Alnylam Pharmaceuticals - Q4 2023

Transcript

Operator (participant)

Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Q4 2023 Earnings Conference Call. At this time, participants are in a listen-only mode. 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 (SVP 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 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 in slide two, 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. 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 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 recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only up to 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'll turn the call over to Yvonne. Yvonne?

Yvonne Greenstreet (CEO)

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 owned 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 the 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 a KARDIA-1 phase II study. Further, with zilebesiran, we strengthened our business for the future through business development with a landmark collaboration with Roche.

Looking forward, we're 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're aware, a key clinical milestone anticipated this year is the readout for HELIOS-B phase III study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy. As we indicated in our press release this morning, we're 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 support 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 of 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 (Chief Commercial Officer)

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 four 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've been able to facilitate the development of a multidisciplinary-centered 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 the 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're 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 (Chief Medical Officer)

Thank you, Tolga. And good morning, everyone. I'm going to begin with some important updates that we're 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 25,000-30,000 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. And furthermore, we're 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. Thus, 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've 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 a substantially higher cost. And even today, where tafamidis and AMVUTTRA have non-overlapping labels, about 90% of commercial plans restrict combination use.

More importantly, we've 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 experience disease progression with stabilizers, and to be combined with a 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're 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 six-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.

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 nine months and continued 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, an 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 I and II, and the HELIOS-B study is enriched specifically for these patients as they're 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 baseline and drop-in rates that are below the expectations we used 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. Putting all this together, we have several key takeaways. First, existing plan restrictions and prior precedent 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 demonstrates 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. 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 in 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.

But 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, 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're sharing today that we are increasing the minimum follow-up in the study from 30-33 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 on study will have greater follow-up, with about 20% or a 1/3 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're 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, that is, the subgroup of patients not on tafamidis at baseline. We're 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're confident that there is a combo effect, as demonstrated by the fact that the overall population remains in the primary endpoint. In parallel, we're 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 a 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, then 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. The 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've streamlined the secondary endpoints. Specifically, the structure now includes six-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. 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've shared today were made after consultation with the FDA and other health authorities who 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 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're 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 help the inexorable 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 monotherapy use for the next several years.

We look forward to sharing top-line results from HELIOS-B in the late June to early July time frame, 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 Aβ 42 and Aβ 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 multidose Part B of the phase I 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 I study. The FDA has confirmed that multiple dosing in the phase I study may proceed at doses as high as 180 mg every six months, while a partial clinical hold remains for doses that are higher or more frequent than that. We're delighted by the FDA's decision and are encouraged that we will be able to proceed in phase I 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've already seen with single doses of 75 mg 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 II results, which demonstrated over 16 mm 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 I 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 I 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.

With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff.

Jeff Poulton (CFO)

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 KARDIA-1 and KARDIA-2, two of our phase II 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 P5x25 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, AMVUTTRA, GIVLAARI, and OXLUMO. Our guidance assumes foreign exchange rates as of January 31st, 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-$1.5 billion, corresponding to a 13%-21% growth rate at January 31st FX rates. Consistent with 2023, we are providing constant exchange rate growth guidance for our net product revenues with a projected range of 13%-21% as well, highlighting no current difference between our guidance using January 31st FX rates and 2023 constant exchange rates. Collaboration and royalty revenue guidance is $325 million-$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 arranged between $1.675 billion-$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, TTRsc04, and APP programs, as well as growth in pre-DC 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 II 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 a phase II study of ALN-APP in patients with cerebral amyloid angiopathy, Part B of the phase I study of ALN-KHK and type 2 diabetes, and a phase I study of ALN-BCAT and hepatocellular carcinoma. As Pushkal previously noted, we expect to report top-line results from the HELIOS-B phase III 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 (SVP of Investor Relations and Corporate Communications)

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.

Operator (participant)

Thank you. As a reminder to ask a question, please press star one, one on your telephone and wait for your name to be announced. To withdraw your question, please press star one, one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Ritu Baral from TD.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Good morning, guys. Thanks for taking the question. Quick question on the updated stats analysis. This 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, for second line or something, based on your interactions on the SAP, on this final SAP? Thanks.

Yvonne Greenstreet (CEO)

Thanks, Ritu. That's a great question. I just want to kind of underscore that we're really confident on the potential effects that vutrisiran will deliver on cardiovascular outcomes and that HELIOS-B 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. Clearly, as Pushkal said, we consulted with the FDA as we made these changes.

It's important to note that this is a study that is focused on outcomes, and it's outcomes that are most important to physicians, patients, and payers. That's very different from a scenario where you're assessing endpoints like six-minute walk test and KCCQ. Really, if we're able to deliver the primary endpoints 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 (Chief Medical Officer)

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 where we see the market being for the next several years, that we've elevated our analysis of the monotherapy group.

As I mentioned, as Yvonne has highlighted, we've made these adjustments after consultation with FDA and other health authorities. So we think that will support an approvable package.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line, Paul Matteis from Stifel.

Paul Matteis (Managing Director and Head of Therapeutics Research)

Hey, thanks for taking my question. I appreciate it. I totally agree with Ritu that these changes at face make sense, but I think my main question is why now? It feels like when this study started, we all knew that 33 months is better than 30, that your drug alone would probably have a bigger effect size alone than 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's going to be a small delay versus initial guidance? Thank you.

Yvonne Greenstreet (CEO)

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, but 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 lock. And also, as Pushkal emphasized, to make sure that we consulted with the FDA and other health authorities. And that takes time.

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 it's not possible to make changes.

Pushkal Garg (Chief Medical Officer)

Yeah, 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. They're to the analytic plan. 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 (Managing Director and Head of Therapeutics Research)

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

Pushkal Garg (Chief Medical Officer)

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 in 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. We saw mortality separation. As we've looked also in the combination group over time, what we saw was favorable effects on outcomes there as well. 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, it 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 (Chief Innovation Officer)

Yeah, let me just jump in as well, Paul, this actually. I think if we stand back and look, just to put some numbers to what Pushkal just mentioned, in APOLLO itself, the hazard ratio for mortality was 0.53. And that showed up as early as six months, and then the curve started separating. In APOLLO-B, the hazard ratio for mortality was 0.36 at 12 months. Both in the monotherapy as well as the tafamidis arms, placebos around one, is 0.67, as you said, at 24 months. And this is now APOLLO-B, a study that's half the size. And changes showing up at nine months and continue to separate since then. So I think the changes we've made today, I'm glad you agree are wise.

And a three-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 to folks.

Yvonne Greenstreet (CEO)

Thanks, Akshay. That's great. We'll have the next question.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Ellie Merle from UBS.

Ellie Merle (Executive Director)

Hey, guys. Thanks for taking the question.

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 (CEO)

Yeah, no, that's a great question, Ellie. And as you noted that we took the decision to streamline the secondary endpoints because we really want to focus on the most clinically important endpoints that 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 have therefore removed some of the endpoints from the hierarchical structure.

But obviously, we'll 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 (Chief Medical Officer)

Yeah, absolutely. So Ellie, what we've done is obviously, the primary, as we've talked about, remains a focus on outcomes of death and recurrent CV events that we'll be looking at in two populations. Then going down, we've put six-minute walk tests and 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 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'll 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 emerging 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 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 (Chief Innovation Officer)

Yeah, and just building off that last point, Pushkal, I think you went through the different endpoints very carefully. And from our perspective, we're focusing on the most stringent outcomes, whether it's mortality, hospitalization, quality of life, New York Heart Association class, mortality. This is what matters to us. It'll 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.

I hope that's a surrogate for the confidence we feel in what we can achieve with vutrisiran. I'll leave it at that.

Yvonne Greenstreet (CEO)

Thanks. Thanks, Akshay. Next question, please.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Kostas Biliouris from BMO Capital Markets.

Kostas Biliouris (Director)

Hello, everyone. Thanks for taking our questions. One question from us on the changes to HELIOS-B. 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 that you are making help you position AMVUTTRA compared to eplontersen, which is reading out next year and also has a well-powered trial? Thank you.

Yvonne Greenstreet (CEO)

Okay, if I heard you correctly, Kostas, I'm trying to understand whether there's any information from the acoramidis study that influenced these changes. Maybe, Pushkal, if you can take that question. And then there was a second question around how did 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 (Chief Medical Officer)

Sure. Kostas, 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 non-invasive means as opposed to what was done in the original ATTR-ACT trial.

What it showed is that patients in those earlier stages of disease can continue to have true events at a precipitous rate if they're 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 ATTR-ACT study that patients with earlier stages of disease like NYHA Class I and II 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 without stabilizers continued 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 looked at, again, and sort of helped inform some of the choices we made, in particular, but most importantly, it was the APOLLO-B results as well. And 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 endpoints 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 (CEO)

Thanks, Pushkal. Great answer. Tolga?

Tolga Tanguler (Chief Commercial Officer)

Yeah, I mean, as Pushkal indicated, these analytical enhancements obviously make us very confident in HELIOS-B's ability to show added benefit on vutri on top of TAF, as well as obviously demonstrating the value of vutrisiran in a pure placebo. Now, HELIOS-B really empowers us to position our AMVUTTRA in a very unique way, both in first-line utilization as well as on the switch with the tafamidis until eplontersen comes into market. A couple of key, I think, attributes that we really need to highlight is the rapid knockdown and sustained knockdown of disease-causing protein is very unique to our AMVUTTRA.

It had, along with clear outcomes benefit in total population as well as in mono, halting the decline in functional capacity and quality of life, demonstrated years of safety, which we have already established with our cardiomyopathy indication, attractively sub-Q quarterly dosing, and also limited copay burden in patients. These are really going to be unique for our AMVUTTRA, which we believe is going to position us a year before potentially even eplon coming into the marketplace.

Yvonne Greenstreet (CEO)

Yeah, no, that's great. Just to add, this is in the context of a market that is growing really rapidly and a market where we know that patients who are on current treatments continue to progress. So with the profile that Tolga describes, we think we're in a really good position to drive broad commercial uptake of our AMVUTTRA, obviously assuming positive results from HELIOS-B and approval.

And both in first line, as Tolga described, but also switch from stabilizers. We've shown how AMVUTTRA has led to a significant switch in the polyneuropathy market. And we anticipate we'll see the same in cardiomyopathy as well with positive data. So I think the changes that we've made, I think, continue to support our confidence in the profile of AMVUTTRA and the potential that will be delivered in the cardiomyopathy market. Next question, please.

Kostas Biliouris (Director)

Super helpful. Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of David Lebowitz from Citi.

David Lebowitz (Senior Research Analyst)

Thank you very much for taking my question. In terms of the primary readout, I know historically, you've released p-values as part of the update.

Will you be sticking to that plan, or is there 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? And just kind of attached to that, when you look since you're 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? I mean, given that the trials are quite different, and it's not necessarily going to be able to be easy to compare on a head-to-head basis. Thank you.

Yvonne Greenstreet (CEO)

Yeah, just briefly, first question, look, we'll do what we normally do, and we'll 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. I hope that answers that question for you, Tolga. If you could just very briefly respond to David's commercial question.

Tolga Tanguler (Chief Commercial Officer)

Right. Look, we have extensive research that suggests physicians believe 75% of their patients on a stabilizer continue to progress or experience inadequate treatment, which indicates to us that there's a significant remaining unmet need and a sizable potential to switch to AMVUTTRA, and particularly prior to the tafamidis LOE when payers are implementing already restrictions on combo use. And as Yvonne indicated, we have actually already that great experience starting with ONPATTRO first and now with AMVUTTRA in ex-US markets where we actually did compete with great data.

Yvonne Greenstreet (CEO)

Great. Next question, please.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Jessica Fye from J.P. Morgan.

Jessica Fye (Managing Director)

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?

Pushkal Garg (Chief Medical Officer)

Yeah, Jessica, thanks for the question. Look, I think it's important to note this was not a head-to-head study looking at AMVUTTRA versus tafamidis. This is a study looking at AMVUTTRA or vutrisiran versus placebo where a proportion of the patients, 40%, are on a background tafamidis. And so really, the comparisons are of vutri to placebo in those two situations. And as we've said, the primary analysis will be looking at this in the two populations, the blended population overall as well as the monotherapy population.

Yvonne Greenstreet (CEO)

Thanks for your question, Jessica. Next question.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Luca Issi from RBC Capital.

Luca Issi (Senior Biotechnology Analyst)

Oh, great. Thanks so much for taking my question. Yeah, yeah, yeah. Thank you so much for taking my question. Maybe, Pushkal, actually, if I may, circling back on a prior question, maybe ask a little more directly, is this informed by blinded event rate tracking below your expectation? And then maybe separately, is this considered a formal protocol amendment? And if so, will you incur any statistical penalties for changing the trial so late in the game? Any call there, much appreciated. Thanks so much.

Pushkal Garg (Chief Medical Officer)

Yeah, Luca, let me take your second point first. There's no change to the operational conduct of the study. This is just a change in the statistical analysis plan. And we outlined in the slides really how the statistics around the primary endpoint are going to be analyzed.

So there's no statistical penalty for that at all. It's just a change to the analytic plan that we've talked about. So no, not at all. And with regard to your first question, I think I tried to highlight the changes are really driven by what we've seen with APOLLO-B over two plus years and the patterns that we're seeing there and our heightened confidence in terms of the impact of this class of medicines on this disease and what we can do to further optimize the study and set it up well for a strong and competitive label. Of course, we have, as we've said before, teams that are looking at the blinded data primarily to ensure excellent study conduct and execution, make sure the right patients are enrolled, make sure that the data are clean, make sure that we've got complete capture of all the events, etc.

And of course, they're looking at event rates, etc. But we're not going to be sharing dribs and drabs of the data, and that's not the driver here. Those types of event rates are extremely variable, subject to a lot of variability and interpretation. If I told you we had a very high event rate, you might say, "Well, that's because that's great. The placebo event patients are accruing events." Or you might say, "Wow, the drug's not working." Or conversely, if we have a low event rate, that might indicate that, "Oh, we haven't enrolled the right patients," or maybe the drug's working remarkably well. So the primary drivers here are what we understand about science, biology, and prior precedent from clinical medicine and clinical trials. And that's the driver.

Akshay Vaishnaw (Chief Innovation Officer)

Great. Let me just add, Pushkal. I think we've got to stand back a little bit.

It's obviously in Alnylam's interest for patients and for everybody concerned to show a definitive outcome for vutrisiran. If there had been mass panic at Alnylam that the study design is wrong or too small or too short, there are many changes we could have made, and we could have made them well in advance. We have reiterated our confidence over and over again in the study, as Pushkal's outlined today, deep insights from APOLLO-B, understanding the landscape. What you see today is a three-month extension for the last patient, giving a reasonable amount of additional data to just further enhance the robustness of what we're going to share with the world come June, July. I think it's well worth it. It reiterates our confidence in this study. We haven't fundamentally changed the design to a 1,500- or 2,000-patient study for five years.

If we were panicked, you would have seen those things some time ago. Others have done what they've done. You've seen what we've done. And on the backdrop of the scientific edifice we've built with the TTR mechanism in APOLLO, in APOLLO-B, I think we should have the confidence.

Yvonne Greenstreet (CEO)

Thanks, Akshay. Great. Next question..

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Salveen Richter from Goldman Sachs.

Salveen Richter (Biotechnology Equity Research Analyst)

Good afternoon. Thanks for taking my question. How much of a differential does extending the duration by three months provide instead of conducting the primary analysis at 36 months for all patients? And I'm asking this in the context of recently announced studies in the field that have flexible duration up to 48 months or based on events. So just any clarity there.

And then secondly, does the monotherapy analysis heighten the need to show significance on all-cause mortality alone, just given TAF's unlabeled benefit for frontline use?

Yvonne Greenstreet (CEO)

Pushkal, are you good to take this?

Pushkal Garg (Chief Medical Officer)

Yeah, absolutely. So Salveen, look, I think what we've done here is we think meaningfully add to the duration of the study or the experience in the study in the tail end. And what we've done is actually for patients who are on the back end of the study, which is where the greatest events accrue in the placebo arm and where you see the curves diverge, we've added exposure. It turns out that 60% of patients will actually have additional exposure in the study. And about a 1/3 of those, 20% more, will actually complete all the way out to 36 months, which is when patients roll over into open-label extension.

And so we think that critical addition, frankly, becomes a no-brainer for us. And it's an important way to further add to study power. And so that's why that was done. And again, based on all the trends we've seen in APOLLO-B, where we started to see separation, as we've highlighted much, much earlier, this is just we think this is a great enhancement that we were able to institute in the study. With regard to your question around monotherapy and all-cause mortality, look, I think it's really important to just remember that in cardiovascular disease, we have about 40 or 50 years of doing outcome studies. And they typically focus on MACE type of endpoints, which include death and hospitalization. And the reason that that's been the focus and accepted by regulators and by the clinical community is because, in general, those events all go hand in hand.

Hospitalization events predict mortality. Doing mortality-alone studies typically tend to be inefficient. They're too large and too long, and we need to get therapies to patients. We've designed a study that is focused on death and hospitalization. We expect to show a positive result in that study, as well as we will, of course, have the breakdown of events under those two, and we expect them to go in a consistent manner, which is what you would expect to see based on the biology and precedent in almost every other cardiovascular outcomes trial that's been done.

Yvonne Greenstreet (CEO)

Next question.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Gena Wang from Barclays.

Gena Wang (Managing Director)

Thank you for taking my questions. I have two very quick questions. One is for the 60%, the monotherapy subgroup.

For your stats analysis or assumption, do you assume most of the tafamidis dropouts will be in the placebo arm? My second question, just want to double-check, my math is correct. And that's based on the slide 17. You said 60% of the patients remaining on study will have a greater follow-up. 20% more patients will have follow-up to full 36 months. So my calculation will be 40% + 20%. That equals 60% of the patients that will reach full 36 months. Just want to make sure that my math is correct.

Pushkal Garg (Chief Medical Officer)

Yeah. So Gena, in terms of your questions, as we've said, our TAF dropout rates are lower than we expected, obviously, when we designed the study. So we're very encouraged by that. That represents another tailwind that supports the success and the powering of the study.

And so I can't get into any more specifics other than that, but to tell you that we're encouraged by those data. In terms of the additional follow-up, maybe what I can clarify is those are changes relative to what the study looked like when it was a 30- to 36-month follow-up study. And so what we're saying is and of course, what we're focusing on is patients who remain on study. Throughout the study, we've had patients, for example, who have passed away because of their disease, etc. And so what we're saying is that in the patients who remain on study, approximately 60% of them will have some extension of their follow-up in the study. And roughly a 1/3 of those, or 20% additional, will get to the full 36 months. So I hope that clarifies.

Yvonne Greenstreet (CEO)

Great. Okay. Next question.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Maury Raycroft from Jefferies.

Maury Raycroft (Equity Research Analyst)

Hi. Thanks for taking my question. With the new stats plan and the latest conversations with regulators, can you talk more at this point on what the minimum delta and the composite endpoint is that you need to achieve to be stat-sig for monotherapy and combo therapy? And in the topline update, can you commit to reporting when you first hit stat-sig on the separation of the curve so we get a sense of kinetics versus competitor drugs?

Pushkal Garg (Chief Medical Officer)

Yeah. Maury, I think what I would say is a couple of things. First of all, I think it's widely accepted that death and hospitalization are incredibly clinically relevant endpoints. And there's no sort of minimum threshold there. Obviously, there's always benefit-risk. But in general, any benefit in terms of death and hospitalization is considered clinically significant.

It's very different than scenarios of looking at NT-proBNP or six-minute walk test or things like that. As we've said, what we're committing to in the topline results is we will provide p-values on the primary and secondary endpoints. We will provide a statement on safety, and we will provide information on relevant subgroups, including the TAF subgroup. Of course, we will be providing a lot more data. As is our custom, we tend to be quite transparent with our data at scientific congresses, etc., thereafter.

Akshay Vaishnaw (Chief Innovation Officer)

Yeah. As for the kinetics of the effects of either patisiran or vutrisiran, for that matter, it's quite clear that the onset appears to be much more rapid than has been seen with other trials, with other drugs.

So for example, in the original APOLLO with patisiran, by six months, you're seeing the separation post-hoc analysis, but you were seeing a separation in mortality and hospitalization. The same was true in APOLLO-B, emerging at nine months. Now, you look at recent studies in the ATTR-CM space, it's nothing like that. And my point is that mortality are further attested to by the time separation for things like six-minute walk distance or KCCQ, which also promptly occurred within the first few months of the study. So I think not just the magnitude effect, but the kinetics of how our drugs work by depleting the pathogenic protein, which certainly in the peripheral neuropathy setting seems to be very potent ways to treat the disease, will undoubtedly show the impact, I think, ultimately in HELIOS-B towards the cardiomyopathy.

Maury Raycroft (Equity Research Analyst)

Great. Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Mike Ulz from Morgan Stanley.

Mike Ulz (Research Analyst)

Good morning. Thanks for taking the question. Maybe just one on APOLLO-B. You highlighted the AMVUTTRA monotherapy arm did better than the combination arm of AMVUTTRA and tafamidis. And I think you highlighted that back at the R&D day. But just curious, what's the rationale or the mechanism or reason why the combo performs worse than the monotherapy arm? Thanks.

Pushkal Garg (Chief Medical Officer)

Yeah. Mike, maybe just to clarify a couple of points, right? I think, first of all, what we were saying is that when we look at the monotherapy data, you're looking at the effects of one drug and certainly comparing that to placebo. And so those placebo patients tend to decline. And it gives the cleanest perspective on the impact that your drug is having, right?

And what we've seen out of APOLLO-B, Mike, was really quite potent, substantial effects on the four key powered endpoints that we looked at in that study, six-minute walk test, KCCQ, NT-proBNP, and troponin, that were sizable and durable. We also saw benefits on mortality, as we've been talking about. Some people have brought up some of the data around time to event or in the recurrent CV events. And I would just point out that, one, it's one endpoint out of all. So I think you'd have to kind of question why that would be the case and if that makes any clinical or biologic sense. Moreover, when we look at those data, actually, the lack of apparent separation was due to a few early events that happened in the patisiran arm in the first 3 months.

If you look beyond three months in the first three months, the drug is just starting to take effect. Beyond three months, we actually see good separation, even in the monotherapy group, even on outcomes and recurrent CV events specifically. So I think all of that bodes very well. And as it relates to combination, as we've said all along, we're very encouraged. But certainly, just like you see in blood pressure medicines or other things, when you start to combine effective therapeutics together with different mechanisms of action, it can change the magnitude of effect that you might detect. But everything that we're seeing coming out of APOLLO-B suggests that there will be an effect there. And it's most visibly seen by the outcomes data that we talked about in that study.

Yvonne Greenstreet (CEO)

Yeah. And of course, we have a much larger study with HELIOS-B and much longer study.

Pushkal Garg (Chief Medical Officer)

Larger and longer study.

Yvonne Greenstreet (CEO)

Absolutely.

Pushkal Garg (Chief Medical Officer)

Yeah.

Akshay Vaishnaw (Chief Innovation Officer)

In reference to that larger and longer study, that is our friend here, the friend for the patients and physicians ultimately showing a positive outcome. Just before this call, Pushkal, you and I were looking at the tafamidis data. If they'd looked at month 18, tafamidis was faring worse than placebo for mortality. Looking at the wrong time point in a study that's smaller can really lead you astray. Apollo-B was highly informative. It's not surprising that one or two of the endpoints didn't line up, where the vast majority did. Ultimately, our friend is the largest, longest study that's ever been conducted and will shortly be completed in ATTR-CM, and that's HELIOS-B. I think getting too over-indexed on one endpoint that went in the wrong direction, you have to be careful about that.

You can be easily misled.

Yvonne Greenstreet (CEO)

Good. I think we've got time for one more question, one last question.

Operator (participant)

Thank you. Our last question comes from the line of William Pickering from Bernstein.

William Pickering (Senior Analyst)

Hi. Thank you for taking my question. What is the powering of the study with respect to the overall population at the 0.025 significance level? I think a lot of the changes make sense, but you've also said in the past that the study is not powered for stat-sig and monotherapy. So if that doesn't hit, are you then in a more difficult position than you were before the stats plan change? Thank you.

Pushkal Garg (Chief Medical Officer)

Yeah. Well, no.

I think what I would take away from today is that the changes we make, really, we think we've actually enhanced the overall statistical power of the study by adding extra follow-up for those patients at the tail end of the study, who remain in the study. We think we've added we certainly have added statistical power there. The way that we've constructed this endpoint, which again remains focused on the most critical endpoint, which is outcomes, we were allowed to we were able to look now in the full totality of the population, 660+ patients in the combination, in the overall, as well as in the way I think about it, in enriched populations of the monotherapy patients who we expect to have the largest treatment effect and the purest demonstration of what patisiran can accomplish and do in this disease.

And so we really think that's really what we've done here. And so we don't think that we've in any way made it harder. We think that we've actually made the study better and aligned it where, as Tolga's highlighted, where we think the market's going to be for the next several years.

Yvonne Greenstreet (CEO)

Absolutely. That's great. Look, I think we need to bring the call to a close. I'd like to thank everybody for joining us today. As I said, we're really pleased with the execution we delivered in 2023. And we're looking forward to executing on our 2024 goals, on our path to becoming a top-tier biotech company. So thank you all, and have a great day.

Operator (participant)

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