Good day and thank you for standing by. Welcome to the CDX-one hundred and fifty nine Data Update Call. At this time, all participants are in a listen only mode. After the speakers' presentation, there will be a question and answer session. Please be advised that today's conference is being recorded.
I would now like to hand the conference over to your speaker today, Sarah Cavanagh. 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 1b study of CDX-one hundred and fifty nine in chronic inducible uticaria. With me on the call today from CellDex are Anthony Marucci, Co Founder, President and CEO Doctor. Margot Heap Chiosi, Senior Vice President of Regulatory Affairs Medical Lead on the program Doctor. Diane Young, Senior Vice President and Chief Medical Officer Doctor.
Tibor Keller, Co Founder, Executive Vice President and Chief Scientific Officer and program. We are also very pleased to welcome Doctor. Markus Maurer, Professor of Dermatology and Allergy at Charite in Berlin. He is conducting the study and will present the results alongside Margo. In the Investors section of the seldex.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 can join us today to review the positive Phase Ib chronicle inducible RECARIA clinical trial data from CDX-one hundred and fifty nine, our humanized monoclonal antibody that specifically binds the receptor tyrosine kinase kit. Today, we are discussing the evaluation of 159 in 2 of the most common forms in chronic inducible urticaria, cold urticaria and symptomatic thermographism, where the mast cell activation is the key pathogenic driver of the disease. These data were presented this past weekend by Doctor. 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 Doctor. Mao 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 159. These responses were rapid and durable with a favorable safety profile.
These data are unprecedented in this patient population and clearly demonstrate that 159 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. Margot now will provide you an overview of the results. Margot?
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 triggers, but it's 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 Doctor. Mauer and his team to conduct this study And I want to thank them and the patients on this study for their commitment to the trial. This Phase 1b study as detailed on Slide 5 is an open label clinical trial evaluating a single dose of CDX-one hundred and fifty nine in patients who are refractory to antihistamine with cold urticaria, symptomatic demographic and more recently added to the study, the cholinergic urticaria. 159 is administered to patients as add on treatment to standard of care H1 antihistamines 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 high smidgen.
They are evaluated for signs and symptoms of their disease, undergo blood draws and skin biopsies to assess TRIP case and mast cell activity and are assessed for safety and tolerability. The presentation at AIHII reported on data for the cold and symptomatic dermatographism cohort. As of June 11, 2021, the data cut date, 20 patients received a single intravenous infusion of 159 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 159. The patient population in this study clearly have high disease activity.
The patients with older to carry 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 COVID into perspective, this means that half of the patients on the study developed highs under baseline temp test between 62 and 81 degrees Fahrenheit, well within room temperature, which highlights the extreme sensitivity to temperatures below their normal body temperature. Patients with dermatographism had an average baseline Frit 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 a shirt that rubs on their skin or even comb their hair without inducing highs. Slide 6 shows the impressive response data.
We are very pleased to report that all patients experienced the 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 bradycaria experienced a complete response and 8 of the 9 patients with symptomatic dermatographism experienced a complete response. The remaining patient 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. The 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 dermatographism 7 of the 8 experienced their 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 dromatograft is in patients 57 plus days for more than 8 weeks. Both patient and physician global assessment results are consistent with the complete responses for the provocation test and reinforce the observed clinical activity. These global assessments score the patient's current disease severity on a 0 to 3 scale with 0 equal to no activity and 3 showing severe activity. Prior to 159 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 89 highlight what is really exciting science. We are particularly impressed with the marked reduction in skin mass cells that follows the suppression of serum triptase elucidating 159's mechanism of action. We found that a single 3 mgkg dose surprised skin mass cells with their survival factor, stem cell factor, leading to rapid, marked and durable suppression of serum tritase and depletion of skin mast cells as measured through serial skin biopsies. The kinetics of serum triptase and skin mast cell depletion mirrors the clinical activity and confirms serum triptase 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-one hundred and fifty nine 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 cells 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 benefits that these patients experience.
As in the HealthEast volunteer study, infusion reactions generally mild highs and itching that resolve spontaneously were observed. As we have previously discussed, a single severe infusion reaction of 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 triptase 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 observation, we are really pleased with this data. We would like to comment briefly on one patient in the study with symptomatic demographic system that also had a diagnosis of the 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 the complete response of their symptomatic dermatograph of them and notable disease improvement in their paribon nodularis after a single dose of 159. This anecdotal finding was of interest to us as we are on track to initiate a study in prurigo nodularis in the Q4 of 2021. In closing, we could not be more excited with these early results, which demonstrate the potential of 159 to be a groundbreaking new treatment option for patients with these often severe and debilitating diseases. We look forward to completing enrollment of the 3rd cohort of 10 patients with cholinergic urticaria and presenting additional data at upcoming medical meetings. I would now like to ask Doctor.
Mauer to share some of his thoughts on the data. Doctor. Mauer is one of the world's leading medical experts in urticaria and his research focuses on the physiologic and pathologic functions of mast cells. Doctor. Marrow, would you please tell us what the opportunity to utilize a mast cell depleting agent like 159 means for these patients and the implications of these data on the wider medical and scientific communities.
Marcus?
Thank you. Thank you. Well, but let me start by saying thank you for having us on this program. 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, up dose antihistamines, some of them on normalize them up, practicing incredible avoidance behavior, which adds, 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 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, controlled their life, and that makes it all the more important and remarkable in terms of what happened to them 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 so many different levels, of course, primarily for patients to finally have someone or something that can help them. But it's also, Margot said, this is a mast cell 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 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 cell deficient. This is a 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 triptase, a marker that we commonly use in clinical practice in mastocytosis and in 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 muscle. But this is the first time that a reduction, a depletion of muscle comes with making triptase 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 triptase, 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 demographics who can't wear normal clothes. They can't dress like you and me. They are in wide clothes that 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 side. 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. 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 touching 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 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 their disease goes into spontaneous remission. Let me talk a little bit before we go to the Q and 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, 1st of all, the huge clinical benefit. And 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.
Uticaria is a female disease and many of these patients dye their hair anyway. Some of them started to do that when they noticed 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 manage in 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-one hundred and fifty nine 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. 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 demographic. Well, I'd be very, very surprised if that does not work in all the other urticarias, including chronic spontaneous urticarias because just like for cold urticaria, just like for symptomatic demographic, 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 muscle 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, Doctor. Mauer. As you've just heard, these data are very encouraging and show the potential of CVX-one hundred and fifty nine to provide a real benefit to patients who desperately need treatment options for their disease. We believe these exciting early data also indicate 1 hundred and fifty nine'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 into 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 Q1 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 1 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 2 studies in both spontaneous and inducible urticaria in the first half of twenty twenty two as we have previously guided. In addition, we continue to plan to introduce the subcutaneous formulation into a healthy volunteer study in the Q3 of this year and to initiate the clinical study in prurigo NERGYOLARIS during the Q4 followed by a 4th indication in 2022. I'd like to now open the call
Our first question comes from Yatin Sunja with Guggenheim Partners. Your line is open.
Hey guys, congrats on the data and thank you for taking my questions. Just a couple for me. Could you first comment on the regulatory strategy for SINDU 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 patient, 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, Yatin. I'll have Margo answer that question.
Yes. So, Yatin, clearly, we are so excited about this data that alignment with the health authorities 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 2 studies need to be to explore a range of doses and a range of dosing intervals. And so we see the Phase 2 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 2 is to get the patient's symptoms controlled and keep them there.
And so that's the study that comes next inducible and will 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 week was enough to get patients into clinical response?
Yes. And I'll have Diego answer that question for you.
Yes, I think good morning. 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 particularly 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, I think it is very exciting to have a biomarker, both from the point of view of triptase and mast cells that really correlates with disease activity. And something that we plan to leverage in the future for dose selection.
Got it. And maybe one final question for Doctor. Mauer. Doctor. Mauer, given that the onset and the durability of clinical improvement was a little bit different between cold urticaria patient and and ST patient?
How do you or how does the cholinergic urticaria fit into the picture? Do you expect any major differences? And 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?
Thank you. Yes.
Thanks for the two 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 license 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 this disease goes into spontaneous remission, which in the inducible urticaria takes longer than in chronic spontaneous urticaria.
And chronic spontaneous urticaria on average is 5, 7 years. So we have many patients with cold urticaria who've had their disease for 10, 15, 20 years. And that's how we intend to use it. There's 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 beauty carrier will be very interesting.
We do not know much about the heterogeneity of patients and endotypes in the different chronic induced urtic areas. There must be some because when studies were done, when we did studies, for example, with omalizumab, and this is true for antihistamines, we do see responders and non responders. And that must mean that different mechanism 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, I'm making air quotes again because, of course, they still have the disease, but they no longer have the cells that bring the signs and symptoms. Well, that means that you've hit all endotypes in terms of different muscle activators, different mediators.
Now for cholinergic cuticle, 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 syndus 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 patients and like the symptomatic demographics in patients 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 dendrographism patients as in cholinergic 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 Sindhu 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, mast cell does not seem to be sufficient to drive the response anymore. And I've seen completely muscle deficient, skin muscle deficient patients where none of the microscopic fields that I looked at had any muscle cells. And that's very encouraging across all of chronic urticaria. Now I forgot your first question. What was that?
I think I answered it about the colonoscopy urticaria.
Yes, you did. Thank you so much.
Okay, sure.
Thank you, Jan.
Thank you. Our next question comes from Sam Sluski with LiSci Capital. Your line is open.
Hey, good morning, everyone. Thanks for the conference and presentation and congrats on the data. Just jumping to questions, Doctor. Bauer, to start and kind of build off what Jatin was discussing, can you put into context how the outcomes achieved with 159 compared to what's been seen with other drugs that are used during late stage development for Syndus? 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, melizumab, he's kind of off label. I know leglizumab, they want to
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, 1 in cold urticaria and 1 in chronic inducible urticaria sorry, in symptomatic demographics. Now what these two studies showed is that omalizumab as compared to placebo works. Interestingly, the 2 doses used, 150 mgs and 300 mgs, were equally effective. It also showed that there was a wide range of responses from complete non response to complete response.
And that in many of these patients, the response really fell into one of these two 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 drug, you mentioned a range of conditions for 159 to be expanded. Just looking at prurigo nodularis where selodex is developing 159, could you just comment on the extent of improvement on itch and nodule size in this patient who had overlapping PN? And then then are there other overlapping conditions seen in the study where patients responded? I think there was one patient with rhinos and conjunctivitis 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 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 experience.
Now this hasn't happened in the patient we're looking at. Plus the rationale for treating prurigo nodaris or chronic prurigo with a mast cell targeted treatment is very high. You have, I'm was going to say tons of mast cells, of course, not tons of mast cells, but markedly up regulated numbers of mast cells in these lesions. And that's 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 patients will show a similar benefit from mast cell targeted treatment with 159 as we have seen here with the chronic induced urticaria patients.
Got it. Okay. And then lastly for me, just on the infusion reaction seen in some patients, it looks like it's been generally mild. But one, can you just describe what it'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're 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 an allergy.
Chronic urticaria does not come with an increased susceptibility to develop hypersensitivity reactions. So these people are not at risk of having hypersensitivity stops patients from having infusion reactions or ejection reactions, so really systemic ones. Got it.
I guess just real quick building on that, would we expect to just need an IV for it to go down on subsequent doses? I know we've seen that with other drugs as well, biologics?
That was hard to hear. Do we expect to see that?
It also decreased with ID 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.
Got it. Thank you.
Sure.
Thank you. Our next question comes from Kristen Kewska with Cantor Fitzgerald. Your line is open.
Hi, good morning, everyone. Thanks for taking the questions and 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 in the few patients with Xolair? And Doctor. Mauer, I saw in your Q and A this morning that you did note some have failed 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, 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 cold, why they have wheals. So there is delay in 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 wheel. 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 control their disease, it's really quite amazing. They have had every antihistamine antihistamine that you can get your hands on in combination, old ones, sedating antihistamines, tetotifen, a horrible drug, some of them on chronic continuous use of steroids, so that's cortisone, some of them on cyclosporine.
Most of them have used, in addition to a high dose antihistamine, a combination of this antihistamine with the leukotriene 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, to not scratch, to not let anything touch your skin, to stay in the dark when you have sold a 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.
Thank you. 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, were there any patient reported outcomes while recognizing that you didn't I mean,
these studies are
out there, but there are also others
that say 5% to 10% 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% 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 Sindhu patient who walks into your office also has chronic spontaneous urticaria, and these patients did not.
Okay. Thanks. And I wanted to ask your thoughts on the time to onset here. I know the studies for Sindhu with Xolair involved multiple doses treated, so it's hard to make head to head comparisons. But for off label usage in 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 if 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 Zindu 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 non responders, 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 Zendoo. 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, 5, 6 months of treatment before they start to see the benefit in chronic spontaneous urticaria. And this is because 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 patients to treat for 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 159. But what's more important is this predictability. If you as a physician can tell your patient, I've got something that will work in 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 Sindhu and hopefully all of chronic urticaria.
Thank you, Doctor. Maurer. And my final question is for the seldex team. There's a pretty extensive list of indications you could look to target with CDX-one hundred and fifty nine 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? Thanks again.
Yes, Kristin, 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,
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 rate more number of KOLs and see where the next indication will come from, which we believe will identify in the early part of 'twenty two.
Diane, you want to add some?
Yes. Hi, Tush, it's Diane. So, yes, so as Doctor. Mauer started to list, there are many, many diseases in which mast cells have been implicated either as primary drivers of the disease or some 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.
Thanks all.
Thanks, Chris.
Thank you. We have a question from Joe Pantginis with H. C. Wainwright. Your line is open.
Hey, everybody. Good morning. Thanks for taking the question and thank you for all the details today, especially the patient anecdotes and their impact on their lives. So two questions for Doctor. Mauer and one for the company.
So first, Doctor. Mauer, just wondering if you could just give your general or as specific as you'd like 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 on 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 firsts and you don't really have drugs available 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 regular in a pivotal study? Thanks. Okay.
That's a really interesting 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 SIN do 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 nice threshold testing for many of the syndos.
And that includes the development of a machine called TEMTEST, which we used here in this trial for cold urticaria, the development and use of dermal graphometers, which allow threshold testing in SD. There is pulse controlled ergometry to assess thresholds in cholinergic urticaria. There is UVA, UVB, visible light dosing in solar urticaria and so on. So these provocation tests are 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 Sindhu's, 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 eutekaryologists 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, Sindhu specific quality of life patient reported outcome measures like the cold UQUAL, the COL UQUAL, the SDQUAL. 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 here, 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 Syndu and also AIMA, 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 tests 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 license for chronic induced 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 muscle cells. The few patients who've had these focal spots of hair deep pigmentation. They don't get hair deep pigmentation because we depleted them of mast cells. We have other cells in the human body that express KIT, the target of CDX-one hundred and fifty nine. 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 would be possible to deplete these patients for long term with this approach. I'm not concerned about the hematology. If 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 air. We don't really understand what 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. Thank you so much for all those comments. And then my quick question, pretty simplistic for the company is, as you're expanding the number of indications for 159, how are we doing on the manufacturing front and manufacturing needs?
So I'll ask Tibor to answer that question.
Hi, Joe. This is Tibor. Yes, so we're doing quite well. We're obviously manufacturing currently still at seldex, but we're working with a number of CMOs to move this towards a Phase 3 commercial compliance manufacturing. But we have plenty of drug supply to manage all of our studies and everything is going well on the CMC front.
Great. Thanks a lot guys.
Thanks, Tim.
Thank you. We have a follow-up from Yatin Sundar with Guggenheim Partners. Your line is open.
Hey, guys. Thank you for taking a follow-up. Similar question to the previous question that was asked. So and I would love for both Doctor. Mauer and company to address.
I think Doctor. Mauer 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, Jan, I agree with Marcus that what we've seen has been mild transient changes in the heme parameters. 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 12 week observation period. So dosing again when kits 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, so 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.
Thank you. 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'd like to close by extending my thanks to all of those who made today's update possible, including Doctor. Mauer, 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 CVX-one hundred and fifty nine 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.