Exploring two new, validated disease specific outcome measures to assess severity of Chronic Hand Eczema

00:00:00: You are listening to an ADIS Journal podcast.

00:00:06: Hello, my name is Dr.

00:00:07: Raj Chovatia.

00:00:08: I'm an associate professor at the Roslin-Frank University Chicago Medical School and founder and director of the Center for Medical Dermatology and Immunology Research.

00:00:16: It gives me great pleasure to introduce my co-authors with me today, Dr.

00:00:19: Jonathan Silverberg and Dr.

00:00:21: Ben East.

00:00:21: Jonathan?

00:00:22: I'm

00:00:23: Dr.

00:00:23: Jonathan Silverberg.

00:00:24: I'm a professor of dermatology and director of clinical research at the Georgia Washington University School of Medicine and Health Sciences in Washington, DC.

00:00:31: Looking forward to a great conversation.

00:00:34: Thanks so much, Jonathan.

00:00:35: And Ben, I'll let you introduce yourself.

00:00:38: Yes, my name is Benjamin East.

00:00:39: I'm a medical dermatologist and clinical trialist in Portland, Oregon, affiliated with Oregon Health and Science University and Oregon Medical Research Center.

00:00:49: Our objectives here today during our discussion for dermatology and therapy is really to talk about what CHE is, understand the impact of chronic hand eczema on quality of life.

00:01:01: and really delve into the unmet needs in this disease state.

00:01:05: Secondly, we're really going to take a deep dive into some clinician and patient-reported outcomes and talking all about two new validated disease-specific outcome measures, the investigator global assessment of chronic hand eczema, the IGA-CHE, and the hand eczema symptom diary, or HESDI.

00:01:22: Finally, we're going to get a chance to talk a little bit about how these measures might be different than other measures that you might be familiar with from other clinical trials and other programs.

00:01:32: To start things off, Jonathan, can you maybe give us a quick primer or let's say overview about how you define chronic hand eczema?

00:01:40: Chronic hand eczema is hand eczema that persists for more than three months or relapses at least two times a year.

00:01:49: It's a polymorphic disorder and it's one that can affect the palmar surface of the hands.

00:01:54: and the digits, the dorsal surfaces, as well as the wrists.

00:01:58: There's different estimates, depending on the populations that you're looking at.

00:02:02: From one systematic review, it's estimated that lifetime prevalence be as much as fourteen percent.

00:02:08: If you're looking at more recent intervals like in the past year, it'll be less than ten percent.

00:02:14: There are not as much data for the United States in terms of epidemiology, but we have a lot of studies done internationally.

00:02:22: Any additional thoughts, Ben?

00:02:25: There's a large multinational study just this year which took about sixty thousand survey participants and showed the annual prevalence of CHE of about five percent.

00:02:37: and interestingly when they looked at subgroups it was found to be more prevalent in females the ages of thirty to thirty nine those that had employment and those living in urban areas.

00:02:49: Again surveys vary but There's an estimated lifetime prevalence of somewhere between fifteen and twenty percent.

00:02:57: We have to recognize this is super common in the population and certainly super common in the dermatology treated population.

00:03:04: There's a big symptom burden similar to the way we might think about atopic dermatitis, big component of itch.

00:03:10: Although in this disease, an even bigger component of pain, depending on how it presents and how severe it is, can have major impacts in terms of activities of daily living.

00:03:21: work, school, social life, sleep, and mental health, especially when patients feel this sense of stigma.

00:03:29: I have many patients who often say they have people give them side long glances, worried that they're infected or contagious.

00:03:36: There's a physical inability to work because of fissuring and cracking and oozing that can occur.

00:03:42: There's a large impact on patient well-being.

00:03:45: Absolutely.

00:03:45: There's definitely a lot there for us to be thinking about in terms of the clinical presentation and taking all this into account recognizing the burden of the disease.

00:03:55: When patients present on the hands, we don't have a perfect diagnostic tool.

00:04:01: And so sometimes we're not even sure if we're looking at hand eczema versus psoriasis.

00:04:06: We have to recognize that there are different etiologies and that can be hand eczema in the context of atopic dermatitis.

00:04:11: It can be allergic contact dermatitis, the irritant contact dermatitis.

00:04:15: We really have to not necessarily make assumptions about that just on the morphology alone.

00:04:20: I might pause you on that point, and I'm sure your training was quite similar to mine, where you really were told, it's got to be atopic dermatitis.

00:04:28: It's got to be irritant or allergic contact dermatitis.

00:04:30: It's got to be contact or grecaria.

00:04:32: Choose one.

00:04:33: And that's what the diagnosis is.

00:04:34: And I think what you're saying and what I agree with is this idea that sometimes it's really hard to just choose one in many cases.

00:04:42: Even if there is only one diagnosis, it's really not that simple, because many patients will have atopic dermatitis plus contact term.

00:04:50: Many of them will have irritant exposures from work, which are exacerbating the underlying atopic term.

00:04:55: Sometimes they get allergic contact dermatitis.

00:04:57: that starts the process, but now it's a whole chronic process with irritancy as well.

00:05:01: So you really need to recognize this, you know, multifactorial aspect of the disease and incorporate that into different clinical decisions.

00:05:11: There's always this balance that one really needs to have between appropriate workup and diagnostics, but also not delaying treatment for your patients as well.

00:05:19: Touching on treatments, this has been one of those disease states like many of what we see in the chronic inflammatory skin world where people are oftentimes mired in years and years of usually inappropriate but sometimes appropriate topical corticosteroid use.

00:05:33: I'd love to hear your thoughts on general approach to treatment where we have been historically and what's changed recently.

00:05:40: Like our other chronic inflammatory skin diseases, topical steroids are somewhat of a mainstay.

00:05:47: At least that's a starting point.

00:05:49: we really have no officially proved drugs in chronic hand eczema at this point in the U.S.

00:05:57: Technically, topical steroids are approved for hand eczema because they have a broad label for all inflammatory diseases, but really

00:06:06: responsive dermatosies.

00:06:07: Yeah.

00:06:08: And then you have nonsteroidal therapies as well, like topical calcium and inhibitors, not approved for them, but they've been used over the years with variable efficacy.

00:06:17: Even in the world of topical steroids, I find that most of the topical

00:06:20: steroids,

00:06:21: whatever you like using, let's say it's a mid potency like Trimicinolotum or Metazone or something like that, it works the least on the hands.

00:06:28: And so for that reason, you often have to go to stronger ones and then you start running into adverse events.

00:06:34: We've got a limited amount right now in the US and we're hoping that's going to change soon.

00:06:40: Now we look worldwide and there's a fascinating and important addition to our toolbox.

00:06:47: And that is the recent approval of delgocitinib cream, which was recently approved in Europe and in the UK and adults with moderate to severe chronic hand eczema.

00:06:56: Hopefully we'll be able to get to see that in the US soon in other regions of the world.

00:07:01: It's shown a good efficacy and safety profile, and it actually gives us something that works.

00:07:07: I don't have to worry about those limitations potentially of long-term chronic steroid use, adverse events of thinning of the skin, et cetera.

00:07:15: So I think.

00:07:16: The landscape is changing.

00:07:17: That's a big deal.

00:07:19: Absolutely.

00:07:20: With topical corticosteroids, I feel like we're perhaps finally arriving at a precipice with a lot of the research both in CHE and non-CHE disease states that are allowing for the approval of many novel therapies.

00:07:32: I really try to be intentional and position topical corticosteroids as an acute strategy, but one that if you find that you're having to use it extraordinarily frequently or for long periods of time, then it's perhaps time to think about other approaches that are going to be much safer in the long run.

00:07:49: From an ex-US standpoint, we'd be remiss if we didn't mention Allytretinoan, which is an oral retinoy that's out there, approved in several countries for severe hand eczema, unresponsive to TCS.

00:08:00: It's one that does have a pretty substantial side effect profile with nausea and headaches and intolerably can be an issue.

00:08:06: And one very interestingly, that has actually been studied head to head with Delgo Sitnip and Delgo Sitnip actually did the job in comparison to this oral therapy.

00:08:14: So really exciting to see approvals around the world for Delgo Sitnip and hopefully for us here too.

00:08:20: And with Delgo Sitnip, allow me to transition to some of those very well designed studies where we actually got a chance to study a. bonafide CHE population.

00:08:31: With CHE and the clinical trial world, we have a handful of tools that are out there that we use.

00:08:36: Talk a little bit about what some of those historical tools are, some of the pluses and maybe some of the drawbacks.

00:08:45: Sure.

00:08:46: There is no single tool or measure that fully does justice to what this disease is in terms of whether it's on the morphology, on the symptom side, etc.

00:08:56: So we've got a bunch of different tools.

00:08:59: Some that are just looking at lesion severity.

00:09:01: Some that are going to look at symptoms.

00:09:03: They're all good, but none of them comprehensive, fully in the trial space and arguably in the real world, we need to look holistically at a multiple domains.

00:09:14: So the one that in the U.S.

00:09:17: has been a necessity to get any dermatology drug approved in like skin inflammatory skin disease or these different IGA scales that are out there.

00:09:28: and getting to an IGA treatment success.

00:09:30: And this is in the FDA's approach for forty plus years.

00:09:34: But the IGA scales look at like overall legional severity or representative legional severity, not a terrible scale, but certainly doesn't tell us everything we need to know.

00:09:45: In the case of hand eczema, there's a specific tool called the HEXY, which has emerged now as one of the more preferred ones in the clinical trial space.

00:09:56: It's something that's assessed by the clinician or the investigator in the trial setting.

00:10:01: It looks at a combination of five different areas of the hand trying to essentially say, okay, how much of the hand is filled with these lesions and how severe are these different aspects of the lesions?

00:10:13: Personally, I don't love it that much.

00:10:15: I just find that it's very hard for the human eye to get that degree of resolution.

00:10:22: And as a result, we see quite a bit of inter-radar reliability issues, where if you and I were looking at the exact same patient, we might be somewhat close, but the likelihood of us having the same score for that same patient is quite low.

00:10:39: And I think that gives me some pause in terms of being able to recommend that, certainly in the rank and file dermatology setting.

00:10:46: But in the trial setting and with expert training, it has been an important one for getting drugs approved and for understanding how drugs perform.

00:10:54: There have been some interesting approaches that have been developed as well, even in terms of using photo atlases to help anchor investigators and get better results that way for a variety of different endpoints.

00:11:05: I think that's something that can definitely assist and help with our ability to get the right scores and the right assessments, but they're not taking into account the symptom aspect and that's super important.

00:11:17: Now, when you think about symptoms, we talked about itch and pain being the big ones.

00:11:22: And we've done a fairly good job over the years with validating a number of measures in the atopic dermatitis world and others as well.

00:11:30: And it comes to thinking about some of these numerical rating scales and other scales that are out there.

00:11:36: Do you feel that the existing scales really apply one-to-one to chronic hand eczema thinking about some of those peak parietus or worst itch scales that are out there or worse pain scales?

00:11:46: or are there limitations to really porting something that was validated in one disease to another?

00:11:53: Yes, we are now starting to see validation of these different numeric rating scales in chronic hand eczema and they overall are performing well.

00:12:04: But I think it's fundamentally important to understand that chronic hand eczema is not the same thing as atopic dermatitis.

00:12:13: Because with atopic dermatitis, every patient has itch.

00:12:16: That's not the case with chronic hand eczema.

00:12:19: This is a disease that in clinical practice, we really need to ask both about pain and itch universally or otherwise we're running a real risk of missing

00:12:27: what's happening

00:12:28: in the patient.

00:12:30: It turns out that these NRS itch scales and the NRS pain scales are overall pretty good.

00:12:36: I don't know if they tell us the full start because you can have a patient who's got severe itch for five minutes of the day right before bedtime and you can have a patient who's got moderate itch or moderate pain for ten hours of the day.

00:12:49: For the trial setting these tools are okay.

00:12:52: I think for the real world we need to as clinicians dig in a little deeper and understand the temporal profile of when they're getting itch and pain, how long, how bad is it?

00:13:02: Does

00:13:04: it vary?

00:13:04: It makes sense when you think about the fact that if you have outcome measures that are not specific for a disease state, you just may not be able to capture the appropriate amount of variability and change over time.

00:13:14: that is inherently different from disease to disease.

00:13:17: And I'll repeat what was said already, because that's an important thing.

00:13:20: If anyone listens to this and walks away with one thing, Atopic dermatitis, chronic hand eczema, not the same disease, not the same thing.

00:13:28: And that inherently means that your actual measures are going to behave slightly differently.

00:13:33: when thinking about some of the examples we talked about.

00:13:35: What do you think about that, Ben?

00:13:39: Some of our more prevalent and study diseases have groups that are trying to harmonize these outcomes.

00:13:44: There is a hand eczema core outcome set initiative, HECOS, and that's one of the more prominent groups that are trying to do this for.

00:13:52: chronic index as well.

00:13:55: Most of these outcome measures that exist either focus on objective findings, so something that you can observe, or subjective findings, something that the patient reports.

00:14:06: The best outcomes harmonize between the two.

00:14:09: It's always nice to have a medication that's been shown to be not only efficacious from an observer standpoint, but from the patient's outcome as well.

00:14:18: Absolutely.

00:14:19: And from the suggestions that have been out there so far, the candidate domains are ones that have come up in our discussion already, emphasizing signs, emphasizing symptoms and itches are part of that.

00:14:30: And then of course, quality of the life.

00:14:32: And so it's a similar structure to what we've seen in other disease states, but definitely one where there needs to be much more work done and appropriate.

00:14:40: really validation.

00:14:41: And that kind of leads us to talking all about the newer IGA scale, the investigator global assessment of a chronic hand eczema, or the IGA CHE.

00:14:50: Tell me a little bit more about what the purpose of the study was and talk a little bit about this measure that you work to help develop.

00:14:57: Sure.

00:14:58: As I mentioned

00:14:59: earlier,

00:15:01: IGA scales have become a foundational tool or approach for getting drugs approved for the US.

00:15:08: Does an IGA skill that was developed for atopic dermic sense in CHE?

00:15:12: No, it really doesn't.

00:15:13: We want a tool that reflects specifically the CHE disease state.

00:15:19: And this tool that we're talking about, the IGA CHE was developed to be a disease specific for CHE and then validated to determine how well does it work?

00:15:30: How well does it perform in that trial setting?

00:15:33: And so using data from the phase three, Delga-Cittinib, cream trial, the DELTA-I trial.

00:15:40: Now that population included patients with moderate to severe chronic hand eczema.

00:15:45: But this particular study looked at the psychometrics, essentially all of the different things that we look at to say, is a tool valid?

00:15:54: And I was objective to understand the psychometrics and how well is it performing in this trial setting, and then potentially what its value would be in clinical practice as well.

00:16:05: This IGA scale was developed using feedback from different experts around the world in hand x-men, from different regulators in terms of making sure that it really holistically assessed the lesional severity for patients and was used not only to establish the severity at baseline, but really perhaps even more importantly to assess the progress that patients made with treatment over time in the trial.

00:16:30: So this IGA is a five point scale.

00:16:33: ranging from zero, which is clear all the way through to four, which is severe.

00:16:37: Each of the severity levels is based on the specific signs of CHE.

00:16:43: And looking at erythema, scaling, hypercharatosis, desicculation, edema, and fissures.

00:16:50: Recognizing that, again, this polymorphic nature of CHE, we want to capture all of the key signs.

00:16:57: And it was found to be sensitive to meaningful change.

00:17:02: where even just a one level shift can be considered clinically meaningful.

00:17:06: And I think that's important for us to recognize and certainly to think about clinical practice.

00:17:12: So the conclusion of the study was that the IGACHE is psychometrically valid and the data really support its use both as a valid tool in clinical trials, but as really something that we can use feasibly in a busy practice setting.

00:17:27: I couldn't agree more.

00:17:28: I think that if there is a severity evaluation happening in real world practice, it's going to be some version of an IGA.

00:17:36: Given that CHE, especially where we live in the United States is still a bit of a newer term and a newer diagnosis.

00:17:42: I really hope that these results will inform individuals that in fact this is something that's pretty simple and easy to look at and one that hopefully can be allowed to apply a lens to every other study that comes after it.

00:17:53: to really understand a one indirectly compares to another.

00:17:57: But even beyond IGAs, we talked about how symptoms are an important part of this disease, just right alongside the signs itself.

00:18:05: And this includes itch and pain, but the cracking and bleeding, skin changes that patients oftentimes focus on heavily.

00:18:11: And there was another measure which was actually validated using data from phase two trial with patients with mild severe CHE and the phase three delta one study as well in patients with moderate to severe CHE.

00:18:23: Do you mind talking a little bit about the HESD and how?

00:18:27: maybe this is reminiscent of some of the composite measures we've seen in other dermatitis disease states and why this one is different in terms of the six items that were chosen?

00:18:37: How about I start things with you, Ben?

00:18:39: Yeah, certainly Raj.

00:18:41: The hand eczema symptom diary or HESD.

00:18:44: It's a novel development in this paper by Mullen et al.

00:18:47: This came out in twenty twenty four.

00:18:50: This was a large undertaking again to address some of the limitations we talked about earlier in terms of finding signs of symptoms that are clinically important to patients that you can accurately measure improvement in over time based on your intervention.

00:19:10: And what was great is it involved actual CHE patients who were interviewed and they were asked about what different definitions of terms, sign symptoms meant to them, could they describe them reliably.

00:19:25: All of this is designed to be captured in a clinical trial setting on a patient diary.

00:19:30: It's actually captured on an electronic diary.

00:19:33: And after multiple rounds of interviewing at these patients and then also getting expert opinion from dermatologists and input from the FDA they narrowed the hezdy down to six different items and those are the scientific symptoms including itching pain cracking redness dryness and flaking and Each of those measurements is captured over the past twenty-four hours on a scale between zero and ten, zero again being no symptoms and ten being severe symptoms.

00:20:10: Some of the insight they gained from this actual study was that the language around the score of ten in many other scales is usually worst imaginable.

00:20:20: So again, take itching.

00:20:21: So the worst imaginable itch and the patients or participants in this actual validation process said that That doesn't mean a lot to them.

00:20:30: It's a bit hard to wrap to your head around what the worst imaginable edge could be.

00:20:34: So they felt actually that the tent should be labeled severe.

00:20:37: So again, even some of these small changes can make big differences.

00:20:40: And I think that's the importance of doing these new trials.

00:20:45: And the additional thoughts, Jonathan.

00:20:48: Yeah.

00:20:48: So this is one that I think it can be really valuable in clinical practice because how simple it is to use and what is represented by it.

00:20:57: They're fast.

00:20:57: They're easy for patients to do.

00:20:59: They're tailored specifically to CHE, right?

00:21:01: And they found that the individual items performed well, and that about a four-point change was considered clinically meaningful.

00:21:09: It's actually really the first validated CHE-specific patient report outcome measure that's now been used in the clinical trial setting and then shown to be valid in this way.

00:21:22: I like it.

00:21:23: And I think that if there's anything to take away from something like the HESD, even for folks that feel like the ability to ask a number of NRS questions in my clinic is maybe a little challenging.

00:21:34: If you just understand the questions that go into it, it can give you some insight into the types of questions you generally may want to ask in your conversation with your patients to understand maybe what's driving a lot of their symptomatic burden.

00:21:46: Yeah,

00:21:46: absolutely.

00:21:47: And I think one of the nice things about the validation work was they looked at the overall test score and showed the validity there.

00:21:56: but specifically that they were able to look at the individual items around itch and pain.

00:22:00: So if you're not feeling quite as bold as to assess the entire HESTI, but at least to assess the itch and the pain questions there because they're so quick to get in clinical practice.

00:22:12: And individually, those were also shown to be valid in the disease state.

00:22:17: So in the last part of our discussion, I really want to get everyone's thoughts on sort of these measures, the IGACHE and HESD and not really necessarily the validation side, but how are these perhaps similar or different to what's out there and what might be some of the advantages these could provide?

00:22:37: compared to what we might have used in the past.

00:22:39: And I'll start the question with the IGACHE.

00:22:42: We talked about how.

00:22:43: there's a number of different IGA scales out there.

00:22:46: Some of them make more subtle versus much more clear delineation between the individual levels in terms of that particular variable.

00:22:53: There's physician global assessments out there that are a bit more gestalt-like.

00:22:58: What are some of the, let's say, advantages compared to measures that are already come before it?

00:23:04: of the strict criteria and validation that we've seen with the IGACHE.

00:23:09: Yeah, I like the IGACHE.

00:23:11: I think there's a potential use for physicians global assessment.

00:23:15: I like the Gestalt assessment too.

00:23:18: But I think the challenge that comes up with the global Gestalt assessments is there's too much subjectivity potential there.

00:23:25: Having a structure tool that gives you some pretty clear and prescribed guidance on what you should call moderate or what you should call severe, I think can be very helpful.

00:23:33: help standardize the assessment.

00:23:35: So we're all speaking the same language, both in a trial setting, but also in the real world.

00:23:40: So I like having this kind of structured assessment, especially because it's so easy and feasible to do.

00:23:46: Focusing in also on the severity of lesions, not taking into account sort of the extent, I think it makes it more sensitive and I think it actually improves the reliability.

00:23:58: both intra- and intra-reader liability in the long run for us to be able to assess severity and changes of severity over time.

00:24:06: I might offer something very similar with the PESD as well when thinking about some of the other patient reported outcome measures that when used in practice may sometimes have limitations.

00:24:16: And of course, I'm thinking a lot about the peak periodis NRS and skin pain NRS, which as we discussed earlier, A lot of their validation work has come for the overall body when thinking about patients with atopic dermatitis, and this is of course a disease of the hands that we're focusing on.

00:24:30: Simple changes in those types of scales just may not be sensitive to what we're thinking about.

00:24:35: as it relates to the hands itself.

00:24:37: And the HESD takes it even one step further where it adds on some of those key CHE symptoms.

00:24:42: And we oftentimes think about symptoms as just being itch or just being itch in pain, but we've seen cracking, redness, dryness, flaking.

00:24:49: These are symptoms that are near the top of patients' complaints in terms of what they're thinking about as well.

00:24:55: So I really like this idea about how it tries to bring some of these symptoms, which may oftentimes be confused as clinician-rated signs into the forefront.

00:25:05: Absolutely.

00:25:05: And I think the beauty of these different scales is a complementary nature.

00:25:09: We're not advocating to only do the IgA CHE or only the HESTI, but really take into account both what you can visualize in a structured way, but also making sure to get that patient experience and that will really elevate our ability to assess patients in the real world.

00:25:24: So

00:25:25: I'd love to bring everything together of what we talked about today and think about what our sort of key messages are moving forward when thinking about chronic hand eczema.

00:25:33: We had a really nice time today.

00:25:34: discussing what is chronic hand eczema, why it's such a common condition, why we really need to be concerned about the burden that it places on our patient's lives, and why our conventional treatment approaches have just been limited.

00:25:48: Now, when it comes to clinical development, the pivotal phase three trials of Delta I and Delta II with Delgo-Sitin and Prima have been very exciting, not only for the approval of a new therapy in several countries and hopefully more, but also the utilization, development and validation of new concrete measures like the IGACHE and the HESD, including the HESD itch, HESD pain and overall HESD itself as primary and secondary endpoints respectively to really allow us to have a set of tools that should translate into real-world practice but also studies as well.

00:26:25: Any last thoughts on your end?

00:26:27: I guess I would end with a little bit of my own experience using similar devices.

00:26:33: are these.

00:26:33: I think the real importance of using a global outcome measure is that it can be a

00:26:40: quick

00:26:41: and fairly simplistic tool to allow disease to be measured across weeks or months between patient care visits.

00:26:55: And again, I think many of us know that without some type of device or tool, to show that improvements, you can have patients and even providers who may not feel a certain treatment is actually working as well as it might be.

00:27:13: So I think it's really important to help guide your treatment decisions if you have some objectivity that you can use in the clinic.

00:27:19: So again, the IgA CHE to me is a fairly straightforward device like most global scales.

00:27:24: It's a pretty quick across the room type of diagnosis to show, gosh, your hands look severe versus they look almost clear.

00:27:33: I think, again, the definition of almost clear in the IGACHE that was used in these Dug Ascendant trials is important because it really allows you to distinguish between someone who's almost clear and someone who's mild.

00:27:47: And that's actually a really strict endpoint to get to that almost clear where you can just have barely perceptible redness.

00:27:54: So I think those are important things about the IGA, CHE.

00:27:58: The HESD, again, is robust because it takes into account these meaningful signs of symptoms to a patient dealing with chronic hand eczema.

00:28:06: And again, it's fairly straightforward and something you can, if you like, choose even the most prominent concerns to a patient, which is itch and pain, and use those scales in clinic.

00:28:17: So these are things I'm starting to use.

00:28:18: I don't use them on all patients yet.

00:28:21: I think the more we develop tools, and again, when they're validated with proven medications, I think they become easier and easier to implement.

00:28:32: What an exciting time that we now have not only better outcome measures, but now we actually have great therapies in our toolbox for CHE.

00:28:41: And I think the future is really bright for this disorder.

00:28:45: Thanks again for everyone joining us on behalf of myself.

00:28:48: Dr.

00:28:48: Silverberg and Dr.

00:28:49: East.

00:28:50: It's been

00:29:09: a pleasure.