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

Thank you for standing by, and welcome to the UBS Health Conference fireside chat with BridgeBio. [Operator Instructions] Please be advised that today's call may be recorded. I would now like to hand the call over to U.S. Biotechnology Analyst at UBS, Ellie Merle. Please go ahead.

Thank you so much for joining us. I'm Ellie Merle, one of the biotech analyst here at UBS. Very happy to have BridgeBio with us here today. Presenting or joining us for a fireside chat from BridgeBio will be Neil Kumar, Founder and Chief Executive Officer. And with that, Neil, I'll pass it to you.

Maybe just to kick off the discussion. It's been an eventful past 12 months for BridgeBio. Can you maybe frame the strategy and pipeline focus from here?

Yes, sure. First of all, thanks so much, Ellie, and thanks to the UBS team for having us. Maybe I'll just describe a little bit of what's been -- or trying to put into context a little bit what's been going on over the last couple of months here at post our Part A disappointing results at the end of December. So it's sort of defined by, I would say, 3 legs to a strategic stool. Leg #1 is that we continue to be optimistic about our late-stage pipeline, which includes Phase II and Phase III assets that are potentially best or first-in-class in very large marketplaces, and that includes our ATTR cardiomyopathy program. So when we look at those programs, and I know we'll probably walk through some of them, we've got in Phase III ATTR-CM with a readout first half of next year. We've got in Phase II and hopefully progressing on to Phase III in the near term. Our ADH1 asset, which should read late next year in terms of its Phase III, should the Phase II be positive. We've got our achondroplasia program, where we should have Phase II data again mid this year. We've got our Limb-Girdle Muscular Dystrophy Type2i program where we announced positive proof-of-concept data earlier this year and should be in a Phase III this year. And then finally, we have our congenital adrenal hyperplasia program. So those are all very, very large marketplaces that most people are familiar with, at least most of them. And when we look at that and we look at the burn that's required, which sort of brings us to the second leg of our strategic stool, which is a hypothesis that the markets will likely continue to stay or at least it is prudent for us to plan for a market that is incredibly tough to the end, at least, of next year. And so what that means is we may have very difficult access to equity capital certainly, lots of other levers to pull in a diversified portfolio like ours, but now is the time to pull them. And so the third leg of the strategic stool is knowing that we continue to be optimistic about our late-stage pipeline. We want to keep doing the discovery work that this company was founded on really 6 years ago. And we also bear in mind that the market is very tough, we needed to dramatically reduce our cost. And so we've been in the process of doing that and then extend our runway and we've been in the process of doing that as well. And so on the cost reduction side, I think we've talk about layoffs and some of the other things that we've done on the runway extension side. We've been engaging in a number of partnering discussions, which I think have been fruitful and we'll engage in more going forward so that we can continue to bolster the balance sheet and then we were able to restructure our senior secured debt to put off the first-time payments for almost 2 years. So with all of that, we feel like we're in pretty good shape in terms of runway now and hope to further boost that. So we were into 2024, mid-2024, and hopefully, we can continue to put a little bit more underneath us here as we look at a challenging marketplace, but we look at now, I think, the next 12-month period where if we deliver some great data, the company will be a materially different shape than it is today. So that's kind of an overview. I don't know if that's helpful. Then we could dive into whatever.

Yes. No, that's certainly helpful. And we appreciate the color on some of the financing front. I think that's been interesting and notable strategic decisions made there. Maybe diving into some of the specific programs, not starting with ATTR. Maybe if you could tell us a bit more about ADH1 and encaleret. I think this is an interesting program that, in my view, doesn't get enough attention. Can you tell us a little bit more about the disease and your program and some of the data we've seen so far?

Yes, sure. So I agree with you, actually, this one doesn't get as much attention probably because there's not as much competitive intensity within this space. But bad news about this disease is a very large unmet need and as much as that there's almost 12,000 people affected by it via carrier frequency and almost 3,500 that are already identified in the U.S. alone. And so the numbers of patients that are affected with moderate or severe symptomatology is quite large. And upon being affected, there is a subpopulation of about 25% to 30% that we typically don't identify today that have very mild symptomatology, meaning they don't appear to have the symptomalogy associated with low serum calcium levels, but they do importantly have long-term kidney complications arising from higher urine calcium level. But suffice it to say, a vast majority of patients that are affected by these mutations, and I'll describe the disease in a moment, have both symptomatology associated with a low serum calcium which could be as severe as things like seizures, tetany fatigue and the like, as well as high urine calcium, which can include nephrolithiasis and stage renal disease. And so as we put it together, [ diasporas ] symptomatology is quite severe, and the patient population is quite large. And we sort of see this as an XLH like market. The good news -- that's the bad news is how large the unmet need is. The good news is that it's a well-described disease, some 70 mutations or so that are all doing the same thing in as much as that they're hyper activating the calcium-sensing receptor. And as usual, we've taken a very simple approach to target the disease at its source. We developed an antagonist or calcilytic agent that allows us to directly inhibit the CaSR, therefore, normalizing hopefully, both serum calcium and urine calcium levels in one fell swoop. And yes, I can just basically get to what we've demonstrated so far and then what we're sort of looking forward to, I would say, at the end of the conference here, upcoming in mid-June. So we -- as I mentioned, took this calcilytic agent and filed the IND and went through a Phase I/II campaign relatively quickly, again, about 3.5 years and under $40 million. And on the back end of that, what we've shown to date are periods 1 and 2 of our Phase II ongoing campaign, which are inpatient dose escalation and titration, where we did show data after 5 days, suggesting that we were able to fully normalize both urine and serum calcium levels in these patients. By the way, the response levels of standard of care today, which is vitamin D and calcium supplementation are well below 20%. And so you can see that's a profound improvement on standard of care, a profound advance with patients if we're able to keep it up. And what I say, if we are going to be presenting our [ SAFC ] data, which is outpatient data, much longer live data, 6-month data at the ENDO Conference upcoming. And I think what we'd like to see is a continued high response rate in that outpatient setting and hopefully, based on that, a very clear regulatory path toward approval. And we've been engaged with the agency on those types of discussions over the last couple of months.

That's really helpful as an overview. It seems like, if I'm understanding correctly, it's pretty clear biomarker and way to understand the efficacy and normalization to some extent of the disease. Maybe can you tell us more about what this could potentially look like in a Phase III design and what your confidence level is in terms of Phase III success and ability to get to the market? If I heard you correctly, you're testing Phase III data by the end of next year?

Yes, that's right. So yes, as I mentioned, the symptomatology is a direct consequence of that low serum calcium and high urine calcium. And so -- and the agency, I think the best sort of analog would be how they've approached the HP market, both with Natpara as well as with the Ascendis' product. And so my expectation would be you're talking about a trial that would have serum and urine calcium as registrable end points. And if we were able to get that, then that's obviously what we looked at in Phase II. With the responder rates that we have, it would really come down to if the responder rate is maintained at a high level in our Phase II data, it would come down to how many patients for adequate safety. So yes, I would say something in that 40 to 60 range or something like that would make sense to me, but we should know more in the very near term. So probably a technical success wise, this is one of those programs where I think you're not looking for that final translation into a -- from a if indeed the registrable endpoints in serum and urine calcium, that's very different than, let's say, how much someone walks or a quality of life questionnaire or something like that. It's much more straightforward in terms of the standard deviation versus the mean, and so I would expect that the quality -- the probability of technical success is fairly high for a program like this. But we have to see post Phase II data and what that regulatory path looks like.

Understand. Yes, I appreciate being assured. But yes, not having a 6-minute walk endpoint and a much more straightforward potential measurement of modulating the disease, I think, is interesting here. Turning to limb-girdle Type 2i. Maybe you can talk a bit about the data that you've seen so far here and what the next steps are for development in this medication?

Yes. By the way, just going back to the earlier comment you made sort of struck me as interesting. I do -- it's sort of interesting when you look back at the last 18 to 24 months. we've had, as an industry, have had a small decline in probability of technical success. And a lot of that has been due to functional behavioral endpoints that may have changed. Distribution you may have changed over time. And one wonders, we're obviously living very differently. So I'm wondering what the impact of COVID was on that. But I think that the probability of technical success associated with disease is where one might measure the insults in a relatively straightforward way, like oxalate reduction or like serum or urine calcium, things of that nature. Those have stayed pretty high. So I do agree with you that probably a technical success should be fairly high for measures like that, and those are interesting programs to have in the -- in your pipeline. I'd say the other one that is analogous to that, that we have is congenital adrenal hyperplasia, what I'd imagine steroid sparing in relationship to endogenous quarters all increases would be the sort of key things that physicians in the agency would be interested in, although we're far away from doing that for sure. But yes, LGMD2i, another big disease that I think people have heard a little less of because there's not a ton of competitive intensity in this area, either a few gene therapy programs that are well behind our approach. This is, again -- the bad news here is it's a devastating disease, some 7,000 patients affected between the U.S. and EU and uniformly arising from -- well, I should say that it's both high numbers of patients and also a devastating disease. A couple of different types of manifestations here depending on whether you're homozygous loss of function or a compound heterozygous loss of function patient. The latter be more severe. But in either case, in the second decade of life, you're typically talking about declining ambulation, ultimately leading to loss of ambulation and for a significant fraction of the patient population, there is unfortunate cardiac involvement and elevated mortality. So I think when you put all that together, you're looking at one of the largest unmet needs certainly in limb-girdle landscape, larger probably than 2B or 2D that folks are, I think, more familiar with from Sarepta[indiscernible]. But the good news here, like those other diseases, as it's well described, uniformly arising from loss of function in an enzyme called FKRP that's responsible for glycosylating the alpha-dystroglycan complex in the muscle. And the reason that it's important to say that is -- that's really the proximal biomarker that we look at to see whether or not we're having impact with these patients. And what's happening in this disease is that you've got about of 30% of wild-type activity in FKRP, probably somewhere between maybe 10% and 30%, mass spec study suggests that. And so the enzyme is not completely off. And the way to overcome it is to come in with quite a bit more substrate. So this is the classic substrate replacement therapy approach, but it's intracellular. And what we're doing is we're giving ribitol, which gets converted into CDP ribitol, which is the substrate for this enzyme. So we're doubling or tripling up in some context, the amount of substrate with the goal to rectify the abnormal glycosylation of that complex. And what we showed in our positive proof-of-concept data, was the following: #1, a dramatic increase in glycosylation of that complex within the patient context. And just as you well know, the sort of bar that we had seen both in mouse studies as well as from genotype phenotype was we were looking at about a 10% increase in glycosylation. That was our goal. And we saw over 40% increase in glycosylation and a commensurate decrease of 70-plus percent in creatinine kinase, which is a noisy but reasonable biomarker for muscle cell death. And I think what was very heartening was when we sort of line those 2 things up against each other, creatinine kinase decreases and glycosylation increases, you saw a very nice correlation between the 2 suggesting that what we're seeing is real. And then this was -- there was no placebo control here, but there was a really nice natural history study, and this owes back to the fact that this is a large unmet need. There's Atrium Health, who we work with very closely, has a natural history study of almost 100 patients and there's thousands that have been identified already between the U.S. and the EU that are in various studies. So in this case, what you can see is a decline against the 2 functional things that we might measure, which is 10 Meter walk time or a modified North Star test and the decline typically occurs over a 6-month period, which was measured here. And what you can see on drug was actually a flatlining or a numerical increase or improvement in against both of those endpoints. So again, no placebo control. I don't want to go too overboard on that, but extraordinarily heartening, I would say, for the physician and patient community. And coupled with the biochemical markers suggests hopefully, we can drive this program forward very quickly.

And I mean, correct me if I'm wrong, but it seems like the ratio and glycosylated alpha-dystroglycan to [indiscernible] alpha-dystroglycan. It seems to be a fundamental kind of measure of the underlying biology, and it seems like there's real proof that you're correcting that.

Exactly right. Yes. It's very analogous to DMD. I mean what is uniformly driving this disease is the lack of glycosylation. And if you look at the western blot, it's like off and then on, off and that [indiscernible]. So yes, a really profound increase in glycosylation. So I think it's getting a lot of people excited and people call around to the community. I think both scientific community as well as the physician community here would feel like this could be a really interesting part of the solution to patients.

Absolutely. And could those enzyme measures be potential registration end points? Or do you think that we're looking at sort of longer-term functional measures like the 10-meter walk test? And I guess how are you thinking about that? And when can we expect to learn more?

Yes. Certainly, the severity of the disease, coupled with the deep understanding of the path of mechanism, coupled with our ability to measure those markers like glycosylation. I think -- would suggest that this would be a nice candidate for accelerated approval. We've just begun to engage the agency in a series of end of Phase II discussions. And so it's preliminary right now for me to understand exactly what the path forward could be and incumbent upon us to continue to present the strength of our understanding of the disease or the community's understanding of the disease. But I do think that this one could be a great candidate for accelerated approval.

Got it. We'll stay tuned there. Turning to achondroplasia. Obviously, you have a oral program which could be differentiating versus some of the injectables in the space. Can you tell us a little bit about the Phase I/II ongoing and what data we can expect to see at the update or initial data mid this year? And I guess, what would be good data in your view?

Yes. So just as a reminder, achondroplasia is one of the larger mendelian or monogenic disease conditions out there uniformly driven by gain of function mutations in FGFR3. And our approach is to inhibit FGFR3. So again, a very simple approach. In doing so, we're actually inhibiting both of the key effector pathways, both the JAK-STAT pathway as well as the MAPK [ signaling ] pathway, the latter of which is targeted by the other competitors in the space, both BioMarin and Ascendis. BioMarin having a now approved product called vosoritide for the condition. And the Phase I/II was meant to assess both the safety and efficacy of directly targeting FGFR3 in the context of almost 40 children across 4 cohorts. And we started dosing very low and because of the fact that we're taking a low dose but still oncologic agent into the context -- into the pediatric context and then we have elevated since then to get to more efficacious doses as we move from cohort to cohort. So we're now dosing the fourth cohort, and the expectation is that we'll have average growth velocity data from that cohort sometime late July, early August here this year. And kind of you asked what the victory is, the current standard of care in as much as BioMarin will establish themselves as standard of care is a once-daily injection, which can be quite onerous for children. Any parent would know that. And so -- and the efficacy that they've delivered is about 1.35 centimeters per year in terms of average growth velocity. So my expectation is if we're in that ballpark of 1.35 in terms of AGV and we are safe, which is going to be critical here. We'll have a -- that's a win scenario for the drug. And I think anything incremental past that in terms of efficacy makes it even more and more compelling for people. But certainly, the oral coupled with, I would say, same in-class efficacy would be a nice starting point for patients and physicians. Our expectation is that we should be able to do better, and we've shown that pre-clinically enhanced inhibition of both pathways can lead to more profound bone growth coupled with actual impact on some of the other areas that we haven't seen impact on with the CMPs like the spinal stenosis oriented types of manifestations you've seen in the mouse model. But we'll have to prove that out in the clinic.

And I guess how would you think about -- I mean I know that annual growth velocity can be a bit of a noisy endpoint. But say, in the higher dose cohort, you see an increasing annual growth velocity but maybe a little bit less than, say, what was seen with BioMarin to say you're a little bit under 1 centimeter increase in annual growth velocity. How would you approach development for [ Marin ]? On the one hand, you are hitting on some of these unique pathways that might be involved and sort of other factors longer-term like proportionality, would you push those further higher? How would you think about decision-making and excess from there?

Yes. Good question. I mean you're right to say average growth velocity has a very high standard deviation as compared to the means. So I would -- what's clinically meaningful. I think we would say that if we're at 1 or greater that is effectively the same thing as 1.3, I mean it's better to be numerically closer, obviously, or better. But I think that would still warrant development if physicians were and the community remained excited about it. I think the second key thing would just be to look at the safety profile because if it's very safe still at this fourth cohort then there may be a license for us to go to a fifth cohort and we're doubling dose every time. So if you're already at -- if you're already in range, but you're still safe, then I think that would be quite exciting because we could just continue to escalate dose to find the dose limiting dose here in Phase II, and hopefully, you could provide incremental efficacy but continue to be safe. So it depends if we see a safety signal or not at that cohort 4 dose.

Makes sense. And I know with 4 minutes left, I would be remiss if I didn't hit on ATTR at all. Maybe in the near term, I guess, how you're thinking about the APOLLO-B data? And I mean what this could mean, if at all, for your program? And I guess maybe just from your side, what you're most focused on in learning from that data?

Yes, good question. I mean, I think our primary focus continues to be the fidelity of our ongoing clinical trial. We -- for reasons you and I have discussed, we continue to believe and are quite optimistic about the potential for acoramidis to provide a mortality and CDH benefit in Part B. So that really is our focus. And against all of that, we continue to like what we're seeing just in terms of the dedication of the patients and physicians in our trial and everything from dropout rates to dropping on to canvas rates to overall event rates continues to suggest that the trial is reasonably robust against Part B. So that's kind of primary focus #1, I would say. Comment #2 on the APOLLO-B data is, obviously, as a person who is involved in the field, I'm rooting for them. I hope that their data is positive. I think patients need alternatives here. And so I continue to be optimistic for what they can deliver. I think for us, what we can learn from it is, did we -- there's kind of 2 hypotheses around the abnormal lack of placebo response, if you will. #1 is that we drew a statistical card that was a little odd. And I think that if they have a placebo decline of like 30 or 40 meters or something like that, and they're all going to demonstrate efficacy against that. And that would suggest that something was just a little off either on our 6-minute walk or something that is not picked up by baseline characteristics or baseline evolution -- our patient characteristics. So that -- so that would be #1 or #2, if indeed the placebo does not decline and now I guess to what ours was then I think -- and analogous to what was published in some cohorts post the start of our trial, like the [ Locator ], et cetera, out of the [indiscernible]. I do think that just suggests that we're in a new era where 12 months, 6-minute walk may not be the right endpoint for these ongoing trials. And so I think we'll learn a little bit more about what 6-minute walk means in the context of this disease from their data set, but not a whole lot more about the potential impact on mortality, which I continue to believe is going to be the big commercial driver here.

And you alluded to it in the first part of your answer, but can you elaborate a bit around your confidence in the event rates? And maybe any color if you can give any on what you're seeing on a blinded basis on the event rate of the trial? I know maybe COVID could impact whether someone opt to go to the hospital or not, for instance? And then also if there's any color that you can give us in terms of the latest that you're seeing in terms of Tafamidis drop-ins on the trial?

Yes. So I think the last we looked at the event rates alongside the DSMB and where the blessing of the agency was median 21 months at the end of February. And when we corrected for the fact that there were more people on drug in our trial versus the track, and we have a slightly healthier patient population. And when you adjust for those hazard ratios, we thought the event rate was right on top of where we wanted it to be. So that, I think, was good news at that data point, which again was end of February. And I think the last we commented on Tafamidis drop in it was, I think, I said 3% at JPMorgan, so we haven't commented on that since then. So -- and that was median 19 months, I guess, or 20 months. So yes, all in all, we continue to be satisfied with what we're seeing as the trial is going on here. And most importantly, admiring of the -- of the courage of the patients and physicians who see this experiment through because I think it could be an important one.

Absolutely. And I appreciate the color. I think we're unfortunately 1 minute over time. And I'm told we have a hard stop, but thank you so much, Neil, for joining us today and sharing your insights. And that it will be an exciting year and a couple of years ahead. So I really appreciate it.

Yes. Thank you. It should be an exciting next 12 months. So thanks for the time.

Yes. I'm looking forward to it. Have a good one.

Yes. Bye.

This concludes today's conference call. Thank you for participating. You may now disconnect.