Alnylam Pharmaceuticals Q4 2023 Earnings Call Transcript

Quartr
Provided by Quartr
February 15, 2024

There are 14 speakers on the call.

Operator

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 speakers' presentation, there will be a question and answer session. Please be advised that today's conference is being recorded.

Operator

I would now like to hand the conference call over to the company.

Speaker 1

Good morning. I'm Christine Lineboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are Yvonne Greenstreet, Chief Executive sir, Tobit Tangler, Chief Commercial Officer Vishal Garg, Chief Medical Officer and Jeff Colton, Chief Financial Officer. Also on the line and available for Q and A is Akshay Vishnal, Chief Innovation Officer. For those of you participating via conference call, the accompanying slides can be access by going to the Events section of the Investors page of our website, investors.

Speaker 1

Alnylam.com/events. During today's call, as outlined in Slide 2, Ivan will offer some introductory remarks and provide general context. Toba will provide an update on our global commercial progress. 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.

Speaker 1

Actual results may differ materially from those 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'll turn the

Speaker 2

call over to Yvonne. Yvonne? Thanks, Christine, and thank you everyone for joining the call today. Alnylam made great strides in 2023, delivering strong progress across all areas of our business. This includes the robust product growth For our 4 wholly owned commercial medicines, delivering $1,240,000,000 in global net product revenues and hitting the remarkable milestone of over 5,000 patients now on an Alnylam commercial RNAi therapeutic.

Speaker 2

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. Zalbiziran also made exciting progress for hypertension with encouraging results in the CARDIA-one Phase 2 study. Further with zalbusiran, 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 a readout from our HELIOS B Phase 3 study of betrisab in patients with ATTR amyloidosis with cardiomyopathy.

Speaker 2

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 boutrisiran's impact across the entirety of the patient population and supports a strong and competitive label. Pushkar will walk through these updates in detail later in the call. We believe all of this puts us on track With our Alnylam piece of it by 25 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 1st 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

Speaker 3

our commercial performance. Tolga? Thanks, Ivan, 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 4th 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.

Speaker 3

Let me now turn to a summary of our 4th quarter TTR performance. Our TTR franchise $254,000,000 in global net product revenues, representing a 10% increase compared with the 3rd quarter and 33% growth compared with the Q4 of 2022. At the end of the Q4, more than 4,060 patients were on commercial ONPATTRO or AMBUTRA Treatment worldwide, up from over 3,790 patients at the end of the 3rd quarter, representing 7% quarterly patient growth. Now let me provide highlights of our U. S.

Speaker 3

And international TTR performance. In the U. S, combined sales of ONPATTRO and AMUTRA increased by 5% compared with the 3rd quarter and a robust 38% year over year driven by Amuser's launch. The U. S.

Speaker 3

Quarter over quarter growth was primarily driven by an increase in demand, resulting from the strength of ongoing AMUTRA patient uptake, more than offsetting A decrease in ONPATTR patients switching to AMUTRA. At the end of the Q4, more than 85% of US hATTR pulmonarypathy patients are now on our Muttra, a testament to its clearly differentiated market leading profile including rapid knockdown, reversal of pulmonarypathy 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 Ambutra was launched in the Q3 of 2022. While we've been able to facilitate the development of multi Disciplinary center approach for the treatment of hATTR pulmonarypathy 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 3rd quarter and a strong 28% year over year.

Speaker 3

The quarter over quarter growth was driven by the following: Demand growth driven by Amutra's performance, including recent launches in Spain and Italy and continued strong ONPATTRO performance in markets where Amutra 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 4th quarter was also favorably impacted by increased inventories in Japan and the timing of orders in various partner markets. In summary, Amutra 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, GIVLARI and OXLIMO delivered $92,000,000 in combined product sales during the Q4, representing an 11% increase compared with the 3rd quarter and a solid 30% growth compared with the Q4 of 2022.

Speaker 3

We ended the quarter with more than 10 80 patients on our 2 ultra rare products with approximately 6.50 patients on GIVLARI and approximately 430 patients on OXLUMO, representing an 8% combined quarterly growth in patients on our ultra rare products compared with the Q3 of 2023. For GIVILARI, product sales increased by 10% in Q4 compared with the 3rd 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 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 3rd quarter, which was driven by the following: a 9% increase in the U. S.

Speaker 3

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 Q4 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 Q4 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 and D and pipeline progress. Pushkar?

Speaker 4

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 Ambutra to include in patients with hereditary ATTR amyloidosis with an estimated prevalence of 25,000 to 30,000 patients worldwide. Assuming successful results from the HELIOS B study and regulatory approval, we expect to expand into a market approximately 10 times larger with a global prevalence greater than 300,000 patients. And furthermore, we're committed to continuing to innovate for patients with this disease as we advance ALN TTR SCO4, another medicine that can deliver rapid knockdown with the potential for greater efficacy and once annual dosing through clinical development.

Speaker 4

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 Centimeters 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 a substantially higher cost. And even today, Where tafamidis and Ambutra have non overlapping labels, about 90% of commercial plans restrict combination use.

Speaker 4

More importantly, we've seen very limited instances in which 2 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 newly diagnosed ATTR Centimeters 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.

Speaker 4

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.

Speaker 4

And accordingly, as we shared at 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 tatestrant 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 Centimeters 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 twice as large and 3 times as long as APOLLO B. Previous studies have shown that intervention in ATTR cardiomyopathy most benefits patients with NYHA Class 1 and 2 The HELIOS B study is enriched specifically for these patients as they're most likely to show the largest treatment effect.

Speaker 4

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% 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'd assumed when powering the study. So 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.

Speaker 4

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 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.

Speaker 4

We 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 Centimeters. Let me review the key changes 1 by 1.

Speaker 4

First, we're sharing today that we're 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.

Speaker 4

2nd, we're modifying the methodology used to analyze the primary endpoint. The primary outcome measure remains the composite of all mortality in recurrent cardiovascular events. This will now be tested in parallel in 2 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 The overall population remains in the primary endpoint.

Speaker 4

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, analysis in the monotherapy population allows us to demonstrate the true impact of vutrisiran As a standalone treatment, providing a data set 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, the statistical significance can be claimed for both. Alternatively, the study will be declared a positive study if either of the P values for the 2 analyses is less than or equal to 0.025.

Speaker 4

This study will be deemed positive if both or either of the analyses achieve the predefined criteria for statistical significance. Based on our assumptions as informed by Apollo B and other studies as well as the conduct and execution of HELIOS B, We remain confident about Hesos B and its ability to deliver a positive result. Finally, we've streamlined the secondary endpoints. Specifically, the structure now includes 6 minute walk test, KCCQ OOS, all cause mortality and change from baseline in NYHA class. These endpoints are considered clinically meaningful and will help to demonstrate the impact of vatrisiran 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.

Speaker 4

Based on the 3 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 were 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 endpoints as well as key details regarding safety. We also expect to provide some high level information on subgroups, including patients on baseline tafamidis.

Speaker 4

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 in 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 0 out of pocket costs and where we also expect payers to favor monotherapy use for the next several years.

Speaker 4

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 CTAB, we presented data showing that single doses of ALN APP achieved sustained pharmacodynamic activity up to 10 months after administration with marked reductions in abeta42 and abeta40, amyloid fragments implicated in Alzheimer's disease and CAA respectively, as well as 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.

Speaker 4

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're 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've 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 zolbesiran, we presented the CARDIA 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.

Speaker 4

On ALN TTRS-four, 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 ALNKHK 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 and 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 into 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 9 programs by the end of 2025 against targets in the liver, CNS, muscle and adipose. We include partnered programs.

Speaker 4

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?

Speaker 5

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 and L results for the full year. Total product revenues for 2023 were $1,240,000,000 or 39% versus 2022 with both our TTR and Ultra Rare franchises reporting strong growth of 35% or greater for the full year.

Speaker 5

The full year net revenue from collaborations was $546,000,000 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 Ambuetra. Our non GAAP R and D expenses increased 15% for the full year, primarily related to increased headcount and infrastructure related cost to support our growing pipeline and increased clinical costs driven by CARDIA-one and CARDIA-two, 2 of our Phase 2 studies in support of our hypertension program. Our non GAAP SG and A expenses increased 6% for the full year, lower than in prior years as we seek to increase 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 IMBOOOTRA.

Speaker 5

Our non GAAP operating loss for 2023 was $60,000,000 representing a nearly $500,000,000 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 for our p5 by 2025 goals. Finally, we ended the year with cash, cash equivalents and marketable securities of $2,400,000,000 compared to $2,200,000,000 at the end of 2022 With the increase primarily related to the $310,000,000 upfront payment from our albusiran co development, co commercialization collaboration with Roche, $100,000,000 from Regeneron for achievement of the ALN APP proof of principle milestone and approximately $150,000,000 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.

Speaker 5

Starting with net product revenues, we are providing combined net product revenue guidance Ron Patro, Ambutra, Gevlari and Oxlomo. 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 and $1,500,000,000 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 $325,000,000 to $425,000,000 We anticipate that collaboration revenue associated with our Partnerships with Roche and Regeneron and Letvio royalties from Novartis will drive the majority of our collaboration in royalty revenue in 2024.

Speaker 5

Our guidance for combined non GAAP R and D and SG and A expenses is a range between $1,675,000,000 $1,775,000,000 with the midpoint of the guidance range representing 9% growth versus 2023. Growth highlights for R and D expense in 2024 include increased 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 and D OpEx for some partnered programs highlighted by Xyprusserien is accounted for as collaboration revenue. Growth highlights for SG and A expense in 2024 include increased medical and commercial investment as we prepare for the potential launch of done slated for early 2024. We will of course be executing on global commercialization of our products ONPATTRO, IMVUTRA, GIVLARI and OXLUMO.

Speaker 5

We also intend to report top line results from the CARDIA-two Phase 2 study of vabisiran as well as initiate the CARDIA-three multi agent combo study. We also expect 3 other trial initiations in early 2024 including a Phase 2 study of ALN APP in patients with cerebral amyloid Part B of the Phase 1 study of ALN KHKI 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. I'll now turn it back to Christine to coordinate our Q and A session. Christine?

Speaker 1

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

Operator

Thank Our first question comes from the line of Ritu Baral from TD.

Speaker 6

Good morning, guys. Thanks for taking the question. Quick question on the updated stats analysis. 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.

Speaker 6

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 spinal SAP? Thanks.

Speaker 2

Thanks, Ritu. That's a great question. And I just want to kind of underscore that we're Really confident on the potential effects that Blue Tree will deliver on cardiovascular outcomes and that Helios B 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 Kushkol said, we consulted with the FDA as we made these changes.

Speaker 2

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. And that's very different from a scenario where you're assessing Endpoints like 6 minute walk test and KCCQ, really if we're able to deliver The primary endpoint as we described, we're confident that this will be a study that should be approved by health authorities. But Happy for Pashkol to add any additional comments to that.

Speaker 4

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.

Speaker 6

Thank you.

Operator

Our next question comes from the line of Paul Matteis from Stifel.

Speaker 7

Hey, thanks for taking my question. I appreciate it. I totally agree with Virtu that these changes at base 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.

Speaker 7

What changed? What are you seeing 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.

Speaker 2

Thanks, Paul. That's a great Look, I mean these changes were primarily influenced by learnings from APOLLO B. And important to note, not just the 12 month 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 data based lock.

Speaker 2

And also, as Pushkar 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 date based on obviously database log beyond which is not possible to make changes.

Speaker 4

Yes. I think building on what you said, Yvon, Paul, I think look, it makes sense for us 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. And again, it makes the most sense to have as much information that's come out of APOLLO B.

Speaker 4

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.

Speaker 7

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?

Speaker 4

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 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, and we saw 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.

Speaker 4

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 getting a strong and competitive label.

Speaker 8

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 Bushgard just mentioned, in Apollo itself, the hazard ratio for mortality was 0.53, and that showed up as early as 6 months and then the curve started separating. In Apollo D, The hazard ratio for mortality is 0.36 at 12 months, both in the monotherapy as well as the TAVRIS arms, You know, Patusiran 1 is 0.67, as you said, at 24 months.

Speaker 8

And this is now Apollo B, a study 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, are wise 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, we are 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.

Speaker 2

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

Operator

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

Speaker 9

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 secondaries like mortality and your latest expectation for what we could see, on the mortality secondary, particularly in the monotherapy arm? Thanks.

Speaker 2

Yes. I know that's a great question, Eddy. 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 stabilizes. 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 is exploratory endpoints. But Pushkar, perhaps you could just go through a little bit of specific changes that we've made To the secondary endpoints?

Speaker 4

Yes, 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 2 populations. Then going down, we've 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 2 pivotal trials would stabilize our therapies.

Speaker 4

And so we look forward to hopefully seeing those patterns emerge again in Helios B. The 3rd endpoint is all cause mortality. Obviously, that's higher bar than the primary endpoint. But again, based on what we're seeing And while the study was 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.

Speaker 4

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.

Speaker 8

Yes. And just building on that last point in push go, think you went through the different endpoints very carefully. From our perspective, we are focusing on the most stringent outcomes, Whether it's mortality, hospitalization, quality of life, New York Association Cost Mortality, 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.

Speaker 8

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 vitreousrant. So, I'll leave it at that.

Speaker 2

Thanks. Thanks, Shay. Next question please.

Operator

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

Speaker 8

Hello, everyone. Thanks for taking our questions. One question from us on the changes of Helios B. Looking back at the Aperamidis trial, we are wondering whether there was 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 Ambutra compared to which is reading out next year and also has a well powered tile.

Speaker 8

Thank you.

Speaker 2

Okay. If I heard you correctly, I'm trying to understand whether there's any information from the AKRAMIDUS study that influenced These changes maybe, Pushkar, if you can take that question. And then there was the 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.

Speaker 4

So, Prashkol? Sure. Katas, 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 1st 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 TRACK trial. And what it showed is that patients in those earlier stages of disease can continue to go through events at a precipitous rate if they're not treated and that an effective therapy can show a benefit on top of that.

Speaker 4

2nd of all, it also showed sort of Confirming what was seen in the original ATTRK study that patients with earlier stages of disease like NYHA Class I and II appear to have the largest magnitude of effect, Right. And 3, 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 Unstabilizers 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 looked at, again, and sort of were in they helped inform some of the choices we made. In particular, but most importantly, it was the APOLLO B results as well.

Speaker 4

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, 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 data sets seem to suggest.

Speaker 2

Thanks, Pushkar. Great answer. Tolga?

Speaker 3

Yes. I mean, as Pushkar indicated, these Analytical enhancements obviously makes us very confident in Gilead's ability to show added benefit on UTRIO on top of TAV as well as obviously demonstrating the value of utrisiran in a pure placebo. Now HELIOS B really empowers us to position Almutra in a very unique way, both in first line utilization as well as on the switch with tafamidis until eflotersen comes into market. 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 Ambutra. 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 indication, attractively sub quarterly dosing and also limited co pay burden in patients.

Speaker 3

These are really going to be unique for Amultra, which we believe is going to position us a year before potentially even eflon coming into the marketplace. Yes. No, that's great. And just to add, this is in the context of

Speaker 2

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 has described, we think we're in a really good position to drive broad commercial uptake Obalon, which 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 AMVUTRA 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 Ambuetra and the potential that will be delivered in the cardiomyopathy market. Next question please.

Speaker 2

Thank you.

Operator

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

Speaker 10

Thank you very much for taking my question. In terms of the primary readout, I know historically you've release 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 AMVUTRA and the other therapies? And just Kind of attached to that, when you look since you're targeting really the frontline 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?

Speaker 10

Thank you.

Speaker 2

Yes. So 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, which is looking challenges subgroups. I hope that answers that question for you, Tolga, if you could just be just very briefly respond to David's commercial question. Right.

Speaker 3

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 is a significant remaining unmet need and a sizable potential to switch to Ombutra and particularly prior to the tafamidis LOE when payers are implementing already restrictions on combo use. And as Ivan indicated, we have actually already that great experience starting with ONPATTRO first and now with Almutra in ex U. S. Markets where we actually compete With great data. Great.

Speaker 2

Next question please.

Operator

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

Speaker 11

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 and bootra patients looks relative to the monotherapy tafamidis patients?

Speaker 4

Yes, Jessica, thanks for the question. Look, I think it's important to note, this was not a head to head study Looking at ambutra versus tafamidis. This is a study looking at ambutra or vutrisiran versus placebo, where proportion of the patients 40% are on A background tafamidis. And so really the comparisons are of VUTRITA placebo in those two situations. And as we've said, The primary analysis will be looking at this in the 2 populations, the blended population of overall as well as the monotherapy population.

Speaker 2

Thanks for your question, Jessica. Next question?

Operator

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

Speaker 7

Great. Thank you so much for taking my question. If I may circling back on the prior question, maybe ask a little more directly. Is this informed by blinded event rates tracking below your expectation? And then maybe separately, is this considered a formal protocol amendment?

Speaker 7

And if So will you incur any statistical penalties for changing the trial so late in the game? Any color there much appreciated. Thanks so much.

Speaker 4

Yes. 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.

Speaker 4

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 the first question, I think is Trying to highlight, the changes are really driven by what we've seen with APOLLO B, over 2 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.

Speaker 4

Of course, we have, as we've said before, have 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, etcetera. And of course, they're looking at event rates, etcetera. But we're not going to be sharing dribs and drabs of the data and that's not the driver here. Those types of events rates are Variables 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.

Speaker 4

Placebo event patients are accruing events or you might say, wow, the drug is not working. Or conversely, if we have a low event rate that might indicate that, We don't we haven't enrolled the right patients or maybe the drug is 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.

Speaker 8

Let me just add, Vishkal. I think we will go to stand back a little bit. It's obviously in Alnylam's interest for patients and for everybody concerned to show 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 Pujols outlined today, deep insights from APOLLO V, understanding the landscape and what you see today is a 3 month extension for the last patient Giving a reasonable amount of additional data just further enhance the robustness of what we're going to share with the world come June, July.

Speaker 8

So I think it's well worth it. It retraced our confidence in this study and we haven't fundamentally changed the design to a 1500 or 2000 patient study for 5 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.

Speaker 8

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

Speaker 2

confidence. Thanks, actually. Great. Next question.

Operator

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

Speaker 11

Good afternoon. Thanks for taking my question. How much of a differential does extending the duration by 3 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 in the field that are flexible during up to 48 months or based on events. So just any clarity there.

Speaker 11

And then secondly, Does the monotherapy analysis heighten the need to show significance on all cause mortality alone just given tasks on label benefit for frontline use?

Speaker 2

Scott, are you good to take this?

Speaker 4

Yes, 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 study, which is where the most 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 third of those, 20% more, will actually complete all the way up to 36 months, which is when patients roll over into open label extension.

Speaker 4

And so we really and we think that critical addition Frankly becomes a no brainer for us and it's an important way to further add to study power. So that's why that was done. And again, based on all the trends we've seen in APOLLO B, which where we started to see separation as we've highlighted much, much earlier, 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.

Speaker 4

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 and doing mortality alone studies typically tend to be inefficient. They're too large and too long and we need to get therapy patients. So we've designed a study that is focused on death and hospitalization, and we expect to show A positive result in that study, as well as we will, of course, have the breakdown of events under those 2 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.

Speaker 2

Next question?

Operator

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

Speaker 12

Thank you for taking my questions. I have 2 very quick questions. One is for the 60% monotherapy subgroup. For your stats analysis or assumption, do you assume most of the tafamidis droppings will be in the placebo arm? And my second question, just want to double check my math is correct and that's based on the Slide 17.

Speaker 12

You said 60% of 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% plus 20% that equals 60% of the patient that will reach for 36 months. Just want to make sure that my math is correct.

Speaker 4

Yes. So Gina, in terms of your questions, as we've said, our TAP drop in 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 that's we're encouraged by those those data.

Speaker 4

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, etcetera. And so 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 third of those or 20% additional will get to the full 36 months. So I hope that clarifies.

Speaker 4

Great. Okay.

Speaker 2

Next question.

Operator

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

Speaker 13

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

Speaker 4

that you need to achieve

Speaker 13

to be stat sig for monotherapy and combo therapy? And in the top line 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?

Speaker 4

Yes. 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 the general, any benefit in terms of death and hospitalization is considered clinically significant, is very different than scenarios of looking at NT proBNP or 6 minute walk test or things like that. And as we've said, What we're committing to in the primary in the top line results is we will provide P values on the primary and secondary endpoints.

Speaker 4

We will provide a statement on safety and we will make We'll provide information on relevant subgroups including the TAP subgroup. And 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 and congresses, etcetera thereafter.

Speaker 8

Yes. And as to 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 in other trials with other drugs. So for example, in the original APOLLO with patisiran, by 6 months you are seeing a separation post hoc analyses, but you are seeing a separation in mortality and hospitalization. The same was true in APOLLO B emerging at 9 months.

Speaker 8

Now you look at recent studies in the ATTR space is nothing like that. And my point is that mortality are further attested to further time separation between by 6 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, The kinetics of how our drugs work by depleting the pathogenic protein, which certainly in the peripheral neuropathy setting seems to be very important ways to treat the disease, will undoubtedly show the impact, I think, ultimately, and it'll just be towards the climate.

Speaker 13

Great. Thank you. Thank

Operator

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

Speaker 7

Good morning. Thanks for taking the question. Maybe just one on APOLLO B. You highlighted the AMVUTRA monotherapy arm did better than the combination of arm of Ambutra and Tafamidis. And I think you highlighted that back at the R and D Day.

Speaker 7

But just Curious what's the rationale or the mechanism or reason why the combo performs worse than the monotherapy arm? Thanks.

Speaker 4

Yes. Mike, maybe just to clarify a couple of points, right? I think first of all, what we are saying is that When we look at the monotherapy data, it's you're looking at the effects of a effect of 1 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 4 key powered endpoints that we looked at in that study, 6 minute walk test, KCCQ, NT proBNP and that were sizable and durable.

Speaker 4

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 and 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 patisteiran arm in the 1st 3 months.

Speaker 4

And if you look beyond 3 months, In the 1st 3 months, the drug is just starting to take effect. Beyond 3 months, we actually see good separation even in the monotherapy group, even on outcomes in recurrent CV events specifically. So I think all of that bodes very well. And as it relates to combination, as we've said 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.

Speaker 4

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.

Speaker 8

Yes. The course has

Speaker 2

a much larger study with

Speaker 8

EDSP. Larger and longer study. Absolutely. Yes. And in reference to that larger longer study, that is our Bren here, Bren for the patients and physicians also have been showing a positive outcome.

Speaker 8

Just before this call, Bussa, you and I were looking at the acryamidis phase. And If they look at month 2018, acramadust was faring worse than placebo for mortality. So, Looking at the wrong time point in a study that's smaller can really lead you astray. And so APOLLO B was highly informative, but It's surprising that 1 or 2 of the endpoints didn't line up where the vast majority did. And ultimately, AFRIEND is the largest, longest study that's ever been and will shortly be completed in APPLCM and that's Helios B.

Speaker 8

So I think getting 2 over index on one endpoint that went in the wrong direction, You have to be careful about that. You can easily get swept.

Speaker 2

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

Operator

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

Speaker 4

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? Like 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 like a more difficult position than you were before the stats plan change? Thank you.

Speaker 4

Yes. Will, 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, the MAN study, we think we've added we statistical power there. And 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, 6 60 plus patients in the combination in the overall as well as the way I think about it in an enriched population of the monotherapy patients who we expect to be have the largest treatment effect and the purest demonstration of what boutriesiran can accomplish in this and do in this disease. And so we really think we've that's really the what we've done here.

Speaker 4

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

Speaker 2

Yes, absolutely. That's great. I think we need to bring the call to a close. I'd like to thank everybody for joining us today. I've said we're really pleased with the execution because of the 2023.

Speaker 2

And we're looking to start hitting on our 2024 goals on our part of becoming a top tier

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Key Takeaways

  • Commercial growth: Q4 net product revenues rose 32% year-over-year, contributing to $1.24 billion in 2023 and marking over 5,000 patients now on Alnylam RNAi therapeutics.
  • HELIOS B enhancements: The Phase 3 study of vutrisiran in ATTR cardiomyopathy has extended follow-up from 30 to 33–36 months, added parallel primary analyses in overall and monotherapy populations, and streamlined key secondary endpoints to strengthen the eventual label.
  • Alzheimer’s program progress: The FDA cleared multiple dosing of ALN-APP in the Phase 1 study up to 180 mg every six months after single-dose data showed sustained Aβ42/Aβ40 knockdown and a favorable safety profile.
  • Hypertension data: Zilbesiran’s CARDIA-one Phase 2 trial demonstrated a placebo-adjusted reduction of over 16 mmHg in 24-hour mean systolic blood pressure at three months following a single dose, with encouraging tolerability.
  • 2024 financial guidance: Net product revenues are forecast at $1.4–1.5 billion (13–21% growth), collaboration and royalty revenues at $325–425 million, and combined non-GAAP R&D and SG&A expenses of $1.675–1.775 billion.
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Earnings Conference Call
Alnylam Pharmaceuticals Q4 2023
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