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

Awesome. Great. Thanks very much everybody, and thanks for everyone who's been tuning in all day. Happy to be here with the CEO of Alnylam, John Maraganore, from your apartment in Boston. Is that what we're looking at right now?

We're in Boston in my apartment. That's right. You got it.

All right. Awesome. Well, thanks so much for joining, John. I really appreciate it as always. Everyone knows Alnylam well, but do you want to just kind of set the stage and maybe just quickly recap your recent quarter, program updates and then we can get into specifics?

Yes, let's do that. Let's do that. I'll give you a short, a quick elevator speech. Well, first of all, Paul, thanks for having me. It's great to see you. Look, Alnylam is in a very exciting place as a company. We've brought 2 products to the market. We're making a big difference in patients' lives. I mean these are very transformative medicines, one is for hereditary ATTR amyloidosis and patients with polyneuropathy. The other is for acute hepatic porphyria, as you know. We're selling these products in about 20 countries around the world. We had Q3 revenues for ONPATTRO of $82.5 million and for GIVLAARI of $16.7 million. Those were results that were certainly above our internal expectations and I think also the external expectations as well. So we're good about that. Our confidence in the fourth quarter allowed us to raise our range for our year-end performance for ONPATTRO, where we do give guidance currently. So we've increased our midpoint by 4%. So we're happy about that, and we do have confidence going into the fourth quarter. It's -- the other thing that's exciting, Paul, is that we're just now under $100 million of quarterly product revenues as a business, just got under it -- just under this year, this quarter, in Q3. So likely in Q4, we'll start being in that triple-digit quarterly numbers for our products, which is really terrific. We're now at the cusp of having 2 additional products that come to market. That includes OXLUMO, which is the brand name for lumasiran. That's the primary hyperoxaluria 1. We have a December 3 PDUFA date. We've got a positive CHMP opinion from the EMA. We also have Leqvio, or Leqvio rather, which is the inclisiran product that has a positive CHMP opinion from the EMA has a December 23 PDUFA date. So we should exit the year with 4 products on the market generating 4 sources of product revenues for the business, which is obviously very exciting. And then if you turn the corner into early '21, the big news there, and I know we'll talk about it, is the top line for HELIOS-A, which is our vutrisiran Phase III trial, which we're very excited about. On the earlier to mid-stage pipeline side, a dozen programs in clinical development, ranging from additional rare disease products to some large market opportunities such as hypertension and then a pipeline that continues to deliver 2 to 3 new INDs, 2 to 4 new INDs per year based on our organic product entrant. So we're in a great place and excited about the progress we've made. We obviously have a long way to go, but we're excited about all the progress and we know where we're heading, which is a very good place.

Awesome. Yes. It's been great to say. So let me ask you maybe a question about vutrisiran that I think also will allow you to speak to the things you're seeing with ONPATTRO. And that's really if this medicine succeeds and it can be given once quarterly or even once or even twice per year, how many more patients do you think immediately become candidates from one of your TTR medicines even with the same label? Do you think that, that would materially inflect how much use there is in the mixed phenotype population? And the reason why I ask is, I think Barry had started to kind of say that you hit a point in the launch where a lot of the new use was driven by new diagnoses or new recognition of polyneuropathy. So I'd be kind of curious if a more convenient product can inflect that or if it's still in that kind of linear patient atä time until you actually get a true label expansion?

Yes. Well, okay, let's just take a step back in terms of the vutrisiran product just for everybody in the call. Vutrisiran our subcu-TTR drug. It is a very, very potent molecule, most potent molecule we've ever developed within the company and based on human data. It's currently given as 25-milligram quarterly subcu injection. But we've just recently shown data based on clinical pharmacology modeling that we can achieve a biannual dosing regimen with a Q6 monthly approach. And with a 50-milligram dose. And I think we're going to talk about that in just a minute, so I'll wait to get to that. So quarterly subcu, Q6 monthly subcu as a possibility. The HELIOS-A study is currently the study that we're doing to get vutri to the market, specifically in the hereditary ATTR polyneuropathy segment, that will include the mixed population as well, but it's based on the primary endpoint of the study, which is a neuropathy impairment score measured at 9 months. There's also an 18-month assessment that we do. The 9 month is the primary, but there's also an 18-month assessment that we do in that clinical study. Study is fully enrolled. We expect to have data in the early part of 2021. So we're just really at the cusp of looking at results from that study. Now to answer your question about how does it change the market dynamics. It certainly will, I think, help in addressing some greater share of the market. I think, obviously, we are the market leader right now in the markets that we can test for hereditary ATTR polyneuropathy. Without a doubt, we're the drug of choice. And I think the physician community has recognized the efficacy and safety profile of ONPATTRO. But vutri, once it gets to market, will help certainly provide yet further differentiation compared to competitor products that are out there. It will certainly, in our view, grow the market share that we have already from the current leadership position to a more enhanced position overall. So I do think relative to ONPATTRO, I think that it can do yet -- further yet more in even the polyneuropathy and mixed population that we're serving right now. But Barry's comments were right. I mean, we are right now, in some of the markets that we're in, very much in a patient-finding mode to grow the market. The good news is disease awareness is getting stronger in these markets. We're also seeing some interesting dynamics in these markets around combination use with TTR stabilizer drugs. That's more of a U.S. phenomenon. In the rest of world, we're seeing a lot of switching take place from stabilizer drugs onto ONPATTRO. We expect that to continue with vutrisiran as well. I think in general, our sense is that the subcu option, especially when we get to biannual is going to help and is going to grow further above and beyond where we are with ONPATTRO at a faster rate and certainly will help with market share.

Yes. Yes. Yes, that's great. So what -- so for this upcoming readout, it would seem pretty straightforward, right? You can use the APOLLO-A placebo arm, in this scale, very well characterized. Beyond that, what else is a win here and what else we might -- and I think specifically, I'd be curious, what data, if anything, any, what we see in the top line readout from this biannual regimen?

Yes. Well, there won't be any biannual dosing regimen data in the HELIOS-A data set, right, because we haven't integrated that into the study. We'll come back to that in terms of how we can get that approved, and I think we've got some good news on that side of it. But as it relates to the HELIOS-A study, other things that we'll see, there is cardiac -- prespecified cardiac subpopulation that we've included in the study, just like we did with the original APOLLO study. And we're going to look at endpoints like echocardiographic measures, functional measures like 6-minute walk distance. We're going to look at biomarkers like NT-proBNP. So those data will be available. Those are still exploratory endpoints. Those are critical endpoints that will necessarily support labeling, but they are important endpoints that we think are a measure in an exploratory fashion of the activity of the drug toward the cardiac manifestations of the disease to patients that have them at baseline. But the primary focus here really is on the mNIS+7 neuropathy impairment score, very much like we did in APOLLO. And we do expect that, if positive, that the HELIOS-A study will support a label that is similar to what we have with ONPATTRO.

Yes. Yes. Okay. And as you integrate this product into your business, I had a question about this before the recent vutrisiran setback. But the margin or the royalty that you owe to Sanofi is -- it's pretty significant. Is there anything you can do there to manage that or buy that back from a BD perspective in order to kind of maintain the profitability profile that you have with ONPATTRO?

Yes. I mean, there may well certainly be things that we can do there. When we've looked at how the franchise overall will grow with vutrisiran coming to market and when we think about the significant opportunity we have with wild-type ATTR at the end of the day. Obviously, we recognize that there is a higher royalty bearing burden on vutrisiran than there is on ONPATTRO, but the benefit of having that product in the portfolio, obviously, will overwhelm the downside of that royalty being higher than any third-party obligations we have with ONPATTRO. So there's certainly potential things that we can consider in the future as a way of addressing that royalty and improving it. We'll see how that goes, and we'll see if there are opportunities. But I think it would be premature to say anything at this point.

Yes. No, fair enough. So it's interesting. If we think about the implications from this study to then the APOLLO-B study in cardiomyopathy in the future, you might smile, but one of the questions I still get from an investor occasionally is around revusiran and then the imbalance in AV block and the ONPATTRO label and things like that. Do you think the cardiac subgroup in the vutrisiran trial can kind of -- I know it's not powered for this, but at least help elucidate that maybe some of those ONPATTRO findings were simple chance or an artifact of small numbers?

Well, I mean, a couple of things on the so-called ONPATTRO findings, which I don't think are anything untoward whatsoever. I mean, we found when you do exposure adjustment of patients in the APOLLO study. The cardiovascular mortality was lower in the ONPATTRO arm relative to the placebo arm. People forget that 30% of the patients in the placebo arm of the original APOLLO study discontinued and they -- because they were progressing in their disease and only 5% discontinued on ONPATTRO. So people just magically forget that important detail because when you look at exposure-adjusted mortality rates, they're lower on the ONPATTRO arm. And then when you look at all the other cardiac data that we have with ONPATTRO and then you look at the fares database, if you'd like to and look at every evidence out there, there is just simply no -- nothing but comforting and encouraging evidence around the cardiac safety profile of ONPATTRO from our perspective. So we think that a lot of that, which is sort of fed off of the -- partially the unfortunate revusiran story is what fed that narrative, which we don't see any foundation for all whatsoever.

Yes. Okay. Fair enough. So maybe switching gears to APOLLO-B. Look, it would seem like you just take the preponderance of evidence with the silencers, with tafamidis, what the subgroup data you have, like it's almost hard for me to -- I don't want to ask such a way to question, but why would that study -- it seems like you should -- what -- kind of what's the biggest risk? Is it endpoint risk? Is it the population you recruit? I mean, how do you think about that? Like if it ever went wrong, what would be the factor that would drive it?

Yes. Look, we have a lot of confidence in the study. But as you know and as everybody knows on this call, studies can always not make it for 1 reason or another, it could be patients' -- patient characteristics, baseline characteristics. It could be potential imbalances that occur between the placebo and drug arm. But when you look at the totality of the data to your point on ONPATTRO or patisiran, the nonbranded name in cardiomyopathy, it is very encouraging. If you look at the Solomon paper, published in circulation that included the endpoint data from -- of the original APOLLO study, then more recently, there was a presentation at ESC, but also a paper just published in JACC, J-A-C-C, that looked at a series of patients out of the national amyloidosis center in the U.K., looking at cardiac imaging, along with other measurements like biomarkers and functional data. And the data there are very encouraging, showing very clear evidence for cardiac amyloid regression with patisiran given over a 1-year treatment period. So lots of very encouraging data. Obviously, for all those reasons, we feel very confident around APOLLO-B. But I mean there's no trial that's ever risk-free. But I don't think there's anything that's based on the mechanism of action of the drug or the underlying pathophysiology that gives us reason to be concerned. Look, we've been enrolling the study through the pandemic. The enrollment is going well. But we've also had to incorporate a lot of measures to safeguard patient safety or ensure patient safety and make sure that we're doing monitoring at home and so forth and so on. The 6-minute walk distance test is done is done at a hospital facility with a group that is trained. So obviously, there's some greater complications now in doing measurements that are in the hospital than they were before. So those are just sort of the nuts and bolts, blocking-and-tackling aspects of clinical trials that potentially can create challenges. But I'm very confident in our team and on our ability and our track record of delivering on results. So I feel very good on that front. But those are all the sorts of things that can always occur as risks. The -- yes.

Yes. And the 6-minute walk endpoint, is that -- has that been well described and well characterized from a natural history perspective in this population?

Yes, it has very well described. Not only have we done work with some of the leaders in the field many years back, looking at 6-minute walk in both wild-type and hereditary patients, but we have the ATTR-ACT data for tafamidis. We also have other functional measures with 4 patients that are on ONPATTRO. that JACC study, I just commented on used the 6-minute walk distance endpoint and showed very favorable results compared to historical match controls. So I think for lots of reasons, we feel very good about it, Paul.

Yes. Yes, yes. Okay. Great. So there's so much we could talk about. We could talk about givosiran and lumasiran. I really want to talk about AGT, this data. And so I wanted to kind of get your input. We heard from some physician calls, and that's really -- the feedback has really been -- these data are really promising. Love the idea, kind of pharmacoeconomically and also not just economically, but from a compliance and clinical perspective on quarterly or biannual dosing of a medicine in a space with low compliance. But physicians' key question that they pose to us is really, how is this drug going to look like, look, when it's combined with an ACE or an R? And I think that there's maybe a bad taste in the mouth of some of these cardiologists with dual RAS pathway blockade. So I know that's a very specific question. I'm sure you'll want to take a step back and kind of talk about the broader concept of the asset and the data. But I'd be curious how you think about that. And you also have some combo data coming up, I think, next year. And what should we be looking for to kind of get confident in that next layer of derisking for this?

Right. Yes. Great, Paul. Yes. So just to level set everybody on the program, ALN-AGT is an RNAi -- investigational RNAi therapeutic that targets angiotensinogen for the treatment of hypertension. And look, we think this molecule creates an opportunity to reimagine the management of hypertension because of the fact that it offers the potential for a tonic control of blood pressure with a very infrequent dose regimen once every 3 months, once every 6 months. That still is to be determined, but we're optimistic that at least once quarterly and potentially once every 6 monthly dose regimen can provide that sort of tonic control of blood pressure. And that obviously is very beneficial compared to existing drugs that are out there right now where there's a significant adherence issue for patients, which leads to wide variation in blood pressure for patients. But there's also just the intrinsic normal pharmacology of an oral medicine that has a higher effect when you take it and then it wax -- wanes over time. And so that type of pharmacology, that sought to pharmacology, is something that we don't expect to see. We just presented data at the heart meeting last week, we showed extremely robust knockdown of angiotensinogen of up to 97.6%. Mean levels that were around 95% for the product. We also, on blood pressure, showed a mean reduction at the 200-milligram dose of 11 millimeters mercury and systolic blood pressure and about 7.7%, almost 8-millimeter mercury on diastolic blood pressure, which is impressive. So these data are really quite encouraging. Now regarding the potential when added to other existing anti-hypertensives to have potential side effects related to dual RAS blockade, that remains to be proven. But the data that we have clearly point to the fact that we get a hepatic mechanism of action. We're targeting angiotensinogen-native liver. We don't affect angiotensinogen or the RAS pathway in the kidney. And so we believe that the liver-specific effects of ALN-AGT will avoid the renal toxicity that see with dual RAS blockade. Now we're going to prove that in -- ultimately in our Phase II study. We are going to do a small arm of the Phase I study that will include some RAS inhibitors so that we can evaluate that. But that will be a small sample size. I don't think we expect to see anything in that part of the study. It's really going to come out of the Phase II study where we look at a much larger sample size where we'll look for safety of dual RAS blockade. Regardless, there's no doubt that this is a promising agent that can offer significant potential for patients with hypertension.

Yes. And is this something that you would take to market and launch independently?

Look, we will take it to market. We're going to have a cardiology-based sales force out there with our wild-type ATTR program. To not leverage that commercial infrastructure for the benefit of a new program like -- in hypertension would be a mistake. Whether we choose to add more boots on the ground by having a copromotional partner that goes after [ cardiac ] customers for this product is something which we can decide at the time. I think it's also worth noting, Paul, that the nature of marketing and selling products is going to change over the next 5 years, just like it's changed over the last 12 months based on COVID. So we'll have to see how that evolves over time. But certainly, we're going to -- we're in a lead development. We're going to lead commercial. We're going to leverage our cardiology-based sales force that we have built and will have expanded by the time our wild-type ATTR market opportunities open up. And whether we add some more boots on the ground with a co-promotional partner, something we can decide at the time.