Good morning. I am Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Medical Officer; and Jeff Poulton, Chief Financial Officer. Also on the line and available for Q&A is Akshay Vaishnaw, Chief Innovation 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, as outlined on Slide 2, Yvonne will offer some introductory remarks and provide general context; Tolga will provide an update on our global commercial progress; Pushkal will review pipeline updates and clinical progress; and Jeff will review our financials and guidance, followed by a summary of 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 of 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 recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as 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 turn the call over to Yvonne.

Thanks, Christine and thank you everyone for joining the call today. Alnylam made great strides in 2023, delivering strong progress across all areas of our business. This includes robust product growth for our four wholly earned commercial medicines, delivering $1.24 billion in global net product revenues and hitting the remarkable milestone of over 5,000 patients now on an Alnylam commercial RNAi therapeutic. We also extended our leadership in RNAi, including the first-ever demonstration of RNAi-mediated target gene silencing of a human brain and preclinical data showing for the first time delivery of RNAi therapeutics to adipose and muscle tissues. Zilebesiran also made exciting progress for hypertension with encouraging results in the KARDIA-1 Phase 2 study. Furthermore, with zilebesiran, we strengthened our business for the future through business development with a landmark collaboration with Roche. Looking forward, we are excited to continue this progress in 2024, delivering continued commercial execution, notable clinical trial readouts, and advancing programs across all stages of development. As you are aware, a key clinical milestone anticipated this year is the readouts from our HELIOS-B Phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy. As we indicated in our press release this morning, we are announcing a few updates to the analysis plan that we believe will enhance the study, enable the best demonstration of vutrisiran’s impact across the entirety of the patient population, and supports a strong and competitive label. Pushkal will walk through these updates in detail later in the call. We believe all of this puts us on track with our Alnylam P5x25 goals, making Alnylam a top-tier biotech developing and commercializing transformative medicines for patients around the world with rare and prevalent diseases driven by a high-yielding pipeline, the first and/or best-in-class product candidates from our organic product engine, all while delivering exceptional financial results. With that, let me now turn the call over to Tolga for a review of our commercial performance.

Thanks, Yvonne and good morning everyone. Q4 was another strong quarter for our commercial portfolio, with both our TTR franchise and our Ultra-Rare franchise, delivering growth in excess of 30% compared with Q4 2022. Total net product revenues grew 32% in the fourth quarter versus the prior year or 30% at a constant exchange rate as we continue to steadily increase the number of patients on each of our therapies. Let me now turn to a summary of our fourth quarter TTR performance. Our TTR franchise achieved $254 million in global net product revenues, representing a 10% increase compared with the third quarter and 33% growth compared with the fourth quarter of 2022. At the end of the fourth quarter, more than 4,060 patients were on commercial ONPATTRO or AMVUTTRA treatment worldwide, up from over 3,790 patients at the end of the third quarter, representing 7% quarterly patient growth. Now, let me provide highlights of our U.S. and international TTR performance. In the U.S. combined sales of ONPATTRO and AMVUTTRA increased by 5% compared with the third quarter and a robust 38% year-over-year driven by AMVUTTRA’s launch. The U.S. quarter-over-quarter growth was primarily driven by an increase in demand resulting from the strength of ongoing AMVUTTRA patient uptake, more than offsetting a decrease in ONPATTRO patients switching to AMVUTTRA. At the end of the fourth quarter, more than 85% of U.S. hATTR polyneuropathy patients are now on AMVUTTRA, a testament to its clearly differentiated market-leading profile, including rapid knockdown, reversal of polyneuropathy manifestations, well-established safety profile with thousands of patient years of experience, along with only four times a year administration. We also continue to progress on increasing our prescriber base, which has grown over 50% since AMVUTTRA's launch in the third quarter of 2022. While we have been able to facilitate the development of a multi-disciplined center approach for the treatment of hATTR polyneuropathy, driven primarily by cardiologists and neurologists in these centers. Now, let me turn to our international markets, where the TTR franchise growth increased by 18% compared with the third quarter and a strong 28% year-over-year. The quarter-over-quarter growth was driven by the following: demand growth driven by AMVUTTRA’s performance, including recent launches in Spain and Italy and continued strong ONPATTRO performance in markets, where AMVUTTRA is not yet available, an improvement in gross to net deductions in the quarter following price reductions in Q3, primarily in Germany that were highlighted on our Q3 call. Lastly, consistent with our prior years, growth in the fourth quarter was also favorably impacted by increased inventories in Japan and the timing of orders in various partner markets. In summary, AMVUTTRA with its market-leading profile is now available and reimbursed in all major markets across the U.S., Canada, Europe and Japan, driving robust patient and revenue growth in 2023 and we believe we are well-positioned for future growth. Moving to our Ultra-Rare franchise. GIVLAARI and OXLUMO delivered $92 million in combined product sales during the fourth quarter, representing an 11% increase compared with the third quarter and a solid 30% growth compared with the fourth quarter of 2022. We ended the quarter with more than 1,080 patients on our two Ultra-Rare products with approximately 650 patients on GIVLAARI and approximately 430 patients on OXLUMO, representing an 8% combined quarterly growth in patients on our Ultra-Rare products compared with the third quarter of 2023. For GIVLAARI, product sales increased by 10% in Q4 compared with the third quarter, with the following regional dynamics. A 7% increase in U.S. primarily driven by a higher net price achieved in the quarter due to favorable gross to net adjustments, a 16% increase in our international markets, driven by continued demand growth, timing of orders in partner markets, and favorable gross to net adjustments. For OXLUMO, well positioned as the market-leading therapy in PH1, we delivered a robust 14% increase in product sales compared with the third quarter, which was driven by the following: a 9% increase in the U.S. driven by demand growth; a 16% increase in our international markets, driven by increased demand; and the timing of orders in our partner markets. In conclusion, we are very pleased with the results in the fourth quarter with both our TTR and Ultra-Rare franchises, which delivered strong growth in patients on therapy during the quarter as well as robust year-over-year growth in revenues with both franchises delivering 30% or greater growth versus the fourth quarter of 2022. We are well positioned as we enter 2024 to continue delivering our medicines to more patients in need around the world. Now with that, I will turn it over to Pushkal to review our recent R&D and pipeline progress.

Thank you, Tolga and good morning everyone. I am going to begin with some important updates that we are announcing this morning regarding HELIOS-B. As you know, HELIOS-B is an outcome study being conducted to expand the label for AMVUTTRA to include the treatment of cardiomyopathy in patients with hereditary and wild-type ATTR amyloidosis. Today, ONPATTRO and AMVUTTRA are approved to treat polyneuropathy in patients with hereditary ATTR amyloidosis with an estimated prevalence of 25,000 to 30,000 patients worldwide. Assuming successful results from the HELIOS-B study and regulatory approval, we expect to expand into a market approximately 10 times larger with a global prevalence greater than 300,000 patients. Furthermore, we are committed to continuing to innovate for patients with this disease as we advance ALN-TTRsc04, another medicine that can deliver rapid knockdown with the potential for greater efficacy and once annual dosing through clinical development. Moreover, as illustrated in this graphic for the United States, we expect this already sizable market to continue to grow substantially in the coming years due to increasing disease awareness, earlier diagnosis and the availability of new treatments. Given these dynamics, we are laser-focused on bringing our industry-leading portfolio of potentially transformative therapeutics to ATTR-CM patients and being leaders in this important growth category. Now as we previously highlighted, between now and tafamidis loss of exclusivity anticipated in late 2028, we expect the market to be primarily monotherapy-driven given the cumulative costs of combination therapy. Our research with payers has confirmed that they plan to restrict combination use, given that it would drive substantially higher cost. Even today, with tafamidis and AMVUTTRA having non-overlapping labels, about 90% of commercial plans restrict combination use. More importantly, we have seen very limited instances in which two branded rare disease products are used in combination regardless of the therapeutic area. Assuming positive data from HELIOS-B and regulatory approval, we anticipate that vutrisiran has the potential product profile, including compelling efficacy, safety, and a quarterly subcutaneous dosing regimen to become primarily a first-line treatment for newly diagnosed ATTR-CM patients and a switch therapy for those who experienced disease progression with stabilizers and to be combined with the stabilizer in those limited situations where payers support access. Once tafamidis goes generic and again, pending the label, we believe that combination therapy will become more common. With this backdrop in mind, let’s now turn to HELIOS-B, why we are confident it’s poised for success and the endpoint refinements that we are announcing today. The reasons for our continued confidence are summarized here. The impact of TTR silencing with an RNAi therapeutic on cardiomyopathy was demonstrated in the 12-month APOLLO-B study. We believe these data are exceedingly informative and support the potential for vutrisiran to demonstrate an outcomes benefit in HELIOS-B. On functional outcomes such as the 6-minute walk test as well as quality of life, we saw evidence of disease stabilization over time. We also saw a profound impact on NT-proBNP and troponin, which are highly validated indicators of disease severity and prognosis. These four parameters, all of which showed the greatest magnitude of effect in the monotherapy setting are important predictors of cardiovascular outcomes, which we would expect to manifest in a larger and longer study like HELIOS-B. Accordingly, as we shared at AHA last November, we were encouraged to see a favorable trend in mortality that began separating early and continued expanding over the course of 24 months. While not powered for mortality, the hazard ratio at 24 months was 0.67 favoring patisiran and the benefits were seen in both the monotherapy and combination settings. We find these data very compelling as while APOLLO-B was too short and too small to establish an outcomes benefit, the impact on mortality appeared to occur earlier than seen in other ATTR-CM studies to date, was durable and in fact grew over time, despite crossover of all patients to active treatment at 12 months. Now moving on to HELIOS-B itself, the study is designed and powered to deliver outcomes and is twice as large and three times as long as APOLLO-B. Previous studies have shown that intervention in ATTR cardiomyopathy most benefits patients with NYHA Class 1 and 2, and the HELIOS-B study is enriched specifically for these patients as they are most likely to show the largest treatment effect. HELIOS-B provides the longest follow-up of any study conducted in ATTR cardiomyopathy to date. The study was conservatively powered at the outset with additional tailwinds that include over-enrollment by 10% and tafamidis based on the drop-in rates that are below the expectations of use to power the study. In fact, the tafamidis rates at baseline were 40%, substantially less than the 50% we had assumed when powering the study. So putting all this together, we have several key takeaways. First, existing plan restrictions and prior precedents suggest that for the next several years, the market is expected to be primarily monotherapy driven. Second, we have data from APOLLO-B that demonstrate substantial effects on multiple endpoints that provide evidence of a differentiated profile with disease stabilization, along with evidence of an early emerging benefit in mortality. Finally, and as expected, the treatment effect in APOLLO-B was shown to be largest in the monotherapy population, which was the dominant population of the study, and best suited to demonstrate the treatment benefits of patisiran. Today, we are announcing enhancements to the HELIOS-B statistical plan to optimize the study for success and a strong and competitive label. These changes are informed by the insights from the APOLLO-B data and emerging data from the field. With these optimizations, we remain focused on clinical outcomes of death and hospitalization, which are critical to all stakeholders, and plan to evaluate this in the overall population as well as the monotherapy population, which is expected to have the largest treatment effect and best demonstrate the drug’s true impact. We also are focusing the secondary endpoint structure on critical clinical elements that highlight the drug’s potentially differentiated profile and its benefits on stabilization of this progressive disease. We are enhancing the overall statistical powering of the study by incorporating up to an additional three months of event collection at the tail end of the study period, the most critical period for firmly establishing HELIOS-B as the longest placebo-controlled study conducted to date in ATTR-CM. Let me review the key changes one by one. First, we are sharing today that we are increasing the minimum follow-up in the study from 30 to 33 months, with variable follow-up to 36 months. This adds up to three months of event collection for the patients who enrolled later in the study, thereby providing greater statistical power. With these changes, approximately 60% of patients remaining in the study will have greater follow-up, with about 20% or a third more having follow-up all the way out to month 36. This is an important change as these three additional months of observation constitute a short, but meaningful prolongation during the critical late part of the study, which is when we expect to see the greatest number of outcome events happening in the placebo arm. As a result, this enhancement leads to greater study power as we know that survival curves typically diverge more and more over time, a phenomenon that was seen in the 24-month APOLLO-B data as well. Second, we are modifying the methodology used to analyze the primary endpoint. The primary outcome measure remains the composite of all-cause mortality and recurrent cardiovascular events. This will now be tested in parallel in two populations: the overall population and the monotherapy population, which is the subgroup of patients not on tafamidis at baseline. We are maintaining the analysis in the overall population, which has the largest sample size and an opportunity to show a broad effect across the full patient spectrum. We are confident that there is a combo effect as demonstrated by the fact that the overall population remains in the primary endpoint. In parallel, we are elevating an analysis of the composite in the monotherapy population, which constitutes the majority of the study population at 60%. Additionally, the analysis in the monotherapy population allows us to demonstrate the true impact of vutrisiran as the standalone treatment, providing a dataset that will be particularly relevant to patients, prescribers and others as it closely aligns with where we see the treatment landscape over the next several years. It’s important to note that these are not co-primary endpoints. Rather, the primary endpoint will be tested in parallel in both populations such that if each p-value is less than or equal to 0.05, statistical significance can be claimed for both. Alternatively, the study will be declared a positive study if either of the p-values for the two analyses is less than or equal to 0.025. This study will be deemed positive if both or either of the analyses achieve the predefined criteria for statistical significance. Based on our assumptions, as informed by APOLLO-B and other studies as well as the conduct and execution of HELIOS-B, we remain confident about HELIOS-B and its ability to deliver a positive result. Finally, we have streamlined the secondary endpoints. Specifically, the structure now includes the 6-minute walk test, KCCQ OS, all-cause mortality, and change from baseline in NYHA Class. These endpoints are considered clinically meaningful and will help to demonstrate the impact of vutrisiran on disease stabilization, and including them as formal secondary endpoints enables them to potentially be included in the label and support differentiation in the marketplace. Based on the three optimizations I’ve just outlined, here is the updated study design. I do want to note that the changes I have shared today were made after consultation with the FDA and other health authorities. We are supportive of this approach, particularly as it relates to the handling of the primary endpoint. With the three-month extension in the overall study duration, we are sharing today that the top line results are now expected in late June or early July. At that time, we plan to provide p-values on the primary and secondary endpoints as well as key details regarding safety. We also expect to provide some high-level information on subgroups, including patients on baseline tafamidis. Full results are expected to be presented at a scientific congress soon thereafter. Assuming positive results from HELIOS-B, we expect to submit a supplemental NDA to the FDA in late 2024. We are confident that the study updates I’ve just reviewed, refinements to endpoints and extension of the blinded study period further enhance the power of the study and our confidence that HELIOS-B will deliver a positive result. Assuming positive data and regulatory approval, we believe that vutrisiran will be well positioned to serve patients with ATTR cardiomyopathy, addressing unmet needs with the potential for a highly competitive market-leading profile, including a unique mechanism of action that works upstream of protein production and enables rapid knockdown of TTR, an impactful clinical profile with the potential to reduce mortality and cardiovascular hospitalizations, and helping to slow the decline in functional capacity and quality of life, an attractive quarterly dosing schedule that aligns with physician visits, supports strong adherence and provides the flexibility of in-office or at-home dose administration, and favorable payer dynamics, where coverage under Medicare Part B is expected to result in the majority of patients having zero out-of-pocket costs and where we also expect payers to favor monotherapies for the next several years. We look forward to sharing top-line results from HELIOS-B in the late June to early July timeframe, bringing this transformative medicine one step closer to patients. Let me now turn to some recent and exciting developments with ALN-APP in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy. The early clinical data from this program continue to be very encouraging. At CTAD, we presented data showing that single doses of ALN-APP achieved sustained pharmacodynamic activity up to 10 months after administration with marked reductions in A beta 42 and A beta 40, Amyloid fragments implicated in Alzheimer’s disease and CAA, respectively, as well as an encouraging safety profile. As we announced in our press release today, we are very pleased to share that the FDA has provided clearance to initiate the multi-dose Part B of the Phase 1 study in the United States. This decision came after we submitted additional non-clinical data as well as emerging clinical data from the ongoing Phase 1 study. The FDA has confirmed that multiple dosing in the Phase 1 study may proceed at doses as high as 180 milligrams every six months while a partial clinical hold remains for doses that are higher or more frequent than that. We are delighted by the FDA’s decision and are encouraged that we will be able to proceed in Phase 1 with multiple doses at levels up to and even exceeding all the dose levels that we plan to test in Part B of the study based on the high and sustained levels of knockdown that we have already seen with single doses of 75 milligrams in Part A. Let me now move on to highlight recent progress across the rest of the pipeline. For zilebesiran, we presented the KARDIA Phase 2 results, which demonstrated over 16 millimeters of placebo-adjusted reduction in 24-hour mean systolic blood pressure at three months after a single dose, with an encouraging safety and tolerability profile. On ALN-TTRsc04, we recently shared single dose data, which showed deep and rapid knockdown with mean serum TTR reduction up to 97% with durability supporting the potential for annual dosing. We also announced positive initial results from the Phase 1 study of ALN-KHK with robust target engagement and encouraging safety that supported continued development as a novel treatment for Type 2 diabetes. Wrapping up on the pipeline, we announced several exciting updates from our research portfolio at our R&D Day, including progress with extrahepatic delivery of RNAi to muscle and adipose, compelling new targets in areas of high unmet need, and advancement of RNAi in oncology with a Phase 1 study for ALN-BCAT, hepatocellular carcinoma on track to initiate early this year. This progress is accelerating as we plan to file proprietary INDs for nine programs by the end of 2025 against targets in the liver, CNS, muscle, and adipose. If we include partnered programs, we anticipate 15 new INDs by the end of 2025, representing a doubling of the Alnylam clinical pipeline by the end of next year. This remarkable and unique pace of innovation puts us in a great position to have a robust, self-sustainable pipeline that can deliver meaningful impact to patients across multiple disease areas. And with that, let me now turn it over to Jeff to review our financial results and upcoming milestones.

Thanks, Pushkal. Good morning, everyone. I’m pleased to be presenting Alnylam’s full year 2023 financial results and providing our financial guidance for 2024. Starting with a summary of our P&L results for the full year. Total product revenues for 2023 were $1.24 billion or 39% growth versus 2022 with both our TTR and ultra-rare franchises reporting strong growth of 35% or greater for the full year. The full year net revenue from collaborations was $546 million, representing more than a fourfold increase compared with 2022, with the increase being primarily driven by revenue recognized under our co-development and co-commercialization collaboration with Roche as executed in July 2023. Gross margin on product sales was 78% for the full year, representing a 6% decrease compared with 2022, primarily due to increased excess and obsolete charges due to canceling manufacturing commitments and the impairment of ONPATTRO inventory that had been manufactured for future demand associated with the ATTR cardiomyopathy indication for patisiran for which we did not receive regulatory approval, in addition to a higher royalty rate payable on net sales of AMVUTTRA. Our non-GAAP R&D expenses increased 15% for the full year, primarily related to increased headcount and infrastructure-related costs to support our growing pipeline and increased clinical costs driven by Cardio 1 and Cardio 2, two of our Phase 2 studies in support of our zilebesiran hypertension program. Our non-GAAP SG&A expenses increased 6% for the full year, lower than in prior years as we seek to increase the operating leverage associated with our existing commercial and corporate infrastructure. The 6% increase for the year was primarily driven by increased headcount-related costs and other investments supporting our strategic growth, including the global launch of AMVUTTRA. Our non-GAAP operating loss for 2023 was $60 million, representing a nearly $500 million improvement compared with 2022, primarily driven by strong top-line results, both in product sales as well as revenue from collaborations, as I previously highlighted. Delivering non-GAAP operating profit by the end of 2025 remains a key focus for the organization per our 2025 goals. Finally, we ended the year with cash, cash equivalents, and marketable securities of $2.4 billion compared to $2.2 billion at the end of 2022, with the increase primarily related to the $310 million upfront payment from our zilebesiran co-development and co-commercialization collaboration with Roche, $100 million from Regeneron for the achievement of the ALN-APP proof-of-principle milestone, and approximately $150 million from employee option exercises, offset by our operating loss for the year. We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile. Now I’d like to turn to our financial guidance for 2024. Starting with net product revenues, we are providing combined net product revenue guidance for ONPATTRO and AMVUTTRA, GIVLAARI and OXLUMO. Our guidance assumes foreign exchange rates as of January 31, 2024, which are noted in the footnote on our guidance slide. We anticipate combined net product revenues for these four products will be between $1.4 billion and $1.5 billion, corresponding to a 13% to 21% growth rate at January 31 FX rates. Consistent with 2023, we are providing constant exchange rate growth guidance for our net product revenues with a projected range of 13% to 21% as well, highlighting no current difference between our guidance using January 31 FX rates and 2023 constant exchange rates. The collaboration and royalty revenue guidance is $325 million to $425 million. We anticipate that collaboration revenue associated with our partnerships with Roche and Regeneron and LEQVIO royalties from Novartis will drive the majority of our collaboration and royalty revenue in 2024. Our guidance for combined non-GAAP R&D and SG&A expenses is a range between $1.675 billion and $1.775 billion, with the midpoint of the guidance range representing 9% growth versus 2023. Growth highlights for R&D expense in 2024 include increased clinical investment in our zilebesiran, TTRS-C04, and APP programs as well as growth in pre-PC and IND-enabling efforts across our preclinical portfolio as we continue to invest in creating new organic growth opportunities for the future. As a reminder, reimbursement from partners for R&D operating expenses for some partnered programs highlighted by zilebesiran is accounted for as collaboration revenue. Growth highlights for SG&A expense in 2024 include increased medical and commercial investment as we prepare for the potential launch of vutrisiran in the U.S. for ATTR amyloidosis with cardiomyopathy. Let me now turn from financials and discuss some key goals and upcoming milestones slated for early 2024. We will, of course, be executing on global commercialization of our products ONPATTRO, AMVUTTRA, GIVLAARI, and OXLUMO. We also intend to report top-line results from the KARDIA-2 Phase 2 study of zilebesiran as well as initiate the KARDIA-3 multi-agent combo study. We also expect three other trial initiations in early 2024, including the Phase 2 study of ALN-APP in patients with cerebral amyloid angiopathy, Part B of the Phase 1 study of ALN-KHK in Type 2 diabetes, and a Phase 1 study of ALN-BCAT in hepatocellular carcinoma. As Pushkal previously noted, we expect to report top-line results from the HELIOS-B Phase 3 study of vutrisiran in late June or early July. Let me now turn it back to Christine to coordinate our Q&A session.

Thank you, Jeff. Operator, we can now open the call to 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.

Good morning, guys. Thanks for taking the questions. Quick question on the updated statistical analysis. It makes a lot of sense, but I’m wondering about a certain scenario that is outlined on Slide 18 versus some of the proceedings of the APOLLO-B Adcom. If you succeed on the monotherapy population with a p-value of 0.025 only, what has FDA feedback been on this, just given the importance placed on combination therapy and lack of benefit from the prior proceedings? And could that lead to a more restrictive label for the drug versus second line or something based on your interactions on the SAP on this final SAP?

Thanks, Ritu. That’s a great question. I just want to underscore that we’re really confident in the potential effects of the HELIOS-B outcomes and the study was already well designed and executed to deliver these results. The changes that we’re announcing today enhance an already robust study, given how important the study is for patients and for Alnylam. As Pushkal said, we consulted with the FDA as we made these changes. It’s important to note that this study is focused on outcomes, which are most important to physicians, patients, and payers, and that’s very different from base scenarios assessing endpoints like 6-minute walk test and KCCQ. If we’re able to deliver the primary endpoint as we’ve described, we’re confident that this will be a study that should be approved by health authorities. But I’m happy for Pushkal to add any additional color to that.

I think, Yvonne, you’ve really covered it. Ritu, I think we remain focused on both the overall population and the monotherapy subgroup. What we’re doing today is highlighting that based on all the learnings from APOLLO-B, we’ve emphasized delivering a strong and competitive label and that we’ve elevated our analysis of the monotherapy group. As I mentioned, we made these adjustments after consultation with FDA and other health authorities. So we think that will support an approvable package.

Hey, thanks for taking my questions. I appreciate it. I totally agree with Ritu that these changes at base make sense. But I think my main question is why now? It feels like when the study started, we all knew that 33 months is better than 30, that your drug alone would probably have a bigger effect size alone and effect size, that could be a little bit diluted by tafamidis. So what changed? What have you seen in the blinded data? Is there something that’s more nuanced here that’s leading you to make these changes? And accepting the fact that there is going to be a small delay versus initial guidance?

Thanks, Paul. That’s a great question. These changes were primarily influenced by learnings from APOLLO-B. It’s important to note not just the 12-month data but also the open-label extension data at 24 months and beyond. These data have really informed the enhancements announced today. For us, it’s important to make sure we had as much information as we possibly could prior to making any changes before database lock, and also as Pushkal emphasized, to make sure that we consulted with the FDA and other health authorities, and that takes time.

Yes. I think building on what you said, Yvonne. Paul, it makes sense for us to have the maximum amount of information before we make changes to an analysis plan. These are not changes in the operational conduct of the study; they are to the analytic plan. And again, it makes sense to have as much information that’s come out of APOLLO-B over the extended follow-up.

Yes. Let me just jump in as well, Paul. This is Akshay. I think if we stand back and look at the data, we have had a lot of encouraging evidence supporting positive outcomes. The changes we’ve made today, just further consolidate our confidence in our approach.

Thanks, Akshay. That’s great. We will have the next question.

Hi, thanks for taking my questions. Can you just elaborate a bit more on the changes you did on the secondary endpoint analysis? Specifically, what the hierarchy is of this streamlined secondary endpoint analysis? And what this does for powering key seconds like mortality? And your latest expectation for what we could see on the mortality secondary, particularly in the monotherapy arm?

Yes. No, that’s a great question, Ellie. We took the decision to streamline the secondary endpoints because we really want to focus on the most clinically important endpoints to support differentiation. We’ve seen evidence of disease stabilization, which doesn't appear to be true of evidence generated with stabilizers. We’ve been thoughtful about what are the endpoints that focus on important clinical learnings, and therefore removed some of the endpoints from the hierarchical structure, but obviously, we will be looking at all those data as exploratory endpoints. Pushkal, can you go through specific changes that we’ve made to the secondary endpoints?

Yes, absolutely. So Ellie, what we’ve done is the primary remains focused on outcomes of death and recurrent cardiovascular events that we will be looking at in the two populations. We put the 6-minute walk test and KCCQ next, which we have ample power for. The third endpoint is all-cause mortality. This is a higher bar than the primary endpoint, but we think it’s important to be able to demonstrate and will be testing that formally in the secondary endpoint structure. Lastly, we’ve added an endpoint of NYHA class because we saw some very encouraging data emerging out of APOLLO-B that suggested that this class of drugs can actually delay disease progression and stabilize the disease. We think all of these are clinically important differentiating factors that may enable us to include them in the label.

Yes. Just building off that last point, we’re focusing on the most stringent outcomes, whether it’s mortality, hospitalization, or quality of life. This is what matters to us and would show the true impact of this drug, which matters to patients and doctors, and we hope to get this into the label.

Hello, everyone. Thanks for taking our questions. One question from us on the HELIOS-B study. Looking back at the acoramidis trial, we are wondering whether there was any information there in the readout last year that helped you decide on the changes you are making? And maybe looking forward, how do these changes position AMVUTTRA compared to its competitors which are reading out next year and also have well-powered trials?

Okay. If I heard you correctly, Kostas, I’m trying to understand whether there is any information from the acoramidis study that influenced these changes? Pushkal, can you take that question? And then there was a second question around how do these changes influence our views on the commercial opportunity? Tolga, it would be great if you would take that question.

Sure. Kostas, I think it’s important to note that both the acoramidis study and APOLLO-B enrolled patients in a contemporary era where we know patients are being diagnosed earlier in their disease. This shows that patients in those earlier stages of disease can continue to grow events at a rapid rate. The study highlighted that patients with earlier stages of disease, like NYHA Class 1 and 2, have the largest magnitude of effect. The longer exposure leads to greater separation of curves. This influenced some of the choices made today, particularly with lessons from APOLLO-B. The enhancements made to HELIOS-B are about increasing statistical power, optimizing the primary endpoint structure, and including secondary endpoints that elaborate on potential differentiation.

Yes. As Pushkal indicated, these analytical enhancements instill confidence in HELIOS-B's visibility to show clear benefits from vutrisiran on top of tafamidis as well as demonstrating the value of vutrisiran in a pure placebo comparison. HELIOS-B empowers us to position AMVUTTRA uniquely in first-line use as well as on the switch with tafamidis. The rapid knockdown and sustained effect of disease-closing proteins is very unique to AMVUTTRA, with a clear outcomes benefit and years of established safety. We believe AMVUTTRA will be well-placed prior to the potential market entry of eplontersen.

Absolutely. This is in the context of a rapidly growing market where we know that patients on current treatments are continuing to progress. So, with the profile described by Tolga, we are in a good position to drive broad commercial uptake of AMVUTTRA.

Thank you very much for taking my question. In terms of the primary readout, I know historically, you have released p-values as part of the update. Will you be sticking to that plan or is any additional data points you might be able to offer in the top line to allow for some level of differentiation between AMVUTTRA and the other therapies? When you look – since you are targeting really the front line here with your new analysis plan, what do you actually need in your mind to achieve in the study to be able to unseat tafamidis in the front line? Given that the trials are quite different, it’s not necessarily going to be easy to compare on a head-to-head basis.

Yes. To briefly answer your first question, we’ll do what we normally do, and we will share p-values on the primary endpoints and key secondary endpoints, as well as some qualitative assessment on safety. We will also present information on subgroups such as the tafamidis subgroups. As for your second question, we believe 75% of physicians think that patients on a stabilizer are still progressing, indicating there’s a significant remaining unmet need and a sizable potential to switch to AMVUTTRA, particularly before tafamidis’ LOE.

Hey. Good morning. Thanks for taking my question. Another one on HELIOS-B. Recognizing that the comparison is going to be versus placebo, what do you want to see in terms of how the event rate in the monotherapy AMVUTTRA patients looks relative to the monotherapy tafamidis patients?

Yes, Jessica, thanks for the question. It’s important to note this was not a head-to-head study looking at AMVUTTRA versus tafamidis. This study is primarily looking at AMVUTTRA or patisiran versus placebo where a proportion of the patients, 40%, are on background tafamidis. The primary analysis will be looking at this in the two populations: the overall population as well as the monotherapy population. We can certainly share more data as we go.

Great. Thank you so much for taking my questions. Pushkal, circling back on a prior question. Is this informed by blinded event rates tracking below your expectation? And then maybe separately, is this considered a formal protocol amendment? If so, will you incur any statistical penalties for changing the trial so late in the game? Any color there I much appreciate it.

Yes. Luca, let me take your second point first. There is no change to the operational conduct of the study. This was just a change in the statistical analysis plan. We outlined in the slides how the statistics around the primary endpoints are going to be analyzed, and there is no statistical penalty for that. With regard to the first question, the changes are really driven by what we have seen with APOLLO-B over the longer term and the patterns we’ve seen there.

I think it’s in Alnylam’s best interest to show definitive outcomes for vutrisiran. If there had been mass panic that the study design is wrong or too small, we could have made changes sooner. However, we have reiterated our confidence, and we now have a three-month extension to provide additional data that enhances the robustness of our work.

Good. I think we need to bring the call to a close. I would like to thank everybody for joining us today. As I have said, we are really pleased with the execution looking at 2023, hitting on our 2024 goals and continuing to develop the company. So thank you all and have a great day.

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.