which really is what the FDA is most concerned about to say yay or nay. But I really love the investment, creating new validated scoring tools, whether it be about quality of life, looking at pain, looking at itch, looking at sleep, even diving into, ‘Can we redirect the systemic course?’ Looking at comorbidities and can we limit them over time or even maybe prevent them eventually in patients we know are high risk for a litany of conditions? I think it’s exciting. I do like the idea of trying to take high-risk individuals or early disease and identifying them first and foremost, which has been a problem with HS, and treating them early. You’re right. By the time someone is eligible for an HS study—and of course, the early staging system is a surgical staging system, so if you’re a two, you’re already a surgical candidate—it would be great to identify people before they have that permanence and see if we can prevent that in the first place. Certainly an ideology that is in progress, hopefully. But the problem is we also don’t know which early disease patients will progress. So I think that’s another thing I would love to see once we have some validated biomarkers. Maybe that could be integrated into some of these studies as well. James, thank you so much for your time, for your insight, for your friendship. I’m glad we didn’t have to talk about how I out-bench press you every single time we both go to the gym.

Dr. James Song: Ha!

Dr. Adam Friedman: It didn’t have to come up. And so I’m glad I didn’t have to say anything about it. That is a total lie, ladies and gentlemen, no chance, no way, no how. But I felt like I had to somehow get that in there. So thank you for being here with us, James.

Dr. James Song: Adam, likewise, thanks for having me. This has been a lot of fun.

Dr. Adam Friedman: Great. And thank you all for joining us for this edition of the JDD Podcast.