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

Good day, and thank you for standing by. Welcome to the Celldex conference call. [Operator Instructions]. 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. Ma'am, please go ahead.

Thank you. Good afternoon and thank you all for joining us to discuss the 52-week results from our Phase II study of barzolvolimab in chronic spontaneous urticaria. These data were presented earlier today in a late-breaking oral session at EADV. The EADV presentation can be found on our website in the Science section under Publications. The slides for this call can be found on our website on the Events page. With me on the call, I have 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 the call. I'd now like to turn the call over to Anthony. Anthony?

Thank you, Sarah. Good afternoon, everybody, and thank you for joining us. We are really looking forward to walking you through the data Dr. Metz presented at EADV this morning. When our team first saw the tryptase data from our healthy volunteer study in summer of 2020, we quickly suspected barzol had incredible potential to be a transformative treatment option for patients with mast cell mediated diseases. This 52-week data in CSU brings us full circle. We believe this data set is a landmark event for the barzol program and for the CSU field, setting a new bar for efficacy in a very difficult disease setting and validating the mechanism of mast cell targeting, which we fundamentally believe can be broadly applied across a number of serious diseases. We have a lot to cover this afternoon. And in the interest of time, I will turn the call over to Diane to discuss the data. Diane?

Thank you, Anthony. I am now on Slide 3. CSU is a miserable disease characterized by painful, itchy hives, swelling and inflammation of the skin that can go on for years or even decades. It causes significant emotional distress including sleep deprivation, anxiety and depression. It is also known to be a mast cell mediated disease, which is why we were so excited to study barzolvolimab in this indication. To remind everyone, barzolvolimab is engineered to be a best-in-class inhibitor of KIT, which is required for mast cell function and survival. Treatment options for patients with CSU are very limited. The first line of treatment is antihistamines, which may be increased up to 4x the label dose. Many patients do not achieve good control with antihistamines and there are no approved therapies for patients who inadequately respond to the only approved second-line therapy, omalizumab. This makes the results we are presenting today all the more exciting in that we see remarkable efficacy in both omalizumab-naïve and refractory patients. As we disclosed earlier this year, our Phase II in CSU met its primary endpoint, the maintain face line to week 12 in the urticaria activity score 7 across all 3 doses while also demonstrating a favorable safety profile. We are looking at the 52-week data to really answer 2 major questions. Does efficacy deepen over time? And does the drug maintain its well-elevated safety profile with longer-term treatment? The answer to both these questions is a resounding yes, and I am excited to share the data with you. Slide 4 outlines the study design and eligibility criteria. This trial enrolled 208 patients across 72 sites in 8 countries. It's a randomized, double-blind, placebo-controlled parallel group Phase II study designed to evaluate the efficacy and safety profile of multiple dose regimens of barzolvolimab in patients with CSU who remain symptomatic despite antihistamine therapy. All patients were on a stable dose of antihistamines at up to 4x the label dose upon study entry. In addition, the study also allowed prior biologic use with an appropriate washout period before study entry. Patients were randomly assigned on a 1:1:1:1 ratio to receive subcutaneous injections of barzolvolimab, 75 milligrams every 4 weeks, 150 milligrams every 4 weeks, 300 milligrams every 8 weeks or placebo every 4 weeks during a 16-week placebo-controlled treatment period. After 16 weeks, patients then entered a 36-week active treatment period in which patients not already randomized to barzolvolimab at 150 milligrams 4 weeks or 300 milligrams every 8 weeks were randomized 1:1 to receive 1 of these 2-dose regimens. Patients already randomized to these treatment arms remained on the regimen as during the placebo-controlled treatment period. After 52 weeks of treatment, patients entered a follow-up period for an additional 24 weeks, which is ongoing now. As I mentioned, the primary end point analysis was at 12 weeks. The analysis we are discussing today reflects data through the end of the 52-week treatment period. Slide 5 outlines patient baseline characteristics. There are 2 things I'd like to point out on this slide. First, if you look across the treatment groups, including placebo, this is a very well-balanced study. Second, patients on study had significant urticaria symptoms, mean UAS7 at baseline ranged from 30 to 31.3 across the groups with 69% of patients classified as having severe disease with UAS7 greater than or equal to 28. Most patients on study also had angioedema, which is associated with more severe disease. We think these factors further speak to the strength of the data. We have achieved an exceptional outcome in a well-balanced study in a severely impacted patient population. Slide 6 shows the patient disposition. Approximately 75% of patients completed the full 52-week treatment period, 10% of the patients discontinued treatment due to adverse events with hair color change, urticaria and macrocytic anemia occurring in more than 1 patient. All other events occurred in single patients. Slide 7 shows the primary end point data, which we presented earlier this year. We observed a profound decrease with barzolvolimab treatment in UAS7 at week 12. All 3 barzolvolimab doses separated from placebo with statistical significance. The results are clinically meaningful and highly statistically significant at the 150- and 300-milligram doses, where we saw mean decreases of 23 points and 24 points compared to 10 points in the placebo group with comparisons having p values less than 0.0001. Itch and hive scores, the secondary endpoints for the study also achieved statistically significant difference from placebo as shown on Slide 8. Let's begin to dive into the reason we are on this call today, the new 52-week data, which we believe is truly remarkable. We couldn't be more pleased that with continued treatment, patients experienced even greater clinical benefit. On Slide 9, we show the change in urticaria activity scores over 52 weeks. In the gray shaded section, you can see how quickly the curve for the active treatment arm separate from placebo with improvements in UAS7 observed as early week 1. On the right side, you can see that the benefit was sustained to week 52. You should note the improvement in across both the placebo group, the gray line on the graph and the 75-milligram barzolvolimab group, the blue line on the graph, when these patient groups crossed over and were rerandomized to either the 150- or 300-milligram dosing groups at 16 weeks. This time period after crossover is represented in orange and shows meaningful clinical benefit. In summary, this slide pictorially paints a future where barzolvolimab has an incredible opportunity to greatly improve outcomes for patients with CSU. Slides 10 and 11 represent the major goals of treatment for both patients and physicians, achieving complete disease control. Let me orient you to how the data are displayed on these slides. If you look at the chart on Slide 10, for each arm, we showed a 12-week experience in the pattern bars on the left with the corresponding 52-week experience in the solid bars immediately to the right. So if you look at the 75-milligram arm, you see the 12-week experience in the blue pattern bar, and then you see the experience for these same patients after being rerandomized and treated for 36 weeks with either barzolvolimab 150 or 300 milligrams in the orange bar to the right. Next, for the 150 and 300-milligram arms, you see the 12-week experience in the pattern bars and the 52-week experience in the green and red solid bars. This same concept also applies to the placebo group. The gray pattern bar shows the placebo period and the orange bar shows 36 weeks of treatment with either 150 or 300 milligrams of barzolvolimab. Let's focus first on the 150-milligram arm. These patients had an impressive 51% complete response rate or UAS7 score of 0 at week 12. At week 52, that complete response rate increased to 71%. It's important to reiterate here that this means 71% of patients reported that they experienced no itching and no hives at all at 52 weeks. These results are unprecedented in the CSU disease setting, and this outcome is remarkable for patients, their families and physicians. Overall, these results establish a new bar for efficacy in CSU and demonstrate barzolvolimab's potential to become a transformative treatment option for patients suffering with this disease. Importantly, sustained improvements were seen across all dosing groups. Again, we see the complete response rate in the 300-milligram arm increase from 37.5% at week 12 to 52% at week 52. You also see the robust complete response rates over 50% on both crossover arms at week 52. On Slide 11 a deepening of disease control improvement was also seen across all doses in the well-controlled category, which is defined as UAS7 less than or equal to 6 and, with 74% of patients treated with barzolvolimab 150 milligrams every 4 weeks and 68% of the patients treated with 300 milligrams every 8 weeks, reporting well-controlled disease at 52 weeks. Across all treatment groups, over 68% of patients treated with barzolvolimab reported well-controlled disease at week 52. Slide 12 shows you the time course of complete responses or UAS7 equal to 0. Complete responses with barzolvolimab were observed early and as you can see, were sustained or improved to week 52. I would like to draw your attention to the bottom curve, the placebo group and note the dramatic rapid improvement these patients experienced when they crossed over to barzolvolimab treatment. While both doses have impressive clinical activity, the complete response rate for the patients receiving 150 milligrams every 4 weeks appears to separate from those given 300 milligrams every 8 weeks. We are working to understand what factors could be driving this observation. Regardless we feel very good about including both of these dose regimens in our Phase III studies, where, to remind you, we have also included loading doses. As seen on Slide 13, approximately 20% of patients on study were omalizumab-experienced or refractory. If you look at the bar graph, it outlines the change in UAS7 from baseline for each dose for all patients and then for the oma-naïve, oma-experienced and oma-refractory subsets. You can see that the oma-experienced and refractory patients have the same remarkable clinical benefit as the overall treated population. This has now been our consistent experience across multiple data sets and adds further validation that targeting the root cause of the disease, the mast cell, offers the greatest opportunity for patients with CSU to experience clinical benefit. Turning now to safety on Slide 14. Barzolvolimab was generally well-tolerated with a favorable safety profile through 52 weeks. In the first 2 columns of this table, we are summarizing the adverse event data from the 16-week placebo-controlled period comparing the pooled barzolvolimab doses 75, 150 and 300 to placebo. These results, at the end of the placebo-controlled period, 16 weeks, are similar to those presented in the 12-week analysis earlier this year. The next column includes the 52-week experience for all patients who received barzolvolimab from the beginning of the study. It's important to understand that the numbers shown are cumulative over the entire 52 weeks of observation. The last column shows the barzolvolimab experience for patients who initially received placebo and then crossed over to active treatment where they then received barzolvolimab for 36 weeks. The top 3 most common emergent -- treatment-emergent adverse events over the 52-week treatment period in barzolvolimab-treated patients were the same as what we observed at 12 weeks, hair color changes, neutropenia and urticaria. With longer-term exposure at 52 weeks, we also observed skin hypopigmentation and as is commonly seen across longer clinical trials, nasopharyngitis or the common cold, which is not treatment-related. Most adverse events were mild on-target effects of KIT inhibition, and all are expected to be reversible. Let's talk about the KIT-related events first. As we all know, neutropenia has been a much discussed topic with the investment community. As we expected, the data observed over 52 weeks are entirely consistent with what we have seen across all our studies of barzolvolimab to date and confirm our observation that after an initial decline in neutrophil count, these values stabilized in our sustained [ true ] treatment. Almost all neutropenia reports were Grade 1 or 2. There was a single patient with a confirmed Grade 3 neutropenia that led to protocol required discontinuation, which we reported in the 12-week data analysis. With a full year of observation it's clear that long-term treatment did not lead to further declines in neutrophil counts and most importantly, we have seen no association between low neutrophil counts and infection. Hair color changes, as expected, increased with longer duration of exposure and led to treatment destination in 6 patients with 5 of the 6 reporting resolution of hair color change to date. Skin hypopigmentation is an event that primarily occurred with long-term treatment with barzolvolimab. These events are described as small spots of skin lightening, are characterized as mild and severity and see most obvious in sun-exposed skin. No patient discontinued barzolvolimab treatment due to skin hypopigmentation during the 52-week period. Like hair color changes, based on data from other KIT inhibitors, we believe this is an on-target effect that will be fully reversible and are monitoring for resolution during the post-treatment period which has already been observed in some patients. During the placebo-controlled period, the rate of urticaria reported as an AE was the same in barzolvolimab and placebo-treated patients. We were pleased to see that new reports of urticaria flares were less common with continued treatment. There were 2 treatment-related SAEs of worsening urticaria in patients who had received multiple doses of barzolvolimab. Both patients were briefly hospitalized for evaluation and treatment. Both patients discontinued barzolvolimab and fully recovered. Urticaria flares are common in CSU and typically reported in studies of antihistamine refractory CSU, especially in more severe patients. Overall, we are extremely pleased with the safety data showing that barzolvolimab was well-tolerated through 52 weeks of administration with a predictable and manageable safety profile. The most common adverse events are KIT-mediated toxicities, which are mostly mild and expected to be fully reversible and the rate of discontinuation associated with these events is low. In summary, on Slide 15, we believe the 52-week data we shared with you today are the best results achieved to date with a therapeutic in this disease setting. This is particularly meaningful for the CSU patient community who we know, from their experiences, are inadequately served by current treatment options. Barzolvolimab treatment resulted in rapid, profound and durable improvement in UAS7, with a deepening of response over 52 weeks. Up to 71% of patients achieved complete response and similar robust movement was also seen in patients previously treated with omalizumab, including refractory patients. Importantly, barzolvolimab was also well-tolerated through 52 weeks. It is clear to us, with these data, that barzolvolimab has the potential to be an important new treatment option for CSU. And to this end, we are actively enrolling patients in 2 ongoing Phase III studies. Before I hand the call back to Anthony, I want to acknowledge the recently reported tragic death of Dr. Marcus Maurer. Dr. Maurer was a champion for patients suffering from chronic urticaria and serious diseases. He made it his life's work to, not only raise awareness of these diseases, but to advocate for better treatment options. We were so fortunate to have had the opportunity to collaborate with him, and we will be forever grateful for the contributions he made to the barzolvolimab program. Beyond this personally, I can attest to the fact that he was a joy to work with, and I and the other members of the Celldex will deeply miss him. Our hearts go out to his family, colleagues and patients. Now I'd like to turn it back to Anthony.

Thank you, Diane. As I said at the start of the call, we believe barzolvolimab has incredible potential to be a transformative treatment for patients with mast cell mediated diseases. This data set is a landmark event for the barzol program and for CSU, setting a new bar for efficacy in a very difficult-to-treat disease setting. Importantly, it also speaks to the barzol's broad opportunity to be a pipeline and a product, validating mast cell targeting as an important mechanism, which we fundamentally believe can be broadly applied across a number of serious diseases. As you can see on Slide 16, we are doing just that as we continue to make excellent progress, both advancing and expanding barzol's development across a number of serious mast cell-driven diseases. Our global Phase III program in CSU initiated in July 2024, EMBARQ-CSU1 and EMBARQ-CSU2 and both studies are actively enrolling patients. These Phase III studies mirror the Phase II study design with the only notable difference being that we are adding loading doses. We entered the Phase III studies with great confidence based on the 12-week results. The 52-week data certainly reinforces this and supports our confidence that we will deliver positive Phase III results. We are currently planning our Phase III program in CIndU and have ongoing Phase II studies in CSU, CIndU, EoE and PN. We are also planning to initiate a Phase II study in our fifth indication for barzol, atopic dermatitis by the end of this year. I want to echo Diane's comments and thank the patients and investigators that have participated in our studies. We look forward to carrying this momentum forward and continuing to advance our clinical programs. Operator, we are now ready to take questions.

[Operator Instructions]. And our first question is going to come from the line of Thomas Smith with Leerink Partners.

Congrats on the data. On the efficacy here, can you just elaborate on the 52-week data? Are these ITC or per protocol analysis around the complete response rates and the well-controlled response rates? And I guess, how are discontinuations being handled in the efficacy analysis? And then I have a quick follow-up.

Sure, Tom.

Yes. So they're as observed data. Does that answer your question? It's not per protocol, it's all patients.

Understood. Okay. That makes sense. And then just on safety, could you just put the discontinuation rates here into context? I think remibrutinib also saw kind of, like, 20% to 25% discontinuation rates over the course of their 52-week experience. But how are you guys thinking about real-world compliance and persistence with barzol.

Yes. So I think it's not uncommon at all to see discontinuation rates in a trial this long. We're -- you're asking a lot of patients in a clinical trial and people just sort of don't -- sometimes don't want to continue with all that activity. Our rates are similar, as you mentioned, to the REMIX-2 trial with remibrutinib, so I think it's quite comparable.

Okay. Great. That's helpful. And if I could just sneak in 1 last question. Just on the -- wondering if you could provide a little bit more color on the 2 cases of macrocytic anemia that led to the treatment discontinuation. Was this -- what was the patient experience here? And then are there any relevant factors in the patient's medical history? I guess how should we be thinking about the macrocytic anemia?

Yes. So the macrocytic anemia occurred in 2 patients. It was extremely mild. It's really a laboratory finding, not -- the patient did not have any symptom of anemia. They did have hemoglobin levels that were Grade 1 and also the increase in the macrocytic anemia refers to an increase in the size of the red cells and the level of that, which is called the MCB, was just over the upper limit of the normal range. So I think these happened kind of late and the physician noted them and just decided to discontinue and they fully recovered. But it really was not a clinically significant event for the patient.

Our next question is going to come from the line of Yaron Werber with TD Cowen.

A couple of questions. Maybe just -- I think there's a little bit of confusion out there, so I just wanted to just level set. In terms of Grade 3 AEs, I mean, it sounds like you saw on neutropenia, which was disclosed in the first 12 weeks and none since then. And there were those 2 cases of worsening urticaria that you noted, right, 2 out 208 or 1%. Is that it? Am I missing any other kind of grade 3s?

Diane?

So those -- yes, those were the significant ones that led to discontinuation. Margo?

Yes. This is Margo. I can add, this is 52 weeks of treatment for a severe urticaria population. And so there's a range of other reported AEs, some of which were characterized as Grade 3, but meaningful neutropenia case occurred in that 1-month mark, and that's the only grade 3 in neutropenia that led to this protocol-led continuation. And again, none of the neutropenia cases were associated with infection.

Okay. But there's only 1 Grade 3 neutropenia, regardless of whether it was discontinued or not, right? There's no other grades 3s?

There's a single case that confirmed Grade 3 neutropenia that led to discontinuation.

Got it. And then in terms of hypopigmentation, I mean, it looks like it's mild, it's patchy. I think the on the presentation, they said it was around the follicles and you noted more in sun-exposed areas. Does it get worse with time? Like, maybe give us a little bit of a sense kind of when does it pop out? And is it stable? Or does it get worse?

Yes. So it does occur later in treatment. So during the time of the 12-week data readout, we had cases which didn't reach our threshold of reporting, but we really start to see these later in treatment, like, after 30 weeks or so of treatment. They appear -- we're still observing in the follow-up period. Some have already started to reverse. But they sort of appear at one time and don't seem to get worse over time for the individual patient.

And Yaron, they're very pin-like in nature. I mean, very, very small pin-like looks. But as Diane says, we've already had patients resolve of their hypopigmentation as they complete studies.

And our next question is going to come from the line of Kristen Kluska with Cantor.

Congrats on these great data. And I just wanted to echo your comments around Dr. Maurer. He was certainly a very important person and always friendly when working with our community as well. So we will definitely miss him. So I wanted to ask 1 question on efficacy and 1 question on safety. So on efficacy, when I look at these data, I mean, you literally have 3 out of 4 people in the 150 dose not experiencing any hives or itch. I'm curious if the durability data as well as the rapid time to onset is making you think a little bit differently about where this could be positioned best commercially.

I don't think it's getting us thinking differently, Kristen. So we think that Xolair is going to continue to be front line, especially here in the States because it has been on the market for so long. But certainly, these data show that we can treat all patient populations, whether they're naïve, experienced or refractory. So I think these data just reaffirm the power of these data and the number of patients that we can treat across the paradigm.

Okay. And then on safety, I listened to the presentation and Dr. Metz described the hypopigmentation as being around where the hair follicles diffuse, not necessarily patches on the skin like vitiligo. And so I wanted to ask on the hypopigmentation and the hair color changes, are these things that are not all that visible? I mean, I think when you hear hair color changes, you initially get scared. But when your team started showing us pictures, we found that it was a gray hair there and there. So just wanted to get a sense of how it's looking and whether or not that's going to get more usage in your opinion.

Yes. So yes, for the hair color change, as you know, we showed the pictures and it could be a very subtle finding in some patients, individual hairs or little tiny patches of hair. But yes, in terms of the hypopigmentation, it's described as small spots. And it is more obvious in sun-exposed skin. In some people, it's actually a very subtle finding. And they're all -- they're rated as Grade 1 for the most part. And I think it's important to note that no one discontinued due to the hypopigmentation on the study.

Okay. But then again, with the hair color change, is it's just a matter of you're seeing this more, but you're not necessarily seeing the degree of it get worse, is that a fair statement?

Yes. I mean that's -- so far, that's been our experience.

Our next question is going to come from the line of Yatin Suneja with Guggenheim.

Just a question on the dose [ regimen ] data. Just curious to -- from you to understand how are you thinking about the doses between the 150, 300 and also the induction that you're using potentially in the pivotal. Any modification you might need to make? So that's one. And I have just 1 more quick question on the safety side. There was this 1 case of macrocyte anemia. Could you articulate what happened there?

Sure. So...

Sure. Yes, I'm going to let Tibor answer the first -- I'll let Tibor answer the first question and have Diane answer the second. We're not in the same area. Obviously, Diane's in Amsterdam, and we're here. So there may be a little back-and-forth. But I'll let Tibor answer the first question.

Yes. With regard to the dose regimens, frankly, we were a little bit surprised at the separation. We're clearly very happy with the data with both the 2-, 8-week dosing of 300 or the 4-week dosing of the 150. We are looking very carefully. We need to understand these are flat doses, of course, and we want to understand the impact of weight and other variables to better understand what may have led to differences here. We have incorporated a loading dose that we think is going to be important, particularly for patients who are on the heavier side to initially tackle that mast cell and systemic KIT suppression, which we think will help both dose regimens. But yes, we don't have the answers yet. We're certainly pleased with the 2 regimens that we have moved into Phase III and just need to better understand if there are variables about the monthly dosing that have led to somewhat better results here.

Does that answer your question, Yatin?

Diane, do you want to answer the...

Yes. So regarding macrocytic anemia, there were 2 cases of macrocytic anemia which were reported and the physician discontinued the patient because of it. As I said, the findings were really laboratory findings. There -- it was Grade 1 hemoglobin decrease in both patients and a slight increase in the mean corpuscular volume, really just above the upper end of the normal range. The patients didn't have any symptoms of anemia at all. It was just really a lab finding and the patients were discontinued from barzolvolimab and recovered very quickly.

Our next question is going to come from the line of Sam Slutsky with LifeSci Capital.

Just any difference in tryptase suppression between the 150 mg and 300 mg doses over the 52 weeks to kind of explain the differences in activity between the 2 doses?

We're still looking at that, Sam. I would say nothing dramatic, but this is something that -- we just received these results pretty recently and need to better look at that. Both certainly led to profound and rapid tryptase suppression and we'll look at that more carefully coming up.

Okay. If I can fit one more in, just to confirm, I think Tom's question earlier. For patients who dropped out, were they lost observation carried forward? Or just, how were they counted into the complete response rate?

No, they're as observed data. We did look at sensitivity analyses, including last observation carried forward and also nonresponder imputation and we think our results are very solid.

Our next question is going to come from the line of Alex Thompson with Stifel.

This is Patrick on for Alex. Congrats on the data, I guess can you guys expand a little more on whether there are any dose-dependent increases in AEs? And then just to -- just want to confirm, there were no cases of anaphylaxis or investigator-reported anaphylaxis?

So the AEs...

Diane, on the AEs?

Yes, so the AEs were -- we do not see a clear dose response in terms of the common AEs.

Yes. And Alex, as we said in the CIndU call, we studied all 500 patients to date, and we still have the 1 confirmed anaphylaxis to date.

And our next question comes from the line of [ Lee-Yun Tsin ], Jefferies.

I guess 2 questions for me. One is about the dosing. So it looks like the 150 appears to be have a better profile versus the 300. So just wondering for the patients that are randomized for the -- from the 75 and placebo, do you also see that same trend?

So a very good question. We are definitely looking at that analysis. It's not really an apples-to-apples because, as you know, when they do rerandomize, their UAS7 score is a little bit different. So yes, we will be looking at that to understand in that case as well, and certainly, we'll be reporting that in future meetings.

Great. My another question is about the omalizumab experience versus naïve. So I think it's really good to see the comparable mean change from up baseline for UAS7. So I wonder, do you see a similar pattern of the responses regarding the UAS0 and the control over time?

Yes. We see similar patterns when you divide up the population like that, you get into smaller and smaller groups as you're doing those analyses. But overall, we do see a similar pattern that those that have been treated with omalizumab and those that are refractory to omalizumab have a similar response to the overall population in the naïve population.

Our next question is going to come from the line of Anthony Chen with Wolfe.

It's Drew going here for Andy. With the new safety findings of today, would you have to modify your Phase III enrollment protocol and patient disclosures? And would that impact enrollment rate. And another one, there are some -- different differences in q4 and q8 dose. So based on the data today, assuming central approval, can you just speculate on whether q4 would be the go-to product going forward for your indications?

So let me address the safety questions about changing anything. Nothing in the safety profile that we've shown or discussed today is going to change anything as far as our Phase III discussions. I know there's concerns and questions about the hypopigmentation. But as we said, these are all Grade 1 of events. Nobody discontinued study dosing. They went through 52 weeks and had no concerns about the hypopigmentation or any appearance. And as Diane has said on a couple of occasions already, patients that are still on study, they're resolving as we speak. And we've completely believe that these are going to be completely reversible, just like the hair color changes and others. So we think the hypopigmentation questions that we're getting out there right now are completely overdone. And certainly, over time, we'll explain them and have everyone get more comfortable with it. As far as the other questions, I'll let Tibor answer.

Sure. So I think it's way too early to declare what dose is going to be preferable for commercial use. We're very pleased with the data we have on both doses and certainly, it's beneficial to have options for patients and physicians with different regimens. So I think that will certainly be based on the Phase III data.

And our next question comes from the line of Derek Archila with Wells Fargo.

I guess first question from us is, I mean, do you have a sense about what time point most of the discontinuations due to AEs, like, when those occur? And then our second question is given the Phase III loading dose protocol, I guess, is your expectation that we would see higher rates of AEs during that treatment period versus the treatment period in the Phase II?

Thank you, Derek. Diane?

My impression is that it's -- I would have to look exactly, but I think that the discontinuations to AEs are more earlier in the -- but I'd have to put exactly at that...

Diane, It's Margo. I have kind of scoured this over time. And they occur across the long observation period through 52 weeks. But as Diane said, there is some early discontinuations that -- and so I would say I agree with her that they skew early, but they -- there was random discontinuations out through the 52 weeks.

And then in terms of what we're going to see in Phase III, I think your question was, do we expect to see more things than a 24-week placebo-controlled period than in a -- is that what you're asking?

No. I think the question was whether the loading dose would enhance the number of AEs. And we really haven't seen AEs related to dose level, and we've certainly used much higher exposure levels both in IV and in our initial subcu studies. So one of the loading doses is 300 milligrams for the 150 group, so we know the AE profile there. The 450-milligram loading dose for the 300 group, we think will not raise the AE profile whatsoever.

Yes. And Derek, just so you know -- of the patients that got off the study or discontinued, more than half of them had a complete response at the time of discontinuation. So it could have been just patient preference at that point. These are long studies.

Our next question comes from the line of Joe Pantginis with H.C. Wainwright.

Great data. Congratulations, and thanks for all the details, especially for Diane having to repeat the macrocytic anemia details a few times as well. So first question, I just wanted to make sure I understood the crossover data. So if I heard you correctly, you were randomizing the crossovers 1:1 between 150 and 300. Can you discuss, did it follow the dose response that you saw in the 12-week data where 300 appeared better?

I think I -- go ahead, Tibor.

Yes. So we haven't provided that level of data analysis yet. This is the kind of data that we're looking at right now, Joe, in terms of really getting into the details about the differences between the dose regimens and how they respond, whether it was from the beginning or after transitioning the placebo patients or 75 mg patients.

Got it. Got it. And then my follow-up is when you look at the overall product profile, if it's approved and talking to the on-target effects that you're seeing, if it does lead to discontinuations or versus how you manage these on-target profiles, if a patient discontinues the drug, would you anticipate or could you see then restarting dosing of the drug following the reversal of these impacts?

Absolutely.

Yes. And I would say that's definitely something that we are going to look at in our clinical trials in terms of the durability to restart therapy if you've discontinued.

And this does conclude today's question-and-answer session. And I would now like to hand the conference back over to Anthony Marucci for closing remarks.

Thank you very much, operator. And thanks, everyone, for joining us on the call today. We know it's in the middle of a busy day, and we really appreciate your time. Have a great day, and we look forward to our CIndU presentation in October in Boston. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.