Celldex Therapeutics, Inc.

ladies and gentlemen this is the operator today's conference call will begin in two minutes until that time your lines will again be placed on hold thank you for your patience again ladies and gentlemen this is the operator today's conference call will begin in two minutes until that time your lines will again be placed on hold thank you for your patience Thank you. Thank you. Ladies and gentlemen, thank you for standing by and welcome to the Celltex Therapeutics year-end 2021 conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. please be advised that today's conference call is being recorded. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Sarah Cavanaugh. Thank you. Please go ahead.

Good afternoon, and welcome to the Celldex Therapeutics fourth quarter and full year 2021 financial results and corporate update conference call. Just to remind everyone, certain matters discussed in today's conference call and or answers that may be given to questions asked are forward-looking statements that are subject to risks and uncertainties relating to future events and or the financial future performance of the company. Actual results could differ materially from those anticipated in these forward-looking statements. The risk factors that may affect results are detailed in Celldex's most recent filings with the U.S. Securities and Exchange Commission, including our annual report on Form 10-K for the year ended December 31, 2021, which can be found on our website, celldex.com, or on sec.gov. A question and answer session will follow the formal presentation. As a reminder, the call is being recorded. Our press release and the slides that accompany today's call are posted on our website. I will now turn the call over to Anthony Marucci, CEO of Celtics Therapeutics. Please go ahead, Anthony.

Anthony Marucci Thank you, Sarah. Good afternoon, everyone, and thank you for joining us. On today's conference call, we are excited to provide a recap of our recent progress and discuss our ongoing development plans in more detail. Joining me on the call today are Dr. Tibor Keller, co-founder and chief scientific officer, Dr. Diane Young, senior vice president and chief medical officer, Dr. Margot Hicciosi, senior vice president of regulatory affairs, and Dr. Diego Alvarado, our executive director of research, are also joining us remotely from our New Haven office for Q&A. We had a very strong year in 2021 with promising clinical data across our programs and follow-on offering that further secured our balance sheet, providing us with an expected cash runway through the end of 2025. In July 2021, we reported positive data from our lead candidate, CDX0159, a unique mast cell depleting antibody. The Phase I and chronic-inducible urticaria results were presented during a late-breaking poster discussion session at the IACI Annual Congress and demonstrated that patients 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. Importantly, we validated our serum biomarker, tryptase, by demonstrating correlation with depletion of skin mass cells and with the clinical endpoints. In September of 2021, at the EADV Congress, we further bolstered these results when we reported additional data demonstrating notable improvements in symptom control and quality of life for the patients on study. In total, these data are unprecedented in this patient population and clearly demonstrate that O159 has the potential to become an important new treatment option for patients suffering from chronic inducible urticaria. In the latter part of 2021, we initiated two additional studies for CDXO159. The first, a phase one healthy volunteer study with our subcutaneous formulation And the second was the initiation of CDX0159 and perigo nodularis in a Phase 1b placebo-controlled study. Today we are pleased to report positive results from our Phase 1 subcutaneous formulation of CDX0159 in healthy volunteers. Subcutaneous administration of CDX0159 eliminated the mild infusion reactions observed in some individuals dosed with the IV formulation, and we were very pleased that none of the volunteers had injection site reactions as sometimes observed with subcutaneous formulations. The study also demonstrated favorable pharmacokinetic and pharmacodynamic properties, supporting the use of the subcutaneous formulation in our upcoming Phase II studies in CSU and Sindhu, as well as other indications moving forward. The successful development of the CDXL159 subcutaneous formulation is a key step forward in the development of this program as it offers a convenient administration route for patients and physicians. T-Ball will discuss these data in more detail later during this call. Our strong in-house development capabilities allowed us to rapidly advance this formulation and complete in-house manufacturing activities. In Q1 2022, we initiated the transfer of our current CDX 0159 manufacturing process to a contract manufacturing organization to optimize and scale up current process to support late-stage trials and to prepare for future commercialization. In further support of our Phase II readiness activities for the urcaria studies, we are pleased to report positive interim data after completing the in-life dosing portion of our six-month chronic toxicology study in non-human primates. Results from this study were fully in line with our expectations, and we believe these data strongly support our upcoming phase two trial initiations at CSU and Sindhu next quarter, and continued expansion into future indications. Tibor will also discuss these findings in more detail. In addition to our preparation for our Phase II studies in CSU and Sindhu, we are expecting more data this year from CVX0159 with data from the Phase I Multiple Ascending Dose IV Study in Chronic Spontaneous Urticaria, planned to be submitted for presentation at IACI 2022 in July. On today's call, Diane will provide updates on our pipeline programs and discuss in more detail our expansion into our fourth indication for CVX0159, eosinophilic esophagitis, or EOE. In assessing future indications for expansion, we consider multiple factors including the patient need, scientific rationale, and what other insights these indications may give us into the potential future opportunities for CVX0159. EOE is the most important type of eosinophilic gastrointestinal disease, and recent studies have suggested that mast cells may be an important driver in the disease. Given the lack of effective therapies for EOE and CVX's O159 potential as a mast cell depleting agent, we believe that EOE is an important indication and look forward to initiating this new study in the fourth quarter. At Celldex, our core focus is to mine our deep experience in antibody drug discovery to develop therapeutics for patients with devastating diseases. We seek to design and execute robust, rigorous clinical trials as efficiently as possible and in order to support regulatory approvals and provide the broadest possible access to patients who might benefit from our investigational medicines. We believe the updates to our programs outlined today and the emerging data strongly position us to execute on these future goals. With that, I will turn the call over to Tibor to go through the CDX-0159 subcutaneous formulation data results and discuss the completion of the Phase II readiness activities. Tibor?

Tibor O' Thanks, Anthony. On slide six, you can see the trial design for our randomized double-blind, placebo-controlled, Phase I subcutaneous formulation of CDX-0159 in healthy volunteers. This study evaluated single ascending doses of CDX-0159 at 50, 150, 300, and 600 milligrams administered subcutaneously to healthy volunteers who were then followed for 12 weeks. We enrolled four cohorts with eight volunteers per cohort, six active, and two placebo. On slide seven, you can see an overview of the positive results from the study. The key takeaway here is that CDX0159 subcutaneous administration demonstrated a favorable safety profile and profound tryptase suppression. A single dose resulted in rapid and sustained decreases in serum tryptase relative to placebo. O159 was well tolerated at all dose levels, and no injection site reactions were observed. On slide 8, you can see the triptase data in detail. As I just highlighted, a single dose of O159 decreased triptase in a dose-dependent manner, demonstrating profound and sustained triptase suppression, which, importantly, we have shown correlates with mast cell depletion and relief of clinical symptoms of urticaria. Slide 9 shows the serum tryptase kinetics of the sub-Q 300 milligram dose compared to previous studies with the IV 3 milligram per kilogram formulation in healthy volunteers and chronic inducible urticaria patients. I'd like to draw your attention to the fact that tryptase reduction kinetics with the sub-Q administration are rapid and comparable to the kinetics of tryptase decrease observed with the IV dosing. On slide 10, we show the circulating stem cell factor levels mirror the tryptase data with a rapid dose-dependent increase, which plateaued between three- and four-fold over baseline values, suggestive of systemic stem cell factor blockade. Again, when sub-Q dosing is compared with IV administration, we observe similar kinetics for this biomarker between the two routes of administration. Pharmacokinetic data has been completed through day 42 for the 50, 150, and 300-milligram dose cohorts and are shown on slide 11. The PK demonstrate dose-dependent exposures consistent with a subcutaneous administration. For comparison, we also show the pharmacokinetics of CDX0159 dose in healthy volunteers by IV administration. Consistent with the similar pharmacodynamic effect on tryptase and stem cell factor, we see that exposures to IV 3 mg per kg is similar to the sub-Q 300 mg flat dose. Together, the PK and PD data give us great confidence in selecting appropriate doses for our Phase II studies. A key highlight of the study, as outlined on slide 12, is that sub-Q dosing was well tolerated across all dose levels. Consistent with our IV healthy volunteer study, no pre-medications were allowed on study. We were pleased to see that there were no injection site reactions observed with sub-Q administration. As a reminder, this compares favorably to the IV administration, where we previously reported 45 to 50 percent of patients experiencing mild infusion reactions. The vast majority of volunteers treated with O159 did not report any treatment-related adverse events. The events we did see over the 12-week follow-up period were mild, almost all Grade 1, and resolved quickly, most on the same day they were observed. There were three Grade 2 events reported, one in a volunteer treated with 50 milligrams O159 that developed allergic contact dermatitis on her lips, one week after receiving blinded study treatment. The event resolved following treatment with topical creams. The other two events occurred in a second volunteer treated with 600 milligrams O159, who reported urticaria four days post-dosing and a sore in her mouth eight days after treatment. The urticaria resolved upon treatment with topical cream and antihistamine, and the sore resolved without treatment. Slide 13 outlines the mild and asymptomatic decreases in hematology parameters that were observed in the study. Presented here are the mean values over time for each of the active groups overlaid on the placebo 95% confidence interval of the mean, shown as the blue shaded region. The dotted line at the bottom displays the lower limit of normal. As you can see, the mean white blood cell and absolute neutrophil count generally fall within the 95% confidence interval for the placebo and are within the normal range for the analytes. Overall, we are very satisfied with the results from this study and are excited to provide patients with a more convenient form of drug administration that will also benefit the execution of the upcoming Phase II clinical trials. In further support of our Phase II urticaria program, we recently completed the in-life dosing portion of our six-month chronic toxicology study. This study was a standard chronic toxicology study designed to support longer-term dosing in our Phase II studies. We conducted the study in sexually mature non-human primates to allow us to also capture data on potential impact on reproductive organs. In the study, dosing was every two weeks at 10 or 75 milligrams per kilogram for six months. resulting in much higher exposure than we will use in humans. Tox studies by their nature are designed to inform about potential toxicities by exceeding the exposure expected in man. Today we are summarizing the high-level findings from the interim data report that is based on analysis at the completion of the dosing portion of the study at 26 weeks. This study will also continue to follow a subset of animals beyond clearance of the CDX0159 antibody. On slide 15, we provide an overview of these findings. The only clinically adverse finding reported was on spermatogenesis, an expected and well-understood effect of KIT inhibition. Importantly, previous studies have demonstrated full reversibility of impaired spermatogenesis upon removal of KIT inhibition. I want to emphasize there were no other clinically adverse findings or unexpected results reported in the study. Extended dosing and exposure did not further impact hematology, and these data were consistent with prior results from our 13-week study and within normal ranges for this species. We believe these data support our previously stated expectations that chronic dosing with CDX0159 will prolong but not enhance kit suppression. CDX0159 continues to demonstrate a well-tolerated safety profile, and we believe these data strongly support the company's Phase II programs and future indications. I will now turn the call over to Diane to expand on the clinical update.

Thanks, Tibor. As you can see outlined on slide 17, In the two years since we first introduced this molecule, we have made considerable progress, even with the backdrop of a global pandemic. We have advanced through phase one development, completed the critical sub-Q and chronic tox studies necessary to support the initiation of phase two clinical trials in CSU and Sindhu next quarter, and have expanded development into two additional indications, perigonodularis last year and eosinophilic esophagitis this year. As Anthony mentioned and supported by the data presented today, our Phase II CSU and CINDU trials are on track and expected to initiate later in the second quarter of this year, an important next step for this program. The chronic tox study results were exactly as we expected and planned, and with the biologic activity seen in both our CINDU study and the SubQ Healthy Volunteer study, We are confident we have identified the appropriate therapeutic doses to advance into our Phase II clinical studies. We believe that with the compelling data we've seen to date across our clinical trials and with the success of the sub-Q formulation, our future O159 studies will be very appealing to patients and their physicians. We are initiating two Phase II studies in urticaria to begin next quarter. one in chronic spontaneous urticaria, and one in chronic inducible urticaria. In the inducible study, we plan to enroll patients with the two most common forms of inducible urticaria, symptomatic dermagraphism and cold urticaria, which make up over 75% of all inducible urticaria. The CSU and CINDU studies will both be placebo-controlled, double-blinded, multi-dose studies, in 150 to 200 patients each. We are planning to evaluate doses of 75 milligrams and 150 milligrams administered every four weeks and 300 milligrams administered every eight weeks. These doses will be administered as 0.5 to 2 milliliter injection volumes, allowing for a single injection as we advance towards potential commercialization. Our Phase I IV studies in both spontaneous and inducible urticaria and prurigo nodularis continue to enroll patients. We remain on track to submit data from the CSU multi-dose study for a late-breaking presentation at the July IACI meeting, including the 0.5, 1.5, and 3 mg per kg cohorts. Our focus and priority moving forward will be on advancing later stage programs with the sub-Q formulation and exploring O159's potential across a growing broad development plan as we also complete the ongoing IV studies. With this in mind, we have amended our Phase I Paragonodularis trial to make this trial simpler for patients and physicians and support our enrollment goals. We have decreased the study population from 40 to 30 patients and will assess single doses at 1.5 and 3 milligrams per kilogram compared to placebo, following patients for 24 weeks after dosing. These changes to the PN study enable us to achieve our clinical goals in a more efficient, patient-friendly manner so we can move into subcutaneous studies. As we've discussed in the past, after reading out the CINDU data at IAACI last summer, we added two additional exploratory cohorts to increase our learnings, a 1.5 milligram per kilogram cohort in cold urticaria and a 3 milligram per kilogram cohort in cholinergic urticaria. Enrollment to both these cohorts is ongoing. We are working to expand outreach for the cholinergic cohort. We were hopeful that by including this cohort, we could learn more about cholinergic urticaria as it is less well understood than other forms of inducible urticaria. That said, it has been challenging to identify appropriate patients. In multiple cases, patients who have presented to the clinic with symptoms consistent with cholinergic urticaria have not tested positive on provocation testing and exercise spike tests. We will continue the study because we would like to add to the knowledge base in the field on this indication, but we will not have data in July as we'd originally hoped. And moving forward, we will allow it to enroll at its own pace in the background. As I said earlier, this has no impact on our future plans for inducible urticaria, where we have planned to advance in the more common forms of the disease, cold urticaria and symptomatic dermagraphism. We are also excited to expand clinical development of CDXO159 into eosinophilic esophagitis, the most common type of eosinophilic gastrointestinal disease. As you see on slide 19, EOE is a chronic inflammatory disease of the esophagus characterized by the infiltration of eosinophils. This chronic inflammation can result in trouble swallowing, chest pain, vomiting, and impaction of food in the esophagus, which is a medical emergency. One of the more interesting things we have learned as we explored this indication is that thought leaders in the field have suggested eosinophilic esophagitis may be a misnomer, and it may more aptly be called allergic esophagitis. This is where we believe CDX0159 comes into play. Several studies have suggested that MAT cells may be an important driver in the disease, And slide 20 outlines some of this evidence. Mast cells are significantly increased in the biopsies of the esophagus in patients with EOE, including the esophageal epithelium. There is also strong evidence of mast cell activation and degranulation, which is correlated with inflammation, immune infiltration, fibrosis, and pain associated with the disease. Furthermore, mast cells are associated with EOE-specific molecular signatures. Increased mast cells have also been found in biopsies of patients with histologic eosinophilic remission, but who still have persistent symptoms and endoscopic findings. Currently, there are limited treatment options for EOE. Individuals often participate in an elimination diet to identify potential food allergens that may contribute to EOE, avoid difficult to swallow foods, and undergo esophageal dilation. While not approved for EOE, proton pump inhibitors and the swallowing of topical corticosteroids are also used to address the disease. Industry sources estimate there are approximately 160,000 patients in the United States with EOE who have undergone treatment within the last 12 months, and of these, approximately 48,000 would be biologic eligible. Given the high unmet need in EOE, the compelling science that mast cells may be key drivers of esophageal inflammation, and CDX-0159's potential as a mast cell depleting agent, We believe EOE is an important indication for future study. We look forward to initiating a Phase II study using our subcutaneous formulation in EOE in the fourth quarter. We are very pleased with the progress we have made overall, and in particular with our successful efforts toward the advancement of CDX 0159 to the next stage of development. We believe CDX 0159 is a potential pipeline and a product, and 2022 should be an exciting year. Alongside CDX 0159, our oncology programs, CDX 1140 and CDX 527, continue to enroll patients, and we look forward to providing updates on these programs later in 2022. With that, I will ask Anthony to close the call.

Thank you, Diane. To summarize on slide 22, we believe the data presented today further support the unique profile of CDX 0159 and suggests a potential treatment option which could represent a significant advancement over current standard of care in the treatment of diseases with mast cell involvement. On slide 23, you can see an overview of our expected initial 2022 milestones. We ended the year of 2021 with $408 million cash supporting a cash runway through 2025. With multiple ongoing clinical trials and expected data readout this summer, we are very well positioned to execute and further advance our pipeline. Lastly, I'd like to thank all the patients and the physicians who are collaborating with us to advance treatment options in these diseases. I'd like to now open up the call for questions. Operator, if you can begin the Q&A session, please.

As a reminder, to ask a question, you will need to press star 1 on your telephone keypad. Again, that's star, then the number 1 on your telephone keypad. Please stand by while we compile the Q&A roster. Your first question comes to the line of Yatin Suneha from Guggenheim Partners. Your line is now open.

Hey, guys. Thank you for taking my question. Just a couple for me. Maybe first on the Phase 1B question. data that's coming at Iyaki. Number one, do you anticipate including any refractory, any patient that are refractory to biologic? And then with regard to your disclosure, it seems like the 4.5 milligram cohort data might not be there. Do you need data from that cohort before you hone in a dose for future study or you think the three milligram is enough to get you the full information as you think about the dosing?

Yeah, thanks, Jatin. I'll let Diane take that question.

Hi, Jatin. Yes, we have included in the study, we have allowed patients to enroll that are refractory to biologic therapies, so we expect some of those patients in the study. And in terms of the 4.5 milligram cohort, no, we don't believe that we need that data to move forward. We believe that, you know, based on the compelling clinical activity we've seen at the 3 milligram per kilogram IV and then the recent data with the sub-Q with the, you know, profound reductions of tryptase at 300 milligram that we will, you know, not need that dose to go forward.

Got it. Then maybe just one more on the sub-Q and then I'll go back in the queue. Can you just talk about the heme profile that you are seeing with SubQ, how it might be relative to the IV dosing? And with regard to the two heme parameter that you disclosed, neutrophils and white blood cell counts, did you see any patient that went below the normal range? Thanks.

Yes. So basically we see a similar, you know, very similar and consistent profile to what we've seen before. in terms of just mild decreases in heme parameters. Margot may want to comment further.

Hi, Yatin. This is Margot. As shown on slide 13, the panels are very similar to what we saw with IV and normal volunteers. We did include the shaded area, which is the 95% confidence interval on the placebos. In terms of any excursions out of the normal range, as we've said from previous studies, again in this study, the subjects who start closest to the bottom of the normal range are the ones that are most likely to see a transient excursion below and then come back. So the consistent pattern of A drop that then stabilizes and comes back with continued observation is what we've seen across normal volunteers and the patients that were dosed at 3 mg per kg in the inducible urticaria study. So it really is a very consistent pattern and doesn't look different than what we've previously seen.

Got it, got it. Thank you very much. If I can squeeze one more question. So with regard to the new indication, the EOE indication, I think you touched on a certain phenotype that are more associated with mast cell activity. Are there biomarkers that can help you find these patients or enroll these patients as you plan a Phase II? Thank you so much.

Diego may know that. Diego, do you know the biomarkers that we're looking at?

No, I don't think there's any biomarker that I know of necessarily that would predict that. I think maybe Diane can comment further on this, but we plan to just enroll from the point of view of mast cell involvement?

Yeah, so for our study we're going to, you know, for this initial study we're going to, you know, look at really what we consider a biologic eligible population that's clearly diagnosed with EOE because we really want to, you know, really understand what happens to the mast cells and then understand better what biomarkers might be used in the future.

Does that help, Yann?

Yeah, very good. Thank you so much.

Thank you.

Your next question comes to the line of Chris Howerton from Jefferies. Your line is now open.

Great. Hey, thanks so much for hosting the call and taking the questions. I guess the one for me was just maybe an easy clarification with respect to the CSU data. For the Phase 1b, I assume that's informing your Phase 2 work in that indication. Is that going to be gating before you actually start the Phase 2? Or do you already have those data and you're just not sharing it? Or I guess I was just a little confused as to how the current Phase 1b is going to inform and gate going into the Phase 2, if at all. And then the second question I had was, I guess, was there any kind of other findings with respect to gamete production, let's say with female non-human primates? Was there any observations there? And as the just sequelae to that, I guess for Diego, you know, what would be the kind of kinetics in terms of the expectations for normalization for spermatogenesis to kind of resume? Thank you.

Okay, so let's go with Diego first, since that was your last question, and then we'll work backwards. Diego?

Yeah, thanks. So obviously from the point of view of a 159, we don't know necessarily the kinetics. What we do know is that at least in mice, it takes about a month for sperm count to resume once it's been ablated. So we might expect a bit of a lag once a drug clears.

So Chris, it's Vardo. Just to point out that we need O159 to clear out of the system before you'd expect primate recovery of spermatogenesis. And so because O159 was given at such high doses, we expect it to take a good long time before the antibody gets cleared, and then we'll see sperm recovery. So it's not going to be something that occurs quickly. People might have a better understanding of what we think the time profile would be, but it'll take quite a long time to clear the primates first.

Yeah, that's a good point, Margo, and we expect to be able to inform further about the recovery from the spermatogenesis probably late this year.

Okay. And was there any observations in female gamete production?

No, so we were very pleased to see that from this study, we did not observe any effects in terms of from a histology analysis of female reproductive organs. So that certainly is very, very comforting. And we do have additional work to do on potential reproductive effects, but our data so far really supports you know, lack of any significant concern from a female reproduction point of view.

Okay. Yeah, this is Diane. So in terms of the CSU data, it's not gating. We don't need that information to, you know, to plan the study or to initiate the study.

Got it. Okay. All right. Well, I really appreciate you taking the questions. I'll hop back in the queue in case there's any follow-ups. And thanks again for taking the questions.

Thanks, Chris. Appreciate it.

Your next question comes in the line of Thomas from SVB Lyric. Your line is now open.

Hey, guys. Thanks for taking the questions, and congrats on the progress. sort of follow up on the Phase 1b CSU study and the 4.5 mg per kg dose. Understand that the data aren't going to be IACI and they're not going to be gating for the Phase 2 study, but are you still planning to enroll this cohort? And if so, when do you think we'll have visibility into that data? And then separately, when can we expect to see the initial data from the Phase 1b 1.5 mg per kg cold year to carry a cohort?

Okay, this is Diane again. So, in terms of the Phase 1b CSU, we are planning to enroll that cohort. That's really a matter of, you know, just wanting to have additional data at exposures higher than you're planning to go forward early in a drug development program. In terms of the 1.5 milligrams per kilogram dose data, we're going to enroll that, and we'll present it at a subsequent meeting when we have sufficient data. We haven't really guided a specific date.

Okay, great. And just to follow up, I guess, Tibor, on maybe your comments, can you just walk us through, I guess, the remaining reproductive tox work, both if ongoing as well as planned?

Sure. So these are standard toxicology studies that are required by and well outlined by FDA guidelines that we would look at the effect of antibody treatment through pregnancy and birth And these are called ETPND studies, and those are studies that will evaluate the effect of 0159 on fetal development and birth. Again, our expectation there is, based on what's known in the literature, is really not concerning, but of course we need to go through those studies. We also believe we will need to do some juvenile toxicology studies before we go into pediatric populations. And, of course, there's some evaluation in terms of development of reproductive organs there as well. The findings of those are not fully developed yet, but we're working with the CROs to get those done soon.

Okay. Got it. All right, guys. Thanks for taking the questions. Appreciate it.

Thanks, Tom.

Your next question comes to the line of Tom Slapsky from LifeSci Capital. Your line is now open.

Hey, good afternoon, everyone. Thanks for taking the questions. Just two quick ones for me. First, for cholinergic urticaria, I guess, is there potential to include that SINDU subtype in a registrational study? or should we mainly be focused on SD and cold urticaria as we think about potential approvals?

Hi, Sam. Yeah, this is Diane. I mean, I think potentially for the Phase III, we might include it. You know, I think, you know, right now we're focusing on, you know, the two most common forms, the ones that are best understood, which, you know, are cold and symptomatic dermagraphism and you know, we're continuing to enroll in our cohort to see if we can learn more, you know, about finding the right patient population and treating them.

Okay, got it. And then lastly, too, just outside of the ongoing reproductive preclinical studies, I guess any other key ones that are needed at this point, or are we through with both of them?

I'm sorry, Sandy. We didn't quite hear that. Can you say that again?

Yeah, I was just saying outside of the ongoing reproductive preclinical studies, I guess are you through the bulk of preclinical top studies or are there any others that we should expect updates on?

No, these are the major studies that need to be executed for support of 0159. So the current six-month chronic study is one that performs to support, you know, the chronic dosing that we plan to do with our Phase II programs going forward. So we're in good shape, yeah.

And Timor brought up the other studies that we would need to do, the juvenile indications, and we're working on those as well.

Okay, thanks.

Thanks, Sam.

Your next question comes from the line of Christian Kuska from Cantor Fitzgerald. Your line is now open.

Hi, good afternoon, everybody. Thanks for taking my questions. The first one I had is whether you had any thoughts on how the placebo arm might perform in the CSU study across the key endpoints at different times based on what we've seen from other data sets, including some findings that were reported over this weekend. And then on efficacy, getting a lot of questions specifically about what you would view as a success here, excuse me, and how much of this might be determined based on understanding the patient profiles on an individual basis, such as their previous exposure to biologics?

This is for the CSU study. Kristen?

Yes.

Yeah, so, yeah, in terms of the placebo response, you know, I think there are you know, it depends on what endpoint you're looking at and what study. There can, you know, there's anywhere from, you know, 20 to 40% in some of the endpoints we're looking at. I think, does that answer your question? Did you have something more specific?

Yeah, no, that's fine, thanks.

Okay, and then in terms of success criteria for the CSU study. You know, we've always said that we're, you know, we're expecting to see, you know, results similar to or better than, you know, what's been seen with Zolair, which, you know, in one or more dose groups, given that we're looking at several doses and reasonably small numbers of patients, but, you know, so, you know, about a 50% increase in terms of having well-controlled urticaria by the UAS7, and then hopefully having, you know, a good percentage of those be complete response.

Right. And we're also anxious to see how we would do with the recurrent patients in the study as well, Kristen.

Yeah, and we expect that the people who are recurrent after Zolair should respond as do Naive, you know, with the same way that we saw that in our Shady patients.

Okay, thank you for that. And then I know part of your strategy in choosing indications for O159 has been to understand specific disease aspects, such as itch for PN. So when you chose EOE as the fourth indication, maybe could you speak to what you're hoping to learn more broadly across the platform with this indication, as well as some future opportunities that could go beyond EOE in understanding the role of O159 in mast cells here?

Yeah, so we're very excited about EOE because of the recent data that suggests that mast cells can be a driver in the disease, as well as the unmet medical need. Another really nice thing is that as routine care in these patients, they require biopsies. So we'll be able to see really, really well what actually happens to tissue mast cells you know, in the GI tract and really understand what's going on. And, you know, that could lead us to other, you know, gastrointestinal diseases where, you know, mast cells are involved.

Got it. Thanks for taking the question.

Thanks, Kristen.

Your next question comes from the line of Joe Panchines from HC Wainwright. Your line is now open.

Hey, guys. Good afternoon. Thanks for taking the question. I guess I just want to go back in regarding the spermatogenesis observation in the non-human primates. So I guess can you – I'll do three things, clarify, expand, and even repeat a little bit of what you just said, that these non-human primates obviously are – a couple of you said are receiving very high doses. So that's part of the observation, these doses are much higher than what would be seen in the clinic. So what level of confidence do you have that this may or may not be seen once it reaches, with regard to human doses?

This is Tiwar, Joe. I'll take that question. So let me start by clarifying or expanding or repeating what we said, which was that the one single clinically adverse finding reported from our six-month chronic tox study was an impact on spermatogenesis, which we fully expected because this has been well described and studied as an effect of kit inhibition. We also discussed that prior studies that have published on antibodies that impact that block kit signaling have reported this effect in spermatogenesis both in mice as well as in non-human primates, and in both cases have reported full reversibility of that. The dose response with regards to what our expectations are is unclear. As you mentioned, we use extremely high doses when we do toxicology studies and repeated dosing, which accumulates in these animals. So that's perhaps something that we can learn in terms of as the antibody clears and we see reversibility, we might be able to make some predictions about dose levels that are relevant to you know, to impact spermatogenesis. But at this point, that would be speculation.

Sure. No, that's helpful color. Thanks, Tibor. And I guess, you know, I'd like to maybe just go to a higher level now with regard to urticaria from a macro standpoint. Obviously, you know, even over the last month or so, the field's seen a lot of additional news from other competitive products or other assets in urticaria. for treating urticaria. And I guess I'm not asking for a compare and contrast, but look, you've certainly made the case already regarding the role of mast cells as the underlying, you know, core part of the disease. So I guess I would ask my question this way. Do you feel that any of the other approaches out there may be complementary to 0159's approach?

Complementary? Or are they all competitive?

Yeah.

You know, I don't like to use the word competitive because I think just our mechanism of action is different. Where they're targeting receptors on the mast cell, we are targeting the mast cell itself. So I just think that our mechanism of action is different than the others that are out there.

Sure. No, very fair. And just to switch gears real quick, thanks for the patience, regarding 1140 and 527, Diane, you mentioned about how things are going, and hopefully get a little view on how enrollment is going overall, and how should we view your communication strategy around those two programs? Are you really gating, obviously it's data-driven, but are you gating around certain patient numbers, or overall what should we expect?

This is Timor again. Joe, I think we're, as you know, in the expansion cohorts for both of those programs, And our view is we'd like to complete enrollment into those expansion cohorts, and then we'd have something more meaningful to say about the next steps for each of those.

Understood. Thanks a lot, guys.

Thank you, Joe.

We have a follow-up from Chris Howard and from Jeffries. Your line is now open.

Hey, thanks so much for taking the follow-up. I guess one would be I just wanted to clarify, Anthony, I think you were saying that you had started a tech transfer for CDMO for 0159. Is it started or has it been completed? Or I guess how would you characterize the status of that process was just a clarification.

Yeah, it's been started and we'll complete it sometime this year. But it has been started. Work is already being done.

Got it. And then the other one is, you know, probably early, and I am sure you guys, I know what you'll say already, but I'll ask anyway, which is, you know, if you look at the volumes of your subcutaneous formulations, probably can't be self-administered. So, you know, I guess, is that correct in my estimation that that will probably be administered by some sort of medical staff? And if that's true, do you think that that matters from a commercialization perspective?

I think that long-term we are going to try to formulate it so it is self-administering, Chris. I mean, obviously, we'll try to work through that through clinical development, but we're going to start it out as being administered by a professional in the clinical trials and then work our way that upon commercialization that they would be self-administered.

Yeah. Just to add to what Anthony said, the current doses that we're planning range from 0.5 to 2 milliliters, which, you know, are, you know, within the range of what patients eventually could, you know, self-administer.

Okay. All right. Well, again, I really appreciate you taking the follow-ups, and congratulations on the progress.

Thanks, Chris. Appreciate it.

We also have a follow-up from Yatin Suneha from Guggenheim. Your line is now open.

Guys, thank you for taking the follow-up. This is on EOE, and it's more related to the mechanism of action. Can you just talk about what is the relationship or what do we know about the relationship between mast cell numbers and eosinophil numbers? Because it is our understanding that in EOS, in EOE, the clinical endpoint is actually, you know, you have to show reduction in EOS numbers. I'm just trying to get a sense of what is that relationship.

Sure, I can ask Diego to take that. Diego?

Yeah, thanks, Yad, and I appreciate the question. So there is a lot of evidence in the literature, both I think in EOE and in other disorders, in just biological studies, that eosinophils and mast cells regulate one another from couplets, and mast cells are known to secrete. One of their mediators, for example, is interleukin-5, which is known to recruit eosinophils. And we know based on preclinical studies, albeit in different eosinophilic disorders, that the precursor molecule to 159 actually significantly reduces eosinophil infiltration into the relevant tissues. So I think this is a strong rationale for believing that mast cells will influence eosinophil infiltration after the secretion of Th2 cytokines, including IL-5.

Got it. Very good. Thank you so much.

Thank you, John.

I am showing no further questions at this time. I would now like to turn the conference back to Anthony Marucci.

Thank you, Operator. And thanks, everyone, today for joining with us. We are very excited and look forward to providing future updates soon throughout the year. So have a great night and look forward to catching up soon. Thank you.

This concludes today's conference call. Thank you all for your participation. You may now disconnect.