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

Great. Good morning, everyone. My name is Jess Fye. I'm a large cap biotech analyst at JPMorgan. Delighted to be continuing the conference this morning with Alnylam, driven by a number of members of the company's management team up on stage. And just as a housekeeping note, we don't have to switch room for Q&A this year. We're going to stay in this room. There's going to be mic runners if you want to raise your hand and ask a question. If you don't want to do it the old fashion, then you can also enter a question electronically on the portal and I can read it off the iPad out here or you can listen to my question if you don't want to ask your own. But with that, I will pass it over to the company's CEO, Yvonne Greenstreet, for the presentation.

Thanks, Jessica. I have to say it's wonderful to be here in person to give us an opportunity to share an update on our progress at Alnylam. And I'm delighted to be joined on stage with my colleagues: Akshay Vaishnaw, our President; Jeff Poulton, our Chief Financial Officer; Pushkal Garg, our Chief Medical Officer; and Tolga Tanguler, our Chief Commercial Officer. Just heads up, as you know, during my remarks this morning, I'll be making some forward-looking statements. Now as many of you know, Alnylam has been the leader in advancing RNAi therapeutics as a whole new class of innovative medicines. RNAi therapeutics selectively target messenger RNA that encodes disease-causing proteins. And by doing so, it's able to act upstream of established classes like small molecules and monoclonal antibodies. We've established over the last 20 years or so, a modular and reproducible approach to designing new medicines and with 100% of the human genome in theory available for targeting for RNAi. This technology represents a substantial opportunity to significantly expand our ability to fight human disease. And leveraging this, we truly believe that Alnylam is poised to become a top-tier biotech in the years to come. So you can see here, 2022 was a banner year for Alnylam. We had many, many important achievements, particularly proud of all these achievements in my first year as CEO. But I'd like to highlight 3 on this slide. Firstly, the excellent progress with our commercial performance with strong growth in all of our wholly owned brands. We got landmark results from the eagerly anticipated APOLLO-B Phase III study. And then, in the summer, the regulatory approval and launch of AMVUTTRA, our fifth RNAi therapeutic. Now 2023 promises to continue this momentum with the first ever clinical data from RNAi therapeutic in the CNS and pending regulatory review, expansion of ONPATTRO into ATTR amyloidosis with cardiomyopathy. This will mark an important inflection point in the build-out of our TTR franchise. So we're now an established commercial organization. As I said, 5 RNAi therapeutics approved notably in under 4 years, a remarkable achievement. And here, you see results from the 4 products that we commercialize ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. And we're really pleased with the continued steady growth we delivered across this portfolio. We preannounced strong preliminary fourth quarter and full year 2022 global net product revenues. And in total, we achieved $894 million. Now this represents a year-over-year growth of 35% with Q4 quarter-over-quarter growth of 13%, a particularly impressive result. And these results reflect a couple of things. They reflect robust patient demand for our innovative and transformative products as well as excellent commercial execution. Now we're absolutely thrilled by our launch progress with AMVUTTRA, approved this past June in the U.S. for hereditary ATTR amyloidosis patients with polyneuropathy. In fact, we've added 400 patients on AMVUTTRA in just the fourth quarter last year, and this is double for patient adds in prior quarters achieved by ONPATTRO. And you know this reflects the attractiveness of the product profile to physicians and patients. We'll provide 2023 product revenue guidance and much more color on our commercial performance in our earnings call in February. But of course, we look forward to continuing this trend of commercial excellence across our marketed portfolio. In addition to our commercial assets, Alnylam has a robust, high-yielding clinical pipeline with the diversity of opportunity that you can see here across more than a dozen programs at all stages of development, seeking to address unmet medical needs in rare but also in prevalent diseases, silencing gene targets, not just in the liver, but also in the central nervous system. This is an industry-leading platform and arguably one of the most fulsome clinical pipelines in the biotech industry today. You can also appreciate on this slide, the substantial product ownership that we've retained for our pipeline, where we have global or 50-50 rights for the vast majority of our programs. Our focused R&D strategy driven by the selection of genetically validated targets has led to an impressive probability of success rate. And as you can see on the right of this slide, currently, our cumulative POS from Phase 1 to 3 over the last decade is a remarkable 62%, and this is far greater than industry averages of around 5% to 10%. This is a real testament to the power of our platform, combined with our focus on genetics. Now we've talked about our P^5x25 vision. And this is really aimed at establishing Alnylam as a top-tier biotech company with transformative medicines in rare and common diseases for patients around the world and with a robust and high-yielding pipeline of first and/or best-in-class product assets from our organic product engine, while at the same time, delivering exceptional financial performance. We believe that 2023 is going to have many milestones that's going to move us even further along in our quest to realizing this exciting vision. So how do we get to P^5x25? What I'd like to share with you a few key potential growth drivers that we believe can propel us on our journey to a P^5x25 and beyond. And I'm going to spend a few minutes just touching on each of these. Starting with the potential near-term expansion of our ATTR amyloidosis franchise, where we aim to become the global leader in delivering impactful and highly differentiated medicines to patients with all forms of ATTR amyloidosis. And most of you know, ATTR amyloidosis is a debilitating, progressive and oftentimes fatal disease caused by misfolding of the TTR protein, which accumulates in and damages a wide range of tissues, including the heart, the nerves and the gut. Now we're just at the beginning of this exciting growth opportunity for our TTR franchise. We're building off a foundation with ONPATTRO, where AMVUTTRA is off to a strong initial launch following as I said, approval this past June. Next, with positive APOLLO-B results in hand, we submitted the sNDA for ONPATTRO to potentially expand the label to include the many patients with ATTR cardiomyopathy. We expect a decision from the FDA by the end of 2023. Thereafter we see yet further expansion of the TTR franchise as we look forward to outcomes data from my HELIOS-B study and the potential approval of vutrisiran for ATTR with cardiomyopathy. And ultimately, ALN-TTRsc04 from our IKARIA platform, which provides the potential for a once annual dosing regimen with a greater than 90% knockdown of TTR. And we were thrilled last year -- truly thrilled to deliver positive results from the APOLLO-B Phase III study, where patisiran demonstrated important benefits in patients with TTR cardiomyopathy, hit on the primary end point with a statistically significant and clinically meaningful improvement relative to placebo in the 6-minute walk test at 12 months. Also achieved a statistically significant and clinically meaningful improvement relative to placebo at 12 months on the Kansas City Cardiomyopathy Questionnaire, the study's first secondary endpoint and a key measure of patient self-reported health status and quality of life. These are important measures: validated regulatory endpoints of how patients function and feel and a remarkable results when you consider this was just a 12-month study in 360 patients with cardiomyopathy. Importantly, in the study, patisiran demonstrated an acceptable tolerability profile. We're very encouraged by the overall safety of patisiran, including cardiac safety. Also shown on this slide is some exploratory results that highlight the clinical importance of the primary study results. In the 12 months of the APOLLO-B study, patisiran-treated patients were less likely to experience disease progression than those given placebo according to biomarker-based expert consensus criteria. And the planned cohort of patients in the same time frame, approximately 1/3 of patisiran-treated patients experienced a reduction in cardiac uptake of technetium, an indicator of amyloid in the heart. Now collectively, we believe that these results validate the therapeutic hypothesis that RNAi-mediated silencing of TTR has the potential to result in a disease-modifying impact on the cardiac manifestations of ATTR amyloidosis and further enhance our confidence as we look ahead to HELIOS-B. To that end, we also intend to expand the AMVUTTRA label to include the treatment of cardiomyopathy and hereditary wild-type ATTR amyloidosis patients. So we're doing this through the HELIOS-B Phase III study with vutrisiran. HELIOS-B is fully enrolled, has an endpoint of all-cause mortality and CV events assessed after at least 30 and up to 36 months. I'm pleased to say we're on track to share top line results in early 2024. Now if this study is successful and pending regulatory review, we believe that vutrisiran as a quarterly subcutaneously injected therapeutic could potentially become a best-in-class product for the treatment of all forms of ATTR amyloidosis, like the rest of you are eagerly awaiting the conclusion of this study. Now taking a step back and reflecting on the TTR franchise overall, we believe that we've successfully established a strong foundation in this space over the last 4-plus years. And given this foundation, we're now well positioned to potentially serve the needs of a much larger ATTR amyloidosis patient population with an established suite of commercial, clinical and manufacturing capabilities which could also be efficiently scaled to support our other programs addressing prevalent diseases in our pipeline. And now this is the key second growth driver for the company. Our expansion beyond rare diseases to also address some more common disease areas. Now encouraged by the efficacy and safety results from the many studies we've delivered with RNAi programs, we plan to leverage our platform to also address the many unmet needs of more common disease settings like hypertension, NASH and diabetes. Importantly, the pharmacological features of RNAi therapeutics are uniquely suited for the treatment of chronic prevalent diseases, where durable effects enable infrequent dosing to maximize adherence, and where clamped pharmacology creates the potential for improved efficacy and outcomes. Our first out-of-the-gate in this regard, is what we believe is a very compelling opportunity to address unmet needs and hypertension. Hypertension as you all know, is a highly prevalent disease with over 200 million people with primary hypertension in just the 7 major markets. And despite the widespread availability of treatments to manage the disease, more than 70% of hypertensive patients are not at their target BP goal. An increased cardiovascular risk is further exacerbated by variability in blood pressure control, inadequate nighttime control and poor adherence to therapy. And all of these factors together contribute to a substantial risk of CV morbidity and mortality. In fact, hypertension is the #1 preventable cause of cardiovascular morbidity and mortality. And this highlights the critical need for new differentiated therapies that can provide tonic control of blood pressure and improve adherence. Zilebesiran is our investigational RNAi therapeutic for hypertension, and we believe could transform the treatment of this disease. Our Phase I data highlight this potential, outstanding results, where we've demonstrated clear preliminary evidence the greater than 90% dose-dependent knockdown of angiotensinogen. A greater than 20 millimeters of mercury reduction in systolic blood pressure at 6 months following a single injection, tonic blood pressure control over 24 hours and durable reductions in the mediators of hypertension, namely ANG2 and aldosterone. And these attributes offer a highly differentiated profile from all existing antihypertensives, including RAS inhibitors. We're announcing today that our KARDIA-1 Phase II study is fully enrolled, thanks to our clinical colleagues as of December. And we're excited to deliver top line results in mid-2023. We also look forward to KARDIA-2 results at or around year-end 2023. So great progress with zilebesiran. Now we also look forward to growth opportunities and value creations not just from programs that we are driving, but from programs that were discovered by Alnylam but driven by partners. You can see a few of these here. One is ALN-HBV02 or VIR-2218, led by Vir Biotechnology. They're evaluating combination regimes as a potential functional cure for chronic HBV infection. We're looking forward to additional Phase II readouts this year, and we'll be making an opt-in decision ahead of Phase III. Another program, partnered with Sanofi is fitusiran. this is a first-in-class RNAi therapeutic targeting antithrombin. Sanofi is conducting multiple Phase III studies designed for patients with hemophilia A or B and with or without inhibitors. An additional Phase III data are expected later this year with an NDA submission potentially on track for 2024. And the last program I want to highlight is cemdisiran, an RNAi therapeutic targeting complement C5 combined with pozelimab, an antibody against C5 discovered by our partners, Regeneron. And Regeneron are evaluating the role for combination therapy with potent inhibition of C5 in ongoing studies in 2 complement-mediated diseases, myasthenia gravis and PNH. The third growth driver for the company comes from our sustainable innovation engine. Here, we'll continue to deliver future growth by finding novel targets, driving pipeline expansion to 2025 and beyond. We've continued to invest in major databases associated with rich genomic and phenotypic data like the U.K. Biobank and our future health. We'll also continue to maintain our leadership in RNAi chemistry. We are a platform-based company. And push the boundaries of this technology, bringing forward new program enhancements like IKARIA platform, the Reversir antidote, RNAi knockdown and the GEMINI, Bis-RNAi targeting 2 genes with 1 formulation. Extrahepatic delivery provides further opportunities for growth. We had great success targeting genes in the liver, but it's just one organ system, and there are a myriad of opportunities to target genes outside the liver, CNS, eye, muscle, adipose tissue, even tumors, and we continue to make good progress in this regard. Indeed, we're on the cusp of seeing important data from ALN APP which is our first investigational conjugate RNAi therapeutic targeting a gene expressed in the CNS and in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy. ALN APP has the potential to offer a highly differentiated approach in Alzheimer's disease by targeting APP upstream of where antibodies currently target. APP also has the potential to act both intracellularly and extracellularly to reduce disease causing peptides. We believe these initial clinical data with ALN APP, if positive, will be an important milestone, not just for this particular program, but for our overall CNS platform, where we hope to show that RNAi can achieve clinically relevant degrees of target knockdown to CNS with a safety and dosing profile to support further development. And we look forward to sharing top line results from this study in early 2023. So I'd like to wrap up now with a full list of our company goals for 2023. And these show that we have a very exciting year ahead. And in the interest of time, I won't walk through all of these. But at a high level, we look forward to ongoing commercial execution from the 4 Alnylam-earned products. 10 clinical readouts from proprietary and partner-led programs, the potential label expansion for ONPATTRO in ATTR amyloidosis with cardiomyopathy, assuming successful regulatory review. The first human data for RNAi therapeutics in the CNS and filing 2 to 4 new INDs from our organic R&D engine to bring new programs into the clinic and position Alnylam for sustainable future growth. Ultimately, we have an amazing platform, but our secret source at Alnylam is our people. And we're so proud of everything that we've been able to achieve in this remarkable company. Thanks to the employees who are fully committed to our mission. And we continue to be recognized across biotech and other industries for multiple elements of our culture, our leadership in scientific innovation, diversity, equity and inclusion is so important to our social responsibility, but first and foremost, a steadfast commitment to the patients that we serve. In closing, I hope I've conveyed to you the excitement that I and my colleagues share about building Alnylam into a top-tier biopharmaceutical company. We've got a bold vision, but the road map to get there is clear and actionable. And I hope that all of you share the same enthusiasm. So I'd like to thank you for your support and your attention and now transition to Q&A, which is in Jessica's capable hands.

[Operator Instructions]. So you preannounced some numbers, can't remember if it was yesterday or this morning at this point. But it looks like you're seeing really strong conversion over to AMVUTTRA to some extent from ONPATTRO. Can you talk a little bit about the dynamics you're seeing between the 2 products in polyneuropathy?

Yes, happy to that, and I'll turn it over to Tolga on the move, but I just really want to underscore how incredibly well received AMVUTTRA has been by patients and physicians. And I think it really comes down to efficacy and safety, but also the quarterly subcutaneous regimen, which essentially helps liberate patients from their disease. And we're seeing patients being treated earlier in the course of the disease. We're also seeing switches. And that's an area that I think we'd like to elaborate on a bit. So maybe Tolga, you can kind of talk about some of the dynamics that we're seeing.

Great to be here. It really is exciting to see the progress that we made with AMVUTTRA since the launch first in the U.S. 6 months and last November, December period in Japan and Germany. And when you look at the progress we made, I think it validates a couple of things. One is, first and foremost, there are a lot of patients still at need. This is a rare disease and there are thousands of undiagnosed and untreated patients that AMVUTTRA's profile is really providing support. Second is what Yvonne indicated, it validates the fact that AMVUTTRA's safety, efficacy and subcutaneous quarterly profile really sets it apart as the -- potentially to be the standard of care. And last but not least, is our commercial capabilities. We built the foundation over 5 years about the commercial capabilities. And we've been able to, from supporting patient diagnosis, securing formulary inclusions, all the way to making sure that the patients get access to this without any headwinds. Those are the dynamics. Now when you look at all these points, you essentially see that we've now added nearly double the number of patients within the last quarter that we've done historically with ONPATTRO in every quarter. So we're growing the pie. And last but not least, because the profile is so attractive both patients and physicians are switching over to ONPATTRO, but only -- that only represents 50% of our current total patient basis. So essentially, this is really growing the pie, and that's what we're really excited about.

Yes. We're really pleased with the dynamic. I think it demonstrates just how well AMVUTTRA's being received and the difference that we're able to make to patients. And I think the really important point that Tolga made is that we see this as an opportunity to grow the overall franchise.

So how important is the every 6-month data? And how much of a tailwind could that create on -- sort of on top of what you're already seeing?

Yes. That's a great question. But maybe just to kind of reiterate some of the points we've already made around vutrisiran, a quarterly subcutaneous regimen, which has been so incredibly well received, actually, I think, beyond our initial expectations. And I think 6 monthly would be a nice to have. But it's absolutely not a must-have. I think what we really have in our hands right now is a winning profile with the current formulation of AMVUTTRA. Anything else talk, Tolga?

Well, I mean, also, if you think of the competitive landscape, this -- the subcutaneous quarterly administration really sets us apart regardless of the 6-month data. But obviously, with the 6-month data, it could certainly help us as Yvonne put it, it's nice to have.

Yes.

Question in the audience? We have a mic up front.

Anybody who wants to ask questions, particularly about maybe our TTR franchise while we're on the topic, [ I am told you're ] very excited about it? Somebody?

Speak up and we can repeat it.

Would it benefit you if you had 100,000 family whole genomes and within each family, there's amyloidosis. Would it help you have that data set?

Well, I mean, look, we believe in the power of genetics. We already invest in a broad range of as I said, genomic and phenotypic data sets. So I don't know if you've got anything specifically in mind as you make that comment, but happy to follow up with you afterwards if there's something specific.

Well, I was told to ask the question by our Chief Medical Officer, he's not here, but it's Dr. Reynolds Delgado who's in the Texas Heart Institute in the Texas Medical Center and with 6 of the leading cardiologists primarily, transplant people primarily with amyloidosis, we've developed a whole genome screenings of entire families with the amyloidosis.

Yes. Well, we'd love to hear more about it. And maybe Pushkal Garg, our Chief Medical Officer...

I just happened to have our book.

Okay. Awesome.

So maybe sticking with TTR, but switching to the patisiran submission for cardiomyopathy. Have you gotten any initial feedback from the FDA on the sNDA? And do you expect a priority review or standard review time line?

Look, I'd just like to start off by saying that, as many of you know, we aligned with the FDA on the design and the conduct of the APOLLO-B study and we're absolutely delighted by the results, having flawlessly executed the study. And I shared with you some of the highlights of the data that we were able to generate for patisiran across multiple, multiple endpoints, not just the primary endpoint that I described, the 6-minute walk test or the KCCQ but also improvements in cardiac safety, patients receiving placebo compared to -- patisiran compared to placebo, numerical benefits and mortality and a number of exploratory endpoints. So we feel that what we've been able to submit to the FDA is actually a very compelling data package. And of course, is against the backdrop of significant unmet medical need in this area where patients continue to progress despite currently available treatments. So we think there's a real need to bring forward an innovation like ONPATTRO for patients with ATTR amyloidosis. That being said, we expect a standard review and the details of the review by the FDA as they consider the risk benefit will be something that I'm sure they will declare on in due course. And as I said, with the submission of the sNDA in December of last year, we expect a PDUFA date in quarter 4 2023.

We have one question on the portal here. Do you expect an advisory committee for that filing?