Connect Biopharma Holdings Limited ($CNTB)

Ladies and gentlemen, thank you for standing by, and welcome to the Connect Biopharma Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would like now to turn the conference over to David Szekeres, President of Connect Biopharma. Please go ahead.

Thank you, operator. Good morning, everyone, and thank you for joining us. With me today from Connect are Barry Quart, Chief Executive Officer and Director; and Kimberly Manhard, Executive Vice President and Chief Development Officer. For those of you participating via conference call, the slides are made available via webcast and can be accessed by going to the Investor Relations page of our website following the conclusion of today's call. Before we begin, I would like to remind you that this call will contain forward-looking statements under applicable securities laws. These statements involve substantial risks and uncertainties and include statements concerning Connect's future expectations, plans, prospects, corporate strategy and performance, including with respect to research and development programs, clinical trial plans and results, regulatory strategy, timing and approvals, market research, assumptions and projections, cash runway and anticipated catalyst milestones. Actual results may differ materially from those indicated by these forward-looking statements due to various important factors, including those discussed in the safe harbor slide, the press releases issued by the company today and our filings with the SEC. Forward-looking statements represent our views only as of the date of this webcast and it should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update these statements. Now I'll turn the call over to Barry.

Thank you, David. Welcome, everyone, to the call. We are extremely excited to have this opportunity to provide 2 important updates on the development of rademikibart, a highly differentiated IL-4 receptor alpha monoclonal antibody designed by Connect. We will be reviewing this morning preliminary top line results from our IV clinical pharmacology study of rademikibart in asthma and COPD patients. And a Phase III atopic dermatitis results presented Saturday morning in a late-breaker session at the American Academy of Dermatology Conference. But before the data, I will quickly review the differences in biology that make rademikibart remarkably different from other drugs in the category and ideally suited to treat both acute exacerbations of asthma and COPD and chronic management of these diseases. After the presentation, we'll be happy to answer questions. Next slide, please. So the biology of IL-4 receptor alpha obviously is very well known and an ideal target for multiple diseases. The components that make rademikibart unique and highly differentiated, first and foremost is the faster onset of the product, which was identified in a prior chronic asthma study. And we'll go through some of that data and identify for you really, what is the very intriguing biology behind that. We also see substantially greater responses in terms of FEV1 in asthma patients. We've demonstrated in atopic dermatitis that the product works Q4 week. So as compared to dupilumab, a more convenient dosing option. And we had noticed early on a reduction in eosinophils versus the increase observed with dupilumab. That led us to understanding some of the significant biology differences of the products. Next slide. The differences stem from completely binding -- a different binding orientation of rademikibart versus dupilumab. We bind at a different epitope. The tightness of the binding is substantially greater than with dupilumab. And because of these differences, we see significant differences in internalization which results in significant differences in the observation in the clinic. Go to the next slide. And so what we'll be talking about is differences in eosinophils, as I previously mentioned. We have information that was generated in human airway smooth muscle cells and human precision lung slice data. Next slide. So initially, the differences between rademikibart and dupilumab were noted in the clinic with the observation of decreasing eosinophils in the chronic asthma study that was previously conducted. This was a surprising observation considering that dupilumab is well known to increase eosinophils, and in some case, quite substantially. And this is not just a lab observation, next slide. We see here hundreds of serious adverse event reports submitted to the FDA for dupilumab in asthma patients related specifically to increase eosinophils. Next slide. So we spent significant time trying to understand this very different profile. And ultimately, we determined that the likely origin of this difference is substantially greater internalization of the rademikibart receptor complex. This substantially greater internalization results in greater turnover of eosinophils, which would certainly explain the decrease in eosinophils versus the increase. Because we have significantly enhanced internalization of the complex, we also would be removing receptors from the cell surface. And that may play a role in the fact that we see such excellent activity at Q4-week in AD where dupilumab was unable to demonstrate good activity Q4 weeks. The other associated potential benefit of decreasing eosinophils is that I'll be showing you clinical data that demonstrates we see really no significant increase in conjunctivitis versus the 10% conjunctivitis seen with dupilumab in early 16-week studies and even higher rates over time. We consistently see low rates of conjunctivitis really not differentiated from placebo. Next slide. And so we'll go now into some very intriguing data collected in preclinical models, specifically looking at airway function. Next slide. It's well understood that IL-13 and IL-4, but particularly IL-13 has direct effect on airway smooth muscle and has been shown to shift the dose response curve of beta agonists. Next slide. So we spent significant time looking at the biology of how beta agonists produce relaxation in human airway cells to see if that understanding that pathway would give us a clue as to the differences in biology. Next slide. So the right panel here in the graphic. This is looking at human smooth muscle airway cells and specifically looking at phosphorylated HSP20 which is a marker of relaxation. It was downstream on the prior schematic. And you can see that in the cell culture addition of rademikibart significantly increased that marker relaxation, whether it be alone or in the presence of the inflammatory cytokines and a very different presentation than what was observed with dupilumab. To go further, we went into human precision-cut lung slice model. And here, we see the classic shift in the dose response curve for motorol potent beta agonist, making that drug less effective in the presence of the inflammatory cytokines for bronchodilation. Next slide. when we add rademikibart, we see that we get an improvement in bronchodilation and move the curve back towards baseline. But very interesting, next slide, when we add dupilumab to this experiment, we see no effect. So this is not simply binding to the receptor and blocking attachment of the inflammatory cytokines. This is through a secondary biology probably similar to what was seen in the human airway cell increasing phosphorylation of HSP20. Because this was such a surprising observation, next slide, we went to another lab that has a significant experience in doing precision-cut lung slice work. And they -- even larger number of samples was able to reproduce the observation where there was no effect of dupilumab on the reduction in the benefit of the bronchodilator, but a significant improvement with rademikibart. Next slide. And so based on the rapid onset of FEV1 increases that were seen in the original chronic asthma study. Current development of rademikibart is focused on treatment of acute exacerbations in asthma and COPD. Ultimately, the goal would be to have both the acute and chronic indications but we've put our current focus on demonstrating a benefit in the acute setting. Next slide, I'll go through all of the details underlying asthma and COPD. But the most important focus of this discussion is the large numbers of patients going to the hospital for acute exacerbations, over 1 million ED visits for asthma patients, 1.3 million for COPD patients. Next slide. And that's really the tip of the iceberg because we see with that 1 million asthma patients going to emergency departments, there's even more patients going to urgent care or doctor's clinics to get treatment for the acute exacerbation. Next slide, very similar numbers in Europe. This is clearly a global issue. Next slide. And again, the information on the speed of onset came from original Phase IIb chronic asthma study, a fairly straightforward design. Next slide shows the FEV1 improvements in that study. We -- because we collected information starting at 1 week, in the clinic, it really spurned our interest in how fast their drug was working because by 1 week, we already saw a very significant improvement in FEV1 almost 250 mil on average. And by drilling in further into homes barometry, we found that the majority of this benefit was observed the morning after, so in less than 24 hours. We were seeing significant improvement in FEV1 much faster than what would be anticipated from a biologic. Next slide, this just helps to put the significant improvement in FEV1 into perspective versus other biologics. As you can see on the far right, when we look kind of as close to apples-to-apples as we can across study, patients with greater than 300 eosinophils, we see certainly a -- what appears to be the greatest magnitude of improvement with rademikibart compared to other biologics, including dupilumab. Next slide. And so with that information on the very rapid onset of effect from the chronic study, which was conducted with subcutaneous administration of rademikibart, we set out to initiate Phase II trials to see if we could demonstrate a benefit in patients having an acute exacerbation. And in parallel, we started to evaluate the opportunity to potentially use IV administration to speed up the onset even more. And so what we'll be sharing with you today is for the first time, as I mentioned, there's preliminary top line results from the IV study. Next slide. So the IV study, what we'll be talking about is Part A and Part B. Part A was healthy volunteers. We had very little information on IV dosing. So the first question is, can it be done safely and more quickly than the 30-minute infusion that was initially tested back in the initial development of rademikibart. And in that Part A section, we found that a 2-minute IV push was very well tolerated, no different than slower administration with similar PK and so we chose that to move forward into the patient component of the study where we were evaluating stable asthma patients and COPD patients to see whether or not the improvement in FEV1 could be accelerated. And this slide describes some of the entry criteria. Next slide shows the baseline characteristics of the patients that were enrolled in the study. And I think that the most important observations here is a high percentage of smokers. So these are difficult patients to treat in general. Eosinophil lower limit was 200 in order to make sure that we were selecting patients with a T2 mediated disease. But we wanted to have as close to real-world data as we could. So we set that bar fairly low. And in fact, the majority of patients were 200 to 250. So right at that entry criteria even though the means are about 330. And then finally, pheno, while we would love to have patients with greater than 25 pheno, in order to really preselect patients that will do very well on this mechanism because of the high proportion of smokers, Pheno in this case was really not predictive of how much airway inflammation patients had, smoking has been shown to decrease pheno. Next slide. So here, we have the top line preliminary results, looking at change from baseline and placebo corrected FEV1. And you can see here that we have immediate effect at 15 minutes in terms of improvement in airway function. It bounces around some. This is a small study of 12 patients, 2 placebo, 10 active but certainly by 3, 4 hours, we see a stable improvement in the 200, 250 range, which is, as you recall, from the chronic asthma study, what we achieved, at least in the clinic at 1 week and with home spirometry in a couple of days. Here, we're shifting that now to several hours. And certainly, by the end of first day, we are now in the 200 to 300 mil improvement territory and we continue to maintain that through 29 days. All of these data points are pre bronchodilator. So bronchodilators were withheld for the first day in order to get the cleanest data of what rademikibart does on its own. And then you see 2 data points that were collected post-bronchodilator and fairly typical increases with the bronchodilator in asthma patients. So from our perspective, we were successful in demonstrating an acceleration of the FEV1 improvement by using IV administration, and that improvement was maintained through a 29-day follow-up in these patients. Next slide. I know we had never treated a COPD patient with rademikibart, although in the prior Phase IIb asthma study there were patients that had characteristics similar to COPD patients. We pulled those patients out, and we see that this data predicted a robust improvement in FEV1 in these COPD-like patients. And as everybody, I'm sure, understands COPD patients generally respond less well to these drugs, improvements of less than 100 mil have been observed with most of the products developed for COPD, and we'll discuss that in a few slides. But if we go to the next slide, which is the actual results from the COPD patients treated with IV rademikibart, you see here a very robust improvement in FEV1 occurring within 15 to 30 minutes. And that improvement is generally maintained in that 300, 400 mil range again with a fair amount of variability. If one looks at the data from the dupilumab Phase III studies, where they had 400 to 500 patients in arm. You see very substantial error bars, spirometry itself is variable and among COPD patients, particularly highly variable. And so that's really the underlying reason for this bouncing around. But nonetheless, we see really remarkable improvement in FEV1 in these patients and the speed of onset is so rapid. We believe that this definitively identifies a second mechanism is occurring with rademikibart to improve airway function this quickly. And we believe that some of the preclinical data that was previously reviewed, is giving us at least an indicator of that differential pharmacology that's going on. Next slide. So how do we put the improvements of 300, 400 mil and greater into perspective for COPD patients. Well, we can take a look at the older agents in what's a clinically important improvement with dose and you see it ranges from 45, 50 mils to 100, 164 mils for combination treatment with Dupixent. They have in their package inserts post-bronchodilator change from baseline placebo corrected at 2 weeks. We see about 10 to 80 mil difference at 2 weeks, which compares to our almost 400 mil increase with rademikibart at day 15 post-bronchodilator. So very substantial difference observed in again, in this small study. Odori, very effective agent for COPD, produces peak improvement on day 1 of 152 to 157 mils. That compares to almost 600 mil peak improvement at 3 hours with rademikibart IV administration. And the drug Odevari actually approved based on AUC change 0 to 12 of FEV1 and that was in the order of about 87 to 94 mil in their 2 Phase III trials, where AUC 0 to 12 for rademikibart is on the order of 400 mils on day 1. And so to conclude the observations we see extremely robust improvement in FEV1 around 200 to 400 mils. And this is very significant compared to both the old line agents used in COPD patients as well as the newer products. And as we've been identifying for some time, treatment of acute exacerbation, our current target is a complete white space as it currently approved drugs, the biologics or Odevari are all approved for chronic management. and have explicit warnings in their package insert to not be used to treat acute exacerbations or bronchospasm. And so there are no biologics or innovative products approved for acute exacerbations. And in fact, they are all prohibited from being used. So this is an opportunity to have a completely differentiated indication. And we'll talk about the value of that in a minute. But first, the next slide is the safety observations of which as you can see, none to speak of in the small IV study. Next slide, just the highlights in addition to faster onset of airway improvement that we now have demonstrated with the IV administration. There's other additional benefits to us that accrue from using IV in the ER setting. First of all, it's a lower dose bioavailability of rademikibart, from a subcu administration it's about 50%. And so we can need a lower dose given IV, and we will likely evaluate an even lower dose going forward just to satisfy FDA requirements for appropriate dose evaluation. And by having an IV product with a different indication dose presentation. So for example, a hospital use only vial for IV administered product. It gives us the opportunity to price differently in the hospital setting versus the outpatient auto injector, have here an example of that pricing difference. Ours wouldn't be nearly this large but by being able to optimize the price in the hospital setting and in the outpatient setting results in the greatest commercial opportunity. And so moving forward, we have 2 acute exacerbation studies ongoing, and the data from those will read out midyear, next slide, is the design of those 2 studies. They're basically identical aside from some modest differences because of the differences between asthma and COPD. Patients come in with an acute exacerbation. They receive standard of care which is steroid prednisone and beta agonist, bronchodilator. And then they're randomized to receive rademikibart or placebo. And then we follow them for the endpoint for 28 days and then another 4 weeks just for a safety assessment. And the goal here is to show a reduction in what we call treatment failure. And so these -- this endpoint is patients coming back to the emergency room back to the clinician looking for additional medical treatment, for example, another round of prednisone because they continue to get worse or they may get better briefly and then have another exacerbation during that 4-week period. Now when we were designing this study initially, we had found through the literature and through claims database that look like around 50% of patients, what I find as a shy number actually in the real world go back to the ER or to another point of care because they're continuing to get worse or they have another exacerbation in that 4-week period. And then about that same time, next slide, the APRA study was published. This is an investigator-initiated trial out of the U.K., contemporary data on what happens in patients, both asthma and COPD have been exacerbated. And in their study, they found 45% of patients coming back to receive medical care during that 4-week period. So it gave us another piece of data in order to power the 2 Phase II studies that we just reviewed. And so we've used this 45%, and we are looking for a 50% reduction, which based on the benralizumab curve, certainly looks like a very doable outcome considering the fact that benra had really no effect on the treatment failure for the first 2 weeks. It starts to separate after that. What that tells us is that benra is doing a very nice job of reducing new exacerbations, but had no real benefit for the index exacerbation, that acute setting in the first few weeks. With a product like ours that starts to work overnight with significant benefit accruing to patients in terms of airway improvement in that very short period, we anticipate seeing the act treatment curve much flatter than was seen here with benralizumab. Again, top line results from the 2 Phase II studies anticipated midyear. Next slide. And so we've done extensive market research with the product, both clinicians and payers, et cetera. Very significant interest in using a biologic or any new tool to treat acute exacerbations. But the data that we presented in these market research studies I will tell you, was not as robust as the IV data that we just reviewed. And so we'll have to go back and do another round because the magnitude of the effect, particularly in COPD patients that we tested was nothing like what we're actually seeing in patients. And so even with the less exciting data, we found worldwide peak sales forecast of approximately $5 billion for acute and chronic indications in asthma and COPD. Next slide. This just highlights the fact that there is significant interest in using rademikibart acutely and patients coming in with an exacerbation and then significant interest in using the product chronically, particularly in COPD, which is a less crowded space and where the recent approvals have not allowed enough time for dominant positions of any of the recently approved products. But what was really the most profound was the preference share of 75% in both asthma and COPD, where clinicians told us if a patient received the drug acutely and did well they would want to maintain that patient on the same drug to a very high proportion of clinicians. So we see that the acute indication, number one, changes the perception of the drug in the mind and the clinician. And number 2 is really a gateway to chronic administration because the patient starts on the product acutely before they see another biologic and then the clinicians have a very high preference to maintain the patient on the same drug. Next slide. So that concludes the new data in the respiratory area. I'll now move to the late-breaking data in atopic dermatitis. This is a study that was sponsored by our partners in China, Simcere Pharmaceuticals, who has rights to develop rademikibart in Greater China for all indications. We received significant milestones and tiered royalties for their development and ultimately commercialization activities. And so we'll go into the data in the next slide. The design of the RADIANT-AD atopic dermatitis study, pretty classic design, 16-week blinded induction phase, and then patients are then put on long-term management out to 52 weeks. Next slide, baseline characteristics, pretty classic for AD studies in terms of baseline disease. Next slide. Here, we get into the data, and we found this data to really be quite impressive in terms of the response rates, both at 16 weeks, but particularly at 52 weeks. This first slide is the classic endpoint of investigator global assessment. And here you see 87.1% responders at 52 weeks. Next slide is EZ75. Again, a pretty standard endpoint for these trials. We've never seen a 96.6% response rate. And so this is, we believe, about as good as you can get for this endpoint and then provide even greater benefit to patients. The next slide is EZ90, so a 90% improvement in the EZ score with eczema area and severity index. Again, very high response seen in this endpoint. And then last but not least, pruritus improved substantially as well in this study. Next slide. And this was all done with very low side effects. You can see here, the left panel is the blinded placebo-controlled and the right is the longer-term follow-up. And probably the most important to highlight is the conjunctivitis, which is one of the most common side effects of dupilumab and many products in this category. You can see here that in the blinded placebo phase, the conjunctivitis rate was really not differentiated from placebo. And while it goes up to a very small extent in the 52-week period, it's substantially lower than what's seen with other products. And I'll give you an example of that in the next slide or 2. Next slide. And so the conclusions from this data, obviously, rapid and sustained efficacy out to 52 weeks with a very high proportion of patients obtaining near maximal response. So long-term benefit in this study with the 52-week data and a very clean safety profile with low rates of conjunctivitis. If we go to the next slide, this is from our prior atopic dermatitis study. It just highlights 2 points. One is patients at 16 weeks. In this study, we random -- rerandomized to either maintain Q2-week dosing or go to Q4 week dosing, you can see clearly, there's no loss of benefit by moving to Q4 week. In fact, if anything, it was slightly better in terms of the IGA endpoint. But more important, this also highlights that with rademikibart, you see excellent maintenance of responders. So these are patients responding, whether it be IGA or EZ75. And so for example, EZ75, you take the responders at 16 weeks, and you're looking to see how many continue to respond out at 52 weeks with almost 92% on Q4 week dosing. In the 2 dupilumab solo trials, only 54% of patients with the IGA endpoint maintained response from 16 weeks to 52 weeks. So that's versus our 87%, substantially higher rate of patients maintaining that benefit over that period of time. And then as you saw from the graphics that there's a continual improvement in the proportion of responders. And so we're gaining new responders and we're not losing current responders, that's how we can get to that 90-plus percent response rate at 52 weeks. And similar observations were made in the current AD study, that data and data from the adolescents will be presented at upcoming scientific meetings. And then the next slide I couldn't help myself as you may be aware, a week ago, there was new information presented by Apogee on their long-acting agent in atopic dermatitis. And they presented a lot of comparative slides. So I took the same tack and present comparative data to what they observed at 52 weeks. This is looking at their Q3-month dosing, which was their best data. You can see at 52 weeks, we have a 10% to 15% higher response rates across the 3 key measurements and a substantially lower rate of conjunctivitis. Next slide. And so just to put all of this information into perspective, in asthma and COPD, we have the difference in binding of rademikibart to the receptor results in enhanced internalization of that drug receptor complex, which then results in a clear difference in eosinophils observed with chronic administration where we see a reduction versus an increase with dupilumab. We've also demonstrated a very unique mechanism of action in terms of directly increase phosphorylation of HSP20, a marker of relaxation in the cells and in bronchodilation in the whole lung. And so we see -- and we've been able to reverse the negative effects of IL-4, IL-13 on the dose response curve of beta agonist in lung slice experiments, something that was not observed with dupilumab, we're in the process of testing other potentially competitive agents. The rapid onset that we see in subcutaneous administration of significant improvements overnight, we can successfully accelerate with IV dosing, with substantial increases as early as 15 minutes, ideally suited for emergency department setting. And we see larger increases in FEV1 than has previously been observed. And that's probably due to this ancillary pharmacology in addition to the IL-4 receptor alpha, no new pharmacology in terms of FEV1 improvements. Atopic dermatitis, very high rates of response for all of the key endpoints. We see a very high proportion of patients going on, maintaining efficacy through 52 weeks compared to specifically to the dupilumab Phase III studies. We see in the prior study, excellent efficacy Q4 weeks. And so Q4 week dosing is something that we would go forward with in asthma and COPD patients as well. And based on the information so far, from all of these trials, it appears that we have a substantially lower rate of conjunctivitis based on the data to date. Next slide, just put everything into perspective, we also have very long exclusivity out into the early to mid-2040s. So plenty of time to benefit commercially. And then on the financial slide next, we have cash, cash equivalents and short-term investments at the end of third quarter, last reporting period. of $55 million, plus the proceeds from the raise that we announced this morning. We have cash that's expected to cover operations into second half of '27. Next slide. And so this is just a final summary of all the information that we just reviewed. But most importantly, in terms of catalysts, most important catalysts coming forward is the completion and top line results of the 2 Q2 acute asthma and COPD studies, which we're anticipating mid-year. There's also a pending new drug application in China for atopic dermatitis, which we're hopeful to see approved sometime between midyear and end of year. And so with that, thank you for your attention and happy to take some questions.

[Operator Instructions] Our first question comes from Thomas Smith with Leerink Partners.

This is Nan on for Thomas Smith. Congrats on the data. So we have a couple of questions. So the first one, how do the IV results affect your strategy in future studies of rademikibart in acute asthma and COPD.

Yes. Great question. And so this is very fresh off the press data from that study. We're still need to -- there's still a few patients going on. We need to get the full data set and really delve into understanding the responders and making sure that we can move forward and identify the best patient population to respond. But we definitely are planning to switch to IV dosing ultimately moving into Phase III for acute treatment with the IV. And so we'll be looking at whether there is a need to do any additional bridging work between the small IV study and moving forward early next year with the IV in the Phase III. So stay tuned. We'll -- once we have the full -- and analyze it will make a decision on, is there a need for additional work?

Got it. And briefly on the economics from Simcere partnership, so Connect remains eligible for about $110 million from milestone plus tier royalties. So which milestones are the nearest term and what an approval would unlock? .

Yes, a great question. So we have not divulged the specific individual milestones. You're exactly right that there's still $110 million in milestones that is due to Connect from our partners Simcere based on both development, regulatory and commercial endpoints. So we haven't given the explicit numbers but milestone for the first approval which, in this case, we would anticipate being AD. And then Simcere is also currently conducting a large chronic asthma study. And so early next year, we would hope to see excellent results from that study, and we anticipate that they would be filing for approval in asthma sometime later than that, and we would receive another significant milestone for an approval in asthma as well.

Got it. Congrats on the data. .

Thank you.

The next question will come from Brandon Folkes with H.C. Wainright.

Congrats on the data. Maybe just 2 for me. So in Part B of the IV study, any color insight into the number of subjects which returned to the ER within 29 days? Granted these were stable patients but I think it would just be interesting to sort of see if there's any data there ahead of CBRE? .

Yes. Excellent question. We will have to delve into that when once the last patient is completed and -- but definitely something that we'll be looking at. I'm currently unaware of any exacerbation in this small cohort of patients over the 28 days. But there may be something interesting in there, and we'll certainly make that known if we find something interesting.

Okay. And then secondly, so on the asthma cohorts, why do you think FEV1 comes down until 19 minutes. Is that just given sort of the law of small numbers? How does that potentially compared to the subcu? Do you have any data there? And then I guess, going forward, would you expect similar curve to what we saw today between COPD or asthma, would you expect as much to sort of look a little bit like or a lot more like COPD going forward? And then on that, if we do see that asthma curve like today, does that bring in any risk of symptoms or exacerbations between minute 15 and 90 in sick patients.

Thank you, Brandon. Good question. And we believe based on looking at the individual patients that this is just inherent variability of spirometry and in that early period, as you know, I mean we are collecting a very sizable number of tests over a short period of time. And so there's always a possibility of patients, asking them to do a baseline and they may do 6, 7 attempts and then 15 minutes later, another 6, 7 attempts and 15 minutes after that at 30 minutes. And so amongst all of those assessments, there's a substantial amount of variability. We don't see that as a real observation in terms of something happening with the drug effect. I think the COPD base for whatever reason, were more stable, actually, in general, than the asthma patients. In both settings, we're talking about very small numbers. This was a small clinical pharmacology study. I don't think we want to read too much into an individual data point. And so no, we expect in larger scale studies to see more consistent results early on. And even if it did bounce around, it certainly should not have an impact on patients who are having an acute exacerbation, they're already there having an acute exacerbation. They're already on the standard of care in that very acute setting, certainly not going to have a negative impact on those patients.

Congrats again on the data.

Thank you. Good to talk with you.

And the next question will come from Thomas Flaten with Lake Street Capital Markets.

Barry, just a follow up on that last response. I mean what stood out to me with those 2 charts and asthma and COPD was the rapid or more rapid response into the bronchodilated responses, on the green zone in COPD versus asthma? I'm just assuming the answer is the same as you gave the last question that it's inherent variability in small number of patients, et cetera. But that's the one thing that stood out to me. Just curious to get your thoughts on that.

Yes. Well, it's an excellent observation. There's no question that the response in the COPD patients was much more robust than in the asthma patients in that first several hours and actually even beyond that, it's very intriguing in because we are still trying to understand the reasons why we see such rapid improvement in FEV1. Clearly, it is not a direct IL-4 effect because at least in cell culture and in lung slices, we don't see these kinds of effects with dupilumab. And so there's that ancillary pharmacology that we're really still trying to get our hands around. Ultimately, I won't be surprised if that pharmology has potentially greater impact on COPD because I'll point out that we had looked at the COPD like patients and found really remarkable increases in FEV1 in that subset of patients. And it was actually kind of too good to be true, given how resistant COPD patients tend to be. But remarkably, we actually duplicated almost exactly that same magnitude in the small study. So I feel that it is real. It's a real observation. We're going to spend some time drilling into it to figure out what is -- what's the underlying biology.

And then just kind of a 50,000-foot question. You got the Seabreeze studies ongoing. So acute seems to be -- acute exacerbation seemed to be the #1 priority. How are you thinking about allocating resources across chronic asthma, COPD and AD given this excellent data set that was presented over the weekend.

Yes. Thank you. I appreciate the question. So number one, we've been pretty clear that we are personally at the Connect company not going to be expanding resources on atopic dermatitis at this juncture. We think that the drug has an opportunity to be best-in-class in atopic dermatitis, but it is not our current focus. And so we'll continue to focus on the respiratory side. In terms of the -- how we'll move forward, as I previously noted, our intent is to be in both acute and chronic. We put the chronic studies on pause while we generated the acute data. Once we have the acute data, we already have agreement with FDA on moving forward in chronic asthma into Phase III based on the great Phase II data we generated. And so early next year, we would certainly look to initiating both acute and chronic Phase III studies. And at that same juncture, we'll be likely getting the results from the Simcere Phase III asthma study. The great thing is, is that virtually everybody in the world uses GINA guidelines for treating asthma. And so that study from China, we believe should be acceptable for submission to FDA and acceptable as at least a supportive Phase III trial. And so based on the results of that, we'll certainly plan to move forward into both acute and chronic. But as we've also maintained our interest is finding a commercial partner for rest of world to help defray the cost of certainly not interested in going out and raising Phase III dollars for multiple acute studies and Phase III in chronic and -- chronic asthma and chronic COPD. So the goal is to be able to move forward early next year, but have somebody help pay for it.

The next question is going to come from Julian Harrison with BTIG.

Congratulations on these results. In your IV study, the FEV improvements, especially in COPD looked very high, like multiples higher compared to other treatment options. I understand there maybe was an expectation for faster efficacy with the IV formulation, maybe TMAX driven. But I was wondering if you're expecting such a large treatment effect from this study. And if so, maybe any thoughts on what was driving that?

Yes. Thank you for the question. And so we had the data from the prior Phase IIb chronic study, where we pulled out the COPD-like patients and showed particularly in people with T2 mediated disease, 4, 5 plus 100 mil improvement, which I will say I thought was a wonderful observation but highly unlikely that we would be able to replicate because COPD patients tend to be much more resistant to pharmacologic intervention, there's more remodeling and other factors involved in their airway dysfunction. And so seeing almost identical results in this small IV study certainly gives me a greater expectation that we will, in fact, continue to see that kind of magnitude going forward. We only won't know for sure until we do larger experiments. But being able to replicate that almost exactly certainly would indicate to me that, that is, in fact, a real observation and not just an artifact of very small numbers. And in terms of your second question, we have every interest in trying to figure out exactly the underlying pharmacology. We haven't got there yet. We have analyzing pieces of information that I showed you, but we have a lot of work ongoing, and we will figure that out and I look forward to being able to present that in the future.

Excellent. And a follow-up, if I may. It was also interesting to see the data showing rademikibart potentiates beta agonist. I understand that was also an unexpected effect, but just wondering if there was a prevailing explanation there? Or is that kind of just left as an empiric observation for now?

Well, we know it's real. We know we're differentiated from at least dupilumab in that regard, and I expect probably from every other biologic that's used for asthma and COPD. It is clearly an off-target effect of the drug. We don't know if it's associated with this internalization or some other factor. And that's really our -- a significant focus in terms of the preclinical area of understanding exactly how it is doing that. We know it's doing it. We understand from the HSP20 data that is doing it downstream. We know that the cytokines block beta agonist activity upstream. So that all fits together, but the exact molecular basis for doing it is still unclear. But as I said, looking forward to presenting that in the future. And I think we are out of time. So I thank everybody for joining the call today.

This does conclude today's conference call. Thank you for your participation, and you may now disconnect.