Alnylam Pharmaceuticals Inc

NASDAQ:ALNY

Earnings Call Analysis

Alnylam's Strong Q1 2024 and Future Outlook

Alnylam Pharmaceuticals had a robust start in Q1 2024, achieving $365 million in revenue, marking a 32% increase year-over-year. The TTR franchise saw a 29% rise, driven by strong AMVUTTRA uptake. Collaboration revenues surged 225% to $119 million, benefiting from partnerships with Roche and Regeneron. Looking ahead, the company maintains its 2024 guidance, expecting product revenues between $1.4 billion and $1.5 billion and collaboration revenues from $325 million to $425 million. R&D and SG&A expenses are projected between $1.675 billion and $1.775 billion. Alnylam is on track to double its clinical pipeline by 2025【4:1†source】【4:6†source】.

Strong Start in 2024

Alnylam Pharmaceuticals has kicked off 2024 with robust performance. The company reported total product revenues of $365 million for the first quarter, marking a 32% growth compared to the same period in 2023. This growth was driven primarily by strong performances in their TTR franchise and rare disease product lines which saw increases of 29% and 40%, respectively.

Pipeline Advancements

Alnylam’s pipeline is showing substantial progress. A significant highlight is the development of zilebesiran, an investigational treatment for hypertension. The KARDIA-2 Phase II study showed positive results, and the initiation of the KARDIA-3 trial aims to further evaluate its efficacy. The company is on the verge of reporting results from the HELIOS-B Phase III study, which could support a supplementary New Drug Application (sNDA) by the end of the year if successful.

Financial Highlights

Financially, Alnylam saw net revenue from collaborations increase by 225% to $119 million, largely due to milestone revenues from Roche and Regeneron agreements. Royalty revenues also saw a significant 63% increase to $11 million. However, the company expects gross margins on product sales to be slightly lower for the rest of 2024 due to increased royalties on AMVUTTRA.

Investment in R&D

Investments in R&D saw a 13% year-over-year increase, driven by spending on the zilebesiran program, HELIOS-B trial, and the preclinical pipeline. Similarly, SG&A expenses grew by 15%, mainly owing to marketing investments related to the TTR franchise and preparations for a potential launch in cardiomyopathy next year.

Guidance and Cash Reserves

The company has reiterated its 2024 guidance, expecting product revenues to be between $1.4 billion and $1.5 billion, showing a growth rate of 13% to 21%. Collaboration and royalty revenues are estimated to range between $325 million and $425 million. The company remains confident in its financial health with $2.4 billion in cash, predicting it will sustain their financial requirements moving forward.

Commercial Performance

Alnylam’s commercial portfolio continues to grow with a 32% increase in Q1 year-over-year. The TTR franchise contributed $264 million in global net product revenues, with a notable 35% year-over-year growth in the U.S., driven by increased demand for AMVUTTRA. The international market also showed growth, albeit tempered by price cuts in countries like Germany.

Future Prospects and Key Milestones

Alnylam remains committed to filing proprietary INDs for nine new programs by 2025, potentially doubling its clinical pipeline. Upcoming milestones include the final trial results for HELIOS-B expected by mid-2024, which will be critical for the company’s future trajectory in treating TTR amyloidosis with cardiomyopathy. The company foresees initiating Phase II studies in early 2024 for new treatments targeting conditions like cerebral amyloid angiopathy and hepatocellular carcinoma.

Earnings Call Transcript 2024-Q1

[Operator]

Good day and thank you for standing by. Welcome to the Alnyam Pharmaceuticals Quarter 1 2024 Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. And I would now like to hand the conference over to the company for their remarks. Please go ahead.

[Christine Lindenboom, executive]

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 Hilton, Chief Financial Officer. .

For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events.

During today's call, as outlined on Slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress, Pushkal will review pipeline updates and clinical progress and Jeff will review our financials and guidance, followed by a summary upcoming milestones before we open the call to 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 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 call over to Yvonne. Yvonne?

[Yvonne Greenstreet, executive]

Thanks, Christine, and thank you, everyone, for joining the call today. 2024 is off to a very strong start and shaping up to be an impactful year for Alnylam. Commercially, in the first quarter, we delivered robust product revenue growth for our 4 wholly owned medicines, achieving $365 million in revenue or 32% year-over-year growth compared to Q1 2023.

An important part of this was the continued momentum from our TTR franchise, which delivered 29% year-over-year growth versus Q1 2023. From a pipeline perspective, our zilebesiran hypertension program was a major highlight with positive results presented from the KARDIA-2 Phase II study, evaluating zilebesiran in combination with certain standard of care antihypertensives and the initiation of KARDIA-3.

This program represents a significant opportunity to reimagine the treatment of hypertension, and to position our nylon as the leader in treating cardiovascular disease. To that end, we're on the cusp of reporting top line results from the HELIOS-B Phase III study of vutrisiran in patients with TTR amyloidosis with cardiomyopathy. As we've highlighted previously, we have many reasons to be highly confident in a positive HELIOS-B outcome, including the encouraging data from the APOLLO-B study of vutrisiran, and we remain on track to report top line data from HELIOS-B in late June or early July, which, if positive, is expected to support the filing of an sNDA by the end of this year.

With this progress, we continue to advance our Alnylam P5 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 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, executive]

Thanks, Yvonne, and good morning, everyone. Q1 was another strong quarter for our commercial portfolio delivering $365 million combined net product revenues as we continue our growth momentum with our rare and TTR franchises.

Our overall portfolio grew by 32% in the first quarter versus prior year as we continue to steadily increase the number of patients on our therapies. First, let me summarize our first quarter TTR results.

The TTR franchise achieved $264 million in global net product revenues, representing a 4% increase compared with the fourth quarter of and 29% growth compared with the first quarter of '23. Our U.S. combined TTR sales of ONPATTRO and AMVUTTRA increased by 3% compared with the fourth quarter of '23, and a robust 35% year-over-year, driven by continued strong AMVUTTRA uptake.

The U.S. year-over-year growth was primarily driven by the following: a 39% increase in total demand versus the first quarter of '23, which was driven by the strength of ongoing AMVUTTRA patient uptake, more than offsetting the decrease in patients on ONPATTRO that switched to AMVUTTRA.

Inventory dynamics decreased reported growth by approximately 4% as both ONPATTRO and AMVUTTRA inventory in the channel decreased in the quarter, another favorable sign of robust Q1 demand.

Now let me turn to our international markets, where TTR franchise growth increased by 5% compared with the fourth quarter of '23 and 23% year-over-year. The year-over-year growth was primarily driven by increased demand for AMVUTTRA as new patient adds remain robust, including launches at the end of last year in Spain, Italy and Sweden, and continued strong ONPATTRO performance in a few markets where AMVUTTRA is not yet available.

As a reminder, AMVUTTRA is now reimbursed in all major international markets. Demand growth in international markets was partially offset by lower pricing in certain countries, primarily in Germany at the end of the initial 6-month free pricing period for AMVUTTRA occurred in Q2 2023, as previously reported. I would also like to provide additional color on the continued growth momentum of our TTR franchise in the U.S.

We remain confident and very pleased with the impact we're seeing from AMVUTTRA in expanding the opportunity for our TTR franchise and is reflected by the robust 35% year-over-year growth that we achieved in the first quarter of 2024. This is a growing category with significant unmet needs remaining. Importantly, leading market indicators remain aligned with our demand growth galvanizing AMVUTTRA's market leadership, both in patients and health care providers for the treatment of patients with hATTR amyloidosis with polyneuropathy.

Here are some key highlights. More physicians are prescribing AMVUTTRA evidenced by the more than 50% year-over-year growth in our prescriber base. We strongly believe hATTR is a condition that requires high engagement between health care professionals and their patients.

AMVUTTRA offers the flexibility for this engagement to happen at the hospital as an outpatient center or for many patients at home. In alignment with our patient access philosophy, we continue to demonstrate seamless access to AMVUTTRA with more than 99% of our patients having confirmed access and approximately 70% of patients having 0 out-of-pocket costs.

Last, we are monitoring and compliance metrics, which show that more than 95% of our patients remain on therapy and comply with AMVUTTRA's quarterly dosing regimen. As we have previously communicated, we believe approximately 80% of the 25,000 to 30,000 patients with hATTR polyneuropathy globally are undiagnosed or untreated, which represents a significant opportunity to find and treat more patients.

Given that hATTR polyneuropathy is also a rapidly progressing disease, we believe patients and physicians stand to benefit most from a therapy that rapidly knocks down the disease-causing protein with unparalleled speed, depth and duration. AMVUTTRA offers these benefits in a single quarterly dose and has the ability to reverse the polyneuropathy manifestations of hRTTR amyloidosis, combined with a favorable access track record and well-established safety profile.

With this foundation, we are in a position of strength as we embarked on a branded patient awareness campaign to raise patient awareness of the disease and the benefits of AMVUTTRA and its unique rapid knockdown profile.

Shifting to our rare franchise and the performance of GIVLAARI and OXLUMO. Our global rare franchise delivered $101 million in combined global net product revenue during the first quarter, representing a solid 9% increase compared with the fourth quarter of 2023 and and an impressive 40% growth compared with the first quarter of 2023. For GIVLAARI, revenues increased by 21% in Q1 compared to the same period last year. with the following regional dynamics, a 28% increase in the U.S., primarily driven by growth in new patients on therapy with modest additional upside from favorable gross to net changes 10% growth in Rest of the World, primarily driven by demand growth, which was partially offset by an increase in gross to net deduction year-over-year.

For OXLUMO, we delivered a robust 77% increase in revenues year-over-year, which was driven by the following regional dynamics, a 47% increase in the U.S. primarily driven by demand growth with additional favorability from lower gross to net deductions, a robust 94% growth from rest of world markets driven by increased demand, a favorable gross to net adjustments and the timing of orders in partner markets.

Given the nature and magnitude of the Rest of World Q1 gross to net and partner market timing benefits, we anticipate that we will see a reduction in global sales for OXLUMO in Q2.

In conclusion, we are very pleased with our continued growth momentum, delivering a robust 32% revenue growth versus prior year that positions us well to reach our 2024 net product revenue guidance. With that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

[Pushkal Garg, executive]

Thanks, Tolga. And good morning, everyone. Let's begin with our TTR franchise, where we eagerly await top line results from HELIOS-B, our outcome study designed to expand the label for AMVUTTRA, to include the treatment of patients with hereditary and wild-type ATTR amyloidosis with cardiomyopathy.

As you're aware, on our Q4 earnings call in February, we announced enhancements to the HELIOS-B statistical plan to optimize the study for success and to best support a strong in competitive label. These changes were informed by insights from the APOLLO-B data and emerging data from the field.

With these optimizations, we remain focused on critical outcomes of death and hospitalization, which are critical to all stakeholders, but now plan to evaluate these outcomes in the overall population as well as the monotherapy population, which is where we believe AMVUTTRA will have the largest treatment effect and will best demonstrate the drug's true impact. We also streamlined the secondary endpoint structure to focus on those clinical measures that we believe will best highlight AMVUTTRA's potentially differentiated profile and its benefits on stabilization of this progressive disease.

And we enhanced the overall statistical powering of the study by incorporating up to an additional 3 months of event collection at the tail end of the study period, the most critical period and firmly establishing HELIOS-B as the longest placebo-controlled study conducted to date in ATTR-CM. We remain on track to report top line results 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.

And assuming positive results from HELIOS-B, we expect to submit a supplemental NDA to the FDA in late 2024. Turning now to zilebesiran, our investigational RNAi therapeutic being evaluated as a treatment for hypertension. We made some very exciting progress in the first quarter on this program. Hypertension is a global health crisis and the leading addressable cause of cardiovascular morbidity and mortality around the world.

Unfortunately, despite available therapies, up to 80% of patients have uncontrolled disease and beyond poor control, there are a number of other aspects of hypertension management that contribute to increased cardiovascular risk, namely for medication adherence, variability in blood pressure and lack of nighttime dipping.

We believe that zilebesiran has the potential to address all of these unmet needs and improve cardiovascular outcomes by providing tonic control of blood pressure. At the ACC conference a few weeks ago, we presented the full results from the positive KARDIA-2 Phase II study that evaluates the efficacy and safety of a single subcutaneous dose of zilebesiran when added to 1 of 3 standard of care anti-hypertensives, a thiazide like diuretic, indapamide, a calcium channel blocker, amlodipine or an angiotensin receptor blocker or losartan.

The study achieved its primary endpoint, demonstrating clinically and statistically significant placebo-adjusted reductions of up to 12.1 millimeters of mercury in 24-hour mean systolic blood pressure at month 3 as measured by ambulatory blood pressure monitoring when zilebesiran was added to 1 of the 3 background medications.

The study also achieved a key secondary end point demonstrating clinically significant ad lib reductions in office systolic blood pressure at 3 across all 3 independent cohorts.

Finally, zilebesiran demonstrated an encouraging safety and tolerability profile when added to standard of care and hypertensives. We are very excited by these results, showing additive efficacy and good tolerability on top of 2 agents with orthogonal mechanisms and on top of an arm which also works in the RAS pathway, which support continued development.

To that point, we recently initiated the KARDIA-3 Phase II study, which will evaluate zilebesiran on top of 2 or more agents in patients who are at high cardiovascular risk. As this slide shows, we and our partners at Roche have robust plans to bring zilebesiran forward as an agent that can reshape the treatment of cardiovascular disease. This includes our intention after KARDIA-3 to run a cardiovascular outcome trial, where we can demonstrate the benefits of tonic blood pressure control in patients with high CV risk by showing reductions in cardiovascular morbidity and mortality.

Wrapping up with the pipeline, our extrahepatic efforts in the CNS continue to progress this quarter as well. As we announced on our Q4 earnings call, we received FDA clearance to initiate the multiple dose portion of the Phase I study of mivelsiran, formerly known as ALN-APP in early onset Alzheimer's disease and remain on track to initiate a Phase II study in cerebral amyloid angiopathy early this year.

So in sum, we've made great progress in advancing our pipeline and platform with much more to come. As a reminder, we plan to file proprietary INDs for 9 programs by the end of 2025. They get 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 our 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?

[Jeffrey Poulton, executive]

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q1 2024 financial results and discussing our full year guidance. Starting with a summary of our P&L results for Q1 2024 compared with Q1 2023.

Total product revenues for the quarter were $365 million or 32% growth versus the first quarter of 2023, with both our TTR and rare franchises reporting strong growth of 29% and 40%, respectively, primarily driven by strong demand, as Tolga previously highlighted.

Net revenue from collaborations for the quarter was $119 million or a 225% increase compared to the first quarter of 2023. The increase was primarily due to revenue recognized under our collaboration and license agreement with Roche, including $65 million of milestone revenue associated with initiation of the zilebesiran KARDIA-3 clinical trial and an increase in revenue recognized under our collaboration agreement with Regeneron.

Royalty revenue for the quarter was $11 million or a 63% increase compared to the first quarter of 2023. The increase was driven by higher LEQVIO sales compared to the same period in 2023. Gross margin on product sales was 85% for the quarter, which was consistent with the first quarter of 2023.

We expect our gross margin on product sales will be lower for the balance of 2024 driven by higher royalties paid on AMVUTTRA, as AMVUTTRA growth continues at a brisk pace.

Our non-GAAP R&D expenses increased 13% in the first quarter compared to the same period in 2023 and primarily driven by increased investments in zilebesiran, our HELIOS-B trial and our preclinical pipeline. Our non-GAAP SG&A expenses increased 15% in the first quarter compared to the same period in 2023, lower than our 32% growth in product sales as we continue to deliver operating leverage on our journey to achieving profitability.

The source of SG&A expense growth was primarily related to TTR marketing investments to help drive polyneuropathy patient finding efforts as well as increased investment in preparation for a potential launch in cardiomyopathy next year. Our non-GAAP operating gain for the quarter was $2 million, representing more than a $100 million improvement compared with Q1 2023 and primarily driven by strong top line results, both in products with sales as well as revenue from collaborations, as previously highlighted.

Finally, we ended the quarter with cash, cash equivalents and marketable securities of $2.4 billion in line with the $2.4 billion we reported at the end of 2023. We continue to believe our current cash balance will be sufficient to bridge us to a self-sustainable financial profile. Now I'd like to turn to our financial guidance for 2024.

Today, we are reiterating our 2024 guidance as presented during our earnings call in February. We anticipate combined net product revenues for our 4 wholly owned commercial products will be between $1.4 billion and $1.5 billion, corresponding to a 13% to 21% growth rate at January 31 FX rates.

Q1 was a strong start to the year, giving us confidence in our ability to meet or exceed our product sales guidance. We will, of course, carefully review our progress in Q2 to determine if any changes to our guidance are warranted. Our collaboration and royalty revenue guidance range is $325 million to $425 million.

And lastly, our guidance for combined non-GAAP R&D and SG&A expenses remains a range between $1.675 billion and $1.775 billion, the midpoint of which reflects 9% growth compared with 2023.

Let me now turn from financials and discuss some key goals and upcoming milestones slated for early and mid-2024. We expect 3 trial initiations in early 2024, including a Phase II study for in patients with cerebral amyloid angiopathy, Part B of the Phase I study of ALN KHK and type 2 diabetes in a Phase I study of ALN DCAT in hepatocellular carcinoma.

And has been highlighted, we remain on track to report top line results from the HELIOS-B study of vutrisiran in late June or early July. Given how important the readout is, we plan to enter a quiet period beginning May 13, May 13 in advance of those results.

Let me now turn it back to Christine to coordinate our Q&A session. Christine?

[Christine Lindenboom, executive]

Thank you, Jeff. Operator, we will now open the call for your questions. [Operator Instructions].

[Operator]

[Operator Instructions] Our first question comes from the line of David Lebowitz with Citi.

[David Lebowitz, analyst]

I'm curious, there has been some talk reason about what is considered to be the relevant improvement over the control arm certainly on the monotherapy side to make it easier to compare one drug versus another. And numbers have about 30% relative improvement versus 42% relative improvement. I'm just curious, I know that information won't come in the top line release, but what are your thoughts on that discussion? And how do you think we should think about it?

[Yvonne Greenstreet, executive]

Thanks, Dave, for the question. Just as a reminder, Helios-B is an outcome study. And that's really what we need to deliver from the study. And it's quite clear in discussions with regulators, payers and physicians that if we're able to show a benefit on outcomes, this will be an important medicine.

Clearly, we made some changes to the statistical plan, which we shared in some detail on our last call, and we're happy to reprise the rationale behind that. But at this point in time, I think the best way to look at this is delivering outcomes in the study will be the importance results. And we also expect to see some other aspects of differentiation if we consider the results that we got out of HELIOS-B with respect to stabilization of disease. And so I think if we're able to deliver all this, we believe that will have a differentiated profile that will be an important contribution to managing the disease of these patients. Pushkal, is there anything you want to add?

[Pushkal Garg, executive]

Yes. I mean we agree with everything you said, Yvonne. Dave, maybe just a couple of other points. I mean, again, when it comes to clinical outcomes such as death and hospitalization, any change is considered clinically significant. And I think it's important to again go back to the unmet need in this disease. This is a steadily progressive disease, where month-on-month patients continue to decline.

They experienced hospitalizations, worsening quality of life, worsening physical function, and ultimately, unfortunately, succumb to this disease. And whether you're on a once-a-day stabilizer or twice-a-day stabilizer patients that the clinical trial data suggest that patients unfortunately continue to decline. And the orthogonal class of medicines could be helpful here. So we're encouraged by the APOLLO B data. We're looking to demonstrate outcomes. And we think that clinicians will be looking at the magnitude of effect as well as when separation occurs as well as whether there's evidence of disease stabilization, which is really important, looking at the total data. So we're looking forward to report the results in late June and early July.

[Operator]

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

[Paul Matteis, analyst]

I wanted to ask just about what Alnylam may look like organizationally in a scenario HELIOS-B works versus 1 word fails. Jeff, if HELIOS-B succeeds, do you expect to be changing guidance as it relates to spending and ramping up infrastructure ahead of the cardiomyopathy launch?

And then conversely, HELIOS-B doesn't work as you guys talk about 9 INDs by the end of 2025 or 15, if you include partner programs, do you feel like that still stands? Do you think Alnylam is still going to have the balance sheet to execute upon that? Or are you going to have to prioritize within the R&D pipeline?

[Jeffrey Poulton, executive]

Yes. Paul, thanks for the question. Let me start with the first one, which I think was around our guidance this year and whether or not that would need to change on the spending side if we have a positive HELIOS-B result? The answer is no. The guidance reflects what we think we need for the year with the positive HELIOS-B results.

So I don't anticipate that we would be raising the guidance. We think we have plenty of opportunity to invest behind the opportunity to drive success. I think the other questions were around how might things evolve if we were in the unlikely scenario failed HELIOS-B.

Certainly, we would need to look at prioritization across the business in that scenario. And we're doing the work on that. If we're in that scenario. Again, we think that's unlikely, but we would be prepared to talk to the market about the prioritization decisions that we would make in that outcome.

[Yvonne Greenstreet, executive]

I also think it's important just to reflect on the magnitude of opportunity that we have in front of us as a company. I mean, first of all, we touched on the richness of our pipeline, currently 15 programs in the clinic. We're looking at doubling that number by 2025. So as we look out at the opportunity set in front of us in [indiscernible] we couldn't be more excited about being able to move forward the programs that we have. So we're obviously looking forward to a positive outcome from HELIOS-B and then really continuing to drive the pipeline that's in front of us.

[Operator]

Our next question comes from Maury Raycroft with Jefferies.

[Maurice Raycroft, analyst]

In both ATTRIBUTE and ATTRACT studies, the slope of the KM curve for events get steeper in the last few months of those studies. And I think it was mentioned in the prepared remarks that, that's a critical time for HELIOS-B, should we expect a similar trajectory for the placebo arm in the last few additional months for HELIOS-B that you added to the stats plan? And would that widen the delta? And can you talk a little bit more about what your expectations are for the events during that time of the study?

[Yvonne Greenstreet, executive]

Yes, that's a great question. And clearly, I think a critical period of a study, as you say, is at the end of the study in this disease where patients continue to progress. So we do expect that, that's a period where we'll see most events. Pushkal, anything else you want to add?

[Pushkal Garg, executive]

I think there's nothing to add, Yvonne, you covered it.

[Operator]

And our next question comes from Gary Nachman with Raymond James.

[Gary Nachman, analyst]

So in ATTR-CM, are you still just thinking of blue tree as primarily a monotherapy drug as tafamidis continues to grow as standard of care in ATTR-RCM if the combo data with TAF are positive enough and show enough of a benefit over TAF alone, would you reconsider that thinking? And what are you doing now to prepare for the launch in CN? Just some details there would be helpful.

[Yvonne Greenstreet, executive]

Yes. Some really good questions. So Tolga, maybe you want to talk about how we're looking at the cardiomyopathy market and how we're preparing for launch. I mean clearly, we're playing to win in this space. We're very excited about the opportunity of getting into this very rapidly growing category. Tolga?

[Tolga Tanguler, executive]

Yes, no, thank you. That's exactly right. We're really here to play to win. And look, at the end of the day, we need to look at the fundamentals of this category. There are 80 patients -- 80% of the patients remain undiagnosed. This is a rapidly and progressing disease with irreversible damages. And frankly, patients and physicians are both looking at quickly be able to deal with the disease as quickly as possible.

So if you look at the pharmacodynamics of what AMVUTTRA has to offer and how we impact the disease causing protein at the upstream and rapidly knocking down the toxic protein. That is going to be a key clear differentiator. At the end of the day, we know that AMVUTTRA provides speed, depth and duration as early as the first dose, and this is what physicians are really looking for.

It is true, and it's great to see tafamidis is making great progress, but it's not just the standard of care. It's the only care in this category. So 1 needs to remember that. And I think they've just reiterate the fact that the LOE in the U.S. in particular is going to remain until the end of 2028, which really means mainly because of the access pressures, but also, again, the way this product is going to be positioned and obviously, pending on the data we need to demonstrate.

We believe we're going to be able to actually be the first-line agent. And after all, there are going to be, as Pushkal indicated, a substantial number of patients who are being treated that are continuing to progress. And we believe physicians and patients are looking for an alternative. And in that case, we believe it's going to be a very important option in the armamentarium of the physicians in this difficult disease.

[Yvonne Greenstreet, executive]

That's actually spot on. So then I think it's just instructive when you reflect on our expanded access program, where within a matter of a very short space of time, we max out on the program. I think that, again, is just an illustration the level of unmet medical need as is based on the fact that patients continue to progress on tafamidis and they're looking for alternative therapies. .

[Operator]

Our next question comes from the line of Tazeen Ahmad with BofA Securities.

[Tazeen Ahmad, analyst]

Question. I appreciate all the color you've been giving about expectations for what to show at the top line. But in terms of trying to drill into the detail on mortality specifically, fully understanding there's a lot of unmet need even with what's available right now. How important is it going to be to know when the mortality benefit kicks in for So I think with tafamidis that benefit in the Pfizer study started around month 18. Is it going to be important to have a number at the end, that covers around that month 18 or potentially, could it be better than that?

[Yvonne Greenstreet, executive]

Pushkal that one for you.

[Pushkal Garg, executive]

Yes. Thanks, Tazeen. Look, I think what we've seen in terms of mortality separation, if I call both for tafamidis and the acoramidis data that are under review is around month 18 is when we start to see the mortality separation.

Look, we're encouraged by what we saw coming out of actually the original APOLLO data and then the APOLLO-B data, where we seem to see evidence again, in underpowered studies of separation on mortality occurring earlier, roughly month 9 or so. So we'll have to see in HELIOS-B if we're able to recapitulate those results in this larger-powered study.

Again, I think it's going to be important to look at the totality of all the data that come out. Obviously, that will be 1 parameter. What is the mortality difference, when is it emerging, what about hospitalizations. And then again, what's happening in terms of disease stabilization. So we think all of those are going to be important parameters. But look, the early data that we've seen from APOLLO and particularly APOLLO-B, which is in the same patient population, gives us a lot of confidence that we should be able to see a substantial effect and potentially earlier separation.

[Operator]

Our next question comes from the line of Ritu Baral with Cowen.

[Ritu Baral, analyst]

I want to thank you for the detail that you've given on the top line release, but I wanted to just dig a little further, if I could. Pushkal and Yvonne, when you mentioned that you would give us some more details on subpopulation, will you be able to give us sort of drivers of potential composite benefit of the TAF subpopulation or the composite -- I'm sorry, combined subpopulation as well.

Just given the conversation, investor conversation and focus on hospitalizations driving previous data sets? Will we get sort of a a tell on what the major drivers are? And then just a very quick follow-up on data release. You drop proBNP and echo parameters to exploratory endpoints. And those are ones that at least our KOLs actually deeply, deeply value. We were wondering if those would be released with first medical presentation?

[Yvonne Greenstreet, executive]

Yes, Ritu, I mean, yes, it's a good question. And I think we've been quite clear about how we're going to be handling the release. I mean, clearly, we're going to show kind of p values for the primary endpoint and key secondary endpoints.

So we're going to provide some information on safety. Obviously, that's an important consideration. And we've said we will give some information with respect to subgroups. was particularly interested in the tafamidis subgroup. But I think that's where we stand at this point in time.

We're kind of obviously looking forward to being able to share the top line results. We're still on track for end of June, early July. And then, of course, we'll present fulsome data at a proximal medical congress. So stay tuned. We will be providing some additional color over and above p-values for the primary and secondary endpoints. But that's probably all we can say at this point in time. Your second question?

[Pushkal Garg, executive]

[indiscernible] just talking about the NT-proBNP and the ECHO data. Look, I think we haven't mapped out exactly what will be the top line presentation. Obviously, it will be limited in terms of what we can -- we want to make sure that we work with the investigators to make sure that there's a fulsome presentation. But you can imagine with a data set like this, that there will be a number of presentations to speak to the various aspects of the data. And certainly, BNP, ECHO, et cetera, where 2 are important parameters that we're really reporting on.

[Yvonne Greenstreet, executive]

Absolutely, Pushkal. I mean we're clearly very interested in those parameters, but you kind of have to prior size how many secondary endpoints you have with respect to managing also. And clearly, we're pretty confident about what we're going to be able to demonstrate for those additional end points. But they're going to be endpoints that we'll be able to share, but we really wanted to prioritize the very clinically relevant secondary endpoints, and we discussed what those are with respect to disease progression, mortality as well as 6-minute walk up in KCCQ.

[Operator]

And our next question is from Jessica Fye with JPMorgan.

[Jessica Fye, analyst]

For HELIOS-B, when you talk about any impact on outcomes being clinically meaningful. On the 1 hand, I completely hear you there are outcomes, but then again, when we ask physicians about this, they usually have a magnitude or a threshold in mind that's not just any benefit. So I'm curious how to kind of reconcile that or maybe you could just elaborate there?

[Pushkal Garg, executive]

Yes. Look, Jessica, I think I don't know that I can give you a lot more information other than to say, just have to again remember what the unmet need in this disease is that there are patients who currently -- a large number of patients, as Tolga has outlined, many of them are undiagnosed and untreated who have a steadily progressive disease that leads to irreversible damage and ultimately, patients pass away.

And so what I think and as evidenced by -- as Yvonne highlighted, our EAP experience after APOLLO-B, and that was in the setting without any outcomes benefit being demonstrated in an IV drug, we rapidly enrolled a population of patients, many of them were progressing on tafamidis, which was the only available therapy to them.

So it highlights the unmet need. So we think that when we come forward with hopefully a positive HELIOS-B, showing an outcomes benefit, a mortality and hospitalization along with these other differentiating factors that we've talked about and an orthogonal mechanism that rapidly knocks down the disease-causing protein of this disease that we think that, that's going to address the key unmet needs for these patients. So we're looking forward to that, and we'll let the data speak for themselves.

[Operator]

Our next question comes from the line of Kostas Biliouris with BMO Capital Markets.

[Konstantinos Biliouris, analyst]

Congrats on the progress. A question from us on HELIOS-B just for a take. How important do you think is the ratio between hospitalization events and death as the metric, especially when we compare different drugs? Do you look at this ratio as an important metric or you just look at those 2 types of events together as a composite?

[Yvonne Greenstreet, executive]

Thanks for the question, Kostas. Pushkal, this one is for you.

[Pushkal Garg, executive]

Yes. No, I think it's an interesting question, cuts. I think in general, we look at them together, and we don't make a huge distinction here. I mean I think part of the reason that composite endpoints like this were created was because hospitalizations tend to correlate very strongly with mortality events.

And so -- and these are both clinically meaningful outcomes. And so we would expect that they will both go directionally in the same direction. That's what we've seen with other drugs, that's what we've seen throughout the cardiovascular disease area with lots of drugs and lots of different diseases, disease classes. So we would expect them to go in similar directions, Kostas. And I think the main thing is seeing a benefit, hopefully, in both of those, the trend in the right direction.

[Operator]

And our next question comes from the line of Ellie Merle with UBS.

[Eliana Merle, analyst]

In ATTR, what proportion of patients do you think car mix phenotype in the real world? And how is this being defined both by doctors and by payers? And do you see silencers is more likely to gain a larger share of this population versus stabilizers longer term when we look to the cardiomyopathy expansion?

[Yvonne Greenstreet, executive]

I think Pushkal first and then Tolga will follow up.

[Pushkal Garg, executive]

Yes. Ellie, I think you raised a very important question and I think we've -- oftentimes, people have sort of classified these as 2 very distinct diseases, polyneuropathy and cardiomyopathy. When in fact, it's the same protein, when it's misfolded, it's causing both manifestations of the disease.

And I would -- we've seen, for example, that in the hereditary population, when we looked in APOLLO and HELIOS-A that more than half of those patients had concomitant cardiomyopathy and conversely, studies that have been done in cardiomyopathy patients suggest that a significant proportion of those patients may have polyneuropathy manifestations.

So there are reports ranging from 15% to 30% or more of patients with wild-type ATTR or V122I, for example, which might have a primary cardiopathy manifestation have concomitant polyneuropathy. And certainly, we've seen that with the silencer class of drugs, particularly with and AMVUTTRA, that the magnitude of effect in polyneuropathy is really quite unsurpassed in terms of its clinical profile. And so it will be interesting to see, and Tolga can probably comment more about this, how clinicians will make decisions when they have patients who have multiple manifestations of this disease when they hopefully have multiple classes of therapies available.

[Tolga Tanguler, executive]

Yes. No, I mean, just to add 1 quick point on that is, if you look at the clinical practice of how physicians actually diagnose and treat this disease, it starts with the suspicion. And the suspicion usually doesn't necessarily start whether you have cardiac manifestation of diseases or the polyneuropathy manifestations of this disease.

Eventually, based on the data we have, obviously, both with ONPATTRO and AMVUTTRA physicians are absolutely looking for neuropathic manifestations to make sure that they can treat this as effectively as possible. And the disease is treated always through multidisciplinary centers. So at the end of the day, physicians don't just look at the patients with whether they have CM, PN or mixed phenotype, they go through how to best understand the disease and then through a multidisciplinary approach, try to treat the disease in the best possible way and based on the indications of the products.

[Operator]

Our next question comes from the line of Gena Wang with Barclays.

[Huidong Wang, analyst]

Sorry, I will ask another question. So regarding the subgroup, the top line you will share will you share the subgroup information on both primary and secondary end point? And also in the scenario that HELIOS-B is positive, will you also, at some point, lower in vitro price to be competitive compared to, say, tafamidis and other drugs?

[Yvonne Greenstreet, executive]

I'll just take the pricing question. I mean I think it's really too early for us to talk about kind of specific kind of pricing approaches here. Just to remind you, and Tolga touched on this in his introductory at remark. I mean, we will obviously bear in mind our patient access principles, and we'll be making sure that we have considerations around access and affordability to make sure that patients are going to be able to benefit from what we hope will be a medicine with a very robust profile. Pushkal, do you want to take the question on...

[Pushkal Garg, executive]

Yes. I mean, Gena, I don't know that there's a lot more that I can add in terms of the remarks I made and then Yvonne has reiterated in terms of the top line. We plan again to speak to the primary endpoint, which is now in the 2 populations, the secondaries across those populations, safety and we'll make some commentary around subgroups. But it's hard to give you anything more than that today. That's our plan.

[Operator]

Our next question comes from the line of Salveen Richter with Goldman Sachs.

[Tommie Reerink, analyst]

This is Tommie on for Salveen. So beyond the top line and regarding data analysis, [indiscernible] would you include detailed analysis on AMVUTTRA impact in patients who were defined as past professors given the unmet need in this population and just to see how AMVUTTRA can benefit in patients?

[Pushkal Garg, executive]

Yes. Tommie, I think what you're asking about is actually deeper cuts of the data. And certainly, this is going to be a very rich and large data set. So you can imagine that we'll be looking at this in a lot of different ways. But again, I guess the primary thing I would focus on is the fact that we will have a pretty robust data set both with the drug treated as a monotherapy and in patients who came in on tafamidis.

And I think you have to ask yourself, why would someone who's on a drug decide to enroll in a 3-plus year clinical trial. And that really indicates that they will -- they are obviously not satisfied with how they're feeling or functioning at that moment in time. And so I think our combination group, where we do have a sizable proportion of patients, and we'll be able to report on that will help address part of your question.

[Operator]

Our next question comes from the line of Mike Ulz with Morgan Stanley.

[Michael Ulz, analyst]

Maybe just a follow-up on the launch preparation question. Just curious what you guys have sort of done so far in preparing for a potential launch? And then what are the sort of remaining steps that will be triggered by positive data from HELIOS-B?

[Yvonne Greenstreet, executive]

That's a great great question. I'm going to pass it on to Tolga. And I just want to kind of underscore how pleased I am actually with the commercial footprint that we've built. And I think if you look at our performance with respect to AMVUTTRA and patients with polyneuropathy. I think we're really demonstrating strong growth momentum here, and I'm just really pleased with how the commercial organization is focusing on meeting the needs of patients in this indication.

I have no doubt that we'll do the same assuming HELIOS-B and being able to launch into the cardiomyopathy indication. But Tolga, you may have some specific comments on how we're thinking about launching. So what I think is going to be actually one of the most exciting categories.

[Tolga Tanguler, executive]

You took a little bit wind away, on because I was just going to highlight the fact that despite competition, the growth of our TTR franchise in the U.S. is 35% year-over-year, which is quite important, and I think it's an important indicator of the growth momentum that we've built.

Look, we have a great brand, great data in polyneuropathy, which clearly demonstrated 90% market share in Europe and Japan, where we actually do compete with tafamidis in the same indication. And now in the U.S., we're essentially established very important stronghold in centers that actually treat both cardiomyopathy and polyneuropathy. We obviously strictly promote our polyneuropathy indication.

But it's -- the assay -- the product is now known by -- both by cardiologists who also tend to diagnose this disease as well as neurologists. Therefore, we're really well positioned to launch the pending the HELIOS-B outcome results, which is going to be obviously very critical. And as Yvonne indicated, we're going to play to win.

We have a great footprint well-informed and trained organization, not just in the customer-facing side but also a patient-facing side. And we also are very cognizant that this opportunity is going to be tenfold of the opportunity that we currently have. Therefore, we're going to make the right appropriate adjustments and make sure that we are clearly differentiated and more importantly, I said ourselves so that the product is affordable and accessible to the patients.

[Operator]

And our last question comes from the line of Whitney Ijem with CG.

[Whitney Ijem, analyst]

I'm just going to throw 1 non-HELIOS-B question in there because there will be catalysts after that. So can you help remind us, I guess, for Part B of the ALN-APP study, what we should expect to see later this year, particularly around any biomarker or imaging data?

[Pushkal Garg, executive]

Yes. Thanks, Whitney, for your question about APP. It's a program that we're incredibly excited about the data that we shared last year really suggested that we can have pretty profound impacts on the protein on amyloid precursor protein as well as the downstream of AB40 and 42 that are involved in both Alzheimer's disease and CAA.

We have the Part B that's ongoing, and we hopefully will show ongoing data with regards to knockdown safety as well as imaging and biomarker data. So look for that as something we're also going to be initiating our CAA study soon. We're very excited about the opportunity. That's the second leading cause of hemorrhagic stroke, major -- with really no available treatments for these patients. And we think that lowering APP could be beneficial in that disease will be kicking off a Phase II shortly.

And we've also announced that we plan to kick off an Alzheimer's disease study at or around year-end of this year. So this is a really exciting program. And then it allows us then with our colleagues at Regeneron to move forward a number of other programs in the CNS space. So thanks for your question, lots of excitement there.

[Yvonne Greenstreet, executive]

Great. Thank you, Pushkal, and thank you, everyone, for joining us on the call. We're really proud of our strong start to 2024. We delivered robust commercial growth and exciting pipeline progress and we look forward to executing on the remainder of our 2024 goals, our path becoming a top-tier biotech chemical. So thanks, everyone, and have a great day.

[Operator]

Thank you, everyone, for your participation in today's conference. This does conclude today's conference call and you may now disconnect.