Thank you. Good afternoon, everyone. Welcome back to another session here at Oppenheimer's 33rd annual healthcare conference. I'm Leland Gershell, one of the analysts on the biotech equity research team here at Oppenheimer, and we're very delighted to have with us Alnylam Pharmaceuticals. We'll be having a fireside chat with Akshay Vaishnaw, who's the President of Alnylam. We do cover Alnylam's stock with an outperform rating. We will have about half an hour to have a good discussion. If you do have any questions, feel free to send those over. I will see if I can work those in, but I think we're pretty good in terms of our roadmap for this. Akshay, thank you very much and welcome to the chat.
Hey, Leland. Thanks so much for inviting me in today. It's my pleasure.
Wonderful. I think we'll, you know, maybe touch a bit on kind of some of the current dynamics in the market with AMVUTTRA. That's a launch that's been proceeding very well. It's been really encouraging to see that product bring more people into treatment. Maybe wondering if you could discuss kind of how the AMVUTTRA ONPATTRO dynamic has been shaping up so far as we've been getting into the first few months of 2023.
Yeah. Yeah. I mean, just to do some scene setting for folks, you know, AMVUTRA got approved last year in hATTR with peripheral neuropathy. Delighted with this profile that we have with the drug, you know, once quarterly SubQ. The results look very, very similar to the original ONPATTRO drug in the APOLLO study. You know, the launch has gone exceptionally well. The franchise revenues for TTL last year grew to $651 million, which is a 37% growth year-on-year, which is super. Almost 3,000 patients on drug between ONPATTRO and AMVUTRA. If you look at the scripts, it looks like a 50/50, where at the end of the year about 53% were of the start forms were AMVUTRA new prescriptions, and 47% were ONPATTRO patients switching.
The new patient number is really interesting and encouraging because when we look at the U.S. prescriber base last year, there seems to have been a 30% growth in terms of U.S. prescribers attracted largely by AMVUTTRA. You know, that is a really terrific start, and we're hoping to obviously build on those numbers this year, although it's early in Q1, so not much to say yet, but exciting times.
Great. You know, let's talk a bit about ONPATTRO's near-term prospects for its label expansion to TTR cardiomyopathy, for which you do have an October 8th PDUFA. You know, although the APOLLO-B trial met its primary six-minute walk endpoint, there were, you know, there are a few lingering concerns among some investors related to that endpoint itself, as well as perhaps to factors such as background use of tafamidis, which I believe was around 30%. Might you be able to briefly speak to some of those concerns as we head into this FDA decision?
Absolutely. Look, we read the study out last year. The top-line data were, we think, very exciting and very supportive. Lots of internal consistency in the study with the primary endpoint being around six-minute walk distance. I think one of the concerns we've already batted away, some people said we might get a refusal to file. Well, we're delighted the FDA has accepted the application for review. You know, the data themselves, if we look at the primary endpoint of six-minute walk distance, the significant, statistically significant difference between patisiran and placebo was notable. In fact, the patisiran arm showed an almost flattening in terms of decline in six-minute walk distance. In other words, patients maintained, by and large, their six-minute walk distance from baseline across a 12-month period.
There was a slight decline of about 8 meters, but this population at this age of this type declines by 5 meters per year anyway. In other words, the difference between placebo and ONPATTRO was so significant statistically, but also restoring, we think, patients on patisiran to something like the kind of decline they would have experienced through age anyway. We really couldn't have done much better than that in this particular study. We feel we regard it as a rather notable result. you know, that primary endpoint was then supported by a lot of other endpoints in the study, like the KCCQ, which was the first secondary quality of life. That too was statistically significant. A whole host of, you know, biomarkers like BNP, and Echocardiogram and Technetium scans, all of them favoring patisiran.
Finally, you know, mortality. 10 patients died, I believe, in the placebo arm and 4 in the patisiran arm. You look at that kind of internal consistency and the impact on functionality of a six-minute walk distance, quality of life, pretty exciting package. We're looking forward to further talking about our data. There's gonna be an advisory committee, which everyone knows. We're ready to engage with the FDA at that time.
Great. With obviously that outcome, you know, to come up obviously sometime before the October FDA action date. Any updates there on when we may, you know, see that meeting be held?
Yeah. I mean, you know, it's hard to predict. They schedule it. The PDUFA day is October eighth. Typically these outcomes occur about 60 days or so prior to that. One can anticipate late July, early August, you know, some kind of timeframe like that if things go to form. We just have to wait for FDA to give us more on the scheduling. Yeah.
Great. As we look forward to, you know, hopefully ONPATTRO coming in to serve, this part of the population. You know, with oral tafamidis-having demonstrated benefit to outcomes, then it's already obviously quite familiar to cardiologists who've been prescribing it. Wonder if you can relate your view as to how you see, ONPATTRO segmenting, you know, into the TTR cardiomyopathy population.
Yeah. You know, the APOLLO-B study was done both in wild type and hereditary TTR patients, so we've covered the full gamut with cardiomyopathy there. The study was positive, so we hope that, you know, all those patients are available to access drug. You know, in the specifics of how Tafamidis has done, and as you noted, they've got outcome data. The drug reduces mortality and hospitalizations, but, you know, there's still plenty of unmet need, unfortunately. It's not like people stop dying or stop going to hospital because of Tafamidis. So, you know, clearly more drugs are needed in the space. Patients who are progressing on Tafamidis obviously will be of concern to physicians. People who can't access Tafamidis for one more reasons, whether it's the copay or other reasons.
This is especially when we consider the wild type cardiomyopathy a large disease, with a growing number of patients, relatively easy to diagnose via a Technetium scan. As we look at the kinds of segments I've mentioned, there are a lot of patients we think we can help, both with wild type and hereditary TTR cardiomyopathy.
To that point, again, with the broadening, not just to the indication, but to the type of, you know, background, whether hereditary or wild type. As you mentioned, do you see kind of the mixed phenotype patient as being the one who offers, you know, kind of the greatest prospects for at least, you know, ONPATTRO uptake in the, in the near term? Have you done any kind of market studies or market research to help maybe understand that?
Yeah. We, you know, we haven't shared, you know, a lot of that kind of market research data yet, but clearly, you know, with ONPATTRO being so impactful in the neuropathy, you know, from our estimates, Not our estimates, but what people tell us, they regard it as, you know, one of the most potent drugs for the neuropathy by far. I mean, if you look at the Phase III data for APOLLO, it's quite clear that this is a very, very important drug for patients with hereditary TTR-related disease and the neuropathy.
If you combine that now with the cardiomyopathy data, I agree with you that the mixed patient population, when we talk about the hereditary space, is very important and one that, you know, all the organs should benefit, we think, with what is a drug that's been on the market for, you know, 4+ years now and with a very nice safety profile which was further validated in the APOLLO-B study in the cardiomyopathy population. That's definitely a segment that's of import. You know, provided ONPATTRO is approved, it would be the drug with the broadest label in some senses in the U.S. because tafamidis is not approved, you know, for hereditary neuropathy. Let's see.
I think there's a lot of opportunity to help patients, both in terms of the different types of patients, some of the segments we've discussed, as well as quantitatively, because you just look at the size of the wild type opportunity.
Right. Vutrisiran is, you know, making its way into HELIOS-B trial. That's also in TTR cardio. That's gonna read out, I believe you guys expect, you know, early next year, so maybe in about a year's time. That does have outcomes data built into the primary analysis. Obviously that's not gonna come too long after what you could have as ONPATTRO with its label expansion. When might you see a label expansion for vutrisiran then come, assuming that the HELIOS-B is positive?
Those data, as you said, are expected early next year. We're super excited about that study. I mean, the APOLLO-B data are encouraging, but let's recall HELIOS-B is 2x as large and 3x as long. The power to really demonstrate impact on the full range of endpoints is significant here. You know, we're looking forward to that readout. If we get the data early next year, as I said, you know, it could lead to approval late 2024 or early 2025. We'll guide closer to the time once we've filed the NDA and so forth. You know, that'd be pretty exciting.
A question that I want to ask just came up from the last quarter's update with respect to GIVLAARI. You know, you've been reporting kind of a consistently growing number of patients on GIVLAARI. The sales have been a bit flattish, you know, over the past few quarters. Just, you know, would this suggest that we should see kind of a catch up, but like a robust, you know, maybe inflection for GIVLAARI sales as revenue may kind of true up to the patients who are actually being treated?
I mean, you know, we've got about 500, over 500 patients on drug at the end of 2022. The U.S. growth in particular was, you know, revenue growth looked flattish. The demand growth was 3%, driven by an increase in patients on therapy, but offset by modest changes in the inventory stocking. Rest of the world, you know, has done better with Givlaari in terms of growth, 10%. Oops, let me turn this off. Sorry. Overall, you know, the picture is this is a really important, powerful drug that's helping a significant number of patients. We expect steady and continuous growth, you know, for Givlaari in this year and in the coming years. Obviously, the TTR franchise is dominant, this is an important part of the portfolio.
You know, it'll be a meaningful contribution to the top line this year, which we've said will be between $1.2 billion and $1.28 billion. That's the outlook currently on Givlaari.
Let's move over to, you know, some of the pipeline opportunities, you know, in the later stages of your portfolio and, you know, moving certainly much more toward the common condition direction. You know, we've seen very supportive data out of zilebesiran to date. Could you just review for us the designs of the ongoing Phase II KARDIA studies, which you have 2 that are ongoing, and your, you know, what your goals are here. I think we'll be seeing data from those kind of, you know, middle to then, you know, late this year.
That's right. Yeah. You know, one of the things about zilebesiran that is so interesting and exciting is we're now in a space hypertension for which, you know, there are literally dozens of drugs. But despite that, we haven't had any true innovation for patients with hypertension in a very long time. You know, another thing that we should all be familiar with and is very important in terms of the unmet need is 50% or more of patients with hypertension just don't take their drugs after 1 year, you know. This is a terrible situation because it's not like antihypertensive oral meds don't help. They do help, but you've got to take the drug. If patients aren't taking the drug, they're not getting the benefit.
With zilebesiran, our product concept is to create something that will help both qualitatively and quantitatively. In terms of qualitative, can we give this injection once every 3 or 6 months? It can be a very infrequent med. People can forget their disease in between take tablets every day. Can we have a significant impact on blood pressure? The Phase I results were, we think, really quite impressive. Over 90% reduction in angiotensin, that's the target associated with more than 20 millimeters mercury drop in systolic blood pressure. You know, a single injection can give those kinds of numbers beyond 3 months, out to 6 months, is really mind-boggling and exciting. The Phase II studies have been underway for a little while now.
There are 2 studies, as you said, KARDIA-1, which is the kind of dose ranging and regimen finding study, different doses and regimens being evaluated against placebo. That will help us figure out the dose regimen for Phase III. 375 patients in that study fully enrolled. We expect data in mid 2023, that's coming up fast on us now. You know, in addition to that, KARDIA-2, which looks at zilebesiran as an add-on therapy in patients with hypertension not adequately controlled by standard of care. We're looking at the 3 major classes of agents. You know, you've got your RAS axis inhibitors, so ACEs and ARBs, calcium antagonists like amlodipine, and then you've got diuretics.
How does zilebesiran behave on top of those drugs in patients with hypertension that's not well controlled? That study is larger, about 630 patients, and we expect enrollment to complete early 2023 and top line at year-end or around there. Between the two, we'll get a very complete picture of the safety and efficacy in large numbers of patients, both the monotherapy, but also in combination with other drugs, most importantly, RAS axis inhibitors. That rather complete picture really gives us a great springboard to go into Phase III.
Do you think, obviously you're testing this with several of the commonly used antihypertensives, but do you think given the mechanism of this drug with respect to the RAS and angiotensin system that the efficacy, let's say, in patients who are on ARBs or are ARB-resistant, would that be most interesting to look at? What would you expect to see maybe out of that kind of subsegment?
If I got your question right, Leland, let me just reiterate. Are you saying that do we expect to see efficacy in combination with ACEs and ARBs? Is that?
Yeah. I'm just wondering since that's kind of a particular case with respect to that pathway, you know, would you expect it to, you know... Could zilebesiran have a particularly good opportunity in patients who are resistant to the orals, but maybe if you hit them with, you know, a much heavier like a silencing type of?
Yeah.
that could actually restore.
Yeah.
the ability to show an improvement.
No, look, that's going to be one of the key questions in KARDIA-2, the Phase II study. First of all, we know that patients who even if they're taking their drugs, you know, patients that take their ACE or ARB, and they're kind of cornerstones of treatment, don't always achieve, you know, the level of blood pressure reduction they need. We're gonna have to evaluate whether, you know, additional zilebesiran can help there. Both drugs would be in the same axis, the RAS axis, but the current oral medications, whether it's, ACE inhibitors or ARBs, they're acting down here, at the level of the, of the kidney, essentially. What we're doing is turning the tap off at the top, right? The angiotensin that feeds the whole cascade.
There's plenty of reason to believe that the two might, in concert, give a better impact on blood pressure reduction. Specifically, if you go back to our R&D Day presentation, from December, we go a little bit into the mechanistic aspects here, where, you know, when you give conventional ACEs and ARBs, you often get a state of renin and Angiotensin I and Angiotensin II, depending on which drug you take. That's not desirable. That's creating a countervailing effect to your attempts to reduce blood pressure. We showed that when you give zilebesiran, that doesn't happen. You know, one would imagine that by starving the system of the substrate, you prevent that counterregulation.
It'll be very interesting to see, you know, those results and whether they add up to meaningful, additive effects on blood pressure in KARDIA-2, Phase II study in that specific arm, you know, where we combine with the, with the oral RAS axis inhibitors. Let's see. You know, the data are hotly awaited, but plenty of reasons to believe mechanistically that we should see an impact.
Thinking kind of downstream, you know, given that hypertension is a market that even if it's not well-served, it certainly has a number of therapies available, lots of generics and so forth. Even though one could perhaps use this as a product which would address a number of issues that keep people from getting benefit. In other words, you know, you can't forget to take... You know, it's like if you're taking a daily pill versus, your RNAi, it's a very different type of picture. So you have kind of tonic control. I guess I'm wondering in the marketplace, given pricing pressures and payer reluctance, you know, would you expect to see zilebesiran kind of being first used in those types of patients who really clinically aren't able to improve by any other means?
Do you think there will be allowance for patients who don't necessarily have to have failed or have become refractory to, you know, all of these drugs to get access to zilebesiran?
Yeah. You know, there are many areas of unmet need in hypertension, zilebesiran, right, where a drug like zilebesiran could help. Ultimately, we're only gonna know, you know, once all is said and done, we have the Phase III data. You know, some segments to think about are patients that are on existing two, three meds and not getting good blood pressure control. They clearly need help. There's an unmet need argument, there's a medical argument, there's a payer argument to help those individuals and one where, you know, a new powerful therapeutic like zilebesiran could be accommodated. The other area that's of great interest to cardio, obviously, as we've been wandering around and discussing the future of zilebesiran with them.
They're all intensely interested also in how we can help patients who are on one or more med and have already demonstrate cardiovascular issues, in terms of morbidity, you know, angina, heart attack, stroke, those kinds of events. I mean, those patients, sadly, you know, they're a ticking time bomb, right? That unless we can help their blood pressure control further and control their other cardiovascular risk factors, that they're gonna have more events. Obviously, ultimately, they could be terminal events. These kinds of segments are where the unmet need medical, feedback says we want drugs and, you know, payers, would be motivated, we think, because these patients are doing badly, despite, as you say, the availability of rather cheap oral drugs.
Let's get on with the Phase III after we get the data later this year, and we'll share more about the exact positioning. There's a lot of opportunity here and a lot of ability to do good. We're talking about. Just the kinds of segments I'm talking about are tens of millions of individuals. You know, even if we can make a small dent in that's a significant contribution by our measure.
Yeah. We look forward to seeing the cardio. KARDIA-1 will be mid-year. It's not too far away.
Yeah.
Very interesting earlier candidates coming forward, ALN-APP, part of go through Regeneron, that's in development for neurodegenerative conditions, Alzheimer's, and works upstream of Amyloid beta in the CNS. You know, obviously, this is an area where we've seen some antibody drugs which themselves target that protein gain approvals. Wanted to know, actually, if you could maybe highlight some of the differences here, you know, with ALN-APP versus those and any thoughts you may have on your strategy versus those other drugs.
Yeah. you know, so the APP data, around the corner, we've said, you know, by mid-year 2023, the Phase I data, there'll be early data, single dose. The good news is that, you know, on top of safety, which is very important, this is our first CNS drug. The, the other really sort of insightful piece will come from the biomarker data. With amyloid precursor proteins, the target, host of biomarkers that will be available to us, including APP alpha, APP beta, A beta itself, to show that we've engaged the target and that in fact, RNAi can be harnessed in the nervous system and knock down a target very specifically. There's the future of the APP program, but also the future of our whole CNS pipeline.
You know, we will be able to say something about that once we see the data. You know, I think the advent of antibodies for Alzheimer's is obviously an exciting step and the recent events at Biogen. We hope to add to that and build on that because in every disease we've been in, going very proximally and getting right to the start of things has shown to have the greatest impact. By, you know, contrasting antibodies which are kinda the tail end of what's happened, where the A beta fragment has been proteolytically processed, comes out, deposit, creates a plaque, and then after all of that has happened, you're trying to clean it up with the antibody.
That process of ligating the target with an antibody, whether it's Fc-mediated clearance or no one really knows what's happening, can lead to inflammatory events, as we know, called ARIA. To what extent that then is a countervailing factor. It doesn't help you do what you're trying to do in terms of improving cognitive function. I don't know if it's well understood. What we want to do is cleanly turn off the tap in a substantial way on the production of Aβ. What we know from a lot of work now is that APP processing within the neuron results in a host of neuropathic, proteolytic, fragments. Not just Aβ, but others as well.
We have shown data which, you know, people can go to our website or look at the R&D data from December, showing the impact of these other APP-related fragments on neural function and neuronal function and survival. So by going proximally, we're able to impact all the intraneuronal aspects of APP processing that harm these patients and also reduce the extracellular deposition of A beta. This would be we think a step up on what the antibodies are doing. Doing it more cleanly, we hope, without inflammation. In the long run, I think, could be clinically much more impactful than just sort of mopping up the floor after, you know, you've got a flood going on, and all the data's deposited. We'll see. I think the first step is to get these Phase I data out there.
We look forward to doing that, yeah, by mid-June.
Could be some very important, clinical proof of concept for sure. At the same time, you know, the drug is given intrathecally, so you know, wondering, you know, should we see, you know, great things come out of those initial reveals? You know, would there be a technical strategy by which, you know, you could move to what would be a CNS targeted but systemically delivered, RNAi therapy?
Yeah. I mean, there are two points there, Leland. You know, one is that the intrathecal administration is not as much of a barrier as we might think for the following reasons. You know, provided it's done in expert hands, and most neurologists can give intrathecal, you know, drugs. Although it sounds exotic, it's quite a manageable procedure in most settings. Secondly, provided is not frequent. Clearly, you know, giving an intrathecal administration, you know, I'd concede is not like giving a SubQ or an IV, which you can give relatively frequently, you know, over days or weeks, kind of frequency. This would have to be less frequent.
The good news is that our animal data, including the monkey data, suggests that these could be once every six or 12 months intrathecal administrations. That really makes the value proposition much more attractive and doable, particularly in settings like these neurodegenerative disorders where the unmet need is so high, you know. As we were just discussing Alzheimer's, that despite the advent of antibody, we know we need more agents in this disease. Not to mention all the other disorders like Parkinson's and Huntington's and others, where clearly more agents are required. Okay. I think we feel rather optimistic.
I think another aspect of the Phase I data that we bring out is if we see knockdown, then we'll also see as the durability of the knockdown and so the viability of what I'm talking about in terms of infrequent administration intrathecally. Separately, again, as we shared December last year, we have a lot of efforts going on on delivery now, and one of them is, in fact, to explore systemic administration for CNS delivery. As I think we all know, there's been a holy grail in the industry, right? Not just for siRNAs, but for all sorts of modalities and how we improve CNS delivery. It's not a easy nut to crack.
You know, we've solved quite a few delivery problems before now, and so we feel like we've got to give that a go because clearly if we can unleash that, then that's just wonderful for patients and physicians and really opens up lots of possibilities. You know, it's in the research shop right now. We're in animals testing various approaches, but we'll keep you updated as we get data.
In the last few minutes, just to touch on, one pipeline program of yours that's caught my attention is ALN-KHK.
Mm-hmm.
which is in early development for Type 2 diabetes, and Alnylam has global rights. Maybe just spend a moment or two telling us a bit about the target for this candidate.
Yeah. Ketohexokinase is a target expressed in the liver and the gut, for the metabolism of fructose. One of the things that, you know, people will be familiar with is if you read the label on the side of pretty much anything we eat or drink now, you go to the supermarket, you'll see fructose in there. Fructose, increasingly, I think people believe is the ultimate evil in terms of, you know, allowing massive empty calories to be accumulated in our bodies. Those calories all go via the gut to the liver and, they're turned via the kinase pathway into fat, basically. So you accumulate fat in the liver and predisposes to fatty liver. You also create a liver that is now profoundly pro-diabetic in its metabolic profile.
These individuals are very predisposed to Type 2 diabetes. This phenotype of, you know, hyperglycemia or diabetes and somewhat fatty liver is extremely common and largely driven by fructose in our diets, not just in the U.S. but around the world. You know, here's an agent that by stopping the pathway right at the top in the hepatocyte, prevents the entry and metabolism of fructose from the diet. We know from hereditary fructose intolerance, which is a inherited disorder which is relatively benign, where people are missing this enzyme ketohexokinase, that they just pee the fructose out. You know, we think that this is a way to prevent the excess exposure of the liver to this highly, effectively toxic substance, fructose, and just getting rid of it in the urine.
In doing so, helping with the metabolic aspects in the liver being an anti-diabetic compound and also reducing fat accumulation in the liver. Certainly, we have a, you know, wealth of animal data suggesting that that would be the case. Phase I study is underway. The first part, which we'll report out later this year, is just to kind of show the target engagement. We will go on after that to do work in the diabetic population itself and, you know, explore how much of an anti-diabetic effect we can have once we have the dose and regimen figured out.
Terrific. Well, a number of other candidates that are interesting at Alnylam. I wish we had more time, but I think we're right up at the end of the session here. Actually, thanks so much for the discussion, and thanks everyone for Zooming in, and wish everyone enjoys the rest of the Oppenheimer conference. Thank you.
Thanks. Thanks for the conversation. Cheers.
Take care. Bye-bye.
Bye-bye.