Thanks for joining us. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. I'd like to welcome Yvonne Greenstreet, the CEO of Alnylam. Thanks so much for joining us today, Yvonne.
Yeah, it's a real pleasure to be here, and glad to see such a full room. Wonderful. Is my microphone working? Yeah. Great.
We're gonna do fireside chat format. So, for those who may be new to this story, maybe give a one-minute intro to Alnylam and some of the key catalysts, coming up in the next 12-18 months.
Absolutely. So Alnylam, as you know, some of you may know, is the leading RNAi company, and we're particularly proud of the fact that we've brought to market four RNAi therapeutics, actually in a space of four years, which I think is a remarkable achievement, and I think a testament to our development capability, but also our commercial capability. So we have four products on the market. We have ONPATTRO and AMVUTTRA for patients with TTR amyloidosis with polyneuropathy, and we have two ultra-rare opportunities: OXLUMO for patients with primary hyperoxaluria type 1, and GIVLAARI for patients with acute hepatic porphyria. These are really quite transformative medicines for patients with these rare diseases.
But not only do we have marketed products where we're growing commercial performance in a robust fashion, we also have a really rich clinical pipeline of a dozen or so programs in development, which we're continuing to progress. And underneath it all, I think what is really one of the special sources, if you like, of Alnylam, is given the fact that we're a platform company, we now have this de-risked platform, very high probability of success. I mean, in the order of magnitude of POSs that we have from programs coming from our pipeline are north of 60%, which I think compares very favorably to the industry average of somewhere between 6%-10%. And I think this is going to fuel continued innovation for the foreseeable future.
So we're very excited about what we have in our hands, the opportunities that we have to transform health of patients with many, many diseases. As we look forward, I mean, there are, you know, despite what I've shared already and the success that we've delivered to date, there's some very exciting catalysts ahead of us. As we think through to the end of this year, we'll be delivering data on a program called KHK for patients with type 2 diabetes. We'll be delivering data on TTR-sc04, which is our next-generational opportunity for patients with TTR amyloidosis. So we started with ONPATTRO, which is delivered through lipid nanoparticles. We moved to AMVUTTRA, which is GalNAc, and now we're developing an even more potent and durable approach called TTR-SCO4.
We'll be delivering data from that in a phase I study at the end of this year. And as we look forward into the early part of next year, we're really quite excited about delivering the phase II study for zilebesiran, which is our program in development for patients with hypertension. We just shared some recent exciting data from one phase II study called KARDIA-1 at the AHA just this last weekend. So happy to talk about zilebesiran if you get there. And then I think obviously the catalyst that a lot of folk are really interested in, which is the top-line results from the HELIOS-B study, where we're studying vutrisiran in patients with hereditary and wild-type TTR cardiomyopathy.
Lots to come over the next 12 or so months, Maury, and we're very excited about moving all of these things forward.
Yeah. Yeah, it's a great intro, a lot going on, and, you did mention the Phase III HELIOS-B study, which is definitely a big event in the space for Alnylam and for the sector.
Yeah.
You've guided to having the top-line data in early 2024. We're estimating you could report the data in April. That's our estimate.
Yeah.
Can you provide more granularity on, when the last patient visit is expected?
Yeah. So what I can say, just to take people back, the study was initiated in December of 2019, and then we completed enrollment, which we shared in August of 2021. Now, there's variable follow-up for these patients between 30 and 36 months, so we will close out the study when the last patient has had 30 months of observation. Then clearly, you know, we'll have to look at the data and analyze it, et cetera, before we're able to share a top-line report from that study. And what we've said is that we'll be providing results from that study in early 2024. Now, for those of you that are not familiar with the Alnylam lexicon, it's very confusing. So early 2024 means either Q1 or Q2 in 2024.
What I can say, I can't narrow the guidance, you know, much, much more than we have done to date. But what I can say is nobody should expect to see the data at JP Morgan, at the beginning of next year.
Okay. Okay, that's, that's helpful. And for the top-line update on the third quarter call, it was mentioned you'll report the hierarchical endpoints along with P values. Can you clarify if you're gonna break out mortality from hospitalizations and provide a P value on mortality?
So, look, that's a great question. I know people are very interested in the primary and secondary, you know, endpoints of the study. The primary endpoint, just to make sure that everybody knows what that is, it's all-cause mortality and recurrent CV events at this 30- 36-month period. What we'll do for HELIOS-B is actually consistent with what we've done for our phase III studies as we've reported them to Alnylam. We report P values in a hierarchical fashion for the primary and secondary endpoints, and that's really all I can say about what we're gonna report at this point in time. We also share some qualitative statements on safety, et cetera. So with respect to, you know, any further detail of what we might share-...
you know, with respect to the top-line report, I think the best assumption is to be guided by what we've done historically.
Got it.
Yeah.
Makes sense. And you've had interactions with FDA recently with the APOLLO-B study. Has FDA given you any feedback on the HELIOS-B study conduct and design based on the recent APOLLO-B CRL?
Yeah. So again, just to bring everybody up to speed. So APOLLO-B was a study that we did with patisiran in patients with hereditary and wild-type cardiomyopathy. And really, the purpose of the study was to try to take advantage of the fact that ONPATTRO was approved in the marketplace for patients with polyneuropathy. And there was a window of opportunity to try to bring forward an RNAi therapeutic to patients with cardiomyopathy in a very expeditious fashion. Now, we've talked about HELIOS-B, that's an outcome study, you know, over the course of three years. APOLLO-B was a 12-month study, which looked at functional endpoints. So not hard outcomes, functional endpoints, six-minute walk test, and, say, KCCQ.
While the study delivered statistical significance on those endpoints, there was an advisory committee, and we actually ended up with a CRL, and the issues there were around the interpretation of clinical meaningfulness from this very short study. We believe that actually the HELIOS-B study design addresses all the questions that were raised in the advisory committee. So I—you know, just to touch on some of the key points, you know, it's an outcome study, number one. I think you know, there's a lot of discussion around, you know, the relevance of functional endpoints and what were the hurdles one needed to achieve for clinical meaningfulness. When you've got an outcome study, you've actually got unequivocal outcomes here. It's either, you know, death or, you know, a severe event or hospitalization.
So we believe that having an outcome study, which is obviously then of a much longer duration than the APOLLO-B, three years as opposed to 12 months, and it's twice the size of APOLLO-B. We think we've actually, you know, addressed the concerns that were raised, and we're looking forward to sharing the results with the community as soon as they're available.
Got it. Makes sense. And, you've got longer-term data from your open-label extension going out to 24 months for APOLLO-B. Talk about that, and some of the events in that study were slower at 24 months relative to Pfizer's ATTR-ACT study and BridgeBio's ATTRibute-CM Phase IIIs. Is the slower rate driven by the combo patients, or is it primarily due to the patient population just progressing more slowly?
I mean, so I'd encourage all of you to take a look at that 24-month data from APOLLO-B. So I told you that the, you know, primary endpoint of that study was at 12 months, but we actually followed up the patients for 24 months, and at the end of 12 months, patients that had been taking placebo were switched to patisiran treatment. What was really encouraging, what we saw in the data, the patients that had stayed on patisiran throughout the whole period, we continued to see stabilization of benefits, stabilization of six-minute walk tests and KCCQ, and actually continued encouraging outcomes with respect to mortality. So the data were really quite strong.
Then patients that switched from placebo to patisiran at this point, then followed out for the 12 months subsequent, began to show quite encouraging improvement as well. So, you know, I think the 24-month data are really give us a lot of confidence about what we might see in HELIOS-B, where we're looking at patients for even longer, another year, 36 months. So I think this is really, you know, quite encouraging with respect to our level of confidence in HELIOS-B. Now, it's important that we are really careful about making kind of study-to-study comparisons. So that study was with patisiran, obviously, HELIOS-B is with vutrisiran. With respect to the ATTR-ACT and ATTRibute-CM study, I think ATTR-ACT, it was done a long time ago, in a very different patient population with much less understanding of the disease.
But I do think an interesting study to look at is what's called the ATTRibute study, which is the acoramidis outcome study, where in a contemporaneous patient population, so in the modern era, if you like, very similar to the period of time where we enrolled HELIOS-B, acoramidis was able to deliver, you know, positive outcomes, which is very encouraging for us, particularly as that study failed at the 12-month endpoint with respect to six-minute walk test. So I actually think that when we look at the emerging information that, you know, we're getting in this field, and it's just such an exciting area, the market is just growing so rapidly, we feel actually very encouraged, not just by the data that we have in our hands, but also looking out at studies like ATTRibute.
Got it. Makes sense. You probably can't say much on this, but for your blinded look at HELIOS-B data, is it showing a consistent pattern as the ATTRibute data set, and what can be extrapolated from the placebo arm, from the acoramidis phase 3 as it relates to HELIOS?
So with respect to blinded data, you know, we're not gonna be sharing any details on that. Really, the purpose of a small internal team at Alnylam looking at blinded event rates is to make sure we can maintain study integrity. So, yeah, I'm not gonna be able to kind of add very much on that, on that point.
Okay. Okay, and there's been some investor debate on whether the Finkelstein-Sonnenfeld method of win ratio from a stats perspective would have been better than the Anderson-Gill method, which you used for APOLLO-B and HELIOS-B-
Yeah
... for increasing chances of statistical success.
Yeah.
You've mentioned with the 30-36 months and variable timelines-
Yeah
... it gives you some additional power. Can you talk about the other benefits of this method and where there could be-
Yeah
... some risk related to the method?
This is a great question, and you know, quite enjoying getting asked deep statistical questions with respect to the study. I think if we take a step back, both these methods are very reasonable ones to use for heart failure studies. I think that's the first point. I think the other point to make is if you think about the ATTRibute study, because the primary endpoint was a composite endpoint that included six-minute walk test as well as NT-proBNP, which are continuous variables, actually, you can't use the Anderson-Gill method. You have to use the SF method. Now, we decided to use the Anderson-Gill method for HELIOS-B because of this differential duration of observation that I described to you earlier.
You know, patients being assessed between 30-36 months, depending on when they were enrolled in the study. The Anderson-Gill method is actually one that captures, you know, recurrent events out for a longer period of time. Rather than having to make, you know, pairwise comparisons at an earlier time point, which is what you'd have to do in the SF method with the win ratio, we can actually utilize the data that comes downstream for these patients at later time points. We think that with HELIOS-B, given its study design, the Anderson-Gill method is a preferable one. You know, they're both very reasonable methods and probably subtle differences between them.
Makes sense. Makes sense. And so Anderson-Gill gives you some more flexibility, could be more optimal for your, for your study.
Yeah.
A key question is whether you'll see added benefit in the 50% or less patients who are on baseline tafamidis. FDA was focused on the magnitude of treatment effect for this combo population in APOLLO B. After APOLLO B, have you gotten clarity on what is a meaningful-
So-
- delta-
Yeah.
- for the combo patients?
So, you know, as I reflect on, you know, the advisory committee discussion with respect to APOLLO-B and the questions raised around clinical meaningfulness, and also the questions raised about how to use vutrisiran in combination or sequentially with tafamidis, I think, I think the real driver for that discussion was actually because, you know, we were comparing apples to pears. The APOLLO-B study was never designed to be an outcome study. It was never designed to be a study that looked at comparisons and this, that, and the other. And, you know, I think it's important to reflect on the fact there were only 45 patients in the taf subgroup. So, you know, you're not actually going to be able to really discern, you know, much robustness of evidence there.
Nevertheless, actually, with respect to outcomes, there was a trend in both groups, both the monotherapy group and the taf combination group. I think when you're thinking about an outcome study, I think it's a completely different scenario, and as I said, if we're able to deliver success in the study, which is demonstrating a benefit of vutrisiran on hard outcomes, I think the conversation with respect to tafamidis shifts some because you're comparing outcomes to outcomes. You're not comparing functional endpoints to outcomes. So, as I said, I think if we're able to deliver a positive p-value for the primary endpoint, and we're able to show, you know, consistent kind of benefits with respect to all the key subgroups, I think we'll be in a very, very good, very, very good position here.
And I think the other thing to say is, given the larger size of HELIOS-B, we've actually got much larger subgroups as well, so hopefully it'll be able to give us a, you know, better indication of how a medicine like vutrisiran performs within those different subgroups.
Makes sense. And, for APOLLO-B, you had a 25% threshold for patients on baseline tafamidis, and then for HELIOS-B, it's closer to 50%. Talk about why those thresholds were chosen?
You know, lots of factors. Those who design clinical studies know there are a lot of factors go into kind of how you think about setting up a clinical study. You know, obviously, design considerations, but also feasibility considerations. And as you compare APOLLO-B to HELIOS-B, as I said, some of the key differences are around the duration of the study, and with a 12-month study, we felt it important to have a smaller number of TAF patients. For a longer study that goes out to three years, you know, 50% seemed an appropriate cap. I think it's important to note that 50% was our operational target. We actually came in somewhat below that 50%, target, and our, you know, TAF drop-in rates were also below our internal assumptions.
I think we think we're in a pretty good shape with respect to the taf population in the HELIOS-B study.
Got it. Okay, and, for, ONPATTRO Expanded Access Program, this has been ongoing. You've mentioned that there's 200 patients in there. What proportion of these patients are on combo with tafamidis, and what data are you collecting from this study? And maybe talk about what you're seeing in the study.
Actually, what was really quite interesting about setting up the expanded access program, we didn't really expect it. I mean, you do an expanded access program 'cause you're trying to provide patients with the opportunity for a drug that's already delivered safety and efficacy in advance of an approval. And we set a limit to the study, actually, of 200 patients, and actually, that study was filled up really, really very quickly. We had something like, you know, three patients coming into the study every couple of days. And the study is really, the purpose of the study really is to collect safety data.
But I think what was quite striking about the rate of enrollment in that study was that most of the patients who came into the expanded access program were already on taf, and they wanted to come into the expanded access program because they were progressing on taf, and they wanted to avail themselves of an additional treatment option. So I think what this says to me, actually, is when you think about patients that are being treated in the real world, there's a significant unmet medical need that remains despite the availability of stabilizing treatments.
Makes sense. And, you've also talked about, patients in the real world where there's about 20% of patients-
Yeah.
that are on tafamidis stabilizer and also on vutrisiran or ONPATTRO. How does information from these patients that are on combo inform how you think about HELIOS-B?
Again, I think, you know, to make a point that, you know, in the U.S., which I think is what you're referring to, this combination use, it's important to remember that tafamidis has a different indication. It's indicated for patients with cardiomyopathy, not polyneuropathy, and obviously our indication with vutrisiran and ONPATTRO at this point in time is for patients with polyneuropathy. So I think you're seeing the multisystem impacts of TTR amyloidosis, where patients have cardiomyopathy, but they also have polyneuropathy. And so, you know, about 20% of patients are on both agents, and I think what this speaks to is actually the differentiated profile that I think clinicians are excited about with respect to bringing a new modality to patients who have features of polyneuropathy.
Makes sense. You've mentioned for HELIOS-B that the drop-in rate's been below your internal thresholds.
Yeah. Yeah.
What's the latest you can say on...
I think I've spoken to that already.
Okay.
Yeah.
Let's see, for market research ahead of the APOLLO-B PDUFA, what have you done there, and
Yeah. So what I think is really quite striking about TTR amyloidosis is it's hard to reflect, you know, 10, 15 years ago, but 10, 15 years ago, it was thought to be very rare disease. You know, physicians were pretty much unaware of the disease, both neurologists and cardiologists. And over the last several years, with the efforts of companies like Pfizer that have been raising disease awareness and education and efforts from, you know, obviously Alnylam as well with respect to polyneuropathy, we're seeing this explosion in diagnosis and the numbers of patients treated. And I think what this says to me is TTR amyloidosis is a very exciting, rapidly growing market category. And I think, you know, there's going to be room for multiple participants, as we've seen in other disease states like multiple sclerosis or rheumatoid arthritis.
When you have a large, growing patient population where diagnostic rates and treatment rates are increasing, I think it's a very exciting area. And obviously, cardiomyopathy is much larger than polyneuropathy, hence everybody's interest in us being able to access the cardiomyopathy market, as well as obviously our leading position in polyneuropathy.
Makes sense. And what proportion of patients would you expect would start on vutrisiran monotherapy versus vutrisiran add-on to...
We just say label to inform.
Sure. Yeah, that's... I guess, I mean, can you comment on that? Any-
Well, you know what I'm trying to do, we've got two minutes and 56, 55, 54, 53, 52 left, and I think, you know, not inappropriately, we've spent a lot of this fireside chat talking about our prospects at Alnylam with, you know, TTR. I think it's very important, and I just want to, you know, assure everybody that we are laser focused on ensuring that we deliver a positive HELIOS-B. We feel very confident, but we're not in any way, shape, or form complacent. We continue to look at the external data sets that we've discussed. We also internally, there's a small team that looks at blinded data.
And, you know, we will continue to assess, and you know, we will be prepared to tweak, if we need to, some of the levers that we have at our disposal if we feel that's the best way to delivering a positive outcome with the best possible profile. But I do also want to turn our attention to everything else that's going on in the, you know, pipeline and you know, what... You know, a couple of things I'm really excited about.
What's your...
I'm really excited about zilebesiran for hypertension. I think this is an area that has seen very little innovation for the past couple of decades, and there's a huge medical need. You've got over 200 million people with hypertension, many of whom are at high cardiovascular risk. It's actually the number one preventable cause of cardiovascular morbidity and mortality. And we have a program in our hands, which, if it results in a medicine with a profile that we think it could have, you could be talking of a couple of injections a year. We're looking at both quarterly and six-monthly regimens, but allow me to dream for a moment.
Six-monthly administration of an agent which, by knocking down angiotensinogen, essentially is able to reduce, and we've shown this at the recent meeting at the AHA, systolic blood pressure by 50 millimeters of mercury and also achieve tonic control, restore nighttime dipping, all with a few injections a year, which will overcome, you know, much of the compliance issues that we see with existing hypertensives. So I think this is a medicine that could really transform the paradigm for the treatment of patients with hypertension. So I'm really excited about that. And more to come, we talked about what's coming with KARDIA-2. It's obviously very important that we're able to deliver additive, additive benefits on top of existing hypertensives in a safe and well-tolerated fashion. And then I'm also really excited about our first forays into CNS.
Huge medical needs there, as you all know, neurodegenerative diseases, not just Alzheimer's, but so many others. Having demonstrated that we can get into the CNS, we can knock down relevant targets, and I'd urge you all to look at the recent ALN-APP data that we just shared at the recent CTAD conference, where with one intrathecal administration of 75 milligrams of ALN-APP, we're able to knock down some very relevant biomarkers in the disease, without any safety issues. So we're really excited. Obviously, early stages of the journey, it's. We're going after what's a very important disease, but we know it's a tough disease. But we're really excited about being able to achieve success in the CNS, as we have done in the liver.
You've got an R&D day coming up December thirteenth?
Thank you. Absolutely. Please do join us. It's virtual, so it's very easy. You can dial in, and you can hear some of the exciting developments we have, both, you know, in the pipeline, but also earlier with respect to our platform.
So, any other key events you wanna highlight for the next-
I think that's-
... couple months?
I think we've highlighted the catalysts and
For the R&D day, what could we see there? Any surprises that you can preview?
Well, look, we always try to excite people on R&D Day, with what we're doing in our labs. So we'll be providing a full, you know, range of updates on where we are with accessing other tissues. So we don't wanna stop at CNS, our ambition's bigger than that, so we're gonna be looking at some other tissues as well, and some early programs that are beginning to move through that that we're very excited about.
Great. Okay, thanks so much for joining us today.
Okay.