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

Great. Good morning, everyone. My name is Ted Tenthoff. I'm a senior biotech analyst at Piper Sandler. And before we begin, I'm required to point out certain disclosures regarding the relationship between Piper and our next presenting company, Alnylam, which are located at the back of the room and also at the registration desk. So Alnylam is a leading developer of RNAi therapeutics. Now with four drugs approved and a rich pipeline of future therapies. Perhaps most important is the sNDA filing for ONPATTRO for hereditary and wild-type ATT amyloidosis with cardiomyopathy. In addition, I'm looking forward to ALN-APP data in the early onset Alzheimer's disease and also zilebesiran for hypertension data next year. In addition, a fifth drug, Leqvio, has been approved, which is partnered with Novartis for high cholesterol, on which Alnylam receives royalty. Here today with us is CEO, Yvonne Greenstreet. Yvonne, thanks for being with us. It's always great to see you.

Ted, it's great to see you and a pleasure to be here. And thanks for just a wonderful introduction. I think you've hit on a lot of the key points. I think we're in this remarkable position as a company right now where we have as you would think, 4 marketed products that we commercialize as well as Level think of it commercialized by Novartis as well as its rich pipeline and sustainable innovation engine. So we really feel that we're in a terrific place to continue to build this company.

Well, what I love about the story and we'll be sure to touch on is you've really validated the technology in orphan diseases and are now expanding into much larger areas with the chemistry based on the safety profile that you've established. So I want to start out just one quick commercial question. We could probably spend the whole entire conversation these days on commercial, but I think there's so much important stuff in the pipeline. You guys just launched AMVUTTRA, which is a subcu quarterly injection for ATTR amyloidosis with polyneuropathy. First quarter launched to $25 million. Nothing wrong with that. And I appreciate it's early. How are the launch time dynamics going between ONPATTRO and AMVUTTRA and really is this a situation where you're actually expanding the market?

Yes, that's a really good question. We're thrilled with the progress of Ambu's early days yet. We got approval in the U.S. in June of this year. And at our last quarterly earnings, we reported it said $25 million for AMVUTTRA and $130 million for ONPATTRO. So we're really, really pleased with how things are going. And I think as you said, we have an opportunity here to really build a leading TTR franchise. If we think about the start of AMVUTTRA, all the metrics pointing in the right direction. The launch has gone off to an incredibly good start. And I think that's driven by the profile that we have with AMVUTTRA quarterly regimen. I think that's going down very well with physicians and patients. And I think we do see an opportunity to grow the overall franchise. Just to touch on a few of the AMVUTTRA launch metrics, I think the first thing to say is that we are actually seeing about to 46% of new patients going on AMVUTTRA. And I think that speaks to your cannibalization question, it really is important to think about the franchise in its totality. But I think what's incredibly impressive as a metric is our run rate of start forms. Prior to the launch of AMVUTTRA, we were getting a run rate of about 30 start forms and month with ONPATTRO. We've doubled that now to 60 start forms a month, which is really great progress. We've had 375 start forms with AMVUTTRA since the launch and about half of those are new patients, which again is encouraging. We're broadening the prescriber base. You've had 17% of new physicians coming on stream to prescribing AMVUTTRA. So when we sit back and think about where we are as said, it's early days yet, but we really, really are pleased with the progress. We think this is going to be a best thing.

As you said, I think it's the data and the patient experience, the efficacy and the safety that's driving that. Now just to talk about expanding the franchise. You recently presented full Phase III data from APOLLO-B on ONPATTRO at the heart failure society. Walk us through the data and remind us on your plans on where you are in terms of filing the sNDA.

Actually, the results from this study, APOLLO-B is a study with patisiran in patients with hereditary and wild-type cardiomyopathy. And this was an eagerly anticipated results, and we were delighted that we were able to deliver positive results. So I actually was a pretty small study. 360 patients and pretty short study, 12 months duration, the primary endpoint of that study was the 6-minute walk test at 12 months. And we were really, really pleased with the results that we're able to deliver in this short, small study. So for the primary endpoint, the 6-minute walk test, then you were able to return patients to the decline that is seen with healthy aging adults who don't actually have TTR amyloidosis of about 5 meters decline per year. So we're essentially taking patients back to the rate of decline that you see in healthy adults. And we were able to deliver what we believe is a clinically meaningful as what a statistically significant difference compared to placebo 15-meter delta. That was our primary endpoint. We also hit on our secondary endpoint, which is the KCCQ, measuring functional status and quality of life. And again, that's -- it's very important to patients. We missed on the first composite endpoint, which was cardiovascular mortality events and the 6-minute walk test, didn't meet statistical significance and narrowly missed that. And so we didn't formally test the other composite endpoints. But I think when you look at the totality of the data in holistically, think about the safety. We actually saw a better cardiac adverse event rate with placebo, with patisiran compared to placebo. We saw fewer deaths numerically. And all the biomarkers points in the right direction, anti-proBNP, troponin, imaging, et cetera. So what we've really been able to achieve here is, I think, results that are going to be important from a regulatory perspective. Just to remind everybody that 6-minute walk test and the KCCQ, a validated endpoints by regulators. As well I think addressing the issues that patients and physicians are particularly concerned about how they function 6-minute walk test and how they feel the KCCQ. So we're in a -- we believe we have a very compelling data set here, and we're looking forward to filing the NDA. I just want to just emphasize that we're on track to submit the sNDA to the FDA before the end of this year.

Yes. Thank you for punctuating that. That's a very important point because I know everyone is very focused on it. And I was just going to say that we know the disease is caused by an accumulation of plaque in the peripheral neuropathy, but in this case, in the cardiomyopathy in the heart muscle. So we know this knocks down production of that plaque pretty effectively. So we know the drug is doing what it's [indiscernible] to. In fact, a lot of patients who really had a mix phenotype, we're seeing benefits already too. So I do think this is a very validated data set.

Yes [indiscernible] I think -- again, I think we've validated the hypothesis that actually TTR lowering through a silencing mechanism has the potential for therapeutic benefit to patients with not just polyneuropathy, but cardiomyopathy as well.

And if what is -- what would expansion of the label actually do for ONPATTRO revenue? Like, what are we talking about in terms of patient size?

Yes. Well, there are about 30,000 addressable patients with our current label for both ONPATTRO and AMVUTTRA. So patients with hATTR with polyneuropathy with success in the APOLLO-B study and, obviously, regulators review the package. We open up a much larger opportunity for ONPATTRO. There are probably something like 300,000 patients with wild-type cardiomyopathy there. So I think it's a very important step forward for ONPATTRO as well as the TTR franchise going forward.

So about 10x. You guys recently decided not to conduct an interim analysis in the HELIOS-B trial, and that's of AMVUTTRA. So in cardiomyopathy, we open into this decision and when could we get data from that outcome study?

Yes. No, that's a great question. Just to remind everybody that HELIOS-B is our outcome study with vutrisiran. So looking at all-cause mortality and cardiovascular outcomes at 30 to 36 months. So it's a larger study than APOLLO-B and it's obviously over a longer duration. And we were incredibly pleased, as I said, with the APOLLO-B data because we were able to demonstrate clinically for socially significant results in that very short small study. I mean most but it's for heart failure, much larger.

And that's small.

And much longer. So those's actually remarkable results. So we feel increasingly confident about the outcomes that we'll see from HELIOS-B. What we want to do is make sure that we're able to bring to patients the best possible profile for vutrisiran in addressing the needs of patients with cardiomyopathy. And we don't think it's worth taking the risk and spending alpha to do an interim assessment. I think the other important point is actually, we enrolled HELIOS-B much more quickly than we anticipated. So we're getting results from that study early 2024. So given the likely time benefit of doing an interim analysis plus the additional risk as I've described, it made much more sense to us to continue the [indiscernible]

Well, I am excited to see that.

Oh, we are too. We can't wait.

I'm excited to see the results of the ONPATTRO sNDA. Before we move on from ATTR, I just want to see if there's any questions from the audience on ONPATTRO, on AMVUTTRA, on the different markets. Yes, David, please.

On the APOLLO-B [indiscernible]

And just to repeat the question, where the subsector is too small to draw a signal or is there something there from APOLLO-B in terms of some of the other endpoints?

Look, I think you're spot on. As I said, the overall population was quite small. So when you cut that into subgroups, you're talking of even smaller numbers. And I think the important thing to do with the study is actually look at the holistic data set that we have and draw conclusions from that.

Great. Thanks, David. So I'm going to move into the pipeline because it's just -- it's such an exciting time for the company. As I mentioned, you're moving really the RNAi chemistry to treat major diseases. And I think we're going to see RNA go to a lot of different important areas. One of my favorite drugs that you're working on is zilebesiran, which targets angiotensinogen for hypertension. Maybe you can describe that target. And what's going on with the cardia trials that should report next year?

Sure. Sure. I mean that's a really good question. And I think you talked about the opportunity for RNA therapeutics for our platform in treating much more present conditions. And I think zilebesiran for hypertension is an exemplary program for this, where the potent and durable knockdown that we're able to affect the infrequent regimens, tonic control. I think, really has the opportunity to transform the treatment of some of these larger diseases, if you like, bring kind of a vaccine-like approach to some of these larger diseases. So we're very excited by this. And of course, the numbers of patients that were studied with inclisiran and treated with Alexion have really emboldened us about the sort of safety profile of this platform. So our Bison is a very innovative approach, targets angiotensinogen and already in our Phase I studies, we've shown the ability of sand reduce systolic blood pressure by 20 millimeters of mercury, which is actually pretty impressive considering you need a reduction of 5 millimeters of mercury to achieve regulatory approval. So we feel this is a really, really exciting program that I completely concur with you. especially given that hypertension is actually the biggest driver of cardiovascular mortality and morbidity. So it's going to be a really important medicine. We could not think two studies. The first, the Cardio 1, which is assessing zilebesiran as monotherapy in patients with mild and moderate hypertension. And really, the objective of the study is to identify the appropriate dose regimen for Phase III. And that study is in about 375 patients study should be enrolled by early 2023, and then we get the results, obviously, after that. The second study is Cardio II, which is assessing zilebesiran on top of standard of care. So the patients who are already receiving antihypertensives like RAS inhibitors inclisiran channels, blockers and success there would actually be replicating what we saw in Phase I combination cohorts, again, demonstrating the ability to robustly and durably knock down angiotensinogen and see those benefits through blood pressure. But importantly, of course, safety and tolerability, avoiding some of the adverse events that are seen with other antihypertensives. And so it's a large study, about 800 patients. So again, we'll be seeing those results in the not-too-distant future. So I think zilebesiran is definitely a program to watch. And I personally hope that if we're successful with the program, we'll be able to change the outcomes for patients.

There really hasn't been a lot new in that space in a long time. So this could be really innovative, meaningful therapy.

I mean this could be a game changer both for individual patients, but actually if you take a step back and think about the impact of the 100 million patients in the U.S. that have hypertension, much of which is poorly controlled as well as those that actually are at a high risk of cardiovascular adverse events. We have an opportunity to really make an impact not just at an individual patient [indiscernible] sort of population, I would say.

So in the summer you guys talk about kind of now doing even multiplexing. And I think you talked about this cool Cardio Gemini program. Maybe I don't want to spend too too much on there because there's some much to cover, but just to introduce that concept because that's really cool.

So again, just kind of take a step back. I mean we are the leading RNAi company as you described upfront. And I think we're a platform company. And that means that we need to continue to invest in enhancing our platform. We have developed a [indiscernible] enhancement called [indiscernible], where we're able to deliver profound knockdown and durability that lasts a year. So that's one platform enhancement. Another opportunity is the multiplex siRNA,so you could address more than one target with a couple of SIs. So this is again an opportunity as we think about expanding the opportunity for the platform going forward.

In the region of [indiscernible] cardiovascular makes so much sense, you could hit hypertension, lipids, one therapy. It's really cool.

Yes. There are all sorts of opportunities with this multiplexing approach going forward.

You guys have a strong relationship with Regeneron. One of the drugs you guys are working on together is some [indiscernible], which targets C5 component [indiscernible] You reported positive data in IgA nephropathy. Tell us about the data and what are your plans to develop that with Regeneron there, but also another in the case.

So we've partnered with Regeneron, both for [indiscernible] and monotherapy as you say, weekly shared results from a Phase II study in patients with IgA nephropathy. We were leading that program. with Regeneron. Regeneron, again, partnered with us, a leading combination approach with both cemdisiran as well as their C5 monoclonal antibody. And they're progressing two sets of studies. One with a combination in patients with myasthenia gratis, in the second combination of patients with PNH. And whilst we're partnered with them. They are actually leading that set of studies. So we are really pleased with these results then I think we're able to -- it's just another proof point, if you like, for the platform where cemdisiran a very small study. in patients with IgA nephropathy, we're able to demonstrate a 37% reduction in UPCR, which we believe is clearly meaningful 24 and that was at 32 weeks. And obviously, there are many, many glomerianephistic diseases that could be considered actually for a program like around. But at the moment, kind of given the positive results from that Phase II study, we're currently working on plans for Phase III study with our partner, Regeneron.

Again, a massive unmet medical need yes. The program that I'm super excited to hear about next year also partnered with Regeneron is ALN-APP for early onset Alzheimer's disease. I mean this is walk-off home run, win the World Series and the Super Bowl, all in one.

And the World Cup.

And the World Cup. And the Stanley Cup.

I am a soccer fan.

And the World Cup. Maybe just the World Cup. That's Even bigger than the others.

Yes. Well, well done to U.S.

So please describe this approach. And why my an RNAi approach be superior to the antibodies, and we've seen kind of going after these targets?

Yes. [indiscernible] also very excited about ALN-APP. It's our first CNS program. It's using the C16 ligand, which we've been able to demonstrate has very broad distribution in the brain and penetration into a variety of cell types in the brain. And in nonhuman primate studies shown that a single intrathecal administration is able to maximally lower APP by 80% and out at 50% at 6 months. pretty impressive data in the nonhuman primate setting. Of course, how many in a huge business yes. And that study is ongoing Phase I study. And in that study, obviously, very important to tree that we're able to engage with the target and knock down APP and we're measuring that through soluble APP alpha and beta. And obviously, safety and tolerability very important here as well. So that study is progressing, and we anticipate having results from that single ascending dose part of the study in early 2023. Now I think the monoclinal antibodies, I'm so pleased that we're beginning to process for patients with Alzheimer's with a monoclonal antibody approach, but we think there are some unique features of RNAi that actually bode well for addressing the needs of patients and early onset Alzheimer's disease. We're also thinking about a power program in patients with cerebral amyloid angiopathy. The reason to believe I think personally by knocking down amyloid precursor protein, we're actually switching off the tap at a resource and preventing all the downstream products as opposed to addressing specific isoforms, like the monocline antibodies do. I think the second thing I think is quite intriguing is the antibody is, obviously, buying to amyloid protein outside the cells. The opportunities that we have with the mechanism RNA interference is that we can address the production of APP not just outside the cells but also inside the cells. So we're progressing thoughtfully with the study, as I said, first venture into CNS, but we're also looking forward very much the results in early 2022.

And it's not the exact thing, but I've always actually thought that ONPATTRO and AMVUTTRA in terms of knocking down aggregates, obviously, not in the brain and in a different tissue type. To me, we're kind of an initial proof of concept for what you're ultimately hoping to achieve here in the CNS.

You're spot on.

I've always thought that.

You are absolutely spot on. I mean I think what we're hoping to do in CNS is replicate exactly what we're able to do in the level with amyloid. So obviously, it's a different tissue. different disease but still good luck that because that's a really, really important I mean if we can achieve success here, I think it really opens up the opportunity for addressing just the enormous unmet medical need that we all know existence [indiscernible]

So we don't have a ton of time left. If you haven't taken a look at on Alnylam pipeline side recently, take a look at it because we could literally spend probably another 1.5 hours going through individual programs.

Yes, that actually is a remarkable thing about Alnylam. I think a lot of people focus on TTR appropriately because we've launched ONPATTRO and now and AMVUTTRA being able to address these of many, many patients there. But I think it really is the fact that we have the sustainable innovation engine that can continue to deliver innovation on an ongoing basis for the [indiscernible]

Multiple CTAs are indeed every year now going forward.

Absolutely.

And you ended the third quarter with a very strong cash position, $2.27 billion. I think that's around $1 billion. How long does this fund the company? And what -- and even more important than that, what enabled you to achieve?

Yes. Well, as an important question. We really have a very strong foundation, a very robust balance sheet. And clearly, given that we have revenue generating products on the market, we have the opportunity to grow revenues throughout the next period. And we intend to obviously grow revenues much faster than we grow expenses. And that should allow us to become profitable -- we've talked about our [indiscernible] '25 goal, profitable -- sustainably profitable by the end of that period. And therefore, we don't need to tap the capital markets to get additional investment to progress our pipeline. And as well as that, we're able to commit to developing, as you pointed out, a number of INDs. Two to four INDs is the goal, steady state. And so I think we're able to continue to deliver great commercial performance of our marketed drugs as well as progress these pipeline opportunities, as you said, without having to access additional capital.

And it is a great team that you are honored to lead. I know so many people at on Alnylam and they just open what they do. So congratulations on what you're doing, [indiscernible]

Yes. I mean just to build on that, that I think you've touched on. I'm so enjoying this interview because we've touched on some of the key points. I think I think really what is unique about Alnylam in my view is not only do we have this technology that allows us to deliver transformative medicines on an ongoing basis. But we have amazing people that I'm very privileged to work with. And we have an incredibly enabling culture where people feel really excited about being able to bring this novel modality to meet the needs of.

We'll keep up the important work thank you for everything you're doing.

Thank you.

Thanks, everybody.

Awesome. Thanks, everybody.