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

Good morning, everyone. Welcome to day 2 of the 2022 Cowen Healthcare Conference. Thanks for joining us for the Alnylam fireside chat today. I'm covering biotech analyst, Ritu Baral. And with us from Alnylam today, Akshay Vaishnaw, President and Head of R&D for Alnylam. Akshay, thanks so much for joining us today. Relatively recent promotion for you, end of last year, correct? So congratulations. I do have to say I still love the fuzzy dice in the back. I'm glad you didn't take those down.

I keep those on there for you, Ritu. I'm delighted to be here with you. Thank you.

Which brings us to my first question of what you think the placebo effect in APOLLO-B is going to be. I'm kidding. You wouldn't rely on dice for that. But that has been the main investor focus recently, APOLLO-B, just given what your competitor, Bridge -- how surprised everybody was by BridgeBio's placebo arm and the way that their Phase III TTR trial functioned. How are you feeling about your placebo arm? Can you give us a little background on, again, the data set that informed your placebo assumption and how you're approaching just conduct quality control really for that?

Yes, yes. I mean just -- thanks for that question, Ritu. Just to step all the way back, I want to compare and contrast our 10-plus-year track record designing and executing Phase III studies, including most intensively in the TTR space, including walking tests in the TTR space that we've been doing for 10 years. I think that matters, and I'll come back to that in a minute. I think the BridgeBio news obviously was surprising to most people, and there's been a lot of discussion about that. I think one thing that surprised me is how there hasn't been more discussion about the fact that per BridgeBio's commentary in the public space, the baseline BNP and 6-minute walk distance, et cetera, for their study, it seemed quite similar to us to what we're seeing for tafamidis [ attract ]. And that's good. That's how they sort of designed and modeled the study, and that's what they got. And then curiously, they sort of missed the 6-minute walk distance, as everyone has discussed. But the surprising part is no one discusses the fact that the BNP change and the change in KCCQ was rather similar to tafamidis. So they have 2 endpoints that behave rather well given the starting population they had, one endpoint that doesn't. The one that doesn't is rather -- can be a subjective one, an effort-dependent one, and requires a lot of training and careful execution. And then most recently, to add to the discussion from my perspective was that I believe BridgeBio said that their analysis of hospitalization mortality events is within expectations as well. So seeing the kinds of numbers of events they were expecting, in other words, patients are declining per expectation. So you have a decline for expectation for BNP, KCCQ, hospitalizations, mortality, but not for 6-minute walk distance. And I don't know how to add all of that up scientifically, at least, other than you wonder whether a study that has 2:1 randomization with the drug type that everyone expects to work influences outcomes and patient efforts and [indiscernible] have been not properly trained to do the 6-minute walk distance or the design and execution at the science is not vigorous. You could end up with that kind of a result. I think the last comment about BridgeBio is I've wondered about the ends. If you look at the data output they've had, they've not clarified the numbers of patients they're reporting on, and I don't know how much of what happened has been influenced by COVID, missing data points or things of that type. So that's that. I think for our part, apart from our track record, we obviously take care to identify or track vendor with the proven track record to help us deploy a test like 6-minute walk distance. We had experienced previously in other studies with 6-minute walk distance, sites are trained and qualified, and then there are a series of metrics to walk sites during the study to make sure they're performing within expectations. If there are widely differing outcomes between visits, you'd want to understand. We've done a lot of experience for all this, by the way, during APOLLO as well. The mNIS+7, which has subjective elements in neuropathy but also needs to be very carefully watched. Sites need to be trained, qualified and they need to be monitored during study [indiscernible]. So that's why we feel confident in the population we've accrued. The study is behaving very nicely. We think the [ taf ] drop in rate is well within expectations. We'd set a 30% cap. So I have given you our best analysis of what might be going on with BridgeBio, but obviously, it's for them to ultimately speak about [indiscernible].

Triangulating all of that, it does sort of point to a 6-minute walk potential conduct issue versus a sort of fundamental biochemical process that reads out into the endpoints. I guess that begs the question -- and if you did have that sort of anticipation effect, if anything, it might be actually stronger for you guys because all the KOLs will say all day long that knockdown drugs are even stronger than the stabilizers. But as you think about the conduct, if there's now something inherently different about conducting a 6-minute walk, if your secondary endpoint data looks like what Bridge is alluding that theirs looks like, how complicated is that regulatory path for the indication? Do you know what I mean? Like what if [indiscernible]?

No, I didn't get your question there, Ritu. Sorry, just sort of redo that for me.

What if your secondaries hit and 10-minute walk did not? What's your regulatory path?

So the primary misses, but the secondaries hit. I see. Look, I -- all I can say is that would mean a conversation with regulators, depending on what misses the primary endpoint means exactly. There's miss and there's a big miss, right? And there's internal inconsistency if there's internal consistency. And so -- and what happens to the primary endpoint and the secondaries? It could still all hang together potentially, depending on the picture. And that's why it just will matter what the actual data are and how the [indiscernible]. But we will obviously engage with the regulators. Whatever the outcome, we always do. And they've guided us. They've said that 6-minute walk distance is the most efficient way for us to get the drug approved. That's why we designed it the way we did. As far as the secondaries are concerned, I think we're confident about the secondaries, but I also wanted to manage expectations. We didn't power the secondaries for more [indiscernible] hospitalization rate. So we have to manage that. And so we're not going to get a big -- a huge difference that we can go and get the drug approved. I doubt, given the size and length of the study. It doesn't speak to the mechanism action of the drug, which we're very confident in. But that's why we're doing HELIOS-B, which is bigger and longer, right, to accrue all those events and show an impact on the ultimate output.

So we have gotten a lot of questions just again on the nitty-gritty of the conduct of the 6-minute walk. Can you walk us through that just like a little bit? Like do these patients walk in a straight line? One of the -- and I'll tell you where this is coming from. One of the conversations I've been having with clients is older people with mobility assist devices and turns -- do you get -- do you have to -- are people learning how to negotiate a turn in their 6-minute walk with like a walker, which they might not do -- a steep turn every single day? Can you just -- can you walk us through what a 6-minute walk actually looks like and how you know whether that does or doesn't differ from what the BridgeBio conduct looks like?

Well, we don't know what the BridgeBio guys did, right? That's -- you have to ask them that question in terms of their training and execution. We can only speak to our situation. We -- the vendor that we have and the approach that we have is very mindful of the fact that the literature clearly shows that everything like what the patient says, what the doctor or health care supervisors says in return, the script that's used for the actual conduct of the test, the footwear and clothing that patients wore on each occasion, the course that's laid out that. That is consistent. All of these have been shown to influence outcomes with 6-minute walk distance. So hence, the comments about the details around design and execution are important. We have done 6-minute walk distance before. And so we're quite comfortable with the way these different facets that I've just laid out are being conducted. And that's before training and qualifying aside right at the beginning, right, and different from monitoring them during the study for errant, disparate results. So you take that package together, I think, again, ultimately, we can only speak to what we're doing. And quite confident that attention to details of the type that I'm saying will help with a good outcome and an accurate outcome, just as we have shown in the past with 10-meter walk test. We just had a very nice 10-meter walk test result with HELIOS-A, vutrisiran. We did it with APOLLO ONPATTRO. So these kinds of tests are difficult. But with the right kind of training attention, they can be wrestled to the ground and be used in international [indiscernible] trials. And I hope the explanation I'm providing illustrate the care we take.

Yes. The protocols for like an older TTR population is -- are they the same as like the protocols -- good protocols for like a PAH population? Just because investors are familiar with that.

I don't know the exact details of the protocol that was used in the PAH studies, but we know that, again, that's another setting in which 6-minute walk distance was very effectively used and was deployable in a reliable and accurate fashion. And so all I can say is the people we're working with, the experiences we've had, the way we work with the test when the study is in fly in terms of training monitoring sites, that's the best we can do. And as I've said, we've kicked the tires on the study, and we continue to guide that we're excited and looking for the result in a year.

Got it. Can you give any additional color on potential data timing and what you'll disclose with the top line? Just given how important outcomes become in the whole conversation, will that be included?

Yes. So we will -- we said midyear this year. I think we reported last year, the enrollment finished in June of last year. So 12-month study, and then you go to kind of add on a little bit of time to do database log and do the readouts and be sure of the results. So I assume a few weeks for that. So people can kind of guess kind of the time frame that we're in. And so top line data release at that point, we'll stick to our practice, which is report the primary and secondaries via PR in a hierarchical fashion at 12 months, and that will be associated with P values and, of course, safety. And we'll go from that. That's -- that will be the primary data release.

Will we get the deltas? Because in the past, you've oftentimes reserved the deltas and just given us the P values and -- we never really bugged you about the deltas because the P values had 12 0s, but it would be different here.

Yes. I mean, look, I think we will be consistent with our past practice, Ritu. And if the study is hit and there are nice P values, then I think people will be able to walk away from that PR satisfied that things are on track. No doubt, we'll elaborate further, both these types of conversations as well as sort of scientific meeting soon after that where we'll get into much more detail. But if the P value has hit, I don't think we're going to give out, "It was 228.2 meters versus..." If the P value is hit, then I think we can remain confident in our cost practice and the quality of our science that we are happy with the result. And no doubt there'll be a conference call associated with it.

Got it. Okay. Are you monitoring background events, cardiac events, just to see how powering secondaries are going?

Yes. I mean not so much from the viewpoint of how secondaries are going as [indiscernible]. I mean all those cardiac events are safety events, and the data monitoring committee expect to see those. And so far, we've always got a green light from the data monitoring committee.

Is the event rate sort of matching up with what you anticipated given the population such as...

Yes. We haven't commented on that. Again, I want to emphasize that with our focus and emphasis on high-quality science, reporting on -- let's look at this thing whilst the study is in flight. It's not a good thing to do. We need to log databases. We need to be sure of the data before we share it with you. And so that's what we'll wait for.

Got it. ACC is coming up. Will there be any data from HELIOS-A, cardiac subgroup data at ACC? Or any sessions of interest to you and your team that might inform, frankly, the whole TTR cardiac space, not just placebo?

I don't know how to answer the second part of that, actually. I haven't seen the full agenda yet. But as far as HELIOS-A is concerned, I think people will get to see pretty much what we shared at the French meeting, I think, in January, where you can see the details of echo findings, BNP, 10-meter walk test. And importantly, all of which very consistent with what we saw in APOLLO, I think you'd agree. But then we added to that these fascinating new findings, first time ever in a study of this magnitude. People have shown regression -- we've shown regression [indiscernible].

[indiscernible]

And again, that's another nice pebble on the side of this mechanism of action. And hopefully, what it will provide patients in terms of ultimate clinical outcomes, 6-minute walk distance, hospitalization, mortality, et cetera. So that's exciting that we saw that.

Got it. Okay. Can we talk about potential further penetration into the mixed phenotype data? If APOLLO-B data is positive and in hand, I think the assumption is ONPATTRO, just because of the first-generation treatment burden, is only going to make it so far. But is there any thoughts about why any benefit wouldn't automatically translate to vutrisiran in your April 14 PDUFA date? So it'll be commercially available at the time of -- well, assuming an approval, commercially available at the time of the data. How do you think about further penetration?

Yes. I mean just to start with the vutrisiran aspect, the drug will be labeled for hATTR with polyneuropathy. So the imperative form of the disease, not the wild-type form of the disease, so it won't be being prescribed for the wild-type forms of the disease. Now what doctors choose to do out there is their business, but formally speaking, the label and the commercialization effort will focus on hATTR-PN and -- just as we've done with ONPATTRO. And I think it will be, again, depending on what the label says and how doctors interpret the totality of the information, what they decide to do with it all. I think if ONPATTRO 6-minute walk distance is positive as we believe it will be and then the secondaries look encouraging, then that's going to be a significant shot in the arm for the TTR reduction hypothesis and its impact on cardiomyopathy both in the mutant and wild-type forms. Now how doctors use that information and they put that into their thinking for the use of vutrisiran, I don't know. What I know is we'll be commercializing and we need to get to patients with hATTR-PN. Now the important thing, having said all of that, and the necessary framework for how vutrisiran should be used is that within hATTR-PN, there's still a huge and growing opportunity. We've got ONPATTRO currently in just over 2,000 patients, right? We reported that earlier in the year. And there are roughly 50,000 hATTR patients around the world, of whom 20,000 to 30,000 have PN and mixed disease. So the eligible population is probably of the order of 10x what the population ONPATTRO is being currently administered to. Well, that's a great way of growing the pie and helping more patients both with ONPATTRO and vutrisiran. And we know there are a number of types of patients that will be helped. I mean there are patients sitting on the sidelines who want access to obviously a once-a-quarter highly convenient subcu approach. Great data. And so I said, with -- so there's that wait-and-see group, and then there are also patients who, because of COVID, couldn't come into -- want the treatment, they couldn't come in every [ 3 months ] for one or more reasons. There are patients who are switching from stabilizer to ONPATTRO. And ex U.S., we've seen a lot of that behavior both in Europe and Japan. And we don't know to what extent that will grow. We anticipate that will grow with the advent of a subcu once every 3 months, which is a very attractive profile for patients who are declining with their hATTR-PN and they're on tafamidis and they're progressing. That's been more important. And then there are segments like adding on vutrisiran to a background stabilizer in an appropriate patient with hATTR-PN, which we certainly know has happened here in [indiscernible] where that's permitted. And then finally, currently, there are some patients on an antisense oligonucleotide, inotersen. And for them, given that, that drug's been with all sorts of safety issues that have been discussed before in [indiscernible], this is a much cleaner, efficient alternative. So that's how we grow from the -- just over 2,000, we ended the last year with 2 -- many more thousands with both drugs. And that's why we're excited. And we don't have to worry about the cardiac data. That's just starting with hATTR-PN, right? And then we'll see what the cardiac data do in the long run. But...

Got it. And then just as you do think about the franchise and the potential approval, do you think that you'll see -- well, actually, you mentioned something. Akshay, you mentioned that there were patients who are on the sideline who didn't choose to start ONPATTRO during COVID. But you've had home infusion. You've had just really great growth during COVID. But with home infusions, didn't everybody who wanted to start over the last 2 years get to start? Or is there some component of having to start in a hospital setting?

It's a good question, Ritu. I don't actually know those numbers. We'll have to get back to you on that. But clearly, having an IV that either has to be given in the office or at home is a very different prospect from a subcu once every 3 months, right? And that's -- I think that's a really exciting [indiscernible] for patients. And hopefully, we [indiscernible] a very important alternative given just the sheer numbers that need treatment.

Yes. And it sounds like you're expecting more combination use with vutri, because if it's a patient who cares about convenience, there...

I think per the label, ONPATTRO is indicated for hATTR-PN. We think that will be the same with vutrisiran. And if there are 30,000 or so patients in the world with PN/mixed disease, they would all be eligible for the drug. Now it will depend on the individual territory and [indiscernible] actually has its own rules and guidances about the use of all these drugs. But certainly in territories where it's approved in the fashion that I described and reimbursed, we've seen combination usage with tafamidis patients who are declining on to tafamidis.

And a much more long-term question. How are you seeing potential competition to the full TTR franchise from gene editing programs that are advancing in the early clinic right now?

Yes. Look, I think the gene editing data continue to be of great interest for everybody, understandably so. There's definitely exciting data there. I think it was last week, they released some more data showing durability of effect. Interestingly enough, I think the one and done approach idea was important. We have to look at all the pros and cons. So what if you didn't get decent knockdown? In the small numbers of patients they've treated at the highest dose, we saw there was 93% knockdown. But not everybody got 93%, right? There were some patients who were down 80%. And as you expand the numbers of patients that are treated, you will start seeing patients go lower than 80%. That's just the laws of pharmacology, I'm afraid, in heterogeneity of gene responses. And you'll see patients above 93% as well. But as you get to such a broad spectrum, if we all agree that you need at least 80% or higher knockdown, which is what our work has shown, then is it one and done? Or is one and done for some, but not all? These are questions they'll have to answer, right? I think they also will have other additional development challenges down the line in terms of doing active head-to-head studies given the numbers of drugs that are approved in this space now. And then finally, I think what we'd say that we're very excited about TTRSc04 where we'll file an IND or CTA in the coming months. And we're very confident data at R&D Day, I shared those, why we think once a year with TTRSc04 giving above 90% knockdown in almost everybody. It looks very tractable. And we can share those data with everybody as soon as the Phase I gets going. So I think that allows us to become the leader in this space around vutrisiran and with the convenient nongenome altering therapy that gives known pharmacology and safety, that we have 10 years of experience within the space. So that's how we think about it.

Got it. Well, that leaves 4 minutes for the rest of your pipeline. So this is going to be the lightning round. GIVLAARI and OXLUMO. Any expectations for reacceleration of growth after COVID hopefully rolls off through the end of the year?

Yes. I think COVID obviously had an impact on so many aspects of all our work. We're looking forward to the impact of recent launch of GIVLAARI in Japan and other countries, further penetration in Spain, Italy, Germany. Unsurprisingly, COVID influenced some of those things. So I think all of that's going to help. Similarly, with OXLUMO, it came online as COVID started. So that's never going to be as comfortable a situation to maximize getting the drug to patients as hopefully we're entering now. And again, the global approvals are still coming online and the reimbursements. So these are all reasons for both GIVLAARI and OXLUMO, why I think things will continue to look up. And with respect to OXLUMO, of course, we had ILLUMINATE-C data last year and the supplemental filing with that, making OXLUMO clearly the only agent available for this disease, PH1, with dosing in kids, dosing in adults, dosing regardless of degrees of renal failure, et cetera. So it's the preeminent choice, we would think, per the label for patients with PH1 around the world.

Got it. I'm going to skip around a little because I want to move to where the client questions are. Your EP data by the end of the year. A lot of focus on that. What doses are we going to get data for? And what target knockdown are we shooting for? Are we going to get -- and are we going to get anything past just target knockdown?

Yes. I mean I think in the top line, which were released by the end of the year for KARDIA-1, placebo-controlled study, dose regimen, degree of knockdowns, statistical significance and safety, I mean, I think these are...

I'm sorry, I'm talking about your -- the CNS program.

Oh, I'm sorry.

Yes. I skipped all the way to the end, and we're going to [indiscernible]. Yes, no, no. You know how I love KARDIA-1. So...

Yes. APP, yes, super exciting, right? It's the start of our CNS platform first and -- safety, first and foremost; and then secondly, a number of very interesting, important, direct target-related biomarkers, APP alpha, beta, AB42, et cetera.

Not just knockdown. Actual -- like PD -- potential PD biomarkers.

Right. Yes, yes. And so the potency and durability and how it's translating to animals where the [indiscernible] primate single dose gives 9 months, 80% knockdown. We generally see gaining potency and durability as we go from monkey to man. So this all bodes well. Everything we've done before in monkey has translated into man, so we feel confident about the translation of this technology and giving the kind of safety and quality data that I just described. But the study has just gotten going, and those are data to come later in the year.

Got it. Now AGT. I said that too fast. KARDIA-1, that data is by the end of the year. And now KARDIA-2 is -- KARDIA-2, I think, has already started. How is that going?

Yes. Look, they're both going well. And again, they both started in the COVID period. So we'll update you on the enrollment, characteristics and so forth. But we continue to guide the KARDIA-1 data will be by the end of the year, top line.

Any comments on ongoing KARDIA-2 sort of safety and conduct? That's the combo therapy study. And I think that's been -- safety and tolerability has just been the focus.

Yes. We're obviously blinded to the studies and so forth, but I think I would have heard if there was any significant concern. And we remain very confident in the mix of action and the hypothesis in these 2 studies.

One last question from clients. Any comments on LEQVIO?

It's a terrific drug. It's once every 6-month subcu. I think Novartis had a really exciting approach to commercialization of that drug, which takes into account all the learnings from Repatha and Praluent and other cardiovascular experiences to bring patients a really, really important alternative. They will obviously guide much more about the details of how that launch is going. We, too, will be giving you updates as appropriate based on what they're sharing. But it's a tremendous effort. It -- we think it will be the leading effort in this space, and we are very, very excited to what LEQVIO is going to do in cardiovascular disease.

Great. Well, Akshay, thank you for taking all of the questions, especially the pipeline speed round. Really looking forward to what you've got at ACC and the APOLLO-B data.

Absolutely. Thanks for the time, and thanks for the questions and everyone's interest. Great to see you. Bye-bye.

Bye.