BridgeBio Pharma, Inc. — Call Transcript 2025

All right, perfect. Thanks, everyone, for joining us. I'm Chad Lefauche, I'm a biotech analyst here at Wells Fargo. We're joined today by the BridgeBio team. We're going to have a fireside chat, focus a little bit on the pipeline and some upcoming catalysts that we have. Towards the end, we'll talk a little bit about the commercial execution that has been the main focus. For a change, perhaps let's start with the pipeline. The ADH-1 readout, so again, the Killerat data phase II looked really good. What are some of the risks in terms of translating some of those findings to the phase III? Any notable protocol changes, formulation changes, baseline characteristics changes? What are some of the considerations when trying to assess the probability of success for the phase III? Yeah, Chad, that's a great question. I'm going to hand it off to Ananth to answer that. Before I do that, I just wanted to start by thanking you and the entire Wells Fargo team for hosting us and for inviting us to this great conference. Let me pass it on to Ananth with that. I just wanted to start there. Yeah, Echo, thanks for hosting us, Chad, here. On ADH-1, we announced this morning that we will be hosting a webinar next week, a week from today. We'll cover some more detail on the program in that webinar, and I hope you all can join us. To your question on the translatability of phase II to phase III, I think the main criteria that I would say is different is the number of sites and the number of patients. Our phase II was conducted as a single-center study at the National Institutes of Health here in Bethesda. The phase III is a global study with over 25 sites across the world. We expect more CSR variants to be evaluated, likely a more heterogeneous patient population just as a result of the geographic breadth of the study. Overall, the formulation is the same as we studied. The dosing regimen is analogous to what we studied in phase II. Importantly, I think the eligibility criteria for our phase III study mirrors what we evaluated in our phase II cohort. Are the titration protocols for standard of care and drug similar, same swapping rules, same everything? Yes, the titration is done to blood calcium levels. Okay. Similar as it was performed in phase II. Got it. Perfect. One of the pushbacks that we still hear from investors on the program is just related to using PTH replacement therapy to potentially address these patients. Some physicians I spoke to seem to address that that could partially solve some of the issues, but perhaps not all. Can you just kind of recap what are some of the case studies on PTH in this ADH-1 patient population, why that wouldn't be necessarily the best or the optimal treatment solution for these patients? Sure. In ADH-1, as just a brief reminder, the parathyroid glands are generally intact for these patients. They have the capacity to synthesize and secrete endogenous hormone in response to blood calcium levels. This is the gold standard for what would be ideal for care because it's a tonic hormone that's secreted in response to blood calcium levels. There is a diurnal flux to it that would be ideal to mimic, which can't be attained today with classic PTH replacement unless it's delivered by a pump. Biologically, PTH replacement is not the ideal mechanism of choice for these patients. What we've seen in some of the case studies that Chad alluded to is I think there is an observation of blood calcium effect that increases blood calcium. What we have seen, conversely, is that the urine calcium benefit is not complete. Some recent case studies, even on long-acting PTH replacement for these patients, suggest similar dynamics where there is a benefit, but it's not completely addressing the root cause of the condition, nor the mineral biology that we observe for patients. Urine calcium levels remain high when on PTH replacement. Got it. Perhaps kind of talking about the patient journey, because I'm just trying to think from an endocrinologist's perspective, would they pursue genetic testing? What are some of the hallmarks that would make them think that this is something else and not just use PTH replacement or try to solve it in the quick, easier way of trying to address that? We'll kind of fold that into the whole prevalence patient identification discussions. The patient journey, and again, what are some of the key factors here that will make physicians take that extra step, perhaps? Yeah, I think in order of probably prominence, it's going to be compelling clinical data. I think seeing compelling clinical evidence for a targeted patient population we've historically seen in rare genetic disease, including ATTR, to really drive diagnosis rates. The second element is new treatment guidelines that have been published just this year recommend genetic testing for any nonsurgical hypoparathyroidism patients. As those guidelines spread through the community and the practice starts to shift in the breadth of genetic testing, we'll see that as a driver. The third factor here is that we're seeing a new ICD-10 code was implemented about two years ago for ADH-1. Even in the last year, we saw about 900 claims attributed to this ICD-10 code. I think as more awareness builds, more familiarity with the condition, and more testing is utilized, we'll see the gap between the diagnosed prevalence and the carrier frequency start to shrink. Got it. Pivoting back to just the clinical data, because you did mention compelling clinical data, where do you guys feel like the bar is specifically for this readout, right? I think it's a little bit more nuanced than the TransCon PTH discussion where you had that bar. You had a couple of other comps there. Here, do you need to recapitulate exactly the phase II profile? Is there some budge? What is the feedback from treating physicians on the bar? Yeah, as a reminder for phase II, if we looked at that cohort, which is an open-label population of about 13 individuals, none of those patients responded to standard of care as we define it in our phase III primary endpoint. About 70% responded to encaleret. If that translates to phase III, what we would expect is that very few patients respond to conventional therapy or standard of care, which is our control arm. A meaningful benefit that we've heard across the patient provider research that we've done is a majority of patients responding to the drug would drive meaningful utilization in the clinic and adoption in the clinic. That is the criteria that we expect to drive kind of that home run benefit. Ideally, that would be paired with a successful study given what we know about the inadequate or low response rates on standard of care. Got it. No, perfect. In terms of patients with confirmed diagnosis versus not, you guys put out some additional data relative to the theoretical prevalence of these patients, which is bigger than what folks were expecting. We still hear some mixed feedback from investors in terms of where are these patients? If they were severe, wouldn't they have been identified by now? What is kind of your latest take in terms of the number of patients that have been identified? What's the severity spectrum across that? Yeah, that's a great question. Our knowledge in the space continues to evolve with time. We're learning. As part of that learning, we published our most recent efforts here, which was we had previously seen data from the Geisinger biobank cohort, which is about 50,000 individuals, which estimated a prevalence for ADH-1 about 1 in 25,000. We replicated that work across three other biobanks, including the UK biobank. This would entail about 750,000 exomes of data. What we learned in that broader cohort is a very consistent finding of about 1 in 25,000 have the carrier genes related to or variants related to ADH-1. We're finding a replicable cohort of prevalence. In terms of where these patients are, I think a lot of them are diagnosed as hypoparathyroidism, whether it's idiopathic, nonsurgical, or just broadly genetic, but without a confirmation. I think those are where these patients are today. Certainly, the onus is on us as a sponsor to drive disease education and utilization of genetic testing. Like I mentioned at the top, I think clinical data and compelling profile for a disease-modifying therapy will really catalyze that diagnosis. What are some helpful comps, perhaps, in terms of thinking about this launch, both on the patient identification perspective, but also pricing, the size of the population? Sure. Yeah. Yeah, on the patient identification, I alluded to ATTR because that's a field that we have some experience with. If you guys recall, in 2018, I believe the diagnosis rate was estimated in the low single digits. The field has evolved tremendously since then. That really, as we've discussed, is catalyzed by the availability of a targeted disease-modifying agent and more to follow. I think that's a reasonable comparator for what we could observe in ADH-1 in terms of just the rate of diagnosis. In terms of the overall marketplace, it reminds us a lot of X-linked hypophosphatemia and the work that Ultragenyx and KKC have done in that field. It is a very similar disease prevalence. It is the one and only game in town for that condition. Those sponsors have done a tremendous job in not only finding the patients, but also developing the market such that burosumab is used quite widely now for the treatment of XLH. Got it. One final one on encaleret, and then we'll move on to the rest of the pipeline. The chronic hypopara initial data, again, you guys put out some very early data suggesting that this could be effective. Some skepticism there just related to just how good the efficacy is for the new standard of care in that space. It has to be a PTH-independent mechanism of driving benefit. Is that the optimal way of addressing the disease? What's the optionality here? What are the next steps to try to unlock or figure out what could be the position for encaleret? Yeah, so hopefully, we can address some of the skepticism. We have some data that will be presented at a medical meeting this weekend, which is our full phase II cohort, n of 10 patients with postsurgical hypoparathyroidism. I'd guide the audience to try to pay attention to that presentation. Hopefully, that will resolve some of the concerns or the skepticism around the evidence. In terms of the features or the differentiating aspects that we hope to see with encaleret, one is on route of administration. I think what we hear from the patient community is a daily injection associated with about a 40% injection site reaction rate is not ideal. The therapy is very effective, but there may be opportunities to improve tolerability and convenience. The second is on the urine calcium benefits. No drug in the category of hypoparathyroidism has been evaluated on a labeled effect of urine calcium reduction. I think if we are able to do that with encaleret, it would really differentiate the market and the product in the market because it is probably the third most important feature of treatment goals for the patient population from providers. The third aspect is long-term safety. The long-term activation of the PTH receptor in the bone has been associated with a bone resorptive trend. While the data are still emerging, we know that there's an anabolic activity for pulsatile PTH increases. This is why teriparatide Forteo was initially approved and used in the osteoporosis population. Long-term activation of that same receptor may drive a trend towards bone resorption. This is a patient population that's primarily postmenopausal women. That's a risk that we could avoid with a PTH-independent mechanism that is being explored with encaleret. Got it. Okay. We'll stay tuned to see that full update then. Great. Perfect. Let's move to 418 again. Kind of a similar playbook here. I guess the main thing that folks ask us is, how can I be confident that you can replicate the same trends that you saw in terms of stabilization and ambulation and some other clinical measures from the proof of concept phase II in a larger phase III? Again, any noticeable protocol changes? How are you thinking about the translation from the phase II findings to the phase III? Yeah, so I think there's a couple of different reasons that give us confidence that those findings will replicate. I think one, and first and foremost, is just the disease pathology and the fact that we're treating disease at a source. It isn't a therapeutic mechanism, which we would expect to replicate. The disease is caused by a mutation in the enzyme FKRP that glycosylates alpha-dystroglycan. So these patients have lower levels of glycosylated alpha-dystroglycan. Glycosylated alpha-dystroglycan acts as a shock absorber in the muscle fibers that protects the muscle. So the glycosylated alpha-dystroglycan acts as a shock absorber in the muscle fibers that protects the muscle from being damaged over daily use. What we're doing is basically providing supraphysiological doses of the substrate to drive residual enzyme activity, thereby increasing the levels of glycosylated alpha-dystroglycan. That mechanism has been validated by the natural history data where people who have—this is off and on. Should I go work? It's back on. It should be back on. Okay. I don't care. Anyway, basically, higher levels of glycosylated alpha-dystroglycan are correlated with less severe disease. That's replicated or validated by the natural history data. I needed other mic thoughts here. Okay, time to issue. Is this mic still working? Should I just continue on this one? I think if you pull it up a little, might be. Is it working? Okay. Anyways, so where am I? On the clinical data, why we think it's going to replicate is, no worries. We're pretty confident in the biomarkers showing a robust effect. With the clinical data, back to the clinical trial, the phase II study was a small study, 14 patients, open label. The fact that we could see a difference in the clinical measurements relative to natural history was a win. The phase III study is a much larger randomized controlled study with a very similar patient population. Given that we saw that trend in the phase II, we would hope to see the same trend in phase III. It is important to note, however, that at the interim analysis at 12 months, the study is not powered to show statistically significant benefit on the clinical outcomes. That's not what we're looking for. The FDA has indicated that's not what's required for accelerated approval. We're basing both the interim analysis and accelerated approval off of a robust effect on the biomarkers on glycosylated alpha-dystroglycan. All we're looking for in the functional measures is basically a trend that would be supportive of a benefit for these patients. Got it. No, that was going to be one of our questions. Related on the kinetics of the treatment effect that you saw in the phase II, do you feel like the interim analysis is good enough of a point in time to see those trends in clinical effects? Which endpoints, I guess, which one of those secondaries are you more likely to see a benefit versus not? Some could take a little longer. How should we think about that? Yeah, yeah, absolutely. Again, the primary endpoint for the interim analysis is the change in glycosylated alpha-dystroglycan. That's the primary endpoint that we're looking for, and that's what the basis of the accelerated approval is going to be. If you looked at the phase II data, we saw approximate doubling of glycosylated alpha-dystroglycan that was already present at month three, and that was sustained out to month 12. For the interim analysis, we're looking at change in glycosylated alpha-dystroglycan both at month three and month 12, which we would expect to see replicated from the phase II. We would also expect to see a reduction, a robust reduction in CK, which is also what we saw in the phase II, supportive of the pathology of the disease. On the functional endpoints, what we're looking to see is a trend in one or more. What we saw in the phase II study is a stabilization of the ambulatory measures at 12 months relative to natural history, because that was an open-label study. The study is not powered to show any statistically significant on the functional endpoints, but what we're looking for is trends that would be similar to what we saw in phase II. Got it. Do you feel more confident about any specific endpoints in terms of seeing the trend, or is it more about the whole picture and the overall product profile? Yeah, I mean, I think any data is going to be supportive here. I mean, it's the totality of evidence here. The primary endpoint of the study is the North Star composite. That's the gold standard that the FDA wants everyone to use for these muscular dystrophy diseases. It is a relatively insensitive instrument, which is why we want to put a 36-month treatment duration. We would not expect to see really much ability to discern treatment benefit at 12 months. At 12 months, you're more likely to see treatment benefit on the ambulatory measures and FVC. Those are going to be more important for the interim and supportive secondary endpoints for the final endpoint. Got it. Given the lack of treatment options here, just thinking about both the commercial outlook and the regulatory outlook, is a delta on disease progression good enough? Do you need to show stabilization? How much elasticity could there be commercially depending on what kind of product profile you show in this setting? Yeah, I don't really think there's much of a difference in the adoption and commercial uptake based on what we show, either stabilization or just a slowing in decline. If you speak with the patients, first of all, there's nothing on the market today for these patients. This would be the first to market for a disease-modifying therapy. If you speak with the patients, what they're really looking for is just something to stop the progressive loss of function. These are patients that know they're ultimately going to be unable to walk. They're going to be unable to get up from a sit. They're unable to go to the toilet by themselves. They just constantly lose daily functions of life. Anything that stops that progressive decline or even slows it is a win for these patients. Got it. In terms of comps, both from a prevalence perspective, pricing, and whatever, again, DMD is generally the market folks look at the most. How are you guys thinking about that right now? Yeah, I think that's a good comp. I think it's probably comparable to the initial exon 51-skipping market for DMD. We believe there's about 7,000 patients with LGMD2i in the U.S. and Europe. This would be kind of first to market with an oral therapy, kind of well-tolerated safety profile so far. I think the one difference between that initial target market for DMD and LGMD2i is there is a pretty significant European population here. There is a founder mutation that is present in Northern Europeans, so there's a pretty meaningful European market here in addition to the U.S. Got it. Perfect. I guess we can pivot to talk about Attruby a little bit. You're not going to get away from that. Of course, happy to talk about it. Consensus right now for Attruby for the year is about $350 million. I would say most of the buy-side investors I talk to are a little ahead of that. The execution so far has been pretty good. Are you guys comfortable with hearing some of those numbers? I know it's probably too early to issue any specific guidance. Overall, how do you feel about investors' expectations going into the end of the year? Yeah, that's a good question, Chad. I think what I would say is we feel very good about the launch. The metric which we track most closely is share in treatment-naive patients and just the overall number of treatment-naive patients, just because that is the best. We think that that is the best marker of long-term success for Attruby. What we have said on that front is every month of the launch, the number of treatment-naive patients on Attruby has increased. We feel like that trend has continued even after we last reported our earnings in the month of August. We feel good about where we are. I think that all the data being generated, as well as all the commercial tactics by our team, have really helped us continue to gain share. I think that that gives us a lot of confidence. I think that some of our, what I would say, net revenue per patient type metrics, we had flagged that we had some one-time benefits in Q1. We've also flagged that they've normalized in Q2. I think that they're going to be stable going forward. I think whether it's compliance at around 80% or sort of low monthly drop-off or gross-to-net being stable, all of that, I think, is now sort of more steady state, which means that as we get more patients, you should start to see that sort of show up in relevance. Going through it more directly. Yeah. You mentioned right now your share in treatment-naive. You see more treatment-naive patients getting on drug on a month-to-month basis. It seems like that part is tracking really well. Initially, there were some questions about a bolus of switch patients being responsible for the early stage of the launch. Do you have any sense of what percentage that makes up from here? I'm assuming that's going to decrease even further over time. Again, some support from the treatment-naive. What about the switches? Yeah, it's a very good question, Chad. We've always said that a majority of our patients were treatment-naive. The first time we reported numbers for Attruby was at another conference earlier in the year in January. At that point, we said majority were treatment-naive. In our Q4 PR or Q1 PR, we said that. In Q2 PR, we've always said that it's majority treatment-naive. That share continues to go up, which obviously means that the portion of switch in our total patient base has continued to go down. Really, that's driven by the fact that up until March, we had 100% share in the switch market. After that, we had another competitor enter the market. Of course, that 100% share has since come down. I think that overall, we feel good about the number of patients who are getting on Attruby. We're very excited to have reported that 3,751 patients were prescribed Attruby as of August 1. Got it. No, perfect. You kind of touched a little bit, but drilling down on the gross-to-net debate, some investors felt like the change from Q1 to Q2 was really abrupt on the gross-to-net and the net revenue per patient. We already talked about some of the things that drove that, the payer mix, some other things. How can we be confident that those are not going to change? Can you talk more about the current payer mix? What could actually decrease or increase gross-to-net going forward, depending on how that shakes out over a longer period of time with the launch? Yeah, that's another very good question, Chad. I think that if you look at the sort of things which change, if we take a step back, we have said for a very long time that we think stable gross-to-net is somewhere in the 30%-40% range. I think that hasn't changed. The reason why we flagged on our Q1 call that it was favorable compared to those expectations is we just saw a payer mix which we didn't think was representative of the steady state. We know that we're going to have some ordering from specific ISPs. We understand the end payer mix for ATTR CM patients. We have seen that more representative payer mix as of Q2. Because of that, we feel more confident that that's not going to change. That was exactly what we expected before we launched also. I think those things give us confidence that it's going to be stable from here on out. Got it. What about potential impact from competition? I think everyone's thinking Pfizer specifically. Going forward, do you expect to see more pressure from a formulary perspective? Do you need to give bigger rebates? So far, we haven't really seen any policies that are highly favorable or highly unfavorable on a mass scale. There have been some wins, some losses here and there. How should we think about the competition perhaps taking a stand here on share loss? Yeah, that's an interesting question. I think we would say that our strategy has always been parity access. We think we're not looking to sort of pay for preferred access or anything like that. We also feel like we've done the responsible thing by being 10% cheaper in terms of list price. Of course, we have best-in-class hospitalization data of 50% reduction at 30 months. That's better than what anyone else has been able to show in the category. That's very favorable for payers. I think as we think about all of that, we don't really see the value in the category being lost. We feel very good about our conversations with the payers. Of course, we are sort of a new company, so we have new-to-market edits and things like that. They're slowly starting to come off, all the things you would expect in a new launch. We haven't really seen any sort of broad pressures like you were also mentioning. I think we just expect that to continue. Got it. I guess one of the most frequently asked questions that I need to check the box is related to tafamidis ID. There is a lot of nitpicking on Vyndaqel versus Vyndamax. What happens if there's actually generics a little earlier than what folks are expecting here? What are some of the potential scenarios and impact to the trajectory you think, depending on how that shakes out? Yeah, so I think that our thesis on this has always been that the Form 1 or the polymorph patent protects the entire tafamidis franchise. That's based on the fact that no one has been able to manufacture at a commercial scale Vyndaqel or Vyndamax, which does not have Form 1 present in it. As soon as you have a little bit of Form 1, you're infringing on the patent. That hasn't really changed. That's always what we've believed. You might be referring to the recent news of the Vyndaqel discontinuation. What we see there is even in the small off chance that someone was able to somehow manufacture Vyndaqel without Form 1, which again, no one's been able to do so far. There's been a case in Europe also where there's been a preliminary ruling already on this. The loss of Vyndaqel means that it's going to be much harder for any generic to enter because there's not going to be a natural patient base or a natural physician base or a payer base. It's also important to note that Vyndaqel and Vyndamax are not therapeutically equivalent and so substitutable at the pharmacy, which further sort of protects it. I feel like there are layers of protection one after the other, all of which together have just reinforced our confidence that this market is going to be sustained. It's going to be long term. I think that gives us a lot of confidence in sort of the overall trajectory for Attruby. Perfect. I know we're almost running out of time. I do want to just get a couple of infographics just in case. The main question that we have, there again, a lot of counter-detailing on the safety. How do you adjust efficacy for different baseline characteristics? We've discussed that at length already. Perhaps a question more on safety. That has been kind of the permanent overhang on the program. How frequently does the DSMB meet for the phase III? I'm curious what you might have seen or heard from a safety perspective so far from the clinical trial. The trial has not been halted or anything like that. I'm assuming so far, so good. Anything you can say in terms of the cadence and communication from the DSMB? Yeah, I think the trial continues to go along. I think what's important to note is sometimes people focus on hyperphos. Sort of grade 1, grade 2 hyperphos is really not a phase. Physicians we spoke to don't seem overly concerned about that. Exactly. I mean, I think if you have a little bit of ice cream or something like that, your phosphorus levels can increase. I'm certainly guilty of that. I think that actually our phase II data really gave us confidence on that front. We saw a very clean safety profile. We saw best-in-class efficacy. We're the only sort of agent which has shown statistically significant effect on proportionality. As we look at the overall data, including the safety data, we feel like infigratinib is really poised to become the standard of care. Of course, you have to read out our phase III trial. What we didn't mention is that the oral profile really does differentiate us. I think no one really wants to have 4,000 injections for a child. It's just a hard setup. We feel good about it. I know we're going to have more time to talk about infigratinib as the year wraps up, as that trial is reading out in early 2026. Yeah. The final one there, perhaps just in terms of the baseline characteristics, again, probably some meaningful changes from the phase II to the phase III. Anything noteworthy so far that would kind of hurt the translatability of the phase II findings to the phase III? Yeah, our phase II data, I think it really validated the best-in-class safety and efficacy profile. It really gave us the confidence to go. Our phase II was five and up children. Our phase III is three and up. That 3-5 means that we're going to have a negative. That's usually not good in terms of the absolute number. We'll get a broader label. I think that more children will be able to benefit from it if it is approved. I think that that's kind of important for folks to know, just the baseline characteristic is different. It's three and up for phase III and not five and up, which is for phase II. Got it. Perfect. Fair enough. With that, we're out of time. Again, thank you all very much for joining us. Thank you, Chad. I hope the audience appreciated it.

Speaker 2: All right, perfect. Thanks, everyone, for joining us. I'm Chad Lefauche, I'm a biotech analyst here at Wells Fargo. We're joined today by the BridgeBio team. We're going to have a fireside chat, focus a little bit on the pipeline and some upcoming catalysts that we have. Towards the end, we'll talk a little bit about the commercial execution that has been the main focus. For a change, perhaps let's start with the pipeline. The ADH-1 readout, so again, the Killerat data phase II looked really good. What are some of the risks in terms of translating some of those findings to the phase III? Any notable protocol changes, formulation changes, baseline characteristics changes? What are some of the considerations when trying to assess the probability of success for the phase III? All right, perfect. all right perfect Thanks, everyone, for joining us. thanks everyone for joining us I'm Chad Lefauche, I'm a biotech analyst here at Wells Fargo. i'm chad lefauche i'm a biotech analyst here at wells fargo We're joined today by the BridgeBio team. we're joined today by the bridgebio team We're going to have a fireside chat, focus a little bit on the pipeline and some upcoming catalysts that we have. we're going to have a fireside chat focus a little bit on the pipeline and some upcoming catalysts that we have Towards the end, we'll talk a little bit about the commercial execution that has been the main focus. towards the end we'll talk a little bit about the commercial execution that has been the main focus For a change, perhaps let's start with the pipeline. for a change perhaps let's start with the pipeline The ADH-1 readout, so again, the Killerat data phase II looked really good. the adh-1 readout so again the killerat data phase ii looked really good What are some of the risks in terms of translating some of those findings to the phase III? what are some of the risks in terms of translating some of those findings to the phase iii Any notable protocol changes, formulation changes, baseline characteristics changes? any notable protocol changes formulation changes baseline characteristics changes What are some of the considerations when trying to assess the probability of success for the phase III? what are some of the considerations when trying to assess the probability of success for the phase iii

Speaker 4: Yeah, Chad, that's a great question. I'm going to hand it off to Ananth to answer that. Before I do that, I just wanted to start by thanking you and the entire Wells Fargo team for hosting us and for inviting us to this great conference. Let me pass it on to Ananth with that. I just wanted to start there. Yeah, Chad, that's a great question. yeah chad that's a great question I'm going to hand it off to Ananth to answer that. i'm going to hand it off to ananth to answer that Before I do that, I just wanted to start by thanking you and the entire Wells Fargo team for hosting us and for inviting us to this great conference. before i do that i just wanted to start by thanking you and the entire wells fargo team for hosting us and for inviting us to this great conference Let me pass it on to Ananth with that. let me pass it on to ananth with that I just wanted to start there. i just wanted to start there

Speaker 3: Yeah, Echo, thanks for hosting us, Chad, here. On ADH-1, we announced this morning that we will be hosting a webinar next week, a week from today. We'll cover some more detail on the program in that webinar, and I hope you all can join us. To your question on the translatability of phase II to phase III, I think the main criteria that I would say is different is the number of sites and the number of patients. Our phase II was conducted as a single-center study at the National Institutes of Health here in Bethesda. The phase III is a global study with over 25 sites across the world. We expect more CSR variants to be evaluated, likely a more heterogeneous patient population just as a result of the geographic breadth of the study. Overall, the formulation is the same as we studied. Yeah, Echo, thanks for hosting us, Chad, here. yeah echo thanks for hosting us chad here On ADH-1, we announced this morning that we will be hosting a webinar next week, a week from today. on adh-1 we announced this morning that we will be hosting a webinar next week a week from today We'll cover some more detail on the program in that webinar, and I hope you all can join us. we'll cover some more detail on the program in that webinar and i hope you all can join us To your question on the translatability of phase II to phase III, I think the main criteria that I would say is different is the number of sites and the number of patients. to your question on the translatability of phase ii to phase iii i think the main criteria that i would say is different is the number of sites and the number of patients Our phase II was conducted as a single-center study at the National Institutes of Health here in Bethesda. our phase ii was conducted as a single-center study at the national institutes of health here in bethesda The phase III is a global study with over 25 sites across the world. the phase iii is a global study with over 25 sites across the world We expect more CSR variants to be evaluated, likely a more heterogeneous patient population just as a result of the geographic breadth of the study. we expect more csr variants to be evaluated likely a more heterogeneous patient population just as a result of the geographic breadth of the study Overall, the formulation is the same as we studied. overall the formulation is the same as we studied The dosing regimen is analogous to what we studied in phase II. Importantly, I think the eligibility criteria for our phase III study mirrors what we evaluated in our phase II cohort. The dosing regimen is analogous to what we studied in phase II. the dosing regimen is analogous to what we studied in phase ii Importantly, I think the eligibility criteria for our phase III study mirrors what we evaluated in our phase II cohort. importantly i think the eligibility criteria for our phase iii study mirrors what we evaluated in our phase ii cohort

Speaker 2: Are the titration protocols for standard of care and drug similar, same swapping rules, same everything? Are the titration protocols for standard of care and drug similar, same swapping rules, same everything? are the titration protocols for standard of care and drug similar same swapping rules same everything

Speaker 3: Yes, the titration is done to blood calcium levels. Yes, the titration is done to blood calcium levels. yes the titration is done to blood calcium levels

Speaker 2: Okay. Okay. okay

Speaker 3: Similar as it was performed in phase II. Similar as it was performed in phase II. similar as it was performed in phase ii

Speaker 2: Got it. Perfect. One of the pushbacks that we still hear from investors on the program is just related to using PTH replacement therapy to potentially address these patients. Some physicians I spoke to seem to address that that could partially solve some of the issues, but perhaps not all. Can you just kind of recap what are some of the case studies on PTH in this ADH-1 patient population, why that wouldn't be necessarily the best or the optimal treatment solution for these patients? Got it. got it Perfect. perfect One of the pushbacks that we still hear from investors on the program is just related to using PTH replacement therapy to potentially address these patients. one of the pushbacks that we still hear from investors on the program is just related to using pth replacement therapy to potentially address these patients Some physicians I spoke to seem to address that that could partially solve some of the issues, but perhaps not all. some physicians i spoke to seem to address that that could partially solve some of the issues but perhaps not all Can you just kind of recap what are some of the case studies on PTH in this ADH-1 patient population, why that wouldn't be necessarily the best or the optimal treatment solution for these patients? can you just kind of recap what are some of the case studies on pth in this adh-1 patient population why that wouldn't be necessarily the best or the optimal treatment solution for these patients

Speaker 3: Sure. In ADH-1, as just a brief reminder, the parathyroid glands are generally intact for these patients. They have the capacity to synthesize and secrete endogenous hormone in response to blood calcium levels. This is the gold standard for what would be ideal for care because it's a tonic hormone that's secreted in response to blood calcium levels. There is a diurnal flux to it that would be ideal to mimic, which can't be attained today with classic PTH replacement unless it's delivered by a pump. Biologically, PTH replacement is not the ideal mechanism of choice for these patients. What we've seen in some of the case studies that Chad alluded to is I think there is an observation of blood calcium effect that increases blood calcium. What we have seen, conversely, is that the urine calcium benefit is not complete. Sure. sure In ADH-1, as just a brief reminder, the parathyroid glands are generally intact for these patients. in adh-1 as just a brief reminder the parathyroid glands are generally intact for these patients They have the capacity to synthesize and secrete endogenous hormone in response to blood calcium levels. they have the capacity to synthesize and secrete endogenous hormone in response to blood calcium levels This is the gold standard for what would be ideal for care because it's a tonic hormone that's secreted in response to blood calcium levels. this is the gold standard for what would be ideal for care because it's a tonic hormone that's secreted in response to blood calcium levels There is a diurnal flux to it that would be ideal to mimic, which can't be attained today with classic PTH replacement unless it's delivered by a pump. there is a diurnal flux to it that would be ideal to mimic which can't be attained today with classic pth replacement unless it's delivered by a pump Biologically, PTH replacement is not the ideal mechanism of choice for these patients. biologically pth replacement is not the ideal mechanism of choice for these patients What we've seen in some of the case studies that Chad alluded to is I think there is an observation of blood calcium effect that increases blood calcium. what we've seen in some of the case studies that chad alluded to is i think there is an observation of blood calcium effect that increases blood calcium What we have seen, conversely, is that the urine calcium benefit is not complete. what we have seen conversely is that the urine calcium benefit is not complete Some recent case studies, even on long-acting PTH replacement for these patients, suggest similar dynamics where there is a benefit, but it's not completely addressing the root cause of the condition, nor the mineral biology that we observe for patients. Urine calcium levels remain high when on PTH replacement. Some recent case studies, even on long-acting PTH replacement for these patients, suggest similar dynamics where there is a benefit, but it's not completely addressing the root cause of the condition, nor the mineral biology that we observe for patients. some recent case studies even on long-acting pth replacement for these patients suggest similar dynamics where there is a benefit but it's not completely addressing the root cause of the condition nor the mineral biology that we observe for patients Urine calcium levels remain high when on PTH replacement. urine calcium levels remain high when on pth replacement

Speaker 2: Got it. Perhaps kind of talking about the patient journey, because I'm just trying to think from an endocrinologist's perspective, would they pursue genetic testing? What are some of the hallmarks that would make them think that this is something else and not just use PTH replacement or try to solve it in the quick, easier way of trying to address that? We'll kind of fold that into the whole prevalence patient identification discussions. The patient journey, and again, what are some of the key factors here that will make physicians take that extra step, perhaps? Got it. got it Perhaps kind of talking about the patient journey, because I'm just trying to think from an endocrinologist's perspective, would they pursue genetic testing? perhaps kind of talking about the patient journey because i'm just trying to think from an endocrinologist's perspective would they pursue genetic testing What are some of the hallmarks that would make them think that this is something else and not just use PTH replacement or try to solve it in the quick, easier way of trying to address that? what are some of the hallmarks that would make them think that this is something else and not just use pth replacement or try to solve it in the quick easier way of trying to address that We'll kind of fold that into the whole prevalence patient identification discussions. we'll kind of fold that into the whole prevalence patient identification discussions The patient journey, and again, what are some of the key factors here that will make physicians take that extra step, perhaps? the patient journey and again what are some of the key factors here that will make physicians take that extra step perhaps

Speaker 3: Yeah, I think in order of probably prominence, it's going to be compelling clinical data. I think seeing compelling clinical evidence for a targeted patient population we've historically seen in rare genetic disease, including ATTR, to really drive diagnosis rates. The second element is new treatment guidelines that have been published just this year recommend genetic testing for any nonsurgical hypoparathyroidism patients. As those guidelines spread through the community and the practice starts to shift in the breadth of genetic testing, we'll see that as a driver. The third factor here is that we're seeing a new ICD-10 code was implemented about two years ago for ADH-1. Even in the last year, we saw about 900 claims attributed to this ICD-10 code. Yeah, I think in order of probably prominence, it's going to be compelling clinical data. yeah i think in order of probably prominence it's going to be compelling clinical data I think seeing compelling clinical evidence for a targeted patient population we've historically seen in rare genetic disease, including ATTR, to really drive diagnosis rates. i think seeing compelling clinical evidence for a targeted patient population we've historically seen in rare genetic disease including attr to really drive diagnosis rates The second element is new treatment guidelines that have been published just this year recommend genetic testing for any nonsurgical hypoparathyroidism patients. the second element is new treatment guidelines that have been published just this year recommend genetic testing for any nonsurgical hypoparathyroidism patients As those guidelines spread through the community and the practice starts to shift in the breadth of genetic testing, we'll see that as a driver. as those guidelines spread through the community and the practice starts to shift in the breadth of genetic testing we'll see that as a driver The third factor here is that we're seeing a new ICD-10 code was implemented about two years ago for ADH-1. the third factor here is that we're seeing a new icd-10 code was implemented about two years ago for adh-1 Even in the last year, we saw about 900 claims attributed to this ICD-10 code. even in the last year we saw about 900 claims attributed to this icd-10 code I think as more awareness builds, more familiarity with the condition, and more testing is utilized, we'll see the gap between the diagnosed prevalence and the carrier frequency start to shrink. I think as more awareness builds, more familiarity with the condition, and more testing is utilized, we'll see the gap between the diagnosed prevalence and the carrier frequency start to shrink. i think as more awareness builds more familiarity with the condition and more testing is utilized we'll see the gap between the diagnosed prevalence and the carrier frequency start to shrink

Speaker 2: Got it. Pivoting back to just the clinical data, because you did mention compelling clinical data, where do you guys feel like the bar is specifically for this readout, right? I think it's a little bit more nuanced than the TransCon PTH discussion where you had that bar. You had a couple of other comps there. Here, do you need to recapitulate exactly the phase II profile? Is there some budge? What is the feedback from treating physicians on the bar? Got it. got it Pivoting back to just the clinical data, because you did mention compelling clinical data, where do you guys feel like the bar is specifically for this readout, right? pivoting back to just the clinical data because you did mention compelling clinical data where do you guys feel like the bar is specifically for this readout right I think it's a little bit more nuanced than the TransCon PTH discussion where you had that bar. i think it's a little bit more nuanced than the transcon pth discussion where you had that bar You had a couple of other comps there. you had a couple of other comps there Here, do you need to recapitulate exactly the phase II profile? here do you need to recapitulate exactly the phase ii profile Is there some budge? is there some budge What is the feedback from treating physicians on the bar? what is the feedback from treating physicians on the bar

Speaker 3: Yeah, as a reminder for phase II, if we looked at that cohort, which is an open-label population of about 13 individuals, none of those patients responded to standard of care as we define it in our phase III primary endpoint. About 70% responded to encaleret. If that translates to phase III, what we would expect is that very few patients respond to conventional therapy or standard of care, which is our control arm. A meaningful benefit that we've heard across the patient provider research that we've done is a majority of patients responding to the drug would drive meaningful utilization in the clinic and adoption in the clinic. That is the criteria that we expect to drive kind of that home run benefit. Ideally, that would be paired with a successful study given what we know about the inadequate or low response rates on standard of care. Yeah, as a reminder for phase II, if we looked at that cohort, which is an open-label population of about 13 individuals, none of those patients responded to standard of care as we define it in our phase III primary endpoint. yeah as a reminder for phase ii if we looked at that cohort which is an open-label population of about 13 individuals none of those patients responded to standard of care as we define it in our phase iii primary endpoint About 70% responded to encaleret. about 70% responded to encaleret If that translates to phase III, what we would expect is that very few patients respond to conventional therapy or standard of care, which is our control arm. if that translates to phase iii what we would expect is that very few patients respond to conventional therapy or standard of care which is our control arm A meaningful benefit that we've heard across the patient provider research that we've done is a majority of patients responding to the drug would drive meaningful utilization in the clinic and adoption in the clinic. a meaningful benefit that we've heard across the patient provider research that we've done is a majority of patients responding to the drug would drive meaningful utilization in the clinic and adoption in the clinic That is the criteria that we expect to drive kind of that home run benefit. that is the criteria that we expect to drive kind of that home run benefit Ideally, that would be paired with a successful study given what we know about the inadequate or low response rates on standard of care. ideally that would be paired with a successful study given what we know about the inadequate or low response rates on standard of care

Speaker 2: Got it. No, perfect. In terms of patients with confirmed diagnosis versus not, you guys put out some additional data relative to the theoretical prevalence of these patients, which is bigger than what folks were expecting. We still hear some mixed feedback from investors in terms of where are these patients? If they were severe, wouldn't they have been identified by now? What is kind of your latest take in terms of the number of patients that have been identified? What's the severity spectrum across that? Got it. got it No, perfect. no perfect In terms of patients with confirmed diagnosis versus not, you guys put out some additional data relative to the theoretical prevalence of these patients, which is bigger than what folks were expecting. in terms of patients with confirmed diagnosis versus not you guys put out some additional data relative to the theoretical prevalence of these patients which is bigger than what folks were expecting We still hear some mixed feedback from investors in terms of where are these patients? we still hear some mixed feedback from investors in terms of where are these patients If they were severe, wouldn't they have been identified by now? if they were severe wouldn't they have been identified by now What is kind of your latest take in terms of the number of patients that have been identified? what is kind of your latest take in terms of the number of patients that have been identified What's the severity spectrum across that? what's the severity spectrum across that

Speaker 3: Yeah, that's a great question. Our knowledge in the space continues to evolve with time. We're learning. As part of that learning, we published our most recent efforts here, which was we had previously seen data from the Geisinger biobank cohort, which is about 50,000 individuals, which estimated a prevalence for ADH-1 about 1 in 25,000. We replicated that work across three other biobanks, including the UK biobank. This would entail about 750,000 exomes of data. What we learned in that broader cohort is a very consistent finding of about 1 in 25,000 have the carrier genes related to or variants related to ADH-1. We're finding a replicable cohort of prevalence. In terms of where these patients are, I think a lot of them are diagnosed as hypoparathyroidism, whether it's idiopathic, nonsurgical, or just broadly genetic, but without a confirmation. I think those are where these patients are today. Yeah, that's a great question. yeah that's a great question Our knowledge in the space continues to evolve with time. our knowledge in the space continues to evolve with time We're learning. we're learning As part of that learning, we published our most recent efforts here, which was we had previously seen data from the Geisinger biobank cohort, which is about 50,000 individuals, which estimated a prevalence for ADH-1 about 1 in 25,000. as part of that learning we published our most recent efforts here which was we had previously seen data from the geisinger biobank cohort which is about 50,000 individuals which estimated a prevalence for adh-1 about 1 in 25,000 We replicated that work across three other biobanks, including the UK biobank. we replicated that work across three other biobanks including the uk biobank This would entail about 750,000 exomes of data. this would entail about 750,000 exomes of data What we learned in that broader cohort is a very consistent finding of about 1 in 25,000 have the carrier genes related to or variants related to ADH-1. what we learned in that broader cohort is a very consistent finding of about 1 in 25,000 have the carrier genes related to or variants related to adh-1 We're finding a replicable cohort of prevalence. we're finding a replicable cohort of prevalence In terms of where these patients are, I think a lot of them are diagnosed as hypoparathyroidism, whether it's idiopathic, nonsurgical, or just broadly genetic, but without a confirmation. in terms of where these patients are i think a lot of them are diagnosed as hypoparathyroidism whether it's idiopathic nonsurgical or just broadly genetic but without a confirmation I think those are where these patients are today. i think those are where these patients are today Certainly, the onus is on us as a sponsor to drive disease education and utilization of genetic testing. Like I mentioned at the top, I think clinical data and compelling profile for a disease-modifying therapy will really catalyze that diagnosis. Certainly, the onus is on us as a sponsor to drive disease education and utilization of genetic testing. certainly the onus is on us as a sponsor to drive disease education and utilization of genetic testing Like I mentioned at the top, I think clinical data and compelling profile for a disease-modifying therapy will really catalyze that diagnosis. like i mentioned at the top i think clinical data and compelling profile for a disease-modifying therapy will really catalyze that diagnosis

Speaker 2: What are some helpful comps, perhaps, in terms of thinking about this launch, both on the patient identification perspective, but also pricing, the size of the population? What are some helpful comps, perhaps, in terms of thinking about this launch, both on the patient identification perspective, but also pricing, the size of the population? what are some helpful comps perhaps in terms of thinking about this launch both on the patient identification perspective but also pricing the size of the population

Speaker 3: Sure. Sure. sure

Speaker 2: Yeah. Yeah. yeah

Speaker 3: Yeah, on the patient identification, I alluded to ATTR because that's a field that we have some experience with. If you guys recall, in 2018, I believe the diagnosis rate was estimated in the low single digits. The field has evolved tremendously since then. That really, as we've discussed, is catalyzed by the availability of a targeted disease-modifying agent and more to follow. I think that's a reasonable comparator for what we could observe in ADH-1 in terms of just the rate of diagnosis. In terms of the overall marketplace, it reminds us a lot of X-linked hypophosphatemia and the work that Ultragenyx and KKC have done in that field. It is a very similar disease prevalence. It is the one and only game in town for that condition. Yeah, on the patient identification, I alluded to ATTR because that's a field that we have some experience with. yeah on the patient identification i alluded to attr because that's a field that we have some experience with If you guys recall, in 2018, I believe the diagnosis rate was estimated in the low single digits. if you guys recall in 2018 i believe the diagnosis rate was estimated in the low single digits The field has evolved tremendously since then. the field has evolved tremendously since then That really, as we've discussed, is catalyzed by the availability of a targeted disease-modifying agent and more to follow. that really as we've discussed is catalyzed by the availability of a targeted disease-modifying agent and more to follow I think that's a reasonable comparator for what we could observe in ADH-1 in terms of just the rate of diagnosis. i think that's a reasonable comparator for what we could observe in adh-1 in terms of just the rate of diagnosis In terms of the overall marketplace, it reminds us a lot of X-linked hypophosphatemia and the work that Ultragenyx and KKC have done in that field. in terms of the overall marketplace it reminds us a lot of x-linked hypophosphatemia and the work that ultragenyx and kkc have done in that field It is a very similar disease prevalence. it is a very similar disease prevalence It is the one and only game in town for that condition. it is the one and only game in town for that condition Those sponsors have done a tremendous job in not only finding the patients, but also developing the market such that burosumab is used quite widely now for the treatment of XLH. Those sponsors have done a tremendous job in not only finding the patients, but also developing the market such that burosumab is used quite widely now for the treatment of XLH. those sponsors have done a tremendous job in not only finding the patients but also developing the market such that burosumab is used quite widely now for the treatment of xlh

Speaker 2: Got it. One final one on encaleret, and then we'll move on to the rest of the pipeline. The chronic hypopara initial data, again, you guys put out some very early data suggesting that this could be effective. Some skepticism there just related to just how good the efficacy is for the new standard of care in that space. It has to be a PTH-independent mechanism of driving benefit. Is that the optimal way of addressing the disease? What's the optionality here? What are the next steps to try to unlock or figure out what could be the position for encaleret? Got it. got it One final one on encaleret, and then we'll move on to the rest of the pipeline. one final one on encaleret and then we'll move on to the rest of the pipeline The chronic hypopara initial data, again, you guys put out some very early data suggesting that this could be effective. the chronic hypopara initial data again you guys put out some very early data suggesting that this could be effective Some skepticism there just related to just how good the efficacy is for the new standard of care in that space. some skepticism there just related to just how good the efficacy is for the new standard of care in that space It has to be a PTH-independent mechanism of driving benefit. it has to be a pth-independent mechanism of driving benefit Is that the optimal way of addressing the disease? is that the optimal way of addressing the disease What's the optionality here? what's the optionality here What are the next steps to try to unlock or figure out what could be the position for encaleret? what are the next steps to try to unlock or figure out what could be the position for encaleret

Speaker 3: Yeah, so hopefully, we can address some of the skepticism. We have some data that will be presented at a medical meeting this weekend, which is our full phase II cohort, n of 10 patients with postsurgical hypoparathyroidism. I'd guide the audience to try to pay attention to that presentation. Hopefully, that will resolve some of the concerns or the skepticism around the evidence. In terms of the features or the differentiating aspects that we hope to see with encaleret, one is on route of administration. I think what we hear from the patient community is a daily injection associated with about a 40% injection site reaction rate is not ideal. The therapy is very effective, but there may be opportunities to improve tolerability and convenience. The second is on the urine calcium benefits. Yeah, so hopefully, we can address some of the skepticism. yeah so hopefully we can address some of the skepticism We have some data that will be presented at a medical meeting this weekend, which is our full phase II cohort, n of 10 patients with postsurgical hypoparathyroidism. we have some data that will be presented at a medical meeting this weekend which is our full phase ii cohort n of 10 patients with postsurgical hypoparathyroidism I'd guide the audience to try to pay attention to that presentation. i'd guide the audience to try to pay attention to that presentation Hopefully, that will resolve some of the concerns or the skepticism around the evidence. hopefully that will resolve some of the concerns or the skepticism around the evidence In terms of the features or the differentiating aspects that we hope to see with encaleret, one is on route of administration. in terms of the features or the differentiating aspects that we hope to see with encaleret one is on route of administration I think what we hear from the patient community is a daily injection associated with about a 40% injection site reaction rate is not ideal. i think what we hear from the patient community is a daily injection associated with about a 40% injection site reaction rate is not ideal The therapy is very effective, but there may be opportunities to improve tolerability and convenience. the therapy is very effective but there may be opportunities to improve tolerability and convenience The second is on the urine calcium benefits. the second is on the urine calcium benefits No drug in the category of hypoparathyroidism has been evaluated on a labeled effect of urine calcium reduction. I think if we are able to do that with encaleret, it would really differentiate the market and the product in the market because it is probably the third most important feature of treatment goals for the patient population from providers. The third aspect is long-term safety. The long-term activation of the PTH receptor in the bone has been associated with a bone resorptive trend. While the data are still emerging, we know that there's an anabolic activity for pulsatile PTH increases. This is why teriparatide Forteo was initially approved and used in the osteoporosis population. Long-term activation of that same receptor may drive a trend towards bone resorption. This is a patient population that's primarily postmenopausal women. No drug in the category of hypoparathyroidism has been evaluated on a labeled effect of urine calcium reduction. no drug in the category of hypoparathyroidism has been evaluated on a labeled effect of urine calcium reduction I think if we are able to do that with encaleret, it would really differentiate the market and the product in the market because it is probably the third most important feature of treatment goals for the patient population from providers. i think if we are able to do that with encaleret it would really differentiate the market and the product in the market because it is probably the third most important feature of treatment goals for the patient population from providers The third aspect is long-term safety. the third aspect is long-term safety The long-term activation of the PTH receptor in the bone has been associated with a bone resorptive trend. the long-term activation of the pth receptor in the bone has been associated with a bone resorptive trend While the data are still emerging, we know that there's an anabolic activity for pulsatile PTH increases. while the data are still emerging we know that there's an anabolic activity for pulsatile pth increases This is why teriparatide Forteo was initially approved and used in the osteoporosis population. this is why teriparatide forteo was initially approved and used in the osteoporosis population Long-term activation of that same receptor may drive a trend towards bone resorption. long-term activation of that same receptor may drive a trend towards bone resorption This is a patient population that's primarily postmenopausal women. this is a patient population that's primarily postmenopausal women That's a risk that we could avoid with a PTH-independent mechanism that is being explored with encaleret. That's a risk that we could avoid with a PTH-independent mechanism that is being explored with encaleret. that's a risk that we could avoid with a pth-independent mechanism that is being explored with encaleret

Speaker 2: Got it. Okay. We'll stay tuned to see that full update then. Got it. got it Okay. got it okay We'll stay tuned to see that full update then. we'll stay tuned to see that full update then

Speaker 3: Great. Great. great

Speaker 2: Perfect. Let's move to 418 again. Kind of a similar playbook here. I guess the main thing that folks ask us is, how can I be confident that you can replicate the same trends that you saw in terms of stabilization and ambulation and some other clinical measures from the proof of concept phase II in a larger phase III? Again, any noticeable protocol changes? How are you thinking about the translation from the phase II findings to the phase III? Perfect. perfect Let's move to 418 again. let's move to 418 again Kind of a similar playbook here. kind of a similar playbook here I guess the main thing that folks ask us is, how can I be confident that you can replicate the same trends that you saw in terms of stabilization and ambulation and some other clinical measures from the proof of concept phase II in a larger phase III? i guess the main thing that folks ask us is how can i be confident that you can replicate the same trends that you saw in terms of stabilization and ambulation and some other clinical measures from the proof of concept phase ii in a larger phase iii Again, any noticeable protocol changes? again any noticeable protocol changes How are you thinking about the translation from the phase II findings to the phase III? how are you thinking about the translation from the phase ii findings to the phase iii

Speaker 1: Yeah, so I think there's a couple of different reasons that give us confidence that those findings will replicate. I think one, and first and foremost, is just the disease pathology and the fact that we're treating disease at a source. It isn't a therapeutic mechanism, which we would expect to replicate. The disease is caused by a mutation in the enzyme FKRP that glycosylates alpha-dystroglycan. So these patients have lower levels of glycosylated alpha-dystroglycan. Glycosylated alpha-dystroglycan acts as a shock absorber in the muscle fibers that protects the muscle. So the glycosylated alpha-dystroglycan acts as a shock absorber in the muscle fibers that protects the muscle from being damaged over daily use. What we're doing is basically providing supraphysiological doses of the substrate to drive residual enzyme activity, thereby increasing the levels of glycosylated alpha-dystroglycan. Yeah, so I think there's a couple of different reasons that give us confidence that those findings will replicate. yeah so i think there's a couple of different reasons that give us confidence that those findings will replicate I think one, and first and foremost, is just the disease pathology and the fact that we're treating disease at a source. i think one and first and foremost is just the disease pathology and the fact that we're treating disease at a source It isn't a therapeutic mechanism, which we would expect to replicate. it isn't a therapeutic mechanism which we would expect to replicate The disease is caused by a mutation in the enzyme FKRP that glycosylates alpha-dystroglycan. the disease is caused by a mutation in the enzyme fkrp that glycosylates alpha-dystroglycan So these patients have lower levels of glycosylated alpha-dystroglycan. so these patients have lower levels of glycosylated alpha-dystroglycan Glycosylated alpha-dystroglycan acts as a shock absorber in the muscle fibers that protects the muscle. glycosylated alpha-dystroglycan acts as a shock absorber in the muscle fibers that protects the muscle So the glycosylated alpha-dystroglycan acts as a shock absorber in the muscle fibers that protects the muscle from being damaged over daily use. so the glycosylated alpha-dystroglycan acts as a shock absorber in the muscle fibers that protects the muscle from being damaged over daily use What we're doing is basically providing supraphysiological doses of the substrate to drive residual enzyme activity, thereby increasing the levels of glycosylated alpha-dystroglycan. what we're doing is basically providing supraphysiological doses of the substrate to drive residual enzyme activity thereby increasing the levels of glycosylated alpha-dystroglycan That mechanism has been validated by the natural history data where people who have—this is off and on. Should I go work? That mechanism has been validated by the natural history data where people who have—this is off and on. that mechanism has been validated by the natural history data where people who have—this is off and on Should I go work? should i go work

Speaker 2: It's back on. It should be back on. It's back on. it's back on It should be back on. it should be back on

Speaker 1: Okay. I don't care. Anyway, basically, higher levels of glycosylated alpha-dystroglycan are correlated with less severe disease. That's replicated or validated by the natural history data. I needed other mic thoughts here. Okay. okay I don't care. i don't care Anyway, basically, higher levels of glycosylated alpha-dystroglycan are correlated with less severe disease. anyway basically higher levels of glycosylated alpha-dystroglycan are correlated with less severe disease That's replicated or validated by the natural history data. that's replicated or validated by the natural history data I needed other mic thoughts here. i needed other mic thoughts here

Speaker 2: Okay, time to issue. Okay, time to issue. okay time to issue

Speaker 1: Is this mic still working? Should I just continue on this one? Is this mic still working? is this mic still working Should I just continue on this one? should i just continue on this one

Speaker 2: I think if you pull it up a little, might be. I think if you pull it up a little, might be. i think if you pull it up a little might be

Speaker 1: Is it working? Okay. Anyways, so where am I? On the clinical data, why we think it's going to replicate is, no worries. We're pretty confident in the biomarkers showing a robust effect. With the clinical data, back to the clinical trial, the phase II study was a small study, 14 patients, open label. The fact that we could see a difference in the clinical measurements relative to natural history was a win. The phase III study is a much larger randomized controlled study with a very similar patient population. Given that we saw that trend in the phase II, we would hope to see the same trend in phase III. It is important to note, however, that at the interim analysis at 12 months, the study is not powered to show statistically significant benefit on the clinical outcomes. That's not what we're looking for. Is it working? is it working Okay. okay Anyways, so where am I? anyways so where am i On the clinical data, why we think it's going to replicate is, no worries. on the clinical data why we think it's going to replicate is no worries We're pretty confident in the biomarkers showing a robust effect. we're pretty confident in the biomarkers showing a robust effect With the clinical data, back to the clinical trial, the phase II study was a small study, 14 patients, open label. with the clinical data back to the clinical trial the phase ii study was a small study 14 patients open label The fact that we could see a difference in the clinical measurements relative to natural history was a win. the fact that we could see a difference in the clinical measurements relative to natural history was a win The phase III study is a much larger randomized controlled study with a very similar patient population. the phase iii study is a much larger randomized controlled study with a very similar patient population Given that we saw that trend in the phase II, we would hope to see the same trend in phase III. given that we saw that trend in the phase ii we would hope to see the same trend in phase iii It is important to note, however, that at the interim analysis at 12 months, the study is not powered to show statistically significant benefit on the clinical outcomes. it is important to note however that at the interim analysis at 12 months the study is not powered to show statistically significant benefit on the clinical outcomes That's not what we're looking for. that's not what we're looking for The FDA has indicated that's not what's required for accelerated approval. We're basing both the interim analysis and accelerated approval off of a robust effect on the biomarkers on glycosylated alpha-dystroglycan. All we're looking for in the functional measures is basically a trend that would be supportive of a benefit for these patients. The FDA has indicated that's not what's required for accelerated approval. the fda has indicated that's not what's required for accelerated approval We're basing both the interim analysis and accelerated approval off of a robust effect on the biomarkers on glycosylated alpha-dystroglycan. we're basing both the interim analysis and accelerated approval off of a robust effect on the biomarkers on glycosylated alpha-dystroglycan All we're looking for in the functional measures is basically a trend that would be supportive of a benefit for these patients. all we're looking for in the functional measures is basically a trend that would be supportive of a benefit for these patients

Speaker 2: Got it. No, that was going to be one of our questions. Related on the kinetics of the treatment effect that you saw in the phase II, do you feel like the interim analysis is good enough of a point in time to see those trends in clinical effects? Which endpoints, I guess, which one of those secondaries are you more likely to see a benefit versus not? Some could take a little longer. How should we think about that? Got it. got it No, that was going to be one of our questions. no that was going to be one of our questions Related on the kinetics of the treatment effect that you saw in the phase II, do you feel like the interim analysis is good enough of a point in time to see those trends in clinical effects? related on the kinetics of the treatment effect that you saw in the phase ii do you feel like the interim analysis is good enough of a point in time to see those trends in clinical effects Which endpoints, I guess, which one of those secondaries are you more likely to see a benefit versus not? which endpoints i guess which one of those secondaries are you more likely to see a benefit versus not Some could take a little longer. some could take a little longer How should we think about that? how should we think about that

Speaker 1: Yeah, yeah, absolutely. Again, the primary endpoint for the interim analysis is the change in glycosylated alpha-dystroglycan. That's the primary endpoint that we're looking for, and that's what the basis of the accelerated approval is going to be. If you looked at the phase II data, we saw approximate doubling of glycosylated alpha-dystroglycan that was already present at month three, and that was sustained out to month 12. For the interim analysis, we're looking at change in glycosylated alpha-dystroglycan both at month three and month 12, which we would expect to see replicated from the phase II. We would also expect to see a reduction, a robust reduction in CK, which is also what we saw in the phase II, supportive of the pathology of the disease. On the functional endpoints, what we're looking to see is a trend in one or more. Yeah, yeah, absolutely. yeah yeah absolutely Again, the primary endpoint for the interim analysis is the change in glycosylated alpha-dystroglycan. again the primary endpoint for the interim analysis is the change in glycosylated alpha-dystroglycan That's the primary endpoint that we're looking for, and that's what the basis of the accelerated approval is going to be. that's the primary endpoint that we're looking for and that's what the basis of the accelerated approval is going to be If you looked at the phase II data, we saw approximate doubling of glycosylated alpha-dystroglycan that was already present at month three, and that was sustained out to month 12. if you looked at the phase ii data we saw approximate doubling of glycosylated alpha-dystroglycan that was already present at month three and that was sustained out to month 12 For the interim analysis, we're looking at change in glycosylated alpha-dystroglycan both at month three and month 12, which we would expect to see replicated from the phase II. for the interim analysis we're looking at change in glycosylated alpha-dystroglycan both at month three and month 12 which we would expect to see replicated from the phase ii We would also expect to see a reduction, a robust reduction in CK, which is also what we saw in the phase II, supportive of the pathology of the disease. we would also expect to see a reduction a robust reduction in ck which is also what we saw in the phase ii supportive of the pathology of the disease On the functional endpoints, what we're looking to see is a trend in one or more. on the functional endpoints what we're looking to see is a trend in one or more What we saw in the phase II study is a stabilization of the ambulatory measures at 12 months relative to natural history, because that was an open-label study. The study is not powered to show any statistically significant on the functional endpoints, but what we're looking for is trends that would be similar to what we saw in phase II. What we saw in the phase II study is a stabilization of the ambulatory measures at 12 months relative to natural history, because that was an open-label study. what we saw in the phase ii study is a stabilization of the ambulatory measures at 12 months relative to natural history because that was an open-label study The study is not powered to show any statistically significant on the functional endpoints, but what we're looking for is trends that would be similar to what we saw in phase II. the study is not powered to show any statistically significant on the functional endpoints but what we're looking for is trends that would be similar to what we saw in phase ii

Speaker 2: Got it. Do you feel more confident about any specific endpoints in terms of seeing the trend, or is it more about the whole picture and the overall product profile? Got it. got it Do you feel more confident about any specific endpoints in terms of seeing the trend, or is it more about the whole picture and the overall product profile? do you feel more confident about any specific endpoints in terms of seeing the trend or is it more about the whole picture and the overall product profile

Speaker 1: Yeah, I mean, I think any data is going to be supportive here. I mean, it's the totality of evidence here. The primary endpoint of the study is the North Star composite. That's the gold standard that the FDA wants everyone to use for these muscular dystrophy diseases. It is a relatively insensitive instrument, which is why we want to put a 36-month treatment duration. We would not expect to see really much ability to discern treatment benefit at 12 months. At 12 months, you're more likely to see treatment benefit on the ambulatory measures and FVC. Those are going to be more important for the interim and supportive secondary endpoints for the final endpoint. Yeah, I mean, I think any data is going to be supportive here. yeah i mean i think any data is going to be supportive here I mean, it's the totality of evidence here. i mean it's the totality of evidence here The primary endpoint of the study is the North Star composite. the primary endpoint of the study is the north star composite That's the gold standard that the FDA wants everyone to use for these muscular dystrophy diseases. that's the gold standard that the fda wants everyone to use for these muscular dystrophy diseases It is a relatively insensitive instrument, which is why we want to put a 36-month treatment duration. it is a relatively insensitive instrument which is why we want to put a 36-month treatment duration We would not expect to see really much ability to discern treatment benefit at 12 months. we would not expect to see really much ability to discern treatment benefit at 12 months At 12 months, you're more likely to see treatment benefit on the ambulatory measures and FVC. at 12 months you're more likely to see treatment benefit on the ambulatory measures and fvc Those are going to be more important for the interim and supportive secondary endpoints for the final endpoint. those are going to be more important for the interim and supportive secondary endpoints for the final endpoint

Speaker 2: Got it. Given the lack of treatment options here, just thinking about both the commercial outlook and the regulatory outlook, is a delta on disease progression good enough? Do you need to show stabilization? How much elasticity could there be commercially depending on what kind of product profile you show in this setting? Got it. got it Given the lack of treatment options here, just thinking about both the commercial outlook and the regulatory outlook, is a delta on disease progression good enough? given the lack of treatment options here just thinking about both the commercial outlook and the regulatory outlook is a delta on disease progression good enough Do you need to show stabilization? do you need to show stabilization How much elasticity could there be commercially depending on what kind of product profile you show in this setting? how much elasticity could there be commercially depending on what kind of product profile you show in this setting

Speaker 1: Yeah, I don't really think there's much of a difference in the adoption and commercial uptake based on what we show, either stabilization or just a slowing in decline. If you speak with the patients, first of all, there's nothing on the market today for these patients. This would be the first to market for a disease-modifying therapy. If you speak with the patients, what they're really looking for is just something to stop the progressive loss of function. These are patients that know they're ultimately going to be unable to walk. They're going to be unable to get up from a sit. They're unable to go to the toilet by themselves. They just constantly lose daily functions of life. Anything that stops that progressive decline or even slows it is a win for these patients. Yeah, I don't really think there's much of a difference in the adoption and commercial uptake based on what we show, either stabilization or just a slowing in decline. yeah i don't really think there's much of a difference in the adoption and commercial uptake based on what we show either stabilization or just a slowing in decline If you speak with the patients, first of all, there's nothing on the market today for these patients. if you speak with the patients first of all there's nothing on the market today for these patients This would be the first to market for a disease-modifying therapy. this would be the first to market for a disease-modifying therapy If you speak with the patients, what they're really looking for is just something to stop the progressive loss of function. if you speak with the patients what they're really looking for is just something to stop the progressive loss of function These are patients that know they're ultimately going to be unable to walk. these are patients that know they're ultimately going to be unable to walk They're going to be unable to get up from a sit. they're going to be unable to get up from a sit They're unable to go to the toilet by themselves. they're unable to go to the toilet by themselves They just constantly lose daily functions of life. they just constantly lose daily functions of life Anything that stops that progressive decline or even slows it is a win for these patients. anything that stops that progressive decline or even slows it is a win for these patients

Speaker 2: Got it. In terms of comps, both from a prevalence perspective, pricing, and whatever, again, DMD is generally the market folks look at the most. How are you guys thinking about that right now? Got it. got it In terms of comps, both from a prevalence perspective, pricing, and whatever, again, DMD is generally the market folks look at the most. in terms of comps both from a prevalence perspective pricing and whatever again dmd is generally the market folks look at the most How are you guys thinking about that right now? how are you guys thinking about that right now

Speaker 1: Yeah, I think that's a good comp. I think it's probably comparable to the initial exon 51-skipping market for DMD. We believe there's about 7,000 patients with LGMD2i in the U.S. and Europe. This would be kind of first to market with an oral therapy, kind of well-tolerated safety profile so far. I think the one difference between that initial target market for DMD and LGMD2i is there is a pretty significant European population here. There is a founder mutation that is present in Northern Europeans, so there's a pretty meaningful European market here in addition to the U.S. Yeah, I think that's a good comp. yeah i think that's a good comp I think it's probably comparable to the initial exon 51-skipping market for DMD. i think it's probably comparable to the initial exon 51-skipping market for dmd We believe there's about 7,000 patients with LGMD2i in the U.S. and Europe. we believe there's about 7,000 patients with lgmd2i in the u.s and europe This would be kind of first to market with an oral therapy, kind of well-tolerated safety profile so far. this would be kind of first to market with an oral therapy kind of well-tolerated safety profile so far I think the one difference between that initial target market for DMD and LGMD2i is there is a pretty significant European population here. i think the one difference between that initial target market for dmd and lgmd2i is there is a pretty significant european population here There is a founder mutation that is present in Northern Europeans, so there's a pretty meaningful European market here in addition to the U.S. there is a founder mutation that is present in northern europeans so there's a pretty meaningful european market here in addition to the u.s

Speaker 2: Got it. Perfect. I guess we can pivot to talk about Attruby a little bit. You're not going to get away from that. Got it. got it Perfect. perfect I guess we can pivot to talk about Attruby a little bit. i guess we can pivot to talk about attruby a little bit You're not going to get away from that. you're not going to get away from that

Speaker 4: Of course, happy to talk about it. Of course, happy to talk about it. of course happy to talk about it

Speaker 2: Consensus right now for Attruby for the year is about $350 million. I would say most of the buy-side investors I talk to are a little ahead of that. The execution so far has been pretty good. Are you guys comfortable with hearing some of those numbers? I know it's probably too early to issue any specific guidance. Overall, how do you feel about investors' expectations going into the end of the year? Consensus right now for Attruby for the year is about $350 million. consensus right now for attruby for the year is about $350 million I would say most of the buy-side investors I talk to are a little ahead of that. i would say most of the buy-side investors i talk to are a little ahead of that The execution so far has been pretty good. the execution so far has been pretty good Are you guys comfortable with hearing some of those numbers? are you guys comfortable with hearing some of those numbers I know it's probably too early to issue any specific guidance. i know it's probably too early to issue any specific guidance Overall, how do you feel about investors' expectations going into the end of the year? overall how do you feel about investors' expectations going into the end of the year

Speaker 4: Yeah, that's a good question, Chad. I think what I would say is we feel very good about the launch. The metric which we track most closely is share in treatment-naive patients and just the overall number of treatment-naive patients, just because that is the best. We think that that is the best marker of long-term success for Attruby. What we have said on that front is every month of the launch, the number of treatment-naive patients on Attruby has increased. We feel like that trend has continued even after we last reported our earnings in the month of August. We feel good about where we are. I think that all the data being generated, as well as all the commercial tactics by our team, have really helped us continue to gain share. I think that that gives us a lot of confidence. Yeah, that's a good question, Chad. yeah that's a good question chad I think what I would say is we feel very good about the launch. i think what i would say is we feel very good about the launch The metric which we track most closely is share in treatment-naive patients and just the overall number of treatment-naive patients, just because that is the best. the metric which we track most closely is share in treatment-naive patients and just the overall number of treatment-naive patients just because that is the best We think that that is the best marker of long-term success for Attruby. we think that that is the best marker of long-term success for attruby What we have said on that front is every month of the launch, the number of treatment-naive patients on Attruby has increased. what we have said on that front is every month of the launch the number of treatment-naive patients on attruby has increased We feel like that trend has continued even after we last reported our earnings in the month of August. we feel like that trend has continued even after we last reported our earnings in the month of august We feel good about where we are. we feel good about where we are I think that all the data being generated, as well as all the commercial tactics by our team, have really helped us continue to gain share. i think that all the data being generated as well as all the commercial tactics by our team have really helped us continue to gain share I think that that gives us a lot of confidence. i think that that gives us a lot of confidence I think that some of our, what I would say, net revenue per patient type metrics, we had flagged that we had some one-time benefits in Q1. We've also flagged that they've normalized in Q2. I think that they're going to be stable going forward. I think whether it's compliance at around 80% or sort of low monthly drop-off or gross-to-net being stable, all of that, I think, is now sort of more steady state, which means that as we get more patients, you should start to see that sort of show up in relevance. I think that some of our, what I would say, net revenue per patient type metrics, we had flagged that we had some one-time benefits in Q1. i think that some of our what i would say net revenue per patient type metrics we had flagged that we had some one-time benefits in q1 We've also flagged that they've normalized in Q2. we've also flagged that they've normalized in q2 I think that they're going to be stable going forward. i think that they're going to be stable going forward I think whether it's compliance at around 80% or sort of low monthly drop-off or gross-to-net being stable, all of that, I think, is now sort of more steady state, which means that as we get more patients, you should start to see that sort of show up in relevance. i think whether it's compliance at around 80% or sort of low monthly drop-off or gross-to-net being stable all of that i think is now sort of more steady state which means that as we get more patients you should start to see that sort of show up in relevance

Speaker 2: Going through it more directly. Going through it more directly. going through it more directly

Speaker 4: Yeah. Yeah. yeah

Speaker 2: You mentioned right now your share in treatment-naive. You see more treatment-naive patients getting on drug on a month-to-month basis. It seems like that part is tracking really well. Initially, there were some questions about a bolus of switch patients being responsible for the early stage of the launch. Do you have any sense of what percentage that makes up from here? I'm assuming that's going to decrease even further over time. Again, some support from the treatment-naive. What about the switches? You mentioned right now your share in treatment-naive. you mentioned right now your share in treatment-naive You see more treatment-naive patients getting on drug on a month-to-month basis. you see more treatment-naive patients getting on drug on a month-to-month basis It seems like that part is tracking really well. it seems like that part is tracking really well Initially, there were some questions about a bolus of switch patients being responsible for the early stage of the launch. initially there were some questions about a bolus of switch patients being responsible for the early stage of the launch Do you have any sense of what percentage that makes up from here? do you have any sense of what percentage that makes up from here I'm assuming that's going to decrease even further over time. i'm assuming that's going to decrease even further over time Again, some support from the treatment-naive. again some support from the treatment-naive What about the switches? what about the switches

Speaker 4: Yeah, it's a very good question, Chad. We've always said that a majority of our patients were treatment-naive. The first time we reported numbers for Attruby was at another conference earlier in the year in January. At that point, we said majority were treatment-naive. In our Q4 PR or Q1 PR, we said that. In Q2 PR, we've always said that it's majority treatment-naive. That share continues to go up, which obviously means that the portion of switch in our total patient base has continued to go down. Really, that's driven by the fact that up until March, we had 100% share in the switch market. After that, we had another competitor enter the market. Of course, that 100% share has since come down. I think that overall, we feel good about the number of patients who are getting on Attruby. Yeah, it's a very good question, Chad. yeah it's a very good question chad We've always said that a majority of our patients were treatment-naive. we've always said that a majority of our patients were treatment-naive The first time we reported numbers for Attruby was at another conference earlier in the year in January. the first time we reported numbers for attruby was at another conference earlier in the year in january At that point, we said majority were treatment-naive. at that point we said majority were treatment-naive In our Q4 PR or Q1 PR, we said that. in our q4 pr or q1 pr we said that In Q2 PR, we've always said that it's majority treatment-naive. in q2 pr we've always said that it's majority treatment-naive That share continues to go up, which obviously means that the portion of switch in our total patient base has continued to go down. that share continues to go up which obviously means that the portion of switch in our total patient base has continued to go down Really, that's driven by the fact that up until March, we had 100% share in the switch market. really that's driven by the fact that up until march we had 100% share in the switch market After that, we had another competitor enter the market. after that we had another competitor enter the market Of course, that 100% share has since come down. of course that 100% share has since come down I think that overall, we feel good about the number of patients who are getting on Attruby. i think that overall we feel good about the number of patients who are getting on attruby We're very excited to have reported that 3,751 patients were prescribed Attruby as of August 1. We're very excited to have reported that 3,751 patients were prescribed Attruby as of August 1. we're very excited to have reported that 3,751 patients were prescribed attruby as of august 1

Speaker 2: Got it. No, perfect. You kind of touched a little bit, but drilling down on the gross-to-net debate, some investors felt like the change from Q1 to Q2 was really abrupt on the gross-to-net and the net revenue per patient. We already talked about some of the things that drove that, the payer mix, some other things. How can we be confident that those are not going to change? Can you talk more about the current payer mix? What could actually decrease or increase gross-to-net going forward, depending on how that shakes out over a longer period of time with the launch? Got it. got it No, perfect. no perfect You kind of touched a little bit, but drilling down on the gross-to-net debate, some investors felt like the change from Q1 to Q2 was really abrupt on the gross-to-net and the net revenue per patient. you kind of touched a little bit but drilling down on the gross-to-net debate some investors felt like the change from q1 to q2 was really abrupt on the gross-to-net and the net revenue per patient We already talked about some of the things that drove that, the payer mix, some other things. we already talked about some of the things that drove that the payer mix some other things How can we be confident that those are not going to change? how can we be confident that those are not going to change Can you talk more about the current payer mix? can you talk more about the current payer mix What could actually decrease or increase gross-to-net going forward, depending on how that shakes out over a longer period of time with the launch? what could actually decrease or increase gross-to-net going forward depending on how that shakes out over a longer period of time with the launch

Speaker 4: Yeah, that's another very good question, Chad. I think that if you look at the sort of things which change, if we take a step back, we have said for a very long time that we think stable gross-to-net is somewhere in the 30%-40% range. I think that hasn't changed. The reason why we flagged on our Q1 call that it was favorable compared to those expectations is we just saw a payer mix which we didn't think was representative of the steady state. We know that we're going to have some ordering from specific ISPs. We understand the end payer mix for ATTR CM patients. We have seen that more representative payer mix as of Q2. Because of that, we feel more confident that that's not going to change. That was exactly what we expected before we launched also. Yeah, that's another very good question, Chad. yeah that's another very good question chad I think that if you look at the sort of things which change, if we take a step back, we have said for a very long time that we think stable gross-to-net is somewhere in the 30% - 40% range. i think that if you look at the sort of things which change if we take a step back we have said for a very long time that we think stable gross-to-net is somewhere in the 30% - 40% range I think that hasn't changed. i think that hasn't changed The reason why we flagged on our Q1 call that it was favorable compared to those expectations is we just saw a payer mix which we didn't think was representative of the steady state. the reason why we flagged on our q1 call that it was favorable compared to those expectations is we just saw a payer mix which we didn't think was representative of the steady state We know that we're going to have some ordering from specific ISPs. we know that we're going to have some ordering from specific isps We understand the end payer mix for ATTR CM patients. we understand the end payer mix for attr cm patients We have seen that more representative payer mix as of Q2. we have seen that more representative payer mix as of q2 Because of that, we feel more confident that that's not going to change. because of that we feel more confident that that's not going to change That was exactly what we expected before we launched also. that was exactly what we expected before we launched also I think those things give us confidence that it's going to be stable from here on out. I think those things give us confidence that it's going to be stable from here on out. i think those things give us confidence that it's going to be stable from here on out

Speaker 2: Got it. What about potential impact from competition? I think everyone's thinking Pfizer specifically. Going forward, do you expect to see more pressure from a formulary perspective? Do you need to give bigger rebates? So far, we haven't really seen any policies that are highly favorable or highly unfavorable on a mass scale. There have been some wins, some losses here and there. How should we think about the competition perhaps taking a stand here on share loss? Got it. got it What about potential impact from competition? what about potential impact from competition I think everyone's thinking Pfizer specifically. i think everyone's thinking pfizer specifically Going forward, do you expect to see more pressure from a formulary perspective? going forward do you expect to see more pressure from a formulary perspective Do you need to give bigger rebates? do you need to give bigger rebates So far, we haven't really seen any policies that are highly favorable or highly unfavorable on a mass scale. so far we haven't really seen any policies that are highly favorable or highly unfavorable on a mass scale There have been some wins, some losses here and there. there have been some wins some losses here and there How should we think about the competition perhaps taking a stand here on share loss? how should we think about the competition perhaps taking a stand here on share loss

Speaker 4: Yeah, that's an interesting question. I think we would say that our strategy has always been parity access. We think we're not looking to sort of pay for preferred access or anything like that. We also feel like we've done the responsible thing by being 10% cheaper in terms of list price. Of course, we have best-in-class hospitalization data of 50% reduction at 30 months. That's better than what anyone else has been able to show in the category. That's very favorable for payers. I think as we think about all of that, we don't really see the value in the category being lost. We feel very good about our conversations with the payers. Of course, we are sort of a new company, so we have new-to-market edits and things like that. They're slowly starting to come off, all the things you would expect in a new launch. Yeah, that's an interesting question. yeah that's an interesting question I think we would say that our strategy has always been parity access. i think we would say that our strategy has always been parity access We think we're not looking to sort of pay for preferred access or anything like that. we think we're not looking to sort of pay for preferred access or anything like that We also feel like we've done the responsible thing by being 10% cheaper in terms of list price. we also feel like we've done the responsible thing by being 10% cheaper in terms of list price Of course, we have best-in-class hospitalization data of 50% reduction at 30 months. of course we have best-in-class hospitalization data of 50% reduction at 30 months That's better than what anyone else has been able to show in the category. that's better than what anyone else has been able to show in the category That's very favorable for payers. that's very favorable for payers I think as we think about all of that, we don't really see the value in the category being lost. i think as we think about all of that we don't really see the value in the category being lost We feel very good about our conversations with the payers. we feel very good about our conversations with the payers Of course, we are sort of a new company, so we have new-to-market edits and things like that. of course we are sort of a new company so we have new-to-market edits and things like that They're slowly starting to come off, all the things you would expect in a new launch. they're slowly starting to come off all the things you would expect in a new launch We haven't really seen any sort of broad pressures like you were also mentioning. I think we just expect that to continue. We haven't really seen any sort of broad pressures like you were also mentioning. we haven't really seen any sort of broad pressures like you were also mentioning I think we just expect that to continue. i think we just expect that to continue

Speaker 2: Got it. I guess one of the most frequently asked questions that I need to check the box is related to tafamidis ID. There is a lot of nitpicking on Vyndaqel versus Vyndamax. What happens if there's actually generics a little earlier than what folks are expecting here? What are some of the potential scenarios and impact to the trajectory you think, depending on how that shakes out? Got it. got it I guess one of the most frequently asked questions that I need to check the box is related to tafamidis ID. There is a lot of nitpicking on Vyndaqel versus Vyndamax. i guess one of the most frequently asked questions that i need to check the box is related to tafamidis id. there is a lot of nitpicking on vyndaqel versus vyndamax What happens if there's actually generics a little earlier than what folks are expecting here? what happens if there's actually generics a little earlier than what folks are expecting here What are some of the potential scenarios and impact to the trajectory you think, depending on how that shakes out? what are some of the potential scenarios and impact to the trajectory you think depending on how that shakes out

Speaker 4: Yeah, so I think that our thesis on this has always been that the Form 1 or the polymorph patent protects the entire tafamidis franchise. That's based on the fact that no one has been able to manufacture at a commercial scale Vyndaqel or Vyndamax, which does not have Form 1 present in it. As soon as you have a little bit of Form 1, you're infringing on the patent. That hasn't really changed. That's always what we've believed. You might be referring to the recent news of the Vyndaqel discontinuation. What we see there is even in the small off chance that someone was able to somehow manufacture Vyndaqel without Form 1, which again, no one's been able to do so far. There's been a case in Europe also where there's been a preliminary ruling already on this. Yeah, so I think that our thesis on this has always been that the Form 1 or the polymorph patent protects the entire tafamidis franchise. yeah so i think that our thesis on this has always been that the form 1 or the polymorph patent protects the entire tafamidis franchise That's based on the fact that no one has been able to manufacture at a commercial scale Vyndaqel or Vyndamax, which does not have Form 1 present in it. that's based on the fact that no one has been able to manufacture at a commercial scale vyndaqel or vyndamax which does not have form 1 present in it As soon as you have a little bit of Form 1, you're infringing on the patent. as soon as you have a little bit of form 1 you're infringing on the patent That hasn't really changed. that hasn't really changed That's always what we've believed. that's always what we've believed You might be referring to the recent news of the Vyndaqel discontinuation. you might be referring to the recent news of the vyndaqel discontinuation What we see there is even in the small off chance that someone was able to somehow manufacture Vyndaqel without Form 1, which again, no one's been able to do so far. what we see there is even in the small off chance that someone was able to somehow manufacture vyndaqel without form 1 which again no one's been able to do so far There's been a case in Europe also where there's been a preliminary ruling already on this. there's been a case in europe also where there's been a preliminary ruling already on this The loss of Vyndaqel means that it's going to be much harder for any generic to enter because there's not going to be a natural patient base or a natural physician base or a payer base. It's also important to note that Vyndaqel and Vyndamax are not therapeutically equivalent and so substitutable at the pharmacy, which further sort of protects it. I feel like there are layers of protection one after the other, all of which together have just reinforced our confidence that this market is going to be sustained. It's going to be long term. I think that gives us a lot of confidence in sort of the overall trajectory for Attruby. The loss of Vyndaqel means that it's going to be much harder for any generic to enter because there's not going to be a natural patient base or a natural physician base or a payer base. the loss of vyndaqel means that it's going to be much harder for any generic to enter because there's not going to be a natural patient base or a natural physician base or a payer base It's also important to note that Vyndaqel and Vyndamax are not therapeutically equivalent and so substitutable at the pharmacy, which further sort of protects it. it's also important to note that vyndaqel and vyndamax are not therapeutically equivalent and so substitutable at the pharmacy which further sort of protects it I feel like there are layers of protection one after the other, all of which together have just reinforced our confidence that this market is going to be sustained. i feel like there are layers of protection one after the other all of which together have just reinforced our confidence that this market is going to be sustained It's going to be long term. it's going to be long term I think that gives us a lot of confidence in sort of the overall trajectory for Attruby. i think that gives us a lot of confidence in sort of the overall trajectory for attruby

Speaker 2: Perfect. I know we're almost running out of time. I do want to just get a couple of infographics just in case. The main question that we have, there again, a lot of counter-detailing on the safety. How do you adjust efficacy for different baseline characteristics? We've discussed that at length already. Perhaps a question more on safety. That has been kind of the permanent overhang on the program. How frequently does the DSMB meet for the phase III? I'm curious what you might have seen or heard from a safety perspective so far from the clinical trial. The trial has not been halted or anything like that. I'm assuming so far, so good. Anything you can say in terms of the cadence and communication from the DSMB? Perfect. perfect I know we're almost running out of time. i know we're almost running out of time I do want to just get a couple of infographics just in case. i do want to just get a couple of infographics just in case The main question that we have, there again, a lot of counter-detailing on the safety. the main question that we have there again a lot of counter-detailing on the safety How do you adjust efficacy for different baseline characteristics? how do you adjust efficacy for different baseline characteristics We've discussed that at length already. we've discussed that at length already Perhaps a question more on safety. perhaps a question more on safety That has been kind of the permanent overhang on the program. that has been kind of the permanent overhang on the program How frequently does the DSMB meet for the phase III? how frequently does the dsmb meet for the phase iii I'm curious what you might have seen or heard from a safety perspective so far from the clinical trial. i'm curious what you might have seen or heard from a safety perspective so far from the clinical trial The trial has not been halted or anything like that. the trial has not been halted or anything like that I'm assuming so far, so good. i'm assuming so far so good Anything you can say in terms of the cadence and communication from the DSMB? anything you can say in terms of the cadence and communication from the dsmb

Speaker 4: Yeah, I think the trial continues to go along. I think what's important to note is sometimes people focus on hyperphos. Sort of grade 1, grade 2 hyperphos is really not a phase. Yeah, I think the trial continues to go along. yeah i think the trial continues to go along I think what's important to note is sometimes people focus on hyperphos. i think what's important to note is sometimes people focus on hyperphos Sort of grade 1, grade 2 hyperphos is really not a phase. sort of grade 1 grade 2 hyperphos is really not a phase

Speaker 2: Physicians we spoke to don't seem overly concerned about that. Physicians we spoke to don't seem overly concerned about that. physicians we spoke to don't seem overly concerned about that

Speaker 4: Exactly. I mean, I think if you have a little bit of ice cream or something like that, your phosphorus levels can increase. I'm certainly guilty of that. I think that actually our phase II data really gave us confidence on that front. We saw a very clean safety profile. We saw best-in-class efficacy. We're the only sort of agent which has shown statistically significant effect on proportionality. As we look at the overall data, including the safety data, we feel like infigratinib is really poised to become the standard of care. Of course, you have to read out our phase III trial. What we didn't mention is that the oral profile really does differentiate us. I think no one really wants to have 4,000 injections for a child. It's just a hard setup. We feel good about it. Exactly. exactly I mean, I think if you have a little bit of ice cream or something like that, your phosphorus levels can increase. i mean i think if you have a little bit of ice cream or something like that your phosphorus levels can increase I'm certainly guilty of that. i'm certainly guilty of that I think that actually our phase II data really gave us confidence on that front. i think that actually our phase ii data really gave us confidence on that front We saw a very clean safety profile. we saw a very clean safety profile We saw best-in-class efficacy. we saw best-in-class efficacy We're the only sort of agent which has shown statistically significant effect on proportionality. we're the only sort of agent which has shown statistically significant effect on proportionality As we look at the overall data, including the safety data, we feel like infigratinib is really poised to become the standard of care. as we look at the overall data including the safety data we feel like infigratinib is really poised to become the standard of care Of course, you have to read out our phase III trial. of course you have to read out our phase iii trial What we didn't mention is that the oral profile really does differentiate us. what we didn't mention is that the oral profile really does differentiate us I think no one really wants to have 4,000 injections for a child. i think no one really wants to have 4,000 injections for a child It's just a hard setup. it's just a hard setup We feel good about it. we feel good about it I know we're going to have more time to talk about infigratinib as the year wraps up, as that trial is reading out in early 2026. I know we're going to have more time to talk about infigratinib as the year wraps up, as that trial is reading out in early 2026. i know we're going to have more time to talk about infigratinib as the year wraps up as that trial is reading out in early 2026

Speaker 2: Yeah. The final one there, perhaps just in terms of the baseline characteristics, again, probably some meaningful changes from the phase II to the phase III. Anything noteworthy so far that would kind of hurt the translatability of the phase II findings to the phase III? Yeah. yeah The final one there, perhaps just in terms of the baseline characteristics, again, probably some meaningful changes from the phase II to the phase III. the final one there perhaps just in terms of the baseline characteristics again probably some meaningful changes from the phase ii to the phase iii Anything noteworthy so far that would kind of hurt the translatability of the phase II findings to the phase III? anything noteworthy so far that would kind of hurt the translatability of the phase ii findings to the phase iii

Speaker 4: Yeah, our phase II data, I think it really validated the best-in-class safety and efficacy profile. It really gave us the confidence to go. Our phase II was five and up children. Our phase III is three and up. That 3-5 means that we're going to have a negative. That's usually not good in terms of the absolute number. We'll get a broader label. I think that more children will be able to benefit from it if it is approved. I think that that's kind of important for folks to know, just the baseline characteristic is different. It's three and up for phase III and not five and up, which is for phase II. Yeah, our phase II data, I think it really validated the best-in-class safety and efficacy profile. yeah our phase ii data i think it really validated the best-in-class safety and efficacy profile It really gave us the confidence to go. it really gave us the confidence to go Our phase II was five and up children. our phase ii was five and up children Our phase III is three and up. our phase iii is three and up That 3-5 means that we're going to have a negative. that 3-5 means that we're going to have a negative That's usually not good in terms of the absolute number. that's usually not good in terms of the absolute number We'll get a broader label. we'll get a broader label I think that more children will be able to benefit from it if it is approved. i think that more children will be able to benefit from it if it is approved I think that that's kind of important for folks to know, just the baseline characteristic is different. i think that that's kind of important for folks to know just the baseline characteristic is different It's three and up for phase III and not five and up, which is for phase II. it's three and up for phase iii and not five and up which is for phase ii

Speaker 2: Got it. Perfect. Fair enough. With that, we're out of time. Again, thank you all very much for joining us. Got it. got it Perfect. perfect Fair enough. fair enough With that, we're out of time. with that we're out of time Again, thank you all very much for joining us. again thank you all very much for joining us

Speaker 4: Thank you, Chad. Thank you, Chad. thank you chad

Speaker 2: I hope the audience appreciated it. I hope the audience appreciated it. i hope the audience appreciated it