Hi everybody, I am happy to be here talking about vitiligo clinical studies. We're gonna talk about practical points and how to run a study and look at some of the recent results that are pretty exciting for vitiligo. I'm John Harris, I am professor and chair of dermatology at the University of Massachusetts Chan Medical School. And I run a vitiligo clinic and on research on vitiligo, including clinical trials. These are my disclosures. There are a number of disclosures there. I work with a lot of companies who are interested in bringing treatments to patients with vitiligo. I'm happy to be doing that. And in the process of this discussion, I may discuss off-label drug uses because until just two years ago, all treatments were off-label. Here's a quick primer to begin on clinical vitiligo. Vitiligo is really common, about 1.4% of the population. That's a lot of people. Half the patients who get it, get it before the age of 20. So we're dealing with a lot of children with vitiligo and it has a number of disease associations that we need to think about. Type 1 diabetes, Hashimoto's, thyroiditis, and some others. This is how vitiligo begins. These are small macules of deep pigmentation here and here, and those can grow and coalesce into larger patches. This is a typical presentation on the hands. It can affect any part of the body and can affect wide BSA, as you see here. And this can be psychologically devastating for patients. This is segmental vitiligo. It's a variant of vitiligo that affects only a focal part of the body and does not cross the midline, as you can see here. So here and here. It used to be called dermatomal vitiligo. This has nothing to do with dermatomes. This is multiple dermatomes here and this is crossing dermatomes perpendicularly. And so this we call segmental vitiligo. It's important to mention that vitiligo can be stable or active. And here are two examples of very active vitiligo with rapid progression. This one was published by Dr. Pandya in the JAD in 2015. You can see some subtle vitiligo here on the hands. She declined treatment and just three months later saw rapid progression of disease here with a lot more BSA involved with the area. And hands are very difficult to treat because they're glabrous skin. And so this may not be reversible. This is another case by Khaled Ezzedine in Paris. Patient went to see him looking like this, went to Africa for a vacation, decided to treat once he returned and he returned looking like this with significant progression of his disease. And so it's really critically important to recognize when vitiligo is active because it can spread so quickly. So here are four signs of disease activity that you can look at in the clinic to know when it's active. This is confetti vitiligo. So rather than large patches of depigmentation, you see these small macules of depigmentation that cluster here. This is trichrome where you see three colors, one, two, and three. And this hypopigmented border indicates active disease. Here is Kevner phenomenon where an injury to the skin causes vitiligo to occur at that location. These are linear macules of depigmentation, scratches. And then inflammatory vitiligo where there's a pink erythema and sometimes scale at the edge of a vitiligo lesion, but not in the center. And this is a really vigorous case. And then this is a more typical case with the erythema around the edge of the vitiligo. When you see any one of these signs of vitiligo, the disease may be very active. And this is important when considering enrollment for clinic trials. Woods lamp examination helps visualize vitiligo. So this is under room light, very difficult to see the vitiligo on the fingertips, whereas under woods lamp, this is much more visible. And so this needs to be taken into consideration when designing outcomes of clinical trials. Will you use photography? Will you use a woods lamp exam to help you see the vitiligo? So the good news about vitiligo is it repigments. It's reversible. And you can see that here as little brown macules of pigment is returning in this vitiligo lesion. And those little brown macules are coming from the hair follicles. So we call this perifollicular repigmentation. This is the most rapid repigmentation that we see in vitiligo. This is important because poliosis or leukotrichia, which are descriptors for white hair, mean that those areas will not repigment. And so when enrolling for clinical trials, if there's enough poliosis or leukotrichia in an area, then that area is often excluded. And glabrous skin generally will not repigment because there are no hair follicles in that area. You can see some marginal repigmentation here around the edge, but the lack of hair follicles means this area will not significantly repigment with treatment. This is just another example of that. This patient repigmented in these areas with the white arrows really very nicely to UVB phototherapy, but these two areas were not repigmenting. When we looked up close under a dermatoscope, you could see that those areas had white hair, bellus hairs in that area. And so again, this is responsible for the lack of repigmentation. All right, so what have we learned from vitiligo trials? The first trial we're gonna discuss is a parallel phase three clinical trials to test topical ruxolitib as a treatment for vitiligo. This was in this phase three enrolled patients aged 12 and older. First 24 weeks, you'll see this is typical in the clinical trials we'll discuss today compared to vehicle for the first six months. But then after that, it became open label to look at long-term repigmentation. So the primary outcome for this study was the F-VASI 75 or 75% improvement on the face. And you can see that 30% of people using ruxolitib cream achieved this level of repigmentation, whereas placebo was limited to 7.5%. And these were, again, two parallel clinical trials that were done in over 200 patients each. And you can see that the exact same result occurred in both with a little bit higher placebo response in one of the trials. You can see more responding in an F-VASI 50 or 50% improvement on the face and less at the F-VASI 90. Importantly, you can see that these are the phase two results and it was almost identical to this with 30% improving by six months. In that study, the placebo rate was zero. So higher placebo rate in the phase three. But again, very significant responses here. Adverse events observed were pretty much limited to application site acne and pruritus. I have these highlighted because this is where we see a higher rate in the drug compared to placebo. Others, the placebo rate was equal to others. Here, this is the extension period where we cannot compare to placebo. And so we're really limited to here, acne and pruritus. In the area of application. So it's important to note here, this is a long-term extension of the trial. This is showing two years of treatment now, starting at one year here. I already showed you the earlier study was an earlier time. This is just a long-term extension and you can see patients continue to improve. So this is F-VASI 75, more and more patients over time, up to two years continue to achieve this level. And this continues to improve all this entire time. So it may take some patients two years to achieve this response. This is much slower compared to other diseases like atopic dermatitis or psoriasis that improved much faster. So we need to be patient. These are continuously improving F-VASI 90 responses. Very few achieving this level at one year, but by two years, about a third of patients. So this is really important and impressive that we need to be patient when testing drugs and using drugs long-term. Here, there are two lines. One is just, this was the placebo group that then switched over and then for the next year and a half used it. So it's gonna be lower than those who are using the drug from the very beginning. One thing to consider, remember we talked about active and stable disease. So this topical trial, topical ruxolitinib here, about three quarters of the patients had stable disease and one quarter had progressive disease. And this is gonna be important later. As you can imagine, progressive patients may be more difficult to control. And so keep this in mind, the topical trial where we saw these really impressive results, three quarters had stable disease. And this is contrasted here in the next study. So this is oral ritlicitinib. This is an oral JAK inhibitor tested in a phase IIb clinical trial. And you can see here patients were randomized to placebo for different doses of ritlicitinib. Some actually had a loading dose and then continued on a lower dose later. And then all were entered into the extension period after six months where they were used the same dose. And again, a loading dose with a lower dose long-term. But one of the important things about the study is they required disease activity for inclusion into this study. And so 100% of patients, unlike the last study, had active disease. So there was a dose response of improvement here. This is overall improvement by six weeks, six months, excuse me. And then here there's the extension when all subjects were put on the drug. You can see continued improvement over time here. But this was a 12% achieving an FFASC-75 at six months. This is much lower than what we saw in the topical. But it's important to remember, all of these patients had active disease. So the difference here, this is certainly an oral JAK compared to a topical in the previous study. But then all of these patients had active disease and therefore were likely very difficult to treat. And so it's possible that that is the factor that limits the number of patients achieving an FFASC-75, the primary outcome at six months. And we can see this if we actually separate the lesions. So the patients all had active disease, but they had some active lesions and some stable lesions. And when you separated these out, you could see here that those who are on placebo with active lesions progressed. This is the placebo-treated active lesions. They got worse. Whereas the drug-treated active lesions were stable. They did not change in size. And if you looked at the stable lesions, the placebo-treated stable lesions did not change as you might expect, but the drug-treated stable lesions actually improved. And so this indicates that it's very important when enrolling patients, if you enroll active patients, they may, best case scenario, not change their lesions after six months. And this is actually a good response to the drug. But if you lump all these together and just look for repigmentation, it may look somewhat disappointing. And so I think that the company learned from that. In phase two, remember, they required active disease, whereas in the phase three, now that is ongoing, active or stable disease is allowed. And so I think that that's a lesson learned. Also, expertise in evaluating the VASI is important. So this is the local read in the phase three clinical trial. Sorry, the phase two clinical trial where you can see lots of standard deviation, lots of error here. Whereas the central read, which was done on photographs, same patients, but a single reader had much more narrow standard deviation and less noisy data. And so this is something to take into consideration when designing the trial, the local read versus an individual reader from photographs. Okay, the next study I wanna discuss is another oral JAK inhibitor, upatacitinib, tested in a phase two clinical trial. And this study, again, randomized to either placebo or different doses of the drug, and then extended beyond where all patients received drugs. So some subjects got placebo and then a dose of drug and others got drug from the very beginning. And the primary outcome again was that VASI 75 after six months. So in this case, in contrast to the last one, though, not all patients were required to have active disease. As you can see, active vitiligo was anywhere from 67% to 75% in contrast to the 100%. So you might imagine that this patient population would be slightly less difficult to treat. So these are the outcomes. Again, primary outcome here is FVASI 75, and about 19% of patients at the highest level on the OOPA, 11 milligrams, which was not the highest dose, but the highest responder, about 19% of patients achieved an FVASI 75 after six months. And those who FVASI 50, of course, a much higher rate and those with the total body VASI, this is called the T-VASI, 50% improvement on the body was much lower. And we just see that the body is slower to respond to treatment. When during the open label extension up to week 52, of course, there's no placebo control anymore, but you can see that more patients respond now when treated for a longer period of time. So up to 55% achieving an FVASI 75 now when allowed to treat for 52 weeks. And this data is as observed. The adverse events difficult to determine here where placebo adverse events was 76%. So that's higher than all the drug except for the highest dose here. So a little difficult to know what the drug is responsible for when reported in this way. So I wanna end, that's the data. I just wanna end reminding everyone what are the unique considerations when thinking about running a vitiligo clinical trial. The first here is the time required for the endpoint and for a meaningful response. So while you can see statistically significant results at six months, and that's what the primary outcomes were. If you continue to treat, you can see significant improvement up to two years here with continued improvement. And this is the FVASI 90. So this is incredibly meaningful to patients and requires patients in continued use. So when designing a clinical trial, certainly the longer you follow the subjects, the better the response, but at the same time extends the trial time. So something to consider. The presence of poliosis is very important. A lot of trials exclude patients or lesions that have a significant poliosis of more than 30 to 50% of white hair. And so keep that in mind when evaluating a lesion. If there are pigmented hairs there, you're gonna see nice repigmentation. If there's too much poliosis, then the potential pre-pigmentation is limited. Glabrous skin for the same reason, no hair follicles with the potential to contribute repigmentation. So glabrous lesions typically do not respond. So that needs to be considered when taking into account the total amount of burden of the skin of patients enrolled in these trials. Segmental vitiligo, we didn't talk about this in the beginning, but it is typically excluded from trials. And that's primarily because segmental vitiligo affects the hair follicles very early. So it causes poliosis and therefore poor responses from what we just described. So a lot of times segmental vitiligo is excluded from trials for this reason. Active versus stable disease, we talked about the importance of assessing this, and then thinking about how you wanna recruit into your clinical trials, whether you want all active patients or all comers, some with stable, some with active. The initial topical trial had 75% stable patients, whereas the next oral ritlicitinib trial had only had 0% stable patients. And then the upatacitinib trial had 25% stable. And so those are things to think about when interpreting data from these trials. The central reader here with a much tighter response, cleaner data, think about that as the local readers typically have more error, more standard deviation. And then the importance of the Woods LAMP to help you examine fair skin patients. If you have fair skin, assessing the responses is pretty difficult under room light. And so how do you wanna incorporate Woods LAMP into the read? A live read is pretty easy, but if you're gonna take photographs and read that way, then you have to think about whether these patients need to be illuminated with Woods LAMP. And that's the end of the talk. It's pretty quick, but these are some hints and tips when thinking about clinical trials of vitiligo. A lot more coming. Thanks for your attention.

vitiligo

clinical trials

ruxolitinib

ritlecitinib

Woods LAMP