BridgeBio Pharma, Inc. (BBIO) Earnings Call Transcript & Summary

Good morning. I'm just going to mention the research disclosure for important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. Neil Kumar, very nice to see you and what a difference a year makes. My goodness, when we were sitting here last year, we were having very different discussions. Congratulations on your stunning clinical trial results, both in ATTR-CM and achondroplasia. You've got quite a portfolio, and I think there's going to be a lot to discuss today.

Thanks for having me, and I appreciate it, hosting in the downtimes and I'm so excited for the conversation.

Great. Well, let's start with acoramidis in terms of the recent clinical trial data, and it was also updated at the European Society of Cardiology, and perhaps you can provide some background and we can dig in.

Yes, happy to. As I think most people in the room know ATTR-Cardiomyopathy is one of the larger unmet needs within the genetic disease space. And within the confines of that marketplace, which is now about $4 billion and growing at a 55% CAGR represents about 350,000 people in the United States. We are attempting to design a best-in-class small molecule stabilizer. And as Jessica just mentioned, we announced our Phase III data and presented the full results at the European Society of Cardiology just a couple of weeks ago. And we can delve into the details, but long story short, what we saw as a result of that trial simply put was people surviving more and going to hospital less than has ever been seen before in this disease space. And in fact, even more profoundly, what we were able to show in that clinical trial was on top of improved medical management with an ever more potent stabilizer we were able to achieve survival rates that approximate those of people without ATTR-Cardiomyopathy and hospitalization rates would approximate those without ATTR-Cardiomyopathy. This is the first time this has been shown in this space and there are reasons for it in terms of improvement in the molecular thesis that we can talk about. But overall a hardening data set, and I think a lot of excitement amongst physicians and patients for another therapeutic agent here.

Great. Well, thanks very much. I mean the data set was very comprehensive. I think you reviewed many metrics. And obviously, there's a competitive landscape out there. Perhaps you'd like to touch on some of those parameters, obviously, survival and hospitalization are extremely important, but I think there were some other exciting metrics that allow for differentiation.

Yes. So one of the things that I think was very exciting about the trial was you had both the outcomes and you had continuous variables, against which one could both measure the action of acoramidis, which is our stabilizer as well as the action of tafamidis because we had tafamidis drop in as part of our trial. And so going back to the survival rates, which outstripped what has been seen before, the first thing you can look at is how many patients are actually improving over 30 months. And you can look in that across a number of these different variables, anti-proBNP is one of the better -- varied predictors of downstream mortality. And what you could see there for the first time was actually 45% of patients improving against NT-proBNP over 30 months. The placebo rate of improvement is about the same between our trial and the ATTR-ACT trial with the families, you see those improvement rates in the 20% range or so. And similarly, on 6-minute walk distance, you can see again about 40% of patients improving over 30 -- actually walking further than they did outside of the trial on drug, and that's about 20% in the ATTR-ACT trial. So there again, across functional outcomes like 6-Minute Walk Distance, Kansas City Questionnaire, et cetera, and across continuous variables like serum TTR where we saw a 42% improvement as compared to tafamidis. You can see the contours of a more potent stabilizer and the contours of more potent stabilization leading to better outcomes in an apples-to-apples comparison.

Fantastic. So from your perspective, what are the next steps for regulatory approval basically moving towards that?

Yes. So I think in terms of regulatory approval, obviously, the next immediate step is the submission of the NDA. We have been in touch with the FDA. We're also obviously submitting in parallel to EMA and regulatory authorities in Europe. My expectation is priority review are not really the [ cleanliness ] the dataset. I think everyone here saw everything sort of lined up on the forest plot have been a part of that many trials that sort of that type of consistency even with CVH where we had never seen that before, points us it's all in the right direction. So I'd imagine we've been looking at a launch sometime about late summer or early fall of next year.

And you touched on priority review. What would be the underpinnings of a priority review? And when would we know whether [indiscernible] review is being...

We probably would know beginning of next year. I think it's a long shot basically because tafamidis is already out there but I do think that we would have priority review like time lines. If we've got priority review that -- that's an upside. And I think we'd be launching in July in that case. But otherwise, I do expect an August or September launch.

Right. Okay. Great. You touched on tafamidis. Obviously, there is a competitive landscape. I mean how would one think potentially about the label and key differentiating points that could come from that?

Yes. I mean we have, yes, an interesting slide that we'll include in the next version of the corporate deck, but you can sort of see the labels lined up side by side. Obviously, the primary endpoint was the exact same. So there's not too much of a difference up there. But where you start to see the differentiation really begins with the absolute survival rates, 81% versus 71%. Obviously, the relative risk reduction in cardiovascular hospitalization here was profound, and on a relative basis, much greater than what we've seen in ATTR-ACT. In ATTR-ACT, you had a 30% relative risk reduction. That was only after applying a certain analytic technique called the negative binomial annual mean frequency of hospitalizations went the wrong way for them. In our case, across any analytic technique we see a 50% relative risk reduction in hospitalization. So -- and that's right, clearly on the label. I think stay tuned also for what we're going to present to AHA. We'll see more around the time series associated with that and other data that would go into the label. And then the final piece of the label that I think is going to be important, and it gets back to this improvement piece are the pharmacodynamic and other measures of outcomes that were key secondaries in there and showing what fraction of the patients we were able to improve.

Okay. There's an AdCom for patisiran, obviously, not a stabilizer, but in the field. Any potential takeaways in terms of the impact with respect to your product positioning?

We won't have an AdCom, and there's not -- it's not immediately clear. Obviously, this AdCom is focused on the clinical meaningfulness of the 6-minute walk distance outcome there. I think what was interesting about the briefing document that the agency put out and what we'll be listening for, at least on our side is how physicians think about the combination of a stabilizer and a knockdown. The agency was very clear that they saw no compelling evidence to stack one on top of the other. That is primarily how it's being used since I would guess -- since if you have a cardiomyopathic patient, you do have an agent with outcomes -- and you seem to have 2 agents with outcomes. So that, I think will be an interesting piece of competition. But other than that, I don't think there's much of a read through.

Great. You mentioned American Heart, which is in November of this year. But any other additional next steps with respect to the program? I think there has been at least some thought about an additional clinical trial.

Yes. Yes, good question. Yes. So very excited about American Heart Association and further data reinforcing the differentiation story that we just started to tell at ESC. And then I think we're going to -- and we've been public about starting a primary prevention study. This is a mass action disease. What's happening over time is that toxic monomers [ combine ] together and building up in your heart. We're finding these patients earlier. We see that in our clinical trial, and we see that in other contemporary clinical study. So if we are able to find those patients and then get them on a potent stabilizer early, we think that's the best of all worlds and potentially we could improve patients or stave off even the onset of significant [ attack ]. So that -- ACT early trial that we've been discussing will kick off in short order. And then we're thinking about other ways to basically continue to establish the picket fence around our brand in terms of the superior stabilizer. And that could take on any number of forms in terms of double-blind head-to-head and studies within certain subpopulations. I think you saw at ESC a really nice poster where biochemically we demonstrated the differentiation of our stabilization across all of the salient mutations. And you can see in the V122I mutation again, twice as good stabilization. Biochemically, we see that, but tafamidis will be poor on its KD1 and 2 in that context. So that could be an interesting subpopulation to run a double-blind head-to-head and we just have to think a little bit more about how to power that trial.

Great. Fantastic. Any questions from the audience with respect to this program? No. Okay. Well, that was very comprehensive. Perhaps we'll move on to infigratinib and achondroplasia. Again, I think we had some stunning Cohort 5 data from the Phase II and excellent profile from a product positioning standpoint. Perhaps we can start with that marketplace and the positioning of the program.

Yes. So again, just as a reminder for folks, achondroplasia affects maybe 50,000 people and related conditions maybe double that with hypochondroplasia. The good news about the condition is that it's very well described, uniformly stems from a gain-of-function mutation in a receptor called FGFR3, and we have a small molecule that targets the disease at its source. The design principles behind the program to start, we're, number one, to maximize efficacy by actually targeting disease at its source, all of the competitive agents that I'm sure we'll get into Target 1 of the 2 effective pathways downstream and don't turn off the gain-of-function signaling. So that's what we're hoping to do is to take the gain-of-function signaling and normalize it. The second was to do it more safely. As you may know, many of the competing agents to date have come out of the hypertensive literature, so they have hypertension and injection site reactions associated with them. And then the third was to do it much more conveniently with a single daily oral or a single daily sachet that you can mix into food because these drugs are going to be indicated for folks that are below the age of 14 and oftentimes very young.

Great. And maybe you can touch on the actual clinical trial results to [indiscernible] were in comparison to the competitors?

Yes. So we had a Phase II that we read out at the beginning of this year and then updated recently at an ENDO Conference.

Got even better.

And it got even better. Yes, that was nice to see as we updated it. So we had change from baseline average height velocity in excess of 3 centimeters per year. But I think more importantly, honestly, were a couple of things that have occurred actually over the last couple of months, and it may have been missed in the context of the excitement around TTR. Number one is and consistent with what we've seen in animal models. When one takes the mechanism that we are employing, one should not only be able to have impact on height velocity or growth velocity, but also some of the other symptomatology associated with the condition. And that includes things like spinal stenosis or proportionality. And excitingly at ENDO, we presented some preliminary data around the impact that we were starting to see on proportionality or we didn't review the KOL who was presenting our data did. That was further buttressed by the engagement we had with the regulatory authorities that basically encouraged us to go for a broader label even outside of growth philosophy. So not only do we think we're going to have double effectively the growth velocity that has been seen with the CMPs. And not only do we have a more convenient product, but I think the opportunity for us to really address the broader suite of symptoms that are relevant to these kiddos is going to be important. So that's, I think, what's really exciting.

I mean you actually disclosed that you recently did meet with the FDA and EMA. And I think you've got your Phase III clinical trial design set, had some feedback, perhaps you want to touch on a little bit more on the feedback from those discussions.

Yes. Yes. Thank you for that opportunity. I think a lot of the questions that were certainly arising amidst our operators and investors alike were what would that Phase III look like? Could we actually do a year of data and you do the run and then you have a year of on drug. And certainly, the regulators were very comfortable with that. And again, encouraged us to go for a label that was less than 5 go all the way down to 3 years so that we can start as early as possible, like many of the conditions that we work on, that should hopefully lead to better efficacy over time. And then encourage us to look at some of the secondary endpoints so that we could broaden the label. I'll say, within the context of the interactions that we've been privileged to have with the agency, there were some worry in the community that the agency was getting harder and harder on genetic disease, but I would say under a commissioner or [indiscernible] leadership, we've seen across limb-girdle muscular dystrophy type 2i and in the achondroplasia and hypochondroplasia world and certainly with Cardiorenal, which has always been just a wonderful division to interface with a very, very productive set of conversations for us this summer. So thankful for that.

And I think you expect to commence the pivotal trial by the end of...

Yes, the run-in is already going on. And so yes, we'll dose our first patients here shortly.

Great. Well, maybe we could circle back on the competitive landscape. And again, infigratinib positioning within that.

Yes. So I mean, I think the concept of maximizing efficacy with a more convenient, more safe agent is hopefully pretty obvious to most people here. The focus on additional symptomatology, I think, will be a benefit to the clinical community and the kiddos that we're trying to serve. I would say one thing that's really important to mention is that the median patient on our Phase II had an AHV in excess of 7 centimeters per year. 7 to 9 is kind of like where I'm hoping my 2 children are on a year-to-year basis. And so what that means is you've effectively been able to get to the top of what that efficacy range is because the tox that we saw in our Juvi tox models was effectively too much growth. And that is actually something that both physicians and the agency worry about. So there's no more efficacy really. We had several children that were right at that 9 level. So there's not a lot of efficacy remaining now to go above. So I would say just competitively, we sort of top tick that efficacy piece and alongside of the safety that we've demonstrated and the oral convenience, we feel good about both the opportunity for switching as well as the opportunity for new starts.

Great. You also mentioned that you'd be developing infigratinib for hypochondroplasia. Perhaps a little bit of color on that dimension. And again, read-throughs that potentially you have from hypochondroplasia in terms of clinical trial designs...

Yes, yes. So hypochondroplasia is a condition of similar size actually to achondroplasia. It stems from gain-of-function mutations -- a gain-of-function mutation in FGFR3. It's just a different gain-of-function mutation. Achondroplasia is associated with G380R, hypochondroplasia associated with N540K. Interestingly, that leads to a little less gain-of-function signaling, which we've shown in animal models very similarly to achondroplasia that we're able to normalize. It also leads interestingly and no one really knows why to some CNS associated sequelae which I think is generating a lot of the excitement around infigratinib for this indication because infigratinib is brain penetrant in a way that obviously, the CMPs are not. And so our hope is that we kick off that trial sometime probably late this year or early next year. We'll do a quick proof of concept sort of analogous to what we did in achondroplasia and then we'll move into hypochondroplasia. So we'll be a little bit behind, but right on the heels of BioMarin in there. And then the sort of interesting question becomes where else might you take an agent like this. There's a suite of other conditions, often much more devastating that are associated with FGFR2 or FGFR3 gain-of-function mutations. We'll be looking to take our drug as quickly as possible into those indications again towards the end of this year, beginning of next year. Those are smaller, all told, maybe 3,000 patients in the FGFR2, 3-driven skeletal dysplasia world. And then genetic short stature, potentially. You can see BioMarin and others lagging into these areas. And I think we would aim to either be a fast follower or if there was a clear biologic rationale, we might go into 1 or 2 of those, but we have to be a little thoughtful there.

Great -- any questions on infigratinib? Okay. Thank you. Well, now there's such a broad portfolio here. We'll have your next -- and color in terms of Phase III that's reading out in ADH1 first quarter '24. Perhaps provide the background in terms of the current clinical data set and the market that it's addressing.

Yes. So autosomal dominant hypocalcemia type 1 is a disease that paradoxically now people ask us about, but it is a very common disease. It's a 10,000 to 15,000 folks that are unfortunately affected by it. It's very well described in the sense that you have gain-of-function mutations in something called the calcium-sensing receptor, which is kind of like the thermostat for calcium in your body. So when you have these mutations, you have low serum calcium, high urine calcium. The standard of care is calcium supplementation, which exacerbates the urine calcium piece of this, and it doesn't come close to rectifying the serum calcium piece. And all we're doing is targeting those well-described disease at its source as we always do with a negative allosteric modulator of the calcium-sensing receptor. And what we showed in Phase II very briefly was probably the most profoundly positive data set I've been privileged to be a part of because of 2 things, one is targeting the well-described disease at its source, able to normalize serum and urine calcium. But the second is serum urine calcium are the end points. So when you're dealing with death, hospitalization, growth, there's high variance on these endpoints. We have agreement with the agency that the endpoint here is the rectification of serum and urine calcium, which has much tighter percent go variance. So that trial is reading out as you said, next year, and I think the probability of technical success is quite high there. So really, the game there is market building. And the good news is we're finding substantial numbers of people in a well-described community, which is nonsurgical hypopara. That community basically is about 30% actual ADH1 patients. And so we think we've got the right funnel. I think we've got a great drug. I'm excited for that opportunity.

That's fantastic. Great. Okay. Well, we've got a fourth product that's in pivotal trials with respect to limb-girdle muscular dystrophy type 2i as you mentioned. Again, great to get the background on that. And anticipated clinical readouts that are coming there.

Yes. Thanks for raising that one. I don't think this is in the vein of these positive regulatory interactions that we've been privileged to have. LGMD2i is the most common of the limb-girdle muscular dystrophies. I think some 7,000 folks out there, again, uniformly caused by mutations in an enzyme called FKRP. And once again, we're targeting is well-described disease at its source by providing substrate for the partial loss of function enzyme to rectify the issue with the disease, which is low levels of alpha-dystroglycan glycosylation. And if you reverse back and look at our recent Phase II data, what one can see is that we're meaningfully, almost twofold elevating the amount of glycosylation in patients and compared to natural history, helping to stave off and normalize things like 10-meter walk time and modified North Star test. The question for the agency was, could we apply for accelerated approval analogous to DMD, given the well-known path of mechanism and the unknown variability associated with modified North Star, which is modified North Star and 10-Meter Walk Time which are their functional endpoints. And again, I've really been in FDA meetings that were so positive. I think that they were meaningfully persuaded to say, "Hey, look, like you guys can apply on a primary endpoint based on glycosylation of that complex." That was the product of several meetings that we had over the course of months before educating on path and mechanism unmet need as well as demonstrating the receiver operator characteristics of our Western blot and the way that we're measuring glycosylation. But I think that's another exciting program that could read out late next year, early 2025.

Right. Fantastic. Well, great. Well, again, congratulations, four programs in very late-stage development. You've got a little bit -- you've got some more products in the portfolio. I don't know if you want to touch on some of the approaches in oncology or other areas. And I guess, perhaps for the audience, kind of understanding how you spend your time, prioritization given the plethora of activity that's going on.

I won't belabor the remainder of the pipeline. I'll just say that we do have a lot of ongoing research, and I'll mention that the two attributes of that ongoing research that we tried to do to regardless of whether it's oncology or congenital adrenal hyperplasia, which obviously with some exciting news from Neurocrine today, is that, number one, we're targeting well-described diseases at their source. So hopefully, it's high-probability technical success. And number two, we're trying to do it pretty cheaply. And I think people haven't really appreciated the fact that we did ATTR in $58 million, and we did infigratinib from where we got it from Novartis through this Phase II in $70 million; ADH1 in $45 million. So these are the types of things that I think we producible we can make NPV positive for investors and really help patients in a big way. Yes. So happy to take questions around any of the other pipeline program. I spend my time working with great people. I'm very privileged to have an outstanding team of drug discoveries and developers. So it's easy for me. I just get to talk about it. And they've done a lot of work.

Great. Well, it might make sense, Neil, then just to think through kind of the key milestones through the end of the year 2024, and the fact that you're on the verge of commercialization. How you're preparing the organization in terms of that transition with respect to getting products out to patients?

Yes, that's a good question. Obviously, the focus right now is the preparation for a seamless NDA submission and launch in ATTR-Cardiomyopathy sometime late next year. We've had a commercial organization on the ground. I think it's probably less well understood that we have gone through two approvals that were very small products in both cases, but they helped us build the muscle memory of high-quality NDA submissions and what launch might look like. Obviously, this is a much bigger market that we have our commercial plans in place and we'll continue to update people on that as it goes along. Our best guess is that $300 million, $350 million away from brand profitability there, $600 million away from total profitability for the company. And so I think people can expect that we'll capitalize in a shareholder-friendly way the company going forward since we're always sensitive to dilution and things of that. Yes, then I'd say, finally, as we look at the late-stage pipeline, we want to make sure that we're excavating all of the additional indication opportunities. We talked about hypochon. ADH1, there's not an immediate obvious next indication, but there are a few for the remainder of our oncology assets. So I think all of those things are happening over the next 12 to 18 months. But I'd say the big catalysts are AHA, probably upcoming and in the NDA submission in our label on TTR. The remainder of the Phase III is once they start reading out in '24 and our congenital adrenal hyperplasia Phase II data that I'll read out sometime late this year, early next year.

Well, again, I think it's a really impressive list of activity that are going on. And I guess it is global, right? I think, in terms of you developing these products for global distribution.

For now, yes. Yes.

Okay. Fantastic. Great. Any questions from the audience? No. You've been doing a great job here in terms of summarizing all the activities.

Same number of questions I got last year, but there were 3 people in the audience.

Well, maybe just to circle back because I think it really is important for people to appreciate how robust the clinical trials designs have been and then obviously, the [indiscernible] results. You mentioned AHA. How do we think about the additional data that's going to be disseminated at that point as you're obviously on a path to filing your NDA?

Yes. I mean I think one of the things that we always focus on is working with the KOLs to ensure that we're excavating the information that's really important to them. And in this case, the information that I think is very important has to do with both the timeliness of impact for these ever more potent agents as well as what might improvement look like? What's possible at the heart. I can remember going back to MyoKardia when we were just putting that together, that thought that you could rectify the aberrants in the chemomechanical cycle, could the heart actually improve? Could the heart actually improve here? So those are the types of things we'll be looking at over time. I won't say more about it because I don't want to steal anyone's thunder in terms of abstracts and presentations. And then the second thing is just learning more about what the right setting is for these potent agents. And my hope is, again, is not to belabor the point that earlier the better for the patient population here.

Great. Okay. Well, good. Well, thank you very much. And thank you, everyone, for joining us.

Thank you. I appreciate it.