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

Good day, and thank you for standing by. Welcome to the CDX-0159 data update 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. Please go ahead.

Thank you. Good morning, and thank you for joining us to discuss the updated data set we reported on Friday, July 9, from our Phase Ib study of CDX-0159 in chronic inducible urticaria. With me on the call today from Celldex are Anthony Marucci, Co-Founder, President and CEO; Dr. Margo Heath-Chiozzi, Senior Vice President of Regulatory Affairs and Medical Lead on the program; Dr. Diane Young, Senior Vice President and Chief Medical Officer; Dr. Tibor Keler, Co-Founder, Executive Vice President and Chief Scientific Officer; and Dr. Diego Alvarado, Senior Director of Research and Research Lead on the program. We are also very pleased to welcome Dr. Marcus Maurer, Professor of Dermatology and Allergy at Charité in Berlin. He is conducting the study and will present the results alongside Margo. In the Investors section of the celldex.com website, you will find today's press release and the slides we'll refer to on this call, which are located in the Events and Presentation page. 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 on in the call. I would now like to turn the call over to Anthony.

Thank you, Sarah, and good morning, everyone. We're very excited that you could join us today to review the positive Phase Ib chronic inducible urticaria clinical trial data from CDX-0159, our humanized monoclonal antibody that specifically binds the receptor tyrosine kinase KIT. Today, we are discussing the evaluation of 0159 in 2 of the most common forms in chronic inducible urticaria, cold urticaria and symptomatic dermographism, where the mast cell activation is the key pathogenic driver of the disease. These data were presented this past weekend by Dr. Maurer during a late-breaking poster discussion session as part of the European Academy of Allergy and Clinical Immunology Annual Congress of 2021. On our webcast this morning, Margo is going to give a brief overview of the data, and then Dr. Maurer will provide his thoughts and additional context for these results. As we review this data set, the key takeaways are outlined on Slide 3. The patients on study experienced a 95% complete response rate and an overall response rate of 100% after only a single dose of 0159. These responses were rapid and durable with a favorable safety profile. These data are unprecedented in this patient population and clearly demonstrate that 0159 has the potential to become an important new treatment option for patients suffering from chronic inducible urticaria. We are also very encouraged by these impressive early data, which show that 0159 safely depletes mast cells, indicating its exciting potential to impact other diseases with mast cell involvement. Margo now will provide you an overview of the results. Margo?

Thanks, Anthony. Before we look at the data, I want to pause on Slide 4 because I think it's important to set the stage for what life with chronic inducible urticaria can be like for patients. Many patients with inducible urticaria really suffer. This can be a severe debilitating disease with significant impact on both physical and emotional health, leading to substantially impaired quality of life. Patients work very hard to avoid their trigger. It is often impossible to do so, and there are limited treatment options and a great need for better therapy. For these reasons, we were very excited to partner with Dr. Maurer and his team to conduct this study, and I want to thank them and the patients from the study for their commitment to the trial. This Phase Ib study, as detailed on Slide 5, is an open-label clinical trial evaluating a single dose of CDX-0159 in patients who are refractory to antihistamine with cold urticaria symptomatic dermographism and a more recently added to the study, cholinergic urticaria. 0159 is administered to patients as add-on treatment to standard of care H1-antihistamine, and then they are followed for 12 weeks. During the 12-week observation period, patients undergo repeat provocation testing that utilizes standardized triggering stimuli to induce hives and itching. They are evaluated for signs and symptoms of their disease, undergo blood draws and skin biopsies to assess tryptase and mast cells activity and are assessed for safety and tolerability. The presentation at EAACI reported on data for the cold and symptomatic dermatographism cohort. As of June 11, 2021, the data test date, 20 patients received a single intravenous infusion of 0159 at 3 milligrams per kilogram, including 11 patients with cold urticaria and 9 patients with symptomatic dermographism. Safety results are reported for all 20 patients and clinical activity data are reported for the 19 patients who received a full dose of 0159. The patient population that we clearly have high disease activity. The patients with cold urticaria had mean baseline critical temp thresholds of approximately 19 degrees Celsius or 62 degrees Fahrenheit, with a range of 5 to 27 degrees Celsius, which translates to 41 to 81 degrees Fahrenheit. To put cold into perspective, this means that half of the patients on the study developed hives on their baseline temp test between 62 and 81 degrees Fahrenheit, well within room temperature, which highlights their extreme sensitivity to temperatures below their normal body temperature. Patients with symptomatic dermographism had an average baseline prick test threshold of 3.8 pins out of a maximum of 4 pins. When you think about what this means in terms of daily life, some of these patients can't do everyday activities like pull up their socks or wear shirts that rubs on their skin or even comb their hair without inducing hives. Slide 6 shows the impressive response data. We are very pleased to report that all patients experienced a clinical response as assessed by provocation testing, with 95% experiencing a complete response and the remaining patients experiencing a partial response. All 10 patients with cold urticaria experienced a complete response, and 8 of the 9 patients with symptomatic dermographism experienced a complete response. The remaining patients with symptomatic dermatographism experienced a marked partial response decreasing from 4 pins to 1 pin. Of note, complete responses were observed for all 3 patients with prior Xolair experience, including 2 who were Xolair refractory. Responses occurred rapidly after dosing, as outlined on Slide 7. In cold urticaria, 7 of the 10 patients experienced their complete response by week 1; and in symptomatic dermographism, 7 of the 8 experienced a complete response by week 4. Importantly, these responses were sustained with a median duration of response for cold patients at 77-plus days or more than 11 weeks. And for the symptomatic dermographism patients, 57-plus days or more than 8 weeks. Both patient and physician global assessment results are consistent with the complete responses for the provocation test and reinforced the observed clinical activity. These global assessments for the patients' current disease severity on a 0 to 3 scale, with 0 equal to no activity and 3 showing severe activity. Prior to 0159 treatment, scores reflected moderate to severe disease activity for these patients. After treatment, the scores improved near the time profile of provocation test responses with sustained responses for most patients. Slides 8 and 9 highlight what is really exciting science. We are particularly impressed with the marked reduction in skin mast cells that follows the suppression of serum tryptase, elucidating 0159's mechanism of action. We found that a single 3 mg per kg dose to prior skin mast cells with their survival factor -- stem cell factors, leading to rapid marked and durable suppression of serum tryptase and depletion of skin mast cells as measured through serial skin biopsies. The kinetics of serum tryptase and skin mast cell depletion mirrors the clinical activity and confirms serum tryptase as a robust pharmacodynamic biomarker for assessing mast cell burden and correlates with clinical activity in chronic inducible urticaria and potentially in other mast cell involved diseases. This is a notable scientific discovery in and of itself with potentially broad applications across the study of many important diseases with mast cell involvement. CDX-0159 continues to be generally well tolerated, as shown on Slide 10. The most common adverse events were hair color changes, mild infusion reactions and transient changes in taste perception. Hair color changes, generally small areas of hair lightening and taste disorders, generally partial changes of ability to taste salt, are on target, consistent with the mechanism of inhibiting KIT signaling and other cell types are expected to be fully reversible. Most importantly, in our study, these changes were not bothersome, especially given the clinical benefit that these patients experience. As in the healthy volunteer study, infusion reactions, generally mild hive and itching that resolved spontaneously, were observed. As we have previously discussed, a single severe infusion reaction, a brief loss of consciousness in a patient with a history of fainting, occurred. The patient rapidly recovered without further consequences and continued monitoring. Importantly, this event was not related to mast cell activation based on tryptase monitoring. No further information of significance was received in the workup of the patient after the event, and we have seen no other events of this nature across any of our studies. There were no clinically significant decreases in hematology parameters observed. While mild, transient and asymptomatic decreases in hemoglobin and white blood cell parameters were noted, the hematology parameters generally remained within the normal ranges, an important finding for a KIT inhibitor. The hematology observations to date are consistent with the data from our healthy volunteer study. And while we will continue to monitor heme parameters in larger patient numbers with longer observations, we are really pleased with this data. We would like to comment briefly on one patient in the study with symptomatic dermographism that also had a diagnosis with prurigo nodularis, which is a chronic skin disease that causes hard, intensely itchy lumps and nodules to form on the skin. The patient experienced both a complete response of their symptomatic dermographism and notable disease improvement in their prurigo nodularis after a single dose of 0159. This anecdotal finding was of interest to us as we are on track to initiate a study in prurigo nodularis in the fourth quarter of 2021. In closing, we could not be more excited with these early results, which demonstrates the potential of 0159 to be a groundbreaking new treatment option for patients with these often severe and debilitating diseases. We look forward to completing enrollment of the third cohort of 10 patients with cholinergic urticaria and presenting additional data at upcoming medical meetings. I would now like to ask Dr. Maurer to share some of his thoughts on the data. Dr. Maurer is one of the world's leading medical experts in urticaria, and his research focuses on the physiologic and pathologic functions of mast cells. Dr. Maurer, would you please tell us what the opportunity to utilize a mast cells depleting agent like 0159 means for these patients and the implications of these data on the wider medical and scientific communities? Marcus?

Thank you. Thank you. But let me start by saying thank you for having us on this program. Now being a mast cell biologist and a urticariologist, this is super exciting for these patients, for mast cell science, for many other mast cell-driven diseases, but let's go to our patients first. These are 20 patients who have severe disease. Most of them for many years, 5 years of not having anything that helps, including antihistamines, updose antihistamines, some of them on omalizumab, practicing incredible avoidance behavior, which adds, of course, to the burden that comes from the signs and symptoms of this disease. Not only are they itchy, do they develop wheals and angioedema every time they're exposed to their trigger, cold and scratching of the skin, but they also go to great lengths in their daily lives to avoid that trigger. And in my country, for example, for cold urticaria patients, that means for many of them staying inside from September to May because it is simply too cold outside, and going outside would result in almost immediately swelling of the face, for example, and other skin parts that are exposed to the cold. I'll be happy to put some color to what these patients go through. It's a severely disturbing disease to have, devastating, long-lasting and -- but basically impact on every aspect of life, sleep, interpersonal relationship, performance at work and school, hobbies, traveling, sports, all of these patients have stories to tell where their disease dominated their life, control their life, and that makes it all the more important and remarkable in terms of what happened in this study. These are 20 very happy patients who, all of them, responded with a meaningful reduction and virtually all of them with being completely free of signs and symptoms, even in the presence of their trigger. And not only is it a long-lasting response, which is very important in a disease that can last 10, 15, 20 years, it was also quick. And the last point I really find remarkable is the predictability of the response. So it's not that we don't have any patients who respond to an antihistamine or to oma, off-label, but we cannot predict who will respond. And that makes it, of course, very difficult to find patients excited about these treatments when we do not know whether the individual patients will benefit or not. But here, 10 out of 10 cold urticaria patients, complete response. I mean, this is what you want if you treat patients with chronic urticaria. And really for these patients to come from high thresholds, which you have to turn in your head because a high threshold in temperature means that even high temperatures, as Margo described, room temperature can be enough for you to break out in hives. Even these patients went down to -- well, now they can no longer be made to have wheels, even with an ice cube, they can do everything that they had to avoid before. So that is really, really cool. But this study is full of first times. It's a breakthrough on many different levels, of course, primarily for patients to finally have someone or something that can help them. But it's also -- Margo said, this is a mast cells-driven disease. Yes, we said that, no, for forever. But did we have proof for that? No. Now we have proof for that. And many on the call will know how hard it is to prove something in medicine. This is proof. Targeted treatment that takes out the key effector cell of urticaria and these patients no longer have urticaria. It is a mast cell-driven disease. And it is just very rewarding to see that we are now, for the first time, able to deplete humans of their mast cells. You have no idea how excited I was when I had the samples of these patients under my microscope to look at, for the first time, human skin that's mast cells-deficient. This is the first in the history of mankind. And to me, as a mast cell biologist, super exciting because what that means is that we can now, first of all, help patients with mast cell-driven disease, mast cell-dependent disease, for sure, but also many other diseases where mast cells play a role in the pathogenesis that drives those diseases. And a long list of diseases comes to mind from clearly the type 1 allergies, anaphylaxis, food allergy, allergic rhinitis, asthma to many other diseases where increased numbers of mast cells have been described, activation status of mast cells, mast cell mediators are elevated. And there is in subpopulations of these patients, at least partial response to mast cell mediator targeted treatment. So that's really cool. And if you turn this around, not only will we be able to help a lot of patients with a lot of different diseases, but we will also be able to figure out where and how mast cells contribute to many chronic inflammatory diseases and other diseases where they have been hypothesized to play a role. So really very exciting. Of course, I'm also happy to see that tryptase, a marker that we commonly use in clinical practice, in mastocytosis and anaphylaxis, that it really is a good, albeit not perfect marker for mast cell burden. We knew that mast cell increase in mastocytosis comes with an increase of mast cell. But this is the first time that a reduction -- a depletion of mast cell comes with making tryptase levels unmeasurable. And if you look at the data, the nice correlation between that -- well, between everything, really, the reduction in mast cell numbers in the skin, the reduction in tryptase, the reduction in clinical disease activity, it's just remarkable. Maybe just a couple of stories because these are patients who have lots of stories to tell about what their disease does to them. And there are patients with symptomatic dermographism who can't wear normal clothes. They can't dress like you and me. They are in wide clothes that have don't have seams on the inside because everywhere where their skin is touched by their clothes that rub on the skin, they will have wheels, almost immediately. And for as long as that rubbing doesn't stop, they will not stop. They will continue to develop wheels. And that to some of them is so difficult that, for example, their hair brushing on their neck is enough trigger to make wheels appear at that site. And you can, I think, easily imagine that, that is not compatible with a normal life. You can't do sports, you can't have a relationship, you can't wear a watch, you can't wear normal clothes. You can't wear shoes, in some cases, because that is a trigger of your feet swelling up. So I think you can imagine how happy these patients are to be able to do things that are normal to us but weren't normal to them for the last 5 years and longer. And for cold urticaria, these patients tell me that when they want to eat a yogurt, they need to warm that up because anything that comes from the fridge is too cold for them to eat, and they need to avoid, of course, swelling of the tongue and this very unpleasant feeling of the air getting tight when you have swelling of the upper airways, swelling of the lip by eating or drinking something that is cold. And a lot of things are not possible. I have this one woman who said, for the first time, I can cook again because that, of course, involves cold things, and she wasn't able to do that. And to her, that meant a lot. And these are just very happy patients. And well, I'm not -- I don't know if I'm allowed to say it, but there's not a single patient who doesn't ask when they can get this drug in case their signs and symptoms come back. So this is really a life changer for them, and they're very excited about treating with this drug until the disease goes into spontaneous remission. Let me talk a little bit before we go to the Q&A on the side effects. You can't see that, but I'm making air quotes here because what patients notice from this drug is -- well, first of all, the huge clinical benefit. But second of all, almost nothing that disturbs them. Margo talked a little bit about the changes in taste, which are selective. So it's not that they cannot taste anything anymore. It's transient. They find this peculiar. Those are words used by patients, and interesting, same goes for the hair. Urticaria is a female disease, and many of these patients dyed their hair anyway. Some of them started to do that when they notice these little spots of depigmented hair come and then go again. So to patients, this is not something that they would call a price that I have to pay. It's more of, oh, this is interesting rather than, well, I've never had the discussion with any of these patients, whether even if this were to stay in the future, this would stop them from using this drug. So that will certainly be something that will be straightforward to managing routine clinical practice when we get this antibody as a drug. Of course, these are early days, right? So this is a single treatment with up to 12 weeks-plus of clinical benefit. We will have to explore how often CDX-0159 needs to be given to achieve the goal of treatment, treat the disease until it is gone. That's what we say in the guideline. And we're finally able to live up to that big promise, to that big goal. So that will be exciting to see in the future. And of course, something that works in cold urticaria, something that works in symptomatic dermographism. Well, I'd be very, very surprised if that does not work in all the other urticarias, including chronic spontaneous urticaria because just like for cold urticaria, just like for a symptomatic dermographism, these are mast cell-driven, mast cell-dependent responses. So shutting down, shutting off mast cells, depleting them, is the one size fits all for chronic urticaria patients. We don't have to worry about the different endotypes that are behind the mast cell activation, upstream of that activation or about the mediators that are being released that we hope to neutralize in order to bring benefit to our patients. So we take out the main culprit altogether, mast cells, and that's what makes that approach so very convincing. I'll stop here, but I'll be looking forward to your questions.

Thank you, Dr. Maurer. As you have just heard, these data are very encouraging and show the potential of CDX-0159 to provide a real benefit to patients who desperately need treatment options for their disease. We believe these exciting early data also indicate 0159's potential to impact other diseases with mast cell involvement. Before we conclude our presentation, I'd like to highlight our development plans, which you can see on Slide 12. We continue to enroll patients with the cholinergic urticaria to the inducible urticaria study on our Phase Ib study in chronic spontaneous urticaria, is also actively enrolling patients. We plan to submit data from the cholinergic cohort for presentation at a medical meeting in the first quarter of 2022. As we look at the spontaneous urticaria study, the seasonal enrollment slowdown you typically see as you head into the summer is tracking higher than expected. Phase I studies require significant time commitment from patients. And as COVID vaccines have allowed the gradual return to normalcy in the United States, patients want to enjoy their summer, take vacations and travel. We believe we will capture these patients, but we need a few more months to do so to support a robust data readout. Given the timing of the abstract submission deadlines, we plan to submit the spontaneous urticaria treatment data for presentation at a medical meeting early next summer. Importantly, this positions us well to remain on track to initiate the Phase II studies in both spontaneous and inducible urticaria in the first half of 2022, as we have previously guided. In addition, we continue to plan to introduce the subcutaneous formulation into a healthy volunteer study in the third quarter of this year and to initiate the clinical study in prurigo nodularis during the fourth quarter followed by a fourth indication in 2022. I'd like to now open the call to questions. Operator, if you can begin the question-and-answer session, please.

[Operator Instructions] Our first question comes from Yatin Suneja with Guggenheim Partners.

Congrats on the data. A couple for me. Could you first comment on the regulatory strategy for CIndU now, the size and scope of the pivotal program? What type of competitor you might use? And maybe comment a little bit on the dosing paradigm because it seems like cold versus SD patients, they responded at a different time point and the durability is different. So do you need to do further dosing work? And then I have one more follow-up.

Sure. Yes. Now I'll have Margo answer that question. Margo?

Yes. So Yatin, clearly, we are so excited about this data that you did, alignment with the health authority is very near term. And it's premature to really talk about the exact size of the study because the real goals of the Phase II studies need to be to explore a range of doses and a range of dosing intervals. And so, we -- the Phase II study as a placebo-controlled assessment of how we're able to control patient symptoms and how to keep them controlled in a number of different dosing paradigms. So that, in the near term, is really our goal of Phase II, is to get the patient symptoms controlled and keep them there. And so that's the study that comes next in inducible and we'll start in the first half of next year.

Okay. Helpful. And then could you also just talk a little bit about the correlation you saw between the mast cell depletion in the skin and the response rate. I mean, what level of mast cell depletion you need to drive the benefit because it seems like 40% to 50% reduction in the mast cells that you were seeing at 4 weeks was enough to get patients into clinical response?

Yes. Yatin, I'll have Diego answer that question for you.

Yes. So I think as you noted -- as we've noted, there's a very interesting correlation between mast cell reduction and symptomatic benefit. I don't know if there's a particular threshold that we need to reach. I think it seems to me from the data that the further you reduce mast cells, the better the symptoms get. Obviously, you don't have to reduce them by 100%. A lot of these patients still have a few mast cells left and their symptoms have gone away. So I don't know if there's a particular threshold. But I think it is very exciting to have a biomarker, both from the point of view of tryptase and mast cells that really correlates with disease activity, and it's something that we plan to leverage in the future for dose selection.

Got it. Maybe one final question for Dr. Maurer. Dr. Maurer, given that the onset and the durability of clinical improvement was a little bit different between cold urticaria patient and SD patient. How do you -- or how does the cholinergic urticaria fit into the picture? Do you expect any major differences? And then if you can also talk about how do you envision maybe using this drug in the treatment paradigm. Do patients grow out of this disease? Like how chronic the treatment paradigm is going to look like?

Thanks for the 2 questions. I'll start with the last one. This will be a drug that will be used most likely in patients who fail antihistamines, which is most patients clearly. We do not have other licensed treatment options for chronic inducible urticaria patients yet. And what that means is that when patients start to develop these signs and symptoms and are testing positive in the provocation test, they will get an antihistamine, which works or doesn't work, we will know that after 2, 3 weeks, and then go on this treatment and stay on this treatment, treat the disease until it is gone, until their disease goes into spontaneous remission, which in the inducible urticarias takes longer than in chronic spontaneous urticaria. And chronic spontaneous urticaria average is 5, 7 years. So we have many patients with cold urticaria who had their disease for 10, 15, 20 years. And that's how we intend to use it. There's no not much benefit in only providing a drug that keeps patients free -- complete responders for a year when they are going to have many years of this disease and need good controlling treatment for this. Cholinergic urticaria will be very interesting. We do not know much about the heterogeneity of patients and endotypes in the different chronic inducible urticarias. There must be some because when studies were done, when we did studies, for example, with omalizumab and this is also true for antihistamine, we do see responders and nonresponders. And that must mean that different mechanisms drive mast cell activation and/or that different mast cell mediators have different contributions in different patients. Now what's clear to me is that if you treat 10 patients, and 10 of them lose their disease, making air quotes again because, of course, they still have the disease, but longer have the cells that bring the signs and symptoms, well, that means that you've hit all endotypes in terms of different mast cell activators, different mediators. Now for cholinergic urticaria, we also have different patient populations and we have male patients versus female patients showing a little bit of difference in terms of age at onset, disease severity, response to treatment. Cholinergic urticaria, by the way, is the worst one of all the CIndUs to respond to omalizumab. So that may also mean something. But what we're sure of is that in most patients with cholinergic urticaria, this is mast cell disease. And so they must -- like the cold urticaria carrier patients and like the symptomatic dermographism respond. Do I think that they will respond differently in terms of how long it will take for the benefit to set in? No. If you kill mast cells, then you're doing the same thing in cold urticaria patients as in symptomatic dermographism patients as in colonal urticaria patients. And that would also then be the same in aquagenic urticaria and delayed pressure urticaria, in contact urticaria and solar urticaria. Mast cells, when starved for their SCF, which is what we're doing here, will go into apoptosis. And this will have the same kinetics in essentially all of the chronic inducible urticarias and also in the chronic spontaneous urticarias. The one thing that could make a difference between CSU and CIndU is that some patients with CSU have elevated numbers of mast cells. So it may be that, that factors into the time of onset, we will see. But even if there are higher numbers of mast cells, these doses used here should suffice to kill them. Again, as Diego said, many patients after 8 weeks or 12 weeks, I saw them under the microscope, have 1 or 2 mast cells left. You should see 15 in one of those microscopic fields and that occasional mast cell does not seem to be sufficient to drive the response anymore. And I've seen completely mast cell-efficient -- skin mast cell-deficient patients where none of the microscopic fields that I looked at, had any mast cells. And that's very encouraging across all of chronic urticaria. Now I forgot your first question. What was that? I think I answered about the urticaria.

Our next question comes from Sam Slutsky with LifeSci Capital.

And congrats on the data. Just jumping to questions, Dr. Maurer to start and kind of build off what Yatin was discussing, can you put into context how the outcomes achieved with 0159 compared to what's been seen with other drugs that are used during late-stage development for Synduced? And then if I understood correctly, you would expect similar activity across all urticaria subtypes?

Yes. Thanks, Sam. For sure, I do expect that. I was right 2 out of 2 times. I hope I'll be right, 10 out of 10 times with all the different forms of chronic urticaria, we want to look at. Sam, I'm not sure what other programs you're referring to because...

As you know, use kind of off label. I know label is not [indiscernible]...

Sam, as much as I wish that, that had become a program, it never did. So we did 2 academic investigator-initiated studies with omalizumab versus placebo, actually 2 different doses of omalizumab, one in cold urticaria and one in chronic inducible urticaria Sorry, in symptomatic dermographism. Now what these 2 studies showed is that omalizumab, as compared to placebo, works. Interestingly, the 2 doses used, 150 and 300 mgs, were equally effective. It also showed that there was a wide range of responses from complete nonresponse to complete response. And that in many of these patients, the response really fell into 1 of these 2 categories where they either had no benefit at all or they have complete benefit. And that made us speculate that, well, IgE, which is the target of omalizumab, is probably important in some patients and not important in others and cannot, therefore, be a treatment target that all patients will benefit from. Now we do not have an omalizumab program for chronic inducible urticaria. And my fear is that omalizumab will remain off-label forever in chronic inducible urticaria. And so -- well, as much as I want more programs to come to this group of neglected, underestimated and undertreated diseases, this is the one.

All right. Got it. And then just when thinking of the broader implications of a mast cell targeting drugs. You mentioned the range of conditions where 0159 to be expanded. Just looking at prurigo nodularis, where Celldex is developing 0159, could you just comment on the extent of improvement on itch and nodule size in this patient had overlapping PN? And then are there other overlapping conditions seen in the study where patients responded? I think there was one patient with rhinoconjunctivitis earlier.

Yes. That was Loxam, really. As much as I want to take credit for it, that's great to see that this patient really had a substantial improvement of itch. And you have to understand that prurigo nodularis or chronic prurigo nodularis comes with very stationary lesions that even if you manage to bring them to heal, they will, for a long time, come with hyperpigmentation of the skin and the risk of relapse. That is what most of these patients experienced. Now this hasn't happened in the patients we're looking at. Plus, the rationale for treating prurigo nodularis or chronic prurigo with a mast cell targeted treatment is very high. You have -- I'm just going to say tons of mast cells, of course, not tons of mast cells, but markedly upregulated numbers of mast cells in these lesions and that, together with sensory nerves that have many neuropeptides that can activate mast cells directly. So that's something that makes me very hopeful that chronic prurigo will show a similar benefit from mast cell-targeted treatment with 0159 as we have seen here with the chronic inducible urticaria patients.

Got it. Okay. And then lastly for me, just on the infusion reactions seen in some patients. It looks like it's been generally mild, but one, can you just describe what's like for patients? And then second, can you speculate a bit on what that might look like for subsequent doses or subcutaneous administration?

I expect that subcutaneous administration will take care of that altogether. This is something that you see with many drugs, many antibodies that are applied intravenously. As you said, they are mild, some itch, some hives, very, very small. I don't see that even if that were something that would remain, I don't see that, that would stop us and patients from using this drug for chronic urticaria. Chronic urticaria is not analogy. Chronic urticaria does not come with an increased susceptibility to develop hypersensitivity reactions. So these people are not at risk of having hypersensitivity reactions. But again, coming back to your first question, subcu usually takes care of this and stops patients from having infusion reactions or injection reactions or really systemic reactions.

I guess, just real quick building on that. Would we expect to use an IV for it to go down on subsequent doses? I know we've seen that with other drugs as well in biologics.

That was hard to hear. Do we expect to see what?

It also decreased with IV on subsequent doses. I know other biologics you've seen decreasing infusion rates with longer dosing.

Interesting. Now look, you're depleting mast cells. And if mast cells have something to do with the infusion reactions, well, then they can no longer happen. So that's a plus. I don't think that you'll see more of them. And well, overall, I do hope that the subcu program works because that's what we want, that's what we need. And again, that will then be the end of that. But you're going into a disease where you want to maintain that level of clinical benefit that we have achieved. You don't want these patients to come back and start having signs and symptoms before you then retreat them. And that would make for retreatment in patients who have no mast cells. That's a good thing.

Our next question comes from Kristen Kluska with Cantor Fitzgerald.

Congrats on these data. The first question I had is with half the patients on this trial having the disease for over 5 years, could you discuss any other treatment strategies they may have evaluated outside of antihistamines and a few patients with Xolair? And Dr. Maurer, I saw in your Q&A this morning that you did note some have billed multiple treatments. And then on the other side of that, considering that the youngest patient in the trial was 27, why do you think it's the case that half the patients had a disease duration under 5 years. Was it misdiagnosed, later onset, greater severity with time?

Those are all really, really good questions. So patients, when they are first diagnosed with this disease, usually have had it for quite some time. And that is because awareness in the GP community but also in the specialist community is not where we want it to be. Some patients say that their doctor had never seen a cold urticaria patient and couldn't explain why they have -- when they touch something called why they have wheels. So there is the lane diagnosis, not much misdiagnosis, but really many colleagues are puzzled by this disease and shouldn't be because it's -- yes, it's iconic, really. There's no other disease where if you touch something cold, you get a wheal. So it should be fairly simple. And I think with a bit more of awareness and education, we can make a big difference. Important point is this can hit you at any age. I have 3 year olds with cold urticaria and 93-year-olds with cold urticaria. And it comes with special challenges, of course, especially in the kids and in the adolescents, those who want to swim in the summer. They are at major risk of having systemic, even fatal reactions to exposure -- being exposed to the cold. Now in terms of what they do and what they try in order to disease, it's really quite amazing. They have had every antihistamine that you can get your hands on in combination old ones, the dating antihistamines, ketotifen, horrible drug. Some of them on chronic continuous use of steroids. So that's cortisone, some of them on cyclosporin. Most of them have used, in addition to a high-dose antihistamine, a combination of this antihistamine with the leukotriene antagonist, with an H2 blocker or both of them. Some of them have tried cromoglycate. And the overall experience is that nothing helps. And the only thing that helps, and again, I don't even want to say that, that is a treatment option, is to stay warm, do not scratch, do not let anything touch your skin, to stay in the dark when you have solar urticaria, to not move when you have cholinergic urticaria. This is horrible because you are, in all of your life, in all of your outlook on life, you're dominated by this disease. Physicians don't know what this is, at least many of them. Those who do know don't have anything that can help you. So you're stuck with social isolation, isolating yourself from these triggers for as long as you have the disease. And as you said, many of these patients have it -- in the study, had it for 5 years. That's a long time and some of them for very much longer.

And then some literature that we've read has shown that CIndU overlaps in up to 36% of patients with CSU. So I wanted to see if you could comment on whether any of the 19 patients also presented with CSU, and if so, there any patient-reported outcomes while recognizing that you didn't actually measure for this specifically?

No, no. And those 36%, I mean, these studies are out there, but there are also others that say, 5% to 10%. In my experience, it is somewhere around 15% to 20%, and that is only because we see the very hard-to-treat patients where comorbidity of 2 or more chronic urticarias is more common. So it is not that every third CIndU patient who walks into your office also has chronic spontaneous urticaria. And these patients did not.

Okay. And I wanted to ask your thoughts on the time-to-onset here. I know the studies for CIndU with Xolair involved multiple doses treated. So it's hard to make head-to-head comparisons. But for off-label usage and your experience, how long does it take to typically show these effects? And how long are physicians willing to prescribe it for, to wait to see if any positive effects occur? And I guess, just in terms of time to onset, how important of a consideration do you think this could be approved commercially?

I think it will be very important. But more important will be the predictability of the response. Look, if you know that you're going to respond, then you're going to wait 2 months, if that's the price that you have to pay. At least you know that you'll get there. That unfortunately is not the case with omalizumab. And it's hard to predict in CIndU patients who will and who will not respond. And when I talked a little bit earlier about the different types of response, there are complete responders and there are complete nonresponders, but there's also partial responders. And so it's not as clear cut at all as what we see here where it's black and white. And on top of it, a much earlier response than you see in clinical practice with omalizumab. There are not many clinical trials with omalizumab in CIndU. Well, in fact, there are 2, and we did them both. But there is some clinical experience because people do use it where they can in routine clinical practice. And it takes about as long as it does in chronic spontaneous urticaria, where you have 2 populations. You have one population that responds very early, after the first injection, not necessarily with complete response before the second treatment, but with substantial. And then you have patients who need 4 or 5, 6 months of treatment before they start to see the benefit in chronic spontaneous urticaria. And this is because of different mechanisms of mast cell activation in chronic spontaneous urticaria and the mechanism of action of omalizumab. And the problem then is that, well, many patients and also many physicians do not have the patience to treat for 4 -- 3, 4, 5 months with a biologic in the hope that the onset of the response will happen at 6 months, 7 months after the initiation of treatment. So in that sense, it is good that you have a quick onset here with 0159. But what's more important is this predictability. If you, as a physician, can tell your patient, I've got something that will work on you. Actually, I don't know any other disease where we can be so sure that this will work when we talk about treatment options with our patients. So that's, I think, a big, big plus for plans to -- for the commercial use of 0159 in CIndU and hopefully all of chronic urticaria tiara.

And my final question is for the Celldex team. There's a pretty extensive list of indications you could look to target with CDX-0159 outside urticarias and PN. Could you walk us through the work your team is conducting to understand which indications are thought to be mast cell-driven to understand where you might see the most potential? And then what will be some of your criteria in choosing more indications down the line?

Yes, Kristen, this is Anthony. I'll take it first, and then I'll let Diane expand upon it as well. We do an internal analysis, looking at various weights that we would give to unmet need, clinical regulatory, acceptance of feasibility and so on and so forth. So it's an internal process. Plus, on top of that, we speak to a great number of KOLs and clinical sites to see where we would go. This is -- it's through this process that PN made it to the top of the list this time. And with these new data, we'll basically revisit the same process and talk to a great more number of KOLs and see where the next indication will come from, which we believe we'll identify in the early part of '22. Diane, do you want to add some?

Yes. So this is Diane. So yes, so as Dr. Maurer started to list, there are many, many diseases in which mast cells have been implicated either as primary drivers of the disease or somehow related to the inflammatory process. And these diseases encompass many different therapeutic areas. And as Anthony mentioned, we're doing a very in-depth ongoing process, evaluating these by many criteria, and we expect to start another study next year.

We have a question from Joe Pantginis with H.C. Wainwright.

And thank you for all the details today, especially the patient anecdotes and their impact on their lives. So 2 questions for Dr. Maurer and one for the company. So first, Dr. Maurer, just wondering if you could just give your general, or as specific as you'd like, a comment on the safety profile thus far. -- certainly looks well tolerated, but people I know have been looking at the impact on the heme parameters, but they've been keeping in within normal levels. Do you think that will be impacted with repeated dosing? And just any sort of comments from the safety profile. And my second question is, and I'll preface this by saying that I know this is a very, very early question. But when I'll go to your comment when you said earlier, this is a study with a lot of first. And you don't really have drugs for these patients. So when you look at the potential regulatory path, what do you think as of now, and again, very forward-looking could be the real primary endpoints in a pivotal study?

Okay. That's a really interesting -- well, both of them are interesting questions. I'll take the more interesting one first. That was the last one. We have, over the last years, understood CIndU a lot better. And we also understood that we need to establish robust outcomes that make these diseases measurable. And to that effect, there's now a nice threshold testing for many of the Syndus, and that includes the development of a machine called Temp test, which we use here in this trial for cholinergic urticaria, the development and use of dermographometer, which allow threshold testing in SD. There is pulse-controlled ergometry to assess thresholds and cholinergic urticaria, there is UVA, UVB visible dosing in solar urticaria and so on. So the provocation test very, very cool. First of all, patient sees immediately that exposure to the trigger and also the dose used causes the signs and symptoms. And we get an immediate idea of the disease activity. The smaller -- the trigger strength applied that suffices to produce a clinical reaction, well, the more severe the disease is. When we published our results for oma in Syndus, we were challenged by the New England Journal reviewers to be clear what it means to have a temperature threshold reduction of 4 or 8 or 12 degrees Celsius, for example. And that really prompted us because while it is clear to us as urticariologists that if you move from a threshold of 20 degrees Celsius, room temperature, to 10 degrees Celsius, snowball fight, that really makes a big difference in your daily lives, but we weren't able to show that. So we developed over the past years, disease-specific -- CIndU-specific quality of life patient-reported outcome measures like the ColdU qual, the CholU qual, the SD qual. And on top of that, we also developed disease activity scores, which is very important because you need to assess in the daily lives of patients, the activity, symptom burden, but also the avoidance behavior that patients practice. So these tools are now available. Plus, we have the urticaria control test, which is an overarching tool that allows to measure levels of control of the disease in all of chronic urticarias with an MCID, with a cutoff that allows us to distinguish between patients with poorly controlled disease and well-controlled disease, and of course, completely controlled disease. So these tools are out there now, and they're validated, they're ready to be used, and they're being used in clinical trials, including this one right now. When we talk to FDA about CIndU and also oma, they've learned a lot over the last years. Our very first conversations with them were from the omalizumab program where we also explored the feasibility of basing, the move forward on these investigator-initiated trials and we reported to them what we had. It seems to me that the combined use of these patient-reported outcome measures, including disease-specific quality of life, together with the provocation test, is probably what you want in a clinical trial with preference to the provocation testing as the primary outcome. And that is because we know, and you can look at the data from the omalizumab trial, but also from antihistamine trials done with these threshold test approaches, there's not much of a placebo response, which is great, of course, if you want to measure effect size and responder rates. So my thinking is that while it will be a first to have a drug licensed for chronic inducible urticaria, it won't be difficult. If we do the studies right, if we get the right advice, use the right outcomes, then this is something that is absolutely doable. I'll be short on the safety because I think this has been discussed. As I said, my patients are not concerned. I'm not concerned about any of what we have seen in this program so far. Now the question comes with what do we do if we maintain mast cell deficiency in patients. And of course, we're not only hitting mast cells. The few patients who've had focal spots of hair depigmentation, they don't get hair depigmentation because we depleted them of mast cells. We have other cells in the human body that express KIT, the target of CDX-0159. And so it will be interesting to see how resilient the different cell populations are to multiple dosing. My prediction is that once you allow mast cells to come back, and we still don't know when that happens, and then hit them again, they will show the same response as when you hit them the first time. So I think it will be possible to deplete these patients for long term with this approach. I'm not concerned about the hematology. We did what we did, and there was no major effect here. So I'm not concerned that when we do it again, it will look any different. And well, that's basically what there was. These observations, I don't want to digress here, but they're also interesting in themselves. We don't really understand the whitening of hair. We don't really understand governs very selective taste changes. And this could be a very interesting way to figure that out. So I do hope that we can dig a little bit deeper to establish the mechanism because that may also help us to figure out how best to dose this drug, how best to use it in clinical trials and practice.

That's fantastic. And then my quick question, pretty simplistic for the company. As you're expanding the number of indications for 0159, how are we doing on the manufacturing front and manufacturing needs?

So I'll ask Tibor to answer that question.

Joe, this is Tibor. Yes, so we're doing quite well. We're obviously manufacturing currently still at Celldex, but we're working with a number of CMOs to move this towards a Phase III commercial compliant manufacturing, but we have plenty of drug supply to manage all of our studies. And everything is going well on the CMC front.

We have a follow-up from Yatin Suneja with Guggenheim Partners.

A similar question to the previous question that was asked, so -- and I would love for both Dr. Maurer and company to address. I think Dr. Maurer already addressed it a little bit. Just trying to get a sense of level of comfort you have with the myelosuppression you saw. What is the risk for patient if you give them a second dose? Could that get exacerbated?

Sure. I'll have Margo answer that question.

So I must agree with Marcus that what we've seen has been mild trend and changes in the heme parameters, either they dip and then they stabilize. And so I don't think that they're clinically important, and we have great confidence that we've sufficiently suppressed KIT to control patient symptoms through a 12-week observation period. So dosing again, when KIT's already fully suppressed, really shouldn't lead to any further hematologic change. So we're pretty confident that what we have for hematology is about what we're going to get.

I'll agree with that. Mind you, we're looking at persistent response in terms of the clinical benefit that patients have. So this will be a long interval that patients will be treated with, and that's great, of course, in terms of the treatment burden for patients. But it's also great for all the other systems to recover. And I agree with Margo. I don't think that as for heme, or hair for that matter, we will see a different response. We may see a similar response and we will certainly figure that out moving forward, but I don't think we will see an exaggerated worse response in these other cell populations.

And there's no other questions in the queue. I'd like to turn the call back to Anthony Marucci for any closing remarks.

Thank you. I like to close by extending my thanks to all of those who made today's update possible, including Dr. Maurer, his team and patients participating in this trial. For the patients suffering with this often severe diseases, we believe these results are unprecedented and clearly demonstrate that CDX-0159 has the potential to become an important new treatment option. Thanks, everyone, for participating today, and we look forward to updating you further on our progress in the months ahead. Operator, you may now close the call.

This concludes today's conference call. Thank you for participating. You may now disconnect.