Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Fourth Quarter 2021 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the presentation, there will be a question-and-answer session. Please be advised today’s conference may be recorded. I’d now like to hand the conference over to Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications.

Good morning. I’m Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Akshay Vaishnaw, President; and Jeff Poulton, Chief Financial Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today’s call is outlined on Slide 2, Yvonne will deliver introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Akshay will review our recent clinical and preclinical updates. And Jeff will review our financials, including 2022 guidance, followed by a summary of our upcoming milestones before we open the call for your questions. I would like to remind you that this call will contain remarks concerning Alnylam’s future expectations, plans and prospects which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recently quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I will now turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. 2021 was another year of tremendous success at Alnylam, in which we delivered impressive commercial performance and made significant advancements across our broad pipeline of RNAi therapeutics. To start, our commercial products, ONPATTRO, GIVLAARI and OXLUMO saw continued growth, primarily due to strong patient demand. In total, we achieved $662 million in net product revenue, representing year-over-year growth of 83%, delivering at the upper end of our guidance range. We’re also excited to have ended the year with a U.S. approval of the fourth RNAi therapeutic discovered by Alnylam, Leqvio, which is partnered with Novartis. We also advanced our pipeline programs at all stages of development. This includes our TTR franchise, where we recently presented full 18-month results from the HELIOS-A Phase 3 study of vutrisiran, Akshay will review these shortly. We also completed enrollment in our two pivotal Phase 3 studies in ATTR amyloidosis with cardiomyopathy, APOLLO-B and HELIOS-B. Furthermore, we advanced vutrisiran into Phase 2 with the initiation of KARDIA-1 and KARDIA-2, representing what we believe to be an opportunity to re-imagine the treatment of hypertension. Additionally, we advanced two more prevalent disease programs towards the clinic, including our first CNS program. Looking towards 2022 and beyond, we view a few strategic goals as key potential growth drivers for Alnylam. First is the potential expansion of our TTR franchise. In the near-term, with the potential approval of vutrisiran and the Phase 3 readout of APOLLO-B with vutrisiran, and over time, as we aim to become the global leader in delivering impactful and highly differentiated medicines to patients. The second key growth driver is our expansion beyond rare diseases into prevalent diseases. And the third growth driver for the company comes from our sustainable innovation engine comprised of new platform enhancements, opportunities with extrahepatic delivery and our ability to find new genetically validated targets, which offers the potential to drive further pipeline expansion to 2025 and beyond. Based on these opportunities, we believe we are well-positioned to deliver on our Alnylam P5x25 goals, making Alnylam a top biotech company developing and commercializing transformative medicines for rare and common diseases for patients around the world, driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine, all while delivering excellent financial results. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

Thanks, Yvonne, and good morning, everyone. We’re very pleased with our fourth quarter performance. The ongoing pandemic had considerable impact on our ability to engage customers via face-to-face interactions. However, our ability to leverage data and analytics for our promotional efforts and improvements in our virtual interaction capabilities have enabled us to finish 2021 with significant year-over-year growth. For ONPATTRO, we achieved $139 million in global net product revenues in the fourth quarter, representing 15% quarter-on-quarter growth compared with the third quarter and 53% growth compared with Q4 2020. And we achieved $475 million in global ONPATTRO revenues for the full year. As of December 31, over 2,050 patients were on commercial ONPATTRO treatment worldwide, with patient compliance remaining consistent above 90%. In the U.S., sales of ONPATTRO increased 17% versus Q3 and were primarily impacted by the following: patient demand, which increased 4% driven by the addition of new patients on therapy with patient compliance remaining consistent above 90% as noted. Inventory stocking in the distribution channel during the fourth quarter. Compared with destocking in Q3, favorably impacted U.S. reported growth by 15% during the quarter. This was expected given the low level of inventory in the channel at the end of the third quarter. We ended the year with approximately two weeks of inventory in the distribution channel, which is at the midpoint of our expectations. In our international markets, ONPATTRO fourth quarter performance remained strong, with growth of 14% versus Q3, primarily driven by increased patient demand broadly across Europe, Canada and Japan, as well as favorability in gross net deductions, positively impacting net pricing for the quarter. We also continue to observe a good balance of first-line use and switches from stabilizers. Moving to GIVLAARI. We achieved $41 million in global net product revenues in the…

Thanks, Tolga, and good morning, everyone. I’ll start with our efforts in ATTR amyloidosis, where we’re advancing two late-stage clinical product candidates, patisiran and vutrisiran. Also ONPATTRO is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary ATTR amyloidosis. We’re committed to expanding the product’s label for the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis patients. To this end, we are conducting the APOLLO-B Phase 3 study with, which we expect to report top line results in the middle of this year. We’re also advancing vutrisiran, which is delivered by a quarterly subcutaneous injection and is also in development for ATTR amyloidosis as well as the newly announced exciting opportunity in Stargardt disease. In ATTR, we’re conducting two Phase 3 studies. The first is HELIOS-A evaluating vutrisiran in hATTR amyloidosis with polyneuropathy. In 2021, we presented positive nine-month results from the study. We showed the study met its primary and secondary endpoints of nine months with an acceptable safety profile. These data form the basis for our regulatory submissions to both the FDA and EMA, and we look forward to a potential U.S. approval with the upcoming PDUFA date of April 14, 2022. Additionally, just a few weeks ago, we presented the positive full results for the 18-month endpoints from the study. As a reminder, HELIOS-A is a randomized open-label study in patients with hereditary ATTR amyloidosis polyneuropathy. The study enrolled 164 patients who were randomized 3:1 to receive vutrisiran at a dose of 25 milligrams administered subcutaneously once every three months or patisiran administered intravenously in once every three weeks at a dose of 0.3 mg per kg as a reference comparator. To start, serum TTR reduction in the vutrisiran group was rapid and sustained over a period of 18…

Thanks, Akshay, and good morning, everyone. I’m pleased to be presenting Alnylam’s Q4 and full year 2021 financial results, which underscore Alnylam’s strong commercial capabilities and operational excellence and reflect another impressive quarter of progress on our journey towards building a self-sustainable financial profile aligned with our P5x25 goals. After commenting on our fourth quarter and full year 2021 results, I will also provide our financial guidance for 2022. Turning now to a summary of our full P&L results for the quarter and full year. Total product revenues for 2021 were $662 million or 83% growth versus 2020, with all three marketed products contributing material year-over-year growth. Net revenue from collaborations for the fourth quarter was approximately $60 million, which included recognition of a $25 million milestone due from Novartis following the December FDA approval of Leqvio. Our non-GAAP R&D expenses increased 34% in the fourth quarter of 2021 compared to the same period in 2020, primarily due to an increase in expenses associated with our mid and late-stage pipeline, including investment in our two Phase II studies for zilebesiran in hypertension, KARDIA-1 and KARDIA-2, an ongoing investment in our two ATTR Phase 3 studies in cardiomyopathy, APOLLO-B and HELIOS-B. Our non-GAAP SG&A expenses increased 17% in the fourth quarter of 2021 compared to the same period in 2020 primarily due to increased investment in commercial and medical affairs activities to continue supporting ONPATTRO and GIVLAARI and the first full year of OXLUMO commercialization as well as legal expenses associated with the ongoing Department of Justice investigation. Our non-GAAP R&D and SG&A expenses were approximately $1.2 billion in 2021, representing 16% growth versus 2020 as we continue to advance our pipeline and deliver strong top line growth while maintaining discipline in how we invest in our operations. Our non-GAAP operating…

Thank you, Jeff. Operator, we will now open the call for your questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.

Our first question comes from Ritu Baral with Cowen.

Hi, guys. Thanks for taking the question. I wanted to ask, as you think about the vutrisiran approval and the vutrisiran label, how should we be thinking about potential inclusion of KARDIA subgroup data within the label? And should we expect any additional HELIOS-A cardiac data set presented at upcoming meetings that could either give us more insight into potential APOLLO-B placebo, whether that’s Alnylam data, whether it’s third-party data, et cetera? Thanks.

Thanks for your question, Ritu. I’ll just start off by saying that we’re really excited about the potential launch of vutrisiran later this year, because we really believe that vutrisiran has a compelling proposition really with its quarterly subcutaneous regimen allowing patients essentially freedom from their disease. And just one important point that I’d like to make, we do see the launch of vutrisiran is adding to our overall TTR franchise. We don’t see it as a net zero-sum game. And we also recognize that we’re still early with respect to accessing hATTR patients for polyneuropathy given that ONPATTRO has been able to secure about 2,050 patients, and there are about 30,000 patients worldwide that are still awaiting treatment. You probably are aware, I know this we too, that what we feel so pleased about is that we’ve been able to essentially replicate with HELIOS-A, both the nine months and the 18-month data, what we found in APOLLO. And I think this is an incredible achievement actually when you think about these studies being run at different times. So the patient population was very similar, and the results, as I said, we are very consistent between HELIOS-A and APOLLO. But perhaps, Akshay, I’ll ask you to comment on your views about the cardiac data and what we could expect there and what might be on the label.

Yes. No. Thanks, Yvonne. We were obviously very excited about the exploratory cardiac data, whether it’s the BNP, the echocardiographic and those essentially, as you said, were very similar to what we’ve seen in APOLLO, but most importantly, some new information on technician scan showing – than the potential amyloid mobilization with reduction in uptake in technetium. So that’s really exciting new information. And again, adds to our confidence in our subsequent work in APOLLO-B and HELIOS-B. So we continue to feel very good about the potential for both ONPATTRO, patisiran and vutrisiran in the cardiac context in those studies. As far as the label is concerned, whilst those exploratory data, we believe are exciting and speak a lot about the potential for the drug. HELIOS-A was designed and executed exactly as closely as possible to APOLLO, and we expect a very similar label frankly, Ritu. The data that I’m talking about, we’ve largely shared, but there’ll be additional data coming out at meetings through the year, further going into the HELIOS set. But to your specific question, I don’t know that those data will shed light on the natural history of the cardiomyopathy and the other features you’re alluding to, as we look forward to the APOLLO-B data, which will be handled to food in the middle of the year, actually. So, I think that’s where I’ll leave it.

Got it. Thank you.

And Ritu, just as a reminder, with respect to HELIOS-A, of course, the patient population is hATTR with cardiomyopathy.

Our next question comes from Gena Wang with Barclays.

Thank you for taking my questions. Just one question regarding the guidance assumption. I assume the main driver would be the ATTR franchise. Wondering if you can give a little bit more color regarding the assumption you have for ONPATTRO and vutrisiran for 2022?

Yes, that’s a great question, Gena. This is a very important part of our go-forward growth opportunity, TTR franchise, we believe that we will be the leaders in this area in terms of meeting the needs of all patients with TTR over time. Tolga, perhaps you could speak specifically to how we’re thinking about vutrisiran and ONPATTRO. I know that one the things that we’re really pleased about actually is the stickiness that we’re seeing with ONPATTRO with a greater than 90% adherence, which actually is remarkable for a therapy that’s administered intravenously every three weeks. As I said before, I think the profile of vutrisiran is particularly compelling. As I think – as I said, the important point here is that we see the launch of vutrisiran in polyneuropathy is growing the overall TTR franchise. And clearly, that will continue to grow over time, assuming, of course, positive data for both ONPATTRO and vutrisiran from APOLLO-B and HELIOS-B, respectively. But perhaps, Tolga, you could provide some additional perspectives on how you see ONPATTRO and vutrisiran over the course of this year?

Sure, sure. Good morning, everyone. Listen, I mean, I think you really made the point around the fact that we – the guidance we have provided assumes an accelerated growth for our TTR franchise. That’s our anchor franchise. Also, at the same time, our other ultrarare disease products will certainly be contributing to that and punching above their weight. When it comes to vutrisiran, Yvonne is spot on. I mean this is not going to be a zero-sum game. We do anticipate a number of patients that may not have been benefiting from ONPATTRO will certainly find the profile that we have very appealing, subcutaneous three months and then subsequently six months. We believe that’s going to accelerate overall growth profile. And also, as you also pointed out, we are barely scratching the surface in terms of the number of patients that are being diagnosed and treated. We have 30,000 patients across the world, and a very small number of those are being treated despite the fact that there are three products available out there. So with the product profile, if approved, for vutrisiran polyneuropathy indication, we certainly see an accelerated growth in the U.S. after the PDUFA date April 14. And then subsequently also, we do anticipate two launches in Japan and Germany later in the fourth quarter, which probably will not contribute as much, but it’s going to help the momentum.

Thank you.

Our next question comes from Tazeen Ahmad with Bank of America.

Hi, good morning and thank you for taking my question. Could I ask one on KARDIA-1. You do have your top-line results, Phase 2 that are due by this year-end as you mentioned. What should we be looking for what you would consider to be clinically meaningful data there? And what would be a good comp on the competitive landscape to kind of judge effectiveness against? Thanks.

Yes. No, thank you for that question, Tazeen. As I’m sure you all know, we are really very excited about the potential that zilebesiran has in addressing patients with hypertension. Just to remind you, we’ve already demonstrated what we need to demonstrate from an efficacy perspective for an approval in our Phase 1 study, after just a single dose, we’re able to affect blood pressure lowering of between 10 millimeters and 20 millimeters of mercury, which is actually tremendous. Clearly, we need to deliver only two Phase 2 studies and then move forward into Phase 3. But I think from my perspective, what’s really kind of exciting about zilebesiran is, firstly, the size of the opportunity in a very prevalent population, 1.2 billion people across the world have hypertension, but also the very straightforward path to regulatory approval here. And clearly, KARDIA-1 is a key step along that journey. So, I’ll ask Akshay now to maybe speak a bit more specifically about what we’re looking for with respect to outcomes from KARDIA-1. And then I will turn it over to Tolga to provide some views on the competitive landscape.

Yes. Great. So as Yvonne said, I think we should once again recall really the very dramatic and impressive results from the Phase 1 study with over 20-millimeter mercury drop in blood systolic blood pressure at the top dose and maintained out through six months. Now the KARDIA-1 study will hope to replicate the blood pressure results we saw in the Phase 1 study. Historically, anything above a 5-millimeter mercury drop in blood pressure seems to be notable and people would advance those kinds of drugs into further development. We would hope to do better than that based on what I just told you. Now whether we’ll see exactly what we saw in the Phase 1 study, I don’t know. But I’m confident we can do better than that in KARDIA-1 than the 5-millimeter threshold I just said. I think the other thing to remember about what’s clinically meaningful with the angiotensinogen approach and why maybe sort of not entirely right to just compare it to a blood pressure reduction number is the way blood pressure is being reduced with zilebesiran. So yes, absolute reduction in blood pressure is important but preventing fluctuations in blood pressure and having a smooth and tonic control of blood pressure is important to patients, and we hope zilebesiran can do that, yet inside think of that from KARDIA-1. And restoring the physiological nighttime dipping, but that blood pressure patients often lose, that will be important. So there’s so much more to zilebesiran than just a star blood pressure reduction number is the way it’s done and the features I talked about as well as the adherence advantages with having a potentially once every three or six-month administration of the drug. So, I’ll stop there. Lots to look forward to, I think, in KARDIA-1. But Tolga, do you want to say something about the landscape?

Sure. I mean, look, this is clearly a highly genericized class, but this is why I think Alnylam’s underlying technology is so exciting that allows us to really rethink the entire – how to actually manage medicine. In this, despite the fact that there are easily accessible genericized products in this category, we still have 40 million Americans that are suffering hypertensive-related diseases. And the U.S. is spending about $100 billion according to ACC for that. So, I believe from a category perspective, this approach is going to be a tremendous benefit to the broader society. And we are, obviously, when it comes to different therapy areas, we are obviously ahead of that curve right now in terms of providing an entirely new class of medicine.

That’s great. Thanks, Akshay and Tolga. Tazeen, does that answer your question?

Yes. Thanks for the color, Yvonne.

Thank you.

Our next question comes from Paul Matteis with Stifel.

Great. Thanks so much and congratulations on all the progress and getting close to $1 billion in product revenues, a big milestone. I wanted to ask a question on APOLLO-B. I guess there’s right or wrong debate in the investor community on the trial design and powering and how to make sense of the BridgeBio result. I guess now that you’ve digested their data, can you just point us to the one to two reasons why you’re confident that on 6-minute walk tests, you’ll see decline for placebo and APOLLO-B and that you’re confident in your powering assumptions? Thanks so much.

Thank you, Paul. That’s a great question. So look, we’re very confident, and we’ve reiterated this point about our track record in executing studies in the TTR space. And we believe that we put all the mechanisms and we have the expertise in place to design studies, train the sites, work with vendors, et cetera, to make sure we have delivered the highest quality data. Now you probably know as much about the BridgeBio data as we do. So, we’re not going to really speak to BridgeBio specifically. But I’ll hand it over to Akshay to reprice our perspectives on APOLLO-B.

Yes. Thanks, Yvonne. So Paul, I mean, I think, yes, you know the same data as us, but it’s hardly, I think we’d all agree a full explication of the data, right? We would love a full presentation. There’s lots more to understand. So, we have partial glimpses, I think, a variety of different explanations over time have been offered by BridgeBio colleagues. That’s obviously for them to speak further to their study, but context, bias, trading effects on network distance, all of these have been mentioned by BridgeBio leaders. So more for them to comment there. The one thing that struck us about their data, at least what’s public is that the 6-minute walk distance didn’t seem to perform and yet other parameters, BNP and KCCQ showed exactly or very similar to what happened in the ATTRACT study at 12 months. So it’s hard to reconcile that. And I think there are explanations or putative explanations around trading effects, contacts, bias, et cetera. You should be borne in mind because of the three parameters BNP, KCCQ and 6-minute walk distance, the last one would be influenced by those kinds of features. And so again, that’s what we say see and say from the outside more for them to comment than I think us. For our part, we’ve worked in this area for over a decade. We have designed studies in the TTR basis, significant Phase 3 studies. We’ve replicated data across studies. I think the HELIOS-A example, where we were just discussing earlier in the call, where the design of the study execution and the data delivery looks so similar to what happened in APOLLO, and APOLLO was designed in 2013 or executed in 2013. So it shows that we – I think we take great care, and we know how to test hypotheses in the space very diligently and rigorously. And so we continue to feel very confident in our APOLLO-B work and how we’ve designed it and powered it conservatively to hit the primary endpoint of 6-minute walk distance. And we’ll have the data all too soon, middle of the year.

Our next question comes from Alethia Young with Cantor Fitzgerald.

Hey guys, thanks for taking my questions and congrats on all the progress over 2021. I guess just talking about maybe the trend lines between patisiran and vutrisiran potential approval and launch. I mean, do you expect kind of the ramp speed to be about the same? Or do you think the vutrisiran has the potential to have a faster ramp speed since he’s already if you kind of know about the class of drugs and the subcu things?

Thank you, Alethia. That’s a great question. I mean, look, we’ve been really pleased with the performance of ONPATTRO. We’ve demonstrated steady and continuous growth since the launch in 2018. So, we’re delighted with the contribution that, that has made to patients, but also to building Alnylam. Look, vutrisiran just has such a compelling profile given its quarterly subcu regimen, hopefully soon to become a six-monthly regimen. And we do believe that we have a real opportunity to grow the polyneuropathy market with vutrisiran and then subsequently assuming positive results from HELIOS-B, cardiomyopathy as well. But Tolga, perhaps I’ll hand this question over to you. I mean how do you see vutrisiran and ONPATTRO performing in the market over the next year or so?

Right. Hi, Alethia. Thank you for that question. And thanks, Yvonne. Look, we’re able to grow that franchise at 55% after third year of its launch. So clearly, the progress we made on, in terms of growth has been good. Next year, we will continue to obviously grow ONPATTRO until vutrisiran is in the market. Based on the profile that Yvonne indicated, we would anticipate the source of business we have is essentially mainly coming from academic centers, as is now the business is evolving more into the community centers. And I think the profile that vutrisiran has to offer will be very attractive to those physicians that are looking some different profile. And also, particularly in Europe, where the stabilizers are also indicated for polyneuropathy, a good portion of our growth has been coming from stabilizers, which are, as you know, daily oral tablets. Now instead of having an infusion without any premed and three month subcutaneous injection, clearly, is a very attractive profile for those patients that may still be on the stabilizer. So overall, we certainly see a modest accelerated growth that we’ve been able to post versus last year. And we will see that in an accelerated fashion. That’s the best way I would be able to describe it to you.

Yes, I’ll talk that’s great. So very excited about the TTR franchise overall. vutrisiran affords the opportunity to – for physicians and patients to start treatment earlier in patients with polyneuropathy and obviously, in the U.S., patients who have the mixed phenotype as well. And then as Tolga said, potential for earlier switch, just given the much reduced treatment burden of vutrisiran. So hopefully, that’s answered your question, Alethia?

It does. Thank you.

Our next question comes from Anupam Rama with JPMorgan.

Hey guys, thanks so much for taking the question. I have a quick question on the net product guidance. So what is assumed specifically for OUS growth and sort of geographic expansion driving growth versus a deeper penetration in the U.S. in some of your core countries that you’ve kind of outlined in the slides for ONPATTRO, GIVLAARI and OXLUMO? Thanks so much.

Thanks, Anupam, that’s a great question. Look, if you think about the different products, ONPATTRO been on the market now for three years, less opportunity for geographical expansion because we’ve actually managed to work our way through the various pricing reimbursement systems ex-U.S. very well, and we have incredibly good coverage in the U.S. as well. GIVLAARI, clearly earlier in its launch, and we see their continued geographic expansion. Just recently, the NICE approval in the U.K. speaks to that point. And OXLUMO, we’re really 2021 was our first full year since launch. I think what we’re particularly pleased about there is really broad utilization across all age groups, disease severity. And I think we’re benefiting in Europe with respect to OXLUMO with the centers of excellence that you see there, which meant the patients already being diagnosed as well as being able to transition patients from our expanded access program, and those were dynamics that we clearly didn’t have in the U.S. And as we look forward, I think we see continued geographical expansion for the more recently launched products, GIVLAARI and OXLUMO as well as continued penetration. And for ONPATTRO, we see across the world, increased patient demand to new prescribers. And so we expect to see continued penetration in the U.S. and outside the U.S. But what I’ll do, maybe I’ll hand it over to Jeff to provide a little bit more color on how we’re thinking about the year ahead. Jeff?

Thanks, Yvonne. Good question Anupam. We’re not breaking out specific geographic detail. But I think Yvonne outlined the sort of the key elements of what’s going to drive our ex-U.S. growth. And it really depends on time on the market. The longer the products have been on the market ex-U.S., the more it’s about naive patient finding. And in the case of our ATTR franchise, there’s still a big switch element. Products that have been on the market a shorter amount of time still will benefit from additional geographic expansion. So in this case, OXLUMO will be the one that will benefit the most from that going forward. So that answers the question.

Thanks so much guys.

Yes. Thanks for the additional color.

Our next question comes from Salveen Richter with Goldman Sachs.

Good morning. Thanks for taking my questions. So you have two data reads this year in tissue targets outside the liver. Could you just speak to the ALN-APP and HSD readouts? And whether you could establish a proof-of-concept with these reads and what you’re specifically looking for clinically?

Yes. Thank you for that question, Salveen. Look, I’m particularly excited about the opportunity to extend the power of the R&I platform outside the liver. I think this opens up a whole new horizon for Alnylam we think about our growth over the next several years. And as you said, ALN-APP we’re very excited to be moving that forward in patients with Alzheimer’s disease. HSD is obviously a liver director target. I think what we’re excited about with respect with HSD is the size of the NASH patient population. And therefore, this is a much more prevalent disease opportunity. So I’m going to hand it over to actually to, first of all, just very briefly describe what we’re expecting to see out of our ALN-APP proof-of-concept study, we’ll be getting clinical data at the end of this year and then also the ongoing Phase 1 study with HSD and NASH. So Akshay, over to you to maybe address those two programs.

Yes. Thanks, Salveen. So with respect to ALN-HSD, which, in fact, is a liver target therapeutic and HSDs was exclusively present in hepatocytes. So for NASH, some of the key readouts beyond safety, of course, which is very important, will be evidence of knockdown, and we’re taking biopsies in this study. So you can’t detect HSD in the circulation. And hopefully, the biopsies will support kind of knockdown we’re getting. We’re obviously confident in that, given what we’ve seen with many other liver-directed therapeutics without GalNAc conjugate system. And in addition to that, we would welcome seeing changes in transaminases. They’re often abnormal in patients with NASH, and some improvements there would be encouraging, of course, as would changes in the biopsy because we won’t get definitive biopsies. It’s a small study and a definitive readout that some changes in the histological parameters of NASH relating to inflammation and/or fibrosis would be exciting to see. But again, a small study, short-term treatment. So it would be, frankly, very surprising if we see that, but we would love to see that if we could. So that’s for HSD. For APP, CNS-directed therapeutic for Alzheimer’s and for cerebral amyloid angiopathy. First and foremost, safety. This is our first foray into the central nervous system with our novel conjugate system for neuronal tissues. And then beyond safety, we’ll be looking for and – knockdown tissue target engagement. And so APP, amyloid rise protein generates a host of fragments that are detected in the cerebrospinal fluid, and we’ll be looking for changes in those degradation fragments from the proteolytic breakdown of APP, one of which most importantly is a itself. So that’s what we look forward to from those two studies, but agreed exciting times and great to see the RNAi going beyond the liver.

Thanks, Akshay. And probably of course, we announced today that our Phase I study has kicked off with an ALN-APP. So we’re looking forward to the data that actually described at the end of this year. So terrific progress. We’re very, very pleased.

Thank you.

Our last question comes from Maury Raycroft with Jefferies.

Hi, good morning. Congrats on the progress and thanks for taking my question. I have a question on APOLLO-B. For the study, you’ve got 14 sites in the U.S. and then 52 sites ex-U.S. listed. Just wondering if you can say what proportion of patients in APOLLO-B are going to be from the United States versus ex-U.S.? And then as a follow-up, can you talk about sites overlapping between your APOLLO-B sites and the BridgeBio sites?

Thanks, Maury. I think I’m going to pass that question right across to Akshay.

Yes. So Maury, I mean, I think as we’ve shown before, the performance of our drugs at least in our definitive experiences in hATTR-PN both in the shape of the original APOLLO study with vutrisiran, and now with vutrisiran, in the context of hATTR-PN show very similar effects regardless of geography, frankly. And that’s been published, you can go and look it up, et cetera. So that’s important to bear in mind because of the centrality of TTR to these diseases, whether it’s PN or other disorders like cardiomyopathy as we believe. So we’re looking forward to similar data consistency of effect regardless of geography in APOLLO-B and HELIOS-B eventually regardless of the site split. And with regard to overlap of size, we don’t get into those details. But because largely, we don’t know if it’s that relevant, frankly, again, because of the strength of our hypothesis, we believe that TTR targeting approach is the most potent way to address this disease and the consistency of our prior data speak to that. And again, the encouraging exploratory cardiac data from HELIOS-A to further attach to exciting information we’re looking forward from APOLLO-B later in the year, including I’d remind everybody the potential of cardiac mobilization that we saw with the technician date in HELIOS-A. But I’ll leave it there. Thanks, Maury.

Follow-up question.

Well, maybe a quick follow-up. I guess, if there are overlapping sites between the two studies, are you getting firsthand insight into the training effect in bias issues that you’ve discussed in an walk test? And have you been able to mitigate some of those issues?

Yes. The bias issues and the training issues, we have reflected commentary from BridgeBio. We don’t see any such issue in our studies, either historically or otherwise. And with respect to our studies, we take great care in understanding the natural history of these diseases, in carefully designing the study, in conservatively powering and designing the statistical approach to the study and then selecting the right contract research organizations to work with who have experience with the kind of endpoints and managing the kind of sites we want to work with. And then during the study diligently following up and making sure sites are performing per expectations. That’s a sophisticated approach. That’s one we’ve honed over a decade. We’ve done multiple Phase III studies, all of which have been positive up until now across a range of drugs, including multiple drugs in the TTR space. For BridgeBio, this was their first Phase 3 study, and they would have to answer how many of those kinds of things were put in place. And they have made the commentary about contacts, bias, training effects, et cetera. And so I’ll leave it there Maury. Thanks.

Okay, very helpful. Thank you.

Thanks, Akshay. Look, and thank you, everyone, for joining us on this call. 2021 was a remarkable year for Alnylam. I mean we made significant progress, both commercially and scientifically and we’re very excited about 2022, which is shaping up to build further on that as we continue to fire on all cylinders. Thank you, everybody, and have a great day.

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