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

Thank you for joining the Celldex Therapeutics conference call. I will now turn the call over to your host this morning, Sarah Cavanaugh, Senior Vice President of Corporate Affairs and Administration. Please go ahead.

Good morning. Today, we look forward to discussing multiple data presentations that will be presented this week at the Global Urticaria Forum, or GUF, in Berlin, and providing as previously guided, an update on our 6-month chronic toxicology study after completion of the recovery period. [Operator Instructions]. Just to remind everyone, certain matters discussed in today's conference call and/or answers that may be given to questions asked are forward-looking statements that are subject to risks and uncertainties relating to future events and/or the future financial performance of the company. Actual results could differ materially from those anticipated in these forward-looking statements. The risk factors that may affect results are detailed in Celldex's most recent filings with the U.S. Securities and Exchange Commission, including our annual report on Form 10-K for the year ended December 31, 2021, which can be found on our website, celldex.com or on sec.gov. [Operator Instructions] As a reminder, this call is being recorded. Our press release on the data, the GUF presentations and the slides that accompany today's call are all posted on our website. I'll now turn the call over to Anthony Marucci, CEO of Celldex Therapeutics. Please go ahead, Anthony.

Thank you, Sarah. Good morning, everyone, and thank you for joining us to discuss the results from our Phase Ib study of barzolvolimab in patients with chronic conducible urticaria, which were released today at the Global Urticaria Forum or GUF 2022. Joining me on the call today are Diane Young, Chief Medical Officer; and Tibor Keler, Co-Founder and Chief Scientific Officer; Margo Heath-Chiozzi, Senior Vice President of Regulatory Affairs; Diego Alvarado, our Executive Director of Research, and Sarah Cavanaugh, our Senior VP of Corporate Affairs, will join us for the Q&A session. There are 4 presentations on the barzolvolimab program at the Global Urticaria Forum. As outlined in our press release, 2 of the presentations are encore presentations. They recap the interim Phase Ib CSU results we presented in late June of this year, and review data we previously presented on the limited role mast cells appear to play in human wound healing. On today's call, we will primarily focus on the 2 presentations that include new data from our Phase Ib study and inducible urticaria, the 1.5 mg per kg dose cohort, and longer-term follow-up data from the initial 3 mg per kg cohorts which we presented at EAACI in 2021, and which were recently published in the journal, Allergy. We will also as previously guided use this opportunity to provide an update on our chronic toxicology study. Just to remind you, this study initially evaluated a single 3 mg per kg dose of barzolvolimab administered intravenously to 21 patients with symptomatic dermographism or cold urticaria. All 20 evaluable patients for response experienced a response, with 19 of the 20 experiencing a complete response and 1 patient with symptomatic dermographism experiencing a meaningful partial response. These responses were rapid, profound and durable with most patients still at complete response at the end of the 12-week observation period. Given the striking efficacy and the momentum behind the program, we added additional components to the study to allow us to learn more about barzolvolimab in inducible urticaria as we prepared our Phase II study in CIndU, which we initiated earlier this year. In addition, we added an optional long-term follow-up evaluation period for the patients with cold urticaria, a symptomatic dermographism treated at 3 mg per kg in which 14 patients opted to participate. We also added a separate single-dose 1.5 mg per kg cohort in cold urticaria to provide us with data in inducible urticaria at an additional dose level. We are reporting on both of these cohorts at the Global Urticaria Forum. Lastly, we added a single dose 3 mg per kg cohort in cholinergic urticaria, and we look forward to presenting those data from this cohort in 2023. The data being presented adds to the growing potential for barzolvolimab in chronic urticarias, its unique mechanism of action and the incredible opportunity we have to develop a drug that could profoundly improve the lives of patients with mast cell-driven diseases. With that, I'll ask Diane to talk you through this week's data presentations. Diane?

Thanks, Anthony. Let me start with the cold urticaria cohort we added to the study. As Anthony said, after seeing the dramatic results in cold urticaria in symptomatic dermographism with just a single dose of barzolvolimab administered intravenously at 3 milligrams per kilogram, we wanted to explore a lower dose and selected 1.5 milligrams per kilogram IV, which provides similar exposure as the 150-milligram dose we are administering subcutaneously in our ongoing Phase II studies. We postulated that we would see a similar safety profile and clinical outcome as we saw with the 3-milligram per kilogram dose, albeit with a shorter duration of response, allowing us to better characterize the return of symptoms and biomarker correlates during the 12-week observation period. For the purposes of the Global Urticaria Forum presentation, we present these new 1.5 milligram per kilogram dose cohort data alongside our previously presented 3-milligram per kilogram dose cohort to allow for comparison between the dose levels. On today's call, I will focus on the 1.5 milligram per kilogram dose cohort shown in green, but will also reference the 3-milligram per kilogram dose shown in blue throughout the presentation. As a reminder, on Slide 6, you can see the overall Phase Ib inducible urticaria study design with all the cohorts and provocation tests. Ten patients were enrolled in the 1.5 milligram per kilogram cohort, as shown on Slide 7. Safety results are reported for all 10 patients, and clinical activity results are reported for the 9 patients who received a full dose of barzolvolimab. You can see on Slide 8 that consistent with patients in the 3-milligram per kilogram cohort, these patients had high disease activity as assessed by provocation threshold testing with a mean baseline critical temperature threshold of 18.4 degrees Celsius or 65 degrees Fahrenheit, with a range from 6 to 27 degrees Celsius or 43 to 81 degrees Fahrenheit. I want to pause here for a minute to let those numbers sink in. The numbers really paint what can be an extremely challenging picture for patients. For these patients, cold can be 65 or even 80 degrees Fahrenheit. Navigating your day-to-day activities, trying to stay above these thresholds to avoid the onset of symptoms is daunting to say the least. Disease severity is reflected in the urticaria control test score with patients reporting a mean UCT score at baseline of 5.9 in a range of 1 to 11. As a reminder, a score below 12 represents poorly-controlled disease. Every patient in this cohort enters a study with poorly-controlled disease. All patients had disease that had progressed despite antihistamine treatment and nearly half of them had disease refractory to omalizumab. As you can see on Slide 9, all patients in this cohort shown in green on the right, including the 4 patients with disease refractory to omalizumab, experienced a complete response as assessed by provocation testing. Cumulatively, we have now evaluated 19 patients with cold urticaria for activity and all have had a complete response as assessed by provocation testing, including 5 patients with disease refractory to omalizumab, which supports our assertion that given barzolvolimab's mechanism of action, prior omalizumab experience does not impact barzolvolimab's ability to control disease in this setting. As you can see on Slide 10, these responses occurred rapidly after dosing and were durable. 68% of the patients across both cohorts, 7 of 10 treated at 3 milligrams per kilogram and 6 of 9 treated at 1.5 milligrams per kilogram, achieved a complete response within a week of dosing. As expected, the duration of response is dose proportional when measured across the 12-week treatment period with a median duration of response of 51-plus days or more than 7 weeks in the 1.5 milligram per kilogram cohort compared to 77 plus days or more than 11 weeks in the 3-milligram per kilogram cohort. Most importantly, patients reported meaningful improvements in disease control as outlined on Slide 11. The urticaria control test was used here. Physicians like this test because it asks patients to assess how much they have suffered from the physical symptoms of urticaria, itch, hives or wheals and swelling over the last 4 weeks. The scale for UCT ranges from 0 to 16. As I mentioned earlier, a low score indicates high disease activity and low disease control. A score of 16 indicates complete disease control and greater than or equal to 12 indicates well-controlled disease. As I outlined at the beginning, patients in both cold cohorts reported very poorly-controlled disease at baseline. After a single dose of barzolvolimab, all patients across both cohorts achieved well-controlled disease, a score equal to or greater than 12 on study with 7 of 9 achieving complete control at 1.5 milligrams per kilogram and 7 of 10 achieving complete control at 3 milligrams per kilogram. Not surprising and consistent with the data we have shown across prior studies, the durability of clinical response in tryptase suppression were dose proportional and the kinetics of tryptase reduction mirrored clinical activity at both the 1.5 and 3-milligram per kilogram doses, which you can see on Slide 12. As in our prior data set, on average, maximum disease control correlates with profound tryptase reductions near or below the limit of detection. As you see on Slide 13, barzolvolimab continues to be well tolerated. Adverse events were similar across both treatment groups. The most common adverse events reported across both cohorts were hair color changes, mild infusion reactions and transient case changes. As we have discussed in the past, hair color changes generally small areas of hair lightening, and taste changes, generally partial changes in the ability to taste salt are on target and consistent with the mechanism of inhibiting KIT signaling in other cell types, and are expected to be fully reversible. Most importantly, these changes were not bothersome to patients, especially in light of the clinical benefit they experienced. One patient did not receive a full dose of barzolvolimab in the 1.5 milligram per kilogram cohort. During the infusion, the patient began to develop moderate hives, and the investigator out of an abundance of caution discontinued dosing roughly halfway through the infusion. The patient was given antihistamines and steroids and fully recovered within a few hours with no change in vital signs at any time. While the patient was not included in the clinical response data reported at the Global Urticaria Forum given that they did not receive a full dose, the patient did experience a complete response as assessed by provocation testing and maintain that response for about a month. Hematology parameters generally remain within the normal range. While mild, transient and asymptomatic decreases in hemoglobin and white blood cell parameters were noted, these data are very consistent with data from our prior studies and continue to reflect a favorable hematology profile. Before I turn to the long-term follow-up data, I have to say that while we hope to see similar clinical results in the 1.5 cohort given our mechanism of action, it is immensely gratifying to replicate our previous results in this new cohort. The more we study these indications, the more we come to know how severely patients can be impacted by these diseases. And as a physician to be involved in developing a therapy that has such a profound impact driven by the fact that it is targeting the root causes of the disease, mast cells, is very rewarding. The long-term follow-up data is shown on Slide 15 adds to our enthusiasm and also supports barzolvolimab's significant opportunity to impact disease. To set the stage for these data, let me recap the initial data from the study. 21 patients received a single infusion of barzolvolimab at 3 milligrams per kilogram, including 11 patients with cold urticaria and who were evaluable for activity and 10 with symptomatic dermographism. Patients had high disease activity as assessed by provocation threshold testing at baseline. Slide 16 shows all patients had disease refractory antihistamine and 3 patients had disease refractory to omalizumab. As previously reported, a single 3-milligram per kilogram IV dose in patients with antihistamine refractory cold urticaria and symptomatic dermographism was generally well tolerated and demonstrated a 95% complete response as assessed by provocation testing and 100% well-controlled urticaria, by urticaria control test. This included all patients with disease refractory to omalizumab. Profound reduction in serum tryptase and skin mast cells during the 12-week follow-up period was also observed. At the end of the 12-week follow-up period, most patients were still experiencing a complete response. We added an optional long-term follow-up evaluation period to assess this response and corresponding data over time. 14 patients consented to the long-term follow-up evaluation, 6 cold and 8 symptomatic dermographism. 10 of these patients still had complete responses as assessed by provocation testing at week 12. Data were collected at one or more time points beyond week 12 through week 36. On Slide 17 and 18, you can see most patients had a return of symptoms and/or loss of urticaria control between 12 and 36 weeks. Remarkably, 2 patients remain provocation negative at 36 weeks and 4 had well-controlled disease, UCT greater than or equal to 12, 36 weeks post dosing, suggesting that for some patients, interrupting the disease cycle may lead to longer-term benefits despite the clearance of the antibody. On Slides 19 and 20, serum tryptase exhibited a similar rate of recovery as clinical symptoms while skin mast cells return at a slower rate. Tissue KIT signaling as approximated by stem cell factor levels was rapidly inhibited after dose administration and fully restored approximately 18 weeks after dosing. Tryptase levels returned to pretreatment levels during follow-up, while mast cells continue to recover. I do want to comment on safety for a moment. Most adverse events fully recovered during the 12-week treatment period. The onset of hair color changes generally began several weeks after dosing and fully resolved in all patients participating in long-term follow-up. We think these results are very impressive given that only a single dose of barzolvolimab was administered and are really excited to see the results from our ongoing multiple-dose Phase II studies. Before I turn the call over to Tibor, I want to quickly mention the 2 Encore presentations. As Anthony referenced, we presented exciting interim Phase Ib chronic spontaneous urticaria results in late June that will be recapped in an oral presentation at the Global Urticaria Forum. There is no new data in this presentation. We do look forward to presenting new data from the CSU study in early 2023 at Quad AI. In the second encore, the previous presentation on wound healing will be shared. While this was an encore session, I know we have not discussed these findings in any detail before, but I want to take a moment to highlight them now. In the inducible urticaria study, patients underwent routine punch biopsies to allow us to assess mast cell numbers in the skin prior to and after barzolvolimab administration. This presented an opportunity to assess the role of mast cells in wound healing in humans. Several studies in mice have indicated a role for skin mast cells in mirroring wound healing, but the role and relevance of mast cells and human skin wound healing has been unknown. Skin mast cells were significantly reduced after treatment with barzolvolimab, and we were interested if this impacted the ability for patients' biopsy wounds to heal. In this analysis, investigators assess wound healing before mast cell depletion and then after mast cell depletion following barzolvolimab treatment. These data show for the first time that significant mast cell reduction in humans does not affect the speed or duration of wound healing. Wound healing in mast cell depleted skin had similar closure times to wounds in skin with normal mast cell burden. So with that update, I have reviewed what is being presented at this meeting. We're excited to spend the next several days discussing barzolvolimab with urticaria experts from around the world in Berlin. There is a lot of excitement about the program in the medical community and we certainly share that excitement at Celldex. Before we open the call to your questions, I will turn the floor to Tibor, who will provide an update on our chronic toxicology program. Tibor?

Thank you, Diane. Slide 22 outlines our update on this program. As we discussed last February in our year-end call, and in further support of our Phase II urticaria program that includes long-term dosing, we conducted a 6-month chronic toxicology study. The study was conducted in sexually-mature nonhuman primates to allow us to also capture data on the potential impact on reproductive organs. In this study, barzolvolimab was dosed every 2 weeks at either 10 or 75 milligrams per kilogram for 6 months, resulting in very high exposure. In February, we reported that the only clinically-adverse finding at the completion of dosing was a profound impact on spermatogenesis, an expected and well understood effect of KIT inhibition. As part of a standard toxicology study, some animals from each group continued to be observed through a recovery period to understand the reversibility of any adverse findings. Due to the very high concentrations of barzolvolimab at the end of dosing, the recovery period was approximately one year. As we expected and consistent with previous findings with KIT blocking antibodies, we are pleased to report that during the recovery period, spermatogenesis fully recovered in all male animals as measured by both sperm count and motility. We are encouraged with these findings and expect the final histologic analysis and study report early next year. With that, I will ask Anthony to close the call.

Thank you, Tibor. Thank you, Diane. As I said at the start of the call, we are very pleased to end 2022 with such strong data. We believe the data presented today further supports the unique profile barzolvolimab and suggests a potential treatment option which could represent a significant advancement over the current standard of care in the treatment of diseases with mast cell involvement. We have multiple programs ongoing and upcoming milestones outlined on Slides 24 and 25. To this end, our Phase II subcu studies in CSU and CIndU are actively recruiting and treating patients. We continue to get new countries and sites up and running and will provide guidance next year on our expected completion timelines once we have more of these sites on board. I will say that to date, the studies are meeting our internal recruitment models. In the first half of 2023, we will also look forward to initiating our third Phase II subcu study and a new indication, eosinophilic esophagitis or EoE. EoE is the most common type of eosinophilic gastrointestinal disease, and recent studies have suggested that mast cells may play an important role in the driving of the disease. Given the lack of effective therapies for EoE and barzolvolimab's potential as a mast cell depleting agent, we believe EoE is an important indication, and look forward to initiating this new study. 2023 should be a data-rich year. In February, we plan to present 12-week treatment data across all dosing cohorts from the Phase Ib CSU study. Over the course of the year, we also plan to present 24-week follow-up data from the CSU study along with data from our Phase Ib cholinergic cohort in our Phase Ib study in prurigo nodularis. We are also looking forward to advancing our bispecific platform. CDX-585, which combines a PD-1 blockade and anti-ILT4 blockade, will enter the clinic in solid tumors next year. Also, Tibor and his team are also working on developing bispecifics for the use of inflammatory indications, and will present early data next year on their lead candidate CDX-622, which targets TSLP and stem cell factor, 2 complementary pathways driving TH2 diseases. Before we open the call for questions, I would like to thank all the patients and physicians who are collaborating with us to advance treatment options in these diseases and the investigators who presented the barzolvolimab data at the Global Urticaria Forum. I'd like now to open the call to questions. Operator, if you can begin the question-and-answer session, please.

[Operator Instructions] Our first question is from Chris Howerton with Jefferies.

Congratulations on the excellent data. I guess maybe just 2 questions on me, mostly on the safety side. I guess, first and foremost, with respect to the mild perturbations that you saw for the white blood cell count, and the other hematological parameters, Diane, that you saw, just what were the kind of magnitude that you observed there, if you could quantify those for us? And then related to that, because I think that's been on everybody's mind, with respect to the nonhuman primate study, I guess, can you comment on any kind of hematological parameters that you observed with the chronic and rather high dosing, as you pointed out, Tibor, in that study?

Diane, why don't you take the first question?

Yes, so with regard to hematology, we really saw changes that are very consistent with what we've previously seen. We had one -- a single patient in the new cohort who had one isolated value that was below 1,000 and above 500 but which was not reported as an adverse event and had no clinical consequences.

And Chris to answer the question in the chronic tox study, so it very much parallels what we see in humans. There is a modest decrease in some of the hematologic parameters. They stay within the normal ranges for that species, and there are no clinically adverse effects associated with them despite the really high doses used long term.

Well, that's -- like I said, I mean, the efficacy is excellent, and that's certainly very comforting to hear on the hema side. And I won't press you on it now, but Tibor, I am looking forward to hearing more about that new bispecific for the CF and TSLP. So I look forward to that.

We look forward to talking about it.

The next question is from Thomas Smith with SVB Securities.

Congrats on the data. Maybe just one also on the safety. I was wondering if you could give any additional details on the one patient who didn't complete treatment. Was there any evidence of mast cell activation? It sounds like the patient was able to be managed relatively easily. But I'm just wondering if there's any additional details there. And then second question, just on the preclinical tox, just wondering what other preclinical studies are either ongoing or left to be completed on the reproductive tox side.

So with regard to the patient that had the infusion reaction, they had -- it was really characterized as moderate hives. They had no changes in vital signs, no respiratory symptoms. And the tryptase that we measured went down. So not thought to be any sort of anaphylactic reaction.

And with regards to additional repro tox studies, so the study that remains to be done is ePPND study. This is a study to look at the impact on pregnancy in the mother as well as fetal development and birth and follow-up on the infancy development. These are extremely difficult and complicated studies. There are only a couple of places do it. We're working with some of the best folks that really have expertise in this area. And I think next year, we'll talk more specifically about the timing for data from any of those studies as we get a better understanding. The animals have to be dosed throughout their entire pregnancy, and then the infants are followed for a long time as well. So I think we'll be clearer in terms of the timing for that data, but that's the remaining repro tox study that we'll be looking to do.

The next question is from Yatin Suneja with Guggenheim Partners.

A couple of questions for me. First one is on the patient population. Could you just maybe articulate for us the treatment burden for Xolair refractory patients? And maybe if you can also elaborate on if you have that data to see the kinetic of responses in dose patients versus naive patients. Any comment there would be helpful. And then the second question is around the EoE study. Now that the NHP studies have been completed, can you just talk about like when might we be seeing the initiation of that study, what type of endpoints you might be looking at and what sort of feedback you might have received from the FDA with regard to the EoE study?

Sure. Diane, do you want to take that?

Yes. Could you just repeat what you wanted to -- I just missed what...

Yes. So the first -- with regard to -- so you have 4 patients that were Xolair experienced. So it will be great if you can articulate the responses, the kinetic of responses in dose patients, how they compare to naive patients. Are they sort of seeing at similar time point? Just trying to understand if the burden of the disease is high, how's your drug behaving in these patients.

Yes. So those patients, they were oma refractory. They have had symptoms on prior oma, just to clarify. And in terms of the [ time coursing out ], it's small numbers of patients. In general, the burden of disease, time course and everything looked pretty similar. But we have very small numbers that we're dealing with here. And then your second question was about the EoE study and...

Yes, what sort of end points you might be looking at -- I mean, now that the NHP study is complete, what's the data set?

Yes. So yes, in EoE, we're going to do a placebo-controlled study. And really, the goal is to look at expensive end points in order to really understand the impact of our drug, which has a novel mechanism. So we will be looking at the decrease in mast cells. We'll also be looking at decreases in eosinophils and the histologic remission. We'll be looking at the appearance of the esophagus on endoscopy. And then we will be using the dysphagia symptom questionnaire, which is the validated PRO. And we're going to look at some other PROs as well to try to understand that data. So really, our goal is to have a very data-rich study. So we really understand the impact of the drug.

And we'll start that study in the first half of the year.

One more question, if I may. So with regard to the 10 new patients, are there any comorbid conditions these patients had? Any activity you saw? The reason I ask is because I think in the past, you had a patient with PN and you saw some activity there. So just curious if any comorbid conditions were there. And finally, any update on the cholinergic cohort?

Yes, so nothing -- there was no striking comorbidity in these new patients that we've looked at so far. And in terms of the cholinergic, we have completed enrollment in the cholinergic cohort. And so we will report on that next year.

More than likely at EACCI.

Thank you. The next question is from Sam Slutsky with LifeSci Capital.

Just one quick question from me. On Slide 19, where you have tryptase coming back and then SCF falls, but then skin mast cells stay suppressed, just kind of curious on your thoughts around the biology behind this. Is it that systemic mast cells are coming back, but skin mast cells takes longer? Is there another explanation?

Sam, this is Tibor. Well, that is one plausible explanation. We, of course, don't have the answer to that at this point. So I think we just need to study this more in more patients and get a better sense for exactly what the kinetics of mast cell repopulation are. This was an attempt to gather some data, and we had limited optional samples to look at. But it does appear that those cutaneous mast cells come back slower than tryptase. I think your explanation is as good as any at this point.

[Operator Instructions] The next question is from Kristen Kluska with Cantor Fitzgerald.

Let me also add my congratulations on these data. So the first question I have for you is that the data includes quite a few more Xolair refractory patients versus the previous CIndU update. So given that you are continuing to see the promising effects, both from this study as well as for the CSU study, I'm wondering how you think this impacts the mechanism of action rationale with mast cell targeting versus IgE. And perhaps a hypotheses as to why some patients only seem to be responding to Xolair and others don't?

Yes, so -- yes, so I think that this -- I think that so far, what we've seen, it looks like Xolair refractory patients are responding similarly to patients who have not gotten Xolair. And we -- looking at it from a mechanism standpoint, we think that makes sense because we're depleting mast cells versus Xolair, which is acting specifically on IgE, which is one of the things that triggers mast cells in the case of chronic urticaria. So yes, so we're really pleased to see this growing body of evidence, that it can have effects in the oma refractory population.

Okay. And could you talk or share some patient anecdotes that came out of the trial, especially when you consider the temperature sensitivity threshold that you talked about at baseline?

Well, we've heard from -- regularly from the side of that about how excited the patients are. We've heard things about not being able to go into air-conditioned rooms. We heard obviously, in the 3-milligram per kilogram cohort, the patients couldn't not eat ice cream. So the feedback from the investigators and some of the patients has been very, very positive.

We have no further questions at this time. I'll turn it over to Anthony Marucci for any closing remarks.

Thank you very much, and thanks, everyone, for joining us this morning. We are excited about our programs and look forward to providing further updates soon and throughout next year. I want to wish you all a happy holiday season, and have a great day. Thank you.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.