Good morning. My name is Ted Tenthoff. I'm a senior biotech analyst at Piper Sandler. And before I begin, I'm required to point out certain disclosures regarding the relationship between Piper and our next presenting company, Alnylam, which are posted at the back of the room and also at the registration desk. And that's a long time of disclosures. I remember doing the Alnylam IPO. It's one of the first ones that I did at Piper 20 years ago. So it really shows you the long relationship that we have with Alnylam. As you know, Alnylam is a leading developer of RNA therapeutics with a growing commercial business and a rich pipeline of future therapies. After a rollercoaster review, the FDA issued a CRL for ONPATTRO in hereditary and wild-type ATTR amyloidosis with cardiomyopathy, sending Alnylam shares lower.
But I really want to own Alnylam right now for AMVUTTRA growth and the upcoming phase III HELIOS-B data in early next year, which, if positive, would expand the label and make up for the revenues, and I think the lost value from the ONPATTRO CRL. Here with us today is CEO Yvonne Greenstreet. Yvonne, thanks always for being with us, especially during these exciting times for Alnylam.
It's such a pleasure to be here, and actually, it's wonderful to be in this hotel in New York in the festive season. It starts to get me thinking that the holidays are not far off.
It is a great time of the year to be in New York. That's true. So we're going to start the conversation with AMVUTTRA, but I'll be sure to save some time to focus on the pipeline at the end. So Yvonne, despite the CRL, you guys maintained product sales guidance of $1.2 billion-$1.285 billion this year, maybe at the lower end of the range. Growth has really been driven by quarterly sub-Q AMVUTTRA, which is both cannibalizing ONPATTRO but also expanding the ATTR polyneuropathy franchise. What's driving this strong growth, and how large is that global polyneuropathy mixed phenotype market?
That's a great place to start. But maybe just before I answer your specific question, around AMVUTTRA, just to, you know, for those that may be new to the Alnylam story, just to, you know, make a few introductory remarks.
Sure.
As you mentioned, we are the leading RNAi company. We're incredibly pleased to have been able to deliver five RNAi therapeutics in about four and a half years, which I think is a remarkable achievement to deliver them to patients, and not just patients with ATTR amyloidosis, but also some ultra-rare diseases. And, you know, doing that as well as continuing to build a very rich pipeline of over a dozen clinical programs. And I think what's also very exciting about the company is our ability to keep sustaining innovation through our, you know, research engine, with a plan to deliver at steady state 4 or more INDs per year. So we think we really have a unique profile as a biotech company. We're very excited about the future. Now, specifically around AMVUTTRA, you're absolutely spot on.
AMVUTTRA is a real growth driver for the company, for patients with hereditary amyloidosis, ATTR amyloidosis with polyneuropathy. And I think that the performance of AMVUTTRA has really been driven by its, I think, game-changing profile. You know, what we've been able to demonstrate in clinical studies is a really rapid onset of action. So, you know, within the first three months of therapy, you know, reducing TTR by 88%. And actually, even after just a single dose of AMVUTTRA, demonstrating benefit on some, you know, clinical outcomes within the first month, notably BMI, which I think is a good indicator of how patients feel. So rapid onset of action, but also, you know, impact on polyneuropathy features.
So, nearly half of the patients that we studied in clinical trials actually reversed features, which is remarkable. Reversed features of polyneuropathy, which, you know, kind of in my history is very unusual for a neurological indication, and also improvements in quality of life. That's the second thing, the efficacy that we're seeing. I think the third point is around the very convenient regimen, which aligns with physician visits. So administered every quarter through subcutaneous injection, and, you know, as well as aligning with physician visits. I think there are some benefits with respect to accessing a Part B drug, and also with compliance. So I think there are a number of reasons why we're seeing such strong growth of AMVUTTRA, and it's a pretty sizable market-
Yes.
ATTR amyloidosis with polyneuropathy. Probably about 50,000 patients worldwide and about, you know, 30,000 who've either got polyneuropathy or the mixed phenotype. I think what's interesting to me is that, despite this really strong growth, which we're very, very pleased with, we're still very early, in the opportunity here, where we have about 3,800 patients treated with our TTR therapeutics at this point in time. You can see there's a lot that we can still go after...
Yes.
...with respect to polyneuropathy.
It's a really good point, and you're so right to remind us of the profound efficacy.
Yeah.
As these drugs reach the clinic or as they reach the market, sometimes we forget, but I don't think I'd ever seen that many zeros on a p-value-
Yeah.
... when you reported the AMVUTTRA data. So it is remarkable to actually be able to reverse nerve function. Remind us about the upcoming HELIOS-B trial design. This is going to be a really important readout for Alnylam. When could we get that data?... Why do you think this trial can succeed to expand the label?
Yeah. So maybe to start off by just reminding everybody that we have a phase III study called HELIOS-B that's ongoing, which is looking to expand the label for AMVUTTRA to address the needs of patients, not just with polyneuropathy, but also with cardiomyopathy. And this takes us into a much, much bigger market. I spoke to, you know, 30,000-odd patients with polyneuropathy or mixed phenotype. You're really looking at 200,000-300,000 patients who've either got hereditary or wild type cardiomyopathy. So we really are opening up to a much, much larger market. We are, you know, really confident in the design that we have. And actually the execution of the HELIOS-B study.
I think it's important to highlight that it's an outcome study, so we're looking at the primary endpoints are composites of all-cause mortality and recurrent CV events. I think that's really important for both physicians and patients to be able to demonstrate an impact on symptomatology, but also on outcomes. You know, the other reason why, you know, we're very confident about the outcome of this study is it's a large study. 665 patients. We actually over-enrolled by 10%. We're also studying patients for actually, it's the longest period of evaluation in any ATTR study. We're studying patients out to 30-36 months, which I think is an important point to make.
And when we designed the study, we also instituted an operational cap for patients on tafamidis, which is under 50%. And we've had, you know, low drop-ins of patisiran in the study, well below our internal assumptions. So we feel that we're pretty well set up from a design and execution perspective to deliver successful study. And we're also, you know, really quite pleased with the data that... You talked about the CRL-
Yeah.
But the data that we delivered with another RNAi therapeutic, the TTR, our 1st-generation molecule, ONPATTRO, in a study called APOLLO-B, where despite the fact that we received a CRL, actually it was a positive study. And what's really exciting is that we've been able to look. That was a study that delivered primary outcome, primary endpoint at a year, but we've been able to follow patients out now for two years. And what we've seen is if you follow patients for longer, you actually start to get, you know, see real stabilization around the primary endpoint in that study's six-minute walk test, but also really encouraging trends with respect to mortality. So this gives us a lot of confidence that actually by studying more patients for a longer period of time, we'll deliver a successful HELIOS-B study.
Maybe the final point to make is, you know, we obviously operate in this disease area with other players. So the recent study readout from acoramidis, from BridgeBio, which showed that in a contemporaneous patient population where it's believed that the patients might be a bit milder, there's still an opportunity to demonstrate benefit of an efficacious therapeutic in this modern era.
Yep.
We're really excited about, you know, moving forward with the study, and we're looking forward to sharing results of the study in early 2024. Just to remind those of you that don't follow acoramidis, early 2024 in acoramidis terms is a little bit like broad.
Yeah.
So it actually means first or second quarter in 2024. But we can't wait to, for the readout of the study and, sharing the results more broadly.
Yeah, it's gonna be very exciting. Now, again, you've laid out sort of why you think this can be a positive trial. If you succeed, how do you envision AMVUTTRA competing with oral tafamidis and the other stabilizers?
So, let's just say the other stabilizers. You know, first, I think, obviously, you know, tafamidis is being used widely now for patients with TTR cardiomyopathy. And despite treatment, you know, it's clear that the patients continue to progress. So I believe there's a real opportunity to introduce additional efficacious therapeutics into supporting patients with this disease. You know, there's another stabilizer in development. I touched on it, acoramidis from BridgeBio, and that's another stabilizer. So again, that'll be a useful addition, but really has a very similar mechanism of action. I think what we're, you know, looking to do with vutrisiran in patients with cardiomyopathy is bring a completely new mechanism of action with some of the features that I have already touched on in terms of levels of efficacy.
You know, again, I think what's really important is our long track record in developing and commercializing TTR medicines with really a really robust safety database. We launched ONPATTRO over five years ago now, and the safety that we've generated has been really quite robust. So we think that if we're able to deliver an outcome study from an outcomes endpoint in HELIOS-B study, we'll have a very, very competitive as well.
You guys are going to host an R&D day on December 13, so looking forward to that. Where maybe one of the things you'll be updating would be ALN-TTRsc04, which I believe has the potential of annual dosing. How important is patient convenience? Is there a risk of silencing translocation for that long?
ALN-TTRsc04 is based on what we call our Ikaria platform. The potential here, which we've demonstrated in an NHP studies is, as you say, the opportunity for, you know, potential annual dosing, but also for higher levels of TTR knockdown. We're looking at 90% or greater TTR knockdown, which I think could be quite important, from a, from a, from a, efficacy perspective. The phase I study is ongoing, and we hope to have the results of that we will be able to share, before the end of the year. What we're really looking for there is better understanding of potency, durability, obviously, of course, safety.
So we're really excited about this opportunity because it also, from an Alnylam perspective, I think, just shows what our innovation engine... So we started off with ONPATTRO, which is a three-weekly infusion. We improved that with our 2nd-gen molecule, which we ran AMVUTTRA, which is quarterly subcutaneous, and now we're able to enhance the profile of our approach to helping patients with ATTR amyloidosis with this potential annual regimen. I think it's gonna be great for patients that, you know-
Yeah.
once a year to be able to have an injection that's able to address-
Pretty incredible.
Yeah.
One of the big trends that we're really seeing is a move from orphan diseases to treat more common diseases. I've been seeing the Leqvio commercials now for hypercholesterolemia. Zilebesiran is, I think, a really exciting drug that fits this mold. It targets angiotensinogen for hypertension. Tell us about this therapy. Why did you choose to partner that one with Roche now?
Yeah. Again, I mean, taking a step back, I think it really shows the power of our platform. So, you know, we started off, you know, developing medicines for rarer diseases. But if you look at what the potential of our technology can do, we talked about potency and durability. You know, you know, on the back of a, you know, robust safety database, if you look at all of our programs, you can see how it makes a lot of sense actually to start to point our technology, not just to rare diseases, but to much larger diseases, where we can have, you know, even greater impact on patients. So I think this is something that, you know, is obviously very relevant to zilebesiran.
But as we think about the future of what RNAi therapeutics can do, really opening up the aperture to a lot of diseases, I think is something that's gonna help fuel the growth of the company for decades to come. We're very excited about zilebesiran. You know, zilebesiran, you know, is really entering a disease area that really hasn't seen innovation for decades, and there's a huge level of unmet medical needs. You've got over 219 million patients in the major markets who have hypertension. You know, close to 80 million of those are at high cardiovascular risk, 70% of them, you know, are not compliant. So we really think there's an opportunity with zilebesiran to completely reimagine how hypertension is treated. So we are really excited about this molecule.
We partnered with Roche because, you know, for a large disease like this, it makes sense to work with a larger pharma company that's got, you know, the resources to bring to bear, both to drive development. We're looking at doing, you know, cardiovascular outcome studies as well as ensure, you know, successful commercialization. Partnering with another company also gives us even more opportunity to continue to invest in all the other exciting opportunities that we have in our pipeline. Maybe we'll touch on some of those later. I think it was really smart to partner with a, you know, a large company at this stage of zilebesiran's development, and we decided to partner with Roche because they have a common vision around how they see the potential of zilebesiran in hypertension.
You know, they've actually got a really successful. As well as having a global commercial footprint, they've got a really successful track record in driving innovation in markets. And you know, we're very excited to be working with them and, you know, look forward to continuing to move forward with the program.
So we just got, I think monotherapy data was presented at AHA.
Yeah.
We're gonna get KARDIA-2 data...
Yeah.
...which is on top of standard of care...
Yeah.
...early next year. How do you - y ou mentioned about a shared vision of development. How do you guys see developing this?
Yeah. So just to kind of set the table—if you like. So, we touched on KARDIA-1, which is a monotherapy study, and we presented those results at the AHA, and they were actually, they were actually fantastic. I mean, essentially with, you know, you know, achieving reductions of systolic blood pressure of, you know, around about 15 millimeters of mercury at kind of every dose and every regimen, kind of out to six months. So the profile of zilebesiran looks to be really promising, but that was zilebesiran as monotherapy. KARDIA-2 is looking at zilebesiran, on top of-
Yeah
... three classes of drugs, so on top of either a diuretic, a calcium channel blocker, or an ARB. We think this is really important, replicate what we've seen in the phase I study, which is that adding zilebesiran on top of these agents provides additive efficacy-
Yeah
... but also with no safety penalty. So this is a really important study for us, and you know-
Yeah
... we'll be looking to share those results in early 2024. Then the third phase II study we're doing is called KARDIA-3. So really what this is looking at is a slightly different patient population, those that are at higher cardiovascular risk on top of, you know, two or more antihypertensives. And the importance of this study is to really understand this patient population to de-risk what the patient population that we study in a larger outcome study. And so this is the work that we're doing together with Roche, and we're looking forward to-
Fantastic.
... Updating on the program.
Yeah, I'm really looking forward to that data and that program, advancing. I mean, that could be a company in itself right there.
Absolutely.
Now, yeah, Alnylam also has a strong RNAi discovery alliance with Regeneron, I think really super innovative, and perhaps we can start describing some of that and how the alliance works. So one, I think the lead program coming out of that is ALN-APP, which is really, really interesting, for both early-onset, Alzheimer's disease. Maybe you can describe why an RNAi mechanism may prove superior to antibodies, and what does that development path look like from here?
So, again, just to, you know, provide some context, ALN-APP is the RNA therapeutic that we are developing both for early-onset Alzheimer's disease, and we have plans to also develop for cerebral amyloid angiopathy, which I think is a really-
Yes
... interesting indication. Really impressive that we've been able to show the first human translation of RNA therapeutic in the CNS. We delivered, you know, really strong, you know, phase I data. We're able to show reductions in sAPP alpha and beta of 84%-90%, with a single dose, single intrathecal dose. And so this really, you know, allows us to start to move forward into, you know, the second part of the study, part B, where we're looking at multiple ascending doses, and that study is continuing to move forward. We are under a partial clinical hold in the U.S. that we're working with the FDA to overcome, but, you know, we have the green light to proceed from, you know, a number of other regulatory authorities, so we're continuing to move forward that program.
You know, we obviously, as we get a better idea of results from the Part B, we'll be able to refine dose and duration and those sorts of things, then move into, you know, trying to, you know, deliver clinical outcomes in people.
Yeah, really exciting and, definitely, I think could highlight the unique mechanism of RNAi versus the antibody.
Yeah, I mean, so you're, so you're spot on. I think, I think one of the, I think, I think key points to highlight around the RNAi approach, which contrasts with the antibodies approach. I mean, first to say that actually we're delighted with the progress-
Yeah.
... of monoclonal antibodies in terms of, you know, making an impact on patients with Alzheimer's, so modest, and we think we can do better. 'Cause we're acting upstream of amyloid precursor protein and, you know, impacted all of the isoforms, whereas the antibodies, you know, could only impact select isoforms. And we're also able to, as you know, act not just in the cells but also outside the cells. We think there's some opportunities for differentiation, which we believe could lead to better efficacy for patients.
So, Yvonne, I'll ask you this question: Where do you see Alnylam and RNAi going over the next two decades? The first two decades have gotten us here, commercial franchise-
Yeah.
...Exciting pipeline.
Yeah.
What are you really looking for that's gonna be exciting over the next 10+ years?
Well, we feel that with what we have in our hands, and I touched on at the beginning, you know, growing revenues from our commercial portfolio, rich clinical pipeline, this important kind of, you know, innovation engine, that we will be able to build a top-tier biotech company. We've committed to achieving profitability. We've shared some goals a couple of years ago, which we call P5x25, which really sets out the course for us to be able to be self-sustainable and profitable by the end of 2025, as well as continuing to invest in all these exciting programs in our pipeline. The other thing to touch on is that from a scientific perspective, we really feel that we've only started to scratch the surface of this technology.
Obviously, got programs that are based on our liver-targeted delivery. We're now into CNS, as we've just discussed. We're not just focusing on rare diseases, but we can also look to address the needs and prevalent diseases. We're gonna open up extrahepatic tissues in addition. You'll hear more in R&D Days, some of the progress that we're making in this regard. But really, you know, this is a technology that can, you know, work in every single tissue in the body. So I think we've really only just kind of begun the journey, and there's just so much more excitement ahead of us to sort of keep focus on.
Great. I'll just pause and see if there's any questions for the audience, but I think that's a perfect spot to end this conversation. I always appreciate-
Wonderful.
... Seeing you.
Yeah.
I'm really excited for the HELIOS data, for the R&D day, and in just a couple of weeks, for the HELIOS data in early 20... or in first half of 2024.
Yeah.
And the progress coming both on the commercial side and the pipeline.
Yeah.
Thanks for being here.