Good day, and thank you for standing by. Welcome to the Celldex Therapeutics webcast. At this time, all participants are in a listen only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Sarah Cavanaugh. Please go ahead.
Thank you. Good morning, and thank you for joining us. We are very excited to start our day discussing positive top-line results from our two phase III studies in chronic spontaneous urticaria, EMBARQ-CSU1 and EMBARQ-CSU2. In addition to being available on the webcast portal, the accompanying slides for this morning's call are also on the investor relations page of our website in the events section. Joining me on the call this morning are Anthony Marucci, Co-Founder, President, and Chief Executive Officer, Dr. Tibor Keler, Co-Founder, Executive Vice President, and Chief Scientific Officer, Dr. Diane Young, Senior Vice President and Chief Medical Officer, Teri Lawver, Senior Vice President and Chief Commercial Officer, Dr. Margo Heath-Chiozzi, Senior Vice President of Regulatory Affairs and Quality, and Dr. Diego Alvarado, Vice President of Research.
Before we begin our discussion on this top-line data, I would like to direct your attention to slide two with respect to important information regarding the forward-looking statements that today's speakers will be making. We will hold a question and answer period after the presentation of the data. I would also like to note that these are very large studies encompassing almost 2,000 treated patients, and we received results very recently.
The team has worked very hard to analyze the key data, and you will find today's discussion fulsome. That said, we are continuing to review data, and there will likely be questions we are unable to answer at this time. We look forward to presenting the full 24-week data set, which we intend to submit for presentation to the American Academy of Allergy, Asthma, and Immunology annual meeting in February. With that, we will now advance to slide three, and I will turn the call over to Anthony.
Thank you, Sarah, and good morning, everyone. For decades, we have seen well-controlled disease accepted as an adequate outcome in CSU. Today, we are incredibly pleased to share phase III top-line data that clearly demonstrate that barzolvolimab can do better for patients. Turning to slide four, the data we are going to share with you this morning deliver on barzolvolimab's potential to be a transformational therapy for patients with CSU. Once again, this time across two studies comprising of nearly 2,000 patients from more than 500 sites in 43 countries, the primary endpoint and all key secondary endpoints have been met at both barzolvolimab dose levels. Across each endpoint, the data are clinically meaningful and demonstrate highly statistical significant decreases in disease activity. We are seeing rapid, profound, and durable efficacy that is best in disease in CSU.
This deep efficacy continues to be clearly demonstrated in patients with the highest level of disease burden, severe disease that is refractory to omalizumab, and CSU that presents with severe angioedema, uniquely positioning and differentiating barzolvolimab. While we are primarily going to show you efficacy at 12 weeks today, we saw in phase II these effects are sustained or deepen from week 12 to week 24 across all primary and key secondary endpoints. Our overall safety profile through the 24 weeks also remains consistent with our phase II experience, now in a much larger, diverse patient population. We have dosed about 2,400 patients with subcutaneous barzolvolimab across our phase II and phase III reported studies, delivering more than 11,000 individual doses of either barzolvolimab 150 mg or 300 mg in our phase III studies alone to date.
Our large phase III experience report reinforces that barzolvolimab has a predictable, consistent, well-tolerated safety profile that we believe results in a favorable benefit to risk profile that will support barzolvolimab's broad use across CSU. We couldn't be more excited about these data and what it means for patients and physicians. To remind you on slide five, CSU is a miserable disease that affects 1.8 million people in the U.S. alone. These people experience relentless, unpredictable hives, itch, and disfiguring swelling that affects all aspects of their lives, including sleep and mental health. With barzolvolimab, we believe we have developed a highly differentiated medicine of choice for patients with CSU with the unique mechanism of mast cell depletion that directly targets the root cause of CSU. This mechanism is directly tied to the profound clinical benefit patients experience.
We look forward to completing the phase III study while we are actively preparing for a BLA submission in 2027 and potential commercialization. With that, I will ask Diane to talk you through the data. Diane?
Thank you, Anthony. I want to echo Anthony's comments. These robust data continue to reinforce that barzolvolimab, with its unique mechanism of action, has the potential to redefine the CSU treatment landscape. It's been seven years since barzolvolimab first entered the clinic, and this rapid development would not have been possible without the support of the CSU community, especially patients, investigators, and study coordinators. Their enthusiasm for and dedication to the barzolvolimab program is the reason why we are so excited to share these data with you today. Turning to slide six, let's review the trial design. The phase III program is designed to establish the efficacy and safety of barzolvolimab in adult patients with CSU who remain symptomatic despite H1 antihistamine treatment. Both phase III trials are randomized, double-blind, placebo-controlled, parallel group global studies.
1,939 patients, 963 in EMBARQ-CSU1 and 976 in EMBARQ-CSU2, were randomized evenly to barzolvolimab 150 mg every four weeks following a 300 mg loading dose, barzolvolimab 300 mg every eight weeks following a 450 mg loading dose, or placebo for 24 weeks, at which point patients on placebo were re-randomized to active treatment across both dosing groups. 1,935 patients were ultimately treated on study and 1,634 or 84% of patients completed the 24-week placebo-controlled treatment period. The total treatment period is 52 weeks. As such, this is an ongoing study and remains blinded until completed. A phase III-B long-term extension study or LTE is ongoing, which patients can enter following completion of the phase III trials. The primary endpoint of the study evaluates the clinical effect of barzolvolimab in reducing urticaria activity, weekly urticaria activity score or UAS7 at week 12.
The study is designed to detect a clinically meaningful difference between each of the active arms versus placebo in the overall population, as well as in the subpopulation of omalizumab-refractory patients. The primary endpoint analysis was performed when all patients completed the placebo-controlled portion of the study at 24 weeks. The study was 90% powered to detect at least a 10-point difference between each of the active arms versus placebo in the overall population, as well as in the subpopulation of omalizumab-refractory patients. The key secondary endpoints are listed on the right-hand side of this slide, and we will review these in more detail shortly. Slide seven shows the demographic and baseline characteristics of the patients we enrolled into this study. Both studies are very well-balanced across all arms and enrolled a diverse patient population with severe disease.
As seen in our prior studies, roughly two-thirds of our patient population had severe CSU, as demonstrated by a mean UAS7 score greater than or equal to 28 at baseline. They also had very high rates of angioedema. The Dermatology Life Quality Index indicates a severe population with mean scores of 14 - 16. The DLQI is a validated tool that measures the impact of CSU on daily life, indicating that their CSU had a very large impact on their quality of life. Across the two studies, 288 patients were enrolled who were refractory to omalizumab, representing approximately 16% of patients in CSU1 and 13% of patients in CSU2. Turning to slide eight, we are excited to dive into the efficacy results with you now. On slide nine, let's look at the primary endpoint, mean change from baseline in urticaria activity score over seven days at week 12.
UAS7 is a patient-reported outcome tool. Patients record their daily itch and hive severity, which is totaled every week. We observe profound decreases with barzolvolimab treatment in UAS7 at week 12. Both barzolvolimab doses are clearly separated from placebo in both trials. The results are clinically meaningful and highly statistically significant, with mean decreases of about 20 points on barzolvolimab compared to 10 points in the placebo group, with comparisons having p values less than 0.00001. As we saw in phase II, the primary endpoint result is strongly supported by positive data across all key secondary endpoints, shown here on slide 10. For the purposes of today's top-line results, we are going to share the data across the three secondary endpoints we believe are of highest importance to patients and physicians and reflect the greatest unmet needs with current CSU therapies.
The proportion of all patients with complete response or UAS7 equal to zero, complete response rates in the subset of patients with disease refractory to omalizumab, and the proportion of patients who had no angioedema symptoms at week 12, as demonstrated by an AAS7 score of zero in the subset of patients who had angioedema at baseline. While we will not review the other key secondary endpoints today in detail, all were clinically meaningful and met high statistical significance. Importantly, this efficacy was sustained or deepened from week 12 to 24 across the primary and all key secondary endpoints. We also know that DLQI is not a key secondary endpoint in this trial, but we know that quality of life is important to patients and physicians.
We look forward to sharing data on these secondary endpoints early next year at an upcoming scientific conference that reinforces the profound benefit barzolvolimab can have on quality of life. First, on slide 11, let's talk about what matters most to patients and physicians, complete response. As a reminder, complete response measured by UAS7 equals zero indicates the complete absence of itch and hives. Given the importance of this endpoint to patients and physicians, and barzolvolimab's unique ability to drive sustained complete response, we are showing you this data at both 12 and 24 weeks. The difference compared to placebo is striking, and by week 12, up to 46% of patients have a complete response, which deepens to up to 54% by week 24. Consistent with phase II, barzolvolimab offers complete response levels that are unprecedented in CSU.
Importantly, this profound efficacy is also demonstrated in the patient populations with greatest unmet need, patients with disease refractory to omalizumab, and patients who have angioedema. The proportion of omalizumab-refractory patients with complete response at week 12 is shown on slide 12. Our definition of omalizumab refractory is very strict. Patients who were treated with omalizumab at approved doses for at least three months and whose symptoms never responded, who responded initially but their symptoms subsequently returned, or patients who discontinued omalizumab due to intolerance. Again, even with this very high bar, we see results consistent with what is seen in the overall patient population, with clinically meaningful and statistically significant separation from placebo. As is consistent with our mechanism of action, we know that barzolvolimab tackles the root cause of CSU, and we believe it should have broad applicability across all patient populations.
Up to 55% of patients with CSU refractory to omalizumab experienced complete response at 12 weeks. These two studies are the first phase III studies to demonstrate efficacy in the omalizumab-refractory CSU population, a major advancement in the field. On slide 13, we show the profound benefit for patients with angioedema. Angioedema is marked by painful, deep, and disfiguring swelling beneath the skin, most commonly on the lips, eyelids, face, hands, feet, or genitals. Angioedema is significantly correlated with higher disease burden, and we believe that barzolvolimab has the potential to set a new standard in angioedema control, as shown here. We see clinically meaningful and statistically significant separation from placebo. Up to 74% of patients with angioedema at baseline achieved complete angioedema control at week 12 on barzolvolimab.
As we have now seen across multiple studies in CSU, it is clear that targeting the root cause of the disease yields profound clinical benefit, offering new hope for patients and physicians who need better therapies for this miserable disease. The profound clinical activity demonstrated across the phase III program is supported by a well-tolerated safety profile that is consistent with our phase II barzolvolimab experience. Turning to slide 14, let's review safety results from the trials. As shown on slide 15, the combined placebo-controlled safety data set includes almost 2,000 patients observed for 24 weeks. As a standard practice for clinical trials, in phase II, we reported adverse events observed in 10% of patients or greater. For phase III studies, you typically report AEs observed in greater than 3%-5% of patients. For the purposes of this analysis, we're reporting at 3% cutoff.
Barzolvolimab shows favorable safety consistent with prior experience. There were no new meaningful safety signals identified. Across the study on barzolvolimab, the vast majority of adverse events observed were mild to moderate, and the most common adverse events are KIT-mediated and expected to be reversible, as we have demonstrated in our phase II CSU study. The rate of serious events was balanced between placebo and the barzolvolimab arms. I will provide a brief summary of the serious adverse events reported as treatment-related, which can be attributed to either barzolvolimab or placebo. There were two cases of anaphylaxis following the first dose of barzolvolimab administration, adjudicated by a blinded independent expert committee as probable. The symptoms occurred shortly after dosing, and the patients made a full recovery. A single case of anaphylaxis adjudicated as probable occurred following the first dose of placebo in the 300 mg barzolvolimab Q8-week arm.
As a reminder of our protocol, to maintain blinding for patients in the 300 mg Q8-week cohort, patients received placebo on alternating visits to match the dosing frequency of the 150 mg Q4-week arm. This patient tolerated their first barzolvolimab dose well and then four weeks later, immediately following their first placebo dose, experienced symptoms. The adjudication committee deemed this probable based on the acuteness of the event immediately following blinded placebo treatment. There were five other treatment-related serious adverse events on the two studies. A patient in the placebo arm experienced symptoms after the first placebo dose, reported as Grade 3 anaphylaxis, which was adjudicated as unlikely. The patient discontinued treatment. In the 150 mg arm, one patient reported Grade 2 urticaria angioedema and throat tightness and did not seek medical attention. The patient discontinued treatment.
This potential hypersensitivity event was sent to the adjudication committee and deemed to be consistent with their underlying disease. In the 300 mg arm, one patient experienced Grade 3 anemia and neutropenia that was not associated with infections. Treatment was discontinued, and they fully recovered with barzolvolimab on board. In the 300 mg arm, one patient experienced a single Grade 2 event of malaise, chest pain, and shortness of breath, recovered, and continues on treatment. A patient experienced symptoms reported as Grade 3 anaphylaxis adjudicated to be unlikely, which occurred following the third dose of placebo in the 300 mg barzolvolimab Q8-week cohort. To be clear, there were two adjudicated cases of probable anaphylaxis following barzolvolimab treatment across both phase III studies.
To date, these two adjudicated cases are the only cases observed across the entire barzolvolimab subcutaneous program, including ongoing studies in AD, SD, and ColdU, representing more than 2,400 barzolvolimab-treated patients. This is well in line with what you would expect to see with injectable biologics. On slide 16, we are very pleased to see in this robust phase III study that the results indicate that treatment with barzolvolimab did not lead to increased rates of infections, and there was no association between neutropenia and infection. Most importantly, the rates of infection were balanced across placebo and barzolvolimab-treated patient groups, including the rates of serious infections. This supports that barzolvolimab did not lead to increased infections. Rates of neutropenia are consistent with phase II, 9.1% of patients on the 150 mg arm and 11.7% of patients on the 300 mg arm experienced an adverse event reported as neutropenia.
These events were mostly mild to moderate. To summarize, the safety observations from 24 weeks of placebo-controlled treatment in almost 2,000 patients are consistent with the favorable safety profile we observed throughout this program. The safety profile primarily reflects that the mechanism-related adverse events are generally mild and without clinical sequelae and are expected to be fully reversible. We believe this safety profile, combined with the unprecedented efficacy, results in a highly favorable benefit-to-risk profile. Results support our plan to submit a BLA in 2027, and we are making great progress on CMC and other supporting activities required for a successful submission. Turning to slide 17, I will now pass the call over to Teri to talk about the opportunity to bring barzolvolimab to patients as we plan for commercialization. Teri?
Thank you, Diane. Let's turn to slide 18. With these exceptional results, I want to describe how we see the potential for barzolvolimab to uniquely address large CSU patient populations with significant unmet needs. We have heard time and time again from the CSU community that they are looking for more than just improvement. They aspire to be completely free from their symptoms and the anxiety associated with not knowing when the next flare might occur. In these top-line results, we see barzolvolimab's potential to address these needs. Here we illustrate where we see barzolvolimab fitting into the evolving CSU treatment paradigm, addressing two large CSU populations with significant unmet need. First, we see barzolvolimab as a potential first-line advanced therapy of choice for patients presenting with severe disease or with severe angioedema.
Earlier, Diane reviewed the exceptional EMBARQ-CSU results in delivering both UAS7 equal zero, meaning complete control of disease in up to 54% of patients at week 24, and AAS7 equal zero for complete control of angioedema in up to 74% of patients at week 12. As a reminder, more than 2/3 of patients in our EMBARQ-CSU phase III program were experiencing angioedema at baseline, with mean AAS scores at baseline over 50, indicating severe angioedema. Currently, there are no approved CSU therapies with labeling demonstrating angioedema control. Drawing your attention to the right of this page. We also believe that barzolvolimab has the potential to be the therapy of choice for second-line advanced CSU treatment in patients who remain symptomatic after treatment with any one of the currently approved therapies.
Diane Young previously shared the profound complete response measured as UAS7 equal 0 in up to 55% of patients at week 12 whose disease is refractory to omalizumab. Currently, there are no approved CSU therapies with labeling supporting use in advanced therapy-refractory CSU. Turning to slide 19. I want to reiterate how thrilled we are with today's results as they establish a strong foundation and prepare us well for potential commercial success. Barzolvolimab is a unique, novel, first and only-in-class antibody with the potential to deliver efficacy that is highly differentiated on the endpoints most important to CSU patients and their healthcare professionals. Today's positive phase III readout amplifies our excitement about the transformational impact barzolvolimab can have for patients and reinforces our confidence in the significant potential of this novel therapy.
We remain fully focused on bringing barzolvolimab to patients as expeditiously as possible and on executing a streamlined and robust launch strategy that is fitting of this innovative therapy. With that, I will turn it back to Anthony to wrap up. Anthony?
Thank you, Teri. Let's turn to slide 20. We are incredibly proud of our progress and execution over the past seven years, delivering on our leadership in mast cell biology and bringing barzolvolimab through to phase III. Today's results mark the next phase of the journey of bringing people with CSU what we believe to be life-changing therapy. These results are unprecedented and offer new hope for patients, physicians, and the CSU community. As demonstrated across the life of barzolvolimab program and reinforced in phase III, suppressing KIT with barzolvolimab targets the root cause of CSU and leads to rapid, profound, and durable efficacy. The favorable safety profile is also highly consistent with what we've observed in the past experience, which we are incredibly pleased with these large, nearly 2,000-patient trials.
We continue to work on bringing this important medicine to patients and are focused on completing the EMBARQ-CSU studies and preparing for BLA submission in 2027. As mentioned by Sarah earlier, we plan to submit the 24-week data from the EMBARQ-CSU trials for presentation at AAAAI in February. We also look forward to sharing more about barzolvolimab's potential in additional indications in the near future. We plan to report the p hase II atopic dermatitis results in the fourth quarter of this year, and our phase III CSU and ColdU trials are on track. To conclude, I'd like to thank everyone for your support on our barzolvolimab program, especially the patients, and we are excited about the next phase as we prepare to become a commercial-stage organization. Thank you for joining us.
Before I turn the call back to the operator and opening up the call for questions, I would like to remind you that this is an incredibly large data set representing nearly 2,000 patients, and we have only recently received it. We are thrilled with the results and want to share them as quickly as possible and also want to remind you that we may not be able to answer every question you may have at this time. Operator, please open the call.
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Our first question comes from the line of Tom Smith with Leerink Partners. Your line is now open.
Hi, this is Nat Charoensook on for Tom Smith. Congrats on the data, and we have a few questions. The first one on the onset of efficacy, how quickly did you see responses, and how consistent was the experience between omalizumab naive and omalizumab refractory patients? And have a few follow-ups.
We have rapid responses in these studies. We are going to present more about that data at the AAAAI next year. We are very pleased with the rapidity of response that we have seen.
We are still going through the data. We know we see it as early as two weeks. We are looking to see if we see it even earlier, but it is very rapid, as we said. Again, we are going through all the data now, but at two weeks at minimum, maybe even faster as we go through the data.
Got it. In the two adjudicated cases of anaphylaxis, can you elaborate more on the clinical course for these patients? Was there any additional background that could have contributed to this? Were there any commonalities between these patients that might allow for identification of patients that are at greater risk for anaphylaxis?
Yeah. As we described, we have two cases of confirmed anaphylaxis following administration of barzolvolimab across the whole program. These two cases were adjudicated by an independent anaphylaxis adjudication committee. In both of these cases, the onset of symptoms was rapid. In one patient, it was 10 minutes. In the other, it was 2.5 hours.
One patient actually had hospitalization. The other one was just treated in the clinic and discharged, so less severe. They were both felt to be probable anaphylaxis by the adjudication committee.
Got it. Very helpful.
Right.
Have you looked at the exposure-adjusted rate of anaphylaxis for this sub-Q barzolvolimab, and how does this compare to other biologics that are approved to treat allergy conditions?
We have not looked at the exposure-adjusted rates at this time. That's data we're going to get later.
But at this point, we have two cases out of 2,400 patients, which compares very favorably with other biologics.
Got it. And last question, what are the discontinuation rates observed for these study arms? Can you give a brief comment on that?
Yeah. So the overall discontinuation rate from the placebo-controlled period was 16%. The main reasons for discontinuation were withdrawal of consent by patients, as well as adverse events.
Thank you. Our next question comes from the line of Yaron Werber with TD Cowen. Your line is now open.
Great. Thanks so much. So maybe just a quick question. It looks like the serious adverse events are pretty much identical in the barzol arm to placebo at 1%-2%. I just want to make sure, is that correct? And can you
Yes, that's
Give us a sense. Yeah, go ahead.
No, I was just going to say that the rates of serious adverse events are similar between the barzol treated groups and the placebo group.
That is super encouraging. When you are looking at the Grade 3 and 4, you are calling some of them in slide 16, is there anything else that is worthwhile for us to keep in mind with that respect?
Yeah, no. There was no increase in Grade 3, Grade 4 adverse events on barzolvolimab versus placebo across this study.
Okay, amazing. When you look at skin hypopigmentation, it looks like there were both cases of hyper and hypo. They are all around 10% versus low single. Anything specific worth calling out there? Thanks, and congrats on the data. It looks really good.
Thank you. Hypopigmentation, we have described it before, and you really see similar picture here. Hyperpigmentation shows up here. We actually have seen that previously. We saw that in our phase II studies of CSU and CIndU. The rate was about 4% in those studies, so it did not make it to our AD table based on the 10% cutoff. We do know from the phase II data that those cases are mostly mild. They were reversing. We do believe it is a KIT-mediated effect because similar events were reported on in that therapy.
And then maybe just a final question. Even in patients who discontinue in the study, because we know from your previous data that efficacy is fairly durable, would you still look at their efficacy over time? Thank you.
Oh, we will look at the efficacy in the patients who discontinue the study. We haven't gotten to that yet, but we will do that.
And we expect to see similar numbers, Yaron.
Thank you. Our next question comes from the line of Yatin Suneja with Guggenheim. Your line is now open.
Hey, guys. Thank you for taking my question. Congratulations on very good results. Obviously, the Street is a little bit more focused on investor, a little bit more focused on the safety side today. So quick clarification. It seems to us that you only have just two cases of anaphylaxis out of these 2,400 patients. The percentage is much lower than what we see with many biologics. The question is, what do you think is the implication for the label, if any? The reason I ask is that because some of these widely used drugs, like even DUPIXENT, have anaphylaxis and warning flagged on the label. Is that going to be anything different for you? That sort of is first question, and then I have a follow-up. Thanks.
Yeah. As we discussed, we have two adjudicated cases following the administration of barzol across the entirety of our subcutaneous program, which is about 2,400 patients, and these occurred immediately following the first barzolvolimab dose. As we said previously, and the data support it, we believe that we will have a label consistent with other biologics. That is something in the warning precaution section, for hypersensitivity and anaphylaxis.
Any biologic, with the exception of XOLAIR and Teva's drug, have similar warning labels for hypersensitivity and anaphylaxis. As you know, we've been telling that to people for the last four or five years. These data are extremely encouraging, and two out of 2,400 is well within the range of acceptability.
Got it. Very good. Thank you so much. Then just one follow-up on the angioedema benefit that you're seeing. Could you talk about the baseline severity of these patients, specifically on angioedema? I think that's where you also differentiate, because I don't know if any other drug has shown that level of benefit on angioedema. So I would love to understand how that is.
Sure. Just like in the phase II study, the baseline was pretty high. A number of them came in with severe disease. These data are replicating the phase II experience, what we're seeing. Very severe patients coming in. The differential between us, our drug, and the placebo patients is obviously statistically significant and much better than what you would experience with other drugs out there. On par.
This is Teri. I might add two things. One is the placebo delta on these results is the best-in-class by far with any CSU medicine in any publication. A reminder of the correlation between the incredibly high burden of disease that comes with angioedema. These results really speak to the overall impact of these results.
Thank you. Our next question comes from the line of Kristen Kluska with Cantor. Your line is now open.
Hi, everyone. Huge congratulations on these data set. Very impressive. You mentioned of the 2,400 patients on therapy. Can you just clarify if that includes all studies to date, including other ones that are currently up and running? Just given that it seems that these two cases reported today and the one in PN for anaphylaxis occurred on the very first dose, is there also a case to be made that maybe just if certain physicians are higher risk, they'll just administer the first dose in office?
Sure. Yes, it is across all current and studies done in subcutaneous. That would include the AD study. That would include the ongoing phase III SD and ColdU studies.
And we do agree that these two cases occurred after the first dose as well as the IV case you mentioned.
Great. Kristen, HCP and office administration is the base case for the launch, and we continue to plan for an auto-injector with at-home administration roughly 18 months post initial approval.
Okay. Thank you. And then, Teri, you've talked about the two different patient segments where you think you could have the highest unmet need where barzolvolimab could be attractive. Of the roughly 500,000 or so, what percent or number of patients do you think are applicable to each of the categories? Thank you so much again.
Yeah. In the first line with severe or angioedema, we know that 55% of patients overall present with angioedema. There are no published data on the percent of that breakdown, mild, moderate to severe. But the best data that we have access to tells us that up to a third of those with angioedema are categorized as severe angioedema. Then you can see here on slide 25%-30% of patients with CSU presenting with severe. When we look at the overlap, the intersection of those two, Kristin, we estimate that at about 20% of first-line patients who are on barzolvolimab is uniquely positioned with this clinical profile to be the potential therapy of choice. On the second-line data, this is very much evolving. There was no second line advanced CSU therapy until just 18 months ago.
We do see that number growing, and the trajectory that we see, along with the analogs we've seen in other I&I diseases, would project that the second-line advanced therapy market would eclipse the first-line advanced therapy market within the first two years of the barzolvolimab launch.
Thank you.
Thank you. Our next question comes from the line of Sam Slutsky with LifeSci Capital. Your line is now open.
Hey, thanks for taking my question. Congrats on a positive update. I guess two for me. One, as you move towards commercialization, could you talk about the build-out as you're thinking about sales reps, ex-U.S. versus U.S. plans, and then what has to be done between now and then? Just a quick clarification. I think I heard you mention 16% dropouts due to AEs. Do you know what their rate was between arms? Was there anything driving it, or was it pretty dispersed across AEs? Thanks.
I'll answer the AE question first. There was a 16% overall dropout rate in the study. The dropout rate related to AEs was more like 8%. The most common ones were low rates, but were hair color change, skin pigment changes, and neutropenia. It's really very consistent with what we've seen in our previous studies.
Sam, let me address your question about the commercial build-out. Obviously first, look, these results are unequivocal and give us great confidence in the commercial strategy that we've been discussing for the last several months. In terms of our field team, we will build a competitive, appropriately sized field team. We know based on the data we are collecting, all of the available public data, tracking it monthly, we know exactly who are the HCPs who are prescribing advanced therapy. Our field footprint plan is to be present with a competitive presence in all of the offices where advanced therapy is being prescribed. You also asked about our U.S. plans?
Yeah. Sam, obviously the U.S. plans, we're going to look and consider several things, including for future indications, future pipeline. We're looking at the regulatory and policy environment as we go on. We're looking at all of those things to move forward. Once we get a little bit more clarity, we can give you a better update that way.
Thank you. Our next question comes from the line of Judah Frommer with Morgan Stanley. Your line is now open.
Yeah. Hi, guys. Congrats on the data. Thanks for taking the questions. Maybe first, and I apologize if I missed it, but what are your thoughts on commercialization of both doses? Could you potentially see pushing the every eight-week dose that did not have the anaphylaxis? Could there be kind of different prescribing patterns with one versus the other given the safety profile? Thanks.
Thank you for the question. We see the very strong and consistent efficacy and safety across both doses as giving us optionality. We see there are certain patients and certain HCPs who like the consistency of the potential for every four-week therapy, which is a very manageable dosing regimen. And we know that there are patients and physicians who would prefer less frequent dosing. That Q8-week dosing, 300 mg Q8-week, gives us a very nice potential competitive advantage in terms of frequency. It provides the potential for seven days per year of treatment, which is best in class for any CSU therapy. So we really like the consistency and the optionality, and we will seek the opportunity to present that optionality in the label.
Okay.
And Judah, also, remember, we had the case at 150 mg and the placebo was at 300 mg. The other two cases that were adjudicated unlikely to be anaphylaxis were both placebo as well. So, we do not think it is anything with the 150 mg or the 300 mg, because as you can see, even patients that got placebo had reactions as well.
Got it. Okay. Just on the hair color changes, numerically, those rates look higher than the phase II, and I do not think there were any placebo hair color changes in the phase II. Was there any change in the assay, or the investigation on hair color changes between phase II and phase III?
Yeah. So the hair color changes, as we have said, hair color changes are really expected in the study. It is a KIT-mediated effect. It is mild. It is reversible. So we expect hair color changes in the study. A couple of things to note here is that we have longer follow-up in this study. So this is a 24-week placebo-controlled period as opposed to some other earlier studies with shorter follow-up intervals. But I would say there is much greater awareness of hair color changes. We are looking for them in the study.
We talk about it in the informed consent. The investigators are all aware. So I think people are looking for these things, and we do in fact see, as you mentioned, see all these KIT-mediated effects now in placebo, and I think that is the nature of it. It can be kind of a subtle finding, and people are more aware, so they are calling it. But it is really just reports of patients and investigators. Thanks.
Judah, remember also, this is a population that the mean is in the late 40s. So you are expecting to see hair lightening, and that is why you are seeing it also in the placebo. But remember from the time we started this program in phase I, we were looking for these KIT-mediated on-target effects, hypopigmentation, hair color changes, all these things were part of the history of targeting KIT. As we are learning through clinical development, these are the things that we want to learn. We are not going to shy away from them. But obviously they have no clinical benefit. I mean, risk. They are completely reversible, as we have seen in our phase II, and we will show it again as the patients go through the phase III program, that these are completely reversible and have no clinical impact whatsoever.
Thanks.
Thank you. Our next question comes from the line of Derek Archila with Wells Fargo. Your line is now open.
Hey, good morning, and congrats on the data and thanks for all the color here.
Thank you.
So just two questions. Is it your intent to file for approval of both doses of barzolvolimab, or is there a case to pursue just one? The second question is, just remind us whether you need any longer-term data from this study prior to filing the BLA. Thanks.
Sure. Margo, can you answer the both doses for Derek?
Yes. We intentionally set out to characterize both doses because we would like to offer patients optionality, and since the data looks so consistent across them, we will certainly want to support that that is an appropriate way of using the product. On the what else are we going to need? We have been aligned with the agency throughout the development, and so we are certainly going to share this data and then align with them on how to get this drug to patients as quickly as possible. So we want to share with them where we are, and then we are going to align with them on where to go.
Maybe just to follow up there, I guess the question is really do you need any longer-term data? Do you need to show 52-week data from this study or any additional safety?
Well, this is the 24-week cut with then ongoing data coming in as we are going. So we fully anticipate having These were large studies, so we have a lot of data, and so we will be talking. I do not have a crystal ball in terms of what magnitude, but we certainly will be sharing with them how this large data set is emerging.
Understood. Thank you so much. Congrats again.
Derek,
Oh, go ahead. Sorry.
No, I was going to say we already have over 500 patients treated out to a year. Whatever the FDA needs, we're close.
Excellent. Thank you.
Thank you. Our next question comes from the line of Alex Thompson with Stifel. Your line is now open.
Great. Thanks for taking our questions. I guess, another one on dosing and thoughts about the label moving forward. How are you thinking about the addition of the loading dose here relative to phase II? Does it seem to be beneficial relative to your expectations in terms of clinical efficacy? Is that something that might be up for discussion with FDA, especially when you think about safety profile here? Then, when you are thinking about positioning as a second-line option, as with other I&I markets, should we expect premium pricing here relative to some of the first line comps that are out there? Thanks.
Yeah. So let's take the first part with Tibor, and then Teri can answer the other part.
We believe the loading doses are helpful. We still have data to analyze here, but overall, we certainly don't believe they contributed at all to a difference in the AE profile. We think our profile in phase III is very consistent with what we had in phase II. Again, our loading doses are modest. They're just intended to get patients into the level of KIT saturation more rapidly by giving this loading dose. Again, we'll look at the data more carefully, but we think that certainly we know that rapid response is important to patients, and we think these doses have clearly a good safety profile. I would expect that we will use the loading dose as part of our regimen in the commercial approach.
Yeah. Alex, just to level set everything here. If you remember in the phase II, the 300 mg dose was below the 51% that we saw at 150 mg. It was around 37.5%. We saw that at the six to eight-week timeframe, the 300 mg was coming back a little bit. We saw a 44% blended rate of response in the phase II study.
When you look at the rates now, the 300 mg and the 150 mg are fairly close. We think that loading dose was helpful here, to the point where 44.25% was the blended rate in phase II, and then the phase III rate was 43.6%. The word that keeps coming up with us is consistency on all the data here. This was the same here. Teri, you want to answer that question on pricing?
Sure, Alex, on your pricing question, we do believe a substantial differentiation of the overall profile as well as the differentiation in important patient populations that other therapies cannot adequately address. That combination of factors, we do believe, will translate into economics differentiation as well and will support a value-based premium pricing strategy.
Thank you.
Thanks, Alex.
Our next question comes from the line of Richard Law with Goldman Sachs. Your line is now open.
Hi, everyone. This is Toni Usman on for Rich. Thanks for taking our questions and congrats on the results this morning.
Thank you.
To follow up on the earlier label question, I wanted to ask, given the emergence of the two anaphylaxis cases, do you anticipate any risk of a box warning? If so, how do you anticipate that might impact commercial uptake?
No. As we've said, we really believe that these data are really supporting a label which is consistent with the other biologics out there, which is a warning that includes hypersensitivity, including anaphylaxis, and that's our expectation.
Yeah. Two out of 2,400 patients. Do the math. It's extremely low. We're very happy with it.
All right. Thank you. If I could drop in one more on commercial. How do you expect barzolvolimab will be used between chronic and intermittent use in a commercial setting based on the efficacy and safety profile you've shared today?
CSU is a chronic disease, and this is a chronic therapy. That is how we anticipate the label and the intentionality for use.
Thank you.
Thank you. Our next question comes from the line of Andy Chen with Wolfe Research. Your line is now open.
Hi. Thank you. This is Jason taking for Andy. We just want to ask about the neutropenia. The overall infection rate looks good. But could you break out the infection outcomes specifically among patients who develop neutropenia? And specifically, do those patients have more opportunistic infections or generally more severe infections compared to placebo? Are there any trend of treatment time increasing with infection risk/rate? Thank you.
We have absolute consistency in terms of similarity of rates of infections and serious infections across placebo and barzolvolimab-treated groups here, including serious infections. We do not see an association of infections with neutropenia. In terms of the infections, we do not see opportunistic infections. There's really nothing in this data that indicates any sort of infection signal.
Thank you. Appreciate it.
Thank you.
Our next question comes from the line of Etzer Darout with Barclays. Your line is now open.
Hey, good morning. This is Gustave on for Etzer. Congratulations on the data. At launch, what do you think will be the biggest driver of physician adoption versus remibrutinib or DUPIXENT? Is it more the angioedema control, the efficacy in refractory patients? Completely-
I'm sorry.
What are your thoughts on that?
I'm sorry, you're coming off very muffled. Can you repeat that?
Yes. Can you hear me now?
Still a little muffled, but better. Go ahead.
Okay. All right. We'll take it slowly. What do you think will be the biggest driver of physician adoption versus remibrutinib or DUPIXENT? Is it the angioedema control or the efficacy you're seeing in refractory patients? What are your thoughts on that?
Teri?
We see two very large patient cohorts with significant unmet needs, where barzolvolimab is uniquely positioned to address patient needs, and this is where we see the greatest adoption likelihood. The first is for first-line advanced therapy, so patients who have tried high-dose antihistamines, are still experiencing active disease, and who are presenting with either severe disease or severe angioedema or that combination. For reference on the size of that opportunity in our phase II trials, and we are still in the process of calculating this for our phase III, but in our phase II trials, 36% of patients had both severe angioedema and severe CSU. This is a very meaningful portion of the first-line advanced therapy population. The second likely high adoption opportunity for barzolvolimab is as the treatment of choice for second-line advanced therapy.
This is for patients who have tried any one of the currently approved advanced therapies and are still experiencing symptoms. As we have seen with other I&I biologics, I&I categories, we would anticipate the second-line advanced therapy market, in fact, to eclipse the first-line advanced therapy market within the first two years of barzolvolimab's launch. As a reminder, there are no other approved CSU therapies with label indications demonstrating efficacy in a biologic-refractory population.
Thank you. This concludes the question and answer session. I would now like to hand the call back over to Anthony Marucci for closing remarks.
Thank you, operator. I want to thank everybody for joining us this morning. We are extremely happy to be able to present our data set with you at 12 weeks. As we said, we will present the complete data set at AAAAI in February. We are working hard to go through all the data that we have so far, but we are incredibly happy about our data. We want to thank the physicians, the patients, everyone who has supported us throughout this phase III program. We have got this thing done in less than seven years, which is extraordinary. We continue to want to show you good data going forward. We look forward to it. Have a good day. Thank you.
This concludes today's conference. Thank you for your participation. You may now disconnect.