Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

It's with great pleasure that I'd like to welcome Yvonne Greenstreet, the CEO of Alnylam, and Tolga Tanguler, the Chief Commercial Officer. Thanks so much for joining us today.

Great to be here. Thanks. Great to see everybody.

And we're going to do a fireside chat format. So maybe for those who are new to the story, if you can provide a 1-minute intro to Alnylam, which I know is tough to do. But if we can talk about your key programs and pipeline beyond ATTR.

That's terrific. So look, it's great to be here. And Alnylam is the leading RNAi company and the technology is fantastic. Essentially, what we're able to do is target to harness a natural pathway, target any gene in the genome and knock down disease-causing proteins. And with this technology, we've been able to build an amazing company where we now have 4 marketed programs that we commercialize; AMVUTTRA and ONPATTRO for TTR amyloidosis, GIVLAARI for a rare condition called AHP and OXLUMO for another rare condition called PH1. So we have an established franchise of medicines and glad to have Tolga on stage with me because we've got really robust commercial performance, having built a very highly performing commercial engine. We're in 30 markets directly and another 30 markets through distributors and delivered great commercial performance. Our last earnings, $420 million for that quarter. And we've been growing at a fair clip at 30% year-over-year. So a really strong commercial foundation. But we also have this incredibly rich clinical pipeline. We got 15 programs in the clinic. We're trying to double that to 30 by the end of 2025. Two really exciting programs. I'd just like to highlight; one called zilebesiran for hypertension. And this is an approach that basically knocks down angiotensinogen, really affects tonic control, reduces the variability that you see in managing patients with hypertension, and we really believe this is going to reimagine the treatment of hypertension, I'm also really excited about our CNS portfolio. We can go into that more if we have a bit more time. But with a program called mivelsiran, and we're addressing 2 really important CNS diseases; one, Alzheimer's and the second is cerebral amyloid angiopathy, which is the second common of intracerebral hemorrhage. So very rich pipeline. But underneath all of this, we have a sustainable innovation engine which has outsized probabilities of success. The average industry rates for POS, as you know, average between 6% to 10%. We have a greater than 60% POS going from Phase I to Phase III. So this is quite remarkable. We're in a unique position, having marketed programs, rich clinical pipeline and an innovation engine. I think what we're really focused on right now, we'll get into the conversation, is we now also have the potential for a flagship franchise with our TTR amyloidosis products with a very important approval, assuming regulatory success and launch for AMVUTTRA vutrisiran in patients with TTR cardiomyopathy. So we're eagerly anticipating. And I'm sure Maury is going to ask me a lot about that. Incredible R&D engine, as I said, and I just want to highlight to everybody that we'll be having an R&D day where we have a chance to talk about our progress in this regard. February 25th, in New York. So looking forward to seeing many of you there. Did I do that in a minute?

A little bit over, but I won't hold it against you. That was a great intro. Let's dive into ATTR. So with AMVUTTRA, there, you filed the sNDA quickly for the cardiomyopathy opportunity in less than 4 months from the top line data. You should be hearing back on filing acceptance soon in early December. Has there been any notable feedback from FDA on the sNDA filing package that we can highlight today?

Yes. So I mean, tremendous execution. So yes, we filed the sNDA. We announced that at our TTR day in October. Also important to note that we have also filed in Europe and Japan, so we're going to be opening up hopefully a lot of markets for vutrisiran in patients with cardiomyopathy. It takes about 60 days after filing to actually get a PDUFA date. So there'll be more to come when we know the date. Also worth mentioning that we used a priority review voucher. So that means that we can anticipate approval post regulatory review, of course, 6 months after submission. So we're really looking forward to being able to bring this, I think, important innovation to patients with TTR cardiomyopathy.

Got it. And can you remind us what's in the NDA and whether you plan to supplement the filing with any additional data from the HELIOS-B open-label extension?

So the HELIOS-B study, for those of you that are not aware of it, was really a landmark study, where we evaluate the safety and efficacy of vutrisiran in patients with TTR amyloidosis with cardiomyopathy, both hereditary and wild type. And the important thing about this indication from an Alnylam perspective, is that it opens up the opportunity for us to be able to help not just 30,000 or 40,000 patients, which we can with the indication that we have for polyneuropathy, but 300,000 patients or more for patients with cardiomyopathy. And this really gives us the opportunity to build what we believe is going to be a multibillion-dollars opportunity. So HELIOS-B was a study that delivered tremendous results. We can go into that later if you like. But essentially, the submission is clearly based on the tremendous data set that we delivered from HELIOS-B, which is a very rich data set. And we are looking forward to hearing the FDA, as I said, in due course.

Okay. So no additional supplement that you're anticipating.

We're very pleased with the data set that we have for HELIOS-B. We think that provides a compelling set of data for the agency to review.

Got it. Okay. And then let's talk about the launch in cardiomyopathy. How will a patient's baseline disease profile influence prescribers' choice to pick a silencer versus a stabilizer in the frontline setting? And what proportion of cardiologists you expect to be early adopters and how will that prescriber-base change over time as you move from big center, multidisciplinary centers to broader base?

So I think it's really important to think about the context of this disease. So TTR cardiomyopathy is a progressive, debilitating and ultimately fatal disease. And really, what this means is it's really important to treat with the best available intervention and also treat patients as early as you can. So we're really looking at AMVUTTRA, assuming regulatory approval as being first-line monotherapy, and we believe that it will be standard of care for these patients. That's really the focus of our approach. Now, in terms of how physicians are going to think about AMVUTTRA for patients with this disease, I think it's important to look at what data sources we have. And there was a third-party market research study that was conducted shortly after we share the data from HELIOS-B by Ipsos, which concluded that around about 80% of physicians that were surveyed, it is important to note that the physicians that we surveyed were those that were cardiologists treating TTR patients, indicating that they believe that AMVUTTRA, assuming regulatory approval with the profile that we've delivered, will be first line for these patients. Now we'll have to wait to see exactly how the dynamics shake out over time. But really, we believe that that's going to be where a lot of physicians will be thinking about positioning this medicine.

Got it. And what were your messaging to the prescriber base be to use AMVUTTRA ahead of tafamidis in de novo patients? Do you have any insight into what proportion of patients may want a daily oral versus a quarterly injectable?

It's a great question. So again, going back to the context, debilitating disease. Physicians are going to want to treat early and they're going to want to treat with the intervention that has the best profile, and we believe that, that will be AMVUTTRA now. The study that we did with HELIOS-B, I think, was incredibly compelling. And I think it's important to underscore that, that study was done in what we call the modern era. So evaluating patients who represent the sorts of patients that physicians are seeing today. And these patients are very different from patients that were treated maybe 5, 6 years ago, where there's now tafamidis on the market, the patients are able to be treated with stabilizer like tafamidis in the HELIOS-B study, around about 40 patients, 40% of patients that were seeing tafamidis. And over and above that, they're heavily treated patient population, where they're getting intensive diuretic intervention, they're getting SGLT2s, et cetera. So a very different patient population from what's heretofore to being studied in this disease area. And yet, vutrisiran was able to deliver 10 out of 10 across primary endpoint or the secondary endpoints, clinically significant, statistically significant data. So that was really a high bar, which is uncleared very, very convincingly. And then when you look at the data that we generated from HELIOS-B, I think just a few points to make just the profound impact on not just the primary endpoint, which was a composite endpoint of reductions in cardiovascular hospitalizations and all-cause mortality, but also a prespecified secondary end point of all-cause mortality, which showed a 36% reduction in all-cause mortality at 42 months. These data are not seen that often in heart failure studies. I think the magnitude of impact that vutrisiran was able to deliver on those endpoints is important. But the other thing is across the board. So we looked at a number of really important secondary endpoints that relate to how patients feel, how they function and in fact, we're able to show stabilization of disease, preservation of function of quality of life. These are things that are incredibly important to patients. And the results were just consistent, all the subgroups that were studied, we were able to demonstrate really profound efficacy. So even the subgroup that I spoke to, patients receiving tafamidis, we showed additional efficacy on top of tafamidis, which would indicate that tafamidis is probably leaving some efficacy on the table. And we also showed that if we're able to treat the disease early, right, you're able to have an even more profound effect. So for those patients that were slightly milder in their disease were able to demonstrate a 65% reduction on all-cause mortality. So I think it's a compelling nature of the clinical data that we've demonstrated. I think it's also supported by -- in fact, this is a quarterly subcutaneous the administered medicine. I think that aligns very well with physician visits and Tolga will talk about this more, but when we think about the polyneuropathy indication, we made it really easy for patients to access sites of care or indeed have the treatment given at home, really helps with compliance. This is a disease where you want to make sure that patients are treated, they stay on treatment. And we believe that the quarterly subcutaneous administration is a real advantage compared to orally administered drugs, which really have significant compliance issues. So taken all together, we think that we've got a pretty compelling value proposition for patients, physicians and healthcare system.

Got it. Makes a lot of sense. And I want to talk about the switching opportunity as well. And so Pfizer commented on their third quarter conference call that they expect headwinds due to a new entrant and noted potential switching of existing patients. And at your recent TTR day, you noted about half of current tafamidis-treated patients, which could be about 20,000 of 40,000 patients could potentially switch. What are scenarios and drivers as it relates to the rate of switching? And how you influence and incentivize switching?

So I think that's a great question, Maury, because actually, it reminds us all that TTR amyloidosis with cardiomyopathy is a very large opportunity, and it's a very rapidly growing opportunity. I mean I talked about maybe 300,000 patients, it might even be more. And it's important that only 20% of those patients are currently diagnosed. So this is a disease area that I think is a very exciting one for us to be able to participate in. So as I said, our focus is going to be on establishing AMVUTTRA as first-line monotherapy. The data that we've generated, as I said, demonstrates additional benefits on top of tafamidis. So as patients progress with tafamidis and use the number 50%, we think that's probably about right. There may well be some switching but I think it's important to note that because there's only ever been one treatment available for these patients, tafamidis, switching is not really a behavior that's been well established in the cardiology setting. So we'll have to see how the dynamics go. I'm sure there'll be some additional opportunity from switching, but we have a data package that supports first-line monotherapy, potential combination use as well as switching. So probably no more to add on that.

Okay. Do you anticipate there could be a bolus of switching at the beginning or tough to say on that?

I think it's tough to say at this point in time.

Got it. Okay. Well, you've talked about the cardiomyopathy treatment paradigm being a monotherapy-driven market prior to tafamidis' loss of exclusivity, which is year-end '26 in EU and then year-end '28 in the United States. But we've also heard from doctors who said they would welcome combo use and anecdotally, it could be possible to do this depending on the strength of the prescriber's recommendation. What are you hearing from payers on this topic? And what are you hearing from doctors as it relates to the willingness to get a patient on combo?

Yes. So I think our data support the use of combination therapy from a clinical perspective. I think it's important to realize that as payers think about what they need to deliver, prescribing to medicines for patients with TTR cardiomyopathy will be an expensive proposition. So we think there will be some payer constraints actually. And this has been I think, validated by our learnings from polyneuropathy, where actually most of the plans try to constrain combination use, even though AMVUTTRA currently is labeled just for polyneuropathy and obviously, tafamidis for cardiomyopathy, even with nonoverlapping labels, there are payer constraints. So we think that in the -- in the short term, payers are going to resist the use of combination therapy. Having said that, when tafamidis goes off patent in 2028 in the U.S., earlier actually in Europe, we believe this will open up the opportunity for combination use. And we'll see more combination use in the medium to long term after tafamidis and incentivize expiry.

Got it. Yes, that makes sense. And for AMVUTTRA sales in polyneuropathy, it's been going really well. Maybe talk about that, what you're learning from that? And I'm wondering if you can comment on the proportion of mixed phenotype patients that are currently on AMVUTTRA for the variant versus the wild-type population.

Tolga, you're very involved in ensuring that we continue to be successful in helping patients with polyneuropathy and just to say there's a big runway still for polyneuropathy. We're treating 5,000 patients with TTR amyloidosis with polyneuropathy, and like I said, there are about 30,000, 35,000 patients.

Yes. So, look, I think what we really appreciate is the fact that, we're just scratching the surface in terms of polyneuropathy and how large even that narrow opportunity is. And the fact that we're actually growing at over 35% is a testament to, a, obviously, the large unmet need and b, how we're actually being able to commercialize this effectively across all the world. Now in terms of mixed phenotype patients, I think we need to really think about the diagnostic pathway. So we are obviously a hereditary polyneuropathy. So in cardiomyopathy, there might be some mixed phenotype patients that are not hereditary. We're not indicated for that. And when it comes to sort of looking at the diagnostic pathway, those patients that are already went through scintigraphy, which is the primary sort of step for identifying anyone with the myopathy. And then the second step is neurological workup. And the last space is genetic testing. By the time you get through that, you actually already identified as a polyneuropathy patient, and we are the first and one of the 2 options that are available right now in the United States. Therefore, if you look at the growth rate, I wouldn't necessarily anticipate a mixed phenotype patients coming in just at the eve of HELIOS-B or approval. I think we're going to see that acceleration when we have the broader label.

Got it. Makes sense. And with just large academic centers that are already familiar with HCP-administered drug reimbursement with a buy-and-bill approach, what about community settings? How much update do you expect there? And is there already a broad-based footprint of injection-ready clinics based on your polyneuropathy presence or building out that footprint for cardiomyopathy be a key part of your launch expansion efforts?

Yes. So what's really exciting about sort of our preparation for cardiomyopathy is we're already in this category. So in a way, it's a bit of a running start rather than a standing start. And we've already been able to establish. We talked a lot about this at the TTR day. A lot of optionality for patients. If the cardiologists themselves are not interested in getting the liability, those of you who may not be familiar, U.S. obviously has a pretty complex reimbursement system. But in that system, you have 2 essentially -- if you're a Medicare patient, which a lot of our patients are eligible over 65 years of age, you're either Part B, which is medical benefit, where the physician or HCP-administered product or you get a prescription. And sometimes the concern is, well, if you look at some of those medicines, you have to buy the product and then bill it back to the Medicare and that may create some complexity. So if you think about how we've been able to do that already in the U.S. pretty effectively in polyneuropathy. And we'll be able to transfer all those capabilities into this broader network. That's number one. Number two is, this is not going to be 35,000 cardiologists that are available in the United States, it's still a relatively small number of cardiologists. And you look at our data right now, 90% of these cardiologists actually don't do buy-and-bill themselves. They either rely on the infusion networks that we have been able to establish in the U.S., we have about 1,100. If you look at the how far patients actually are eligible for home care where, again, you don't have to build this buy-and-bill network. So there are a lot of optionalities which we believe we can actually transfer that. That would also include not just academic centers, but also community centers. Again, when we talk about community centers, this is not going to be thousands and thousands of cardiologists. It's going to be still a very limited number which we know from tafamidis is about 3,500, 3,700 cardiologists that actually administers the product.

Got it. And there's been a lot of debate around Part B versus Part D and the trade-offs there. Maybe talk a little bit more about the strategy for choosing a Part B path. And one of the key things that stands out to me is that doctors are incentivized to use Part B drugs because of how they get paid. And so just wondering what your thoughts are on that and if that's an important part of the strategy and how that influences Ionis commercially as well, which really hasn't gotten that much uptake.

Look, I mean I think when we were developing the product, we looked at the severity of this disease and how physicians are actually seeing those patients. And we believe that given that these patients are monitored on a quarterly basis, given the fact that it's a severe disease, we wanted to make sure that is actually consistent with the way doctors actually treat. So that's how we actually picked the way we designed the clinical trial. Now in respect to Part B, there are certain financial advantages, and there are certain maybe restrictions as some analysts have been bringing it up. What we like seeing is the fact that in the U.S., we -- the treatment paradigm for our product starts with a start form. So a physician without knowing how the patient gets reimbursed, fills out a start form. And then we help or they themselves actually bring the patient along to make sure they're appropriately reimbursed. If I look at that process right now, our ability to get from start form to treatment is over 90%, which means actually, there is a relatively healthy access to those patients. And there's no reason for us to believe that we would -- as we expand the category, given the patient types are the same, given that the prescriber base is going to be more or less the same, that would essentially change. And just to give you a perspective, in Part B right now, our products, 70% patients do not have any co-pay, 0 co-pay, up to 80% of patients pay less than $2,000. If I look at a similar category in Part D, that ratio actually goes down to 50% less co-pay and then up to 3,500, 50% of those patients are Part D. So I think it's a highly competitive product profile that we believe we can actually expand as we expand the category.

So we anticipate broad access, no payer headwinds. And I think you demonstrate to that in our successful polyneuropathy, and we hope to replicate that in cardiomyopathy.

Got it. Okay. And let's shift gears briefly. You had great data at AHA with the IKARIA platform sc04, maybe talk about that, is that something we could learn more about the strategy in February at the R&D Day?

So I think I just want to start off by highlighting that -- I talked about flagship franchise. And the other point to make is there's going to be a very durable franchise for Alnylam because we started off with ONPATTRO first-generation, AMVUTTRA second-generation and TTRsc04 third-generation, where we're looking at much more profound knockdown of TTR. We're talking 90%, 95% knockdown of TTR. We believe that, that will translate into greater efficacy. So we're really excited about TTRsc04. It gives us IP out until the 2040s. It's also free of the royalties owed to Sanofi Genzyme. So we're really looking at TTRsc04 as being having a profile that will enable leadership in this category. So we're currently working through the study designs. Obviously, 've got a lot of data from HELIOS-B, which actually helps inform how we might want to think about designing a trial for TTRsc04. So I think there'll be more to come on that in due course. We're committing to sharing the approach, beginning of next year. But the potential profile for TTRsc04 is absolutely a best-in-class profile.

I mean there was a big hypothesis with HELIOS-B about rapid knockdown and its effectiveness on outcomes. Now we're rapidly knocking down about 87%. The latest results show that it's over 95%. So we're really excited about that hypothesis to continue to have that durable franchise.

Got it. And maybe I think we're out of time. In closing up, you've got the R&D Day planned for early next year, what updates can we expect there? And what are the key events should investors be focus on for Alnylam?

Yes. No, that's a great question to wrap up with. I was able to touch on a couple of key programs, zilebesiran for hypertension and mivelsiran for Alzheimer's as well as cerebral amyloid angiopathy. We actually have our third CNS program, which we're really quite excited about for Huntington's disease. And we think we've got a differentiated approach for Huntington's where we are able to not only address full-length mutant and wild-type Huntington, but also the exon 1 fragment, which we think is actually very important part of the disease pathophysiology. So we're really excited to be able to move that program forward. You'll also be hearing a little bit more about the earlier part of our pipeline where we're really making progress with delivery to a number of other tissues. So you'll hear more about programs that we have delivering to adipose tissue, you can imagine that it could be some quite exciting ways of thinking about metabolic obesity if you can get into adipose tissue as well as some other programs in the metabolic obesity space. So we continue to innovate around the platform, and we're going to have quite a lot of progress to share with you at R&D Day. If you remember, we set ourselves a kind of strategy called 225 that we're going to have 2 new CNS INDs by the end of '25. We were going to have 5 new liver INDs by the end of 2025 and we are going to get into 2 extrahepatic tissues by the end of 2025. So expect to see progress across all of those dimensions.

Great. Look forward to it. Thanks so much, Yvonne and Tolga.