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

That's a really good question. I think the first thing to say around nucresiran we're obviously evaluating nucresiran study that's called TRITON CM. It's a large cardiomyopathy study. Nucresiran has 95% TTR knockdown. That's the best of any program that's out there. And we think that's going to play through into improved outcomes. So we definitely have a molecule that is incredibly potent. I think that's the first thing to say. I think the second is that we've been developing medicines for patients with TTR amyloidosis for many, many years and have real insights from all the studies that we've got. We've got patient level data from our HELIOS-B study. And that allowed us to be really thoughtful about the design of Triton CM and we've actually built in a lot of the learnings that were then validated when we saw the data from cardio transform in terms of patient selection in terms of the end point and so we feel that we're in a really, really good place with respect to Triton CM. We're obviously continuing to enroll that study. Obviously, also very thoughtful about the fact that this is an incredibly important study for the company. And so we're going to we're going to sweat the details, as we always do right. And we're going to think about whether there's anything that we need to do to modify the study truly falls into 2 buckets. One is thinking about the patients that we enroll, enriching for certain types of patients potentially, maybe increasing the size of the study. That's another option. And those are decisions that we would have to make pretty soon whilst we're still in this enrollment period. And obviously, if we make those decisions, we communicate that broadly. The other approach might be to think about the analytical plan, a little bit like we did with HELIOS-B. And that's a decision that we can make at any point in time over the duration of the study. It's probably something that we think about kind of later in the course of the study. But I think it's really important to kind of just, I think, underscore that actually, the learnings from cardio transform to a certain extent, have actually strengthened our conviction around the design of the Triton cardiomyopathy study.

If you decide to make some fine tuning to the study, I guess when would that happen? And then I guess, related to that is, obviously, there's a lot of interest in probably the baseline characteristics because those are going to matter as we try and think about the probability here. I guess when might you share those? Or what's the thinking there?

So if we do anything different with enrollment. I mean if you remember, I think it was earlier on this year, we announced that we were upsizing the study, we're adding other 500 patients to the study, and we announced that as soon as we'd made that decision. So if we're making any changes to enrollment, that's something that we would communicate before the end of the year. But as I said, if we're refining the stats plan, we can do that in any point in time. So I wouldn't expect that we would be communicating anything on that front in the near term.

Increase in the confidence is that about monotherapy effect? Is that combo effect? Is there some way to there some limit on background TAF you can have to be successful? I know these...

So what -- I mean, it's important to just say what we're trying to achieve with the study was actually to affect a broad label for nucresiran the way that we have done for AMVUTTRA. And therefore, it's going to be important. There'll be study a range of patients in the study, both monotherapy and combination therapy. Really, the goal is to make sure that we deliver a successful study which could then meet the needs of patients with TTR cardiomyopathy, whatever types of patients those are.

Yes. Another question that comes up for TTR cardiomyopathy is just the impact of generic [ tafamidis ] in 2031. And maybe you can just share the latest thinking there and the impact to your...

Yes. We'd originally thought that generic [ tafamidis ] would become available in 2028. And now we understand is more likely to be 2031. And actually, that's a pretty good thing for AMVUTTRA reduces the pricing pressure of having a generic coming to the market sooner. And it allows us more time really to establish and but to continue to establish on future is the foundational therapy for patients with TTR cardiomyopathy. So we think it's actually a good thing for us. The other thing is actually the timing juxtapose is really nicely with the acres the TRITON CM study because we will be delivering data for the polyneuropathy Triton PM in 2028. And then for Triton CM, round about 2030. So it's actually all comes together rather nicely.

And maybe last question on TTR. I guess as you look sort of near term through the next couple of years, just the key drivers of growth to really push the frontline use up. Is it just helping find more patients more quickly? Is it more occasion around the profile? What's -- what are the key?

So I think if I think about -- I'll step back and then I'm sure John will add some color. But I think about, okay, what are the key drivers of the business over the next period. And you're absolutely right. I think the really important thing is to establish abuts first-line monotherapy and obviously do that in a number of ways in terms of continued evidence generation, continued education of physicians, continued support around patient identification, diagnosis and helping patients get through the various care pathways so they can actually receive treatment. So that's really, really, really important. I think the second area is around continuing to help grow the market. when you've got a market where 80% of patients are undiagnosed and untreated. I think it's a really important opportunity and obligation for us to continue to educate physicians and improve the diagnosis rates and improve the treatment rate. So investing in helping to grow the market is also very important. I think the -- when we think about educating physicians, I think what we also need to do is to broaden the prescriber base. So I said, physicians who use AMVUTTRA prefer. We're currently addressing about 1/3 of the prescribers out there. And so there's a lot of runway. So we're investing in broadening the prescriber base as well as obviously also deep link prescribing within physicians who are already prescribing in it. And then you touched on markets outside the U.S., and we'd like to continue supporting patients who live outside the U.S. and so continued geographical expansion is going to be very important to us. And we spend a little bit of time also talking about crestal. I think AMVUTTRA is a very important medicine for Alnylam. It actually is a method that's going to allow us to fund a very exciting pipeline that we're developing and build the company. So we really are aspiring to ensuring that we are leaders in the TTR space. And we like to be leaders for a long time. And so developing our third generation with an increase, as I said, much better, much 95% TTR knockdown is another important aspect as we think about the long-term opportunity for the TTR franchise and Andrea data was there anything else?

I mean you covered all the levers. I mean just for color commentary, what I'd say is this category is rapidly -- so that's patient volume, but it's also just the number of prescribers that are involved in the category, and that's why being able to expand the prescriber base is important, we're doing more. So we're actually -- we have more physician engagement with more people in the field, more investment. And then the other investments to drive diagnosis, we're not doing this alone. We feel compelled as we aspire to be the leader to do more to drive diagnosis, but we're doing that in partnership with others. AI is an AI provider is one example, the American Heart Association, et cetera. So those are partnerships we're building.

And Yvonne, you brought this up pipeline, which we got about 8 minutes left here. So maybe we can dig in there a little bit and you've got a bunch of updates later this year, but maybe just high level, maybe just talk about pipeline and kind of what -- what do you think investors should focus on there?

Yes. No, I'm really excited about the progress of the pipeline. As I said, a number of important catalysts this year. So I'll start with the first, which is our Huntington's program and I know I don't have to convince any of you here how much unmet need there is for patients with this disease that's been described as being a combination of ALS and Parkinson's and Alzheimer's and the [indiscernible] nothing out there for these patients. And we have at Alnylam, a program, which we believe has a really important mechanism of action where we're able to address not just the full on Huntington gene, but also the [indiscernible] which is increasingly being implicated in the pathophysiology of the disease. So we think we put something in our hands that could be really impactful and I think this has been supported by some of the data from [ uniQure ] a natural history study, which showed the importance of actually having this exon 1 fragment. And this is program. It's a intrathecally. It's probably going to be a couple of times a year. We'll be getting Phase I data in October. So it really is imminent, and we're hoping that they will be able to demonstrate safety and tolerability. We'll be able to demonstrate we'll be able to understand PK/PD, we'll be able to measure Huntington learning through CSF. And so if this program is successful, we think we'll be able to move it very quickly into Phase III. I think there'll be a lot of support for trying to progress this medicine towards patients. So something that we are kind of very excited about, and we hope to be able to move rapidly forward. And there'll be more information being presented at the ED meeting in October. So just around the corner. So I would ask you all to stay tuned. That's a really, really exciting program. Probably the second program to touch on is called ALM 6400, what we call our plasminogen program. It's for bleeding disorders. And really it's got again, a really interesting approach where it can stabilize clot and the potential here is to be able to stabilize clot and, therefore, reduce bleeding without any thrombotic risk and there's some good genetics and biological evidence for this. And the other kind of exciting thing about this program is the mechanism of action could apply across a range of different bleeding disorders. So we're starting with a study in patients with hereditary hemorrhagic [indiscernible] and I'll talk a little bit more about that, but we can we're also then in a Phase II for actions with on Wheeler brands disease. So you can see how start off with one indication that we start to kind of go after one indication after the other with bleeding disorders. So if we have a Phase II ongoing in patients with HHT. And there, we're measuring numbers of bleeds in these patients, various of bleeds. These are patients actually that have incredibly severe nose bleeds. GI bleeds and require the often anemic that acquire transfusions. Those are really significant unmet medical need for these patients, which we hope to address with this particular program, and we'll be able to complete this Phase II study shortly. And if we're able to move this program into Phase III, it's something that actually could also move very quickly. You don't need large outcome studies to measure bleeding. So we're pretty excited about this.

So you just quickly touch on the bar for bleeding, like what's a meaningful decline in the bleeding rate or any particular bar you're looking for?

We'll come back on that as we get the results, but clearly, we only want to progress a program that's going to have a significant benefit to these patients. So it's not just the numbers of lease, but it's also the fact that these patients are anemic alter transfusion. So you also have to think about are you able to reduce the hematological support that these patients require.

Got you. If we just keep going with the pipeline, just the obesity program and your strategy there and when we might see some data?

Yes. So a lot of people are excited about it. There's a lot going on. We're hoping to be able to demonstrate that we're able to deliver our sRNAs and to adipose tissues. That will be a first for us. So that in itself will be a significant milestone. And when we think about what the opportunities are in obesity, you really thinking about beyond [indiscernible] how can you think about better quality weight loss? And as we think about our strategy, it will be thinking about the monotherapy, it will be thinking about in combination with other siRNAs, we'll be thinking about in combination with [indiscernible] as well where sensors are not that we're able to think about how we can progress our pipeline in creative ways to meet the emerging needs of patients. with obesity. And again, we'll be getting sort of proof-of-concept data later on this year. So we're eagerly looking forward to that.

Yes. Great. And maybe we keep going with the pipeline. So [indiscernible] Maybe just give us a quick background there, and I think you're going to have a webinar later this week.

Yes. The webinar coming out on to encourage you all to [indiscernible] Look, I think that best has the potential to transform how hypertension is treated because hypertension is not just about lowering blood pressure. It's about the durability of lowering blood pressure is that continuous control and one of the other issues with patients who are receiving treatment for hypercenters area adherence. They just so take their tablets. And here, we can conceive of infrequent dosing of subcusanas allusions to really maintain continuous control for these patients, restore nighttime dipping, reduce variability, and we believe that all of this will lead to better outcomes for patients. It's not just about blood pressure low. It's about improving outcomes for patients. So we have a large outcome study ongoing where we hope to be able to demonstrate this over the next few years.

Great. Maybe I can ask on another hot topic, the AI topic John, you mentioned some ways you're using it in diagnosis, but any other ways across the company are using it to accelerate development or things like that?

Well, we're using AI broadly across the company as many organizations are to improve our efficiency, improve our productivity. Obviously, some of the approaches that John touched on, on the commercial side of our operations, also very excited that we signed an agreement with a company called inceptive nucleic who are helping us think about how we can combine their frontier models with all the data that we have with respect to sRNAs and actually see whether this could help us accelerate innovation and be able to move our incredibly already productive R&D engine even faster.

Yes. Okay. Great. Looks like we're just about out of time. So why don't we end it there. And on and John, thanks so much. Appreciate your time.

A pleasure. Thank you very much.