All right, we're ready to get started. Welcome, everyone. I'm Josh Schimmer from the Cantor Biotech Equity Research Team. Very pleased to introduce some of the management team from BridgeBio . We have Christine Siu, CEO of ML Bio Solutions. That's the limb-girdle muscular dystrophy program. We have Ananth Sridhar, COO of Calcilytics. So that's encaleret. We've got Chinmay Shukla, Head of Corporate Communication, to cover us on all other things. Starting with Attruby maybe is a good place to start. Chinmay, maybe on that topic, give us a quick snapshot of how the launch has been going and what we should be looking forward to in the quarters ahead.
Yeah, Josh, first of all, I wanted to say thank you to you and the entire Cantor Team for inviting us and for hosting us at this really wonderful conference. We appreciate it and we appreciate the engagement. In terms of Attruby, the launch is off to a very strong start and it continues to go really well. We continue to get a lot of momentum in both the treatment naïve and the switch setting. Of course, treatment naïve has been our primary focus and each month of the launch, we continue to get more treatment naïve patients and that sort of continued as the launch has gone on. I think really all of this is being driven by the superior clinical profile of Attruby . It obviously has roots in genetics and how the molecule is designed, but it is the only near-complete stabilizer on the market.
It acts as quickly as three months in terms of separating from placebo on hard outcomes, as well as the 50% reduction in hospitalization at 30 months and the 40% reduction in ACM and hospitalization at 30 months. I think that has really led to increased adoption, both in the academic centers as well as in the community. As the launch has gone on, one of the other things that's happened is now some of our net revenue per patient metrics have stabilized, whether it's our gross-to-net stabilizing in that 30%- 40% range, which I know you and I have discussed, our compliance settling in at around 80%, which again, I know you guys have discussed, our free trial utilization use, our PAP use. We really are seeing the launch continue to play really well and we are very excited about it.
Q2 was a great quarter for patient ads. I think many of us missed the gross-to-net adjustment that was happening there. Explain to us what happened and why that was something that maybe got pulled forward relative to expectations.
Yeah, so I think we have always sort of our long-term expectation for gross-to-net has always been somewhere between 30%- 40%. There are two components to it, right? There's a mandatory 20% rebate, which we have to pay Medicare. Most of this market is Medicare, as I think all of us know. That is the floor. Beyond that, our strategy has always been parity access, right? What we have seen is in terms of having parity access, we're not looking to have any payment for access, but of course, your specialty pharmacies, the institutional SPs, Medicaid, as well as your specialty distributors do get some margins. Normal rare disease gross-to-nets are somewhere between 10%- 20%. You take the 20% from Medicare, add the 10%- 20%, that's how we got to 30%- 40%.
First quarter, we said had come in below these expectations, and that was just a function of the end payer mix. Earlier on in the launch, some of the folks who ordered had slightly lower gross-to-net. We expected that to normalize, and we had flagged it in our Q1 call, and that's kind of what we saw happen in our Q2.
Got it. I think you fairly recently expressed confidence in the ability to maintain the new patient addition cadence you've been on. Are you still feeling good about that, or is there a potential to either accelerate or decelerate?
Yeah, I think we feel very good about where we are in terms of new patient ads, right? I think people look at it in different ways. The way I personally look at it is I look at it from launch to our last update. When we reported our Q1 earnings, there's about 22 weeks, we had about 2,072 patients. That was about somewhere between 90- 100 patients per week. When we reported our Q2 earnings on August 1, that was about 36 weeks, we had 3,751 patients. That was an acceleration. I think as we report our Q3 earnings, we continue to see two big tailwinds for us, right? I think our share continues to increase, especially in the treatment naïve setting. It doesn't increase overnight, but slowly it inches up in the right direction. The market itself continues to grow.
I think that launch to our next update, we would expect to continue to see a good amount of patient ads. I wouldn't want to comment too much on the exact numbers, but we feel good about where we are.
Because you gave some color throughout the second quarter, do you expect you'll provide additional color throughout 3Q as we get?
Yeah, what we have said in some of our meetings today is that, you know, similar to what we were seeing in the second quarter, our August month in terms of treatment naïve continued to look really good. Maybe it was slightly better than July, and that continues. Also remember that we have the switch market. Our share was 100% there when we were first launched, and then we have a competitor now, so that share has been going down. We kind of have to see how those things balance out. On treatment naïve, we have said that our number of new ads on treatment naïve every month keeps going up.
Your thoughts on the implications of Pfizer discontinuing Vyndaqel to focus on Vyndamax, either near-term commercial implications? It did sound like maybe there were some small pockets where specialists were being pushed to Vyndaqel , and instead they opted for Attruby . You might lose a little bit of that tailwind. Do you see any other near-term dynamics? Then longer term around the intellectual property for the profile, have your views changed around the strength of the polymorph patent covering both?
Yeah, that's a great question, Josh. Maybe I'll first kind of hit on the commercial points OV. In 2026, when Vyndaqel gets discontinued, we think that there's an opportunity for us to potentially get some of those patients who would have otherwise been prescribed Vyndaqel. Those physicians are already predisposed to a stabilizer. We think Attruby is a near-complete stabilizer, and we feel like we could serve those patients and help those physicians serve those patients. That is going to be helpful to us to some degree. Of course, Vyndaqel is a small portion of the overall, ephemeral volume, so it's not like a huge factor in terms of play, but you want to get every patient that you can serve. In terms of your longer term, sort of, IP question, what I would say is our view on the polymorph patent has always remained the same.
It's still the same that it protects both Vyndaqel and Vyndamax. I think the problem for any generic trying to develop generic Vyndaqel is they would have to design around Form 1. Even if there's a trace amount of the polymorph detected, they would be infringing. So far, no one's been able to manufacture Vyndaqel to our knowledge without infringing on the Form 1 patent. I think what this move does is it does further reduce the, I would say, already low probability that if someone could, no one's been able to do it so far, but if in case someone could somehow do it, right now the bar has been raised even higher because there's no existing physician base, there's no existing patient base, there's no payer base. Vyndaqel and Vyndamax are not therapeutically equivalent and hence not substitutable. It just makes the bar even higher.
I think it, as I've discussed with some folks, for us, it increases our confidence in Attruby sort of continuing to grow beyond 2028 and becoming really a major product for us.
Great. Why don't we turn to Christine and talk about encaleret? I know you're going to actually do a webinar on the, on the.
That's announced.
Oh, I'm sorry. I got my.
It's okay.
Ananth, I'm so sorry.
It's no problem.
Yeah, my order of people, my order of topics, threw me off. All right, so ADH1 recently had some data publications to characterize the prevalence of the disorder. Maybe you can give us your latest thoughts on the prevalence out there, the % that are diagnosed.
Sure. Autosomal dominant hypocalcemia type 1, ADH1, is caused by gain of function variants to the calcium sensing receptor gene. What we did in this work that Josh is alluding to is we looked at the major general population genetics databases available to us. That's UK Biobank, gnomAD, TOPMed, Geisinger. That comprised about 750,000 exomes worth of data. We looked for the known variants that cause this condition. We found a prevalence rate of about 1 in 25,000, which is consistent with previously published estimates of the prevalence. That nets to about 12,000 individuals who carry variants associated with ADH1 in the U.S. What we know today is that the diagnosis rates trail the prevalence rates. That's because there's no indicated treatments available for ADH1 at the moment. The impetus to test and do the genotyping for these patients is not quite there.
We've done a lot right now leading up to our potential data coming out in a couple months, to educate the market on what is ADH1 and why to test. We've already identified a couple thousand patients in the U.S. We've even seen the recent guidelines that were published this year that recommend genotyping of all non-surgical hypoparathyroid patients. We're seeing trends that favor increased diagnosis rates. We've seen this play out in a field like ATTR, where up until the evidence supporting a disease-modifying therapy, the diagnosis rates were quite low and availability of therapy inflected those curves.
Are these sort of patients who are diagnosed with hypoparathyroidism? They're just not diagnosed with ADH1.
Correct. They're not genotyped to confirm that diagnosis.
How does the severity of ADH1, say, compare to post-surgical?
That's a great question. I think the key difference for ADH1 is that it's inherited. Individuals who are born with ADH1 tend to suffer from hypocalcemia and hypercalciuria for a lifetime. The area under the curve for the renal injury is higher than relative to post-surgical, where the condition may be observed and diagnosed in middle age. That's one key difference. The other is just the extent of the biochemical disruption is higher because the protein that is responsible for calcium sensing in the body is aberrant. We tend to see lower blood calciums and higher urine calciums over the lifetime of ADH1 as relative to post-surgical patients.
Is it fair to say that the best way to find all those undiagnosed patients is to just let them all try Yorvipath? When Yorvipath doesn't work, it kind of self-declares as something that should be headed to you?
That sounds like an onerous path. I think the less invasive path is just to be offering genetic testing, which is a buccal swab. We know the most common genetic form of isolated hypoparathyroidism is ADH 1. One in five patients with non-surgical hypoparathyroidism have been found to be ADH 1 patients.
You kind of have these two forces colliding, right?
That could be.
Yorvipath is launching right now and probably, declaring unresponsive patients.
That sounds like a more expensive way to identify these patients, but it could be one way to do it.
It's also less patient-friendly. Yeah.
Maybe give us a snapshot of the phase II, a small patient study, but I think fairly compelling results. Then think about the comparison of phase III trial design to the phase II program.
Sure. Our phase II study, which we agree, we were floored by the results that were published in the New England Journal in 2023. It was a cohort of 13 patients studied open-label at the NIH. What we were evaluating in that cohort was first the safety of encaleret and then the efficacy as it relates to blood and urine calcium correction. Over the six months of outpatient care in that study, we saw that 70% of patients roughly were able to normalize both blood and urine calcium when treated with encaleret. At baseline coming into that study, none of those patients were able to normalize both blood and urine calcium on conventional therapy today. That translates into our phase III, where we have a randomized concurrently controlled study, which we did not have in phase II. Phase II was a single-arm open-label study.
What does translate is that our primary endpoint for phase III is a six-month evaluation of the concurrent normalization of blood and urine calcium. We are quite privileged to be able to use our phase II evidence to inform not only the powering, but our conviction in the potential for encaleret to show a clinically meaningful treatment benefit as it relates to standard of care. That is how we designed the study and powered it for success.
For the 30% of patients who did not normalize, did they improve? Would you expect all patients to kind of stay on therapy, or are there some who just don't get any benefit?
Yeah, that's a great question. We observed a treatment benefit and a response in all patients administered encaleret. The 30% that did not achieve that normalization criteria came in with quite high urine calcium, and while a reduction was observed, it did not meet the criteria and the threshold for normalization. I think that relative to standard of care, it is leaps and bounds better than what is available today, but it did not achieve that criteria for a rigorous normalization of urine calcium.
Maybe can you talk a little bit about the titration schedule you used in phase II? I think you went from 5 up to 190 mg BID. How did that kind of inform the titration if you included in phase III?
Yeah, we adopted the same dosing interval, the same dose range from phase II to phase III, given that the safety and tolerability was established in that study population. We're adopting the same titration approach. We learned from our phase II that the optimal way to titrate encaleret was to its blood calcium effect. That's how we informed the titration schema that we have adopted into our phase III study.
Okay. You're also exploring the role in post-surgical hypoparathyroidism. Maybe share your perspective on the phase II data. I think you looked at 162 mg twice a day. How did you kind of get to that dose? I think of that dose, maybe not all patients were able to stop calcium and vitamin D. Is that a problem as you think about the competitive dynamics for the broader unmet need?
Yeah, that's a great question, Josh. It actually helps me give a quick promo for some more data to come out from our phase II study this coming weekend at the ASBMR meeting, where we'll be presenting the full results at a podium presentation from that phase II evaluation. The punchline from the data was that 80% of the study participants, eight out of 10, were able to achieve normal blood and urine calcium within five days of treatment initiation with encaleret, which is quite remarkable. The study was not designed in that five-day period to enable a withdrawal of standard of care because we didn't want to induce a safety risk of hypocalcemia. We are encouraged by the early signals and the preliminary results we've seen, that we believe encourage advancing the development program in that indication.
The reason for the dose selection to your other question is we wanted to test the hypothesis that if you can selectively modulate the renal calcium sensing receptor alone, can you derive a clinically meaningful and differentiated treatment benefit with an oral agent for hypoparathyroidism? That comes from our understanding that this is one of the remaining unmet needs in this treatment category, an effective and safe oral medication. That's why I went to near the highest dose in encaleret just to test the hypothesis, is there a treatment effect to be derived? We were quite impressed and encouraged by the early signal that we saw. We're excited to share those data this coming weekend.
Okay. Is it important to get patients off calcium and vitamin D supplements to be competitive? Or can you have that if you're an all-oral regimen?
If you look at the treatment guidelines, that is not a treatment goal. If we talk to our patients, they certainly don't want to increase their pill burden, as none of us would like to. I don't think the complete elimination or independence from conventional therapy has ever been stated as a treatment goal. The treatment goals that we've been exposed to are articulated well in the guidelines: normalization of blood calcium, normalization of urine calcium, and normalization of phosphate. I think those are the key elements of mineral homeostasis that are important for these patients.
Of course, oral. I think that's one thing which always comes up in market research, right, Ananth?
Sure, yes.
Given how well Yorvipath is doing penetrating into the hypoparathyroidism market, do you see it as important to generate switches off of Yorvipath? Or do you see the landscape of treatment naïve patients adequate to move forward and think about commercializing?
First of all, I think the uptake and the receptivity of the patient population to Yorvipath validates our understanding of the unmet need in this population. I think hypoparathyroidism had been broadly overlooked and the use of standard of care had been felt to be adequate. From our evaluation and interactions with the patients, we've learned that this is a serious disease. I think that's one thing that is worth noting. In terms of the commercial opportunity, I think there's a number of differentiating elements. One is there are plenty of patients who are needle phobic and we do hear about the injection site reactions that are experienced with Yorvipath. The other element is a urine calcium benefit. Like I mentioned for ADH1 and we know for hypoparathyroidism broadly, there is elevated urine calcium at baseline.
If we are able to and successful with the advancement of encaleret in the development for this broader indication and have a labeled benefit on urine calcium, that would be certainly differentiating. The third element that could drive treatment selection of encaleret against the PTH replacement is that we do have a PTH independent effect. That could spare the bone from any resorptive effects that have been seen in some case studies of long-term PTH replacement.
Okay. Christine, why don't we come to you now on limb-girdle? What is ribitol? What produces ribitol, and why is it important for muscle function?
Yeah, so it's an endogenous compound, and so it's made in the body. Why it's important, at least in muscle fibers, is it's the substrate that FKRP uses to glycosylate alpha-dystroglycan. Alpha-dystroglycan is a stabilizing protein in the muscle fibers. It acts as a shock absorber. When alpha-dystroglycan is hypoglycosylated, as it is in this disease, it allows the muscle fibers to deteriorate over time with chronic use.
What controls ribitol production, and what kind of variability might there be, either intra-patient or inter-patient?
That's a good question. I mean, I think ribitol, I think it's measurable at concentrations of 0.5 micromolar in the body. It's not the levels of ribitol that are the problem with the disease. That's not the mutation. The mutation is actually in the enzyme FKRP that glycosylates FKRP. Our therapeutic hypothesis is we're giving super physiological doses of ribitol because we're driving the residual enzymatic activity to increase glycosylation of alpha-dystroglycan.
It does suggest there is this spectrum, though, of the amount of ribitol required for optimal glycosylation of alpha-dystroglycan.
Yeah, glycosylated alpha-DG.
Thank you, glycosylated alpha-DG. Right. You're exploring the super physiologic range. Is there in theory a spectrum of physiologic ribitol where if you're at the high end, you've got more substrate and so less disease burden? Is there any evidence to support that?
That's a good question. I don't know if anyone's measured that. I don't know if there's a correlation there. The correlations that people have measured are the levels of glycosylated alpha-dystroglycan in the disease. That's where there's a genotype-phenotype relationship of glycosylated alpha-dystroglycan, but not really going back to the substrate, if you will.
In muscle diseases, sometimes it can be difficult to discern whether the primary insult is on the myocyte or the muscle stem cell. Do we have any evidence in terms of limb-girdle muscular dystrophy where the insult is? Does it even matter because you've got a small molecule approach that in theory can get into most cells?
Yeah, I think the insult is mostly on the myocyte. I mean, I think the satellite cells are involved with regeneration of the muscle cells. In this instance, because it is a chronic progressive disease, I think they're just overwhelmed by the burden. Ultimately, you get, you know, progressive muscle wasting and deterioration.
Maybe you can share some of the phase I to findings, both for the L276I homozygous and the others, and how you interpret those results to give you confidence in the phase II, III program.
Yeah, what we saw in the phase II, the phase II study is a small open-label study in 14 patients. What we saw was approximate doubling of glycosylated alpha-dystroglycan in the patients. We basically separated the patients into two genotypic groups. There's the L276I homozygous population who have a less severe form of the disease. This kind of goes back to the natural history and the genotype-phenotype correlations. They start out with higher levels of glycosylated alpha-dystroglycan at baseline. They have a less severe form of disease. They do a little bit better in their prognosis. In our study, what we saw is they started out at about 16% levels of glycosylated alpha-dystroglycan, and they went to 40% on treatment. If you looked at the compound heterozygote group who have a more severe form of the disease, they started out at about 6% glycosylated alpha-dystroglycan levels and went to 11%.
We saw approximate doubling in both groups, which gave us confidence that we could have benefit for both forms of the disease, the same form of the disease, but different, I guess, prognosis. We also saw a marked reduction in CK across the patients. We saw over 70% reduction in CK, which was again supportive of benefit in these patients. That was also correlated with a stabilization of functional measures at 12 months. This was an open-label study. We compared their course of disease to natural history. We'd followed these patients for 12 months before. What we saw is basically a worsening of their disease at 12 months. We put them on therapy that stabilized.
How do you measure alpha-dystroglycan? What kind of consistency is there across muscle fibers or across the patient? I guess getting to the question of how much noise is there when you see in an uncontrolled setting, say, a doubling of alpha-dystroglycan, what gives you the confidence that, again, that's a clear signal and not some random noise from variability?
Yeah, yeah. The natural variation that we see in glycosylated alpha-dystroglycan, we've developed a proprietary assay to measure glycosylated alpha-dystroglycan. The natural variation you see both in the disease and with the assay is around 20%. When I say approximate doubling, I mean at an absolute level. We're going from like 16% to 40%, right? 6% to 11%. That magnitude of change is over a bit beyond the natural variation that's in both the biomarker and the assay itself.
We are due for the interim look fairly soon. Are there defined thresholds to trigger an accelerated filing? If so, where are they set?
Yeah. As a reminder, the phase II study is designed with NorthStar as the endpoint at 36 months. The NorthStar is the gold standard, which the FDA strongly encourages sponsors to use for muscular dystrophies. It is a relatively insensitive instrument, which is why we went with a 36-month treatment duration. To make up for that, we've designed the study with the interim analysis, looking at the biomarkers, looking at glycosylated alpha-dystroglycan as the primary endpoint at 12 months. That's the data that's going to read out later this fall in the October-November timeframe. What we expect to see there, or kind of what good would look like to enable us to file accelerated approval, would be a 5% absolute change in glycosylated alpha-dystroglycan. That's what we believe is clinically meaningful based on the natural history data and what we've seen before in diseased animal models.
On CK, we believe that we need to see kind of a 40% or more change in a reduction in CK. Then on the clinical endpoints, what we'd like to see, a win there would be to see a trend in one or more of them to support the biomarkers. It's important to note that the study isn't powered to show a statistically significant change in any of the clinical endpoints at 12 months. The FDA has told us that it is not a requirement to show that at 12 months for accelerated approval.
Do you need to go three for three on those endpoints, or is two out of three enough?
It's ambiguous, to be honest. I think the FDA is looking for a trend. We would be looking for a trend as well, but as supportive of the biomarkers, it's a totality of evidence argument.
It's been a while since I've been asked a question about infigratinib, so I'll ask a question on infigratinib. You've got the PROpel phase III data coming early next year. What do you think you need to show in that trial to be a dominant player in achondroplasia?
Yeah, no, Josh, I appreciate the question. Just as a reminder, LPLV for our achondroplasia trial will happen in December of this year, and we'll have top-line data in early 2026. I think in terms of what we're looking to see, it's really, you know, if you just take a look back at the phase II data, we've sort of shown that infi has the sort of best-in-class efficacy, whether you look at AHV, which I think is very noisy, but more importantly, as you look at proportionality at 18 months, responder rate, things like that. Of course, that is a validation of the scientific hypothesis that hitting both the MAPK, JAK-STAT, and the MAPK pathways would drive a higher efficacy level than the CNPs. We have seen that so far.
What all of our market research shows, including one which we just finished a couple of months ago, is as long as we have a profile which looks similar to the CNPs, so somewhere around 1.5 centimeters per year on AHV, just the fact that we are oral would mean that we would get, you know, a dominant share of the market, 60%. Of course, if the efficacy is similar to our phase II data, or even a little bit better than the CNPs, we would be looking at a 70% or so market share. I think the sort of last thing that I would say about this is it's important that everyone recognizes that our phase I and our phase III trial populations are different.
We are very confident in our infigratinib molecule and, you know, the whole clinical, the whole sort of rationale from the mutation all the way to what we've seen in the phase II. What we've done is we've enabled children as young as three and up to enroll in the trial. Our phase II was five and up. All the other trials in the space which were in phase III were five and up. You cannot really compare these trials directly. It's just an important thing to keep in mind because the younger children, it's harder to show an effect on them. That's kind of what we would say. We are looking to see something in line with what the CNPs have shown, fully recognizing AHV as a noisy endpoint.
When you present the data, will you break out by age just to kind of help normalize for that?
We haven't really decided upon that. I think that we would communicate on that more as it gets nearer to it.
All right. We're out of time. Great discussion. Thank you so much for joining, and thanks everyone for tuning in.
Thank you, Josh.
Thanks, Josh.
Thanks, everyone.