Nothing to say, yet
Transcription
The conference call discussed the top-line results of the Phase 3 ARISE study on ARICAPE in patients with newly diagnosed or recurrent maculine disease. The study showed that the Patient Reported Outcome Tool (PRO) for quality of life in bronchiectasis respiratory domain (QOLB) was successful and will be proposed as the primary endpoint for the ongoing on-court study. The results also showed better performance in culture conversion for patients taking the drug, with a strong trend towards significance. The data demonstrated a safe and well-tolerated profile for the drug. The results exceeded expectations and suggest a potential pathway for accelerated approval. The QOLB respiratory PRO was validated and showed meaningful improvement in respiratory symptom severity. Overall, the data are a clear win for patients with maculine disease. Thank you, Rob. Good day, everyone, and welcome to today's conference call to discuss the top-line results of the Phase 3 ARISE study of ARICAPE in patients with newly diagnosed or recurrent maculine disease who have not started antibiotics. I am joined today by Will Lewis, Chair and Chief Executive Officer, Martina Flamer, Chief Medical Officer, and Dr. Chuck Daly, who is Chief of the Division of Mycobacterial and Respiratory Infections at National Jewish Health, a key opinion leader in the treatment of patients with NPM-MAC lung infections and the primary investigator in the ARISE study. The call will begin with opening remarks from Will before turning it over to Martina to walk us through the results. Following Martina, we will ask Dr. Daly to give his perspective and insights on the data. After their prepared remarks, the presenters will be joined by Kevin Eng, Chief Development Officer, and Sarah Bonstein, Chief Financial Officer, for the Q&A session. Before we start, please note that today's call may include forward-looking statements based on our current expectations. These statements represent our judgment as of today and inherently involve risks and uncertainties that may cause actual results to differ materially from the results discussed. Please refer to our filings with the Securities and Exchange Commission for more information. As a reminder, the information on today's call is for the benefit of our investment community. It is not intended for promotional purposes, nor is it sufficient for prescribing decisions. And now, without further delay, I am excited to turn the call over to Will Lewis. Thank you, Brian. We are excited to share with you that the key takeaway from the ARISE trial is unequivocal success. We have a PRO, or Patient Reported Outcome Tool, in the Quality of Life Bronchiectasis Respiratory Domain Questionnaire, or QOLB, that works. So much so, that we do not intend to make any changes to this PRO when we propose it to the FDA as the primary endpoint for our ongoing on-course study. Furthermore, we see better performance using this PRO for patients taking our drug with a strong trend toward significance. Equally exciting, we see across the board outperformance on culture conversion. Patients on our drug converted earlier, they converted in greater numbers, and they remained converted during the one month after stopping treatment. These results are everything we could have hoped for and more. Let's take a moment to revisit our aspirations for this trial. When we spoke to you on our earnings call last month, we laid out what a good readout from the ARISE trial would look like from our perspective. First, we said that the data would need to demonstrate that we have a PRO that works in this patient population, and can therefore be confidently used as the primary endpoint measure in the ongoing Phase III on-court trial. The QOLV respiratory PRO clearly accomplished that in the ARISE trial, and Martina will go into further detail regarding the many reasons we are so pleased with its performance. I know many of you were worried that this PRO data might be messy and hard to interpret. Today's result is anything but that, as evidenced by the fact that we plan to propose to the FDA that the QOLV respiratory PRO be the primary endpoint in on-court with no changes to the instrument. We also wanted to see evidence of culture conversion. We mentioned we wanted to look at time-to-culture conversion, overall culture conversion rates, and any evidence of durability of culture conversion. Once again, we saw clear wins on all three of these measures. We also said that we would want to see data that show a clear numerical difference using both PRO and culture conversion measures. And while we are not powered for statistical significance, even a trend in that regard would be encouraging. In fact, for the PRO, we saw a strong trend towards statistical significance in the error case arm compared to the control arm with a nominal P-value of 0.107. On culture conversion, the error case arm achieved a nominally statistically significant improvement over the control at month 7 with a P-value of 0.001, despite the trial not having been powered to show that type of a result. In fact, the absolute culture conversion difference between the two arms was approximately 32%, which is far greater than the 10 to 20% we cited as the difference we were hoping to achieve in a trial of this size. In a further positive surprise, we also observed correlation between those who converted on error case and their QOLB performance at month 6 and month 7 with P-values of 0.0167 and 0.0416, respectively, rounding out the argument that culture conversion and improvement on the QOLB PRO are related. Finally, we said that good data would need to show a safe and well-tolerated profile for use in the patients enrolled in the trial. We clearly have that, as we observed no new or unexpected safety signals. The error case discontinuation rate observed was 22.9% versus 7.8% discontinuation of the placebo arm. Discontinuation rate for error case is lower than what we saw in our CONVERT study for refractory patients. This lays the groundwork for a potential advantage in treating NTM MAC patients earlier in their diagnosis. In summary, today's data are a clear win for NTM patients. In fact, the ARISE data are so strong that we plan to discuss these results with global regulators to see if there might be a pathway for an accelerated approval to bring this medicine to newly infected patients even faster. Regardless of whether that is possible, today's data give us a great deal of confidence that OnCor will be able to achieve both statistically significant and clinically meaningful results, leading to a sizable increase in the number of patients who could hope to benefit from error case. These data exceeded even our most optimistic expectations. Now let me turn it over to Martina to walk you through the results in more detail. Thank you, Will, and good morning, everyone. I am pleased to be with you today to share the top-line results from our ARISE study. I will begin with a brief review of the trial design. ARISE enrolled 99 adult patients with non-cavitary lung disease with a newly diagnosed MAC lung infection that had not yet been treated with an antibiotic regimen for their present infection. These participants were randomized on a one-to-one basis to receive either error case plus acitromycin and esambutol or an empty liposome plus acitromycin and esambutol. The trial design was administered over a six-month period, followed by one month off treatment before the final PRO scores were collected. Also guidelines for error case treatment recommend a 12-month duration. This study was intentionally made shorter so we could accelerate the analysis of the PRO data, which would inform the design of the OnCor study well in advance of that study's eventual readout. The primary endpoints in ARISE were meant to validate a PRO instrument in this patient population. Secondary and exploratory endpoints included safety, culture conversion, and then comparisons of changes of the PRO scores by month 7 and culture conversion between study hours. Moving now to the QLB respiratory domain, which we used as one of the PRO instruments in ARISE. This PRO is a very detailed instrument that conveys a great deal of information about the specific symptoms a patient is experiencing and how they change. In order to relate that to a patient feeling better, it is essential to have a parallel measure called an anchor that asks how a patient is feeling in a very general way. In ARISE, we ask patients to categorize the severity of their respiratory symptoms at each visit into one of five categories using the patient's global impression of severity or PTIS, from no symptoms at all to extremely severe symptoms. This one-question anchor provided us with information about whether improvements in respiratory PRO scores could be associated with patients experiencing a meaningful improvement in their respiratory symptom severity. This slide shows the results of that analysis for the QLB respiratory PRO, including data from all patients in the study. We plotted the detailed changes in QLB respiratory PRO scores from baseline to month 7 against the PTIS anchor based on whether there was an improvement, decline, or no change in that anchor score over the same time period. This evaluates if changes in the PRO score are interpretable and can be used to evaluate the symptomatic benefit of a treatment. The very clear separation of the curves shown here, especially the green curve representing symptomatic patients who had an improvement in their PTIS anchor, indicates that changes in QLB respiratory score can be used to assess the clinical benefit of ARICASE in this population of newly diagnosed MAC lung patients. While this is a lot of detail to provide to you regarding the validation of a PRO, the key takeaway is these results convincingly support the use of the QLB respiratory domain score in MAC lung disease patients with a new infection and, in my view, represents the best case scenario for PRO validation that we could have hoped for. Furthermore, as Will mentioned, the results are so clear and convincing to us that we do not believe any changes required to the PRO and plan to propose it as the primary endpoint of the ENCORE study to the FDA, unmodified. In addition, these well-separated PTIS anchor-based curves allowed us to estimate an initial within-subject meaningful change in the QLB respiratory score in this patient population. This value can be arrived at by examining patients who experienced at least a one-step improvement on the PTIS anchor. The median change in score on the QLB for such patients was an increase of 14.8 points, represented by the green vertical line on this chart. As expected, the median score change associated with an improvement varied slightly depending upon the level of PTIS severity at baseline. The boundaries of this variability have been depicted on this chart with the region highlighted in the gray column. However, as you will see shortly, an important point to take away is that patients in error case perform better than patients in the control group irrespective of any specific threshold that is used to define the meaningful within-subject score difference. Let's explore this important point in greater detail on the next two slides. I'm pleased to report that patients in the error case arm showed a meaningfully larger improvement in their QLB respiratory score compared to the control arm. As we have highlighted many times in the past, this trial was not powered to show statistical significance. But we are very pleased and encouraged with these results, which trended towards statistical significance with a p-value of 0.1073. Patients in the error case arm of the study saw a mean improvement in their QLB respiratory score of 12.24 points compared to the 7.76-point mean improvement seen in the control arm. Next, let us compare the change in scores for the QLB using Empiric Cumulative Distribution Function, or ECDF, curves. These curves are important as they aid the understanding of PRO reviewers at the FDA about whether a patient on a given study arm is more or less likely to have a change in PRO score that is meaningful. These ECDF graphs plot a continuous view of respiratory score changes, both positive and negative, on the horizontal axis with the vertical axis representing the cumulative proportion of patients in each study arm experiencing at least S-level of score change. The blue curve represents patients in the error case study group, and the red curve represents patients in the control arm. A positive change of the respiratory score represents an improvement of symptoms from baseline to month 7, and a negative change is a worsening of symptoms. Immediately, you should observe that there is a clear and consistent separation of these curves with the error case group being higher than the control group, particularly in the range of change of scores which estimate a meaningful improvement in the QLB score. These ECDF curves indicate that more patients who are exposed to error case have greater improvement in respiratory score than those who are not exposed. The important conclusion from this slide is the observed clear and consistent separation, which means that no matter what value is chosen as a meaningful within-subject change, error case will result in more patients achieving a change that is important to them. As an example and pending discussion with the FDA, at our presently estimated threshold of within-subject meaningful score difference of 14.8 points, 43.8% of error case patients achieved that level of improvement or more in their QLB respiratory score, compared to 33.3% in the control group. Again, regardless of where the threshold for meaningful change is set following the discussion with the FDA, the error case group is always superior. Regulatory authorities look to these types of cumulative distribution curves to assist in their understanding of the treatment effects of investigational drugs, and curves that show this type of consistent separation are optimal. Turning now to another exciting aspect of the data we saw in ARISE, culture conversion. Consistent with prior clinical studies in the refractory setting, ARISE demonstrated that a larger proportion of patients in the error case arm achieved culture conversion by month 7 compared to patients in the comparator arm. Approximately 79% of error case patients achieved conversion compared to approximately 47 in the control, a difference of approximately 32 percentage points with a nominally statistically significant p-value of 0.001. I refer to this difference as nominally statistically significant because no hierarchical testing or adjustment for multiplicity were conducted in the ARISE trial. What is very striking about these data comparing the month 6 conversion figures to the month 7 conversion figures is that subjects in the error case arm who converted by the end of treatment largely saw that conversion persist for the next month after they had stopped treatment. 80.6% in month 6 and then 78.8% in month 7. Whereas there was a marked reduction in patients who maintained their culture conversion through one month of treatment in the control group. 63.9% in month 6 and then 47.1% in month 7. This is also consistent with what we saw in Fonberg's study in refractory patients where those in error case with durable conversion measured at three months of treatment. Also not illustrated here, it is important to note that at any point from the start of the treatment through month 7, the probability of achieving culture conversion was higher for patients on error case. In addition, for those patients who did achieve culture conversion, we also saw meaningful benefits for the error case treatment arm in terms of how quickly that conversion takes place. On this slide, we show you data from only those patients who achieved culture conversion as of the end of the treatment period or month 6. We chose the time point in order to include the largest number of converters in both arms of the study. As you can see, for patients who achieved culture conversion by month 6, 74% of error case patients achieved conversion at the first possible time period in the trial or month 2 compared to 47% who achieved conversion as quickly in the control arm. As a reminder, in the ARRIVE and ONCOR trials, a patient is only considered converted after two consecutive monthly visits at which sputum cultures are negative. This means that 74% of error case patients who achieved culture conversion by the end of treatment began producing negative cultures at the very first monthly visit after starting treatment, a remarkable outcome. Similar benefits in time to culture conversion for error case over the control arm were observed throughout the entire treatment period. This demonstrates that treatment with error case not only leads to more patients achieving culture conversion, but it also does it more quickly than the control arm. Also demonstrating an association between PRO scores and culture conversion is not a firm requirement for the FDA. We were also excited to see that there was a correlation for patients in the error case arm of the trial between culture conversion and the change in respiratory score. As you see on the slide, those who converted either by month 6 or month 7 in the error case arm showed much larger improvements in their QLB scores at month 7 compared to those who did not convert by month 7. Those differences were nominally statistically significant with a p-value of less than 0.05 at both time points. Importantly, these data show alignment between an important endpoint of culture conversion and the QLB PRO, which we think makes it worthwhile to discuss with regulatory authorities a potentially accelerated pathway for approval in newly infected patients. At a minimum, these data give us added conviction in the probability of success for the QLB respiratory score, which is the primary endpoint for the on-course study. Finally, I want to briefly discuss the safety results from the ARISE trial. The tolerability profile for error case in combination with the two-drug macrolide-based regimen in ARISE was consistent with the known profiles of these antibiotic treatments. No new safety events were observed in the error case treatment group, and safety in general was as expected in both the error case arm and the control arm. The error case treatment discontinuation rate observed in this trial was 22.9 percent, which compares favorably to the 34.8 percent discontinuation rate as we saw in the CONVERT study in refractory MAC patients. And while it is important to note that the CONVERT study was longer in duration, 12 months versus 6 months, the vast majority of discontinuations with this drug occurred in the early days and months of use. So this improvement in discontinuation rate is a very encouraging result. The empty liposome control discontinuation rate in the control arm in ARISE was 7.8 percent. Importantly, the percentage of participants who completed the study was over 90 percent for both arms in the trial. Drilling down a bit further, treatment emergent events were reported by 91.7 percent of patients in the error case arm and 80.4 percent of patients in the control arm. The most common adverse events were dysphonia, cough, diarrhea, and COVID-19. After treatment emergent serious adverse events observed in the trial, none were determined to be related to error case as assessed by investigators, and none were deemed related to COVID-19. One serious adverse event in the error case arm was determined to be caused by a hypersensitivity to esampatol, one of the drugs used in both arms of the study. In summary, the combination of all of these data, which I have shown you today, higher, faster, and more persistent culture conversion, a strong correlation between culture conversion and improvement in PRO scores, and a consistent safety profile with a better discontinuation rate, reinforce our confidence that treatment with error case, and in particular, early treatment with error case, can lead to improved outcomes for MAC patients. With that, it is my pleasure to introduce Dr. Chuck Daly, who is the Chief of the Division of Microbacterial and Respiratory Infection at National Jewish Health in Denver, Colorado, who will share his thoughts on how he views the significance of this data that we have just shared. Dr. Daly. Thank you, Martina. Thank you for that clear presentation of some fairly complex topics. It's a pleasure for me to be here today. I mean, I'm amazed by what I just saw, and you know you got my attention with the culture conversion data because, as a clinician, that is really one of the most important things that we focus on. If we don't have culture conversion, we don't know how long to treat the patient. Current guidelines recommend treating the patient for 12 months beyond that point of culture conversion, so we find that a very, very exciting result. I would say, based on the previous studies, I always expected that there would be improvement in culture conversion in favor of their case, but this separation is really amazing. I did not expect that big a difference. I guess I could also say I didn't expect that in the control arm it would be that low, but we really don't have any data. We don't have randomized trials to tell us what to expect in that arm, and that difference is just dramatic. Regarding the PRO, I would say this is probably one of the clearest results I've seen with PROs in this field. I'm very pleased, obviously, that the PRO benefits for error case will hopefully increase the likelihood of FDA approval and make this treatment available for physicians like myself who manage these patients, these newly diagnosed patients with MAC. Although I know the FDA doesn't require a correlation between culture conversion and the PRO score improvement, I'm impressed by that, personally. I think that's actually a very important finding. Ultimately, if these kind of data are approved by regulatory authorities, I think it will provide us with a new standard of care for treating these patients. The results that we are seeing are a rise. I'm sure we'll see an encore now that we know what the primary outcome will be. I think that these results, particularly for me, the benefits of culture conversion when using error case are really very compelling. The other thing regarding culture conversion is that it happened so quickly. I mean, that is amazing that we were seeing a huge difference as soon as two months. That's faster than what I typically see in practice today, so I think that is very important. And it lasts. It was lasting a month longer than what we were seeing in the control arm, where it really decreased significantly, not statistically, but clinically meaningful, I think. So, to me, if approved, I think that this will be incorporated in treatment guidelines. After all, it will be one of the few randomized control trials that we have and only one in treatment-naive patients. So, it looks like a home run to me. I cannot wait to see the results of ENCQOR. So, I think I'll stop there, turn it back to you, Will, for questions. Thank you, Dr. Daly. Thanks for joining us today and for providing those insights for our audience. We really appreciate your sharing your valuable time with us and your perspectives as well. I hope you can see now why we are so excited about these results. Simply put, a rise has delivered. We see a PRO tool that reliably works in this patient population without any changes needed to be made. We see meaningful separation between the error case and control arms for this PRO in favor of error case. We see nominally statistically significant greater culture conversion for the error case treatment group, which includes faster and more persistent conversion compared to the control. And we see a nominally statistically significant correlation between culture conversion and improvement in PRO performance. Finally, we saw a consistent safety profile with a lower discontinuation rate compared to what was observed in the refractory setting. In summary, by any relevant measure, a rise has shown us that patients taking error case with a two-drug macrolide-based regimen are more likely to feel better, have a greater chance to convert, do so sooner, and stay converted for longer than if they are taking those two drugs without error case. A rise provides us with a clear path to success for the ongoing registration enabling on-core trial. In parallel, we will approach regulatory authorities about the possibility of accelerating the path to approval for newly infected MAC-NTM patients based upon these data. In the meantime, we plan to continue to enroll patients in on-core into 2024 to ensure substantial powering for this pivotal study, whether it is registrational or confirmatory. And we will still expect data in 2025. As we learn more from regulatory authorities and monitor enrollment rates following the release of these data, we will update you on timelines and next steps from here. Today represents the first of multiple readouts coming from INSMED. While we will spend time digging into these exciting results today, we are also excited to alert you to our plans to provide additional information from other pillars within our company. Specifically, we plan to announce additional information about TPIP, PAH, and PHILD on our October quarterly call. Beyond that, we anticipate additional clinical data from our fourth pillar, top-line results from PHILD, and ultimately the Phase III Aspen study in Q2 of 2024. It promises to be a busy 10 months at INSMED. We want to thank our patients, investigators, and all of you for your support on this journey that has brought error case to so many patients, and with the results of the ARISE study today, potentially increases the number of patients who may benefit by many multiples. And with that, operator, I'd like to now open the call to questions. Can we have the first question, please? At this time, I would like to remind everyone, in order to ask a question, press star, then the number one on your telephone keypad. And we ask that you please limit yourself to two questions only. And your first question comes to the line of Jason Zemanski from Bank of America. Your line is open. Perfect. Good morning. Thank you for taking our questions, and let me offer my congratulations on the data. Appreciating that ARISE was more meant to reveal directional trends versus statistical outcomes, the strength of the data kind of does open the door about what it would take to get there. And as you look at the data, you know, whether it's culture conversion or the PRO, you know, some of the data were very close, if not there. But do you think it's a question of just having more patience, longer durations of treatment? You know, what gets you over that hurdle there where you weren't, and what gives you confidence? And then a follow-up, if I may. Yeah, I mean, I think as we've tried to be as overt about this as we can, we could not be happier about the results of this study. It exceeded all of our expectations on every front. And with that in mind, and I think especially, and this is a point Dr. Daley mentioned, we were as struck as he was by the correlation between culture conversion and the improvement in QOLB. And if we return to the original dialogue with FDA, the whole question that FDA had was whether or not there was a, quote, clinical benefit from the drug and the treatment. And they did not consider culture conversion to be a clinically meaningful result. They need something that shows a patient feels, functions, or lives longer in order to meet their standard. Well, this establishes clear data that show a correlation between a known surrogate point, which is culture conversion, and how a patient feels and functions better. And both of those are demonstrated within this trial. So that is the definition of subpart H for accelerated approval in the U.S. Interestingly, of course, in Japan, the primary endpoint is culture conversion. And across every measure, we, I think it would be fair to say we crushed it on culture conversion in this trial. So those are both very strong arguments, I think, in favor of a reasonable dialogue. What we want to be cautious about is that, you know, this is a small number of patients. It's 100 patients. It obviously wasn't powered for statistical significance. And we didn't control for multiplicity. But we do see nominal statistical significance on a number of these measures. So from all those angles, I think there's a reasoned argument to be made. I think regardless of whether the FDA is willing to go there or the Japanese authorities or the European authorities are willing to go there, we see a clear path to approval for this drug, assuming that HONCOR replicates what we see in ARISE. And I'll just remind everybody, we enrolled the patients at the same time. So this is the same patient population in both studies. So I think from all those points of view, we really are in a very strong position here. And as we learn more, we will let you know. I will just say logistically, the first step is to clear the PRO and get the FDA to approve it. Once they have done that, then we would turn and ask them for accelerated approval subpart H. Gotcha. And then just a quick follow-up here. As you look at the culture conversion rates between month 6 and month 7, there was a slight decline in the error case, but larger in the comparator arm. Is that just the bacteria coming back rapidly in those patients? Yeah. So it's interesting. It's important to remember that when you're doing culture conversion, in order to have a negative culture, you have to have two consecutive months that are negative in a row. And these bacteria are ubiquitous in the environment, so you're constantly exposed to them. But in these patients, a culture conversion or a sputum sample doesn't necessarily mean that each and every colony of bacteria has been removed from the lung. It's just the best measure we have to look at that. And indeed, it speaks to the wisdom of the guidelines asking for patients to be treated for a long period of time to ensure total eradication of the underlying bacteria in the lung. So the fact that you see, in our case, one patient pop up as positive, this is consistent with what we saw in refractory. You had some sporadic negative-positive moves, but very, very few. And what is dramatic is that in the control arm, there's almost a collapse, which means that the eradication, in our interpretation, really has not taken place in a thorough way throughout the pulmonary tree. So hopefully, that's helpful. Yep. Thank you so much for the color. Your next question comes from a line of Jeffrey Hung from Morgan Stanley. Your line is open. Hi, this is Michael Reardon for Jeff Hung. Thank you for taking our questions and can wrap again on the data. Maybe our first question, for Dr. Daly, you said that culture conversion occurred more quickly than what you typically see in your practice. Today, what would you estimate is the current time for conversion in your practice today? Dr. Daly, you want to take that question? I know we're in different locations, but yeah. Yeah, sure. Michael, thanks for the question. I would say generally in practice, we're seeing probably the median is around three months, but it's usually sometime between three and six among those who convert by six. And in practice, I would also make the point that we don't define culture conversion as rigorously as we do in a clinical trial. I mean, these patients had multiple negative cultures to be called converted. In clinical practice, we want to see two to three negative cultures over several months. So not only did these patients in the trial convert, but they really converted using very rigorous criteria. Thank you. That's very, very helpful. And then maybe a follow-up question just more generally. Why do you think there's a good correlation between the culture conversion and the QOL, but not for PROMIS? Is fatigue harder to address, or is this just something part of the disease progression where we would see benefits on quality of life first? Thanks so much. Yep. So our belief is that culture conversion, eradication of the underlying bug or bacteria, is key to the patient's ultimate improvement. And I think you've heard that expressed by Dr. Daly in terms of the way they view that in clinical practice. When we think about PROMIS fatigue, it's important to note that we did see improvement. And indeed, we saw a better improvement in error case versus a control harm, but that wasn't as dramatic. And we feel like the fatigue measure is probably a little more derivative. I don't know, Kevin, do you want... Dr. Kevin Mange, who is on the phone with us, our Chief Development Officer, was integral in the design and execution of this study. And I wonder if he might have any comments about that. Yeah. Thanks, Will. So obviously, the organ system of interest here is the lungs. And so the symptoms from there, I think everyone understands, are the respiratory symptoms. So it's very what we call proximal. The fatigue symptoms, something that's a little bit more downstream. So it may take longer, for an example, to have an impact on fatigue. But as Will mentioned, you know, in the study, error case did have an improvement in fatigue symptoms, but not as dramatically as we saw on the respiratory symptoms. And I think the key take-home really from all of this is, you know, the respiratory score as a PRO works. And we're really excited about having that. And that was the thing we were hopeful for, having at least one, we have one, and it works well in this population. Great. That's very insightful. Thanks so much. And your next question comes from the line of Rachel Goldstein from Goldman Sachs. Your line is open. Hi, this is Rachel Goldstein. I'm for Andrea Tan from Goldman. It sounds like this is the best case scenario, given that no modifications were needed. So congratulations to the whole team. Can you remind us on the pathway and the timelines to approval in 1L here, now that we might have accelerated approval? Yeah. So the way the logistics will roll out from here is, I think we've mentioned this before, we will approach FDA with obviously these data. We're still crunching the information and we'll finish the clinical study report and all that sort of work. And then we will submit that to FDA and have a discussion with them. And assuming that they embrace everything that we've described here, and the data is pretty unequivocal. So I don't see any issues or risks with that. We had originally hoped that that could be done by the end of the year, approximately. There's no fixed timeline around that, but that's sort of what we thought was a reasonable timeframe. And so on the heels of that, having established all of the necessary accomplishments of the ARISE trial in terms of the PRO, we would then pivot to engage in a discussion about whether subpart H approval using the ARISE data would be possible. And that would then result in a filing and a review process. And I think at this point, what I would say is, let's get through to the end of the year and then see what the FDA's feedback is. And we will share that with you once we've had a chance to talk with them more thoroughly. In parallel, obviously we'll be approaching the Japanese regulatory authorities about the strength of the culture conversion data and see what their perspective is with regard to that. The one challenge of ARISE for the Japanese regulatory authorities is ARISE did not include patients recruited in Japan. So we need to be cognizant of that. Obviously, ENCQOR contemplates those patients being included, but that will be something we'll be talking about with the Japanese authorities. We haven't seen a historical difference between conversion rates and behavior of Japanese patients versus other patients, but nonetheless, we want to be sensitive to that. And so we'll see what they have to say. And then similarly, we'll explore where Europe and the UK are. And as we learn more, we'll share it. Perfect. Thank you so much. And just one quick follow-up. How much read-through from ARISE to ENCQOR, given the time difference of six months of treatment in the former and 12 months of treatment in the latter, can we expect to see here? Yeah. I mean, I think the direct answer to that is we expect it to only get better. And that's certainly consistent with what we've seen in practice and in the prior clinical trials that we've run. Great. Thank you so much. Your next question comes from a line of Emil Devon from Guggenheim. Your line is open. Hi. Great. Thanks for taking my question. So maybe I could ask two as well. So one for Dr. Daly. Obviously, the company wants to comment. That's great, too. But you mentioned about the quality of the comparator on here, and it was sort of less culture conversion than what maybe you would have expected. So I'm curious just in terms of if there's sort of a two-drug regimen as compared to without the rifampin on board. So I'm wondering how that may, you know, impact how you view the quality of the comparison here. Obviously, the data look very good, but just given that the standard of care generally includes rifampin right now, so any thoughts there would be helpful. And then second, more for the company, it does seem like this is about as good as you could hope for in terms of data. So I'm curious on your comments around Encore, where I think you're planning on enrolling 250 patients. You said you will enroll those by the end of the year, but now you're planning to continue enrollment into next year to, I guess, ensure a higher degree of power. So I'm just curious what drives the decision to increase the number of patients if these data are about as good as you could hope for. Thank you. Yep. Dr. Daly, do you want to take the first question on the two-drug regimen arm comparator? Yeah, happy to. So for many years, there are clinicians who have treated patients with two drugs, and they've done so because rifampin has drug-drug interactions, so it's somewhat problematic in this population with a lot of comorbidities and other drugs. It's also the least active of the three drugs that we use, and that led to a randomized trial, small trial, in Japan comparing two versus three and showed that two was not inferior to three. We did not change the guidelines because of that, because it was just too small, not a pivotal-type trial. But it did lead to another trial called MAC-2 versus three, which is going on in the U.S. We're getting close to 400 patients. Patients are randomized to two versus three, and again, the two would be dropping or has dropped the rifampin. All I can say to date is that there's a DMC monitoring that trial, and with that many patients, we're still enrolling. They have not stopped. So it suggests things, at least the DMC is comfortable with what they're seeing in the efficacy and safety of two versus three. You know, we thought a lot about the two versus three decision when designing this trial, and we were all quite comfortable with that comparator and particularly knowing that these other trials were either planned at the time or occurring. So that's why I think the culture conversion data in that arm is just so, we can all see it, is dramatically different than in the error case arm. And I think, as I said earlier, my practice, I mean, I've been doing this for 30 years, and you know, to see that high a culture conversion rate at two months and then also at a six and seven is very striking to me. Thanks, Dr. Daley. On the second question with regard to continuing enrollment, there are really a couple of reasons for that. The first is we want to resolve our dialogue with FDA, and as long as that's going on, we might as well continue enrolling the study. The second informs the first, which is at InciMed, we like to ensure that our trials are very healthfully powered. We now have the ability to dial in with great precision the number of patients we want to have in this study to get to the powering levels that ensure success. We don't yet know whether this is a registrational or a confirmatory study, and that also is partially informing our approach to continuing enrollment. To be more specific, if this does end up being the confirmatory study because we're able to accomplish an accelerated approval, then we want to make it even more robust. So for the time being, we're going to continue to enroll it, and we'll certainly update you. I don't think we're talking about significant impacts here over the longer term, because we expect that there could be some positive response to these data in terms of interest in enrolling, but we'll have to monitor that as well. However we end up on this, I think what we can say is we are as close to knowing that we have a design that's going to work, and I want to call out the excellent work of Dr. Mang in this regard. This trial hit on every front, and he and all the team at InciMed put a lot of time in designing it, along with Dr. Daly and others, to make sure that we had it right, and they got it right. And the result is that we have a high degree of confidence that whatever ENCQOR is, it's going to win. Okay, thank you. And your next question comes from the line of Ritu Biral from TD Cowan. Your line is open. Good morning, guys. Thanks for taking the question, and congrats on this data. It's certainly much more straightforward than I was expecting. Subdomains of QOLB. Will any specific subdomains of the scale that showed particular benefit, and are there subdomains that are of more import to either regulators or clinicians that we should be looking at? And then I've got my follow-up after that. Yeah, so thanks for the question, Ritu. I have to tell you, I fully expected this would be one of those calls where we'd be going question by question and talking about all this stuff in great detail, but the takeaway here was that it was clear, it was consistent across the board. I'll invite Kevin to comment on the specific question about are any of the subdomains performing better than others, recognizing that the overall theme here is that it worked, and so we don't have to dig too deep. Yeah, thanks, Paul. And thanks for the question. So the focus really was the respiratory domain of the larger instrument, as you know, and so from those nine items within the respiratory domain, they all have good psychometric properties and forms of a similar quality, if you will, from that point of view. So, again, we're really excited about this domain. We're still doing some other analyses in the other non-respiratory domains, but the focus has been the respiratory domain where we see clearly that it works well. It works well in this population, and, you know, again, I think it sets us up for success with the ENCQOR with that serving as the basis of the primary endpoint of the ENCQOR study. Got it. And just to clarify, if that is the primary endpoint of the ENCQOR study, you're looking for buy-in that this would be the primary endpoint if it was confirmatory or if it was pivotal? I'm just wondering, like, if you do get accelerated approval based on the ARISE dataset, would FDA then require a different endpoint for ENCQOR, something like survival, something even harder, or is that part of the discussion? I'm sure it would be part of the discussion. Of course, we're open to their perspective. I don't think that that will be the direction they will want to travel. They've been very focused on the PRO, its validation, and its utility in showing benefit to patients. And when it's clear and convincing, they are, as long as it's safe, they're usually satisfied. And I think here, seeing that and seeing the culture conversion and seeing the correlation sets us up very well for that discussion. I want to be clear. We didn't really prepare for today's call with a lot of detailed reflection and interaction about the regulatory approach because we didn't think the data was going to be this good. So we have a lot of reflection and work to do in that regard, and we'll see where it takes us. But certainly, a fast pass would suggest that this is pretty compelling data. The complications that might arise surround things like duration of use, because this trial was only six months. I think that's important to highlight. But I still think that there is a lot to like here. And so we'll be anxious to hear the regulator's perspective. Very helpful. If I could squeeze one quick last one in. Did you manage to get this into ERS? Will it be there at that conference? Did we manage to get it into ERS? Martina or Kevin, do you want to address that? No, we're not. We're actually expecting it to be at a later conference, but as soon as possible. But it will not be at ERS. That was a bit too tight. The timelines have been several months ago, Ritu. I will say this, Ritu. We are all going to be at ERS, so I'm sure this will be the talk of one of the areas of discussion at that conference. We plan to be there in quantity. And your next question comes from a line of Judah Frommer from Credit Suisse. Your line is open. Yeah. Hi. Congrats on the data here. Just going back to the meaningful score difference, I think you guys had talked about an eight-point difference being meaningful in bronchiectasis patients on the QLB. You're seeing 14.8 here for MAC patients. Just want to confirm that doesn't change anything on powering for ARISE, and is that just a new number that we should have in the back of our minds for clinical meaningfulness for MAC patients as we move forward here? Yeah. So the short answer to that question is that's really the essential discussion we're going to have with FDA. This is what these data show, 14.8. We have to go to FDA. They have to view this and interpret it and agree with that. The most important point of this entire discussion today on the PRO is this. Wherever the FDA chooses to set that meaningful patient score difference, error case outperforms. Error case wins. And that is the strength of the data today. So if FDA chooses to set it at a different level, which they could, it doesn't have any impact on us or our perspective with regard to the likelihood of success of Oncor. And as it relates to powering, we think about continuing to enroll to ensure that we are powered with great accuracy to ensure the success of the trial, be it a registrational or a confirmatory study. And that's all we're focused on. We'll update more on that once we have that final agreement on all of these details with FDA. Okay. Great. And then just from your perspective and maybe from Dr. Daly's perspective as well, in terms of potentially pursuing an accelerated path here, can you just remind us of level of unmet need in frontline MAC and how maybe clinicians and patients would react to having a drug approved under an accelerated basis versus potentially waiting for a more robust trial to support the data here? Yeah. And I think my initial reaction to that is, you know, there's nothing approved right now. There's a clear standard of care that is employed in the treatment of these patients. And so, you know, that'll be part of FDA's consideration for the PRO interpretation in terms of primary endpoint of study. But it is important to remember that in Japan, the primary endpoint is culture conversion. And as Dr. Daly mentioned earlier, that's really of primary importance to the clinical community. That's what they're after. That's what patients are after. Importantly for folks on this phone call, that's what the payers are after. They want to know that we're eradicating the underlying bug. And so that's part of why this data is so exciting to us. But Dr. Daly, perhaps you'd like to comment on the medical need of the newly diagnosed. Yeah. Well, you said, you know, we don't have any drug that's approved for treatment of IEU MAC patients. And, you know, we prefer to have drugs that are FDA approved. You know, as a clinician, again, I mean, to see the culture conversion data, that's what clinicians are going to focus on. And to see that it happens so fast, that it was so much better than the control arm. Granted, as we said earlier, it's not the three drug arm that is currently recommended in the guidelines. But, you know, that could change with the study that I mentioned earlier. I just think that clinicians are going to favor something that is approved, that works so well, and so fast. You know, we have these diagnostic criteria, because we actually struggle over this decision to treat a patient with MAC or not. They have to meet the criteria. And even if they meet those criteria, it doesn't mean we treat them. But those criteria are there because our current standard is so poor that we don't want to put someone through a three drug, you know, revamping containing regimen unless we really have to. That's going to change as we have a better therapy, more efficacious, and maybe someday shorter regimen. So I think clinicians will be very excited about the culture conversion rate. Thanks. Your next question comes from the line of Steve and Willie from Stiepel. Your line is open. Yeah, good morning. Thanks for taking the questions and congrats on the data. Maybe just for Dr. Daly, I guess just to further the discussion around the control arm. I know that these are non-cavitary patients. I don't know to what extent you can kind of speak to how you would think about the risk stratification of patients in ARISE. I know there's obviously a lot of attempts to characterize the risk in this disease setting. But just wondering, you know, if you were to get an ARISE patient in clinical practice, would you treat a patient with a two drug regimen or would you use an intermittently dose three drug regimen, which is what I think the guidelines recommend for non-cavitary MAC? And then just have a follow-up. Dr. Daly, over to you. Okay. Yeah, we follow the guidelines. As you said, in someone with non-cavitary disease, nodular bronchiectatic MAC, we use a three drug intermittent regimen. There are patients in which we use a two drug, as I said, if they don't tolerate rifampin or have drug interactions to mitigate it, we may try to find a substitute. That's not so easy because we don't have FDA approved drugs for that. And we will often use air case off-label in practice to substitute as opposed to using the two drug arm because we're still, as I said, waiting for evidence that that is an appropriate thing to do, which we should know next year. So I think the addition of air case to those two drugs, it made such a difference. And remember, from the patient's perspective, they want to be treated as short as possible. And the sooner you culture convert, the shorter your treatment duration will be. And I think that's, to me, as I said, the exciting part of this is how quickly it occurred and because I've just not seen that happen before. Okay, that's helpful. And then just a question for Will. I know the formalized draft guidance for NTM came out, I think it was late last week, and just curious if there was anything in there that you deemed to be, I guess, maybe different than the original draft guidance that came out. There did seem to be maybe some additional language that suggested a little bit more flexibility on the part of FDA. I'm not sure if you share that perspective or not. Yeah, I'll give you my two cents and I'll turn it over to Kevin and Martina to comment. You know, we just came out last Friday. It is largely consistent with what we had seen a year prior. And in fact, we had provided our perspective on the original draft guidance. So nothing in there surprised us. And if anything, I think you're seeing a lot of echoes in the ARISE trial design, you know, that the guidance was contemplating. Kevin and Martina, I don't know if you want to add anything. Yeah, I would just add, I think we see a lot of this, as you said, reflected on feedback that we had provided to the draft guidance. If you see, if you believe there's a bit more flexibility, I think what you've seen is that it could have been a PRO or a clinician or observer-reported outcomes or performance measures. All of these measures would also take a substantial amount of work as the PRO did. And it's important to understand that the tool we've chosen, we validated in this population. So it's the flexibility just means that you can use certain tools, but you still have to go through the effort and demonstrate that this is the right tool for this patient population. But we see no changes that would impact us from a design perspective on anything in the ARISE case program. And yeah, we welcome the guideline. I think it's very well reflecting of the feedback that we have provided to the agency. Very good. Thanks for taking the questions. Your next question comes from the line of Lisa Baker from Evercore ISI. Your line is open. Hi, there. Thanks for taking the question. And I guess just one question for Dr. Daly. Just stepping back, and this has been kind of asked in different ways, and maybe I can just be a little bit more direct about it. You know, the standard of care today, a triple regimen, including rifampin, I mean, what you're asking people to do with ARICASE is to replace and effectively replace rifampin with ARICASE. Can you maybe compare and contrast, you know, what your experience has been using, you know, rifampin as part of the triple versus ARICASE as part of the triple in the data we see here today? What are the differences in terms of how patients are feeling or culture conversion or tolerability? I'd just be curious because that's kind of what we're asking people to do with this regimen. And by the way, congratulations on the data. Dr. Daly? Yeah. So, you know, we don't have data comparing a three-drug ARICASE to a three-drug rifampin regimen in treatment naive, right? This is a different design, you know, because it's two drugs plus the empty liposome. What I can say is that if you look in the laboratory and look at the in vitro activity, amikacin slams rifampin. Rifampin is just not very active. And as I've already said, of all the three drugs, it's the drug we have to stop the most or we can't even use it because of drug interactions. So, with ARICASE, you know, with amikacin, it's just much more active in the laboratory. And it will be a different regimen, of course, with two oral and an inhaled agent versus all oral. But, you know, that makes a lot of sense because you're getting one of the most active drugs that we have, amikacin, you know, in high concentration into the lung and we already know its safety profile. So, I don't see it as a difficult sell to patient or provider when you see the data. It looks better than what we get out of rifampin. And then as you think about your practice, you know, how would you incorporate ARICASE in a frontline setting? Would you use it in all patients, just some patients? How do you think about, you know, reimbursement and stuff like that? Well, for us, you know, here at National Jewish, we see lots of patients with MAC and other NTM. And I think our first group would be those who met the inclusion criteria of the trial and that's what the label will likely reflect. So, it would be non-cavitary disease. And then, of course, with time, we may spread that out off-label and be using it in other patients like those with maybe more milder cavitary disease. So, I think we'd start off basically with the same population that was enrolled. And that turns out to be the majority, the vast majority of patients with MAC. So, only about 20% of our patients have cavitation. So, you're talking about a very large population that would fit into those inclusion criteria. And in terms of tolerability and ability to, you know, kind of comply with an inhaled regimen, can you speak to that? You know, these patients, almost all of them have bronchiectasis. And if they don't, they have COPD. What that means is that most of them should be or will be on some type of airway clearance at some point. So, they know what it means to have inhaled therapies like hypertonic saline, for example. And so, I think that that's not going to be a big issue. I mean, anytime you have to do a nebulized therapy, there's time involved. But again, people will put in the time when they see the benefit. It's the same with inhaled saline. When they see that it's helping them, they don't complain about the time. But if they're doing something like, let's say, inhaled bronchodilator and they don't see any benefit from it, yeah, then they complain about it. So, I think that the results are going to speak for themselves. And particularly, again, fast. If I tell a patient, yeah, I can give you this or I can give you that. But if I give you this, you're going to culture convert faster. That means your treatment will be shorter. Even two months, they'll take it. Got it. That makes sense. And then, just one more question for Will and the team, if I may. The minimally important difference was about 15 points on the quality of life bronchiectasis aspired to a domain score. And in other validation methods that we've checked, I think the Winthrop paper, in particular, described something more like eight. I've seen it even as low as six. Do you have any sense of why it was a bigger delta in particular? So, I can only speak to what we saw in the study. In a second, I'll ask Kevin to go into the arcana of the actual construction of the numbers, et cetera. But I think the most important point is it could be set at six or eight or 14 or 20, and it wouldn't make any difference to us. Because what the DCDF curves show is that at every point, error case outperformed the control arm. So, Kevin, I don't know if you want to speak to how we got to 14 or the range versus the bronchiectasis sometimes mentioned minimally important difference of eight and how that relates to this. Yes. Thanks, Lisa, for the question. So, as Will was alluding to, again, I think within the Arise Encore program, we've been evaluating this in a way that is very aligned with the FDA and their data needs and that required anchored-based measures. And so, that's what we observed. I think where other studies that look at the respiratory domain have not tended to use anchor-based measures and use distribution-based measures. So, independent, again, as Will had said, of whatever that threshold is and whatever the range of meaningful difference it is for a patient, based on our ECDF curves and doing things in a way that's aligned with what the FDA wants us to do using anchor-based measures, our case patients have a higher probability of having a change that's meaningful for those patients. So, hopefully that got to your question. Thank you. Your next question comes from the line of Jennifer Kim from Cantor Fitzgerald. Your line is open. Hey, congrats on the date. Thanks for taking my question. Maybe a quick first one. Just making sure, were the baseline QOLBs fairly consistent across the arms? And then I have a second question. Kevin, do you want to take the baseline QOLB question? Yeah, they were very similar. Yes. Okay. And then a second maybe unrelated question. I noticed you said that the blinded data for the TPIP studies are coming in October. And I know previously you said that data would depend on enrollment. So, is there anything you can say about the enrollment there and what's positioned you to be able to deliver that data in October? And then maybe like how many patients in PAH versus PHLD? What should we expect? Thanks. Yeah. So, we obviously don't know what we're going to have in hand by then. PAH studies generally enroll slowly, and we're no exception to that rule. But I think that some of what we're seeing in terms of what we've talked about before is sharing titration data and looking at the data on a blended and blinded basis is giving us some information that we think may be valuable to share. And so, I think in one form or fashion, we're going to find a way to to share that information between the October call and the subsequent months. We think it's important that this get out there. And again, this is not the call for this statement, but I will just tell everyone who's listening, I think TPIP is a big sleeper inside this company. And once you're going through this data, I would encourage you to dig more deeply into the potential for that compound and what it would represent to both PAH and PHLD patients. And we'll try to arm you with some data to lean on in that respect as we move forward in the coming months. Okay. And maybe one more question just on on-core. As you think about those continuing enrollment in 2024, is there a way to think about, I guess, the size of additional patients that might be reasonably expected to enroll in that extra time period? Would it be like in the 50s or a magnitude of 100 or any color around there? Thanks. Yeah, we don't have any color on that yet. And I think when we do finally get to where we're going to land on sizing and the expected timing, we'll certainly share that. I think we want to have, first, an understanding of where we are with regard to the PRO and then any possibility in any of the different regions of an accelerated approval, whether that's going to happen or not, because that will also inform how we think about that trial and timing, etc. Okay, that's helpful. Thanks again, guys. I'm encouraged. Thanks. Okay. Your next question comes from a line of Greg Savanove from Mizzouho. Your line is open. Okay, thank you. Congrats on the data. Just two quick questions for me. First, for Dr. Daley, given his patient population, is there any sensitivity from these patients from a pricing perspective, from the drug perspective, given the current standard of care or the triple antibiotic or the double antibiotic regimen versus error case? I just want to get your thoughts there on how price- or cost-sensitive these patients may be. And then my second question, maybe for Dr. Daley or maybe for the company, just on the strength of the data, do you think there's a possible impact that enrollment rates in Oncor could even accelerate? And maybe you'd get to your 250 before the end of the year, just trying to think about, given how positive the data are, whether there's a positive impact on future enrollment. Thanks. Yeah, Dr. Daley, I'll just ask you to address the first one, and then perhaps I can address the second. Okay, thanks, Will. Well, certainly, cost is important. But for an FDA-approved drug, that is usually going to be covered by insurance. So that becomes less of an issue. Obviously, when we're trying today, for example, to get drugs that are not FDA-approved, newer drugs, for example, that is a big barrier to being able to get them, is their cost. But again, these are not approved drugs. So I think with an approved agent, that's going to put us in a much better shape. And again, it's kind of hard to decline the data, right? I mean, the data just are showing how positive this is in terms of both PRO and culture conversion. So we will, even if we got a decline, believe me, we will appeal that. Because it's just, it'd be very difficult not to give my patient what I think would be the best option for their treatment. Yeah, and I think just on the heels of that, I would say, obviously, with the strength of the data, we certainly expect this to get a lot of attention. And that could, as has happened in the past, accelerate enrollment rates. But we want to sort of see where that goes before we make any comments about that. So we'll be back to you, Greg, with guidance on what we're seeing in enrollment as the months unfold. Thanks, Will. You bet. Your next question comes from the line of Joseph Schwartz from Lear Inc. Partners. Your line is open. Great. Congrats to the entire team on such strong execution for a major undertaking. I was wondering if you could talk some more about the MID for the QOLB and tie it back to the actual questionnaire, if possible, and just to put it into perspective for us so we can imagine what degree of improvement that would make in a patient who has NTM in terms of their daily life and whether, in terms of like the notches of improvement, I think is how the questionnaire works. And I think that because the data is somewhat transformed when it's calculated. So what does that actually mean in practical terms? And then were there any patterns at all in terms of the items that are captured in the respiratory symptom questionnaire in terms of cough or sputum or breathlessness or anything else that were noteworthy? Thank you. Yeah. So thanks for the question. I think the first part of your question really goes to the heart of the importance of the anchor score. And following that practice, as Kevin was discussing earlier, is the key to being able to associate what the point difference is and what it means to patients. Because it has to be associated with a one-point difference along that PGIS score. And in terms of the details around that and the patterns that we may have seen or observed, I don't know. Kevin, do you want to take that one? Because this goes back into the weeds of PROs. Yeah. Sure. Just thanks for the question. So I think just broadly speaking into this and that, we did not observe any unique items that drove the overall score as we were evaluating the instrument. And so each item was contributing very similar information to the overall change in that score. And as you were alluding to, that score is a scaled score. So, but I think as the score presently exists and is computed and scored, you know, we don't see any reason that we have to modify it at all. And we're excited about that and think that this sets us up again for a great path of success with discussions with the FDA and the ENCQOR study. Okay. Thanks. And then how many points of improvement is ENCQOR powered to show? Any insight that you can share on that front? So we haven't gone into that kind of detail. And I think at this point, given what we now know, we can revisit sort of how to think about that from a powering perspective. And there are obviously other influences there now, particularly whether this is registrational or confirmatory and those sorts of things. And once we have greater clarity around all that, we'll come back with as much guidance as we can to ensure we're as transparent so everyone can gain the confidence that we now have that ENCQOR is going to work, both statistically and clinically. Yep. Makes sense. Thanks for taking my questions. You bet. And there are no further questions at this time. I will now turn the call back over to Chair and CEO, Mr. Will Lewis, for some final closing remarks. I just want to thank everyone for joining us today, in particular, Dr. Daley. Thank you for spending your time and observations, sharing your observations and thoughts. Have a good day, everyone. This concludes today's conference call. Thank you for your participation. You may now disconnect.
