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

Hey, everybody, it's Alethia Young at Cantor here. I cover large cap, small mid-cap biotech. I'm very happy to have Alnylam Pharmaceuticals. I have Dr. Yvonne Greenstreet. She's the President and COO of the company. Yvonne, maybe in the first 30 to 60 second, just give us kind of -- it's been, again, another exciting year for Alnylam. Just talk about some of the accomplishments over the past 12 months.

Yes. Alethia, thanks for having me, and it's a real pleasure to be here. Look, this has been an amazing year for us as we continue to progress against our P5x25 strategy. And we're making really good progress on all fronts. And I'm sure we'll cover off many of the achievements as we go through this conversation. But bottom line has been a terrific year for us so far.

So let's talk a little bit about the TTR program. So ONPATTRO, has been in the market for a while. Just tell us a little bit about how the TTR space has evolved since the approval and where you see opportunities for TTR and polyneuropathy as well?

Yes. That's a really great question. I mean, if we just reflect on when ONPATTRO was approved in August 2018 for the treatment of polyneuropathy of hATTR amyloidosis. And this is a real landmark for us, right? The first time a therapeutic ever approved and the first treatment approved in the U.S. for hATTR-PN. And if you think about where we started and where we are now, we're being sold in more than 30 countries, there are over 1,725 patients worldwide on commercial ONPATTRO. And at the end of Q2, looking at $114 million in global net revenue. And I think this has just been an amazing commercial performance. And we're continuing to see steady and continuous patient growth. One of the things that actually, I think, has struck me as quite remarkable is the fact that we're seeing more than 90% patient compliance to treatment. This is an IV administered medicine once every 3 weeks. And I think what this tells me is that patients are likely experiencing real benefit. But you asked a question about how has the field emerged? And I think what is happening is that we're getting increasing recognition that ATTR amyloidosis is a multisystem disease, okay. We're also seeing the introduction of new therapeutics in the market as well as investigational programs. And this is really increasing position of patients' awareness and, therefore, driving diagnosis, growing use of PYP scans, and all this is great for patients. So if we think about the market overall, it really has become a market growth story, a bit like MS or RA, and there's room for multiple players. At Alnylam, we're continuing to innovate, right? TTRsc04 are highly potent agent with an annual dosing regimen based on our IKARIA platform, continuing to deliver for patients now and in the future. And I think I'll just end with one last thing. I think it's important to remember that we're early at the beginning, right? We've only addressed a small fraction of the potential opportunity in hATTR for polyneuropathy with our 1,725 patients. And there are approximately 20,000 to 30,000 patients worldwide feeling ONPATTRO to be appropriate. So there's a lot of growth opportunity going forward, which we're very excited about.

Yes. Another thing that everybody is very excited about is APOLLO being and HELIOS being cardiomyopathy, and how that's going to grow the market opportunity. So just how are you thinking about these 2 studies and the probability of those studies like hitting what they need to hit?

No, look, I mean, we're obviously very focused on these 2 studies and excited about the opportunity for both patisiran and vutrisiran to become really important medicines for ATTR with cardiomyopathy, both hereditary and wild type. And just to remind everybody that APOLLO-Bs Phase III study with patisiran in patients with hereditary and wild-type ATTR with cardiomyopathy, we completed enrollment in May with over 300 patients. And the primary endpoint in this study is a 6-minute walk distance at 12 months. This is a validated endpoint in cardiomyopathy. And we think these data are going to be really important in helping physicians understand the activity of ONPATTRO in this spectrum. And we should get top line results from this study in mid-2022. Now HELIOS-B, the other study you mentioned, is our Phase III study of vutrisiran in patients with either hereditary or wild-type ATTR with cardiomyopathy. Remember, vutrisiran is our subcutaneously administered RNAi therapeutic for TTR and, importantly, administered once quarterly and also the potential to be administered just twice a year, which is actually quite remarkable. And from an enrollment perspective in HELIOS-B, we completed that in August with over 600 patients. And the primary endpoint in this study is mortality and recurrent CV events at 30 months. So importantly, it's a hospitalization and mortality outcome study. And the results for this study on the 13-month end point are expected in early 2024. Now Alethia, I'm sure you're going to ask me about the interim analysis. I'll just go ahead and kind of take that with this question. In the protocol for this study, we do have the option to do an interim, and that could potentially allow for an accelerated data readout and subsequent regulatory filings. But what we'd like to do is to wait until we have results from the APOLLO-B study, because we'll then be able to understand better how patients respond in this study and then make a call as to whether we will conduct the interim analysis for HELIOS-B and exactly what that would look like. But I think it's important to say that we're actually delighted to have been able to complete enrollment of HELIOS-B. And we've done this way ahead of schedule. And so now, even with a 30-month endpoint study, we're looking at an early 2024 readout of the study. If we did an interim, that might be able to accelerate that to 2023 compared to 2024 for the full study. So there's about a year in it between the potential outcome from an interim, but also from the full study.

That's interesting. So it seems like kind of we'll see what happens would be and then one can -- we might see what that might relate to what happens with HELIOS-B -- APOLLO-B study. Okay.

You got it.

So I guess one thing that's fair enough for everybody is trying to get grasp on is like confidence, and these studies are written out positive. But you have APOLLO and you have HELIOS-A, where you did see a static improvement, NT-proBNP. And I guess, maybe think about how relevant that cardiac endpoint is in making a read to APOLLO-B or HELIOS-Billion?

No, I think that's a really good question. And as you know, NT-proBNP, it's a well-known biomarker of cardiac stress. And I think what's important is that we've seen in both APOLLO and HELIOS-A, so treatment with either patisiran or vutrisiran, we saw statistically significant reductions in NT-proBNP. And I think this is really good initial evidence that these 2 therapeutics may potentially result in improvement of the cardiac manifestations of the disease. But of course, we're going to have to wait for the cardiomyopathy studies to see exactly how this plays out. But we think it's encouraging.

Okay. Well, there's going to be another one I'm trying to make a read-through on, so get ready. So you -- I think you're going to announce some additional 18-month data in Helios-A, which should have some cardiac endpoints. And just what should we be looking for in that study? And do you -- how important is the 18-month endpoint versus like the 9-month endpoint in your mind?

Yes. So just to remind everybody that earlier this year, we reported the positive 9-month results from HELIOS-A, showing that the vutrisiran led to an improvement in neurological impairment and quality of life in the majority of patients. And these results form the basis of our NDA and MAA filings with vutrisiran. And we're now looking at an FDA decision for vutrisiran in April of next year. And the 18-month results from this study will be reported later this year. And as you say, it will include the additional cardiac endpoints. We've talked about NT-proBNP, but also echocardiographic parameters, like left ventricular wall thickness and longitudinal strain as well as technetium scintigraphy. And I think these exploratory endpoints are going to help us further characterize vutrisiran's potential impact on the cardiac manifestations of the disease. I think it's important to stay tuned with these data as we present them.

Okay. So they're important and interesting as a read.

Yes.

Okay. Can you just remind us for the opportunity for patients and following neuropathy where ONPATTRO could go, if not approved for cardiomyopathy? And then just talk about maybe the opportunity if you are approved or you have positive data for cardiomyopathy?

Yes. So just to remind us all of the patient numbers here. So for hereditary ATTR amyloidosis, we think there are about 50,000 patients worldwide. And of these patients, we believe that about 25,000 to 30,000 patients present with symptoms of polyneuropathy, which means that they're eligible for treatment of ONPATTRO with our current label. But if we're able to successfully obtain label expansion for ONPATTRO, this really has a huge impact on the addressable market to include all the 50,000 patients with hereditary disease, but importantly, the estimated 200,000 to 300,000 patients with wild-type disease. This is likely an underestimate, to be honest. But even with these numbers, it represents a tenfold increase in the size of our opportunity. So very -- a very important potential catalyst for the company going forward.

Definitely. So HELIOS-B really good, it was notable how fast they enrolled, especially during COVID, mind you.

Yes.

What do you think drove that quick enrollment compared to like APOLLO-B? I mean, you think people just know more about the drug? Or how do you all think about that?

Well, you're right. I mean, enrollments in HELIOS-B went really well. And it's -- with these things, it's hard to kind of figure out exactly why. But I do think there are a couple of things. I think you just pointed out the profile of vutrisiran. It's quarterly subcutaneous dosing profile. I think that's created a lot of interest for investigators and patients. I think it's a really exciting value proposition. So I think that's one point. I think the second is, actually, we're just getting kind of just a lot of experience working in the TTR space now, with the investigators, with patients, working globally with all the sites. And I think our clinical development team have done a really good job setting up sites and helping to get patients enrolled. And I think it's one of the benefits actually of having a franchise and really building expertise in an area with first ONPATTRO and now vutri, so. So we're very pleased with where things have got to. And as you said, it's a very important study for us. So great that it's enrolled well.

Yes. It's interesting. I feel like you guys kind of planned your flag in the sand on TTR. So it probably yields dividends. They're unappreciated and appreciable at times. So that's very interesting. Another situation that kind of came out to 2021 was obviously the presence of gene editing via Intellia with in vivo data. I mean, obviously, with people focused on the 3 people at the higher dose where their cell TTR knockdown. So I guess, I just want to get your perspective on potential gene editing. Is that something that you guys are interested in? Or how do you think about that versus the products you have, which could have really long dosing intervals as well?

Yes. Look, I mean, kind of at a macro level, as you know, Alethia, it's great to have lots of options for patients. And I think it's a really exciting milestone, actually, the data that are presented by Intellia for the gene editing field. So that's all good. But I think when it comes down to kind of what we're doing, it would surprise you for me to say that we would believe in the potential of Ionis therapeutics. So ONPATTRO, Vutrisiran, and I already talked about TTRsc04. And we think that this mechanism, the silencing mechanism has the potential to be the market leader in ATTR amyloidosis. So whilst gene editing is exciting, there's still some ways to go, right? I think folks are going to need to be reassured about safety. There's permanent alteration of DNA and potential for off-target effects. I wonder how kind of Intellia is going to manage to do placebo controlled studies. We think they'll need to show superiority against an RNAi silencer in a Phase III study, at least from a value perspective, and that's going to be kind of a big study. So gene editing is going to be competing against a really strong product profile to take vutrisiran, quarterly, 6 monthly doses, potential for. And then TTRsc04, annual vaccine like dosing. So I think that's going to be a tough value proposition to beat, to be honest. And particularly when you overlay all the access and pricing considerations that will need to be addressed. And if we're talking about TTR amyloidosis, particularly wild type, which is where the larger market is, these patients are in their 60s, 70s and 80s. And when you've got alternatives that are proven and less expensive, I think those are the therapies that will win at the end of the day. But all being said, competition is a good thing. It's what keeps us hungry, keeps us focused, keeps us continuing to want to bring forward innovation for patients. So it's all good.

That's a great answer, by the way. But I'm curious about like these polyneuropathy patients, I mean this is not like happening like cold or something. I mean, these patients are quite sick. They're probably seeing doctors anyway. So like, I guess, what's your perspective? Or what have you heard from obviously selling the drug, when you think about like practically like would someone want to take something that's the one and done? Would they rather go in and kind of be under the care of a physician 4x a year or even -- I'm sure you're working on things that can make it even shorter than that potentially.

Yes. Yes. Look, I think these patients, as you say, go and see their physicians on a fairly frequent basis, I would have thought at least 2x or 3x a year. So actually, having an RNAi therapeutic like vutrisiran, which they can get when they go see their doctor and, at the same time, be evaluated by their physician, I think it's going to be really something that patients are going to want, to be honest with you. So I think there may be some disease areas where gene editing is going to play a role, but when we think about TTR amyloidosis, I really do believe that it's going through the RNAi silencers that we'll win out here.

Interesting. So some people worry about like when vutrisiran enters the market, that's going to take share from ONPATTRO. I guess, how do you think about kind of delineating that or clarifying for people? Maybe just that there are tons of patients that are still not treated. But just curious.

Yes. So kind of where are we with vutrisiran. The NDA is under review with the FDA for hATTR polyneuropathy based on the 9-month results in PDSA that we just discussed a few moments ago. And we've also just submitted our MAA for vutri approval in Europe. So that's kind of where things are. And assuming successful approval, we expect to launch in the second quarter of next year. And what we're going to do is use the infrastructure that we already built from ONPATTRO to support commercialization of vutrisiran. So we actually think that, again, going back to this franchise model, starting with ONPATTRO and then kind of bringing vutri to the market is actually going to be a really positive commercial agenda for us. But I think, as you say, some folks kind of think about how many patients are going to stay on ONPATTRO, how many you're going to switch? How are you going to think about both drugs on the market. And we believe that both ONPATTRO and vutrisiran actually are going to both have a place in the market. A lot of patients already being treated with ONPATTRO, some for the 3 years that we've been approved, and they've had a really good experience. So I think some patients with ONPATTRO will not want to switch. But I think the profile of vutrisiran, the efficacy, safety and the dosing and the treatment burden, which is much lower with vutrisiran, I think will encourage a lot of new patients who are initiating therapy to go on to vutri.

Well, there's a lot more products than ONPATTROs and vutri. So let's move on. I want to talk a little bit about how the launches are going of GIVLAARI and OXLUMO. And just remind us of the market potential for those indications as well.

Sure. So just to remind everybody, so GIVLAARI is our RNAi therapeutic approved for the treatment of acute hepatic porphyria. And this is a devastating ultra-orphan disease, and it's got tremendous kind of disease burden. They're all just going well so far. As of the end of our second quarter, June 30, there were 270 patients worldwide on commercial therapy, and we achieved $31 million in global net product revenues. And that's a 24% quarter-on-quarter growth compared to Q1. So it's been a very successful launch, so fine. We're pleased to see that the prescriber base continues to expand, new prescribers coming onboard. What's interesting is they're coming onboard, particularly from community centers and not just porphyria centers of excellence, which we think is a very encouraging sign. Because this is a disease where patient finding is going to be critical. The symptoms of AHP overlap with a ton of other diseases like IBS, irritable bowel syndrome. So we're going to have to do a lot around disease awareness and medical education. You asked a little bit about the size of the market, and we're still learning as we go, still relatively early in this launch. And we're still of the mind that there are about 3,000 AHP patients with active disease who are diagnosed in the U.S. and Europe. And if you look at that, we think GIVLAARI could well represent a $500 million peak market opportunity for us. So that's GIVLAARI, going great. We're very pleased. Turning now to OXLUMO, and that's our RNAi therapeutic. And that was only approved last year, actually, for the treatment of primary hyperoxaluria type 1. And this is another ultra-rare disease. And just -- what's exciting to me actually is that it's our first medicine approved for patients of all ages, including very young children. So that's another first for us at Alnylam. And look, the launch is going well. We're seeing continued demand to the drug's second full quarter of launch. Here, we achieved $16 million of global net product revenues, and we got approximately 100 patients on commercial OXLUMO treatment as of the end of the second quarter. One aspect here is the kind of geographic expansion of OXLUMO being so early in its launch, so that's moving along nicely. We got a recent approval in Brazil. Launch is underway in Germany and got ATU supply in France. And in this disease, we think they're about 3,000 potentially symptomatic patients in the U.S. and Europe. And so with that kind of number, we continue to think that OXLUMO is probably kind of another sort of $500 million peak sales market type of opportunity.

Why do you think kind of the launch is going too fast for OXLUMO? And I guess you cited $500 million, but is there a potential -- potentially a little bigger?

Yes. I mean, I think -- I mean, let's start with kind of why it's going well. I think the EAP conversions, particularly in Europe, have contributed to this initial kind of strength in the launch. I think the other point, and I kind of touched on it a little bit is that is the opportunity for OXLUMO across kind of all age groups, and we're seeing kind of broad use of OXLUMO, and not just across all age groups, but actually all severity types, all eGFR categories. I think our work on the access front has helped too. We've got access to more than 80% of U.S. lives, which is not bad for a recent launch. I think really probably the critical key point here is that OXLUMO is filling up a significant unmet need for patients where there are no approved therapeutic options. I mean, you asked about how we're thinking about the size of the opportunity. We're not updating our estimates at this point in time. Although, as I said, we are pretty encouraged by our progress with the launch so far.

Okay. Fine. I guess, moving on to Dicerna, and that's a competitive agent in the space, I mean, they had data that look like it would work in PH1 patients. Do you -- how you think about them as a potential competitor?

Yes. Look, I don't think there's really anything in the Nedosiran Phase III data that suggests that it has a differentiated profile compared to OXLUMO in PH1. And we're very confident about OXLUMO and its positioning. I mean, really our medicine here is supported by positive data from the most comprehensive Phase III program that's ever been conducted in the PH1 patient population. So we have got ILLUMINATE-A in children who are 6 years of age and all those, as well as adults, we've got a ILLUMINATE-B in pediatric patients up to 5 years of age. And then ILLUMINATE-C in patients with advanced PH1. So it really is a very comprehensive package. And maybe just the final thing to note is that I think we expect Nedosiran to be launched. But if that happens, it will be coming to market about 2 years behind OXLUMO. And so we've got kind of head start here. So Dicerna has got a lot of ground to make up, and I don't think they've got quite as comprehensive a data set as we have with OXLUMO. So we're feeling pretty good about our prospects here.

So you guys have been doing well with like rare diseases and all those indications, getting them approved. And now it seems like you're kind of moving into bigger frontiers. So I guess, just kind of wanted to talk a little bit about how you're thinking about moving into those markets and targeting things outside the liver? And like, why do you feel like at this juncture now it's the time to kind of go for it.

Yes. Yes. Well, look, I think there's so much opportunity, okay, to address the residual unmet needs in a lot of common diseases and hypertension, NASH, gout, diabetes. I think the core of our confidence really lies in the pharmacological properties of RNAi therapeutics. I mean the fact that the durability allows infrequent dosing, which maximizes adherence. The cloud pharmacology really creates the potential to improve efficacy and outcomes. And now we've got like a really well-established safety profile with use of RNAi therapeutics in tens of thousands of patients in trials. And this platform, together with our strategy of really going after genetically validated targets, it's given us a high probability of success so far. I'm sure you've seen the numbers that we've quoted, where we've demonstrated a greater than 60% success rate transitioning from Phase I into the clinic to positive Phase III studies. And that's remarkable. That's a tenfold better success rate than the industry average. I think the other point is just watching how things have gone with Leqvio in hypercholesterolemia. That's really kind of emboldened us to think about applying our platform for much more prevalent diseases. You also talked about extrahepatic opportunities. I'm really excited about this as well. Of course, we're accessing CNS and ocular tissues through our collaboration with Regeneron, the first CNS program there is an ALN-APP. And there, we're targeting amyloid precursor protein for the potential treatment of early onset, Alzheimer's disease with cerebral amyloid angiopathy. And just in terms of the time lines there, we are planning to file CTA by the end of this year. And then that should set us up for initial POC data sometime next year. And I think the remarkable opportunity here is to think about not just success in this one indication, but really this unlocking the CNS opportunity for us across a bunch of different kind of other diseases. So lots, lots to go after from an extrahepatic perspective. The other thing kind of maybe to add in here is just touch on the partnership with PeptiDream that we recently announced, which is going to help us explore delivery of RNAi therapeutics. To additional tissues. So having sold the delivery of RNAi therapeutics, the liver, and having made progress on delivery to the CNS and the eye and actually the lung, we think that there are a bunch of other tissues that we can look to go after through this collaboration, where we're hoping to identify robust ligand receptor pairs for extrahepatic tissue delivery, similar to the kind of GalNAc ASGPR pair that we have pioneered for liver delivery. So lots to do in addressing large diseases, but also really beginning to open up a new frontier for us in addressing diseases through delivery to other tissue types.

Definitely. So maybe talk about zilebesiran, which obviously is kind of the largest indication that you have gone around in hypertension. But talk about some of the early data seen there and how you think about that opportunity.

Yes. So look, I mean, you probably heard us say this before, but zilebesiran, which is our RNAi therapeutic that we're developing for the treatment of hypertension really gives us the opportunity to completely change how people think about treating this disease. This is a disease that hasn't seen any innovation forever in a day. And I think the approach that we have in terms of being able to achieve tonic control of blood pressure as well as addressing the issue of compliance, given the likely very infrequent dosing, quarterly or biannual, should be able to deliver benefits on both product control and adherence. So just to let you know where the program is, we've just started our Phase II study KARDIA-1 in monotherapy and will shortly be starting KARDIA-2, looking at zilebesiran as an add-on therapy in patients taking other agents, RAS inhibitors, calcium channel blockers, et cetera. And data's around the quarter, really, we should have some data from the Phase II program by the end of next year. And from an approval perspective, the regulatory endpoints that are pretty straightforward, we need to demonstrate blood pressure lowering. And we've already seen this. We've already seen that zilebesiran can achieve this in our Phase I study. So this is a big opportunity for patients in terms of transforming the treatment for them to a more kind of vaccine like strategy. And also, it's going to be a significant value driver for our Alnylam as a business.

Awesome. Well, we're at time, Yvonne, and congrats on the progress over the year.

Thank you so much. It's been great chatting with you today, and I hope you enjoy the rest of the conference.

Thank you.