Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY) Q4 2023 Earnings Call Transcript

Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY) Q4 2023 Earnings Call Transcript February 15, 2024

Alnylam Pharmaceuticals, Inc. beats earnings expectations. Reported EPS is $-1.1, expectations were $-1.2. Alnylam Pharmaceuticals, Inc isn’t one of the 30 most popular stocks among hedge funds at the end of the third quarter (see the details here).

Operator: Good day and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Q4 2023 Earnings Conference Call. [Operator Instructions] After the speaker’s presentation, there will be a question-and-answer session. Please be advised that today’s conference is being recorded. I would now like to hand the conference call over to the company.

Christine Lindenboom: 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.

Yvonne?

Yvonne Greenstreet: 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 the 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.

Further 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. Tolga?

Tolga Tanguler: 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 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 4 times a year administration.

We also continue to progress on increasing our prescriber base, which has grown over 50% since AMVUTTRA was launched in the third quarter of 2022. While we have been able to facilitate the development of 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. Pushkal?

Pushkal Garg: 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 10x larger with a global prevalence greater than 300,000 patients. And furthermore, we are committed to continuing to innovate from 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. Just 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.

And even today, with tafamidis and AMVUTTRA have 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 subcu 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 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 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.

And accordingly, as we shared at AHA last November, we were encouraged to see a favorable trend in mortality that separated beginning as early as 9 months and continuing to expand over 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 and 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 3x 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. And 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.

And 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 mortality. And 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, the 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. And we are enhancing the overall statistical powering of the study by incorporating up to an additional 3 months of event collection at the tail end of the study period. The most critical period and 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 3 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 on 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 3 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 in recurrent cardiovascular events.

This will now be tested in parallel in two populations, the overall population and the monotherapy population that 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 end point. 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 and statistical significance can be claimed for both. Alternatively, the study will be declared a positive study either of the p-values for the two analyses is less than or equal to 0.025. This study will be deemed positive in both or either of the analyses achieved 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 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 3-month extension in the overall study duration we are sharing today 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 end points 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 CV hospitalizations and helping exorable decline in functional capacity and quality of life, an attractive quarterly dosing schedule that aligns with physician visits, support 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 6 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 recent – 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 3 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. And 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.

And 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. Jeff?

Jeff Poulton: 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 and 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 head count 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 head count 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 [indiscernible] by ‘25 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, co-commercialization collaboration with Roche, $100 million from Regeneron for 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 OpEx 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.

And 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. Christine?

Christine Lindenboom: 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.

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Q&A Session

Operator: Thank you. [Operator Instructions] Our first question comes from the line of Ritu Baral from TD.

Ritu Baral: Good morning, guys. Thanks for taking the questions. Quick question on the updated stat 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 Adcomm. 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.

Yvonne Greenstreet: Thanks, Ritu. That’s a great question. And I just want to kind of underscore that we’re really confident on the potential effects of [indiscernible] outcomes and the [indiscernible] was already well designed and executed to deliver these results. And the changes that we’re announcing today enhance an already robust study given how important the study is for patients and for Alnylam. And clearly, as Pushkal said, we consulted with the FDA as we made these changes. It’s important to note that this is study that is focused on outcomes, and it’s outcomes that are most important to physicians, patients and payers. And that’s very different from base scenario assessing endpoints like 6-minute walk test and KCCQ, really, 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 happy for Pushkal to add any additional color to that.

Pushkal Garg: No, I think, Yvonne, you’ve really covered it. Ritu, I think we remain focused on both the overall population. And what we’re doing today is highlighting that based on all the learnings from APOLLO-B and in terms of delivering a strong and competitive label and aligning with what is – where we see the market being for the next several years that we’ve elevated our analysis of the monotherapy group. And as I mentioned, as Yvonne has highlighted, we’ve made these adjustments after consultation with FDA and other health authorities. And so we think that will support an approvable package.

Ritu Baral: Thank you.

Operator: Thank you. [Operator Instructions] Our next question comes from the line of Paul Matteis from Stifel.

Paul Matteis: Hey, thanks for taking my questions. I appreciate it. I totally agree with Ritu that these changes at base makes 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? Thank you.

Yvonne Greenstreet: Thanks, Paul. That’s a great question. Look, I mean, these changes were primarily influenced by learnings from APOLLO-B. And important to note, not just the 12-month data, with the open-label extension data at 24 months and beyond. And these data have really informed the enhancements that we’ve announced today. And I think for us, it’s important to make sure we had as much information as we possibly could prior to making any changes before database. And also as Pushkal emphasized, to make sure that we consulted with the FDA and other health authorities and that takes time. So I think we’re in this sweet spot, if you like, between really understanding all the data that we’re going to have prior to database lock and obviously, database lock beyond, which is not possible to make changes.

Pushkal Garg: Yes. I think building on what you said, Yvonne. Paul, I think, look, it makes sense for us to have the maximum amount of information before we make changes to an analysis plan as we’re announcing today. These are not changes in the operational conduct of the study – there to the analytic plan. And again, it makes the most sense to have as much information that’s come out of APOLLO-B. We’ve gotten – we were in a very fortunate position to run that study and gotten all the information that we did out of that study on a variety of endpoints to have that extended follow-up and then to have the opportunity to align with health authorities.

Paul Matteis: In the long-term APOLLO-B data, are you seeing a more pronounced monotherapy effect versus an effect on tafamidis on outcomes and tafamidis-treated patients on outcomes endpoints? Is that part of the nuance here?

Pushkal Garg: Paul, what I’d say is that what we’ve seen in the long-term data, and we presented some data last fall at the AdCom and then I think at HFSA are really encouraging to us in both populations, frankly, as it relates to outcomes, right? If you look at the monotherapy group, what we’ve seen was really sizable effects on a variety of endpoints, as I highlighted in my opening remarks, on a variety of endpoints that predict outcomes. And we saw a mortality separation. And as we’ve looked also in the combination group over time, what we saw was favorable effects on outcomes there as well. And so I think both of this just builds into our confidence. But I think certainly, what we’re seeing in monotherapy. And again, this is not just APOLLO-B, when we look back at the original APOLLO study when we look at HELIOS-A.

All of this really highlights a very compelling effect. When you look at that overall hazard ratio for mortality was 0.67 at 24 months in the overall population. So we have a lot of confidence in what we’re seeing here. And we think these refinements to the analysis plan will only optimize the study for success in getting a strong and competitive label.

Akshay Vaishnaw: Yes. Let me just jump in as well, Paul. This is Akshay. I think if we stand back and look just to put some numbers to what Pushkal has mentioned, in APOLLO itself, a hazard ratio for mortality 0.5:3. And that showed up as early as 6 months and then the curve started separating. In APOLLO-B, the hazard ratio for mortalities was 0.36 at 12 months, both in the monotherapy as well as [indiscernible], patisiran 1 is 0.67, as you said at 24 months. And this is now APOLLO-B, that’s half the size and changes showing up at 9 months and continue to separate since then. So I think the changes we’ve made today, I’m glad you agree why and a 3-month addition to further increase the robustness of the encouraging data we already see from APOLLO and APOLLO-B, I think just further consolidates that we anticipate a positive study, and we’re confident about that.

And today’s changes just further attest to our confidence in our approach. So I’ll leave it at that, but I hope that makes sense folks.

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

Operator: Thank you. [Operator Instructions] Our next question comes from the line of Ellie Merle from UBS.

Ellie Merle: 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 the powering of key secondaries like mortality? And your latest expectation for what we could see on the mortality secondary, particularly in the monotherapy arm? Thanks.

Yvonne Greenstreet: Yes. No, that’s a great question, Ellie. And as you note, that we took the decision to streamline the secondary point because we really want to focus on the most clinically important end points to support differentiation. We’ve seen evidence of disease stabilization and this doesn’t appear to be true of evidence generated with stabilizers. So we’ve really been thoughtful about what are the endpoints that focus on important clinical learnings and had therefore remove some of the endpoints from the hierarchical structure, but obviously, we will be looking at all those data as exploratory endpoints. But Pushkal, perhaps you could just go through a little bit of specific changes that we’ve made to the secondary endpoints?

Pushkal Garg: Yes, absolutely. So Ellie, what we’ve done is – obviously, the primary as we talked about, remains a focus on outcomes of death and recurrent CV events that we will be looking in the two populations. Then going down, we put 6-minute walk test in KCCQ next. We think we have ample power for those, and we think those are great endpoints based on what we learned from APOLLO-B to really demonstrate what we seem to see – be seeing is in terms of differentiated profile. Whereas patients on an RNAi therapeutic appear to have disease stabilization over an extended period of time. And while no head-to-head, it looks very different than the progressive decline that we’ve seen now in two pivotal trials with stabilizer therapies.

And so we look forward to hopefully seeing those patterns emerge again in HELIOS-B. The third endpoint is all-cause mortality. Obviously, that’s a higher bar than the primary endpoint. But again, based on what we’re seeing and while the study is primarily powered for the composite, we think it’s important to be able to demonstrate to look for all-cause mortality. And so we will be testing that formally in the secondary endpoint structure. And last, we’ve added an endpoint of NYHA class because we saw some very encouraging data merging out of APOLLO-B that suggested that, again, consistent with an emerging profile that this class of drugs can actually delay disease progression and stabilize the disease that we may see benefits on NYHA class.

And we think all of those are clinically important differentiating factors that may – that we want to make sure that we look at with the potential to include them in the label and differentiate in the marketplace.

Akshay Vaishnaw: Yes. And just building off that last point in Pushkal, I think you went through the different endpoints very carefully. From our perspective, we’re focusing on the most stringent outcomes, whether it’s mortality, hospitalization, quality of life, new [indiscernible]. This is what matters to us. It will show the true impact of this drug and it’s what matters to patients and doctors. And ultimately, we hope to get this into the label. And you note that we’ve avoided putting things like BNP and other endpoints, which we could have put in but we want to focus on the strongest outcomes. And I hope that’s a surrogate for the confidence we feel in what we can achieve with vutrisiran. So I’ll leave it at that.

Ellie Merle: Thanks.

Yvonne Greenstreet: Thanks, Akshay. Next question, please.

Operator: Thank you. [Operator Instructions] Our next question comes from the line of Kostas Biliouris from BMO Capital Markets.

Kostas Biliouris: Hello, everyone. Thanks for taking our questions. One question from us on the [indiscernible] so far Helios-B. Looking back at the acoramidis trial, we are wondering whether there was any information there in the readout last year that help you decide on the changes you are making? And maybe looking forward, how do these changes that you are making help you position AMVUTTRA compared to [indiscernible], which is reading out next year and also has a well-powered trial. Thank you.

Yvonne Greenstreet: 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? And maybe Pushkal, if you can take that question. And then there was a second question around how do these changes influence our views on the commercial opportunity and Tolga, it would be great if you would take that question. So Pushkal?

Pushkal Garg: Sure. Kostas, I think – look I think what was – a couple of things that we took away from looking at the attribute data that we’ve talked about in the past, I think first and foremost, I think it’s important to note that study as well as APOLLO-B for that matter. Enrolled patients in a contemporary era where we know patients are being diagnosed earlier in their disease through noninvasive means as opposed to what was done in the original ATTRACT trial. And what it showed is that patients in those earlier stages of disease can continue to grow events at a precipitous rate if they are not treated and that an effective therapy can show a benefit on top of that. Second of all, it also showed sort of confirming what was seen in the original ATTRACT study that patients with earlier stages of disease like NYHA Class 1 and 2 appear to have the largest magnitude of effect, right?

And three, as we’ve seen in lots of different outcomes trials, not just in this disease, but right, the longer exposure leads to greater separation of curves, right? And so all of those things were learnings that we learned and that patients with – on stabilizers continue to decline month by month in terms of functional ability and quality of life. And so – on average. And so I think – all of those are aspects that we look at, again, and sort of we’re in – to help inform some of the choices we made, in particular, but most importantly, it was the APOLLO-B results as well. As we look at them, again, no head-to-head studies, but we see a contrast in terms of the profile that’s emerging here of these classes of medicines and the end points and refinements we made really to use the opportunity to extend the double-blind period so that we can increase study power, to optimize the study endpoints – the primary endpoint structure to allow us to elevate the monotherapy and include secondary endpoints that can elaborate on some of those potential points of differentiation and disease stabilization that these other datasets seem to suggest.

Yvonne Greenstreet: Thanks, Pushkal. Great answer. Tolga?