Alnylam Pharmaceuticals Inc

NASDAQ:ALNY

Earnings Call Analysis

Alnylam's Robust Growth and Promising Future

In Q2 2024, Alnylam Pharmaceuticals achieved a 34% year-over-year increase in global net product revenues, reaching $410 million, driven by a 37% rise in the transthyretin (TTR) business. The company raised its full-year revenue guidance by 11% at the midpoint, anticipating net product revenues between $1.575 billion and $1.65 billion. Key highlights include positive HELIOS-B Phase III results for vutrisiran, showing a 35%-36% mortality benefit and potential as a new standard for ATTR cardiomyopathy, pending regulatory approval. Their pipeline remains strong with plans for 15 new INDs by end of 2025, setting the stage for sustained growth and innovation .

Transformative Growth and Expanded Revenue Guidance

The second quarter of 2024 was a milestone period for Alnylam Pharmaceuticals. The company reported 34% year-over-year growth in global net product revenues, reaching $410 million, driven predominantly by a 37% increase in the transthyretin-mediated amyloidosis (TTR) business. This robust performance led Alnylam to raise its annual revenue guidance by 11% at the midpoint.

Breakthrough in Vutrisiran for ATTR-CM

Significantly, Alnylam announced positive top-line results from the HELIOS-B Phase III study of vutrisiran in ATTR cardiomyopathy (ATTR-CM). The study demonstrated that vutrisiran improved cardiovascular outcomes and showed a 35%-36% reduction in mortality compared to placebo. If approved, this would position vutrisiran as the new standard of care for ATTR-CM, potentially unlocking a large market opportunity given the estimated higher prevalence of ATTR-CM compared to hereditary ATTR polyneuropathy (hATTR-PN).

Commercial Performance

Alnylam continued to build on its commercial success, with the TTR franchise generating $307 million in global net product revenues, representing a 16% increase from the previous quarter. The success was fueled by the strong uptake of Amvuttra, particularly in the U.S., where combined sales of Onpattro and Amvuttra grew by 16% quarter-over-quarter and 40% year-over-year. Approximately 90% of U.S. patients on TTR therapies are now on Amvuttra.

Financial Highlights and Guidance Updates

Revenue from collaborations soared to $227 million for the quarter, a $221 million increase year-over-year, largely due to a modification of the collaboration agreement with Regeneron. This agreement alone contributed approximately $185 million in previously deferred revenue. Overall product gross margin improved to 84%, up from 75% a year ago, thanks to decreased costs related to Onpattro manufacturing and inventory adjustments.

Research and Development Progress

Alnylam made notable strides in its pipeline, highlighted by the commencement of several new studies. The perusahaan plans to double its clinical pipeline by 2025 with 15 new Investigational New Drug (IND) applications, with nine being proprietary. This ambitious pace underscores Alnylam’s commitment to developing first-in-class or best-in-class RNAi therapeutics across multiple disease areas.

Upcoming Milestones and Investor Events

Alnylam will host a TTR Investor Day in New York City on October 9 to discuss its leadership in ATTR amyloidosis and detail strategies for the upcoming Amvuttra launch in ATTR-CM. Additionally, key data from the HELIOS-B trial will be presented at the European Society of Cardiology Congress on August 30, 2024.

Confident Outlook

CFO Jeffrey Poulton reaffirmed Alnylam’s optimistic outlook, highlighting increased full-year revenue guidance. Net product revenue is anticipated to reach between $1.575 billion and $1.65 billion, an 11% uptick from previous estimates. Collaboration and royalty revenue guidance were also raised, with expectations now set between $575 million and $650 million.

Operational Excellence and Market Impact

The company is well-prepared for the anticipated regulatory approval and commercial launch of vutrisiran in early 2025. Alnylam’s extensive groundwork with TTR centers and specialized customer teams positions it competitively for expanding the ATTR-CM market. The launch readiness underscores Alnylam's strategic vision and operational excellence in addressing significant unmet medical needs.

Earnings Call Transcript 2024-Q2

[Operator]

Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Second Quarter 2024 Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. And I would now like to turn -- 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 Poulton, 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 financials and guidance followed by a summary of upcoming milestones before we open the call for your questions.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC.

In addition, any forward-looking statements represent our views only of the date of this recording and should not be relied upon as representing our views of any subsequent date. We specifically disclaim any obligation to update such statements.

With that, I'd like to turn the call over to Yvonne. Yvonne?

[Yvonne Greenstreet, executive]

Thanks, Christine, and thank you, everyone, for joining the call today. The second quarter of 2024 was a transformative one for Alnylam. Commercially, we achieved 34% year-over-year growth in global net product revenues, generating $410 million in net product revenues, which is primarily driven by 37% year-over-year growth in our TTR business. And as such, we've raised our revenue guidance for the year by 11% at the midpoint.

The commercial capability that we've established over the last 5 years will continue to drive significant growth for our current business and will be a key to our success as we prepare for a potential launch next year in ATTR cardiomyopathy.

To that end, the major highlights of Q2 was our announcement of positive top line results in the HELIOS-B Phase III study of vutrisiran in ATTR cardiomyopathy showing that vutrisiran improved cardiovascular outcomes, including a 35% to 36% mortality benefit compared to placebo and demonstrated encouraging safety.

These results reflect the true power of the mechanism of action, supporting what we believe to be a highly differentiated therapeutic profile and positions vutrisiran as the new standard of care in ATTR cardiomyopathy, assuming regulatory approval. Moreover, we believe these positive results can establish vutrisiran as an anchor commercial franchise for Alnylam, driving robust top line growth and value creation for many years to come.

With an eye towards our Alnylam P5x25 goals, we are firm in our belief that we are on track to become 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.

Before I turn it over to Tolga, I'm excited to tell you about the TTR Investor Day that we will be hosting in New York City on Wednesday, October 9. This event, which will be webcast live, will focus on our leadership in ATTR amyloidosis, including the efforts that we are undertaking to optimize the success of the launch of AMVUTTRA in ATTR cardiomyopathy.

You'll hear from several of my Alnylam colleagues as well as external experts. We'll be sharing more details about this event shortly, and I hope that you can join us in New York on October 9.

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. Q2 was another strong quarter for our commercial portfolio, delivering net product sales growth of 34% across our portfolio compared with the second quarter of 2023 as we continue to consistently increase the number of patients on therapy in both our TTR and rare franchises.

Let me now turn to a summary of our second quarter TTR performance. Our TTR franchise achieved $307 million in global net product revenues, representing a 16% increase compared with the first quarter of 2024 and a 37% increase compared with the second quarter of 2023. This strong growth, now approaching 6 years from our initial commercial launch, supports our belief that there remains a significant opportunity in hATTR-PN.

We are approaching 5,000 patients on treatment with ONPATTRO or AMVUTTRA globally, still a small percentage of the estimated tens of thousands of patients that suffer from this devastating disease. Now let me provide highlights of our U.S. and rest of world hATTR-PN performance.

In the U.S., combined sales of ONPATTRO and AMVUTTRA increased by 16% compared with the first quarter and by a robust 40% year-over-year as momentum in new patient adds continue to drive strong growth. The U.S. year-over-year growth was primarily driven by the following: a 34% increase in demand driven by the strength of our ongoing AMVUTTRA patient uptake, more than offsetting the decrease in patients on ONPATTRO that have switched to AMVUTTRA. It is worth noting that at the end of the Q2, approximately 90% of our U.S. TTR are on AMVUTTRA.

Now let me turn to our international markets, where the TTR franchise growth also increased by 16% compared with the first quarter and 35% year-over-year. The strong year-over-year growth was primarily driven by increased demand for AMVUTTRA as patient uptake remains robust, including from our markets where we successfully launched AMVUTTRA in recent months.

Finally, timing of orders in our partner markets, particularly Brazil, also contributed positively to the year-over-year growth. As shared previously, our team is looking forward to bringing vutrisiran to patients with ATTR amyloidosis with cardiomyopathy, assuming successful regulatory review and approval. We believe we have a tremendous opportunity to transform the treatment paradigm based on the product profile and recent HELIOS-B results combined with the significant unmet patient needs in ATTR amyloidosis with cardiomyopathy, which is an estimated tenfold larger prevalence than hATTR-PN, where AMVUTTRA is the market leader.

We believe vutrisiran has the potential to address unmet patient needs and become the standard of care treatment of ATTR-CM with a first-line and market-leading profile in ATTR-CM, given its unique highly differentiated mechanism effect, enabling rapid knockdown of TTR at the source that is deep and durable, reduction in mortality and CV hospitalization events as well as substantial impact on measures of disease progression, an attractive quarterly dosing schedule with the site-of-care flexibility and favorable payer dynamics.

We've been deeply committed to advancing treatment options in ATTR amyloidosis and understanding the unique needs of this community over the past decade and have built a strong foundation that will benefit our efforts to address the tremendous potential of ATTR-CM. At the same time, we recognize the critical importance of scaling our capabilities to establish vutrisiran as a standard of care in ATTR-CM.

To this end, we are seriously advancing our launch preparations and expanding our capabilities, leveraging our strong foundation, including our deep and credible relations with TTR centers, a global and highly specialized and integrated customer-facing teams that delivers a seamless experience for patients and physicians, our track record of creating strong payer and health system partnerships that supports exceptional patient access not only in the U.S. but also across all major global markets, including Canada, Europe and Japan and our award-winning patient support services team that have enabled us to help patients access their Alnylam treatments quickly with one of the fastest timelines in the industry transitioning from start form to therapy and also support patient adherence.

We're also proud to have established a sustainable rare disease business that addresses a significant unmet patient need. The performance of GIVLAARI and OXLUMO, which delivered $103 million in global revenues combined product sales during the second quarter remains solid as we continue to increase our patient base. The rare disease franchise grew 2% versus the first quarter of 2024 and 25% compared with the second quarter of 2023.

For GIVLAARI, product sales increased by 7% in Q2 compared with the second quarter of 2023 with the following regional highlights: a 17% increase in U.S. primarily driven by growth in new patients on therapy; an 8% decrease in our rest of world markets primarily driven by the timing of orders in our partner markets, which offset demand growth across European markets.

For OXLUMO, we delivered a robust 68% year-over-year growth with the following regional dynamics: a 79% increase in the U.S. primarily driven by demand growth, a 61% growth from our rest of world markets driven by increased demand in both our European and partner markets.

In conclusion, we delivered strong results in the second quarter and first half of the year with both our TTR and rare franchises delivering continuous robust growth in patients on therapy and revenue. Accordingly, we're pleased to be upgrading our full year net product revenue guidance today by 11% at the midpoint of our guidance range. Jeff will share on that more later.

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. As Yvonne highlighted in her introduction, the major highlight of the second quarter was our announcement of the exciting and overwhelmingly positive top line results from the HELIOS-B Phase III study of vutrisiran in patients with ATTR cardiomyopathy.

With these results, we now have the first clinical trial data that demonstrate the ability of an RNAi therapeutic improved cardiovascular outcomes. We observed truly outstanding results in this study with vutrisiran meeting an extraordinarily high bar for efficacy with statistical significance on all 5 prespecified primary and secondary endpoints in both of the study populations, highlighting the powerful impact of vutrisiran and its mechanism of action on this disease.

Specifically, we observed 28% and 33% reduction in the risk of all-cause mortality and recurrent CV events in the overall and monotherapy populations, respectively, and 36% and 35% reductions in all-cause mortality in the overall and monotherapy populations, respectively. These outcome benefits were accompanied by clinically significant benefits on 6-minute walk, KCCQ and NYHA class, all of which are key measures of disease progression. We observed consistent effects in all key subgroups, including patients who are on baseline tafamidis.

And finally, vutrisiran demonstrated encouraging safety and tolerability, consistent with its established profile. We're announcing this morning that the detailed results from the HELIOS-B study will be presented as a hotline oral presentation at the European Society of Cardiology Congress on Friday, August 30, 2024, in London. We will also host a conference call and webcast during the congress to discuss these detailed results with investors.

We're also hard at work engaging with regulators as we work towards a supplemental NDA filing in the United States in late 2024 with additional global regulatory filings thereafter. As a reminder, we will be using our priority review voucher to accelerate the U.S. regulatory review in hopes of bringing this medicine to patients as quickly as possible.

In addition to HELIOS-B, we made progress across a number of other pipeline programs, highlighting the breadth of opportunity we have with our RNAi platform. As we discussed on the last earnings call, we recently reported positive results from our KARDIA-2 Phase II study of zilebesiran, showing additive efficacy and good tolerability on top of standard of care antihypertensives in patients with inadequately controlled hypertension.

KARDIA-3 is now underway, evaluating zilebesiran on top of 2 or more agents in patients who are at high cardiovascular risk. And following that, we look forward to running a cardiovascular outcomes trial, where our goal is to demonstrate the benefits of [indiscernible] blood pressure control in patients with high cardiovascular risk by showing reductions in cardiovascular morbidity and mortality.

We're also excited to have initiated dosing in the Capricorn 1 Phase II study of mivelsiran, formerly ALN-APP in patients with cerebral amyloid angiopathy. CAA is the second most common cause of intracerebral hemorrhage and remains highly underdiagnosed with major unmet need. We've also advanced ALN-KHK, which is in development for the treatment of type 2 diabetes with initiation of the Part B phase of the Phase I study.

Our partners continue to make great progress as well. Sanofi submitted regulatory filings for fitusiran for patients with hemophilia in China, Brazil and the United States, where the FDA has set a target action date of March 28, 2025.

We've also announced today a pair of updates to our ongoing collaboration with Regeneron. First, we amended the license agreement for cemdisiran, the investigational RNAi therapeutic in development for the treatment of complement-mediated diseases, under which Regeneron gained exclusive rights to the asset as a monotherapy. In exchange, we received a $10 million upfront payment and are eligible to receive certain regulatory milestones and low double-digit royalties on sales if approved.

Additionally, as part of their regular portfolio review and prioritization efforts, Regeneron has decided to opt out of further co-development and co-commercialization of mivelsiran. As such, we now have full global development and commercialization rights to mivelsiran in all indications. We're extremely excited about the potential of this program, our first in the CNS to address the unmet needs of patients in 2 significant disease areas: CAA, where we've just initiated a Phase II study; and Alzheimer's disease, where we plan to start a Phase II study at or around the end of the year.

So in sum, we've made great progress 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 against targets in the liver, CNS, muscle and adipose. If we include partnered programs, we anticipate 15 new INDs by the end of 2025, representing a doubling of 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-sustained pipeline that can deliver a 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 Q2 2024 financial results and discussing our full year guidance.

Starting with a summary of our P&L results for Q2 2024 compared with the same period in 2023. Total product revenue for the quarter was $410 million or 34% growth versus 2023 with both our TTR and rare franchises reporting strong growth of 37% and 25%, respectively, primarily driven by continued strong demand, as Tolga previously highlighted.

Net revenue from collaborations for the quarter was $227 million, representing a $221 million increase when compared with Q2 2023. The increase was primarily driven by the modification of our collaboration agreement with Regeneron, resulting in approximately $185 million of revenue, which was previously deferred.

Royalty revenue for the quarter was $22 million or more than 3x what was recognized in the second quarter of 2023. The increase was driven by higher LEQVIO sales as Novartis continues to grow demand for LEQVIO worldwide.

Gross margin on product sales was 84% for the quarter compared with 75% in the second quarter of 2023. The improvement in margin is primarily due to higher costs in 2023 associated with canceled manufacturing commitments for ONPATTRO and other adjustments to inventory, for which similar expenses were not realized in 2024. I expect our gross margin on product sales will be lower for the balance of the year driven by higher royalties paid on AMVUTTRA as AMVUTTRA growth continues at a brisk pace.

Our non-GAAP R&D expenses increased 14% in the second quarter compared to the same period in the prior year primarily due to increased costs associated with our preclinical activities, increased development expenses associated with start-up activities for the zilebesiran and mivelsiran clinical studies and increased employee compensation expenses.

Our non-GAAP SG&A expenses increased 21% in the second quarter compared to the same period in the prior year primarily due to increased marketing investment associated with promotion of our TTR therapies and increased employee compensation expenses. Our non-GAAP operating income for the quarter was $138 million, representing a $292 million improvement compared with Q2 2023 primarily driven by strong top line results, both in product sales as well as revenue from collaborations as previously highlighted.

We ended the second quarter with cash, cash equivalents and marketable securities of $2.6 billion compared with $2.4 billion as of December 31, 2023, with the increase primarily due to increased net product revenues and increased net proceeds from the issuance of common stock in connection with employee stock option exercises. 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 2024 guidance where we are updating all components of our full year guidance with the specific details as follows. We are increasing our net product revenue guidance from a range of $1.4 billion to $1.5 billion to a range of $1.575 billion to $1.65 billion, representing an 11% increase from the midpoint of the prior to the updated guidance. The primary driver of the increased guidance is the ongoing strength of performance in our hereditary ATTR polyneuropathy franchise.

We are increasing our collaboration and royalty revenue guidance from a range of $325 million to $425 million to a range of $575 million to $650 million. The primary driver of the increase is the modification of our collaboration agreement with Regeneron, which resulted in the recognition of approximately $185 million of previously deferred revenue this quarter.

And lastly, we are increasing our guidance for combined net R&D and SG&A expenses from a range of $1.675 billion to $1.775 billion to a range of $1.775 billion to $1.875 billion. There are 2 primary drivers of the increase. First, the opt out of mivelsiran by Regeneron will result in increased R&D investment as the program is now wholly owned by Alnylam. Second, given the strong HELIOS-B top line results, we are increasing our planned ATTR cardiomyopathy launch prep efforts to optimize our preparedness for an early 2025 launch in the U.S.

Given the strong momentum in our business underpinning these guidance changes, along with the strength of the HELIOS-B study results and our efforts to prepare for a highly successful ATTR cardiomyopathy launch next year, we are very confident in our ability to achieve both of the Alnylam P5x25 financial goals that we established 3.5 years ago, which include achieving a 40%-plus compounded annual growth rate and total revenues across the 5-year period and achieving sustainable non-GAAP operating income within the period.

Let me now turn from financials and discuss some key goals, upcoming milestones slated for mid and late 2024. As was mentioned earlier, we will be presenting detailed results from HELIOS-B at the ESC Congress on Friday, August 30 in London. We will also be hosting a conference call and webcast to discuss the data.

We've also announced today that we plan to host a TTR Investor Day on October 9 in New York City. At this event, we will feature senior leaders from Alnylam as well as external experts to highlight the potential of our TTR business. This will be webcast as well.

We're submitting a supplemental new drug application for vutrisiran to the FDA using a priority review voucher. We plan to report interim results from Part B of the Phase I study of mivelsiran in patients with Alzheimer's disease.

We expect 3 trial initiations by the end of 2024, including a Phase III study of ALN-TTRsc04 in patients with ATTR cardiomyopathy at or around year-end, a Phase II study for mivelsiran in patients with Alzheimer's disease at or around year-end and a Phase I study of ALN-BCAT in hepatocellular carcinoma. And we remain on track to file 3 investigational new drug applications by year-end.

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] We'll take our first question from Ellie Merle with UBS.

[Unknown Analyst]

This is [indiscernible] on for Ellie. So can you discuss the reimbursement landscape in ATTR cardiomyopathy? I know you're thinking about the potential difference in pricing between polyneuropathy and cardiomyopathy for AMVUTTRA. And how could the difference in Medicare Part B versus Part D affect this, especially given some of the IRA changes?

[Yvonne Greenstreet, executive]

Yes. I think that's a question for Tolga. Maybe just to start off by emphasizing how pleased we are with the commercial performance to date and really see so much opportunity ahead of us, both in polyneuropathy and that as we expand the label to include patients with cardiomyopathy, assuming positive regulatory approval. Tolga, you may want to respond to specific question.

[Tolga Tanguler, executive]

Yes. Specific to the PN, I think it's actually a testament of the growth that we've been able to deliver this quarter and the prior quarters where patients get on therapy seamlessly, thanks to our patient support services and preferable position that we have in terms of our access, and patients actually stay on therapy.

And that, again, has a lot to do with our profile of the product in quarterly injectables as well as our ability to continue to secure access for those patients. When it comes to CM, we'll be leveraging a similar level of principles, meaning we'll obviously make sure that patients have seamless access and they stay on therapy as -- without the burden of co-pay as little as possible. And given that we are actually physician administered, which allows patients to be on Part B, we believe is going to be a unique advantage in -- compared to other available or future available products.

[Yvonne Greenstreet, executive]

Thanks, Tolga. That's great.

[Operator]

We'll take our next question from Tazeen Ahmad with Bank of America.

[Tazeen Ahmad, analyst]

Mine is on vutrisiran, and perhaps you can share feedback that you've gotten from physicians about their expectations for use of the product and first line. Based on the top line results from HELIOS-B, which were impressive, it seems clear that there is definitely a market opportunity. I think investors would like to get a better sense of what portion of that market could end up being first line and what kind of feedback you've gotten from physicians on that question?

[Yvonne Greenstreet, executive]

No, that's a great question. And clearly, there is an unmet medical need here in this disease, which is rapidly progressive and ultimately fatal. And we think we have a profile that's absolutely well set up to be standard of care. Tolga?

[Tolga Tanguler, executive]

Yes. I mean what we see with the physicians, and we know this from other therapy areas as well, in any progressive, debilitating and essentially ultimately fatal disease, it really is imperative to start with the most potent treatment option first. And given the top line HELIOS-B results, we believe vutrisiran is going to be well positioned to be the first-line agent.

Look, I mean, at the end of the day, HELIOS-B is the most contemporary cardiomyopathy study completed to date. And patients had real aggressive backgrounds around SGL2, tafamidis. And yet, against this incredibly high bar of contemporary backdrop, we showed a profound impact. I don't know, Pushkal, if you want to add anything else on this, but I believe this is going to be a key driver in physicians leveraging the first-line treatment.

[Pushkal Garg, executive]

Yes. I think building [indiscernible] with everything you said. And I think, Tazeen, it's early days, obviously, but as I think what we've heard repeatedly from clinicians is that they're looking for an orthogonal mechanism of action that could have an impact on this disease.

And the investigators and authors for the ESC presentation that we've shared the data deeply with are incredibly excited. And so we're looking forward to being able to roll those data out, but I think we're seeing a lot of enthusiasm based on the data that we've shared so far.

[Yvonne Greenstreet, executive]

And of course, more to come at ESC, and we look forward to that.

[Operator]

We'll take our next question from Maury Raycroft with Jefferies.

[Maurice Raycroft, analyst]

Congrats on the quarter. I'll just -- I'll ask about ESC for the upcoming data. I'm wondering if you'll report KM curves and time to events kinetics for the different mono versus combo subgroups in the study or maybe talk more about what types of details you plan to disclose at the conference?

[Yvonne Greenstreet, executive]

Great question, Maury. Clearly, we're working on finalizing the details as we speak. Pushkal?

[Pushkal Garg, executive]

Yes. Thanks, Maury. Look, we are working with the investigators and authors to sort of finalize the content. But we plan to go into pretty expansive detail on the end points in the study, results that we presented at the top line if we think -- we're really excited to be able to share that now broadly with the community, both the clinical community and the investor community.

So this will include -- I anticipate this will include baseline characteristics. You'll hear about sort of how this is a very contemporary population of patients that was heavily treated with other medications, effective agents. You'll see the results on the primary endpoint, including the components and all the secondaries.

And we'll also be sharing curves for the primary endpoint and secondary endpoint of all-cause mortality. And you'll see that across the key -- you'll see the consistency of effect across a variety of subgroups. And specifically, we'll be sharing some curves in the overall and based on baseline tafamidis.

So I think you'll get a pretty fulsome view of the results. And of course, we'll have other opportunities to dive deeper into data at HFSA. We're limited in how much we can present at ESC. And there's a lot of rich data coming out of this incredible clinical trial that we'll be sharing in the weeks to come.

[Yvonne Greenstreet, executive]

Thanks, Pushkal.

[Operator]

We'll take our next question from Paul Matteis with Stifel.

[Unknown Analyst]

This is [ Julian Pino ] on for Paul. I was just wondering, with respect to the ALN-APP program, can you provide a little bit more color on what the potential Phase II design could look like in Alzheimer's and what endpoints you'll be looking at? And then further, I didn't see anything unless I missed it on the HBNA obesity program. Is that still ongoing? And curious about the status of that as well.

[Yvonne Greenstreet, executive]

Yes. No. Look, we're delighted with the progress of the ALN-APP program. And my view [indiscernible]. It's advancing well. We've been able to demonstrate rapid and robust and sustained reductions in SAPPL for beta going very well, and we feel there's tremendous potential in the 2 indications that we are progressing, both Alzheimer's disease and cerebral amyloid angiopathy. Pushkal, maybe talk about [indiscernible] we're looking at the future.

[Pushkal Garg, executive]

Absolutely. So taking your 2 questions and building on Yvonne's with APP, a very exciting program. We just presented some data at AIC actually that showed that we had consistent knockdown in both soluble APP alpha and beta, but also the downstream disease-related biomarkers of a beta 40 and 42 that are involved in CAA and Alzheimer's disease and continue to see encouraging safety coming out of that program as well.

So that program remains on track. We're very excited. As we talked about, we've recently kicked off the study in cerebral amyloid angiopathy, which is like a second leading cause of hemorrhage. And as you noted, we will be starting a study in Alzheimer's disease as well. We aren't ready to talk about the specifics of that. We're obviously working through our trial design and -- but we'll share with that with you shortly.

But we're very encouraged about this upstream mechanism, its potential to be very differentiated in this disease space and hopefully have a favorable impact on the disease of Alzheimer's, which I think, as you all know, has a tremendous burden.

With regard to your second question on [indiscernible], look, I think -- I don't think there's any really specific updates I want to give on the early preclinical programs other than to say what you heard in the main comments was just we are pushing very aggressively in terms of our [ 2 2 5 ] strategy to move a multitude of programs forward based on the excitement that we have around the platform here.

And so we are on track for 3-plus INDs this year, 9 proprietary INDs by the end of '25 and a doubling of our pipeline by the end of next year. But we'll give updates on those specific programs in due course and keep you posted.

[Yvonne Greenstreet, executive]

Perfect, Pushkal.

[Operator]

We'll take our next question from Kostas Biliouris with BMO Capital Markets.

[Konstantinos Biliouris, analyst]

Congrats on the tremendous progress here. A quick question from us on all data that recently was published on ATTR polyneuropathy. This study showed that patients under [indiscernible] progress very quickly, actually similar rate to natural history and then switch to ONPATTRO where the disease progression is almost halting. Any read-through from this study to cardiomyopathy? And would you expect similar dynamics with some good [indiscernible]?

[Yvonne Greenstreet, executive]

Great question. Pushkal, I think...

[Pushkal Garg, executive]

Yes. Thanks, Kostas. So I think you were citing a paper that was recently published coming out of a European experience that looked at a cohort of patients who had been on tafamidis and progressed and a proportion of those patients that were put on ONPATTRO and actually seem to have some stabilization of disease. These were polyhereditary, polyneuropathy patients.

Look, I think it's very encouraging. We know that this is a complex disease. Patients do have a progressive -- do progress with polyneuropathy and with cardiomyopathy. And so I don't think there's any question that there's an unmet need here for patients to have additional modes of therapy that can address what Tolga highlighted earlier is a very steadily progressive and fatal disease.

And so I think we all agree. And this is highlighted by the fact that even we have the APOLLO data, APOLLO-B data and we launched an EAP, there was tremendous need for patients who are on stabilizer therapy to get on to an additional orthogonal mechanism of action, and that study [indiscernible] very quickly. So we are very excited about the opportunity where patients need additional therapies and we're bringing that forward we think now for the CM patients as we have for the PN patients with [indiscernible].

[Operator]

We'll take our next question from Jessica Fye with JPMorgan.

[Jessica Fye, analyst]

Can you set the stage around the level of detail we should expect with the interim results for Part B as the Phase I ALN-APP study later this year? And how we should think about the communication or kind of venue for that update? So curious, would you seek another partner for ALN-APP? Or do you now plan to keep that wholly owned?

[Yvonne Greenstreet, executive]

Well, I'll take the second question first. I mean we're actually delighted to be progressing ALN-APP. As I said, we're very excited about the 2 indications. We already kicked off our Phase II in patients with cerebral amyloid angiopathy and planning to start the study in Alzheimer's disease at or around year-end. So we couldn't be more pleased to have another wholly owned program in our pipeline and look forward to moving these programs forward ourselves.

[Pushkal Garg, executive]

Yes.

[Yvonne Greenstreet, executive]

Any other comment?

[Pushkal Garg, executive]

Yes, just to comment on your question. It's a little early to tell you about the specific venue where we'll be talking about the data. But I think what you'll see is starting to see some data with multiple doses in terms of, again, the primary purpose of the study is on safety and pharmacodynamics.

And so what you'll be seeing is that with multiple dosing. Over time, we'll be able to share more and more data coming out of that. But I think, again, our confidence in this program is highlighted by the fact that we've kicked off the study of Phase II in CAA, and we'll soon be kicking off a Phase II in Alzheimer's disease. So we couldn't -- we're very excited about the potential therapy and continue to investigate it.

[Yvonne Greenstreet, executive]

Huge potential, huge medical need. And we're very, very pleased to be moving forward.

[Operator]

We'll take our next question from David Lebowitz with Citi.

[David Lebowitz, analyst]

I'm curious, certainly, since [indiscernible] has been on the market for a couple of quarters now, have the nature of the discussions with physicians change since the drug's launch at all? And can you make any commentary on how the market is evolving relative to a new competitive therapy?

[Yvonne Greenstreet, executive]

Great question. Tolga?

[Tolga Tanguler, executive]

Yes. I mean as we discussed before, this is a highly devastating disease, and there's still tens of thousands of patients that are expecting to get diagnosed and treated. Therefore, any addition in the market with increased promotional share of voice is a good thing.

In respect to the -- how the conversations are shaping up, as you can see from our Q2 results, now this is a 2-player market in the U.S., where we continue to grow very rapidly. And I believe the nuances of the products are becoming a lot clearer.

As you know, the product profile of AMVUTTRA is one that rapidly knocks down the disease-causing protein durably and with a good sustained quarterly injectables. That is becoming a good differentiator.

And last but not least, of how patients get on the reimbursement and how they stay on the reimbursement. And we're very pleased with the results that we've seen in Q2, and we expect to drive the momentum as such.

[Operator]

We'll take our next question from Gena Wang with Barclays.

[Huidong Wang, analyst]

I will also ask another question regarding AMVUTTRA. Given this is a Part B coverage, have you seen any pattern in terms of the patient population regarding -- or sorry, the pattern from ATTR polyneuropathy patient regarding patient population and the geographic locations. And quickly on the TTRsc04, any latest thoughts on Phase III trial design?

[Yvonne Greenstreet, executive]

Yes. Maybe I'll start with the TTRsc04 question. I mean clearly, this is an opportunity to really build a durable franchise in TTR for Alnylam. We've seen rapid knockdown, very durable knockdown. And we're looking at a program that potentially has improved knockdown with 6 months or annual dosing.

So we're really, really excited about moving forward TTRsc04. It's still early to comment on the specifics of the clinical program at this point in time, but there will be more to come as we get to the end of this year. Tolga, do you want to take the question on...

[Tolga Tanguler, executive]

Reimbursement?

[Yvonne Greenstreet, executive]

On reimbursement, yes.

[Tolga Tanguler, executive]

Yes. So I mean I think one thing is really to keep in mind is we strictly adhere to the patient access philosophy that Alnylam has established over the years. And through that, what we really look at is the co-pay burden on the patients.

Given that our product is reimbursed because it's a physician-administered product through Part B, what we've seen is nearly 70% of our patients remain -- have 0 co-pay and up to 80% of patients pay less than $2,000. This really puts us in an important position where the co-pay burden is quite -- is either less or similar to those products that would be reimbursed in Part D with the new IRA redesign.

So we believe this is a good mix of reimbursement. And when it comes to global, we've been able to compete in a very price-sensitive markets across Europe, Japan in polyneuropathy in a very competitive way where we are driving about over 90% market share versus the stabilizer product that's in the market.

Therefore, we really like where we are in terms of our reimbursement policy. And obviously, we're keeping an eye on it to make sure that patients get on this treatment if their physicians decide to do so.

[Operator]

We'll take our next question from Ritu Baral with TD Cowen.

[Ritu Baral, analyst]

I wanted to ask to Tolga just how you are now sort of positioning and it sounds like you've been positioning for a while AMVUTTRA in TTR CM as far as actual commercial strategies. Jeff mentioned a scale-up of the sales force. Can you talk about the magnitude of that? And are you changing the mix of targeting of the sales force?

And then in our doc calls, our doc calls have mentioned that they do expect despite the wealth of data that this is going to be a commercially sensitive market. How are things like label language, KCCQ, New York Card Association, like those are real endpoints in your study. How are they going to factor into your marketing message? How important are they? Or is it going to be mortality driven all the way?

[Yvonne Greenstreet, executive]

Tolga, straight to you. A terrific question.

[Tolga Tanguler, executive]

Sure. I mean one thing I just want to make it clear. Obviously, we're going to start off with a very strong foundation where this disease is being treated by multidisciplinary centers and where our organization is there.

But when it comes to positioning, I want to make it very clear that we are strictly promoting our polyneuropathy indication, and we will adhere to that until, obviously, we receive the label expansion. So I just want to make that clear.

Now again, I think, as you highlighted, one of our great advantages is we have deep experience with TTR centers. We've been able to expand our polyneuropathy prescriber base by 50%. We have a well-integrated customer team.

Now we highlight the fact that the prevalence of this disease obviously tenfold. Having said that, the number of prescribers is not tenfold. it's a lesser magnitude of prescriber base. Therefore, we believe we can actually scale this up in the appropriate way.

And then when it comes to -- in rare diseases, having an integrated customer-facing team where you have good coverage of reimbursement support, you have good coverage of medical and field organization support is going to be key. We have that.

And the last piece, I think, of the puzzle is a very good, strong established patient support services, where we are actually quite pleased with the time to treatment from patient start forms into patients getting reimbursed and starting on therapy. Now those are obviously the capabilities where we're keeping an eye on, and we're going to scale that up.

Now when it comes to your second part of your question, in terms of labeling, how we're going to be positioning the product, obviously, that's going to be depending on the FDA and where we don't comment given the label discussions that we have. I think what you will see at ESC is going to give you further color about the robustness of this data and how we can actually be able to communicate effectively, both primary composite and secondary endpoints as well as the all-cause mortality. We believe there's going to be a clear differentiation for our products.

And last but not least is the product profile itself. I mean the -- given that this is a swiftly progressing, a reversible disease to be able to demonstrate rapid knockdown that really knocks down the disease-causing pathogen as quickly as possible is going to be important. The convenience of quarterly dose is going to be important. Given that how patients actually quickly get on access to this treatment is going to be very critical.

So combining all this with the data that we have with HELIOS-B and the product profile, we really do strongly believe physicians will choose AMVUTTRA if approved as a first-line product, given where the disease is, given what the product is and given where we have the data.

[Yvonne Greenstreet, executive]

Thanks, Tolga.

[Operator]

We'll take our next question from Salveen Richter with Goldman Sachs.

[Tommie Reerink, analyst]

Congrats on the results. This is Tommie on for Salveen. Just a question on your discussion with KOLs and cardiologists. Have you heard a number or range for the additive benefit on top of [indiscernible] that would be considered meaningful [indiscernible]?

And just a follow-up on the commercial questions. Over the longer term, what's your strategy here for growing the market beyond taking share or adding on top of those [indiscernible]?

[Pushkal Garg, executive]

Yes. So maybe I can take the first part of your question in terms of is there some numerical target in terms of benefit on top of tafamidis. I think really, what I would say is the feedback that we've gotten all along and I think has only been accentuated since we've shared the top line results with KOLs is the enthusiasm for a new medicine to help these patients, first and foremost.

Second of all, what they're seeing from top line results is an opportunity for this drug to actually access the broad spectrum of patients with this disease. We saw strong efficacy as a monotherapy across all the endpoints.

We saw equally strong efficacy in the overall population, which I'll remind you includes 40% of patients who start on background [indiscernible] and a good proportion of people who actually add an [indiscernible] and added on SGLT2 inhibitors had diuretic intensification.

And so -- and I think as some have noticed from the top line results, there is -- if you just look at the mortality numbers, the strength of the data in the overall population, both in terms of the actual magnitude of effect as well as the p-value are somewhat stronger, which implies a pretty substantial effect in the add-on population.

Now that's encouraging because it wasn't powered or designed to show an effect in that population. But to see what we're seeing is consistent evidence of additive efficacy, I think, is encouraging. So there's no numerical target, but I think what people are seeing is a picture of a drug that's emerging to them that looks quite -- to be quite effective for this disease.

[Yvonne Greenstreet, executive]

I think, Tolga, a few words about the market. We've talked about how we think about the market pretax loss of exclusivity and post-tax loss of exclusivity if you can make a comment on.

[Tolga Tanguler, executive]

Yes. I mean we believe, given that this is a rare disease, it's unusual for a combination therapy to be used given some of the access challenges. However, I think we believe given the data set, we believe there's going to be some combination use early on prior to the exclusivity.

But to your point, what's really important is the category growth. What we've seen is given that the diagnostic tools have advanced over the last 6 years, there's easy access to -- for patients to get diagnosed early.

I think having increased share of voice and promotional awareness of this category is going to help. The only available treatment has actually done a phenomenal job of expanding the diagnosis rates. And with added voices in this category is only going to accelerate the treatment rates. And we believe those patients deserve many options to be treated to.

[Yvonne Greenstreet, executive]

Jeff, anything you want to add?

[Jeffrey Poulton, executive]

Nothing further to add, no.

[Yvonne Greenstreet, executive]

Great. Thank you.

[Operator]

We'll take our next question from Mike Ulz with Morgan Stanley.

[Michael Ulz, analyst]

Congrats on the quarter as well. Maybe just a quick follow-up on some prior questions in terms of the market opportunity for TTR CM. Can you just talk a little bit about why 80% of patients go untreated currently? It sounds like diagnosis is probably one of the key factors, but what are some of the other factors? And then how do you reduce that going forward?

[Yvonne Greenstreet, executive]

Tolga, I think another one for you.

[Tolga Tanguler, executive]

Yes. Look, this is a disease, especially wild-type cardiomyopathy, patients don't start having these symptoms until sometimes it's too late. So that's one of the key drivers.

The second thing is there are only a few multidisciplinary centers. What we've seen is those multidiscipline centers start more -- expanding more and the awareness of how the disease actually manifests itself is being picked up by authorities as well as much as we say, it's tenfold of the polyneuropathy, it's still a rare disease. In the U.S., it's less than 200,000 patients.

Therefore, it is not as common as what doctors used to seeing, cardiologists or neurologists or even in some cases, orthopedic surgeons where they see bilateral carpal tunnel syndrome or spinal stenosis. It's an area where needs more education, more disease awareness.

And we believe having more voices articulating how disease manifests itself and help the patients to get treated early is going to be key. One of the things we're doing and I believe others will be doing as well is to engage with a lot of centers to make sure that on electronic medical records, patients get start flagged early.

I think these are some of the initiatives that the industry is going to be making to make sure those patients get quickly flagged. I don't know, Pushkal, do you have anything?

[Pushkal Garg, executive]

Yes. No, Tolga, you said it very well. I mean I think what I would just add is just a reminder that until 5 years ago, there was no therapy for these patients at all that was specific, right? And so they were treated as sort of [indiscernible] ejection fraction.

I think to Tolga's point, now we have a therapy, hopefully soon multiple therapies for these patients. We've now, over just the last few years, had the proliferation of noninvasive diagnostic methods to identify these patients. And we're starting to understand more where -- how to identify these patients based on red flag symptoms such as polyneuropathy or spinal stenosis or carpal tunnel syndrome, things like that.

So I think there is just a heavy, heavy need for more disease education awareness because we now have we believe, hopefully, multiple therapies for these patients that can actually stem the progression of this [indiscernible] otherwise progressive and fatal disease. So I think there is a lot of growth here in terms of patients to treat.

[Operator]

We'll take our next question from William Pickering with Bernstein.

[William Pickering, analyst]

Yes. Congrats on the great results. Looking ahead to ESC, there seems to be a lot of investor interest in comparing the vutri monotherapy arm with the [indiscernible] plus placebo arm. Could you talk about the extent to which you think that is a helpful comparison and any limitations relative to just looking at [indiscernible] versus placebo on the background [indiscernible]?

[Pushkal Garg, executive]

Yes. Thanks, Will. Look, I think what we have here with [ VSB ] is really a very, very rich study, right? This was a study done 655 patients in the modern era. These are patients who are diagnosed with noninvasive means.

As we've talked about and we'll share more at ESC, it was a pretty rigorous test. These are patients 40% are already on an effective therapy, a good proportion of the monotherapy arm was started, another effective therapy. In the midst of the study, patients started SGLT2s, other things.

So it was a pretty rigorous test, and the results we believe are very, very encouraging. The one thing the study was not was a head-to-head study with tafamidis. That's the one thing it was not. It was not designed for that purpose.

And so the comparison that you're referring to really is a nonrandomized comparison. And as you can imagine, the patients who entered in on [ TAP ] were different because they've been on the drug for a while. Obviously, there were geographic differences in those patients. The majority of the [ TAP ] patients came from the U.S.

So comparing that then to the [indiscernible] patients who are on monotherapy, it's really unfortunately a flawed analysis. I think what we'll see, as we highlighted in the top line results is that [indiscernible] appears to have really encouraging efficacy on every parameter we measured, both as a monotherapy and evidence of additive efficacy on top of tafamidis and consistent results across a whole series of endpoints that we looked at.

[Operator]

We'll take our next question from Myles Minter with William Blair.

[Myles Minter, analyst]

Just with releasing that draft guidance on TCICM pricing, I know that was in relevance to tafamidis, but there's also some commentary about vutrisiran in that as well. Is Alnylam intending to be at the public hearing in September 20? And if you are, are you going to be presenting something on cost effectiveness or future [indiscernible] in TCICM?

[Tolga Tanguler, executive]

Yes. Thank you for that question. As, I think, noted they made this assessment prior to our disclosure of HELIOS-B top line results, and therefore, it was in a complete analysis. We remain engaged with any health outcomes authority, and we'll continue to engage with ISE and others. We haven't disclosed whether we would be part of the hearing.

[Operator]

That last question will come from Luca Issi with RBC Capital.

[Luca Issi, analyst]

Congrats on all the progress. Maybe circling back on Gena's question here, Pushkal, for TTRsc04, which is obviously super important as we think of the royalty to Sanofi on the Phase III, do you basically need to run another HELIOS-B or you can maybe get away with a smaller PK/PD trial?

And maybe related, what's the dose that you're going to pursue? I think the portion of the trial, you went all the way to 600 milligrams. So just wondering if that is the go-forward dose.

[Yvonne Greenstreet, executive]

Okay. We're going to come back to that question because as I said, we're not ready really to get into the details of what the next detailed steps in our clinical plans. So we'll come back and share more of that later. But thanks for your interest. We're also very excited about the program. Thanks, Luca.

Okay. I think that brings our call to a close. And I just want to thank everybody for joining. I mean, really, the second quarter of 2024 has marked an inflection point in Alnylam's journey. And we really are proud of our progress.

Tolga's described the robust commercial growth. Pushkal has gone through some of the incredible advancements in our pipeline. And now more than ever, we believe that we are firmly on a path to becoming a top-tier biotech company. So thank you, everybody, and have a great day.

[Operator]

Thank you. This does conclude the program. Thank you for your participation. You may disconnect at any time.