BridgeBio Pharma, Inc. (BBIO) Earnings Call Transcript

Good day, and thank you for standing by. Welcome to today's discussion with BridgeBio, which we will cover for the company's additional data from ATTRibute-CM as presented at ISA 2024. [Operator Instructions]. Please be advised that today's conference is being recorded. I would now like to introduce you to the speakers for today: Dr. Neil Kumar, PhD, CEO of BridgeBio; Dr. Mathew Maurer, MD of Columbia University Irving Medical Center; Dr. Ahmad Masri, MD, MS, Oregon Health & Science University. I will now hand it over to Dr. Kumar.

Thank you, operator, and thanks, everyone, for joining this call. I'm grateful to be joined today by the BridgeBio team and Dr. Masri and Maurer. Two physician scientists, pioneers, whose work has helped for this hopeful moment in the ATTR cardiomyopathy field. All of us around the table have felt the energy these last couple of days at ISA and the advances being made in understanding disease path mechanism, diagnosis, early treatment, matching the right treatments for the right patients and patient and family support all auger well for a better future. Today, after I provide some brief context, Dr. Maurer will present findings that tie ever higher levels of stabilization as measured by serum TTR to ever better clinical outcomes, a core belief underline the design of Acoramidis. And Dr. Masri will present findings that look at CV hospitalization, a key component of the composite endpoint in modern trials, given the dramatic decrease in mortality events and the lack of impact Tafamidis generated on CV hospitalization. Dr. Masri will look at the relationship between CV Hospitalization and overall survival in the context of current stabilizers. Before we get into this exciting content, I'd like to provide some brief context. And I guess, even before that, I'll remind everyone that I'm making forward-looking statements today. The slide deck associated with this call is publicly available, and we'll refer to specific slide numbers as we progress in this discussion. I'll start with what's always the most important slide in our documents, Slide 3, a thank you to the amazing and inspiring patients and families, advocates, physicians, clinical research staff and collaborating research partners that make our work possible. We've had the privilege of meeting many of you here this week and hope to do even more of that in future conferences. Yours are the efforts that make whatever impact Acoramidis is to have possible, and in turn, we recognize our responsibility to you to move expeditiously, to provide this medicine to patients as broadly as possible and to engage in deep research. Moving to Slide 4. I wanted to touch briefly on the design principles that we believe underlying our best-in-class hypothesis. Design objective #1 was to create a compound that will continually maximize TTR stabilization for all patients and therefore, minimize the toxic consequence of the destabilized TTR tetramer. Several lines of evidence that complement the research being presented this week suggests that maximizing stabilization should lead to ever better benefits for patients, including, first, historical genotype, phenotype data and the disease productive properties with the [indiscernible] T119M variant. And secondly, the outperformance of the 80 mg tafamidis dose, which is about a 60% stabilizer versus the 20 mg tafamidis dose as previously published in the ATTR-ACT trial. Design objective #2 was to pair toxic monomer minimization with the preservation of the TTR tetramer. A protein responsible for vitamin transport to the eye, a protein that no known species lacks or is haploinsufficient for and a protein that is maintained at high concentration throughout the course of life. Attendees at ISA heard a pretty interesting talk yesterday from Dr. Buxbaum, raising the intriguing potential advantages for keeping TTR around in the long term. On Slide 5, you see much of what the research we are conducting these days relates to. In any disease setting, BridgeBio works on, our goal is to connect the dots so we can form a coherent global understanding of how drug molecular path of mechanism and outcomes all relate. In ATTR cardiomyopathy, we began on the shoulders of tremendous work that have been done linking human genetics to stabilization levels. I referred to some of that on the last slide. Our ATTRibute trial allowed us to connect ever better levels of biochemical stabilization to impact on serum TTR and NT-proBNP. Today, we extend from these measures of evidence of disease and treatment response to hard outcomes and ask how predictive changes are to the well-being of patients. Furthermore, we ask how these hard outcomes interrelate, making crucial connections between going to the hospital less and surviving longer. In all, our goal is to continue to fill in the blank so that we can connect more stabilization to more marked improvements in serum TTR and NT-pro to staying out of the hospital longer, surviving longer and feeling better. Moving to Slide 6. Amidst all of our evolving understanding of the connect dots picture. We tried very simply to articulate the value of a more potent stabilizer to patients and physicians. Simply put, people survive more and go to the hospital less. They improve more and the impact on composite outcomes begins earlier. Slide 7 contains data we have presented previously, showing survival rates north of 80% and close to that of a similar population without ATTR-CM and hospitalization rates of 0.29, again, close to the similar population without ATTR-CM. Rates of 40-plus percent improvement across measures like NT-proBNP and 6-minute walk distance or higher than anything we've seen before. And finally, separation of 3 months on the composite endpoint accompanied by a 42% relative risk reduction and a p-value of 0.0008 stand as the most compelling data we've seen in that arena as well. Slide 8 then builds on these prior data with recent data. I won't walk through at all, but I'll say personally that I'm very excited by, although it's small n, the data that were generated separately in our Phase III Japan trial and the poster that was presented, I believe, yesterday out of the [indiscernible] lab that suggests one can achieve 100% survival with Acoramidis. That, coupled with, again, with small n, evidence of disease regression with Acoramidis alone, as presented recently by Dr. Fontana portends a brighter future for patients with ATTR cardiomyopathy. Slide 9. I won't go through the details here outlines the work we are privileged to do alongside the clinical community of investigators. As we promised when we started our ATTRibute trial, we are moving fast to interrogate the results of that trial and to launch new studies as well. And moving to Slide 10. In that spirit, we are live at the exciting content for today, today's focus, two compelling presentations from world leaders in cardiovascular medicine. I'll ask Matt Maurer, Professor of Cardiology in Columbia University to proceed first. He's going to cover Slides 11 through 14, and then we'll have the privilege of hearing from Dr. Masri, Professor and Cardiologist at OHSU who's been a pioneer and whose work I followed in both ATTR-CM as well as in hypertrophic cardiomyopathy in related areas. Dr. Maurer had to jump on a flight. So he actually recorded his comments a bit earlier. So let's turn around and start those comments and then we'll come back to Dr. Masri.

On behalf of my colleagues, it's my pleasure to present our poster entitled Early increases in Serum Transthyretin level is an independent predictor of improved survival in ATTR cardiomyopathy: Insights from the Acoramidis Phase III study ATTRibute-CM. The objective of this brief report describe the Acoramidis mediated changes in serum TTR, which are an in vivo measure of TTR stabilization and its relationship to all-cause mortality in the ATTRibute-CM trial. As you know, patients with ATTR cardiomyopathy can have lower circulating levels of Transthyretin, also known as prealbumin, which are associated with worsening cardiac function and an increased risk of subsequent mortality. Acoramidis is a novel high affinity TTR stabilized, which achieves greater than 90% TTR stabilization in patients with Transthyretin mediated amyloid cardiomyopathy. In the pivotal Phase III trial, ATTRibute-CM, Acoramidis met at the primary hierarchical efficacy endpoint with regards to mortality, morbidity and functional components as compared to placebo. Acoramadis treatment also resulted in a 25% relative risk reduction in all-cause mortality and a 30% relative risk reduction in cardiovascular-related mortality. Details of the ATTRibute-CM trial have been published previously. In this analysis, modeling and simulations were performed to describe the population pharmacokinetics of Acoramidis and evaluated safety and efficacy of ER relationships for Acoramadis. ER relationships are modeled for all-cause mortality as compared with Serum TTR levels. Change from baseline in Serum TTR showed observed measurements without any imputation. Baseline clinical and demographics were very comparable between the two treatment groups. Increases in Acoramidis concentrations were associated with serum TTR concentration. Acoramidis treatments increase Serum TTR levels, as shown in Figure 1 as elevations remained stable through month 30. As shown in Figure 2, serum TTR levels from baseline to day 28, predicted survival in a univariate analysis for the overall population with a highly significant p-value and the Acoramidis treated population. And as shown in Figure 2, the probability of all-cause mortality as a function of a change in serum TTR levels was highly and statistically associated with increases in serum TTR being associated with a lower risk of all-cause mortality. For every 5 milligrams per deciliter increase in serum TTR, the risk of death was reduced by 30.9% by logistic model and 26.1% by the Cox proportional hazard model. In a multi-variate analysis, changes in serum TTR remained an independent predictor of all-cause mortality, even after adjusting for baseline demographic variables, use of diuretics, New York Heart class, baseline serum TTR, TTR variant versus wild type and the National Amyloid Center Staging System. In conclusion, results from these analysis suggest efficacies and protective effects of Acoramidis' exposure, resulting in increasing serum TTR levels. and the Acoramidis mediated increase in serum TTR levels on day 28 were an independent predictor of improved survival in patients with ATTR cardiomyopathy even after controlling for baseline covariance. Thank you for your time and attention.

Thank you. And now I'd like to hand the call back to Dr. Kumar.

Thank you, operator. I'll turn it over to Dr. Masri.

Hello, everyone. So I'll be talking about the real-world outcomes of tafamidis. It is a study that we've done across five centers. We presented part of it previously at the HFSA conference, and then we presented more of these data at ISA. Next slide, please. And so these were, again, as I mentioned, five centers, patients were enrolled from 2018 to 2021. And we looked at all-cause mortality and CV hospitalizations. All the patients included were receiving or have received tafamidis. So this was an intention to treat analysis, for everyone who received tafamidis during those time periods at these five centers in the United States. Next slide, please. These are the baseline characteristics. So in total, there were 624 patients, about 109 were variant and then 515 were wild type, the median age was 78, 20% were black or non-white as well and about of these patients, obviously, the V122I for the variant was the most common ones. About 1/3 of our patients had NYHA Class III. And then as you can imagine, the diagnosis method is noninvasive in the majority of these patients. And then you see this that the time from ATTR diagnosis that tafamidis start was about 12 months. That's because some of these patients did not receive their diagnosis once tafamidis was commercially available. They received their diagnosis before tafamidis was commercially available, and that's why they were waiting to receive the drug. Next slide. So this is the primary outcome of All-Cause Mortality. The median follow-up was 1.8 years. 1.1, 2.5 for 25th and 75th for the first and third quarter, and 23% of the patients died. If you've plot this as a probability over 13 months, that would be 70% with a 95% confidence interval of 65% to percent 74%. Next slide. So how does all of this kind of fit together with our understanding. So we set to do this to understand how with the evolving landscape of Transthyretin cardiomyopathy things look like compared to ATTR-ACT trial, and as we were preparing our slides before, also ATTRibute CM reported last year. And so here, you see a reconstructed KM Curve. This is not individual patient data, just reconstructed KM curve showing you Acoramidis & Placebo. So you can start from the top, Acoramidis, Placebo in the ATTR-CM is the red line, and then you have tafamidis for ATTR-ACT and for the real-world data that we presented totally overlapping, both are the blue line there. And then you have the ATTR-ACT placebo being shown as other curves there. Next slide. And so we looked at a few things that you can look up from the ISA posters and presentations. But one of the most important things that I think we gleaned from this is, what happens if someone is on tafamidis and gets hospitalized for cardiovascular reasons. And as you can see here, if one does not get hospitalized in tafamidis, there is about 82% of in terms of survival over our follow-up period versus 56% for those who get hospitalized on the tafamidis. And if you look at the split there for these patients, it's kind of an equal split for the numbers of patients 309 for those who got hospitalized versus 315 for those who did not get hospitalized. Obviously, this is a real-world evidence. So we don't know what sometimes we're missing. This represents what we are able to ascertain as a cardiovascular admission. Next slide. And so these are some of the data we presented at ISA looking at ATTRibute-CM in this example of Acoramidis looking at non-cardiovascular hospitalized patients versus those who was had a cardiovascular hospitalization. Showing you that about survival, about 86.8% for those who did not get hospitalized versus 62.4% on Acoramidis for patients who got a CV hospitalization before. And then when you look at the split in the numbers below the curve there, you can see the subjects at risk below there. Next slide. All right. Thanks you.

Thanks so much Dr.Masri. All right. So Slide 22 summarizes the key information you heard today, our belief is and continues to be that an agent that better stabilizes the destabilized tetramer, and therefore, raise serum TTR more effectively should provide better outcomes and these outcomes relate to each other. Of course, none of this matters if we don't get the drug to market in an expeditious way. And we continue to work with the FDA to ensure drug approval and launch late this year. With that, let me stop there. Thank Dr. Maurer and Dr. Masri, once again and open it up for questions.

[Operator Instructions] Our first question comes from the line of Salim Syed with Mizuho.

Great. Congrats on the data. Maybe, Neil, a few from me, if I can, on the -- on the Maurer presentation focused on Serum TTR increase. So I guess like question one, is, so you guys presented this data focused on using month 30 as drawing the relationship between an early increase in serum TTR in month 30 benefit on death and the cardiovascular hospitalization. Any work you guys have done on potentially looking at an earlier time point just given that you have shown separation at month 3, and I think when we look at the tafamidis data, I think they showed separation closer to month 9, at least on cardiovascular hospitalization. So that's question one. And then just related to that, just curious how validated this analysis is in the context of maybe discussions with the FDA? And just lastly, just your updated thoughts on potentially using this as it means to do an efficient head-to-head study versus tafamidis?

Thanks, Salim. Thanks for the questions. I'll see if I can remember them all. Maybe to start, yes, a good question. I mean, a big part of our analysis is we see the response in terms of serum TTR to be almost immediate. I mean, day 28, you can see a really nice elevation and you can see that that's what allows us to compare at least in our trial, do those intra-trial comparisons as well. And so -- and day 28 is predictive of the downstream, both mortality and hospitalization data as well. So yes, it's a great question. You don't have to wait around 30 months to figure out whether or not you're stabilizing the tetramer, you could almost immediately get that signal. And from this work, you can assess whether or not you're doing it effectively. And if you're doing it more and more effectively, you do have better outcomes in terms of obviously, less mortality and fewer days in the hospital. So that was the first question. Let me make sure that, that answers your questions, Salim.

Yes. I guess like versus tafamidis, I mean is this -- at the root cause of this, do you believe or is there -- or what evidence like -- what's the best argument that you can create that this is why you would have an earlier separation in your curve versus the cross-trial comparison with ATTR-ACT, we saw the separation at least on cardiovascular hospitalization, it's a slightly different chart, right? But they showed it, I think, closer to month 9.

Yes. And on composite, they're like a little -- slightly after month 9, we're at 3, which is mostly driven by hospitalization. So that's exactly right, which is a vast majority of the events in our trial. I mean I'd say the way I think about it is this way, the degree to which you are stabilizing the tetramer, again, going back to our first principles as reflected to changes in serum TTR, is the degree to which you can have impact across the diaspora of patients we're looking at. I think the late separations are occurring not because of some biochemistry or something biologic that we don't understand, but rather because you're having muted impact across the population. And we're just having more effective impact just given the rise in serum TTR and therefore, you can elaborate signal earlier. That's my guess, but we'd have to prove that out in further studies. But yes, you're right to say the immediate increase in serum TTR that seems to be higher, at least in our intra-trial comparisons that are post-hoc exploratory analysis in ATTRibute are accompanied by an earlier separation both in hospitalization and against the composite endpoint. Maybe secondly, like we're not -- we're not going to comment. Don't worry, there isn't anything to comment on specifically about what is in our label or not in our label. Those are discussions that are ongoing with the agency. And so whether or not -- I mean, I would expect that post-hoc exploratory analysis generally do not make their way into a label. But certainly, they can be related to the label, which allows for communication and it can also be published, which will -- certainly the latter will be the case here. And then your third question was what again?

Just on the updated thoughts on potentially using early increases in serum TTR and maybe an earlier time but not month 30. If you ever wanted to run a head-to-head versus TAF, how much of this -- how much could you rely on that measure? Like would the FDA be okay with that or potentially okay? There's a needle moving in that direction just given the data that you showed.

Yes. I think the agency would be open to it. I think the -- I think the question stands as to how the physician community would -- I mean, all of these double-blind head-to-head studies that we're going to do are going to be based on the level to which a physician community would take the final answer and say, yes, we believe that this has demonstrated superiority of one drug over the other. So serum TTR is a very clean one in terms of like percent covariance is dealable with, and I think our drug significantly outperforms the other. That would be my ingoing hypothesis. So you'll be able to power a trial to do that study. But we're going to need to take some time and understand the degree to which physicians really look at serum TTR as a discriminator. And I would say that ISA is a really nice opening to that because there is just a lot of discussion about what to better stabilize or how do we think about stabilization, how do discrepant levels of stabilization lead to discrepant downstream outcomes. Those are all the conversations we're excited to be having, just given the profile of our drug. So we'll probably make the determination closer to launch.

Our next question comes from the line of Joshua Schimmer with Cantor.

I just want to clarify a couple of points about serum TTR as a potential biomarker. First, do you expect -- do you expect serum TTR to be available as a predictor or indicator of response at the time of launch? Or is it going to be -- is it going to require additional trials to have a TTR assay in the market.

Jonathan?

It's Jonathan Fox, Chief Medical Officer. So TTR, as was mentioned in the presentation, is the same as serum pre-albumin. That is a CLIA certified standard laboratory test available in any clinical lab, hospital lab. It's been around for decades. In the past, it's been used primarily by the surgeons to assess nutritional status in patients both pre-op and post-op, as an indicator of whether they need to have more intensive nutritional support, for example. But in the Modern era, now we know that well beyond there, it being an index of nutritional status. It's involved as the central player in this pathophysiology of this disease. Does that answer your question?

Yes. Very helpful. Then how do you kind of envision the assay being used practically to guide therapy. For example, if the patients on tafamidis and the specialist tying to decide whether they should consider switching or not. Is there sort of threshold of TTR level below which they should really consider Acoramadis? Could it be used in that way? And if not, how would you see a guiding therapy?

Sure. Well, at a first level, it is a very clear reflection of the pharmacology of the drug. So we have lots of data that we've published, both in vitro and in vivo that upon initiation of treatment with Acoramidis, that there's a prompt and sustained increase as was shown in the graph that was in the presentation. We actually observed this even in healthy adult volunteers going way back to Phase I, that it's essentially within like the -- even with the first dose, we saw increases in serum TTR. So as a sort of an ability to reassure the patient in particular that, yes, we started this new medicine and we know it's working because we can check this biomarker, this widely available lab assay. We've published and presented a lot of data showing, especially in vitro and ex vivo comparisons of patient samples that have been exposed in the laboratory to different concentrations of the two stabilizers and with very consistent results showing that Acoramadis is a better stabilizer. Does that help?

But well, I guess, you're positioning it as, I guess, a tool to illustrate to physicians, the more powerful stabilization of Acoramidis, I'm kind of coming more from that clinical decision-making tree, especially if they have a patient on tafamidis in front of them, they're trying to decide, well, can I get further improvement? Can they use TTR as some kind of indicator that they could do better in choosing which patients on tafamidis might be suitable for a switch to Acoramidis? Or is kind of the idea, well, you don't know until you try it, so try everybody and see what kind of incremental benefit there may be, if that was...

Yes, that's very clear. The short answer is yes, that there's plenty of data to suggest that even in the individual patient, there's a high likelihood that moving from tafamidis, I mean the situation that I heard you describe sounds like a switch and whether or not you -- the physician might want to consider doing that. They can -- they can measure the serum TTR while on the prior therapy and then, again, on a new therapy and do the comparison in individual patient. I would hasten to add that the data from ATTR-ACT from some of the real-world evidence trials that Dr. Masri presented as well as from our clinical trials program that the -- we usually present either means or medians and we give confidence intervals and so forth. But we're describing the behavior of populations, not necessarily you could easily go into the population and pick out the best responding patients and the least responding patient and try to make a case, but that's not particularly scientific. However, you can take the population-based data and make some reasonable predictions about how it might apply to your patients sitting in front of you in the clinic.

Jonathan, if I may add one more thing. This is Uma Sinha, Chief Scientific Officer at BridgeBio. We've also presented data that individual subjects who during our double-blind study, the individuals who were in the placebo group and got tafamidis, during the open-label extension their TTR rose to meet up with what the Acoramidis group active moiety had in sustaining TTR circulating level. And we've also presented the data that within the double-blind period, the placebo plus tafamidis group had 42% lower levels of change from baseline in circulating TTR relative to the active group.

Our next question comes from the line of Anupam with JPMorgan.

This is Priyanka on for Anupam. We just have one question. So we noted that a tafamidis label was updated in 2023 to list the DDI potential of BCRP substrates, including Crestor, given that many of the older patients require concomitant lipid-lowering therapies, would that DDI potential be anticipated for Acoramidis?

Yes. Thanks for the question. Yes, we did note that the DDI with certain types of statins associated with tafamidis and I'm not an expert as to why that's occurring. But certainly, we don't see anything of that ilk with Acoramidis. It is a clean drug.

Thanks so much for answering my question.

Actually, before we get to the next question, I wanted to go back because Salim asked an interesting question about separations of curves over time. And one of the interesting things about this space is time is a little hard to judge since of the left shift that occurred between the original ATTR-ACT study and the ATTRibute study. So another way actually to look at separation is the percent of events and where drugs separate the curves, if you look at the KM curves at those various percent. So like if you take mortality, we're actually separating the curves at 10% versus where tafamidis will separate at 20%. That's just another way, as actually the number of events that have occurred, if you think about time as an event-driven thing. And so it's very interesting to note that a sicker patient population is where they start to see the separation, we are seeing it at an earlier and healthier "time point" in terms of events. But another interesting way to think about that data.

Our next question comes from the line of Paul Choi with Goldman Sachs.

My first question maybe will be for Neil since Dr. Maurer is unavailable. And can you maybe just remind us, if in this analysis of serum TTR changes, is this inclusive of the CKD population? And if not, what does that data cut look like for that CKD population? And also if you add it into the modified intent-to-treat population in terms of the survival changes in other metrics?

It's Jonathan Fox, Chief Medical Officer again. I mean basically, we did the analysis both ways, and there's no difference in the outcome. Just to remind you that the CKD population with eGFR less than 30 was a rather small subgroup of 20-odd people. So the -- you wouldn't expect it to have any real impact, including them in or not. But yes, the results across this analysis as well as across the analyses of the primary endpoint when we went back and did that on the ITT population as opposed to the MITT population gave the same result. If anything the measurable survival benefit even in that sick population with low renal function actually boosted the statistical significance of the all-cause mortality signal when looked at by the Mantel-Haenszel statistical analysis.

Okay. Great. My second question is for Dr. Masri, if he's available. Just in terms of the slides, it does indicate...