Celldex Therapeutics, Inc. (CLDX) Earnings Call Transcript & Summary

Good day, and welcome to the Celldex ACAAI 12-week CIndU Conference Call and Webcast. [Operator Instructions] As a reminder, this call may be recorded. I would now like to turn the call over to Sarah Cavanaugh. Please go ahead.

Thank you. Good morning, and thank you all for joining us to discuss the 12-week results from our barzolvolimab program in chronic inducible urticaria that were presented this weekend in a late-breaking oral presentation at the American College of Allergy and Immunology (sic) [ American Academy of Allergy, Asthma & Immunology ] Annual Meeting in Boston. Joining me on the call today are Anthony Marucci, Co-Founder, President and CEO; Dr. Diane Young, Senior Vice President and Chief Medical Officer; Dr. Tibor Keler, Co-Founder, Executive Vice President and Chief Scientific Officer; Dr. Margo Heath-Chiozzi, Senior Vice President of Regulatory Affairs; and Dr. Diego Alvarado, Vice President of Research. Before we begin our discussion, I'd like to direct your attention to Slide 2 with respect to important information regarding the forward-looking statements that today's speakers will be making. Please be advised that a question-and-answer period will be held later in this call. I'd now like to turn the call over to Anthony.

Thank you, Sarah. Good morning, everyone, and thank you for joining us. We are looking forward to talking with you this morning about the unprecedented positive results from our Phase II study of barzolvolimab in chronic inducible urticaria. We continue to be extremely pleased by the consistency of the data, both the impressive efficacy and the favorable safety profile barzolvolimab has shown across multiple mast cell-mediated diseases. The data we will discuss this morning marks the second large-randomized placebo-controlled study where barzolvolimab has met all primary and secondary endpoints, clearly establishing clinical benefit and safety now in 2 distinct forms of urticaria, chronic spontaneous urticaria and chronic inducible urticaria. We are particularly excited about the results in CIndU because of what it could mean for patients with this difficult-to-treat disease. This is the first large-randomized placebo-controlled study to succeed an outcome in CIndU. We believe these results today will offer new hope in this disease and once again demonstrate that barzolvolimab has incredible potential to transform the lives of patients with mast cell-mediated disease. Let me ask Diane to share the data in detail with you. Diane?

Thank you, Anthony. As you know, on Saturday, we presented positive 12-week data from our ongoing Phase II study in chronic inducible urticaria. The data were presented by Dr. Jonathan Bernstein in a late-breaking oral presentation at the American College of Allergy, Asthma & Immunology meeting, and were extremely well received by the dermatology and allergy community who desperately need effective therapies for their patients with inducible urticaria. Dr. Bernstein is a leader in the field of chronic urticaria, and we are pleased to have collaborated with him on the barzolvolimab development program over the past 5 years. Turning to Slide 3. Chronic inducible urticaria is a miserable disease. Patients go to great lengths to avoid disease triggers, but many find it impossible to do so and are impacted by severe itching, burning hives or wheals and angioedema that impair all parts of their lives: their work; their concentration; their sleep; and their social lives. In this study, we are exploring 2 of the most common forms of inducible urticaria: cold-induced urticaria; and symptomatic dermographism. People afflicted with cold urticaria experience symptoms like itching, burning wheals and angioedema when their skin is exposed to temperatures below body temperature. It is important to know that this isn't necessarily what you and I might think of as cold. We have seen patients where the threshold temperature to develop cold urticaria can be as high as 80 degrees Fahrenheit or even higher. Navigating one's day-to-day activities trying to stay above these thresholds to avoid the onset of symptoms can be a daunting challenge. Symptomatic dermographism is characterized by the development of itchy wheals in response to stroking, scratching or rubbing of the skin and usually occurs within minutes of the inciting stimulus. Patients can experience this from everyday occurrences like the waste band of their pants, their socks or their hair touching their neck. Again, not easy things to avoid in your day-to-day life. As outlined on the bar chart and the table to the right, not surprisingly, patients with inducible urticaria also report high rates of mental health comorbidities, including anxiety and depression as they struggle with a disease they feel rules their lives. They also report high medical resource use, including visits to their primary and specialty care physicians and the emergency room and higher-than-average hospitalizations. For these diseases, mast cell activation leading to the release of soluble mediators is thought to be the driving mechanism resulting in the hives, wheals itch and other symptoms. There are currently no approved therapies for chronic inducible urticarias other than antihistamines. And unfortunately for patients, very little forward progress has been made over the years, including in recent clinical trials. Most recently, dupilumab was determined to be ineffective in cold urticaria in a global Phase III study, reporting no difference between the drug arm and the placebo arm for the primary endpoint at 24 weeks. Omalizumab has only been tested in small investigator-initiated studies in CIndU. In these studies, efficacy was assessed at 10 weeks, with return of disease noted by week 16. To achieve the best outcome in chronic inducible urticaria and to offer patients disease relief, we believe you need to target the root driver of the disease, the mast cell. Barzolvolimab's unique mast cell-depleting mechanism positions it as best in disease and the consistent positive results we have reported to date across our Phase I and Phase II studies, including now the Phase II CIndU data to support this. Before we dive into the data, let me review the study design as you see on Slide 4. This study is a randomized, double-blind, placebo-controlled parallel group Phase II study designed to evaluate the efficacy and safety profile of 2 dose regimens of barzolvolimab in patients with CIndU who remain symptomatic despite being on a stable regimen of antihistamine therapy, which can be up to 4x the label dose. The study also allowed for patients who had prior biologic use. Patients had to have a positive provocation test, temp tests for cold urticaria and FricTest for symptomatic dermographism, and they had to have an urticaria control test less than 12, indicating that their urticaria was not well controlled. 196 patients across 78 sites in 11 countries were enrolled in 2 cohorts differentiated by CIndU subtype. This included 97 patients with cold urticaria, and 99 patients with symptomatic dermographism who were randomly assigned on a 1:1:1 ratio to receive subcutaneous injections of barzolvolimab of 150 milligrams every 4 weeks, 300 milligrams every 8 weeks or placebo during a 20-week treatment phase. Patients then enter a follow-up phase for an additional 24 weeks. The study also includes an open-label extension phase that allows patients with symptoms during the follow-up phase, including patients who were on placebo during the 20-week treatment phase, to receive active study drug for up to 20 weeks. The data we will discuss today are from the primary analysis, which was conducted at 12 weeks. Slide 5 outlines patient baseline characteristics. There are several things I'd like to point out on this slide. First, if you look across the treatment groups, this is a very well-balanced study. Second, patients on study had significant inducible urticaria symptoms and they'd had these symptoms for a long time, with means ranging from 5 to 11 years. In cold urticaria, patients presented with a mean baseline critical temperature threshold of approximately 19 degrees centigrade or 66 degrees Fahrenheit on the temp test on initial provocation testing. In patients with symptomatic dermographism, baseline FricTest thresholds were an average of 3.6 out of 4 pins. Clearly, in both settings, these are challenging dynamics for patients to navigate in their daily lives. The UCT score at baseline tells this same story, reflecting poorly controlled disease across all cohorts. We think these factors further speak to the strength of the data. As I will detail in a moment, we have achieved an exceptional outcome in a well-balanced study in a severely impacted patient population. Slide 6 shows the patient disposition. Of the 196 patients that were randomized, 3 patients were not treated, resulting in 193 patients being included in the modified intent-to-treat population used to evaluate both safety and efficacy. 90% of patients on study completed the 12-week treatment period with more patients on the placebo, 14%, discontinuing than the barzolvolimab treated groups at 8%. Discontinuations were primarily associated with patient decisions and factors that are reported as other, which include, for example, patients moving; coming off treatment because they didn't meet study eligibility requirements; difficulty navigating the demands of participating in a study, et cetera. The rate of discontinuations associated with an adverse event were low and balanced between the barzolvolimab and placebo arms. Slide 7 shows the primary endpoint, the percent of patients who achieved a complete response as assessed by a negative provocation test, the temp test for cold urticaria and the FricTest for symptomatic dermographism. I am excited to share that we met our primary endpoint in both diseases across both doses. These results are unprecedented. As Anthony said earlier, this is the first large-randomized placebo-controlled study to achieve a successful outcome in CIndU. Let's look at the data in detail. First, given that this is the primary endpoint of the study, we assess complete response here using the most conservative approach, nonresponder imputation which means if patients on study did not have a measurement at week 12, they were counted as a nonresponder. The chart on the left shows the results in cold urticaria. 46.9% of patients treated with 150 milligrams of barzolvolimab every 4 weeks and 53.1% of patients treated with 300 milligrams of barzolvolimab every 8 weeks achieved a complete response, which means no hives on provocation compared to only 12.5% of patients in the placebo group at 12 weeks. This was highly statistically significant, as you can see, based on the p-values. Second, on the right, we show the provocation results for patients with symptomatic dermographism, where 57.6% of patients treated with 150 milligrams of barzolvolimab every 4 weeks and 42.4% of patients treated with 300 milligrams of barzolvolimab every 8 weeks achieved a complete response, which again means no hives on provocation compared to only 3.2% of patients in the placebo group at 12 weeks. The p-values here are also highly statistically significant. So in summary, the primary results in both diseases are highly positive and, most importantly, very clinically meaningful for patients. As we saw in CSU, the strength of these data is supported by the fact that this study also met all its secondary endpoints, setting barzolvolimab in a class of its own in CIndU. Let's look at the other endpoints. Slide 8 shows a full responder analysis that looks at both complete and partial response. Partial response in cold urticaria requires at least a 4-degree Celsius improvement on the temp test and in SD, requires at least 2 pin improvement on the FricTest. Up to 75% of patients with cold urticaria and 67% of patients with symptomatic dermographism experienced a clinically meaningful complete or partial response. There is a high degree of statistical significance across all of the barzolvolimab dosing groups compared to placebo. The data on Slide 9 shows the improvement that patients on barzolvolimab experienced in their critical temperature and friction thresholds at 12 weeks, a key secondary endpoint. In the day-to-day life of a patient, this means you are moving the baseline threshold at which patients develop hives, so they can tolerate colder temperatures and more pressure on their skin without resulting hives. Again, patients on barzolvolimab experienced clinically meaningful and highly statistically significant changes here. In cold urticaria, patients experienced an improvement, which, in this case, is a reduction in their critical temperature threshold of approximately 9 degrees Celsius or almost 50 degrees Fahrenheit versus 0.3 degrees Celsius or about 32 degrees Fahrenheit for placebo. In symptomatic dermographism, patients improved between 2.25 to 2.5 pins versus not even a single pin for placebo. These are very meaningful differences that can dramatically improve the day-to-day lives of patients. On Slide 10, you see the time course for the improvements in critical temperature and friction thresholds. These improvements are clearly rapid and sustained over the 12-week period. They are being documented at the first clinic visit post dosing, which occurs at 2 weeks, where patients undergo repeat provocation testing. These outcomes are also supported when we look specifically at itch. On Slide 11, we show the results of the changes in worst itch NRSprovo, which assesses the worst itch that patients experience associated with their provocation test. Here again, patients reported a rapid reduction in itch at their first assessment appointment, and you can see looking at the curves that this reduction continues to improve over the 12-week treatment period. Slide 12 shows urticaria control test results. This is a validated patient-reported outcome tool that asks patients questions about their symptoms, their quality of life and how treatment is working for them on a monthly basis. At week 12, many patients on barzolvolimab achieved complete response, defined as a UCT score of 16 up to almost 38% in cold urticaria compared to just 3% for placebo and almost 35% in symptomatic dermographism compared to 0% for placebo. Looking at well-controlled disease, defined as UCT greater than or equal to 12, almost 70% of patients on barzolvolimab reported well-controlled disease across both indications compared to approximately 30% of patients on placebo. Again, highly statistically significant and clinically meaningful results. In summary, across all primary and secondary efficacy outcome measures we evaluated on the study, barzolvolimab demonstrates clinically meaningful benefit and clear superiority compared to placebo at 12 weeks. This adds further validation that targeting the root cause of the disease, the mast cell, offers the greatest opportunity for patients with CIndU to experience clinical benefit. Importantly, barzolvolimab was also well tolerated by patients on study. If we turn now to safety on Slide 13, barzolvolimab demonstrated a favorable safety profile through 12 weeks of treatment. 98% of treatment-emergent adverse events were mild to moderate in severity. 66.7% reported as Grade 1 and 31.7% reported as Grade 2. As we have seen in our other studies, the most common events are on-target effects of KIT inhibition and are expected to be reversible. The most common treatment-emergent events in barzolvolimab-treated patients at 12 weeks were hair color changes in 17 patients or 13%, with Grade 1 events reported for 15 patients and Grade 2 events reported for 2 patients. We have included pictures of representative hair color changes from this Phase II study on the next slide. The picture in the middle was reported as a Grade 2 event and the other pictures were both reported as Grade 1 events. As we have shown before, these changes are observed as areas of hair lightning on the head base and/or body. They are reversible upon treatment cessation. Neutropenia was reported in 13 patients or 10%. 7 were Grade 1 and 6 were Grade 2 events. Importantly, and consistent with our results in prior studies, these events are transient and the rate of infections was similar between barzolvolimab-treated patients in placebo with no association between neutropenia and infections. There were 5 patients who discontinued on study due to adverse events, 3 on barzolvolimab and 2 on placebo. As we discussed in July, when we reported our top line results, there was 1 treatment-related serious adverse event that resulted in discontinuation. A patient on 300 milligrams developed hives and reported chest tightness and was hospitalized, treated and fully recovered. The patient was noted to have normal oxygen levels and vital signs. We had the event reviewed by an independent adjudication committee comprised of 3 experts, and they concluded there was no evidence of anaphylaxis. On 300 milligrams, a patient discontinued for Grade 2 neutropenia because their urticaria symptoms were persisting at that time. On 150 milligrams, a patient entered the study with active urticaria and angioedema, which persisted on the study. About 3 weeks after her second dose her symptoms worsened and the patient discontinued. The patient did not have a response to treatment, and we believe this event is the patient's underlying disease. We saw a similar adverse event leading to discontinuation in the placebo group in a patient who experienced swelling of the tongue and paraesthesia or burning of the mouth. The second discontinuation in the placebo group was a patient with cystic acne and ulcers in the month. Overall, the growing body of clinical data continue to position barzolvolimab with a very positive benefit to risk ratio as a well-tolerated potentially life-changing drug for patients whose lives have been controlled for far too long by these diseases of misery. The most common treatment-related adverse events are KIT-related effects, which are mostly mild and expected to be fully reversible and the rate of discontinuation associated with these events is low. The emerging efficacy data support that sustained KIT inhibition with barzolvolimab results in unprecedented highly statistically significant and clinically meaningful disease control, including complete response, which is the goal for patients and their physicians. Before I turn the call over to Anthony to close, in summary, on Slide 15, I have to say we are very pleased with this outcome for patients with inducible urticaria and for the barzolvolimab program. Barzolvolimab is the first drug in development to demonstrate statistically significant and clinically meaningful results in a large-randomized placebo-controlled study in this disease setting, and these data clearly support moving into registrational studies. The study met all primary and secondary endpoints with statistical significance, including high rates of complete and partial response. Improvement was marked and rapid across multiple endpoints and was sustained through the 12-week period. Barzolvolimab was also well tolerated with a safety profile consistent with previous studies. As we look across the full treatment period of 20 weeks, the data continue to be exemplary and the safety profile remains the same. We look forward to working with the health authorities to design a successful registration program, moving us closer to our goal of bringing this potential new medicine to patients. In closing, it is incredibly gratifying to see such consistent results across our studies. And as a physician, I am very excited about the potential opportunity that lies ahead for patients who need much better treatment options. On behalf of Celldex, I want to thank the patients and physicians who are participating in this study and playing a direct role in helping to make this a reality. I also want to again recognize Dr. Marcus Maurer who played such a leadership role in advocating for patients with inducible urticaria and encouraging drug development in this space. I know he would be thrilled that patients are 1 step closer to potentially having a new treatment option. Anthony?

Thank you, Diane. I want to echo Diane's gratitude and thank the patients and physicians who are participating in this study. I also share Diane's thoughts on Dr. Maurer. When Celldex first began to explore mast cell-driven diseases, Marcus was instrumental in helping us grow our understanding of these indications and how significantly patients are impacted. The goal of drug development in this space isn't to provide a treatment that helps a patient tamp down their urticaria when they aren't successful at avoiding their triggers. It's to fundamentally change their trigger threshold and allow them to enjoy a full enriched life that isn't governed by a strict set of rules and precautions at every turn. I remember Marcus telling us about a patient with cold urticaria who participated in our Phase I study and came to the clinic so excited because she had been able to drive her car with the window rolled down and that she had eaten ice cream the night before, something she hadn't done in years. He talked about patients with symptomatic dermographism who couldn't wear socks or pants with a belt. It's easy to take these things for granted in our lives and I do as well. But I think if you know how to meticulously plan every aspect of your day, to live your life to avoid your triggers, many of which, when it comes right down to it, are just unavoidable. The data we discussed today gives me great confidence that barzolvolimab can help these patients not just manage their disease, but hopefully regain control of their lives. We believe executing a Phase III program in CIndU and assuming positive data, pursuing approval in CIndU will be important for these patients, their families and their physicians. There are conservatively more than 270,000 patients with inducible urticaria in the U.S. and EU5. We plan to address the 2 largest subtypes, cold and SD. On its own, these markets are sizable. We have great confidence given the rigor of our Phase II study that we can repeat these results in Phase III and become the drug of choice these patients who want to regain control over their lives with a fast-acting, durable drug that offers meaningful opportunity for complete disease control. We look forward to working with the regulators to chart the path forward here, and we'll keep investors updated as we do. With that, I know it's a busy morning and I want to thank you all for joining us. We look forward to taking your questions and letting you carry on with your day. Operator, we're now ready to take questions.

[Operator Instructions] Our first question comes from Thomas Smith with Leerink Partners.

Congrats on the data.

Thank you.

Just one question. And if I could sneak in a follow-up after that, that would be great. Just first on efficacy. It looks like you're having a really rapid onset effect here at week 2. Wonder if you could provide some updated thoughts on how you're currently thinking about the Phase III trial design and whether there's an opportunity to take a look at earlier time points, so you can better define that onset of effect.

So in terms of the Phase III trial design, we need to have discussions with the FDA as far as appropriate endpoints for that study. We're certainly thinking of a randomized placebo-controlled study. We're looking at both forms of inducible urticaria. And we do think that we have positive doses for both doses in this study. So we would certainly consider both those doses and we are considering adding a loading dose as we've done with our CSU study. And certainly, there's the possibility of looking at earlier time points in the study.

Yes. But remember, in this study, Tom, we did the time points at 2 weeks, which was their first visit. So we're really getting that rapid response that we're looking for. I think that going forward with the Phase III, we're just looking to see, because we need to look at weights, we need to look at a bunch of different things, whether it's appropriate to do a loading dose. But we're perfectly happy with the rapidity of the response, the durability that we're seeing. And again, I don't think we would need to look any earlier than 2 weeks because that's when we're looking at their first assessment.

Got it. That makes sense. And yes, just with respect to the data that's still being generated in this study, I know it's designed as a 20-week randomized period, and then you're following the patients after another 24 weeks. Can you comment at all on anything that you're seeing both in terms of efficacy or safety out beyond that 12-week time point that was presented here? Do you have any data out at the 20-week time point or out into the follow-up period at this point?

Yes. So the data beyond 12 weeks is not yet cleaned and we haven't analyzed it, but we're certainly following the data. And I can tell you that we're pleased with what we're seeing both from an efficacy and a safety standpoint.

Got it. That's helpful. All right, guys. Congrats on the data.

Thanks, Tom.

Our next question comes from [ Jana Han ] with TD Cowen. Our next question comes from Yatin Suneja with Guggenheim Securities.

This is Eddie on for Yatin. Congrats on the data. It looks like a lower number of the oma-experienced to refractory patients were enrolled. Did those show consistent efficacy and were there any dupi-experienced patients in the study? Any added color on that would be helpful, even though I know the numbers were lower. And then it looks like the discontinuation rate was a bit higher in SD versus the cold. Is there any explanation for that biologically and could it impact the Phase III design at all?

So in terms of the omalizumab-treated patients, we did see a lower incidence of oma-treated patients. We think that's because it's not approved in this indication and in the countries that we were doing the study, a lot of them, the patients may not have had access to omalizumab as they might in the U.S. But we were very encouraged by the data in that small number of patients and very consistently to what we've seen with other studies. We do see responses in oma-experienced and particularly oma-refractory patients. We had 9 omalizumab-treated patients on the study, 6 were omalizumab-refractory and 2 of those were in the placebo group and had no response, 2 were in the 150 or the -- and 2 were in the 300 group, and out of the barzol-treated patients, 3 out of 4 had response -- complete response on the study. And then in terms of dupilumab, interestingly, we had 4 patients who had prior dupilumab all in cold urticaria, and 3 out of 4 of those patients had responses -- complete responses.

Very helpful. And then after discontinuation?

Yes. I don't have -- I don't really have a reason why the discontinuation rate was higher in symptomatic dermographism at this time. I mean, the most common reasons for discontinuation were common to both, which is things like patient decision just to get off the study, moving, patients not being eligible for the study, but there, we don't really see yet a difference why that rate should be different.

Got you. And then just finally, is the placebo sort of in the range you expected? And then how should we expect that to sort of evolve as the study matures to sort of later time points?

So there isn't that much published actually in these indications that we could know precisely what the placebo was going to be. The placebo varies according to which tools you're looking at. But I will say we were extremely pleased with the placebo rates that we got in the study and the fact that we have differences from placebo in virtually all of the endpoints, which is very encouraging.

Congrats again.

Thank you.

Our next question comes from Kristen Kluska with Cantor Fitzgerald.

Congrats on these updated data. Looks very good. So I wanted to ask more about the current commercial dynamics and reimbursement piece. Obviously, this is a different ballgame than CCU given there are no current approved therapies here. So maybe can you remind us, first, on reimbursement, how Xolair is used, whether it's reimbursed in current regions and also how that might impact the positioning of where barzol could be utilized if approved?

Yes, Kristen. So in the U.S., they are using it off-label. I do believe that they are getting reimbursed to a lesser extent. But also, we also think that they would also have probably some CSU on top of what they're having. In Europe and other parts of the world, we know in Europe that they won't get reimbursed. In fact, in Europe, you have to have an approval of the indication otherwise, you don't get reimbursed. And then there are other parts of the world where Xolair is not even approved. So there's really no ability for those patients to get it for CIndU. Does that answer your question?

Yes.

Next question comes [ Jana Han ] with TD Cowen.

It's Yaron.

Yaron, we can hear you.

Okay, great. Sorry for the confusion on the name. Maybe just a couple of questions that are interrelated. The first one is when you look at the slides, because we get questions on this a lot on the hair color changes, it looks fairly mild and sort of very diffuse. Can you maybe talk about what's the cadence of hair color change? Does it happen early and sort of it's sustainable? And the picture that you're showing, is that sort of typical of what patients see? And then maybe secondly, and I know you're going to give more guidance on your year-end call, but for the EoE data, the Phase II proof of concept, is there a chance to get that data next year?

Sure.

Yes. So in terms of the hair color changes, they start occurring several weeks into treatment. I think the pictures that we have are representative of the kinds of things we see, which, as we've said, are mild hair lightning. It can be on the head, on the body, on the beard or whatever. So I think those pictures are...

They're very indicative.

Are typical of what we've been seeing. And as we've said, they do reverse off of treatment.

Yes. And again, those pictures are very indicative of what's been seen in the clinic. And you can just see very, very light pieces of hair being changed. And what we also see there, a lot of these patients are in their 40s, 50s and even 60s. So they're being told -- the PIs are being told to look for it because it is a KIT-targeting mechanism. So -- but there's really no concern. Nobody gets off study because of this stuff for the most part. And as far as the EoE study, Yaron, we should be completing that in the first half and we'll present those data at the appropriate conference in the second half of '25.

Okay. Great. But I don't know if you can hear me, but just the hair color changes, this is sort of consistent with what is seen even at a year? It's not as if the whole hair everywhere is changing white?

Yes. Very consistent with what you see even longer term.

Yes, correct.

So it's very subtle and it seems consistent from what you see early to what you see later on?

Correct.

Our next question comes from Sam Slutsky with LifeSci Capital.

Just on Phase III for CIndU, can you just discuss the expectations for how easy to enroll in a CIndU study versus CSU? And then any insights from your experience enrolling the Phase II studies, both in CSU and CIndU? Whether it's patients per site and kind of so forth? How do you think about that timing?

Yes. So I think CIndU is a less common disease than CSU. And we have different subtypes you need to select. But beyond that, it wasn't really that difficult to enroll the study. We tend to involve the same investigators in our CSU studies as well as our CIndU studies.

Yes. So Sam, we had a certain time limit on this study that we thought we could accrue it on, and we beat that by several months. I'm sure these data will be very, very helpful to us as we go into the Phase III part of the accrual. Cold does have a little bit more seasonality to it. But as Diane said, we had no problems accruing the study or getting people interested or PIs interested for that matter. And off of that, the Phase III is going to be a lot smaller than the CSU study. So we don't think it's going to take any more time than the Phase II did.

Got it. And then do have time for a follow-up?

Yes.