Welcome everyone, to the second day of the 44th Annual TD Cowen Healthcare Conference. I'm covering Cowen analyst Ritu Baral, and welcome to the Alnylam Fireside Chat. With us this morning is CEO Yvonne Greenstreet. Yvonne, thank you for, for joining us and, squeezing this in before you have to hop on yet another plane, in advance of all your data readouts. So I was gonna start with HELIOS-B, because HELIOS-B. But you did have a release this morning on the KARDIA-2 data, a release that did not contain a single number. However, everything looks good, and you did say that you were going to, present the data at ACC. So looking forward to that data, but can you sort of go over, what you have said, holistically on the KARDIA-2 data to date?
Yeah, no, sure. Good morning, everybody. It's a real pleasure to be here. And it's an even greater pleasure to be kicking off a fireside chat and talking about zilebesiran—which goes to HELIOS-B, so thank you. Clearly, hot off the press today, with our release, sharing very top line a report from our KARDIA-2 study. Now, I'm sure most of you know that, zilebesiran is our investigational RNA therapeutic for treating patients with hypertension. We think, given the potential profile, this has a real opportunity to transform the lives of patients with hypertension, not just in terms of blood pressure lowering, but also in terms of tonic control. The KARDIA-2 study is a really important study on the step to bringing this, transformative program, to patients.
So the KARDIA-2 study is the second of our phase II studies with zlebesiran, and this study is assessing zilebesiran on top of existing standard of care. Our previous study, KARDIA-1, was a monotherapy study, and what we were delighted to see were clinically significant additive reductions in systolic blood pressure, on top of three important classes of standard antihypertensives, so diuretics, calcium channel blockers, and ARBs. So we're really pleased with the results. Importantly, also really encouraging safety and tolerability. It's really important in this indication, where you are potentially treating patients, millions and millions of patients around the world. So we're really pleased with the data. So sorry we can't share any numbers with you-
numbers.
We would have loved to, but ACC is quite restrictive about what you're able to say, and we've indicated, we've shared that we're gonna be presenting more fulsome results at ACC, as you said, April the seventh.
This is a
But it's just around the corner, so stay tuned, for that.
This is twice yearly administration?
We're looking at six -monthly administration.
We did cover zilebesiran, actually, yesterday during the KARDIA panel with Dr. Piña, and there were two things that emerged.
Mm-hmm.
One, she said that the minimum millimeters of mercury difference that she would need on top of standard of care to be meaningful would be five-10. She wanted to see five-10. Does that sort of align with your market research and your medical affairs.
Yeah
U nderstanding of the definition of meaningful?
I mean, yeah, I mean, we're really pleased with what we've delivered thus far. I think you all have pre-seen, you know, the results from our phase one study, as well as KARDIA-1, you know, in the monotherapy setting, showing reductions of sol.
Mm-hmm
S ystolic blood pressure of the order of 60 millimeters of mercury. So I think this is really encouraging. The other thing I want to add is that from a regulatory perspective, what you have to deliver is a reduction of 5 millimeters of mercury.
Mm-hmm
T he systolic blood pressure. So, you know, we're obviously progressing, you know, with the program. Next up is KARDIA-3. We're delighted that we have kicked off that study as well. This is a really important study because it sets us up for the cardiovascular outcome study. This study is looking at, you know, at patients who have uncontrolled hypertension on top of two or more standard antihypertensive treatments. So that, again, is important, but also patients who are at risk of cardiovascular disease. So this is the kind of population that we're going to be looking at, studying.
Mm-hmm
I n our cardiovascular outcomes trial. The three studies, the three study helps de-risk that, so we can march into.
Mm-hmm
D oing a cardiovascular outcome study with confidence. This is a really important program for us.
Two things.
Yeah.
Dr. Piña mentioned that one of her concerns around this program was the long-acting nature of.
Yeah
T he blood pressure reduction, but you did say that safety has been good. So we're not, we shouldn't be expecting any signals of hypotension, unmanageable hypotension or severe hypotension?
No, we're not concerned about hypotension.
Mm-hmm
B ut we do recognize that, you know, it's going to be on prescribing physicians' minds. So we're also progressing an agent called Reversir, which can be administered if
Mm-hmm
... physicians are at all concerned about hypotensive episodes. But even if patients have, you know, an episode of hypotension, these are easily managed in the clinic with pressors and fluids, et cetera. So I think it's more of a theoretical concern.
Mm-hmm. Okay.
T han an actual concern at this point in time. We're really pleased about the safety profile thus far.
KARDIA-3, that is a three-month endpoint, primary endpoint, I believe?
It's a three- and six-month endpoint.
Three- and six-month endpoint. Wonderful. So that is the zilebesiran data, or news from this morning. Let's move to HELIOS-B now. I mean, the biggest question, one of the biggest questions we've gotten around the updated HELIOS-B SAP, where you now have dual, essentially dual primary endpoints, well, dual analyses. Composite outcome of all-cause mortality and recurrent CV events in the ITT overall population, and then the monotherapy populations, or the 60% of patients not at baseline. Why, why now? People are convinced you've seen the blinded data, and you're seeing the event rates, and it's not what you're hoping, and, and that this is why. Has anybody, anybody at all, Alnylam, seen the event rates?
So, you know, here's the thing. We are confident in the outcome of the HELIOS-B study. We are confident that vutrisiran is going to deliver benefits and outcomes for patients, in this study. Now, we made these changes, because we saw opportunities to optimize, the probability of success, as well as deliver a robust, and competitive profile for, vutrisiran in patients with cardiomyopathy. So I think it's really important to kind of, you know, emphasize that, and also we recognize that it's an incredibly important study, you know, for the company, but also for patients. And I think most people who've sat down and thought about the changes that we've made have said to us, "Well, yeah, these are really logical changes. I mean, they make a lot of sense.
Mm-hmm.
The question has been: "Well, you know, why did you make the changes.
Why now?
At this point in time?
Yeah.
If you think about it, what you don't wanna be doing is coming up with incremental changes over the course of a study. What we wanted to do, we indicated to everybody that we may well make tweaks up until database lock.
Mm-hmm.
And what we wanted to do was really assess all the information we were gonna have on the study. And really the most important information, you know, in our mind, is building on the foundation that we already have with RNAi therapeutics. And APOLLO-B was a very confirmatory study for us. It really encouraged us about the likelihood of success of HELIOS-B. And we've been able to, you know, not just share the 12-month data and the 24-month data from APOLLO-B, but we're obviously continuing to assess these patients. We've also been informed by, you know, other studies in the field. So, you know, we wanted to take all of that information. It's also important to us that we align with regulators.
Mm-hmm
N ot just the FDA, but other regulators, around the direction of travel. That takes some time.
Mm-hmm.
So, you know, announcing these changes at our last earnings call was in the sweet spot between understanding all the information we're gonna have, aligning with the regulators, but actually effecting the changes prior to database lock, so that.
So really, it was APOLLO-B?
That was the primary set of information that-
Mm-hmm
H elped us, you know, decide on the changes that we were going to make. Now, you talked about blinded event rates.
Mm-hmm.
All companies, I mean, we obviously have a small team inside the company that,
Not you.
Not me. No, not me, that assess blinded event rates on an ongoing basis. This is important because it allows them to, you know, monitor data quality and ensure that we have data integrity at the end of the study. I think what we've demonstrated to you, kind of in our track record of delivering successful studies, is that we pay a lot of attention to how, not just the design of our studies, but also the execution of our studies. The real driver for making the changes was, you know, APOLLO-B. I think it's also, you know, people get very engaged in kind of blinded event rates, but they're actually hard to interpret.
Yes.
They're actually very hard to interpret. So if you've got a high blinded event rate, what does that mean? You've got lots of events, or maybe your drug's not working. And conversely, if you have low event rates. So, you know, we've made these changes now. We're very pleased with the changes. Obviously, you know, our focus is on delivering a successful study here. And I tell you, we can't wait to open that envelope end of June, early July.
How much did the BRIDGE trial inform this as well, just given the similarities in population?
So, look, you know, kind of with drug development, what you wanna do is you wanna have access to all the information that you possibly can around the population that you're studying, the specifics of the disease that you're studying, to make sure that you're as fully informed as you're ever going to be before making decisions. So obviously, everything is brought into consideration as... You know, and we didn't make these, you know, changes just 'cause we woke up one morning and felt like it, right?
Mm-hmm.
This was a very thoughtful process.
How much more confidence do you have in the data, given the additional three-six months? I mean, how many more events is that tail end gonna capture? Is it? Should we simply think about it as 10% more because it's 10% longer?
Yeah.
Or is there, like, a tail?
Yeah. So look, I don't think it's kind of easy to speculate on specific percentages, et cetera. But I think the important takeaway here is that, you know, TTR cardiomyopathy is a progressive disease, so the longer you observe patients, the more events you're going to see. And kind of extending that duration, so the changes, database lock was gonna happen for the last patient at month 30, now it's happening at month 33. Which means, you know, many patients are getting a extended period of observation.
Right.
M any of them out to 36 months, to be honest. This is actually the longest study that's been done in, you know, TTR cardiomyopathy. What happens at the tail end of the study is actually that's where you start to see the most events occur, and that's where you start to see the greatest separation between active and placebo.
Mm-hmm.
We do think that, you know, the extra three months is actually meaningful. What percentage that leads to, I think, is speculation.
But it should be weighted.
It'll enhance the power of the study.
It'll be weighted.
It'll enhance the power of the study. Yeah, absolutely. I'm sorry, it's not speculation because the biostatisticians are constantly making calculations. But we're not gonna speculate with you. Okay.
Fair enough.
Yeah.
I mean, I guess, are we thinking about it the right way? For the sake, basically, to the same point, these events do tend to be later weighted as patients progress.
Yeah.
And there's a richer sort of event rate. But also, as you think about the TAF drop-ins, you're also giving TAF some more time to work. So how do you sort of think of that balance?
So actually, I think we've got, we've got tailwinds with respect to TAF. Recall, we were assuming, you know, 50% of TAF patients at baseline.
Mm-hmm.
We ended up with only 40% of TAF patients on baseline. We've also talked about kind of numbers of TAF drop-ins, and that remains the case. So I think from a TAF perspective, we actually feel we've got more tailwinds here, in the study than, than we'd anticipated at the get-go.
How are you gonna report top-line data right now? I mean.
Yeah.
S o you have variable follow-up by patients, so the curves will, at least towards the tail end, is there imputation of data out to 33 weeks? Is the hazard ratio going to be an event rate?
Yeah. So look, I mean, you know, what we've said at this point in time is, you know, what we're gonna communicate.
Mm-hmm
Is what we generally communicate, which is P values.
Mm-hmm
For the primaries, secondaries, and obviously, importantly, information on safety. We've also said that we will present some information on subgroups. I know people will be particularly interested in seeing the TAF subgroups.
Mm-hmm.
We will be presenting some additional information, but at this point in time, that's the information that we've committed to showing.
That's the information you've committed.
Mm-hmm.
Leave yourself open to potential effect sizes.
I mean, I'm not gonna... Again, I'm not gonna comment on that. I think, you know, what I am gonna say is.
But you're not saying no.
That's the better. You never say no, right? You always reserve a right. But, you know, I think look at our historical practice. We're quite disciplined.
Mm-hmm
about what we share in the top line, because it's really important-
Mm-hmm
T hat we're able to get data reviewed in important medical congresses. At the end of the day, you're a very important stakeholder here. But, you know, incredibly important from a patient perspective is to make sure prescribers are able to get full information in a timely fashion. So we will be looking for the most, you know, proximal, meaningful, you know.
Mm-hmm
cardiac congress after top line.
So if we look forward to that, potentially ESC. At that point, how is the data reported? And this is a question I've gotten from investors: How will the data be reported, given the variable.
Yeah.
F ollow-up?
I think.
Is it normalized? Is it.
I think we'll wait until, you know.
Okay.
W e have the data, and then we'll obviously prepare, you know, the data for presentations, you know, not just, you know, either press releases.
Yeah.
Engagements with the street, but also to consider what we present at, you know, an upcoming congress.
So what effect size are you hoping for? As you think about the landscape.
Yeah
A s you think about your focus on monotherapy.
Yeah
W hat's the effect size you need?
So look, I mean, look, here's the thing. This is an outcome study, and, you know, if you speak to patients, physicians, regulators, when it comes to outcomes, these are really meaningful endpoints for all those, constituencies. So we would be delighted if we're able to show a benefit in outcomes of, vutrisiran in the study. And if we do that, you know, we feel very confident about being able to bring this medicine forward to patients.
Do you feel like you need to show as much as Acoramidis did?
Again, you know, I think it's not the right time or place to.
Mm-hmm
To make comparisons with competitor studies. You know, if we deliver positive outcomes in the study, I think we really set up the foundation for a successful vutrisiran launch for patients with ATTR cardiomyopathy.
Have you had any conversations with FDA on what they're thinking, especially after that last AdCom?
Yeah.
R ight, where Norm Stockbridge got up and said things? Outside of statistics, any communication on what they're thinking as far as minimal separation?
I think, again, this being an outcome study.
Mm-hmm
Is a very different situation to a study that was a 12-month small study that was really focused on, you know, endpoints of how patients function and feel, so KCCQ and 6-minute walk test. And, you know, these are endpoints that, you know, there can be conversations around, you know, what is the magnitude of clinical benefit that you need to see for this to be a meaningful medicine. I think with outcomes, that's really not a factor here. And I think it's also important to recognize that, you know, while there is existing treatment out there, you know, with C, 75% of patients continue to progress on tafamidis. There's a real need for additional therapeutic interventions here.
I think that level of unmet medical need, I think is going to be very important in helping physicians understand, you know, how they can best treat their patients.
So yesterday, on the cardiac panel, we pressed Dr. Grogan on that, the percentage of patients progressing. Just first a note, for those of you who are in the doorway, there's actually some room over by the sound booth if you wanna come in and stand here with good audio and visual. Just come on in. The 75% that you mentioned, the progressors.
Yeah.
W here did that come from? Is that, is that sort of a real-world database?
So it comes from a variety of sources that we've triangulated to come to that number. And I think as time progresses and more publications are.
Mm-hmm
Brought to bear, I think that number will become, you know, more recognized within the community.
I'm trying to reconcile what I heard on this panel, this cardiac panel, with what I heard on our fall cardiac panel, where we had a doctor who basically says, I'm forgetting now who it was. Maybe Amrita can help me. But he basically said, if you start patients on TAF early enough, they, they, they are stable, they don't progress. And then, our doctor yesterday said the exact opposite. She said, I asked if they progressed in five or 10 years, she's like, "No, TAF hasn't been around for five or 10 years. It's more like two to five years." So.
Yeah. Look, so here's the thing. We're innovating.
Mm-hmm
In TTR. You know, this is a relatively new area of understanding. I think all the studies that we do, us and other companies do, are all beginning to inform, you know, how people think about the field. I mean, I just think about the epidemiology. When we started out in this field, maybe people thought there were like 60,000, 70,000, 80,000 patients with wild type TTR cardiomyopathy.
Mm-hmm.
Now, people are talking about 300,000 or 400,000 patients.
Right.
I think, you know, this is a field that's gonna continue to evolve, and we're gonna continue to improve our understanding.
Andersen-Gill, my favorite topic, statistics.
You and me together.
I know.
Yes.
So, so awesome. Does it reserve any alpha for the secondaries? You're splitting the alpha between the dual analysis.
Yeah. So I mean, I think the way to think about the study is that if we achieve a p-value less than 0.025, okay, in any one of the two populations. If we achieve a p-value of less than 0.05 in both those populations, then we start to progress down the hierarchy of secondary endpoints.
Mm-hmm.
They will be assessed in power in both the monotherapy.
Mm-hmm
Patient population and the combination patient population, and that's the best way to think about the secondaries. I do wanna make a couple of points about the secondaries whilst we're on that topic. I mean, I'm sure you've noticed that actually we've improved the stringency, if you like, of the secondary endpoints that we're gonna be focused on in the study. Now, clearly, you know, a number of other endpoints will be exploratory endpoints. All that data will be available.
Mm-hmm.
But we've really focused on what we believe are the most clinically meaningful, you know, endpoints here. They're also endpoints where we believe that we'll see differentiation. So if you look at the data that we have, we've shared from APOLLO-B, particularly the 24-month data, you'll see that really what, you know, RNA therapeutics are able to do for these patients is actually stabilize disease. I think that's gonna be very important to physicians and patients, so we focused on those kinds of endpoints. We've included, you know, NYHA class as well, because that's an important measure of progression for both our patients and physicians. And again, an endpoint where we believe we'll show differential benefit.
So the streamlining of the secondaries almost seems like there was, you know, the hand of marketing behind it. In the sense that you could really start talking to patients about how it might make them feel better. Because, again, from the panel yesterday, we had an expert who said she would go right back to proBNP. She wants to see the echo measures. For her, as a TTR specialis.
Yeah
That's what's gonna drive her.
Yeah
Assessment of a stable TAF patient. 'Cause if her echoes show thickening, that's not stable, and she wants to put them on maybe a silencer.
Yeah. So, I mean, the important thing to say is kind of actually just reusing what I've said already.
Mm-hmm
Which is that we focus the secondaries.
Mm-hmm
On what are the most important, clinically meaningful.
Mm
Endpoints. But of course, we'll have all the data that you're talking about.
Mm-hmm
As well, NT-proBNP, et cetera, et cetera. Also speak to the real need as this field evolves to have, you know, more consistent kind of guidelines as to, you know, when to treat patients.
Mm-hmm
How to treat them, how to assess progression. And that's clearly something that we're going to be contributing to, together with experts in the field, to help, to help get a... You know, 'cause at the end of the day, you know, this is about patients, right? And it's quite clear that the earlier you treat patients, the better they do. And actually, the earlier you treat patients with the most efficacious intervention, the better you do. What was really striking to me from the APOLLO-B, 24-month data, and I don't know how many of you are familiar with this, but the patient from placebo crossover onto active treatment with vutrisiran. And while the addition of vutrisiran helps to stabilize their disease.
Mm
-they never get back to where those patients who started on vutrisiran.
Mm-hmm
Are, So there really is something very important here about educating physicians, making them aware of the disease, so that the patients can actually get the treatments that they need in the first place.
Clinicians is relatively pleasant, but what about the payers? What have you talked to them about what they need to see to not implement crazy step edits, crazy.
Yeah.
Clinical record requirements for the step edit to silencers? Have you had conversations about potential combination use, even if you are focusing on monotherapy?
So look, you know, as we've sat back and looked at the evolution of this marketplace, it seems pretty intuitive to us, and it is backed up by some research and engagements with payers, and actually our historical context with respect to treating mixed phenotype patients, that payers are gonna be very sensitive.
Mm-hmm.
To to cost. And the cost of combination therapies is quite significant, and I think it's going to mean that it's going to be payer sensitivity in managing combination use. Now, we believe that the vutrisiran is gonna show an additive benefit on top of tafamidis. But we also recognize that it's gonna be challenging for payers to pay for widely expand the market, which.
Mm-hmm.
Which is what's gonna happen with cardiomyopathy, but also increase, increase costs. So even in the current situation where we've got non-overlapping labels with TAF, when you think about the mixed phenotype patient, there are actually restrictions around combination use. So we do believe that up-
Mm-hmm
U ntil TAF patent expiry, it is going to be primarily a monotherapy.
Mm-hmm
M arket. We believe that zilebesiran, if it delivers on the profile we expect, will be first-line monotherapy. We'll also see switches from agents to zilebesiran. We've seen that in polyneuropathy.
Mm-hmm
I n Europe. And there'll be some limited combinations.
Amvuttra will be positioned for in-office delivery, so it would be a Part B question?
That's correct.
Okay.
Also, you know, we are providing services that allow patients to receive therapy in the home setting. Well, a very flexible approach.
Mm-hmm
T o, you know, to allow patients to either receive therapy at home or in the office.
One of the things that does tend to help with payers is the updated guidelines. We talked about potential guideline updates. Is there anything in the works, you know, what with the PDUFA for acoramidis coming up or anything that you know of in the works for updating TTR, either management, diagnostic guidelines from the medical associations that could be helpful or impactful already?
Well, most of the guidelines and the works are focused on, you know, how to diagnose patients.
Mm-hmm
B ecause there's only been.
Right
K ind of one treatment available. But I think when we see the introduction of additional treatments, I'm sure there will be guidelines that start to emerge.
Mm-hmm
T hat actually help physicians understand the context in which to treat patients.
I have left four minutes for the rest of your pipeline. If.
Shall we start with Alzheimer's?
I know. Pushkal over here will be throwing things at me right now.
Yeah.
ALN-APP, your part for phase I Part B recently got the FDA clearance on that partial clinical hold. Can you tell us how you're progressing in this trial now with U.S. and ex-U.S. sites, and is MAD data still guided for late 2024?
So, you know, we're absolutely... Look, I'm so excited about the potential of RNA therapeutics to help patients with, you know, neurodegenerative diseases, that there's just a huge unmet medical need. And I think the important thing about APP that I just wanna emphasize is that, you know, with success in APP, it starts to open up the whole vista of RNAi, our platform, being able to address the needs of patients with neurodegenerative diseases. Now, we were delighted that, you know, the FDA have allowed us to progress into multi-dose studies and, you know, while we're not fully off clinical hold, you know, the doses that the FDA is supporting are well above what we plan to use going forward.
So we're already progressing with the multi-dose portion of the study, Part B, in the U.K., the Netherlands and Canada. That study is up and running. Obviously, we can now include U.S. sites as well, so we are still committing to.
Mm-hmm
D ata from Part B of the study later this year. What I do wanna say that I'm really excited about is also kind of initiating phase II for patients with Cerebral Amyloid Angiopathy. I think that's another indication for people to spend some time thinking about.
2024 start or, will that be next year, the phase II start?
Yeah, 2024.
2024 start. And I have left you a very generous 90 seconds.-
Yeah
T o highlight your favorite children from the rest of the platform, including—I mean, you have, like, 10 cardiovascular programs.
So I've got, I've got loads of favorite children. Look, I think the other, the other exciting thing to say is that we really are spring-loading the pipeline for good. I know a lot of the focus is on TTR right now, and I absolutely get that. But, you know, we're gonna be doubling the size of this pipeline, by the end of 2025. Just so much more potential for, RNAi therapeutics to help patients in a, in a wide range of diseases. I think maybe just to focus on the upcoming.
Mm-hmm
... you know, opportunities. So we've already talked about zilebesiran, so look out for those data. We talked about APP, look out for those data. KHK, you know, look out for those data. We don't often talk about partner programs, but actually, Sanofi have guided that they will be filing an NDA for fitusiran for patients with hemophilia sometime in 2024. And obviously, you know, there's an economic benefit.
Mm-hmm
T o the company there, but also I think just bringing RNAi therapeutics to another group of patients, those with hemophilia A and B, with or without inhibitors. So excited about that too.
Great! We are exactly at time. Thank you, Yvonne.
You've been great.
Thanks for the time.