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

Awesome. Hi, everyone. This is Maneka Mirchandaney from the Evercore ISI biotech team. Very, very thrilled to be here with Alnylam for our next fireside chat at a very exciting time for the company. From the team, we've got Yvonne Greenstreet, who's current President and COO and incoming CEO. So thank you for joining.

And Yvonne, to start, it must be such an exciting time for you. Also, I just want to say how awesome it is to have another female CEO at a leading biotech. But maybe to start, just give us a quick sense for what you've been focused on at Alnylam since you joined in 2016.

Yes, that's great. Thanks, Maneka. And look, it's a pleasure to be here, and thank you so much for having me. It is a real honor to be taking over as CEO of Alnylam next year. I mean I think John has just done such a superb job over the 19 years to bring in RNAi therapeutics and deliver medicines that have a transformative impact on patients. So over the last 5 years, obviously, I been working very closely with John. But my areas of focus has been on really driving our progress -- programs, managing the portfolio, leading strategy and BD efforts and also running tech ops and quality. From a broader perspective, I was very involved with John, obviously, executing and the rest of the team our Alnylam 2020 Strategy from 2016, where we launched [ 4 ] products whilst building a very robust pipeline across our 4 strategic therapeutic areas: genetic medicines, cardiometabolic diseases, infectious diseases as well as CNS and OCA diseases. And at the start of this year, I kind of worked with John to put together our next 5-year strategy, which we're very excited about, our Alnylam P5x25, and we've been working towards delivering this next set of goals. So as you said, a very exciting time for the company, but we've only just begun, Maneka. There's a lot more ahead, so we're very excited.

So I think, Alnylam has clearly been one of the big success stories in biotech. It's so different from others that we've seen in the space that have been single product stories for a large part. As you think about like the next 10 years and your vision for the company, where do you see the biggest growth coming from here? And where are you excited to kind of take the technology?

Yes. I think given our sustainable innovation engine, we see multiple potential long-term growth drivers for Alnylam. I think the first thing to highlight is kind of our expansion beyond rare diseases into prevalent diseases. We believe that we have a derisked platform. We've generated significant safety data across the portfolio. And that given the potency and durability of this platform, yes, there's no better time than now really to address the unmet needs and diseases that affect tens or even hundreds of millions of patients around the world. And so we're developing zilebesiran, our RNAi therapeutic for hypertension and also programs in NASH, chronic HBV, gout and many, many others in the pipeline. So I think that's one key point, that extension beyond rare diseases. I think the second is going outside the liver. We've obviously had tremendous success targeting genes expressed in the liver, but there are so many other tissues to go after, like the CNS and I, which we're progressing with Regeneron, but also lung, muscle, adipose tissue, kind of even tumors. And our recent collaboration with PeptiDream to discover and develop new cyclic peptides to deliver RNAi therapeutics to a range of additional extrahepatic tissues, I think, is one kind of enabler for this strategy. And then I think, look, we have just such terrific scientists at Alnylam. And I think a third source of growth as we look to the long term is just the output of our continued platform innovation. A good example of this is our GEMINI platform, which could enable us to silence 2 separate genes with just 1 molecule, and this obviously has significant potential across a large number of disease areas. I think we'll also be able to continue to find new genetically validated targets, which will continue to drive pipeline expansion way beyond 2025. We invest in major databases, which have rich genome and phenotypic data. And over the last couple of years, our investment in these databases has real delivered a tremendous return, generating new targets like HSD17B13 for NASH, xanthine dehydrogenase for gout, and a recent discovery, which we're referring to currently as Gene X for visceral adiposity. So I think many, many growth drivers for Alnylam as we look out over the long term. And truly, our platform is the gift that keeps giving. So we're, as I said in my introductory remarks, we've really only just started to scratch the surface of this technology. There's so much more here to bring forward for patients.

Got it. And to that point, I mean, biotech is so vast these days, you kind of need eyes on all sides of your head. How do you make sure that other modalities don't overtake RNAi while you guys are focused on that? Which ones are you watching? And would you ever consider broadening the toolbox at Alnylam beyond RNAi?

No, no, that's a great question. I mean if you think about the historical trajectory here, there are many disease areas that have had room for multiple therapeutics and a range of different modalities. The advent of monoclonal antibodies is a very exciting step forward, but it [indiscernible] more molecules and both modalities coexist today. So I think the important thing is to recognize this is all about delivering innovation for patients and it's not a zero-sum game. But that being said, particularly with my kind of background in BD, we keep an eye on everything that's going on outside or competition regardless of modality. And we will, of course, consider value-adding opportunities. They complement what we do. But given how much we have in front of us, we do feel very well positioned across the therapeutic areas we're in. And there's a lot more in RNAi to go after. So we're not being complacent. We keep a close watch on what's going on outside the company. But we've got an awful lot to do within Alnylam at this point in time.

I know this is maybe a difficult question, but as you think about the next era of Alnylam with kind of U.S. as the home, is there anything you're thinking about doing differently versus how things have been done in the past?

Yes. I mean from a strategic perspective, as I said, John and I cocreated the P5x25 Vision, and I'm absolutely focused on ensuring that we're going to execute against that. It is just so rare in the industry to have a sustainable product engine like the one that we do. And we're going to continue to leverage this platform to drive organic growth. This again is so unusual in the industry and continue to bring transformative medicines to patients. Clearly, to meet the ambition that we have, we're going to have to continue to scale the company as we do this, and that obviously is going to be an area that we're going to be focused on doing over the next period.

Got it. Why don't we switch to some product-specific topic now, starting with TTR. And we've obviously got the vutrisiran approval coming up next year for the polyneuropathy population. How should we think about this launch? And is there a large group of patients that you think are waiting for more convenient subcu option? Or do you think this is mostly going to be ONPATTRO such as -- for the time being?

Just to remind everyone that vutrisiran is our subcutaneously administered RNAi therapeutic targeting TTI. It's administered once quarterly and is also being investigated using a biannual dosing regimen. As you pointed out, it's under review by the FDA with a PDUFA dates in April of next year. Assuming that we have a successful review and approval, we see no reason why ONPATTRO and vutrisiran won't have their places in the market. ONPATTRO has been approved now for about 3 years. There are over 1,875 patients. And importantly, an over 90% compliance rate, which I think is a really good indicator of the impact that this therapy is having for patients and their families. And so we expect that there are some ONPATTRO patients who are doing very well and will be reluctant to switch therapies. That being said, with the profile that vutrisiran has, it clearly brings a reduced treatment burden relative to the IV infusions of ONPATTRO. And this is likely to be a highly attractive profile for a significant number of patients, particularly patients that are starting therapy for the first time. I think the important point to make here is that we believe that vutrisiran will actually expand the overall polyneuropathy market opportunity for Alnylam across the franchise. In the U.S., the greater convenience of vutrisiran could mean that more HCPs decide to progress both a stabilizer and a silencer on patients who have a mixed phenotype. Outside the U.S., we may see an acceleration in switches from tafamidis, especially -- specifically in the EU and Japan, where tafamidis is currently approved for polyneuropathy. And importantly, we think that the many patients and health care professionals who are kind of in this wait-and-see category. They've been diagnosed but not yet treated. And they'll want to start treatment earlier with a medicine of the profile of vutrisiran once it's available. So we see that vutrisiran launch actually is expanding the overall polyneuropathy opportunity for us at Alnylam, and we're very excited about the upcoming launch pending successful approval.

Got it. The other big update in 2022 for the TTR franchise is obviously APOLLO-B data midyear. Maybe just give us a sense for what you think would be a win in this data set? I know there's been a lot of talk about stabilization of 6-minute walk. Do you think that's kind of a reasonable expectation for the ONPATTRO-treated patients?

Yes. So APOLLO-B is our Phase III study of patisiran in patients with either hereditary or wild-type ATTR cardiomyopathy. And as you pointed out, the primary endpoint is 6-minute walk distance at 12 months. And we're expecting top line results in mid-2022. What's a win? A win is clearly achieving a statistically significant outcome that will enable a filing of an sNDA because this would allow us to expand a patisiran opportunity to the much, much larger ATTR cardiomyopathy population. Now an even bigger win would be if we see stabilization of 6-minute walk distance. This wasn't achieved with tafamidis and ATTR-ACT, where patients continue to decline, albeit slower than placebo, although we need to recognize that everybody declines in their 6-minute walk distance, simply due to aging, actually regardless of disease condition. But we're confident in the silencer approach, in part due to the stabilization of the 10-minute walk test observed in APOLLO as well as demonstration by academic investigators of the 6 weeks of walked distance stabilization with patisiran treatment. And again, we're encouraged by the recent 18-month top line results from HELIOS-A studies. So we think we're in a really strong position here and I'm looking forward to seeing the data in the middle of next year.

So what's your view on just how large this market could be for the silencer? In terms of just the overall population and where we are with diagnosis right now and how high you think that, that could go over time?

Yes. So I think just starting with ONPATTRO and the initial label that we're seeking for vutrisiran, we think there are about 50,000 patients worldwide with hereditary ATTR amyloidosis. And about 25,000 to 30,000 present with symptoms of polyneuropathy, meaning they're eligible for treatment. If we're able to expand the label, we should be able to capture the full hereditary population of polyneuropathy and cardiomyopathy, so about 50,000 patients, but also importantly, the wild-type ATTR amyloidosis population, and that's currently estimated at 200,000 to 300,000 patients worldwide. So a very significant increase in the patient population that would be amenable with our TTR therapeutics. And we still think it's an underdiagnosed condition. But the introduction of multiple therapies to the market has helped to increase physician and patient awareness and improve diagnosis. As we compare silencers to tafamidis, while there have been no head-to-head studies. We believe that the TTR silencer and mechanism of action has really emerged as the best-in-class approach for the treatment of hATTR polyneuropathy. And so we're looking to extend this into the broader ATTR cardiomyopathy opportunity.

Got it. You guys hosted an awesome R&D Day recently. I wish we could go through every program in that, but unfortunately, we don't have the time. But I guess I'll ask you about hypertension. I think that's been a big focus for investors as well. We've got some Phase II data coming up next year, how are you thinking about, a, that data set? And then also just why the hypertension market is primed for disruption and with the silencer approach right now?

No, really good question. So zilebesiran is an RNAi therapeutic, but we're developing for the treatment of hypertension, as you said. And it really gives us the opportunity to completely transform how people think about this disease, which hasn't seen any innovation for decades. And the approach that we have with zilebesiran in terms of being able to achieve tonic control of blood pressure as well as addressing, which is, I think, a fundamental issue of compliance in hypertension, given the very infrequent dosing, quarterly or biannual, I think has the potential to completely transform outcomes for patients with hypertension. We've initiated both studies in our Phase II program. So there's Cardio-1, which is evaluating zilebesiran as a monotherapy, and Cardio-2 looking at zilebesiran as an add-on therapy in patients taking other agents, RAS inhibitors, calcium channel blockers, et cetera. And we're expecting to get initial results from Cardio-1 in late 2022. And as many people on the call are probably aware, the regulatory endpoints of hypertension are very straightforward. All we need to do is demonstrate blood pressure lowering, and we've already seen that. So we're pretty confident about the prospects for zilebesiran. We see it as a really big opportunity for patients to have a somewhat vaccine-like strategy for the management of the hypertension. And given the size of the market, we also think it's going to be a significant value driver for Alnylam as a business going forward.

Got it. Last question for me. There's a bunch of other data coming up next year. We'll get the first look at ALN-APP in the CNS, and also some updates for cemdisiran, for NASH and ALN-XDH, which one of these are you looking forward to the most to kind of be able to continue to expand the RNAi footprint at Alnylam?

Yes. I mean look, they're all exciting, I think, for different reasons. I mean first of all, ALN-APP, if we're able to unlock the potential in CNS opportunities, this really could give Alnylam the opportunity for significant value creation, but also deliver really meaningful medicines for patients. So I'm very excited about seeing some clinical data from ALN-APP program towards the end of next year. And then with respect to the other programs that you highlighted, cemdisiran, HSD and XDH, it's going to be a catalyst-rich year for us next year. And I think if we think about HSD and XDH, more programs that are being developed to treat prevalent indications. So HSD for NASH and XDH for gout. And I think these programs are going to further expand the clinical evidence of RNAi therapeutics in prevalent diseases and have the potential to contribute significantly to the next wave of growth for Alnylam. So lots of really meaningful clinical milestones to look forward to next year across rare and common diseases, which have the potential, not just impact patients, which is incredibly important, but also drive value for shareholders as well.

Awesome. Yes, definitely looking forward to an exciting 2022. I think that's all we have time for, but I really want to thank you, Yvonne, for joining us and looking forward to all of the data to come next year and beyond.

Thank you so much, Maneka. Thank you. Bye-bye.