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

Thank you for standing by, and welcome to Celldex's Phase II PN Data Call. [Operator Instructions] I would now like to hand the call over to Sarah Cavanaugh with Celldex. Please go ahead.

Thank you. Good afternoon, and thank you for joining us to discuss the results from our Phase II Barzolvolimab study in Prurigo Nodularis or PN. Joining me on the call today 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; and Teri Lawver, Senior Vice President and Chief Commercial Officer. Please note the slides for today's call are available on the Investor Relations section of the website. Before we begin our discussion, I'd like to direct your attention to Slide 2 with respect to information regarding the forward-looking statements that today's speakers will be making. Please be advised that a question-and-answer period will be held later in this call. I'd now like to turn the call over to Anthony on Slide 3.

Thank you, Sarah, and good afternoon, everyone. Thank you for joining us. Today, we are reporting Barzol's results from our fourth indication, a Phase II study in Prurigo Nodularis or PN. PN is a chronic itch-driven skin condition with a highly symptomatic patient population. At Celldex, we are leading important science in the exploration of mast cell biology with the goal of delivering life-changing therapies for patients with allergic inflammatory and autoimmune diseases. We have repeatedly demonstrated Barzol's ability to profoundly deplete mast cells and best-in-disease data observed in 3 indications to date: Chronic Spontaneous Urticaria, Symptomatic Dermographism and Cold Urticaria. All these showed unequivocal Phase II data and progressed quickly to Phase III development. Our interest in understanding if mast cell depletion can provide clinical relief for patients with serious diseases and data from our Phase I proof-of-concept study in PN supported the initiation of the Phase II study. We are disappointed to share that the trial did not meet the primary or secondary endpoints. Results from this study clearly showed profound systemic depletion of mast cells as evidenced by the reduction in serum tryptase. But unlike our intravenous Phase I study, this Phase II Subcu study did not result in improvements in itch or skin lesions for patients, indicating that mast cells may not be the key pathogenic driver of symptoms in PN. Because of this outcome, we are discontinuing the Phase II trial in PN and will direct our resources to the remainder of our present and future portfolio. We remain focused on driving mast cell category creation and delivering on Barzolvolimab's promise for patients, particularly in our 3 ongoing Phase III Urticaria studies, which we expect to share top line data in the September, October time frame. Before I turn the call over to Diane to walk you through the data, I'd like to extend our gratitude to all the patients, investigators and site staff around the world who participated in this trial and supported the advancement of mast cell science. Diane will walk you through the results we have to date. And at the end of the call tonight, we will answer as many questions as we can. As a reminder, this is a top line analysis with additional work still to be done. I will now hand the call over to Diane.

Thank you, Anthony. Before we review the data, let's spend a little time discussing this difficult-to-treat indication. Prurigo Nodularis is a chronic inflammatory disease. Patients are often covered with hard itchy skin lesions. The intense itching causes scratching to the point of bleeding and pain and the scratching in turn can cause more skin lesions perpetuating the disease cycle. PN is further complicated because it is often associated with a range of systemic comorbidities, including chronic kidney disease, metabolic disorders, HIV and tuberculosis infections, hepatic disorders and autoimmune diseases. Patients with PN have also been shown to have increased rates of multiple cardiovascular comorbidities, including heart failure. Not surprisingly, given the relentless itching, patients frequently also exhibit psychiatric comorbidities such as depression, anxiety and obsessive compulsive disorder, further complicating management. While there has been progress in this space with the introduction of recently approved biologic therapies for Prurigo Nodularis, there is still a significant unmet need. As we explored the science of chronic itch, it became increasingly clear that investigating a mast cell depleting agent was warranted in Prurigo Nodularis. Evidence indicated that mast cell interaction with sensory neurons is involved in the amplification of chronic itch and neuro-inflammation and could play an important role in the scratch itch cycle. Additionally, studies have shown that mast cell numbers are increased in PN lesions. We conducted a small 23-patient Phase Ib study with intravenous Barzolvolimab and saw positive results across both itch reduction and nodule resolution at the highest dose tested, and that merited additional exploration in a robust Phase II study. Turning to Slide 4. I will first walk you through the Phase II study design. This was a randomized, double-blind, placebo-controlled parallel group study that evaluated the efficacy and safety profile of 2 dose levels of Barzolvolimab administered subcutaneously compared to placebo in patients with moderate to severe PN who had inadequate response to prescription topical medications or for whom topical medications were medically inadvisable. 140 participants from 6 countries and 48 sites were randomly assigned on a 1:1:1 ratio to receive placebo or Barzolvolimab injections of either 150 milligrams or 300 milligrams every 4 weeks after an initial loading dose of 450 milligrams during a 24-week treatment phase. Participants then entered a follow-up phase with no treatment for an additional 16 weeks through week 40 with an option to enter an open-label extension. The primary objective of this study was to evaluate the clinical effect of Barzolvolimab compared to placebo on itch response as measured by the proportion of participants with greater than 4-point improvement in the worst itch numeric rating scale at 12 weeks. Key secondary objectives include itch response compared to placebo at different time points, the assessment of skin lesions as measured by the investigator global assessment and safety. The primary analysis was conducted after all patients had completed the 24-week placebo-controlled treatment period. On Slide 5, you will see a table of baseline characteristics for this highly symptomatic patient population. Demographics and baseline disease characteristics were generally well balanced across treatment groups and consistent with other clinical studies in PN. As expected in this indication, patients on study tended to be older and had highly symptomatic moderate to severe disease. The next slide, Slide 6, shows the results for the primary endpoint, the percentage of patients who had greater than 4-point improvement in their worst itch numeric rating scale. The worst itch numeric rating scale is a single item patient-reported questionnaire that measures itch intensity over the previous 24 hours. The scale ranges from 0 indicating no itch to 10 indicating worst itch imaginable, and patients at this trial -- in this trial at baseline had a mean Worst Itch NRS score of greater than 8. As you can see here, patients treated with Barzolvolimab did not have differentiated responses compared to placebo across either dose or at any of the time points. Similarly, on Slide 7, we show key secondary endpoints, including the investigator global assessment for chronic nodular prurigo stage, which is a 5-point clinical scale that dermatologists use to measure the severity of Prurigo Nodularis. It evaluates the number and appearance of palpable skin nodules to gauge disease severity. There is also a secondary endpoint that looks at both Worst Itch and investigator global assessment combined. Across these endpoints, Barzolvolimab did not demonstrate differentiation compared to placebo. Based on these outcomes, we are in the process of discontinuing the Phase II study in prurigo nodularis. We just received these data, and we have more work to do to understand the discrepancy between our Phase Ib and Phase II studies in this indication. While the patient characteristics across the 2 studies were similar, the Phase II study certainly included a much larger sample size. The route of drug administration was also different from IV in the Phase Ib to subcu in the Phase II. IV administration is associated with more rapid and higher drug concentrations relative to subcu. We can't rule out that these differences may have contributed to the difference in outcome. However, both studies achieved profound decreases in circulating tryptase. We have biopsy samples that may give us better insight. We will analyze the biopsies from this study in the coming months as we believe this information will increase our learnings. Our current assessment of the available data suggests that mast cells may not be a key pathogenic driver of symptoms in Prurigo Nodularis. And at this time, we are not planning to move forward with further development in PN. If new data or new science changes our thinking, we are open to exploring this question in the future, if it makes sense. For now, we are focusing on indications of higher priority. While we are disappointed that this study did not confirm the promising signal we saw in our Phase Ib study, we are really pleased with these new data that further support the favorable safety profile we have observed to date with Barzolvolimab. The 450-milligram loading dose followed by the 300-milligram Q4-week dosing regimen achieved the highest subcutaneous exposure studied to date. Slide 8 provides a summary of the top line safety data. Overall, Barzolvolimab was well tolerated. We are very pleased with the safety profile demonstrated in this Phase II study, which remains entirely consistent with our prior studies at these dose levels and in an older patient population with high comorbidity burden. As noted on the slide, there was a single serious adverse event reported by an investigator as treatment-related and described as aseptic meningitis. We strongly disagree with the investigator's assessment and our conclusion was also supported by the independent data monitoring committee. The clinical symptomatology does not support the investigator's assessment. There were no typical clinical signs suggested of this diagnosis such as headache, neck pain or fever. This 65-year-old female patient had a primary complaint of chest pain and weakness, which began 3 weeks after completing her Barzolvolimab treatment. She had an extensive workup over a 4-week period, which ruled out cardiac, pulmonary and GI causes and subsequently, neurologic diagnoses were considered. Her cerebrospinal fluid showed mild lymphocytic infiltration with normal protein and glucose, which is not typical with meningitis. Steroids, antiviral therapy and antibiotics were administered and the patient made a full recovery. We believe the time course, lack of symptoms and spinal fluid findings suggest this is more consistent with neuro-inflammation related to a viral infection and is not related to study drug. 11 patients, including 2 patients on placebo discontinued treatment due to an adverse event, 5 considered related to treatment and 6 considered unrelated. Urticaria related and worsening prurigo unrelated occurred in 2 patients each. The other events occurred in single patients and were in line with what has been seen in prior studies with one exception. One death, cardiac failure, which was assessed as not related to treatment by the investigator sponsor and the data monitoring committee was reported on study. This was in a 73-year-old man with multiple concomitant cardiac risk factors at baseline, including diabetes, hypertension, obesity, coronary artery disease, heart failure, COPD and low baseline oxygen saturation. As a reminder, the PN population is an older population with high comorbidity burden and as such, it is not uncommon to see serious adverse events that are not related to treatment. When we look across the totality of the safety data in the study, we see a safety profile that is very much consistent with our other studies. Looking to the bottom of the table, the most frequently reported adverse events observed in more than 10% of participants in any treatment group were hair color changes and nasopharyngitis, all of which were grade 1 and grade 2. Overall, we are encouraged by the consistent safety profile we have seen with Barzolvolimab in this trial where we explored the loading dose and 4-week dosing regimens. These data give us continued confidence in the overall safety profile and particularly the ongoing Phase III studies in CSU, ColdU and symptomatic dermographism, which also include the loading dose. I will now hand the call back to Anthony, who will wrap things up. Anthony?

Thank you, Diane. Turning to Slide 9. While we are disappointed that the study did not confirm the promising signal that we observed in the Phase Ib, we are proud of our progress and continued execution. As leaders in mast cell biology, we are committed to delivering life-changing therapy to patients in need. The learnings from this study are important for the future of the Celldex pipeline across not only Barzolvolimab, but also CDX-622 and additional candidates in development. The new data presented today continue to build Barzolvolimab's highly differentiated profile. While expected, it was reassuring to see that the loading dose combined with 4-week dosing demonstrated a favorable safety profile consistent with our prior studies and drove rapid declines in tryptase, which positions us well for our ongoing Phase III studies. In closing, Barzolvolimab has significant potential to become a transformational medicine for patients, and we are focused on driving mast cell category creation and delivering on Barzolvolimab's promise executing on ongoing trials and continuing to explore diseases of high unmet need where Barzolvolimab could play a role. We look forward to sharing additional important information about Barzolvolimab in the coming months. We expect we will be in a position to report data in both the EMBARK CSU Phase III studies in the September, October time frame. As previously shared, we anticipate a readout of the Phase II data in AD late fourth quarter. And in addition, we look forward to sharing more about our broad life cycle development plans for Barzol later this year as well. We appreciate your support and look forward to answering your questions tonight. As a reminder, these are top line results, and we are still reviewing the data. We will do our best to answer your questions, but may need to follow up at some point. Operator?

[Operator Instructions] Our first question comes from the line of Thomas Smith of Leerink Partners.

A couple, if I could. Just first on safety. I was wondering if you could provide a little more color on the clinical course for the aseptic meningitis case. Was there any neutropenia observed with this patient? Were there any other confounding factors? It sounds like the patient made a complete recovery, which is good. But any other findings you can add from the data monitoring committee review for this patient?

Sure, Tom. Diane?

Yes. So as I said, we don't agree with the investigator on the diagnosis of the causality. As I described, the patient did not have any symptoms consistent with that diagnosis. They did have an extensive workup as I outlined in the description and ruled out many different other causes. We think that the clinical picture of the chest pain, which really went on for weeks and as well as the modest increased cells in the CSF really indicate some sort of neuro-inflammatory process, most likely due to a virus and they did not have any neutropenia. So the patient had absolutely no neutropenia through that.

Got it. That's helpful. And as a follow-up, can you just comment directly, were there any hypersensitivity or anaphylaxis events observed in this study? And then just maybe as a last question, could you just remind us from the Phase III CSU program, the timing and outcome of your latest Data Safety Monitoring Board committee and any potential read-throughs from this PN study to the CSU program?

So in terms of hypersensitivity, there were no cases of anaphylaxis in this study. There were 2 patients who discontinued treatment for urticaria. One was grade 3, one was grade 2. They responded to medications. In terms of the Phase III CSU, we're having regular meetings with the Data Safety Monitoring Committee. There's nothing particularly there. We do not believe that there is a read-through from these results today to do that those studies and those studies are really supported by very robust Phase II studies, both in CSU and in CIndU. And we -- I would say from the standpoint of this study, so we have no concerns about efficacy, we feel, if anything, that this study, the safety profile really looked great even with using the higher dose. And we feel that, that reads through well to all of our indications.

Our next question comes from the line of Yaron Werber of TD Cowen.

I also had a question on -- in terms of some of the read-throughs maybe to atopic dermatitis, I know obviously, each condition is very different from the other, but maybe just remind us the biological support for running the AD study. And then secondly, just on the CSU study, can you give us maybe a little bit of a sense on the DSMB side, kind of like what are they looking for in terms of -- we get a lot of questions as to what are elements that the DSMB is looking for that would drive potentially changing the study in any way? I know you obviously enrolled extremely quickly and 6 months ahead of schedule.

In terms of the DMC, there's really nothing particular. They have a charter. They review all the safety in an unblinded fashion on an ongoing basis and advise us on things that we need to do with the study, but there is nothing particular.

And we also have the adjudication committee. So all that's in place, Yaron, and it's been pretty consistent since we started the program in Phase I and nothing's changed.

Your first question, Yaron, regarding the read-through to atopic dermatitis and our rationale there. Certainly, both indications share some of the components of the pruritic disease and that was the basis for some of our rationale to move into atopic dermatitis after we had the Phase Ib data in PN. However, there are different patient populations. Mast cells are known to contribute to other parts of the inflammatory process in atopic dermatitis. And we certainly plan on completing the atopic dermatitis study and look forward to the readout and the learnings from that study as we do appreciate that it's a different indication despite that they do share components of the role of mast cells and driving the pruritic itch part.

Yaron, do you have another question?

Our next question comes from the line of Iris Gao of Guggenheim.

My would also be on safety. I wonder if you can give more color on the frequency of neutropenia and skin hypopigmentation from this study and specifically in the 150-milligram group and also how soon was onset and stuff like that?

So as I said, we're very pleased with the safety data in this study. We had a low incidence of neutropenia, so it was below the 10% threshold that we are showing in the table. All the neutropenia were grade 1 and grade 2. There was no association with infection, and there was one discontinuation for neutropenia, which was grade 2.

As far as the hypopigmentation, there were 2 cases, 1 on placebo and 1 on drug.

Is any more color on like the onset of the skin hypopigmentation like we know how long it took for them to show up?

The skin hypopigmentation occurred for Barzolvolimab patient occurred at about the 6-month time point.

Our next question comes from the line of Kristen Kluska of Cantor.

First, I wanted to ask if any of the patients presented with comorbidities where you were able -- in a non-direct measurement way, able to see any effects? And then second, recognizing you're still digesting this data, I'm wondering if you're thinking about any thesis where this could be a potential candidate to further look at with a bi-specific in the future, especially considering there is a type 2 inflammation component to PN.

So I can answer. We're going to look at questions like comorbidities and do we have any anecdotal evidence in the study as we do all our programs. It's a little difficult because in the inclusion/exclusion criteria, you tend to want people that are fairly well controlled for their other comorbidities, but we will look. And I will let Tibor answer the question about bi-specifics.

Sure. Certainly, we look at all the learnings that we get from our studies with Barzolvolimab as helping us understand the role of mast cells and how that affects our pipeline development. So Kristen, we obviously consider the option, the possibilities of bi-specifics in the future, and that's something that as we think through this data deeper once we have all of that data in-house, we will look into very carefully.

Yes. And Kristen, we're also looking at biopsies that we've taken on study. We'll be analyzing those and comparing them to the Phase Ib biopsies since that was IV and this was subcu to see what we can learn from that analysis as well. So there's a lot of stuff we still need to do. I mean, we just got these data in a few days ago. But certainly, as we learn more, we'll communicate that out to everybody.

Our next question comes from the line of Sam Slutsky of LifeSci Capital.

This is Oliver McCammon on for Sam Slutsky. So first one for me is just as you think about mast cell biology post the urticaria PN and EoE randomized readouts, how are you thinking about indication expansion going forward and generally, the speed of the indication expansion for Barzolvolimab and CDX-622? And then I have one follow-up as well.