Good morning, everyone. Thank you very much for joining us this morning. My name is Brandon Folkes, and I am one of the equity research analysts here at H.C. Wainwright. This morning, we are hosting a call on Connect Biopharma's rademikibart with a particular focus on acute COPD and reviewing the Seabreeze COPD results with Dr. Bhatt. Dr. Bhatt, thank you very much for joining us. Can we just start by you giving us a brief overview of your current role and your experience with COPD?
Sure. Yeah. I am happy to join. I am a Professor of Medicine in the Pulmonary Division at the University of Alabama at Birmingham. I have a clinical COPD practice, where I run a COPD clinic for advanced COPD, and I also have a research interest in COPD, where I do clinical trials in COPD, and I also direct the Center for Lung Analytics and Imaging Research, where we do AI-based imaging research in COPD.
Fantastic. Before we delve into the data, can you just help us understand the most important differences between asthma and COPD from the underlying biology to reversibility of airflow obstruction to how patients present and respond to treatments?
Sure, yeah. So both of these are chronic airway diseases. Asthma usually can occur during any age. Usually, can sometimes occur in childhood. Sometimes they grow out of it, sometimes it continues into adult life. Some people get late onset asthma in their 20s and 30s. Oftentimes, the symptoms overlap, so most people are short of breath, either episodically or on a daily basis. They have wheezing, coughing, so these symptoms are overlapping symptoms. The diagnosis and the differentiation is mainly based on certain characteristic features. Asthma is characterized by reversible airflow obstruction and high responsiveness to bronchodilators. So if you give a bronchodilator, the lung function markedly improves. There is significant variability. For example, if you measure lung function either with peak flow or spirometry at multiple times during the day or week, it fluctuates quite a bit. So that is the hallmark of asthma.
In contrast, COPD is more later in life. Usually, it can happen in the 30s, but usually after the age of 40, that is when the onset is because the primary risk factor is still cigarette smoking, although we recognize that more often in non-smokers as well. The hallmark of this is, despite the overlapping symptoms, it is characterized by fixed or partially irreversible airflow obstruction, meaning when you give a bronchodilator, there is minimal response, and certainly the low FEV1/FVC ratio, which is what we use for diagnosis, does not get reversed with the bronchodilator.
Fantastic. If we just look at and focus on the acute COPD patient quickly, can you just take us through a typical acute COPD patient presenting with an exacerbation, from that initial assessment, the treatment that they are given, and then the decision of whether to admit or discharge in the ER, and then also that first month of treatment after discharge?
Sure, yeah. An acute exacerbation is every patient has fluctuating symptoms on a daily basis, depending what is going on around them, pollution, heat, humidity, and so on. If the symptoms get markedly worse than usual, that is what we call an exacerbation. There are three grades of severity. One is mild, where the patient kind of roughs it out, takes some additional bronchodilators at home, does not really report it, and this, I think, amounts to about half of the exacerbations. The other half are more severe in intensity, something we call moderate exacerbations, where patient seeks medical attention, gets antibiotics and/or steroids. That could be, if it is treated on an outpatient basis, meaning at home, that is considered a moderate exacerbation. But if they happen to be severe enough to come to the emergency room or to get hospitalized especially, that is considered a severe exacerbation.
The definitions are a little limited in that we make these post hoc determinations as to where they receive their care to determine the severity of these exacerbations. The moderate exacerbations that are treated at home, patients usually get about five days worth of steroids and/or antibiotics, and sometimes longer, depending on response. They usually symptomatically feel better in about 7- 10 days, and it takes a couple of weeks for them to feel like their usual, but their lung function often does not return back to normal, even up to five to six weeks out. In about one-fifth of the people, if you measure peak respiratory flow every day, it stays low below the baseline for up to five weeks out. Severe exacerbations seem to be much more of concern.
These patients can stay in the hospital, usually for about three days, and they start feeling reasonably better that they can be sent home, but sometimes they stay in the hospital for 10- 14 days or even longer sometimes. It is not just an inconvenience for the patients, but these severe exacerbations are associated with more inflammation and likely more lung damage to the point that they lose a lot of lung function. It does not return back to normal after they are discharged home. When we discharge patients, we usually try to bring them back in a couple of weeks to see a specialist or a primary care doctor. May or may not happen often, always, but that is our goal. But certainly the recommendations are to bring them back in two to four weeks.
Again, these patients usually do not feel back to their usual for about three to four weeks. They feel quite debilitated, highly symptomatic, very high risk of having another exacerbation again in the first 30- 90 days post-exacerbation. I hope I covered most of it. With the severe exacerbations, the treatment is again giving steroids and antibiotics, more often IV rather than oral. Then in some people who retain carbon dioxide, they may need additional treatments like non-invasive ventilation. Some of them need oxygen therapy, which they may be discharged home on for short-term or long-term.
Okay. In your views, where do some of these supportive care or steroid antibiotics, some of these treatments you mentioned in the acute COPD patient, where do they fall short, and where is sort of the biggest unmet need in terms of helping these patients through that journey?
Yeah. I think these treatments have been quite limited. The exacerbation treatment paradigm has not changed in almost five decades now. It has always been steroids, either by mouth or IV. The outcomes, not surprisingly, have not changed much immediately after an exacerbation. We know that a single moderate exacerbation increases the risk of another exacerbation by about 70%. Severe exacerbations are much more concerning, like I said earlier, because it is also associated with about a 20% risk of hospital admission again within the next 30 days. Within about 90 days, about 35%-40% of patients get admitted again. Or they could get another exacerbation resulting in the same downstream consequences. About 25% of people die within the hospitalization event.
I think it's very high morbidity and mortality, so we don't have great treatments that have altered the course of this, even in the short term, during an exacerbation, for example, length of stay and so on, or during the first 30 days, where they're very likely to bounce back with another exacerbation or long-term in terms of mortality. I don't think we made a dent in any of those with the previous usual status quo of antibiotics and steroids.
Thank you very much. I do want to move to rademikibart and the data. Obviously, we focus relatively here. Could you just outline your familiarity with rademikibart and the data available to date and maybe encompassed in that, when you look at the Seabreeze results, what does that add for you in terms of what you knew about the data, or, on the other side, what questions does that raise for you?
Yeah. The data I'm familiar with is of rademikibart being given one dose during an exacerbation or right after the, within 48 hours of onset of symptoms. That is, I think, a truly novel way of giving a biologic right during an acute exacerbation, which has never been done before. I mean, it has been done in the ABRA trial, but outpatient admissions, this kind of administration is quite novel, and I think the results are very impressive. In COPD, there was an 81% reduction in treatment failure, which was either another exacerbation, ED visit, hospital visit, or death. I think this kind of result has never been seen before. We have tried all kinds of treatments, especially for hospitalized patients. We've had multidisciplinary interventions which have really not moved the needle at all.
I think obviously these are phase II trial results, need to be confirmed in a phase III trial, but I think they have the potential to be truly transformative in how we treat our patients. This is something we've not done in terms of endotyping the patients, looking at eosinophils during an acute exacerbation and targeting the right treatment for the right patient. Given what we know about rademikibart, I think it makes sense. It is a type 2 targeting biologics. It reduces type 2 inflammation, which these people have come in with a high eosinophil count. It does inhibit IL-13, which has a bronchoconstriction effect, so potential bronchodilator effect with rademikibart. Also, I think it potentiates, we've known from some preclinical studies that it potentiates the bronchodilator effect of albuterol. In all those aspects, I think the results are truly impressive to me. Yeah.
Okay. You mentioned the results being truly impressive and the potential to be transformative. But you also touched on, we need to confirm this in a larger phase III. So, I guess when we look at a phase III trial, and we look at the really strong treatment failure data we saw in phase II, what magnitude of effect on treatment failure do you believe would still be transformative in a larger phase III trial?
Okay. This is always a hard question because obviously we want 100% improvement, right? If you were to ask me before this trial came out, and if I was designing a new trial, I'd never seen this drug before, and if I was to design a trial, and we have done these kind of hospital readmission reduction trials, and we've used a 15%, sorry, 20% reduction as clinically meaningful. So that is the general ballpark that most people would say, "Okay, that makes a clinically meaningful improvement." I think for a drug like a biologic, which comes with its own nuances as opposed to, say, a pill or bronchodilator, I think a 35%- 40% reduction would be considered quite remarkable. I think most people would agree that that is a truly significant effect on treatment failure. Yeah.
Okay. Fantastic. Then just digging a little bit deeper into treatment failure, so what components of treatment failure matter most clinically, right? How much weight do you put on treatment intensification versus ER visits and hospitalizations?
I think some of them, obviously all of them come with a little bit of subjectivity in the sense the patient has to call out and say, "Well, I'm having an exacerbation." Then depending on social circumstances, they go to their primary care or to the emergency department. Then in the emergency department, there are some constraints about bed availability and things like that would result in hospitalization. But in the COPD world, I think a hospitalization is the most objective possible way of determining a severe exacerbation. So from that point of view and all the downstream effects I told you about, the impact of a severe exacerbation, the financial cost that comes with a severe exacerbation, I think all of those combined, I would say ER visits and hospitalizations are the most important chunk of this treatment failure.
Obviously, death is also important, but deaths are not that common. Thankfully, I think it's less than 1% now for COPD exacerbations. But most of the morbidity comes from repeat ER visits and repeat hospitalizations. I think that's what we care about, that's what payers and the healthcare systems care about as well.
Okay. Staying on treatment failure, right, which components of, whether it be sort of treatment intensification or when to admit a patient, can be most influenced by local practice or physician's threshold? I guess, how does that differ perhaps regionally in the U.S., and if you are comfortable speaking to sort of globally different practices.
I think I'm most comfortable with the U.S. system. I think the moderate exacerbations that are treated at home with steroid antibiotics, I think they are more subject to global practices. I know from having conducted clinical trials that the threshold for prescribing these is quite different in, let's say, Eastern Europe versus in the United States. Sometimes it depends on things like, if you call on a Friday evening, you're more likely to get steroids and antibiotics as opposed to a Monday morning when people have more time to consider everything that's going on. I think there's a lot more variability in moderate exacerbations, but once they come to the ER, I think they get a more objective assessment. They're definitely being seen in person as opposed to a phone call-based prescription for moderate exacerbations.
I think the variability is a lot less in who gets admitted. Of course, there are, like I mentioned earlier, hospital bed availability, where they go, time of the day, and things like that. But still, I think the variability is a lot less for hospitalizations than for moderate exacerbations. Of course, the health system availability, for example, if you don't have a primary care doctor, you're more likely to go to the ER, so that obviously plays a role there. But whether you'll get hospitalized is usually based on slightly more objective factors, based on oxygen levels, carbon dioxide retention, how sick do you look, how bad are you feeling, things like that. I think it's a little more objective than a moderate exacerbation.
Okay. Digging deeper into the Seabreeze COPD data itself. The treatment failure curves started to separate, I think, around 14 days, right?
Yeah.
Maybe just from a very high level, is that what you would expect, just given the background therapies? Or, in your view, why would they separate at that time point versus another time point?
Yeah. I think we have to remember that all these patients are being maximally treated when they first come in, both the placebo group and the intervention group, with high doses of IV steroids, being given maximal bronchodilators. I think they're kind of like all their receptors are kind of saturated. This is a type 2 inflammatory endotype, so they're more likely to be responsive to steroids. So we're already kind of diluting what we would potentially see as a difference right at the get-go. And of course, this is being given as a subcutaneous administration, dupilumab, so that also takes a few days to maximize its effect and then have the maximum effect a few days later.
I think all those in combination, perhaps I think it's kind of expected that you won't see a big difference in the first few days to a couple weeks, and then the curves start separating out. Because then they're more in that relatively stable phase compared to when they first came in. So I think that's when I would think the effect of the biologic would start distinguishing itself. When the steroids are off, the bronchodilators are not that many all around the day, I think then you would start seeing the curve separate. Which I think it's not very surprising.
Okay. Fantastic. Just coming back to the treatment paradigm today, and available tools. If we think about a patient who goes to the ER, gets treated, is discharged, does come for the follow-up, as you mentioned, within the following weeks, and it is decided that a biologic, in particular, dupilumab, is the right way forward. How is that patient managed in terms of exacerbation management or potential for exacerbations during the time you initiate that patient on, again, let's use dupilumab in this example, or any biologic, to the point where you actually expect that benefit to kick in? What is sort of the bridge therapy or the bridge sort of background standard of care during that period?
Yeah. The reality is most patients when they come in in the first couple of weeks, they're not started on a biologic. I think ideally some of them who meet criteria should be. Right now, the way the trials were designed, the dupilumab trials and all the biologic trials, they included people who were stable. So they had to have not had an exacerbation in the previous four weeks. So when patients come in with a high eosinophil at the time of exacerbation, and then they see us in a couple of weeks, they don't necessarily meet criteria from those RCTs to say they would be eligible for a biologic straightaway, unless they've had other exacerbations in the past and they've had a high eosinophil during what's considered a stable phase.
I think based on the data alone, I don't think that is straightaway an indication for prescribing dupilumab, at least based on the RCTs that we've seen, or mepolizumab. That said, if they've had previous flare-ups, we know they have had stable phase, high eosinophil count, and they meet criteria. Then in the first couple of weeks when they're really vulnerable to have another exacerbation, readmission, and so on, we're not really doing much for them. They're pretty much on their own. They go home on their steroid tapering course or a fixed-dose steroids, finish their antibiotics, take it easy for a couple of weeks, and then they come back. It may or may not happen in two weeks. Anywhere between two to four weeks is the visit. I think that's the most vulnerable period that we're really not targeting right now.
They're completely treatment devoid during that time period, and that's the highest risk time period. Yeah. If they were to be started on something like mepolizumab or dupilumab, usually it takes maybe about three to four weeks for us to start seeing an effect in terms of lung function, in terms of how they feel. Obviously, exacerbations take a lot longer to determine if it's working or not in terms of exacerbation reduction.
Okay. Very helpful. Bringing it back to Seabreeze, any comments or thoughts on background therapy you saw in patients on the placebo arm in particular of Seabreeze, and how indicative is that to the real-world experience in the U.S.?
Yeah, I think most people were on triple therapy, which is for type 2 endotype. I think that is the preferred treatment now if you've had recurrent exacerbations. I think it meets what we usually see in practice. Yeah.
Okay. Fantastic. Next one, I'm going to talk about treatment failure rates and background treatment failure rates. In your view, what do you believe the 28-day treatment failure rates are for acute COPD patients? We've seen the ABRA study, we've seen the claims data from Connect, and then we've seen the treatment failure rates in the Seabreeze study. Can you just help us think which one is closer to what you see in the real world?
Yeah. It's quite a spectrum, isn't it? Yeah. I think the ABRA study, I would say, is an outlier, at least in my practice, and I think most of my colleagues would agree. They had an extremely high treatment failure rate, which is not usual in practice. Keep in mind it was a single center study. I think there were another small site, so technically it was a multicenter, but it was mostly a single center study, and it combined both asthma and COPD, and the treatment failure rate was far beyond what we would usually see in our own practices here. I think the electronic medical record data has been pretty consistent for some of the studies, and obviously there's variability based on the database, but the 30-day treatment failure rate has generally been in the mid-20%s to low 30%s.
The 90-day treatment failure rate has been in the mid-30%s to around 40%. The hospital readmission rate has been consistently around 18%-20% for the past decade and a half. That's far back I've been analyzing the data, and we've had some publications on it, too. That really hasn't changed, and the Medicare data strongly suggests that everything we've done, all the penalties that have been introduced, and all the medical interventions that have been tried, nothing seems to have made a difference. In terms of the Seabreeze data itself, I think the event rate was a little lower than what I would have expected. I think it's remarkable that despite the lower than expected event rate, which would bias a study toward the null, there was still a marked treatment effect.
To me, that's kind of encouraging to see that maybe if you had a higher event rate, you would see a bigger difference or at least a consistent difference. It gives me more confidence in the findings, even though the event rate was low to see such a marked improvement.
Okay. Fantastic. One thing if you could just help us understand is sort of the new versus recurrent exacerbations. I guess Seabreeze demonstrated a very strong reduction also in new exacerbations. How do we reliably distinguish between a new exacerbation from an incomplete resolution of the initial event within 28 days? What does that distinction mean in practice?
Yeah. This is a tough one because we really don't have an end date on exacerbations other than patients telling us, "Okay. I think I feel back to my usual." It's a really gray soft line. We can't really draw hard lines as to, okay, your lung function. Even lung function takes up to five weeks sometimes in a huge number of patients to get back to baseline. We don't have either subjective or objective ways of saying, "Okay, this is the end date of your exacerbation." That's really hard.
In that landmark study by John Hurst and colleagues in the New England Journal in 2011, they suggested that exacerbations often happen in clusters. They said, "If you have two exacerbations within 120 days of each other, that's a cluster of exacerbations." Their margin was very wide based on what they thought it takes to get completely back to usual. For most clinical trials, people have used the definitions variably to say if two events are separated by seven days, and in some trials separated by 14 days, those are considered two separate events. I think it's a little unclear as to how we should define that. Having said that, the implications for the patient seems to be about the same, and if they have two in quick succession, that's obviously way worse than having two separated out by a wide long period of time.
In that sense, I think it's a relatively soft data point, but I think it's encouraging data point that even if you define exacerbations consistently as a recurrent event or a new exacerbation, that also decreases with this drug compared to placebo.
All right. Fantastic. Going to dig in a little bit to FEV1. Obviously, quite a discussion post Seabreeze with COPD data. Maybe just to start, why might a treatment in acute COPD reduce post-exacerbation failure without showing a clear early FEV1 benefit?
Okay. I think there's a couple aspects to this. One, with COPD, we don't really expect a huge FEV1 improvement across all kinds of studies. COPD is characterized more by fixed or partially irreversible airflow obstruction as opposed to asthma where you would expect a bigger FEV1 response. Also, in this particular study, patients were maximized on bronchodilators, steroids, all of which are good for type 2 inflammation, so both placebo group and the treatment group got it. There is also the confounder of if you just let people be, either they get a lot worse or they get better. But most people tend to get better with minimal treatment over a period of time. But how fast do they get better? Do they have recurrent events? That's the main question. Some of the improvement in lung function would have probably naturally happened over time.
The placebo and intervention groups both had approximately 120 mL improvement in FEV1, but I think the difference was not visible because it was a short period of time where they were on maximum treatment. If you look at the 30-day data or the week four data, there is a good separation, just like for a stable patient, there was approximately 70 mL improvement in FEV1 placebo adjusted. I think that is consistent with, for example, the dupilumab studies, which showed an 80 mL improvement in FEV1. That is one thing about the FEV1 in COPD. We have also seen in several trials, including the recent OBERON and TITANIA studies for tozorakimab, that I think there is, and the Mepo studies as well, there is a big disconnect between reducing inflammation and improving exacerbation frequency in COPD, and the improvement in FEV1.
None of those studies showed an improvement in FEV1, but showed a good improvement in exacerbation frequency. I think it is not uncommon for patients to have that disconnect. In asthma, I think they kind of go together, that if you have exacerbation improvement, lung function goes with it. In COPD, more often than not, we have noticed a disconnect between the two endpoints.
Okay. Another question we get is obviously, how does the role of FEV1 differ in stable COPD patients versus an acute exacerbation COPD patient? You sort of touched on this, but how do you think about the Seabreeze FEV1 and treatment failure data in light of the DUPIXENT studies that we saw, obviously granted differences in the studies, populations, patients, treatment setting, all of that, but just how do we reconcile having seen FEV1 resolve in one of those?
Yeah, I think they are consistent. Obviously, first rule of clinical trials is never compare clinical trials, right? It is hard to compare the absolute results, but directionally, I think they are consistent. Like I mentioned, the Seabreeze studies had a different setting, acute exacerbations, maximal steroid administration, high amount of bronchodilator administration. There was very little room in the beginning to see that difference with the intervention on top of these maximally treated patients. Then once those treatments were tapered off or discontinued, I think you started seeing that difference with that 70 mL improvement in FEV1, and that is very consistent with the 80 mL improvement with the dupilumab studies. Again, remember in dupilumab studies, they were all stable patients, did not have an exacerbation in the previous four weeks to be considered stable.
A completely different population, but I think the lung function improvement with the similar mechanism of action seems very consistent. I don't think they're incongruent at all.
Okay. Fantastic. Now, if we think about a phase III, for acute COPD, designing that trial, and especially looking at it from the FDA perspective. If you're advising the FDA, would you want to see corroborating lung function benefit in a phase III on top of treatment failure? If so, what do you think would be a compelling sort of way to corroborate the lung function benefit?
Yeah, I think in a drug like this and the setting that we're using it for, if we introduce this as an acute exacerbation treatment, whether looking at a short-term endpoint of treatment failure or as to be introduced during an acute exacerbation but then continued long term, let's say over 52 weeks or even longer, I think still the primary outcome in my mind should still be something related to exacerbations. Treatment failure, I think is a solid endpoint. It has not been frequently tested in the COPD world for regulatory purposes. I think that would be a discussion that the company would have to have with the FDA. Whether that can be a primary endpoint by itself, I think there is grounds for it.
The FDA does list treatment failure and exacerbation event treatment itself as a desirable outcome, although they themselves have not defined it well. I think that is a discussion that needs to be had. There is grounds to say that if you design a longer trial where you have treatment failure as a key, either co-primary or secondary endpoint, but then also look at the overall exacerbation frequency like the dupilumab trials, I think there is grounds for that too. I don't think the FEV1 would be a primary endpoint in this, just based on the FDA really likes the FEV1, but then that's not the main consideration. I think it can be a key secondary endpoint as has been done in the other biologic trials. I think it is important to patients.
Showing that relatively long-term would be important, but it doesn't have to improve within the first couple of weeks, for example. Like we've seen in this trial, it didn't improve that much quickly, and I don't think that is a necessary consideration. Treatment failure, I think is a strong endpoint in of itself.
Okay. I do want to just stay on this point and just pop through my questions here a little bit, because you touched on this. If we think about a phase III trial, how do you think about FEV1 as a secondary endpoint at a single time point versus perhaps looking at it as an area under the curve or some other derivative of FEV1?
Yeah, that's a good question. I think you can look at it both ways. Obviously, they come with their own advantages and disadvantages. If you use FEV1 at a certain individual time point, let's say two weeks or four weeks, two weeks may be too early for a study like this because of the steroid effect and bronchodilator effects. So four weeks seems reasonable. But then it's one time point. FEV1 measurements are quite variable. If you measure on one day versus the next, there can be up to a 5%-10% variability just in the same patient over time, even in stable phase. When they're in the acute phase and gradually recovering, I think I would expect more variability due to difficulty performing the test or just intrinsic biological variability from day to day.
For that reason, one time point may be a little tricky. You may need larger sample sizes to prove that. On the other hand, measuring the area under the curve has been used in a couple of ways. One, if you're using a short-term bronchodilator, there's a strong precedent for that to say, "Okay, within 24 hours, what happens if you give a bronchodilator?" Obviously, this is not a bronchodilator primary action. There is precedent in the ensifentrine studies where they looked at the area under the curve of FEV1 over 12 weeks. They got their approval based on such an endpoint.
I think there is precedent for that and that it looks like the FDA is okay with that, and I think that's probably a better path so that you're not biasing your results by just taking one endpoint, which has to be arbitrary as to which day you're going to pick to measure that.
Okay. Fantastic. Last question on FEV1 here. Thank you. I appreciate all your insight. In the earlier small IV study, right? Connect did show rapid FEV1 improvements in COPD. I guess in your mind, what does that do, or how do you reconcile what we saw with the IV study to what we saw in Seabreeze on the FEV1 side of things for COPD?
Yeah. I think the IV study was a proof of concept that if you give a rapid-acting, it's very encouraging to see such a rapid action. If you give IV, it seems to block the receptors quickly. There is a rapid benefit. With the subcutaneous, obviously, there is delayed absorption, slow release, so it takes several days, and we don't know the exact time point when the maximum receptor saturation is, but it definitely takes several days for the action to happen. I think when you give IV, I think you're seeing more of the immediate effects. For example, the blockade of IL-13 and its broncho-relaxation effect. There's also some other data to suggest that it potentiates the bronchodilator effect of albuterol. So those kind of things are helpful. Also, one thing to remember would be the IV formulations were given in, I think they were healthy volunteers.
So we have to keep that in mind. Sorry, I was going to say one more thing. I'm blanking out. Yeah, with the subcutaneous, the other way you can also improve your lung function, which may take a little while, would be, for example, if you start dissolving mucus plugs or decreasing the amount of mucus, that may take a little longer to take effect and stabilize. So I think we have multiple mechanisms by which FEV1 can improve. Some can be a rapid response, some can be a delayed effect.
Okay. Fantastic. I am going to move on to just sort of thinking about a phase III design, put you on the spot with a few questions here. But in an ideal world, if you are designing the phase III trial for acute COPD, what would you like to see from this trial in terms of primary and secondary endpoints? Obviously, there is one aspect of designing the trial for success, and then secondly, in your position as a clinician, what do you think is most meaningful to see in the data to convince you to use this in practice?
Yeah. I think I am most excited by the treatment failure results, because that is a big unmet need, novel way of introducing a biologic to decrease short-term outcomes, which then translate to longer term disease progression. They have not shown that in the trial, but I think it conceptually would make sense that it may impact longer term outcomes as well. I think in an ideal phase III trial, I would like to, if the FDA agrees, I would like to see treatment failure as still the primary outcome. It could be a hybrid design. You could have a trial where you initiate, just like in the Seabreeze trial, initiate the medications, but then continue on for about 52 weeks to show whether these results hold in terms of exacerbation prevention as well. There is reason to believe it will.
That kind of hybrid design, but then also having the short-term treatment failure to be powered to detect that difference, I think will help introduce biologics earlier in these patients and then keep them on it, to prevent future exacerbations.
Okay. Fantastic. Taking a step back, if we look at the Seabreeze and we look at asthma and COPD and sort of the statistical significance of treatment failure in FEV1 and asthma versus what we saw in COPD, right? Somewhat of the mirror image. If we think about Connect going to the FDA and discussing potentially different endpoints for acute indications for asthma and then different endpoints in acute exacerbations for COPD, what is your thought on that approach? What is your thought in terms of the receptivity of the FDA to have different endpoints there, and if the FDA was to reach out and lean on the KOL community, what do you think the feedback would be?
Yeah. I think that's an interesting question. Obviously, I can't speak for the FDA, but they-
Yeah. In your opinion.
Yeah. I think they're two different diseases, although there are some overlapping mechanisms and immunobiology involved. They're substantially different diseases in terms of presentation, age of onset, the prognosis, which is a lot worse for COPD, the coexisting type 1 or neutrophilic inflammation, that is way more frequent in COPD, which kind of blunts a lot of the effects of type 2 biologics, as opposed to asthma, which is mostly type 2. A small proportion have type 1, type 3 inflammation. I think there's substantial differences, and they're two separate diseases. I would think the FDA would be open to having two different endpoints for these studies. That said, I think, the asthma results are also quite impressive for treatment failure, which is another unmet need in asthma as well, not just COPD.
I wouldn't be surprised if Connect were to go to the FDA and say, "Can we have treatment failure as the primary outcome for both asthma and COPD, and if even being a key secondary outcome?" I think it's a win-win either way you do it. I think it's a matter of discussion with FDA to see if they're open to two separate endpoints. I don't see why not if you're having separate conversations because of the differences in the two diseases.
Okay, fantastic. Very helpful there. Coming back to phase III design, do you have a view in whether you should enroll patients that would get hospitalized or patients that are treated in the emergency room and discharged home, both? Just in your view, what population offers the clearest balance of event risk, clinical need and predictability, I guess?
Yeah. I think as a physician, I would strongly support including everybody because as a field in the COPD community, we are moving toward not tolerating a single exacerbation. I think the goal now is zero exacerbations. So we recognize that moderate exacerbations are almost as bad as severe exacerbations in terms of the effect it has on patients and also importantly, on disease progression. Each one is associated with faster lung function decline, faster emphysema progression, and a higher risk of future events. We know they're not random events. People usually used to think that, oh, moderate exacerbation is just bad luck, you got in touch with some sick kid and got some viral infection and got sick for a few days. We know that's not true. They're also predictable. They're associated with underlying disease severity and the susceptibility to an exacerbation.
I think if we interject early and prevent these exacerbations, moderate as well, I think you're less likely to get severe exacerbations in the future, less likely to have disease progression. I think for those reasons, I would encourage inclusion of everybody. From a pragmatic point of view, it makes it a lot easier to enroll in clinical trials if you're including both moderate and severe exacerbations, and not just focused on severe exacerbations.
Okay. Fantastic. In terms of phase III, what background treatment elements would you like to see standardized? Again, in your opinion, how would you ideally like treatment or pharmacological intensification to be defined, and at what stage would you adjudicate intensification?
Intensification of other treatments, background?
Of background therapy.
Background therapies. Yeah. Okay. Some of it is hard to standardize. I think this is with regard to a clinical trial, so I would obviously want people to be on maximum inhaled bronchodila sorry, inhaled controller treatment, so ideally triple therapy. If they don't tolerate inhaled corticosteroids, then on dual therapy. Once they get into the exacerbation paradigm, then I think I would like to try and standardize as much as possible using the current guidelines, which is five days of prednisone. You could standardize the dose. There's high variability in dose administration, but you could mandate a minimum, so say a standard dose of 40 mg once a day. Antibiotics could be according to local practice because sometimes people depend on what did they get last time, the local antibiogram and things like that.
I think there needs to be a little room for those kind of decision-making as long as. Obviously you'd have to adjust for the site or the region because some countries, the practices may differ slightly. I think even if you can't standardize, if you can adjust for the region, I think that controls. Doesn't fully take it away, but controls for some of that variability. Once they get treated, I think there needs to be a little more standardization in terms of their, at least their semi-subjective reported symptoms as to what should result in an intensification of treatment. On the one hand, you could be pragmatic and say, "Well, we'll leave it to the treating physician.
If they get instead of five, if they get extended to eight or 10 days of steroids, we will take care of it on the back end with the analysis. Because that's, I think that's going to be a small proportion of patients, shouldn't impact the trial results in a big way. On the other hand, you could say, "Well, we're going to have daily symptom questionnaires, and if they don't return back to XYZ level, then we can mandate intensification of treatment." I think I'm not a huge fan of the latter because it makes it really hard in the acute setting to dictate how a physician should practice. There's lots of factors that go into this kind of decision-making. Makes it a lot less pragmatic and honestly a big pain to conduct a trial if you were to mandate those kind of decision-making.
My bias would be to say, standard course of five days of steroids and antibiotics, and then if something gets changed a little bit, then deal with it on the analysis. If it's a high proportion, you may need to adjust for that. My guess would be it would be a small proportion, then it shouldn't matter. That's what I would do, yeah.
Very helpful. Just going to remind our audience, if you do have any questions, just pop them in the chat and I will ask Dr. Bhatt. Dr. Bhatt, we've obviously delved very nicely into the data here, so I appreciate all your insight. Taking a big step back, though, in your view, how large a market is this acute COPD opportunity? Again, we've seen some claims data. Is that representative of how you view the market? Any sort of confounding factors that could be in that claims data or any way that you would frame this need or market opportunity?
No, I think it's quite consistent with what we've been seeing. Obviously this trial targets people with type 2 inflammation. So the range of people with type 2 inflammation and COPD has been between 20%-40% of patients. The lower 20% range usually comes because we measure the blood eosinophils to say someone has type 2 inflammation. So it's usually in the mid 20% range when you measure only blood eosinophils. If you were to use slightly more sensitive measures like FeNO or were to get airway samples, it can be as high as 40%. So I think there's still work to be done to identify these people more accurately. But even if you use the relatively easily accessible blood eosinophil count, it's still in the mid 20% range for how many people have this.
These people are more likely to get exacerbations, more likely to get hospitalized. During an exacerbation, some of the data suggests that up to 35%-40% of people have eosinophilic or type 2 exacerbation. I think it is quite a large number of people, and extrapolating to the U.S. population, I think it is several million people. The costs associated with COPD mainly come from exacerbations. Almost 75% of the cost related to COPD come from exacerbations, especially those that are severe enough to result in hospitalization. We have seen some Medicare data, which we used for some previous studies as well, and I am familiar with the data that Connect produced as well. Roughly about $7,500 for each admission related to Medicare insurance. Obviously, different insurances are different, but that is the ballpark estimate for cost of a severe exacerbation.
That is for an average admission, but if they get admitted for longer, obviously the cost will balloon up quite a bit. If they have a readmission, the costs are much more, and therein lies the problem of CMS penalties and things like that, which you could potentially bring down with a drug like this.
Okay. Fantastic. There is the potential for rademikibart to be studied in chronic COPD as well. Assuming acute and chronic labels are approved by the FDA, if a patient went into the ER, got rademikibart, it worked as we have seen it work today, how do you view about thinking about then putting that patient on rademikibart chronically? Do you have a view on trying to keep them on the same therapy? Do you have a preferred therapy or would you just wait and see data?
I think I would wait and see data, but there is usually, as physicians, we are creatures of habit, so I think if you start a drug, there is usually no reason to change it.
Okay.
At least not immediately, because you want to make sure you've given enough time for, especially if it's for a chronic indication approval. If it's already approved for a chronic indication, then generally for a biologic, I would like to keep them on it for at least a year to make sure that you covered all seasons, that they're not exacerbating in other seasons, and either don't declare success too soon or failure too soon. Generally, I would like to keep it on for at least a year. If in a year they continue to have frequent exacerbations, then I would probably think that this particular drug is not the best drug for them, and start thinking about other biologics. We don't have a lot to play with right now in the COPD world. We only have two approved biologics and a third one hopefully on the way.
I think there's limited choices now, but general practice is if you start somebody on a biologic, is to keep it going for at least close to a year, if not more, before altering it, unless there's something to suggest otherwise very quickly, like side effects and things like that.
Okay. Just looking at the other side of that coin, if a patient is on an IL-4 biologic, and does have an exacerbation, presents to the ER, would you have any hesitation using rademikibart on that patient in terms of, would you look to try a different mechanism? Or just given the data, would you be comfortable using IL-4 on top of dupilumab?
I think it's a little tricky. Obviously, we don't have data, so I'd have to guess. If somebody's already on, when you say IL-4 and the only approved one is dupilumab, let's say they're on it, and then they come into the ER with an exacerbation, I think I would think about it in a couple ways. One, if they were recently started on dupilumab, let's say in the last four to six weeks or so, then I probably wouldn't try another drug with a similar mechanism of action on top of it. But if they were on it for quite a while, and then they come in with an exacerbation, then I think it'd be reasonable to try.
I think there's some data to suggest that rademikibart has a higher affinity to the IL-4 receptor. Then I think it might be worthwhile giving it in the acute setting, and also if it's approved by then for the chronic setting as well, change and try that for a little while and see how that goes. But if it's a recent introduction of dupilumab, then I think I wouldn't change or administer another IL-4 drug on top of it.
Okay. Just staying on dupilumab, I guess given what you've seen in Seabreeze to date, what's your view on the differentiation between rademikibart and dupilumab, out of the limited data, but just given different stages of development.
I think, based on what we've seen so far, and obviously Seabreeze is a completely different indication, acute setting during an exacerbation that has not been studied with dupilumab. There's really no comparison there. We're entirely different populations. Stable phase versus acute is like apples and oranges in some ways. I really don't think we can compare a lot of the results. Endpoints are different, population is different, background treatment is different. I think this is the only trial for which we have data on acute exacerbation and treatment failure. Completely different population and results.
Okay. Fantastic. If we just think about IL-33 versus IL-4 and IL-13, in chronic and acute now, how do you think about the treatment decision there, whether to potentially use an IL-33 versus IL-4, IL-13? Do you believe IL-33 could work in acute patients as well?
Well, we don't know. We don't have results. That has not been tested in the acute setting, so honest answer is we don't know. Conceptually, I think it remains to be seen. Sometimes when these people come in, they've already had symptoms for sometimes five to seven days. One could argue that the alarmin pathway has already been initiated early on, and then blocking a more downstream pathway might be of help because the inflammation has propagated quite a bit. But I think that remains to be seen because then it also depends on the type of inflammation, and if they have predominantly type 2 inflammation, then I think this drug is more likely to work as opposed to an IL-33, although it's more upstream and supposed to target both one and two.
If it's late in the course of an exacerbation, then targeting more downstream pathways may be better, but I don't know. I'm just guessing at this point. We don't know the results.
Your guess is better than mine, so appreciate you trying to answer that. The other question we get is sort of, as we get more biologics approved and on label, what is your view on broader maintenance and chronic biologic therapy and what that does to the acute opportunity?
You mean people on biologics continuing to exacerbate?
Yeah. As we have more people on biologics, as we get more biologics coming to market, do you think that reduces the number of acute exacerbations we are seeing today?
Realistically, no. The number of people on biologics is extremely low, the number of eligible people. The COPD field is, we don't have enough data because the real world studies are just now beginning to come out, so we don't know how many of the eligible patients are actually on a biologic. But from asthma studies, we know about 3%- 4% of people who are eligible for a biologic are on a biologic. So for COPD, I would think that number is a lot lower. So I think there's a huge unmet need and undertreated population that are eligible but are not on a biologic. I don't think that's a real problem right now to say, "Okay, if they're already on a biologic, what do we do next?" I think, yeah, we're nowhere close to that.
Okay, fantastic. We're almost out of time, so I'm just going to wrap it up here. If we just take a step back, and I appreciate all your insight, if we look at rademikibart today, what excites you most about this drug and the opportunity to use it in your practice? Then for you, I guess what's the most important and unanswered question with data where we sit today?
Yeah. I think, like I said at the beginning of the call, we've been talking about precision medicine for a while, and we always want to use the right drug for the right patient at the right time. This study is especially exciting to me because we have endotyped the patients, detected type 2 inflammation during an exacerbation, given a type 2 biologic, and in a very novel way in that we're giving it at the time of exacerbation. Steroids and antibiotics have been the mainstay of treatment for decades for exacerbation with the same results, not much improvement in decades now. I don't use that word lightly, but I think it has the potential to be transformative in how we completely change how we are treating an acute exacerbation in COPD.
Obviously, it is not for everybody, but with those with type 2 inflammation and the ones likely to respond, which is a huge proportion of our patients, I think it will completely change how we are treating our patients. I would like to see phase III results confirm that, but the phase II results are very encouraging.
All right. Fantastic. Dr. Bhatt, I am going to wrap it up there. Thank you so much for your insight today. Very, very valuable. Thanks again, and that ends our call.
Thank you.