Good morning. My name is Krista, and I'll be your conference operator today. At this time, I would like to welcome everyone to the Celldex Conference Call and Webcast. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. If you would like to ask a question during that time, simply press star followed by the number one on your telephone keypad. And if you would like to withdraw your question again, press star one. Thank you. I will now turn the conference over to Sarah Cavanaugh. You may begin your conference.
Good morning, and thank you for joining us to discuss clinical results from our Chronic Spontaneous Urticaria and Prurigo Nodularis this morning. On our 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, Executive Director of Research and Research Lead on the program. Before we begin our discussion, I would 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 would now like to turn the call over to Anthony.
Thank you, Sarah. Good morning, everyone, and thank you for joining us on this call. We're very excited to be talking with you this morning about our recent developments in the Barzolvolimab program. Celldex is focused on the leading science at the intersection of mast cell biology and developing transformative therapies for patients. The exciting results we will be discussing today across both Chronic Spontaneous Urticaria and Prurigo Nodularis add to a growing, strong body of clinical evidence and speak to Barzolvolimab's significant potential to address the needs of patients with mast cell-mediated diseases. We look forward to continuing to expand the Barzo program as we plan to advance into registrational studies in CSU and a Phase II study in PN. PN adds to a growing list of diseases Barzolvolimab is being studied in, including our ongoing Phase II studies in inducible urticaria and eosinophilic esophagitis.
We also plan to expand our leadership into additional mast cell-mediated indications in the future. We have a lot to cover this morning, and in the interest of time, I will turn the call over to Diane to discuss the data. Diane?
Thank you, Anthony. As you know, this morning, we issued a press release announcing positive top-line 12-week data from our ongoing Phase II study in Chronic Spontaneous Urticaria. CSU is a miserable disease, causing significant emotional distress, including sleep deprivation, anxiety, and depression. It is known to be a mast cell-mediated disease, which is why we were so excited to study Barzolvolimab in this indication. Treatment options for patients with CSU are limited. Many patients do not achieve full control from the first-line treatment, antihistamines, and there are no approved therapies for patients who do not respond to the only approved second-line therapy, omalizumab. This makes the results we are presenting today all the more exciting.
I am pleased to report that the study met its primary endpoint across all 3 doses, the mean change from baseline to week 12 in the urticaria activity score 7, while also demonstrating a favorable safety profile. I am going to focus my comments on these endpoints. We plan to present a more detailed analysis of the study at a medical meeting in the first quarter of 2024. Slide 4 outlines the study design. This is 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 to determine the optimal dosing strategy. The study also allowed prior biologic use.
208 patients enrolled across 72 sites in 8 countries were randomly assigned on a 1-to-1 to 1-to-1 ratio to receive subcutaneous injections of Barzolvolimab at 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 enter a 36-week active treatment period in which patients not already randomized to Barzolvolimab at 150 milligrams every 4 weeks or 300 milligrams every 8 weeks are randomized 1 to 1 to receive one of these two dose regimens. Patients already randomized for these treatment arms remained on the same regimen as during the placebo-controlled treatment period. After 52 weeks of treatment, patients enter a follow-up period for an additional 24 weeks.
All patients have now crossed the 12-week time point, allowing for analysis of the primary endpoint. Database lock occurred on October 18. I want to point out that patients on study had significant Urticaria Symptoms. Mean Urticaria activity score 7 at baseline ranged from 30 to 31.3 across the dose groups, with 69% of patients classified as having severe disease, with UAS7 greater than or equal to 28. Slide 5 shows the profound decrease we observed with Barzolvolimab treatment in UAS7 at week 12, our primary endpoint. 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 23.02 points and 23.87 points, compared to 10.47 points in the placebo group, with comparisons having P values less than 0.0001. Slide 6 shows what patients care about most, achieving control of their disease. Barzolvolimab demonstrated rapid, durable, and clinically meaningful responses. Well-controlled disease, or UAS7 of 6 or below, was observed in 62.5% of patients in the 300 milligram arm, 59.6% in the 150 milligram arm, 41.7% in the 75 milligram arm, and 12.8% for placebo.
Complete disease control, or UAS7 equal to zero, was 37.5% for patients in the 300-mg arm, 51.1% in the 150-mg arm, 22.9% in the 75-mg arm, and 6.4% for placebo. Approximately 20% of patients on study were omalizumab experienced. These patients had a similar clinical benefit as the overall treated population within their individual dosing groups. Turning now to safety on Slide 7, Barzolvolimab was generally well-tolerated, with a favorable safety profile through 12 weeks. Most adverse events were mild to moderate in severity. The most common treatment-emergent adverse events in Barzolvolimab-treated patients were hair color changes at 9%, urticaria at 9%, and neutropenia at 8%. The rate of infections was similar between Barzolvolimab-treated patients and placebo, with no apparent association between neutropenia and infection.
As of the October 18th database lock date, 107 patients had been treated for at least 24 weeks. While data past 12 weeks has not been cleaned and is subject to change in this ongoing study, we reviewed the safety data in the database as of October 18th. The emerging longer-term safety profile is consistent with the 12-week data results we presented today. We look forward to presenting the complete 12-week study results at a medical meeting in the first quarter of 2024. I want to thank the patients and physicians who are participating in this study. We are very pleased with this outcome for patients with urticaria and for the Barzolvolimab program. Moving to our Prurigo Nodularis Phase 1b study. Tomorrow afternoon, Dr.
Martin Metz, Professor of Dermatology and Allergy at Charité – Universitätsmedizin Berlin and an investigator in the study, will present results at the World Congress on Itch. Prurigo Nodularis is another miserable chronic disease. It causes hard, intensely itchy lumps or nodules to form on the skin. The itching can be so intense it causes people to scratch themselves to the point of bleeding and pain, which in turn leads to the formation of more lesions and perpetuation of the disease cycle. While PN is a dermatologic disease, its effects go far beyond the skin. It can significantly impact quality of life and is associated with sleep disturbances, psychological distress, social isolation, anxiety, and depression. Unfortunately, there are limited treatment options available, and there is significant need to improve on what is available.
Patients and their physicians need therapeutics that offer fast, durable relief that quickly reduces itch and support complete nodule healing to break the vicious cycle of this disease. Mast cells are believed to play a central role in driving chronic itch and neuroinflammation, including PN, where mast cells are increased in number and are physically associated with the itch-causing sensory neurons in the PN lesions. In this context, mast cells and sensory neurons reciprocally regulate one another, where mast cells recruit and activate sensory neurons that specifically mediate chronic itch, as well as other immune cells, while neurons secrete factors that further activate mast cells. We were interested in studying Barzolvolimab in PN because we believe that through its mechanism of rapid mast cell depletion, Barzolvolimab could quickly disrupt the itch-scratch cycle and allow for lesion healing. The results from our phase 1b study certainly support this conclusion.
As we've outlined on Slide 10, this is a randomized, double-blind, single intravenous dose study. The study enrolled 24 adults with moderate to severe PN, 23 evaluable for safety, and 22 evaluable for efficacy across 3 arms. While the primary endpoint was safety, we also focused on key efficacy endpoints, including changes from baseline in the worst itch numerical rating scale and Investigator Global Assessment. The primary efficacy assessment was at 8 weeks. We continued to follow patients to 24 weeks. 8 patients received a single dose of Barzolvolimab at 3 milligrams per kilogram, 7 patients received a single dose of Barzolvolimab at 1.5 milligrams per kilogram, and 8 patients received placebo.
As you can see on Slide 11, patients had moderate to severe PN, with Investigator Global Assessment ranging from 3.1-3.4 out of 4, and worst itch NRS ranging from 8.4-8.6 out of 10. As shown on Slide 12, Barzolvolimab was generally well-tolerated. Adverse events were generally mild to moderate in intensity and considered unrelated to treatment. During the 24-week follow-up period, the adverse events were consistent with comorbidities commonly observed in the PN population and were not considered treatment related. As previously reported, during the initial 8-week observation period in the 3 mg/kg dosing arm, an anaphylactic event occurred in a patient with multiple comorbidities shortly after the initiation of the infusion. Importantly, the patient fully recovered from the event. Let me walk you through this event in more detail.
The patient was a 63-year-old female with severe Prurigo Nodularis. Upon entering the study, her known medical conditions included hypertension and panic attacks, and underlying lung disease, including COPD and continued smoking. Importantly, during management of her adverse event, it was discovered that the patient also had bacteria in her lungs, consistent with a bacterial pneumonia. We believe the patient's undiagnosed pneumonia, combined with her underlying lung disease, predisposed her to this event. Approximately 15 minutes into the infusion, the patient reported shortness of breath and the infusion was stopped. She was noted to have low oxygen. Intravenous antihistamines and steroids were given, and the patient was intubated. As a standard after intubation, a chest X-ray was performed. That X-ray showed infiltrates consistent with pneumonia. A Bronchoscopy was then performed and confirmed Gram-positive bacteria.
The patient was given antibiotics for bacterial pneumonia, was extubated the next day and made a full recovery over the next week. Bacterial infections are known to lead to mast cell activation. As previously described, Barzolvolimab is associated with mild infusion reactions, which rapidly resolve, typically without intervention. In this case, in a patient with an undiagnosed infection and underlying compromised pulmonary function, we believe Barzolvolimab contributed to this more severe hypersensitivity reaction. As a precautionary measure across the current Barzolvolimab program, we tightened the eligibility criteria by excluding patients with currently symptomatic, moderate to severe heart or lung conditions. Now turning to the efficacy data. On Slide 13, we have outlined the data on the worst itch numerical rating scale. A four-point reduction or greater from baseline is considered clinically meaningful for patients when assessing this scale.
As a reminder, baseline scores were high, with a weekly average score of 8.6 out of 10. As you see, at week 8, the percentage of patients with at least a 4-point reduction in itch after a single dose of Barzolvolimab was 57% for the 3 mg/kg arm, 43% for the 1.5 mg/kg arm, and 25% for the placebo arm. This level of response generally persisted out to week 16 across all three arms. What we found striking in this data set is that in the 3 mg/kg arm, the decrease in itch was seen as early as the first week and reached a high of 71% of patients at week 6, which was distinct from the 1.5 mg/kg Barzolvolimab and placebo arms.
On Slide 14, these findings were further validated by the investigators' global assessment of the lesions, where at week 8, the percentage of patients achieving clear or almost clear skin was 29% following a single dose of Barzolvolimab, 3 milligrams per kilogram. Again, this effect was noted as early as the first clinic visit at week 2 and was maintained out to week 12-16. No patients treated in the 1.5 milligram per kilogram Barzolvolimab or placebo arms achieved clear or almost clear skin through week 8. When we look past 8 weeks, 2 additional patients in the 1.5 milligram per kilogram arm, 2 additional patients in the 3 milligram per kilogram arm and 1 patient on placebo had Investigator Global Assessment 0-1 at time points between weeks 8 and 24.
As we have shown in our urticaria studies with Barzolvolimab, tryptase levels in blood, which is a biomarker or surrogate for mast cell load, tells the same compelling story regarding its correlation with the clinical data. The strongest clinical activity is clearly associated with complete and durable suppression of tryptase in Prurigo Nodularis. As seen on Slide 15, at the 3 milligram per kilogram dose, tryptase was profoundly reduced below the level of quantification in the majority of patients, and this level of reduction was maintained at least through 8 weeks. While we saw substantial decreases in tryptase reduction in the 1.5 milligram per kilogram arm and some reduction in itch and the number of lesions, the impact on tryptase was not as deep or as durable as the 3 milligram per kilogram dose.
This suggests that in Prurigo Nodularis, profound and sustained mast cell depletion is required for maximal clinical activity. We have discussed the results from this study with a number of experts in the field, and like us, they are very excited that with just a single dose, we were able to quickly and meaningfully decrease the relentless itching and drive healing of the painful lesions. These data confirm our hypothesis that Barzolvolimab's novel mast cell depleting mechanism could play a meaningful role in breaking the stubborn scratch-itch cycle of this disease and potentially other itch-driven conditions... We look forward to initiating a phase II multi-dose PN study with our subcutaneous formulation early next year. Before I turn the call over to Anthony, I must say this is a very exciting day for the Barzolvolimab program.
We are very gratified to report positive clinical data from two studies of Barzolvolimab in medically important indications. Anthony?
Thank you, Diane. As you can see on slide 16, the data we reported today support our continued broad development of Barzolvolimab in mast cell-driven diseases, and to that end, we expect to advance in CSU into registrational studies in 2024. We plan to advance PN into Phase II studies in early 2024, plan to report out our Phase II CIndU data, which we expect in the second half of 2024, and also continue the enrollment of our current Phase II EoE study. I want to echo Diane's comments and thank the patients and investigators that have participated in our studies. 2023 was a great year for Celldex. We look forward to carrying this momentum into 2024 and sharing more of the CSU data with you in the first quarter. Operator, we're now ready to take questions.
If you'd like to ask a question, please press star one on your telephone keypad. We ask that you limit yourself to one question and one follow-up. Your first question comes from the line of Joe Pantginis from HC Wainwright. Please go ahead.
Hey, everybody. Good morning. Thanks for taking the questions, and congratulations on the data. So, with the CSU data, I guess, how have any of the dosing data and the efficacy data potentially impacted any of your go-forward plans for the pivotal study? And can you provide any sort of broad strokes about the potential design of a pivotal program? And then also, just as the follow-up, with regard to the current data in CSU, you do have follow-up to 52 weeks. Does that impact the timing of the phase III at all? Thanks a lot.
So, Joe, this is Anthony. Thanks for the question. It doesn't impact the starting of the study going out to 52 weeks, so that's the second question first. As far as looking at the dosing and what have you, we just got top-line data. That's what we're reporting on today. And as we get towards the medical meeting in the first quarter, I think, you know, more things we'll learn about the dosing and what have you, and we'll make those decisions as we go along.
Got it. Thank you.
Mm-hmm.
Your next question comes from the line of Roger Song from Jefferies. Please go ahead.
Great. Congrats, the data. And maybe just... Yeah, the first question is related to the, the AE profile. Maybe you can let us know or confirm. So for the anaphylaxis, the case, that's the only case across CSU and, and the PN population. And in terms of the neutropenia, this 8%, what's the grade of the neutropenia? Any febrile neutropenia you have seen? I have a follow-up after that. Thank you.
Yeah. So to talk about anaphylaxis in the Phase II CSU study, Roger, we took the data cut as of October eighteenth, which is where we're reporting the primary data, and there were no cases of anaphylaxis reported. And as far as the rest of the programs, these are ongoing studies, and we don't comment on safety or efficacy in ongoing studies until we report them out at medical meetings.
With regard to the neutropenia that we're reporting is mild to moderate and not associated with infections, as I mentioned.
Excellent. Great. Then in terms of the PN efficacy, all looks pretty competitive and pretty impressive. And in terms of the placebo effect, seems a little bit higher than the other PN trial. Maybe can you let us know what are the key drivers, potential drivers, like the baseline and any other things that you wanna make note for that? Thank you.
Yes. So I would say, just remembering when you look at our data, that we... It is a single, just a single dose of drug. So, you know, we're comparing ourselves to things that are having repeated, repeated doses of drug. But I will say with regard to the placebo effect, you know, we, the number of patients per group is fairly small, so one patient here or there can affect it. But I think you really do expect to see, you know, a placebo effect, particularly with the itch endpoint. You see that across, studies. I think the Investigator Global Assessment seems to be a little bit more stringent in terms of,
Yeah
... You know, that placebo rate tends to be lower.
So Roger, I would agree with Diane, that you do see placebo effects in the other studies that, you know, we've looked at. So there is that, you know, but as far as the efficacy here, we think it looks outstanding considering it's one single dose. The rapidity of getting that control, and following the patients out to 24 weeks, you're seeing a lot of effect of the drug, whether it's at 8 weeks, 12 weeks, or 24. We would have expected the lesion healing in most patients to be a little bit later because of that's the way things work, but we're gratified to see that we've had a lot of benefit here across the range.
But with, remember, a single dose of drug, whereas the other studies you're mentioning had loading doses, were dosed, you know, every other week or monthly, and they've had more doses here.
Yep. Makes sense. Thanks for taking the question. Congrats again.
Thanks, Rogerr.
Your next question comes from the line of Kristin Kluska from Cantor Fitzgerald. Please go ahead.
Hi, good morning. Congratulations on both datasets. Really great to see. The first question I had for you is just on the OMA prior experience. Can you comment on this 20%, if any of them were actually refractory to OMA? And then you noted that the effects on Barzo were similar in this patient population to the overall, but were they durable as well? Can you comment on that?
Yeah, so I can say that the OMA refractory, the majority of them, in fact, about two-thirds. The OMA experienced, about two-thirds are OMA refractory, but, you know, the details as to, you know, the exact nature of that, we're gonna have to present at the later medical meeting when we've really fully analyzed all the data.
Kristin, what was the next? What was the rest of your question? I'm sorry.
Yeah, just on if these effects are durable with what you've reported so far?
They are durable.
Yeah. I mean, in terms of, in terms of looking at the OMA, you know, the, the OMA experience group, it looks very similar-
Yeah
-in nature.
Yeah. Again, we'll have a much deeper, bigger, better detail when we get to the medical meeting, but they're very consistent with what we've seen.
Okay. Thank you. My follow-up is just, you know, the PN data clearly opened the door for itch-driven conditions, but now that you're looking at a dataset in over 200, we're wondering if any had comorbidities or if there's other potential findings that you've looked at beyond the indication that they were studied for. Thank you again.
Yeah, Kristin, we still haven't gotten that deep. We, you know, these data just came in Friday night, so we're gonna work through those. We'll look for comorbidities as we would expect there would be, but at this point, we don't have that information yet.
Okay. Congrats again. Thanks.
As a reminder, if you would like to ask a question, please press star one on your telephone keypad. Your next question comes from the line of Sam Slutsky from Life Sci. Please go ahead.
Hey, good morning, everyone. Congrats on the-
Morning
-updates, and thanks for the questions. First one for me, just in PN, it seems that you have to crush tryptase to see the best effect. So I guess looking back to CSU, what did the tryptase data look like between doses, and did you achieve full suppression of tryptase with any of the doses in CSU?
Diego, take this.
Hi, Sam. Yeah, so as Anthony mentioned, we just got those data, and we're working through our, the tryptase data for CSU. For PN, as described, we have those data analyzed and presented that, and, I think Diane spoke to that already.
Okay. And then, anything that you're able to provide on the speed of response versus what we'd typically see with biologics like Xolair? And then, to that end, too, I realize that you're still waiting on additional data past 12 weeks, but would the expectation be for continued improvement, like we saw in past studies?
We're hoping for continued improvement, but until we get the data and look at it and follow it out, you know, we'll see. We're looking forward to seeing that data and hope that we do see continued improvement.
Okay. And then on the speed of response, anything to note there?
I'm sorry, Sam?
Oh, on that.
Yeah, well, you know, again, we're seeing, you know, as we've seen in the past, we've seen some rapid responses here. But again, you know, we need to go through everything, but everything looks consistent as what we've seen in the past.
Got it. Okay. Thank you.
Thank you.
Your next question comes from the line of Thomas Smith from Leerink Partners. Please go ahead.
Hey, guys. Good morning. Thanks for taking the questions, and let me add my congrats on both datasets. Just on the Phase II CSU study, it seems like you had patients with really high UAS7 scores at baseline. Can you comment at all on sort of the kinetics of response and the magnitude of response across the different patient subgroups? And at least on a top-line basis, how does this compare versus your phase 1b data and I guess your expectations for this Phase II dataset?
Yeah, so in terms of... You know, I think we see a similar pattern to what we saw in our earlier CSU studies. I think, you know, we're not gonna comment on, you know, within this top line, we're not gonna comment on all the details of the kinetics. We're gonna present that-
Yeah
-at a later meeting.
Yeah.
But I think, you know, I think it is consistent with what we've seen previously.
Right. And as Diane said, you know, almost 70% of the patients were considered severe. So we are extremely happy that we've had an impact in the whole population in general, but the fact that severe patients were having a bigger impact as well.
Yep, got it. That makes sense. Just on the safety profile, can you just remind us how the patient neutrophil inclusion, exclusion criteria in this Phase II study compared versus the phase 1B? And were there, I guess, any other differences in how these data were analyzed in the Phase II versus the phase 1B?
No, they, they had to have a normal neutrophil count to enter the study.
Yeah. Tom, this is Margo. The one thing that is different between the phase two and the one B is it was done at a central lab. So we had a consistent eligibility criteria because we used the lab normals for that central lab. So the eligibility of being in the normal range was consistent across the two, but here it's central lab data.
Got it. That's helpful. And then just maybe one last question. As you described, looking at the safety experience for patients who have now been dosed out to, you know, 24 weeks, just wondering if there's anything to note in terms of kinetics of some of the AEs, some of the on-target AEs, when we think of neutropenia, or we think of the hair color changes or taste changes. Are these? Are you finding that these are occurring more frequently within the first 12 weeks, or is it a relatively consistent sort of kinetics out through 24 weeks?
You know, we're gonna have to do the full analysis of all... Break that down into details, but, you know, generally, as we said, you know, the profile-
Yeah
is similar as you go out-
Yeah.
You know, the 12 weeks.
That was good to see. The profiles is consistent going out, Tom. So that was good to see with more dosing.
Got it. Super helpful. All right, guys, thanks for taking the questions. Appreciate it, and congrats again on the data.
Thanks, Tom.
We have no further questions in the queue at this time. I will now turn the call over to Chief Executive Officer, Anthony Marucci.
Thank you very much, and thank you, everyone, for joining us so early on a Monday morning. We look forward to the medical meetings in 2024, and have a great day.
This concludes today's conference call. Thank you for your participation, and you may now disconnect.