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- [00:10]
A
So, everybody, welcome to another episode of the Derms on Drugs. Filming live, we've got with us today Dr. Jason Hawks, one of the luminaries in dermatology for CSU. Dr. Hawks, great to see you again.
- [00:25]
B
Thanks for having me.
- [00:26]
A
So a lot of big stuff happened in CSU right now. We've got some experience. Rapsitter's been on the market long enough that we're going to see. And I know you. You know, you've seen a lot more than the rest of us because you did the trials. You know, Doopie's now been on the market for a little while for it. Zoller's been there forever. We've got Barzo coming first. What is your take right now? What do you want most? Derms. If there's one thing you could tell all the derms out there about csu, what would you tell them?
- [00:57]
B
Yeah, I mean, I think the guidelines that just came out. I was one of the four authors on the international guidelines, but the big message there that came out of that table is that everyone went from antihistamines to omalizumab, but now in that table on an equal level is omalizumab, Remi and dupi. I think this is important for the specialty because they didn't really use a lot of OMA in dermatology. So these patients were getting sent out. But I think the message is you can take. These are drugs that are pretty easy to use, and these patients need access, and allergists just can't cover that group. We outnumber them by four times. So I think it's getting them back. Getting them back to the fact that we want to expand access to these patients and you can treat them. I think the algorithm that you walk through in the guidelines is pretty straightforward, and I think it simplifies it. I think the international guidelines cut out a lot of the nuances that maybe had derm sending these patients away. And I think the message is, you know, you need to learn to take care of these patients, and they're pretty easy, actually.
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C
So do the guidelines recommend any testing?
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B
So they kind of hedge on this a little bit. The statement in the guidelines is that they recommend against extensive testing.
- [02:11]
C
Okay.
- [02:12]
B
The argument for that language is that there are some patients that, you know, could theoretically have some underlying malignancy or something else that I feel like is a hedge. Because when you look at the data, if you put these patients with chronic urticaria through the gamut of tests, right, do an MRI and a CT in all labs, way less than 1% of these patients have something. Now when they do have something, it's usually something like autoimmune thyroiditis or they have celiac disease or something to that effect. And I think the issue is do any of those testings impact management? The answer is no. I think this becomes important with the two new therapies with, you know, Remy Brutinib and Dupilumab. Because they actually work irrespective of IGE level.
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A
Yeah.
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B
So it's even the one test that probably had the best utility in predicting response to omlisia now is off the table. So I think it's a hedge because we know that allergy compared to dermatology, they do a lot more testing, they spend more time with patients. High volume derm. They're not going to do these tests. And the question is, do they change anything? The answer is no. So we rarely do testing in these patients.
- [03:17]
A
You order. So I order nothing on these people.
- [03:19]
B
Agree.
- [03:20]
A
Nothing. Okay.
- [03:21]
B
The only time we're going to order a test for patients is if we're looking for something. Right.
- [03:25]
A
If there's a review of systems. Yeah, oh, I've had a cough, I'm
- [03:28]
B
pooping blood, whatever, or you know, I, you know, we see autoimmune conditions so you know, that's the biggest factor for patients with CSU 2 to 1 female prominence. Why? Because that autoimmune burden, auto antibodies. So we see thyroid problems, you see celiac disease. Occasionally people have lupus. A lot of patients have EoE and asthma. So if there's testing you're doing for these comorbidities, that's one thing. But to your point for csu there is no test that's going to change what we're going to do in the, and the guidelines reflect that we're trying to get people away from testing. Biopsies are non specific. For example, do you tell people to
- [04:07]
A
that for the rest of their life they should get a TSH every year? No, that seems like a reasonable recommendation to me because we just, because we know you're an increased, you know, thyroid is common in women to begin with. Now it's in you. It's not that the CSU caught, but just if you got csu, you're at increased risk for thyroid disease.
- [04:24]
B
But you're confusing two different concepts. One, one is that are they at increased risk? Yes. Is TSH a good screening test every year in this group? The answer is no.
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A
Okay.
- [04:34]
B
So I think symptom driven. Yes. I think that, you know, do you check LFTs in every psoriasis patient every year?
- [04:42]
A
No, no, but they've increased risk for now.
- [04:44]
B
But you could say they're at risk for liver disease. So I think evidence based argument is that it's not a good. It's a good screening test. Exactly. It's a good screening test if you have symptoms. So if somebody comes in and they're like, you know, I've had this unintentional weight gain and they, you know, all the classic symptoms or suggestive, I think it's better to educate them and say, hey, if things change, then, you know, let's pay attention to that. Make sure your other providers know you're at risk for autoimmune conditions. And if you had symptoms, then check tsh. How many times have you checked and it was negative?
- [05:14]
A
It's always negative.
- [05:15]
B
It's always negative. That's my argument. So it's like some of the reluctance may be with derms taking over CSU is omalizumab is still a therapy out there and they may feel, look, I've never prescribed omalizumab. That's part of the armamentarium. I'm still not comfortable. What do you say to that? I mean, I can't help you with your risk aversion for medication. I think you have to see the patient story. If you see this patient that comes into you and you feel good about sending them out to another specialist, like, you just have to, you just have to own that. I, I think the issue around omalizumab that's fair is that in the prescribing label there's a recommendation that you have to have access to an EpiPen or emergency therapy. But that's tough because anaphylaxis didn't happen in urticaria patients, it happened in asthma patients. So if the reason for not taking inheritance patients is based in omalizumab, then I think that's fine. But that's again why I think the guidelines are important, because now you've got two other options and you've got one Dupilumabs. It's pretty hard to argue you're not comfortable with. I mean, it's, that's pretty much the easy button for therapy. So I, I think we have to push that group and say the patients are coming to you, they want to see you, they have a chronic skin disease and you're sending them to an allergist when you're telling them that by definition you have spontaneous urticare, which by definition doesn't have a trigger, it's internal. So what are you sending them to get testing for? And so I think we just have to, we have to do what's right for the patients and they need, they need us to take care of them.
- [06:53]
A
Is there ever a situation other than maybe co even then? Is there ever a situation when you think Xolair would be the best option as a first line for a patient? It's hard for me to think of that situation at this point.
- [07:08]
B
Well, I mean, it's a good drug. Yeah, it's a very good drug. So if you look at, you know, I think it was Tharp and Jamaderm that did the last big meta analysis in urticari and dermatology around Omalizumab, the complete response rates like 75%. So I mean, just equate that an easy seven, an easy 175% of patients. Pause the 175. I mean, that's pushing the highest limits of any drug. So omalizumab's evidence, like many real world studies, I think last I saw was like well over 50 real world studies outside of clinical trials, decade of experience. Like, if you use that first line on every patient with typical csu, you'd be well within guidelines. It would be. I couldn't argue against that. Where it works in patients is it also covers type 2 comorbidities, right? They've got asthma, they've got rhinositis with nasal polyps. So I think Doopie and OMA have advantages there because of the type 2
- [08:07]
A
conditions or do you think, from what you just said, do you think that overall, long term, so we're talking, let's say a year of therapy, do you think? Because I think the data for Rhapsodo is like 50% of people get to complete control at a year, something like
- [08:25]
B
that, it's like 2/3 at 52 weeks.
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A
Do you think Omalizumab is a little more effective at a year than DUPY or Rapsodo?
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B
So if we look at, if you look at the Data for Dupy versus Rapsido at their primary endpoints, the change in the UAS 7, it's about 20. So UAS 7 max scores, 42 average is about 30. The point reduction in that score across OMA, Doopie and Remy's almost the same. Yeah, it's about 20 points. So efficacy wise, they're pretty similar in terms of that endpoint. At 52 weeks, we probably see more patients with rhapsodil go up. It's a Little bit higher. So the well controlled group, which I think is a little more realistic, the UAS6.6, well, US7. You have to remember that unlike a EZ score, a PASI score, that's a snapshot, your IGA0 or IJ1 and these other diseases, that's that day. UAS7 is hives and itch over seven days.
- [09:26]
A
Yeah.
- [09:27]
B
So you can only get to UAS7 of 0, which is complete controlled. You can't have one hive for an entire week.
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A
Yeah.
- [09:33]
B
So it's a really high bar. So it's idealistic. I like the well controlled. And if you look at the well controlled population for rhapsodes, about two thirds. Okay. We start to see like well controlled disease for about 50%. For dupilumab, the complete response at 24 weeks for diploma is about a third.
- [09:52]
A
Okay.
- [09:52]
B
So you're getting a little bit higher rates. It's probably a little better than omalizumab. So efficacy wise I put on my slides like here at Mauiderm that basically raps those probably got the best efficacy of those three drugs. Okay. There are other more effective drugs. And then you start getting the nuance of access and administration and you know, preference of delivery.
- [10:15]
A
What's your take on bars? Rhapsoda works so fast.
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B
So fast.
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A
Does it, do people start to break out if they miss one dose? Like does it stop working really fast? Also.
- [10:28]
B
So also what I brought up, the double edged sword of remibrutinib is the speed. It's fast on, fast off. I mean half life, you're one to two hours. These patients get better quick. We've had patients call same day, literally same day from starting medication. We've had a lot of calls in the same week, multiple days, like so it's a really fast onset. Every single patient, like we're doing the doopie. Remy, head to head. Every one of those patients that come off, if they start flaring that 24 hours, there's very high likelihood they're on Remy. One of the interesting components for DUPY is being an argument in CSU. So you look at their data at 24 weeks, when they stop that, you maintain the response for 12 weeks. That's just when they stopped. Wow. So with Remy, it's a hundred percent recurrence. So every patient we've had and to your point, some people try to space it out. So the problem Is samples are 14 days. So if you give them in the office, you have not a month, you have 14 days. So some patients are going to Run out. They start to space it out or say, what if I just take it once a day? And we've had multiple patients now that said, like within four hours of missing a dose. Of missing a dose. Yeah. If they haven't had consistent twice a day and once a day doesn't control. And I think that gets back into the PK data they have. You need the drug twice a day, so it's really fast off. And once a day doesn't work.
- [11:48]
A
So if you forget your evening dose, there's a reasonable chance you're going to wake up itchy.
- [11:53]
B
Yeah, it's not as bad as your baseline disease, but they have, they have significant number of Ives an itch. So. So I think that's the chink in the armor for this medication. And it doesn't make the medication bad, it's just a practical consideration. So you can't be like, you know, let's come back sometime after a few months and if you need a refill, it's like, you gotta have a plan. You've gotta. Like if your prescription's running out or you need a priorh, you need to see those patients before, because if you have a delay, they're gonna flare. So I think that's the weakness to that medication is that if you're not compliant or compliance is an issue, or you miss it, or you don't have good access to your providers to get medication, you're definitely going to flare after. And we've seen that in real world. So the dupe. One of the things with DUPY is that those were the cupid studies, right? Yep. So Cupid A, Cupid C, Cupid B. I think the really quick. You look at it really quickly, you're like, my highest patient failed omalizumab. They will not respond to dupy. They. Because of that Cupid B data. What would you say to that? Yeah, so you'll hear this a lot over the podium that Cupid B was a failed study. But there's so much nuance to that. So one is that in Europe they prefer the UAS 7. That's their primary endpoint metric. In the US it's ISS 7, which is the itch score. So, interestingly, they met criteria in that study for UAS 7, but they didn't meet it for itch. So it wasn't that the study failed. They still had a reduction. Just the delta between the placebo patients and active treatment was smaller. There's some other statistical pieces that are not worth getting into, but there was a response These patients also had like almost 80% reduction in IGE levels. So I mean it wasn't that the study was a failure. I sort of interpret it as this was a tough group. If you have a patient that fails, fails omalizumab and no response primary failure, their response to a lot of the other medications is much lower. So I think that's a reflective, it's reflective of that. It's a different patient population. It's like a patient psoriasis that has failed in IL23 or IL17. Their likelihood of getting better on some other medications is already lower. So I think it's telling us more about the disease state and the reason that they did Cupid C. Right. Y, A and C. They had A and B. They're different populations. You had biologic naive OMA experience. And then in the pivotal trials you need two studies. So you have cupid C which is also biologic naive. That became the basis of the approval. But it wasn't a failed study. It was just a. It was strategically probably not a smart move to take the hardest group. You want to show proof of concept first against placebo and then maybe you do the head to head. But to do that right out of the gates was pretty bold. And so again I don't think it's a knock on the drug. I think it telling us about more refractory difficult patients.
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C
Can I ask you a question about kind of going back to like old school antihistamines? So I think sometimes people don't know. So the new guidelines still say go up to four times a day of non sedating antihistamines as sort of first line. Right. And that's oftentimes our like N If tolerated. If tolerated. So can I ask you this comes up a lot with patients or residents. They'll say is that four of the exact same antihistamine or could it be like 2 Allegra 2 Zyrtec? I mean 1 do the guidelines specify and 2 do you have a preference with all your experience?
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B
Yeah. So the guidelines actually do specify and the consensus. So these were voting guidelines. So they represent 95% consensus. 75 very high consensus that the addition of two moas of the same moa, like two 2nd gen H1 anti histamines being combined. There's no evidence to support that.
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C
Okay.
- [15:41]
B
The area that gets gray is when you're adding non H1 blockers. So do H2 add MOs? Do leukotriene receptor antagonists add much? And the international guidelines sort of skip that over And I think that's probably ideal. How many patients we had where they're on, you know, high dose, three or four antihistamines added on singular or something like that didn't make a difference. And I almost never, I mean, I
- [16:08]
C
never find it helps, but people do it all the time.
- [16:11]
B
It's like an early thing to get OMA approved. Well, did they take singular? Yes. And they actually do. Yep. And it's, that's a, that's an insurance barrier. But so I think going back, there's no evidence that adding the same MOA helps. So pick one. Adding the other ones, if you feel like you want to do it or it's access required, you can. My experience, I don't think it ever helped. I'm looking at is the patient antihistamine responsive or not? And if you get a patient's like, it got to two and I'm like zonked. I'm like, great, move on. That's a patient. For a systemic therapy, if they get to four and I try to get them quickly. The advantage to antihistamines for CSU is if it works, it works fast. So I'm like, start a pill if you haven't started anything every two to three days, add a second pill, move it where you want it. Don't take them all in the morning. If you're taking in the morning and then you're having symptoms night added at night. If you're doing good and then the afternoons are tough, add your third one or your fourth one. Like, move it where you need it. And then by two weeks, two and a half weeks, you should know if they're responsive or not. And at that point, like didn't work. That's 50% of patients move on. I think the guidelines got a little washy washy on like two to four weeks. You do not need four weeks to escalate antihistamines. You can do it quickly.
- [17:25]
A
That brings up one of my raps to questions. I'm a. I like to think in drugs in terms of like, if it hasn't started to work by this point, give up, move on to the next drug. Biologics for ad, for example, Dupy, Libre, whatever. I'm like, if it's done nothing in three months, not going to be the drug. If you're a little better, you might. If it's done nothing. With rhapsodo, how long is your. If it's done nothing, I'm going to
- [17:52]
C
expand that to all of them. Right. When do you give up on omalizumab, when do you give up on rhapsodo? When do you give up on dupixent?
- [17:59]
B
So there's a layer of this that I don't think is done well in trials. And you'll know this from doing a lot of trials. They rarely specify a treatment failure. Does that mean they had no response? Does that mean they didn't get to a certain level? And then the other layer to what you're asking is primary treatment failure. That's someone that has no response. And that pulling the rip cord is a lot faster than inadequate response.
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A
Because inadequate you do.
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B
You're doing okay.
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A
You see surprising late. You're like, should have worked. But then you'll see people. Son of a bitch. Eight months in. Son of a bitch. It went from okay to like really good.
- [18:33]
B
Yeah. So I think start there with the people that have what's the time point where if they're having some improvement, you would continue and how long do you wait? So with Dupy, probably the optimal response is somewhere close to that 24 weeks. Between 20 and 24 weeks, they get 50% of that response at basically, basically in that first month. So in the first month they kind of get about 50% improvement, but they kind of peak optimize about 24 weeks. Rhapsodyl is the opposite. So within their basically first month, they're getting really close to sort of their full effect.
- [19:09]
A
So do you. So back to the original question. Patient, like, because I'll tell a patient, we're gonna start you on this. If it hasn't started to work by this time, call me. What is your time point?
- [19:21]
B
OMA and Dupy? If you've had no response at three months, you're banning therapy for sure. You're not waiting with Rapsodil. If you've had no improvement, primary treatment failure at one month, you're moving on. Now in terms of these patients start to get better, they're going to have improvement. Where does Rhapsodyl or REMI peak? It's about three months. Somewhere in that two to three months. Because after, after four weeks they've hit a lot of it. It's just kind of fine tuning. And we see with like the UAS 7 data that's less than 6, the well control group, it even keeps going up out to 52 weeks. So there you're like assessing are you a primary failure or you're just not there yet. And if you're not there yet, you're waiting. So dupy, you're waiting a full six months at Remy and that like three months, you have a pretty good idea. Not a lot of improvement out to six months, you're pretty close. And oma, it probably has a good two to three months as the onset. In terms of onset of action, I think of Remy first, almost second, Dupy third. And then with Doopie, you have the prolonged effect, which is something they're studying now. With oma, they probably need that good three to four months to really kind of peak. So I think Remy's going to peak earlier and then you start to see the Oma peak and then Doopie kind of peak. So I do think it's important. I hate when clinicians send us notes that say like, you know, they failed Dupy, I'm like, I don't know what that means. Did they initially respond and fail later? Did they fail because they didn't get to easy 100 or you call them a failure because they only got easy 90 and they weren't happy and weren't completely clear. So the literature is not good on that and clinicians aren't good on that. I try to be really particular about primary versus secondary failure because it means something different to me. Because if you're not responding at all to Remy, then I'm saying, what are we missing? Do we have something else going on? Probably not. Csu, last topic.
- [21:18]
A
Next drug that will be coming is Barzo. Barzilavillian app. Yes. So I'm doing the clinical trial. My take is like magic effectiveness. But the white hair, the white spots, where do you think it's gonna end up? Do you think it's gonna end up like it is so effective it's worth the white hair and the white spots. We should. Or is it gonna be like last line? If you failed all the other stuff, we know this will work, but it's going to make your hair turn white. Like, where do you see it be it?
- [21:53]
B
So a good example. We have a patient, actually the very last, we have probably over 10, between 10 and 14 patients somewhere in that area. We had a lady who's literally failed everything else. And when we put her on the study, she was lucky. She got into the active treatment arm within a week. She's like totally clear. All my hives are gone. No itching. First time in 30 years. So that sort of gives you the power of the drug. We've pretty much seen that across the board. The issues have been, as you mentioned, the not off target but the on target effects. So Kit, the KIT receptor is expressed on mast cells. It's the Master regulator. So I think for the clinicians simply that's the receptor that's driving like the plot, proliferation, differentiation of these mast cells and the activation. So when you block it, it actually depletes those cells. And if you block it well, you're getting rid of mast cells. So it should work in acute urticaria, should work in inducible urticaria, should work in any other thing driven by mast cells. These drugs are depleting mast cells. I think that gets to the effect if you don't have mast cells, you don't get disease. Just like if you don't have T cells, you don't get eczema or psoriasis. So mechanistically it makes sense. But kits expressed on gametocytes, so sperm, eggs, it's expressed in melanocytes. You've got hair where you've got melanocytes. So you start. It's expressed in the bone marrow cells. So what do we see in the trials? We have people that have had neutropenia dose dependent. We give them a shot, their neutrophils drop, we have to hold ip, their neutrophils recover, we put them back on drug, neutrophils drop. So we've seen neutropenia, we've seen leukocytopenia, we've seen macrocytic anemia that's described in their ib. We've had hair changes. I have a great picture of a guy that has this really dark full beard, white guy, but really dark, thick density. And then he started going salt and pepper. He started having some other side effects. Ended up stopping the trial. It was clear, totally clear. Took six months for his hives to come back. Took six months for his hair color to come back. Had another, another patient at every hair on her body went white. She also had macrocytic anemia and neutropenia, but both of them also developed hyperpigmentation. So it's, it's kind of paradoxical. It's like it's hard to. You're blocking it. Shouldn't you have less melanocyte activity? But it's kind of like a reaction, I think like doxycycline, minocycline induced pigmentation. It's a different mechanism there. It's not active melanocytes. It's more of the pigment incontinence. But that bothers patients. So I think when you start looking at CSU patients, most of them are between 20 and 50. High predominance of females. You start telling them you might get Discoloration on your face, white or hyperpigmentation and hair color, it's a problem.
- [24:42]
C
It's going to be a last line for me.
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B
Yeah, there you go.
- [24:45]
C
All the things I'm working at, I
- [24:47]
B
think where it fits is that it's extremely effective for the Ds. Most patients don't have the adverse events, so I suspect it probably falls a little lower. It's hard against these really safe medications, but we need to have therapies that you pull the trigger on some of those when nothing else works. Right. I do think you could make an argument for otherwise healthy people if they don't have the adverse events, it can be a good drug. But these drugs kind of find their space. Our job isn't to say where we put it. You kind of see where it goes in the market where we would. We would use it. It's going to be different where somebody else in the community might use it, but. But very, very effective. And I think now the iterations of what they're doing now are some of these oral therapies. So we have, you know, blue 808 with blueprint medicines was bought by Sanofi. They have an oral kit inhibitor, so they have their mutated form that they block in systemic mastocytosis. So. So it's the mutated malignant form of kit. Now they have wild type kit where they can block kit and it may not deplete the mast cells as much. There's another company, Jasper is working in the same space. So I think this was the first out of the gate for kit, but it's the master control of mast cells. So there may be a role for this. But this is, you know, this is version one. So I think the iteration you build on other drugs, so this as a proof of concept is that when you crush the mast cells, you crush disease and symptoms. So it's pretty amazing.
- [26:15]
A
Okay.
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C
All right, Jason, we got to get you up on stage on this meeting,
- [26:19]
A
so thank you for joining us. This is fantastic discussion. I learned a bunch. Have a great rest of the meeting.
- [26:25]
B
Yeah, thanks for having me.
- [26:26]
C
Thanks for being on.
- [26:27]
A
Thanks a lot.
- [26:27]
B
Thank you.