Jasper Therapeutics, Inc. (JSPR) Earnings Call Transcript & Summary

Good morning, and welcome to the Jasper Therapeutics Preliminary BEACON Data webinar. [Operator Instructions]. As a reminder, this call is being recorded, and a replay will be made available on the Jasper website following the conclusion of the event. I'd now like to turn the call over to Alex Gray, Head of Investor Relations at Jasper Therapeutics. Please go ahead, Alex.

Thank you, Tara, and thank you for those listening in today. Joining us for the prepared remarks are Ronald Martell, CEO; Dr. Edwin Tucker, CMO; and Dr. Thomas B. Casale, Professor of Medicine and Pediatrics at the University of Southern Florida Morsani College of Medicine and Lead U.S. investigator for the BEACON study. Also on the line is Herb Cross, CFO, will be available during the Q&A session. Due to other commitments, Dr. Casale will not be available to participate in the Q&A. We will be presenting slides on today's call, which are available via the webinar link and posted to our Investor Relations website. During today's events, we will be making forward-looking statements based on our estimates and assumptions and our current expectations and projections about future events. All statements other than statements of historical fact made during today's call are forward-looking statements. These statements are subject to a number of risks, assumptions and uncertainties, any of which may be significant, and our actual results may differ materially and adversely from those stated or implied in any forward-looking statements. For a description of risks and factors that could affect our future financial results and business, please refer to the disclosure in the accompanying slides, our most recent Forms, 10-K and 10-Q and the reports that we may file on Form 8-K with the Securities and Exchange Commission. All our statements are made as of today, January 8, 2025, based on information currently available to us. We can give no assurance that these statements will prove to be correct, and you should not rely on any forward-looking statements as predictions of future events. We undertake no duty to update any forward-looking statements, except as required by law. I'll now hand the call over to Ronald Martell. Ron?

Good morning. I'm Ronald Martell, CEO of Jasper Therapeutics. On behalf of my colleagues at Jasper, I'd like to welcome you to our webinar to present preliminary data from our Phase Ib/IIa BEACON trial evaluating briquilimab in chronic spontaneous urticaria, or CSU. Following the press release this morning we issued earlier -- the press release we issued earlier this morning. Before handing it over to Ed and Dr. Casale, I'd like to convey our excitement to be presenting our second set of positive clinical data, demonstrating the ability of briquilimab to deliver rapid and meaningful clinical benefit to patients suffering from chronic urticaria following the spotlight readout last year. As a reminder, we designed the BEACON trial to elucidate the properties of bruquilimab and prosecute an optimal biologic dosing strategy, leveraging the unique attributes of the antibody. The preliminary BEACON data show that briquilimab led to a rapid onset of deep and durable disease control demonstrated by mean reductions in UAS7 of more than 26 points in the 240-milligram single dose and in both the 120-milligram dose cohorts. We also observed complete responses defined as UAS7 score being reduced to 0 at all dose levels of 80-milligram and above, with dose-dependent increases in the durability of responses and the proportion of patients achieving complete responses as well as controlled status. Notably, 100% of patients enrolled in the 240-milligram single-dose cohort achieved complete responses that were durable through 8 weeks post dosing. As expected, we observed dose-dependent serum tryptase reductions from baseline that were rapid and generally correlated with onset of clinical response. We were also pleased to report that a favorable safety and tolerability profile has been observed at all doses through the 240 milligrams. There have been no dose-limiting toxicities, including following repeat doses longer than 24 weeks and the rates of treatment-emergent adverse events seen in the briquilimab population was similar to placebo. Importantly, adverse events potentially related to c-Kit blockade, such as hair color changes, taste changes and neutrophil reductions were infrequent and transient and were generally limited to low-grade events, which resolved on study. We believe the low-grade nature of these events and the resolution of symptoms noted in many cases while on study, is clear demonstration of the potential for a favorable safety enabled by optimal biologic dosing. In addition, no instances of anaphylaxis and no discontinuations or dose delays due to possible on-target effects have been reported in the study. While preliminary, we believe these data both strongly support the potential of briquilimab to serve as an important treatment option in CSU as well as provide positive readthrough to the potential of briquilimab in other mast cell diseases. Following remarks from Ed and Dr. Casale, I'll review the next steps and upcoming milestones in the CSU program. I'll now turn it over to Ed. Ed?

Thank you, Ron, and good morning, everyone. Before we review the preliminary BEACON results, I'd like to quickly remind the audience of our BEACON trial design and the cohorts from which we'll present the preliminary clinical data today. BEACON is a double-blind, placebo-controlled, multi-ascending dose trial in patients with moderate to severe CSU who are intolerant or refractory to prior omalizumab or antihistamines. As such, this difficult-to-treat patient population represents one of the highest unmet medical needs. Investigative sites were located in United States and in Europe for the BEACON trial. The BEACON study tested doses ranging from 10 milligrams to 240 milligrams of briquilimab in different dosing intervals. The key assessments of the trial are safety, PK and efficacy as measured by the UAS7 and UCT. Today's data supports the potential of bruqilumab to serve as an important treatment option in CSU, including the favorable safety profile enabled by optimal biologic dosing. And IDMC reviewed the safety data prior to the next ascending dose start in the trial which enabled the expansion of the higher dose cohorts supported by the safety experience in the preceding cohorts. A higher dose of 360 milligrams single dose was added most recently and we will share that cohort data once it has matured. We plan for further clinical data releases from the BEACON trial in future scientific congresses in 2025. The next slide shows the demographics of the participants enrolled into the BEACON trial. Cohorts were generally well balanced and were representative of a population with moderate to severe CSU disease. As measured by the UAS7 and UCT baseline, age, weight and gender were typical for participants with CSU. Serum tryptases were within normal range at baseline. As noted earlier, this is a population refractory or intolerant to available treatments representing a CSU population enriched with participants most difficult to treat. Now moving to the efficacy endpoints. Briquilimab demonstrated deep reductions in UAS7 scores at doses of 120 milligrams subcutaneous and above administered every 8 weeks or 12 weeks when administered as a single dose of 240 milligrams. The reductions in UAS7 observed were clinically meaningful, with several dose regimens showing UAS7 reductions of 25 points or greater from baseline. The left panel shows the 240-milligram single dose at 8 weeks with a UAS7 reduction of 26.6. The middle panel shows the Q8 dosing schedule for the 80, 120 and 180-milligram cohorts at week 12 with a mean U.S. reduction of 9.3, 27.2 and 13.2, respectively. The right panel shows the Q12 dosing schedule for the 120-milligram and 180-milligram doses at week-16 with UAS7 reductions of 29.8 and 21.7, respectively. Moving to the next slide. This shows the dose-dependent complete responses with CRs achieved in all doses at 80 milligrams and greater. The left panel shows the 240-milligram single dose at 8 weeks with a complete response rate of 100%. The middle panel shows the Q8 dosing schedule at 80 milligrams, 120 milligrams and 180 milligrams at week-12 for participants with a complete response of 16.7%, 50% and 28.6%, respectively. On further review, we noted that in this 180-milligram Q8 dose cohort, there were 2 patients with the potential for having alternative diagnoses. These patients had deep tryptase reductions down to below levels of quantification and if censored, the CR rate in this cohort would have been 40%. Moving to the next slide -- sorry, right panel. The right panel shows the Q12 dosing schedule for the 120 and 180 milligrams at week-16. For those participants, complete response rates were 50% and 57.1%, respectively. Moving to the next slide. Participants treated with briquilimab achieved well-controlled disease, with a UAS7 of 6 or less at all dose levels, 80 milligrams and above. The left panel shows the 240-milligram single dose at week-8 with well-controlled disease in 100% of participants. The middle panel shows well controlled rates at week-12 for the 80, 120, 180-milligram QA regimens and also the 240-milligram single-dose regimen of 33%, 75%, 42.9%, 66.7%, respectively. Again, the 2 patients in the Q8 120-milligram dose who appear to be nonresponders and had deep reductions in their serum tryptase, if censored, would yield a well-controlled rate of 60% in the 180-milligram dose cohort. The right panel shows the Q12 dosing schedule for the 120 and 180 milligrams at week-16 for the participants in those 2 dose cohorts with well-controlled disease at 75% and 57.1%, respectively. When we combine the therapeutic doses of 120, 180 and 240, in an aggregate, 4 weeks post second dose for the serial dosing and after 4 weeks of the 240 milligrams, we see a combined effect of 52% for complete response and 64% for a well-controlled disease. Moving to the next slide. This shows the durability of the 240-milligram dose through 12 weeks. 100% complete response was achieved by week-2, was maintained through week-8. Well-controlled disease was achieved as early as week-1 with 66% maintaining disease through week-12. This slide shows substantial UAS7 reductions over time for the 120 and 180-milligram Q8 and 240 single-dose regimens. Onset of UAS7 reductions was observed as early as week-1 across all those levels. Subsequent doses drove deeper reductions in UAS7, including all patients reaching UAS7 of 0 in the 120-milligram Q8 cohort. The 120 Q12 and the 180 Q12-week cohort showed similar patterns as of Q8-week cohorts through 8 weeks. The next slide shows the reduction in serum tryptase in relation to briquilimab administration. Serum tryptase been a marker of mast cell biology showed rapid decline after dosing, consistent with the rapid clinical responses seen in the UAS scores after dosing with briquilimab. In these analyses, tryptase levels below levels of quantification were imputed to half of the LLOQ value. There was a clear dose response for both tryptase reductions and the durability of those tryptase reductions. Of note, tryptase levels below the level of quantification were reported at week-1 in 6 out of 7 participants, 86% in the 180-milligram Q8W cohort. All patients in the 240-milligram single-dose cohort reached the lower limit of quantification at week-1 and stayed below that level through 4 weeks with deep suppression through 8 weeks. Moving to the preliminary PK results. We see an early Cmax consistent with the rapid clinical responses and serum tryptase reductions described earlier. Our PK results are consistent with prior briquilimab trials, including our healthy volunteer studies. At the 240-milligram dose, we see the Tmax is 4 to 7 days, and the approximate half-life of the drug is 9 days. Based on initial PK modeling, no accumulation is anticipated for a 240-milligram Q8-week dosing schedule. Preliminary data indicate a 34% incidence of antidrug antibodies, and these had no clinically meaningful effect on briquilimab PK in CSU patients. Now moving to safety. Briquilimab was well tolerated and demonstrated a favorable safety profile through doses of 240 milligrams. These data include all safety follow-up for cohorts 1 through 6, representing greater than 24 weeks of exposure for the 10 through 180-milligram doses and 12 weeks with the 240-milligram doses as of the data cut of 31st of December 2024. We continue to accumulate additional safety data at higher doses, and we'll report these at a later time. As the table shows, there was no dose-limiting toxicities reported. Treatment-emergent adverse events were of a similar rate in both briquilimab and the placebo populations. There was a single serious treatment emergent adverse event, which was a CoFAR grade 2 hypersensitivity reaction, which led to the sole discontinuation which is shown in the table. There was a single grade 3 event of neutropenia, which was deemed by the investigator to be unrelated to briquilimab due to the patient having a prior history of idiopathic neutropenia and thrombocytopenia. This slide reflects the safety observations possibly related to c-Kit blockade which were infrequent and generally limited to low-grade events. The majority of events resolved during repeat doses and non-resulted in discontinuations or dose delays. For hair color change, reporting rates observed was similar in the active and the placebo groups. There were no reports of skin discoloration in the active arm for more than 24 weeks of follow-up in multiple cohorts. Mild low-grade transient taste change and hypogeusia occurred in 6 participants following first dose, 4 of which resolved prior to a subsequent dose, one of whom reported recurrence at the second dose which also resolved. The median time to resolution of these events was 31 days. Mild taste change was described as a reduction of salt, bitter, or umami taste. Neutrophil reductions or neutropenia as reported by the investigators are shown in the table. One grade 3 neutropenia was observed deemed by the investigator not to be treatment related as described earlier. The remaining events were all grade 1 and resolved prior to subsequent dosing with no association of these events with fever nor infection. This slide shows the observed neutrophil counts to week-16 for 120-milligram Q8 week, the 180Q 8-week and the 240 single-dose cohorts. As you can see, there is a predictable reduction observed which did not deepen on serial dosing and the mean values remain within the normal limits in all cohorts. More importantly, one can see the neutrophil count recoveries in the weeks prior to next dose. In summary, Preliminary BEACON study results demonstrate that briquilimab achieved rapid, deep and durable responses in moderate to severe CSU patients in 5 dosing regimens presented today. It is remarkable that these results are in a population that is refractory to all approved CSU treatments, including omalizumab. In terms of efficacy, briquilimab administered subcutaneously demonstrated rapid onset of effect with clinical responses as early as one week post dose. Multiple dosing regimens showed mean UAS decreases of more than 25 points with responses as deep as a 29-point reduction. Complete responses were seen in all dose cohorts at 80 milligrams and higher with 100% CRs in the 240-milligram cohort occurring by week-2 and durable to 8 weeks. Importantly, repeat dosing showed deepening clinical responses across multiple dose cohorts. Rapid, dose-dependent tryptase reductions correlated with early onset of clinical response with a reduction to the lower limit of quantification observed in multiple dose cohorts. Briquilimab was safe and well tolerated in the study and adverse events potentially related to c-Kit were mild, transient, low in frequency and did not result in any dose delays or discontinuations. A single discontinuation due to an adverse event was observed. The deep and durable efficacy and favorable safety data collected to date support the commencement of a registrational program in CSU expected to start in 2025. These data, along with additional data from the BEACON study will complete optimal biologic dose selection. Data to support the final dose selection for the registrational program will be generated in the ongoing 240 and 360 single-dose cohorts which we will be expanding with the addition of 2 new Beacon cohorts evaluating 240-milligram Q8-week regimen and a cohort which will examine the 240-milligram induction dose followed by a 180-milligram Q8 dosing regimen, and also the BEACON and SPOTLIGHT Open-Label Extension study enrolling patients at the 180-milligram Q8 dosing regimen. We look forward to commencing our registrational program. Before concluding, I would like to thank the investigators and patients that participated in the BEACON study along with their families and caregivers. It is now my pleasure to hand over to Professor Tom Casale, Professor of Medicine and Pediatrics at the University of South Florida, our lead PI in the U.S. for the BEACON study. Thank you.

Well, thank you, Ed, for that presentation on the initial results from the BEACON study. It's a very exciting study [indiscernible] for patients with moderate to severe chronic spontaneous urticaria. Why is it important that we need treatment? Well, we need treatments because this is a disease that causes a very significant impairment on quality of life. It produces hives and itchiness that take patients from everyday activities, takes patients away from being able to sleep at night and in some cases, even affects their relationships, their ability to work, to go to school and interact with others. You can only imagine how embarrassing it might be if you've had hives on your body and you're trying to go out and socialize or go to work or school. And because of that, there's a number of patients that have not only this impairment of quality of life but associated mental health issues, including depression and a higher risk of suicide, which fortunately can be modified by treatments. We know that there's about 1.4 million patients in the United States, Germany, France, Italy, Spain and the U.K. that have moderate to severe chronic spontaneous urticaria. And we also know that about half of these patients do not respond well to standard treatment with either licensed doses or up to 4x the license doses of antihistamines. We do have another biologic anti-IgE molecule. That has been a significant breakthrough for a number of patients. However, there are many patients that still don't respond, that still have impairment in their quality of life. So having another therapeutic option, I think, is extremely important. Can I have the next slide? And then thinking about this disease, we mentioned that not everybody does respond to omalizumab. And as Ed pointed out, the patients enrolled in these studies were actually failures, could not respond well to either high doses of antihistamines or omalizumab with significant improvement of their hives. What causes hives? Well, what causes hives are mast cells. Mast cells present in the body are degranulated or release their mediators to a number of different factors, some of which we're just beginning to learn about in the pathogenesis of urticaria. Nonetheless, once the mast cell fires and releases chemicals and mediators like histamine, and that's why antihistamines do work in some patients, but also leukotrienes, prostaglandins and a number of cytokines that continually drive this inflammation and itchiness, that's a real problem. So briquilimab blocks c-Kit signaling, which is critical for mast cells to continue a viable path in inducing urticaria. Briquilimab may lead to depletion of mast cells. And of course, if you get rid of that target cell that releases the mediators and chemicals and causes individuals to have symptoms, you can effectively treat patients with urticaria regardless of the cause or regardless of the particular trigger that might make them worse. So the preliminary BEACON efficacy results shows a very large and clinically meaningful decline in UAS7 score. UAS7 is a measure of the severity of urticaria and when you look at the response in the BEACON study, you could see a very dramatic and rapid decrease in urticaria scores. And very importantly, for those of us that treat urticaria is a high percentage of patients either have complete remission or complete response or they have a reduction in urticaria symptoms that is considered to be under reasonable control. So what does that mean? That means that, that patient no longer has the signs and symptoms of urticaria that can affect their daily lives and impair them in doing daily activities and sleep. So important to that is that this drug also appears to work fairly rapidly. So if you have a patient that has urticaria, and they come to see you in the clinic, they're miserable. And what they want is they want relief, but they want it now. They wanted it yesterday. So having a treatment that not only is very highly effective, but rapidly effective and works in patients that did not respond to our currently FDA and EMA-approved therapies for urticaria, that's a significant plus. Now as in any disease state, you're always -- when you see a patient thinking about what's best for that patient in regards to picking the best therapy but also balancing that with any potential adverse consequences from that therapy. And the preliminary BEACON safety results show a very low incidence of adverse events and these adverse events were nothing that were of concern. That is, there was no significant or serious adverse events. So in summary, it appears that briquilimab could be the next important new therapy for the management of this very significant disease. And it's clear to me that it's an exciting time to be able to trial this drug to lead to, hopefully, approval for the 1 million-plus patients that we manage globally with chronic spontaneous urticaria. So thank you again for allowing me to give my perspective, and I'm going to turn it back over to Ron now.

Thank you, Dr. Casale. As I noted earlier, we are extremely encouraged by the preliminary results of the BEACON study in CSU. Rapid, deep and durable efficacy was observed in the study, including disease control as early as one week following the initial dose, complete responses at 12 weeks in doses as low as 80 milligrams and durable complete responses out to 8 weeks achieved in 100% of the patients in the 240-milligram single-dose cohort. The favorable safety profile also underscores the potential of an optimal biologic dosing strategy to allow for the recovery of other c-Kit expressing cells beyond mast cells. Based on these data, we plan to commence a registrational program in the second half of 2025 with a Phase IIb portion to be -- to finalize dose selection for the Phase III studies. The data collected to date support advancing a 240-milligram dose into the registrational program and ultimately, doses and dosing regimens that we will advance into the program will be further informed by the data from the Open Label Extension study enrolling BEACON patients at 180-milligram Q8-week dose level as well as the data from the 3 BEACON cohorts yet to read out, the 360-milligram single-dose cohort in addition to the planned cohorts evaluating 240-milligram Q8 weekly and 180-milligram weekly after a 240-milligram induction dose. Results of these cohorts are expected by midyear 2025 and will support a well-informed, data-driven decision and consultation with regulatory authorities regarding which doses and regimens to bring forward. Beyond CSU, we believe these data support the potential of briquilimab to serve as an important treatment option in a large number of mast cell-driven diseases with significant unmet medical need, impacting tens of millions of patients. In addition to our programs in CSU and CIndU, Jasper is currently conducting a clinical study in patients with asthma, where we believe briquilimab could have impacted across respiratory diseases driven by mast cells. Beyond our ongoing studies, we believe briquilimab has franchise potential in additional mast cell diseases, including food allergy and other dermatological, respiratory and gastrointestinal diseases. Finally, I will briefly review our upcoming milestones before opening up for Q&A. As noted, we are planning to report data from all cohorts in the BEACON trial as well as the SPOTLIGHT trial by midyear, and we expect to commence a pivotal program in CSU in 2025. We look forward to presenting additional data from the BEACON study at AAAAI in February. We are currently enrolling patients in the ETESIAN challenge study evaluating briquilimab in allergic asthma, and we expect to report initial data from the study in the second half of the year. Before opening the line for questions, I'd like to note that due to other commitments, Dr. Casale is unable to join for Q&A. Operator, could you please open the line?

Great. Thank you, Ron. So at this time, we'll be conducting a question-and-answer session with our speakers. Please hold for a brief moment while we poll for questions. So our first question comes from Yaron Werber at Cowen.

Great. This is really useful. So maybe just a couple of questions from me. As you think about doses from hereon as you're going to wrap up the dosing that you're doing, it sounds like 240 and above is going to be the Q8-week dose, and you're still going to look at the 180 mg Q8-week with the 240 loading dose. When -- how many different -- how many doses are you planning on taking into the Phase IIb? And how long would it take to do that upfront sort of dose finding before you start the Phase III? And then maybe the second question, just that Grade 2 hypersensitivity. Can you give us any more information about the patient? Did that patient stay outpatient the whole time? How fast did it resolve? Any information you can give would be useful?

Yaron, thank you for your questions. So before I turn it over to Ed, yes, the 240 will certainly be a backbone in the registrational study. The question will be -- is that 240 Q8 or 240 followed by 180, the data that we'll be generating this year will inform that. We would anticipate that we'd likely have 2 doses in that Phase IIb portion of the registrational program and the data that we're generating could inform that as well or will inform that. I think one of the interesting questions is also the 180 Q8 as Ed noted earlier. In fact, we had really robust data from the 180 Q8 week, but we'll also be evaluating the 240 followed by the 180. But again, our objective here is to not just optimize this drug for the efficacy, but it's optimizing for both safety and efficacy. And I think to your last point, from a timing standpoint, that if we initiate this Phase IIb portion of the study in the second half of this year, it still would likely put us only 12-ish months behind in this arena given that we would then only be taking one-dose regimen forward into the Phase III portion of the registrational study. Ed, I'll turn it over to you.

Yes. Thanks, Ron. Thanks, Yaron, for the question. Yes, so I think that what the BEACON provides is a great deal of clinical data at various different doses and dosing regimens. And so that will inform, as Ron mentioned, the potential doses that we take through into the Phase IIb. We also elaborated on our -- both our dose expansions and also the additional dose cohorts. So I think that we'll have a rich data set to inform the Phase IIb. And the expectation is that we'll take a single dosing regimen into our Phase III study. With regards to your second question, Yaron, the hypersensitivity case was a CoFAR grade 2. We use CoFAR which is a consortium for food allergy research as our grading system for hypersensitivity cases. And that was a grade 2 because it involved a single organ system which was essentially skin manifestations. Those occurred after first dose and occurred about 3 to 4 hours after administration. The patient was observed and made a full recovery.

Our next question comes from Gavin Clark-Gartner at Evercore.

First, just on safety. How did the safety look at each dose level, specifically on neutropenia? And what is the rationale to not break out the safety table by dose level?

Yes. Thanks, Gavin. Yes, I think that we're very pleased with our safety profile. And as you saw, the numbers are quite small and so trying to infer any sort of dose relationship with small numbers is very, very challenging at this stage. So we do not see a clear dose concern or an increase in adverse events as we ascend the doses. We'll continue to observe those in our ongoing and future trials. And with regards to the neutrophils, could you repeat the question on, please, Gavin?

I just wondering how the neutropenia broke out by dose level?

Yes. So we saw neutrophil reductions in a number of the cohorts, including cohort 5, which was the idiopathic neutropenia case, which we presented in the table. We also had a single patient in the cohort 6, that a 240 milligrams. That was a grade 1, and their value was 1,666, so just under the lower limit normal. It was transient and recovered on next assessment.

Got it. That's helpful. And just thinking ahead to the full BEACON study data, which I believe you said you'll be presenting midyear, can you just clarify how many additional patients will be included at the 240 and 360 doses, but I think more importantly, how large are those 2 additional cohorts that you're adding?

Yes. Thanks again, Gavin. So the additional cohorts, the 240 Q8 and the 240 induction followed by 180 Q8, we'll be adding 4 additional patients, randomized 3 to 1 in the same convention in our BEACON trial. That adds an additional 8 in the -- sorry, 8 in each of those cohorts of 16 patients. We're also expanding the single-dose cohorts by the addition of 4 patients in each of those dose cohorts as well. When that data is available, we'll be presenting later in the year.

Our next question comes from Greg Renza at RBC.

Thanks for the detailed presentation this morning and the data. Ron, just circling back to dosing and the go-forward as you expand the trial. As you've discussed, certainly, the 240 mg and the induction as well as the Q8W. Just curious, have you given any thought of exploring maybe more frequent dosing perhaps with 120 or 180 every 4 weeks, maybe even after higher induction doses? Just walk us through the implications of tweaking the frequency a little bit.

Sure. Well, certainly, again, we are very pleased by what we observed in the 240 with 100% complete response at week-8 and durability of the well-controlled through week-12 in 2 of the 3 patients from that cohort, combined with the safety profile as Ed stated. At that 240 dose level, there was only one mild and transient neutropenia and as you saw on the neutrophil graph, the neutrophils all recovered before 8 weeks. So it gives us real confidence in our ability to dose 240 as a Q8-week dose schedule. And I think then that combined with the data that you observed in the longitudinal chart with the 120 dose that even dosing that at either Q8 weeks or Q12, we observed a deepening response on each subsequent dose at the 120 level. And if you were to go back and to look at that chart, those patients had the durability of their response through at least the first 4 weeks or 6 weeks. So the 120 certainly could be a 4- to 6-week dose regimen as well. So -- and we think also if you remember back to the SPOTLIGHT study and what we observed in the SPOTLIGHT study that we had complete responses in SPOTLIGHT at the 120-milligram dose level also that were durable through 6 weeks in the SPOTLIGHT study. So thereby confirming that the 120 dose is absolutely a viable dose at a 4- to 6-week dosing schedule. I think once we conclude the dosing of 240 as a Q8 week and a 240 induction followed by the 180, that will really inform us about what a subsequent dose might look like here.

Great. That's helpful. And then maybe just back on to the safety side, and it was helpful to hear, Mr. Casale's view on the balance, and maybe for Ed, just double clicking a bit on the taste effect, how inhibiting do you think that is as you get up to 240, maybe just double-click a bit on what you saw in these 6 patients and as you pointed to that resolution, how impactful is that the 30-day market that you identified with those 4 patients?

Yes good to hear from you. I think with regards to the taste changes, not unexpected, we did see that in our healthy volunteers at the highest doses. And what we saw in the BEACON study was transient, very mild effects, salt and umami in particular. And patients had a transient event which recovered before dosing and no discontinuations. So these patients can really stay on drug, it does not appear to be a tolerability issue and I think that we look forward to looking at subsequent doses and also higher doses to see if we still see that signal. So we think this is very manageable as Professor Casale mentioned, and we do not feel that this will impact the experience of the patients.

Greg, I think it's also important to note as it relates to the hypogeusia is that this taste change, it's not, let's say, relevant like the [Paxlovid]. So these patients are not aware on a day-to-day basis, if you will, they're not walking around with a certain taste in their mouth. It's a reduction in that taste. And patients really only noticed it when questioned on this. So we'll keep an eye on this moving forward.

Our next question comes from Ben Burnett of Stifel.

I guess first, just a high-level question regarding sort of the competitive landscape. As you look at these data, it feels like there's going to be a fair bit of further exploration with the 240 mg dose going forward, but as you look at these data, what are you seeing is emerging as sort of the key differentiating features for briquilimab relative to landscape of therapies that are out there?

Certainly. So from an efficacy standpoint, these efficacy data stand up to those comparable to the only other antibody in the space, which is superior to all of the other drugs that have been in development and have really set the standard for efficacy. So these are comparable and potentially better. I think that the other important piece here is the attributes of briquilimab and the potency, the Cmax, the time to Cmax and the half-life of the drug lead us to be able to optimize it for both safety and efficacy where the other antibody that's in development has really just been optimized for efficacy. And we think we have an opportunity to not only have a good but potentially best-in-class drug here.

Yes. And I would also add as well. We'll take a look holistically at our efficacy, safety and also dosing schedules for convenience for patients. What I mentioned in the presentation was that this is an over experience. These patients are refractory to all available and approved therapies. So we feel that the -- both the safety and efficacy in patients who have essentially failed all available therapies is a huge plus for briquilimab. And it bodes very well for a broader population of patients, not only those that are oma experience and failed oma patients, but also a broader population of patients as well who are oma naive, and we like to explore that in our registrational program.

Okay. That's great. And I was wondering if you could also speak to some of the variability in the efficacy data that you're seeing. It looks like you're seeing a pretty clear dose response on tryptase. But on other metrics, the 120 mg arm outperform the 180 mg arm, and you touched on this on a call but any more color you can provide here? I mean, I guess, is this just noise given the tryptase data?

Yes. Thanks, Ben. I alluded to this in my presentation that we did see, I think, fantastic dose responses from a biology perspective, and we also looked at our PK. So everything behaved, but we saw 2 patients that potentially have an alternative diagnosis. And in small numbers in these cohorts, it can significantly impact the rates as we show for well-controlled and complete responses. So I laid in some comments around the censoring of those 2 patients because actually, I think, probably at least 2 of those patients may have an alternative diagnosis and that potentially could be an urticarial vasculitis patients or 2. So we're going to take a look a little bit more deeply at this, but I think that's why it skewed the 180 a little bit. And we'll have further 180-milligram experience in the ongoing trials, but also all patients in the BEACON study have the opportunity to roll over into the Open-Label Extension with that 180-milligram Q8. So we'll get a lot more data in there to show that data for the future.

Our next question comes from Pete Stavropoulos at Cantor Fitzgerald.

I believe that the skin biopsies were optimal. I'd be curious if you have sufficient samples across the dosing cohorts to sort of determine the depth of mast cell depletion and population [indiscernible] so that can be tied back to clinical response. And have you been -- have you seen that data to help determine the new dosing cohorts -- with the new dosing cohorts be clinical observations?

We did achieve consents. These patients volunteered for skin biopsies. We have not processed that. As you can mention, this is the preliminary data. So we'll look forward to processing that data and then present that at a later conference.

And the 2 patients that were on 180 milligrams that may be misdiagnosed, did you have skin biopsies from them by some chance to help determine?

We don't know that at the moment, but we'll certainly be following up on that.

Okay. And one question on the Phase IIb which is a little bit more detail about size duration and would you be waiting for a 52-week endpoint to start Phase III or 12-week time point? And will you be focusing on Xolair experience patients or [indiscernible]?

Yes. Thanks, Pete. I think from a Phase II study design, we'll clearly be in dialogue with the regulatory agencies. But our go-to here would be a Phase II adaptive design where we would assess doses and dosing regimens in that trial and then move a dose into our Phase III program.

We would look to enroll both oma naive and oma experienced patients in that study.

Our next question comes from Jay Olson at Oppenheimer.

Congrats on the results and thanks for providing this update. Can you talk about the placebo response observed in the BEACON study, especially in the Xolair refractory patient group? It seems like the placebo response also may have deepened over time. So are there any strategies you may pursue to mitigate the potential placebo response in your registrational trial? And then I have a follow-on question if I could.

Yes, we did not adjust our results for rescue medications. Certainly, the placebo cohorts through the study did receive additional rescue medications as you could anticipate. And so I think we can really interpret the improvement in the placebo as a result of the initiation of the rescue meds in the placebo cohorts.

Okay. Great. And then can you elaborate on other potential indications that you'd like to pursue with briquilimab, especially as you optimize the profile in CSU? What are you seeing that makes you most excited about some of the other indications, you mentioned food allergy, other derm and respiratory mast cells-driven diseases?

So yes, we're very encouraged by these data at multiple dose levels here. So I think that as we think about additional indications, the first one would potentially be in asthma, broader patient populations in asthma and should asthma be successful, then you might imagine COPD being a viable option as well. And given the safety profile that we observed here and what we think we can do with an optimum biologic dosing and giving the other c-Kit presenting cells a drug-free interval that we think that, that broadens our opportunity to go after additional diseases like maybe food allergies or diseases like that as well.

Our next question comes from Matthew Phipps at William Blair.

I was just wondering if you could help me understand the N or the kind of sample size between Slide 7 and 8, there's a couple -- just a little bit difference in particular like the 120 and 180 mg groups. I know Edwin you mentioned 2 patients in the 180 mg Q8 maybe not being true CSU patients. Is that the only difference between the 5 and 7 and the kind of the N there? Or is there some something else?

Thanks, Matt. No, we presented the data, including those 2 patients who I think probably have alternative diagnosis. With regards to the differences in the Ns, that represents missing data that was not available for this presentation. And so we took a conservative invitation for missing data, which is the last observation carry forward. And so that accounts for the differences in the different numbers on the cohorts.

And similarly, for that last observation carry forward invitation, I mean, you also had a patient who discontinued, sounds like fairly early at the 180 mg dose, that kind of negatively impacted, I guess, this number? Or was that patient excluded?

No, that patient is included and yes, again, we are conservative and transparent in how we present the data. So yes, thank you for raising that one.

Okay. And last question, I guess, I understand small patient numbers of the 240 mg group, but can you give us any sense of how many of those 3 patients had hair color change? And just the concern being that -- I mean, obviously, this level had great efficacy, but if you're redosing at that level, maybe you get accumulation of kind of the on-target AEs over time. So can you give us any sense of kind of the on-target AEs at the 240 mg level? I know you already touched on neutropenia, but some of the others?

Yes. Thanks, Matt. We've not seen any high color change in the 240-milligram cohort.

Our next question comes from Justin Zelin at BTIG.

I wanted to ask about the Grade 3 neutropenia event, if you could give us a little bit more color on that patient and how it is deemed unrelated and whether a patient with a similar background would be included in the study moving forward?

Yes. Thanks, Justin. Yes, this patient came into the study, met all the inclusion, exclusion criteria. Our entry criteria for neutrophils is 2,000. So this patient came into the study just slightly above that. And then we noted this grade 3 adverse event with a patient that had a neutrophil counts of about 980, which obviously, we inquired further to the investigator. On deeper look of the patient's prior history, he had a 2- to 3-year history of low normal neutrophil counts with no other clinical sequelae. This was labeled by the [PI] as idiopathic neutropenia and thrombocytopenia. And so the patient has now received several doses and has not had any associated fevers nor infections from their original grade 3 neutropenia and continue in the study without sequelae.

Understood. And maybe just any efforts to mitigate the differential diagnosis during screening moving forward? If you have any strategies to ensure that the patients have urticaria?

Yes. I mean, it's certainly a challenge to ensuring that all patients including in clinical study, our target population. Now we are subject to small numbers in these cohorts. And so 1 or 2 patients can certainly have a dramatic effect on your study. As we move through into our registrational program, those studies will be much larger. And so can accommodate single and small numbers of patients who may not actually have the appropriate diagnosis. Sometimes this happens when we talk to our KOLs that diagnosis can be -- misdiagnosis for CSU, it really happens. But in a patient population that is refractory to omalizumab, I think we've probably enriched for that potential to occur in our study. In the future studies, we'll continue with our inclusion/exclusion criteria, and I think we can maintain a population of CSU patients that is representative of the broad population in the community.

Our next question comes from Emily Bodnar at H.C. Wainwright.

I guess maybe if you could just add some expectations for the -- what you would be hoping to see with the new 240 mg doses to kind of decide which dose to move forward with?

Yes. Thanks, Emily. I think as a clinician in development, we always want more data. And I think that what we have today and what we've shown could potentially move us into the registrational program but having additional data informs our final dose selections into that Phase IIb. And as I mentioned earlier, the potential for an adapted design moving to Phase III. So I think the more data we have, the happier I'll be. But certainly, we feel that with the data we have in hand today from an efficacy and safety perspective, we're certainly informed around the attributes of briquilimab and how it delivers efficacy and maintains the safety profile in patients with CSU.

I think the interesting question, Emily, is we're 100% complete response through 8 weeks with tryptase as you saw below the lower limit of quantification with that dose with no significant impact to the neutrophils. And as Ed pointed out earlier, we didn't see any graying in that population and one grade 1 neutropenia with a very minimal drop in their neutrophils. So that's really encouraging that if we dose 240 on a Q8-week basis, could we, in fact, enhance the efficacy without exacerbating the safety from what's been seen with the other antibody in this space.

Our next question comes from Silvan Tuerkcan at JMP Securities.

Maybe if you can walk me through the details of the tryptase, serum tryptase reductions on Slide 12. I've noticed that the 120-milligram and the 180-milligram is pooled, does that pool me in 8 weeks and 12-week regimen or not, if you help me square that up? And if you can maybe comment on how 12-week would look versus 8 weeks? And then I have a follow-up.

Yes. Thanks, Silvan. Yes, we pulled the 120s and the 180s because essentially, it's a first dose presentation for those 2 cohorts which increases the N for those 2 cohorts. And the redosing, one would anticipate to see significant reductions in tryptase on redosing as well. With regards to separating out the 12-week dosing regimen, we still see rapid reduction in tryptase on first dose, and we anticipate seeing rapid reduction on second dose with tryptase reductions down to LLOQ. We simply presented today the 8 weeks to show the rapid onset in all those cohorts, and we combine those 2 to give a bit more N.

Yes, that makes perfect sense. And then if you help me understand on the previous slide, Slide 11, we have the UAS7 scores, and maybe that ties into the previous question. But the -- you mentioned that the 2 patients that were potentially misdiagnosed in the 180-milligram dose cohort, they certainly may have had an impact on complete response and well managed. But here, it looks like even the UAS7 score 180 underperforms 120. If you can just help us understand how those 2 lines look like in terms of noise or what you're thinking around and if there's a real difference between the 2 or not?

Yes. Thanks, Silvan. I think -- you're absolutely right. I think when we conducted a sensitivity analysis on that Slide 11 and certainly, when you remove the 2 responders -- 2 nonresponders, the lines dropped precipitously in the 180-milligram line which we're showing here in green on Slide 11. So we're assured that there is a clear signal with the 180 and a dose response through 80, through the 240-milligram cohort.

Our next question comes from Etzer Darout at BMO.

I just was curious as to sort of a clarification on the 2 patients with the alternative diagnosis, was that specifically at the Q8W and just trying to understand sort of the exposure efficacy relationship at the Q12W for the 180 mg dose, if you could just clarify that for me, Ed?

Yes. Thanks, Etzer. Yes, we've communicated the 2 nonresponders in the Q8 week, 180-milligram cohorts, as an example of really trying to elucidate why the 180-milligram showed deep clinical responses in some patients and then others did not. So that sort of raised our suspicions that we may have 1 or 2 patients in there. So when we went back and looked at the past medical histories and the preceding information on these patients, they probably don't have the profile of a typical CSU patients. And so when we pull that data out in our sensitivity analysis, it was very clear that they had a very negative influence on the results for the 180-milligram Q8-week cohort.

Got it. And then the Q12W, any impact there on sort of -- any sort of alternative diagnosis. I'm just trying to understand that exposure efficacy? Again, it seems with the 120 outperforming 180 and if there were sort of any commentary you could make around the Q12W cohort of patients?

Yes. Again, I think we're hostage to small Ns and certainly, we'll be taking a look at the 180 Q12-week similarly for ensuring diagnosis. As I mentioned earlier, this is an enriched population of patients who are refractory to approved therapies and so we potentially have brought patients in who potentially may have been misdiagnosed. That's certainly something which we discussed with all of our KOLs and that was certainly something that person pointed to immediately on seeing the 180 data, particularly when we see the biological effects with the tryptase going down to below LLOQ.

So this concludes our Q&A session for today. I'll now turn it back over to Ron for closing remarks.

We'd like to thank everyone for participating in the call today. We're very excited about these data and the clear path forward for us to be able to move to a registrational trial and look forward to updating you on the company and on the BEACON trial as we move forward.