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

Okay. This is Marty Auster. I'm the lead mid-cap analyst at Crédit Suisse, and you are watching Alnylam at the 29th Annual Crédit Suisse Healthcare Conference, and the first and hopefully, only virtual conference. I've got John Maraganore from Alnylam, CEO. And very excited to have you here, and we were just talking in the breakout about how long you've kind of known me and I have been following Alnylam and paying attention to the name for a long time. Catch us up on where you're at. You've had an enormous run of success in several drug approvals in the last couple of years. Maybe kind of frame where you're at now in the life cycle of Alnylam and what the vision is going forward? And kind of we'll jump off that -- from there.

Yes, sounds great, Marty. Well, first of all, thanks for having me. It's great to be here virtually. Look, Alnylam is in a really exciting place as a company. We are -- we brought 2 products to the market that are making a big difference in patients' lives for -- one for hereditary ATTR amyloidosis in patients with polyneuropathy, the other for acute hepatic porphyria. We're selling these products globally. We're in 20 countries directly. We've had distributor agreements in about a dozen other countries as well. So this is really all about bringing these important medicines to patients around the world. And now we're at the cusp of having 2 additional approvals happening in the next weeks to months, plus or minus. This is OXLUMO, lumasiran, which is being reviewed by the FDA and the EMA. This is going to be potentially a transformational first medicine ever for patients with primary hyperoxaluria type 1, a devastating orphan disease. And the other medicine that we expect approval this year is inclisiran, which is our RNAi therapeutic for hypercholesterolemia. So we're going from ultrarare to very common disease opportunities. And then in the coming -- early part of next year, we expect to have our next product readout in Phase III, that's vutrisiran for hATTR amyloidosis in patients with polyneuropathy. That will be a follow-on to ONPATTRO. So very exciting point in time for the company. 5, potentially even 6 medicines that should be on the market by early '22 based on when everything comes together. And in addition, we have a very significant pipeline and then a robust product engine. So exciting time for the company, exciting time for RNAi therapeutics and obviously, we've been the pioneers in that space.

Yes. So I mean, many specific questions on these products I've got. If we could start maybe just talking about the platform, I guess, one of the things that's kind of really intrigued me over the last year, I've been thinking about or talking to you guys about, has been this move from liver-focused RNAi to kind of broadening out, I know you have an active partnership and a lot of focus in CNS and in ocular disorders right now. Could you speak a little bit to kind of what have been the challenges of translating the success you've had in the liver to other tissue types? Is there anything about RNAi that's been slower than the process for maybe some of the ASO approaches, things like that? What are the nuanced differences? What are the challenges? How close do you think you are to cracking the code? And what sort of opportunities could that unlock when you can kind of effectively and confidently replicate what you've done with liver-focused disease with the CNS, for example?

Yes. That's a great question, Marty. I mean, look, we've been very successful over the years in cracking the code, if you will, to use your words for liver delivery of small interfering RNA. And we did that with ONPATTRO using lipid nanoparticles. We then evolved toward a GalNAc conjugate. We pioneered the GalNAc-conjugate approach for the whole industry. That's been incredibly successful without a doubt. And we've also made these molecules safer over time. We've learned how to improve their overall safety profile as best exemplified by inclisiran and the thousands of patients that have been treated with that drug with a very clear line of sight. But we've also been successful in moving beyond the liver. And very specifically, with novel conjugates that we've pioneered at Alnylam, we have achieved very robust and attractive silencing of target chains in the CNS, the eye, the lung. We expect that we will get delivery in other cell types and other tissues around the body. We've got preliminary data in muscle, preliminary data in tumors as well. And so we're very confident that where we're going with this platform is to be able to target a wide range of disease targets in a wide range of tissues. Now today, what's ready for prime time are programs directed toward liver-expressed disease genes and also programs directed toward CNS, ocular and lung disease genes. And that's what we're building the pipeline for in the near term.

Okay. Well, so let's dig into ATTR, where you've kind of had the first successes, and we'll talk a little bit about ONPATTRO and kind of sort of the pipeline. So currently, ONPATTRO is being commercialized for the treatment of polyneuropathy associated with ATTR. I think you said on the last call, you have something like is it 1,200 patients treated, give or take? Is that about right?

Over 1,150. That's correct.

Okay. Over 1,150. And so maybe if you could just talk a little bit about -- so ATTR is a mixed system disorder. There is involvement in different places. And if you could talk a little bit about kind of what the disease is. What you've established so far with ONPATTRO? And where you're going here and where the bigger opportunities might be [ in this ]?

Well, so taking a picture -- taking the big view first and starting where we're labeled today, but let's take the big view first. ATTR amyloidosis is a disease caused by misfolding of the TTR protein in a wide range of tissues in the body. The TTR protein is made in the liver, but its misfolding occurs in peripheral tissues, including the nerves, the heart, the gut, the kidney as well. And so it is a multisystem disease. Now there's wild-type ATTR that includes at least a few hundred thousand patients in the U.S. alone. And then there is ATTR amyloidosis caused by mutations in the TTR protein called hereditary ATTR amyloidosis. And today, Alnylam is and with this lead drug ONPATTRO, is indicated for the treatment of the polyneuropathy associated with hereditary ATTR amyloidosis. But we believe that the opportunity, of course, goes beyond just the polyneuropathy setting, and we're doing additional clinical studies to open up those opportunities.

So historically, you'd focused on polyneuropathy initially. Why was that the case? And kind of -- I know that within that kind of over 1,150 patients, there's going to be a bunch of these patients who will have a mixed picture where there might be some cardio involvement as well. So what have you learned about the ability to kind of have impact by reducing -- by silencing TTR production on polyneuropathy?

Well, I think the data are pretty black and white in terms of the power of knocking down TTR and the impact that we can have on polyneuropathy. I mean we see in the APOLLO study that we published in the journal, we demonstrated highly significant halting of neuropathy progression in patients. And in the majority of patients we even saw a reversal of disease. So an incredibly attractive profile, very encouraging safety profile as well that's been well documented. So there's no doubt that knocking down TTR is an effective mechanism of action in the treatment of manifestations of this disease, and it's been proven for the polyneuropathy. There are quite a bit of data that are not yet labeled for the product around the impact on cardiomyopathy. We could talk about that, if you'd like as well. But that's obviously going to be an important expansion opportunity for the product as we generate clinical data and get regulatory approvals for that expansion.

Right. So APOLLO was the initial Phase III that supported approval of ONPATTRO. APOLLO will be ongoing, and that's targeting specifically this cardiomyopathy subset of ATTR patients. Could you -- so let's talk about that for a little bit and then move on to vutrisiran and kind of how the longer term might unfold for Alnylam. But so could you frame kind of where the APOLLO-B program in cardiomyopathy, where that's at now? And is that's correct to think of that as kind of your first swipe targeting directly cardiomyopathy?

It is. Yes. The -- so let's take a step back with APOLLO. In the APOLLO study, there were a number of exploratory endpoints that related to a prospectively defined subpopulation of patients that had cardiac symptoms in addition to their polyneuropathy. And those endpoints included biomarker, functional and echocardiographic measures of cardiomyopathy. And the data which was published in Circulation, demonstrated that patisiran, which is the nonbranded name for ONPATTRO, was able to have an impact on the cardiac manifestations of the disease. That included a halting of decrease in 10-meter walk time, it included a halting of increase in NT-proBNP levels. It included structural changes in the heart including a decrease in intraventricular wall thickening, which is one of the hallmarks of the disease. So very encouraging data. More recently, we generated some data that we published in JACC just last week, looking at the impact of patisiran given to patients with cardiomyopathy, in addition to their polyneuropathy, looking at a number of different features, including serial PYP scans, and those studies showed evidence for cardiac amyloid regression associated with patisiran administration. So with those data in hand, we're -- we started the APOLLO-B randomized study. It's a randomized, double-blind, placebo-controlled study. It's got a 1-year endpoint of 6-meter walk time -- 6-minute walk distance, rather, which is, of course, a functional measure of disease. We expect to complete enrollment in 2021 for that program and expect to have data from that program in 2022, that should positive lead to an expansion of the ONPATTRO label into both hereditary cardiomyopathy, but also wild-type ATTR cardiomyopathy. So it really is a very important study for the company.

What's the target enrollment in APOLLO-B? And what sort of -- there's -- obviously, there's some other agents approved in that space, I think, VYNDAQEL, I guess, from Pfizer. What is the kind of the background treatment of those patients in the study? And what sort of magnitude of effect are you seeking?

Yes. So the study sample size is 300 patients. The -- we do allow up to 30% of the population to come in on a TTR stabilizer at baseline. And the other 70% we are aiming to have as TTR-naive when they enter the study. They can -- if they need to take a stabilizer later during the course of the study within that 1-year period, they're able to do that, but we are aiming to have 70% of the patients come in that are TTR-naive. So that's the input population for the study, Marty. Again, 1-year treatment with patisiran with the 6-minute walk distance as the primary endpoint. In terms of how we've powered the study, it's very robustly powered. We would expect to see -- and our exploratory data would indicate this, a very nice treatment effect with that type of sample size. And obviously, we look forward to seeing the data in 2022.

Sure. And we were talking before this discussion about some of my background in pulmonary hypertension. I know in that area, 6-minute walk has been used as an approvable endpoint. And I guess, continues to be used as an approval endpoint. But I know that the data also shows that the really important thing for the long-term outcome is kind of halting that decline in the patient, if you can avoid people having kind of 5%, 10% decline, that's really critical. Does that hold true in cardiomyopathy [indiscernible]?

No, it does. Very similar. A lot of the PAH experience of 6-minute walk distance is, in fact, useful for helping us understand the clinical significance in the setting of ATTR amyloidosis. But there's also a lot of data on this, of course, that comes out of the ATTRACT study with tafamidis that is informative in terms of how those type of endpoints can relate to clinical benefit at the end of the day.

Okay. And then just in terms of kind of that combining ONPATTRO with the stabilizing agent. You, at this point, I assume, have quite a bit of kind of real-world safety experience of that. So maybe you can talk a little bit to the safety, and then just kind of the theoretical combinability, kind of what are the attractive features of combining those agents? And what do you see as kind of the risk of kind of having incremental improvements on top of that at this point? Obviously, the question's to be answered in the trial, but yes.

Right. Well, I mean, in APOLLO-B, the real evaluation is patisiran versus standard of care at the end of the day. And there'll be enough patients that are naive to a stabilizer to independently evaluate its activity while it may not be done formally but to independently look at its activity versus a placebo arm or versus a tafamidis or a stabilizer patient from the beginning. So that's something which will be valuable in a post type of manner from the APOLLO-B study at the end of the day. But the primary focus of that study is really looking at patisiran in cardiomyopathy patients versus standard of care. Okay. Now in the real world, we do know that there are a significant number of patients that are getting concomitant therapy of ONPATTRO on top of TTR stabilizers, both diflunisal but also also tafamidis. And that's something which we see quite a bit of in the U.S. market. We see less of that in the rest of world. But we are seeing somewhere between 15% to 30% of patients in the U.S. getting ONPATTRO on top of concomitant TTR stabilizer, either tafamidis or diflunisal. And we are seeing reimbursement happening for ONPATTRO in that setting. So that's an encouraging finding. I think it's based, in part, on the fact that patients have polyneuropathy, they need a drug for their polyneuropathy and that's what ONPATTRO is indicated for. And that's why it's being used in those so-called mixed-phenotype patients. Now in the rest of world, the dynamic is different. Most of the patients are receiving ONPATTRO, either naive to TTR stabilizer therapy or after having progressed on a TTR stabilizer therapy. And in those cases, the patients are being switched from a TTR stabilizer on to ONPATTRO. And over 50% of our patients coming into ONPATTRO outside of the U.S. are in that TTR stabilizer switch type of background.

Interesting. Okay. And then if you think just about kind of what the -- framing the market opportunity between kind of the strict polyneuropathy definition and kind of this mixed / cardiomyopathy and expanding to the wild-type phenotype in a broader way, what is that difference in terms of the size? And then longer term, obviously, there's -- in the near term, anyways, there's potential combinability of modalities but are both fairly high-priced drugs, tafamidis will be generically available in the not-too-far-off future. How do you -- kind of how do you see the market shaking out and the kind of the robustness of the pricing opportunity and the sustainability of that, I guess?

Yes. Well, look, I mean, when -- if we successfully open up a wild-type ATTR opportunity with the APOLLO-B study and then we could talk about vutrisiran later on, we think that it changes the prevalence of the labeled indication from somewhere in the -- worldwide, somewhere in the 20,000, 25,000 for polyneuropathy patients to hundreds of thousands of patients around the world. So it's a very sizable expansion of the opportunity without a doubt. Now obviously, this is a very important therapy. It's still a relatively small orphan-type disease setting, although it really bears on being a specialty market at the end of the day. When we think about pricing of our medicines, we always think about it in the context of the prevalence of the patient population. That thinking will need to evolve probably as we get closer to these wild-type opportunities. And we've demonstrated mechanisms in pricing of our other drug GIVLAARI as to how we might think about that prevalence-based adjustment on price to adjust for a new expansion of the opportunity to the wild-type setting.

Okay. And we can, I guess, jump over to vutrisiran to HELIOS-A and B studies. Where are we...

[indiscernible].

I've got to get me one of those.

Okay. Well, sure.

The -- so you're doing this as an A and B. You're starting with polyneuropathy, which is the kind of very highly derisked indication to kind of establish, I guess, the proof concept. That data that's coming pretty soon. So could you frame just some of the time line on that? What is the -- as investors are thinking about this, so this is -- this should be relatively low risk from a standpoint of you know that vutrisiran is able to knock down TTR, but I'll let you frame it.

Yes. No, we're excited about HELIOS-A. HELIOS-A is the opportunity of getting vutrisiran to the market as quickly as possible. Because it's going into the polyneuropathy setting, it's a very innovative design in this study. We're actually -- it's an open-label study. The efficacy of vutrisiran will be compared against the placebo arm of the original APOLLO study, which is really quite innovative from a design perspective. Obviously, we're doing a lot to control the baseline characteristics of patients in HELIOS-A, so they're very similar to the baseline characteristics of patients that were in the original APOLLO study. We fully enrolled the study in February of this year. We expect to have top line data in early '21. We're on track to doing that, obviously, during the COVID pandemic. We had to focus a lot on ensuring patients were able to get access to dosing, that they were -- that we were able to monitor them closely for safety and efficacy measurements and so forth. So lots of work by our team to make sure that the study maintained its integrity and was done in a high-quality GCP manner. And the good news is that we're very much on track for an early '21 readout of the HELIOS-A study. I think it's a very, very critical study because if it's positive and we get vutrisiran approved, it does allow us to further cement our market leadership in the polyneuropathy segment of this market. Because it is going to have a very attractive profile for patients. It's a once quarterly subcu injected drug, we're also advancing a biannual dosing opportunity with vutrisiran, which we think even takes it further from an attractiveness standpoint for patients. And so we look forward to the results early part of 2021. And again, if positive, it should enable our -- what will be the fifth RNAi therapeutic to hit the market.

You mentioned a few minutes ago, the 20,000 patient population addressable market opportunity in polyneuropathy, and you're treating about 1,150 right now. What's limiting that? Sometimes these rare disease markets can penetrate pretty rapidly, sometimes they're slow and they kind of grow for 10 years straight. Is this an administrative limitation because of the IV? Is it finding the patients? Is it access? All the [indiscernible].