Alnylam Pharmaceuticals Inc (ALNY) 2023 Q2 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Q2 2023 Earnings Conference Call. (Operator Instructions)

Please be advised that today's conference is being recorded. I would now like to hand the conference over to the company.

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 our financials and guidance, followed by a summary of upcoming milestones before we open the call for your questions. I'd like to remind you that today's 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 in 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 recently period out report on file with the SEC.

And then any forward-looking statements represent our views only as 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'd like to turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. In the second quarter of 2023, we continue to make great progress across our business. Starting with our commercial performance.

The AMVUTTRA launch once again drove strong growth in our TTR franchise with 46% year-over-year growth. and in total product sales with 43% year-over-year growth compared to the second quarter of 2022. We also delivered strong execution across our clinical pipeline, where notable results include a positive 18-month data from our APOLLO-B Phase III study, reaffirming the potential of patisiran in ATTR amyloidosis with cardiomyopathy.

In July, we shared updated positive interim results from the Phase I study of ALN-APP in patients with early onset Alzheimer's disease, showing rapid and robust target engagement with sustained effect over 6 months with a single dose and an encouraging clinical safety and tolerability profile.

Additionally, our team executed on the business development side. Most notably, we entered into a strategic partnership with Roche for the development and commercialization of zilebesiran, providing us with what we believe is a remarkable opportunity to bring forward a potentially transformative program with the potential to disrupt the global treatment paradigm for hypertension. We're also pleased to announce this morning that following our full cooperation with the government, the U.S. Attorneys Office for the District of Massachusetts has now concluded and closed their case regarding the marketing and promotion of ONPATTRO in the U.S. with no action. Operating with integrity has always been and will continue to be core to Alnylam, and we will continue to hold our business conduct and in particular, our interactions with health care providers and patients the highest ethical standards. As we move into the back half of 2023, we have several important catalysts, including the initial data from our KARDIA Phase II program as zilebesiran. And pending a successful Ad Comm and positive regulatory review, the potential launch of ONPATTRO in ATTR amyloidosis with cardiomyopathy. We believe all of this puts us on track with our Alnylam P5x25 goals, making Alnylam a top-tier biotech company, developing and commercializing transformative medicines for rare diseases and beyond for patients around the world, 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. Further, before I hand the call over, I'm very pleased to share that Akshay Vaishnaw, Alnylam's President and key scientific leader, will be transitioning to a new and exciting role within the organization, serving as our first Chief Innovation Officer. Akshay has been at the helm of driving science and innovation at Alnylam for nearly 18 years. And that effort has yielded an entirely new class of medicines. In his new role, Akshay will become the company's key innovation leader focused on the future of our R&D engine, which is the lifeblood of how we have and will continue to drive our research and development programs into transformative medicines as we continue to build a top-tier biotech company. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

Thanks, Yvonne. And good morning, everyone. Q2 was another strong quarter for Alnylam, driven by our TTR franchise and the strength of our ongoing launch of AMVUTTRA across several markets. which has started with the U.S., where it has now been available for over a year. Our total net product revenues across all products grew 43% year-over-year in Q2. Let me now review our TTR performance during Q2. The TTR franchise achieved $224 million in global net product revenues for ONPATTRO and AMVUTTRA, representing a 9% increase compared with the first quarter and 46% growth compared with the second quarter of 2022. At the end of the second quarter, -- over 3,490 patients were on ONPATTRO (inaudible) treatment worldwide, up from over 3,160 patients at the end of the first quarter, representing 10% quarterly patient growth. With respect to our international performance, total TTR second quarter product sales increased 6% versus the first quarter driven by strong AMVUTTRA demand in Japan and U.K., U.K. being our most recent launch market. After more than 6 months since its launch, the AMVUTTRA demand growth in Japan is particularly encouraging, with new patient growth being driven by a mix of switches from tafamidis as well as patients naive to therapy.

Importantly, ONPATTRO continued to deliver steady growth in markets where AMVUTTRA is not yet available, a sign of our robust demand generation activities as we position these markets for upcoming AMVUTTRA launches. Now let me turn to the U.S., where combined sales of ONPATTRO and AMVUTTRA increased by 12% versus the first quarter and a robust 72% year-over-year growth, representing the fourth consecutive quarter of achieving TTR growth in excess of 70% on a year-over-year basis in the U.S. since the launch of AMVUTTRA in the third quarter of 2022.

This significant growth was primarily driven by a 15% increase in demand, which more than offset the decrease in patients on ONPATTRO that switched to AMVUTTRA, and the robust demand was slightly offset by inventory dynamics, which decreased reported both by approximately 2% with channel inventory reductions to both products.

AMVUTTRA continues to expand the overall TTR polyneuropathy franchise as reflected by our year-over-year growth. The steady growth of AMVUTTRA performance in the U.S. is a testament to the significant unmet need of patients with TTR polyneuropathy, our commercial capabilities and naturally the product profile of AMVUTTRA.

Our leading performance indicators also continue to trend favorably, including the expansion of our prescriber base and favorable access, resulting in patient compliance rates of over 90%. A year into launch, we have increased our prescriber base by almost 50% through a balanced mix of academic centers and community-based specialists while switching a majority of the patients who are on ONPATTRO at the time of AMVUTTRA launch. Now update on our ultra-rare franchise. We are proud to have developed and commercialized 2 ultra-rare products, transforming small patient populations that suffer greatly.

GIVLAARI and OXLUMO together delivered $82 million in combined product sales during the second quarter, representing a 14% increase compared with the further and a solid 37% growth compared with the second quarter of 2022. We ended the quarter with more than 570 patients on GIVLAARI commercial therapy and more than 350 patients on OXLUMO commercial therapy, representing 8% combined quarterly growth in patients on our ultra-rare products compared with the first quarter of 2023.

For GIVLAARI, global revenue growth of 21% in Q2 compared to first quarter was driven by the following: in the U.S., we had an increase in the number of patients on therapy and an increase in patient compliance rates, a robust 29% in our international markets, which was impacted positively both by demand growth as well as order timing in our partner markets.

For OXLUMO, flat quarterly revenue was a result of fewer U.S. patients on a loading dose regimen, which offset modest patient growth. Growth in international markets was primarily driven by order timing in partner markets, which was partially offset by an unfavorable pricing mix in our European markets.

Overall, Q2 '23 was another quarter of healthy growth in revenues in our quest to serve more patients. With over a year since launch, we are particularly pleased with the steady growth of AMVUTTRA, which represents an important therapy option for hATTR amyloidosis patients with polyneuropathy. With that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

Thanks, Tolga, and good morning, everyone. Let me start by updating you on our TTR franchise, where as you know, we're conducting 2 large studies, APOLLO-B and HELIOS-B, to evaluate the efficacy and safety of patisiran and vutrisiran, respectively, in ATTR cardiomyopathy. The sNDA for patisiran is under FDA review based on the positive results of the APOLLO-B study. And as we recently announced, the application will be discussed at the Cardiovascular and Renal Drugs Advisory Committee on September 13. We also announced today that enrollment in a U.S. expanded access protocol for patisiran that was opened shortly after the APOLLO-B readout last August has completed.

The EAP was established to provide access to patisiran for patients with ATTR amyloidosis with cardiomyopathy who've had an inadequate response to or cannot tolerate currently available treatment. The EAP was offered at 20 centers in the United States, and the prespecified enrollment target of 200 patients was met in about 10 months, indicating significant demand for this potential therapy.

Another important recent update on patisiran was the presentation of 18-month results from APOLLO-B at the recent ESC Heart Failure meeting. As a reminder, after the 12-month double-blind period of the study, all patients were eligible to receive patisiran during the open-label extension period of the trial. In the new analysis, we were very encouraged to see that favorable effects on functional capacity as assessed by the 6-minute walk test as well as on health status and quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire were sustained in patients receiving patisiran through 18 months.

According to both of these endpoints, patisiran appeared to slow the decline in functional ability and health status that is typical for this release. And similarly, in patients who had received placebo during the double-blind period, initiation of patisiran in the early period was associated with initial evidence of stabilization, both 6-minute walk test and KCCQ relative to the double-blind period.

Importantly, patisiran continues to demonstrate encouraging safety profile with 18 months of treatment with no new safety concerns identified. We saw encouraging evidence of efficacy with other secondary and exploratory endpoints as well. Continued treatment with patisiran through 18 months was associated with relative stability in both NT-proBNP, a measure of cardiac stress, and troponin I, a measure of cardiac injury.

In patients who rolled over from placebo to active treatment during the OLE, saw a slowing in relative to stabilization of the rapid increases that were seen during the double-blind period. In addition, while the APOLLO-B study was not designed to show benefits on outcomes of hospitalizations or death, we were encouraged to see nonsignificant trends favoring patisiran treatment in these outcome endpoints with extended follow-up during the early period.

As we previously announced, we've submitted the 18-month results to the FDA as an amendment to our sNDA for patisiran. We look forward to continuing our engagement with the agency, including at the upcoming Advisory Committee. And if patisiran is approved, expanding its label to bring patisiran to patients with ATTR amyloidosis with cardiomyopathy. We were also very excited to share initial human proof-of-concept data on ALN-APP our first RNAi therapeutic designed for CNS delivery, which is in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy.

At the AAIC congress in July, we presented updated positive interim results from the Phase I study in patients with early-onset Alzheimer's disease. At the time of this interim look, 20 patients had been enrolled in 3 single dose cohorts in Part A of the ongoing Phase I study.

To date, we've studied 3 dose levels, 25, 50 and 75 milligrams with 4 to 6 patients dosed in each cohort. Excitingly, ALN-APP treatment resulted in rapid dose-dependent and sustained reductions of both soluble APP alpha and beta, biomarkers of target engagement in the CSF. We saw rapid knockdown as early as day 15 and observed maximum knockdown of 84%, 90%, respectively, for soluble APP alpha and beta. And at the highest dose tested, 75 milligrams, the median knockdown was greater than 55% for both biomarkers and sustained for at least 6 months.

The safety of singles of ALN-APP has been encouraging as well. All adverse events were mild or moderate in severity, and CSF parameters have not revealed any significant abnormalities to date. Further exploration of single doses of ALN-APP is ongoing in Part A. In addition, Part B, the multiple dose part of the study, has been initiated in Canada, where the majority of the Part A clinical trial patients were enrolled.

The multiple dose part of the study remains on partial clinical hold in the United States due to findings observed in prior nonclinical chronic toxicology studies. In sum, I'm thrilled about these impressive human data that provide the first ever evidence that we may be able to use RNAi to found disease-causing transcripts in the CNS and look forward to providing additional program updates in the future. Let me now turn to recent progress with zilebesiran in development for the treatment of hypertension.

We are very excited to recently announce the Phase I data were published in the New England Journal of Medicine, highlighting the medical importance of the substantial and durable lowering of blood pressure seen with single doses of zilebesiran. This now marks Alnylam's 11th publication in this prestigious medical journal.

Yvonne has already highlighted the exciting collaboration with Roche, we recently announced for the development commercialization of zilebesiran on the basis of these impressive Phase I data. We're now looking forward to results of the KARDIA-1 dose-ranging study, which is on track for top line data in Q3. In addition, we're also pleased to have recently completed enrollment in the KARDIA-2 Phase II study, which aims to evaluate the safety and efficacy of zilebesiran in patients with uncontrolled hypertension when added on top of other antihypertensive medications.

We expect to report top line results from this study in early 2024. These are just a few highlights from our broad and innovative pipeline driven by our underlying organic product engine that we expect will deliver sustainable growth for Alnylam in the years to come. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q2 2023 financial results and discussing our full year guidance. Starting with a summary of our P&L results for the second quarter.

Total product revenues for the quarter were $306 million or 43% growth versus Q2 2022. Tolga previously indicated, the increase is primarily related to growth in TTR product revenues, driven by the launch of AMVUTTRA in the U.S. in the third quarter of 2022 as well as increased patients on GIVLAARI and OXLUMO therapies.

The impact of foreign exchange rates on our product sales has moderated on a year-over-year basis with constant exchange rate growth now only 1% higher than our reported 43% year-over-year growth. Net revenues from collaborations for the quarter were $6 million or a 35% decrease compared with the second quarter of 2022, primarily due to operating variability, including the level of work reimbursed in our collaboration with Regeneron.

Royalty revenue during the quarter was $7 million, which was driven by Novartis' sales of Leqvio, which launched in the U.S. in the first quarter of 2022. Despite the modest growth of revenues from collaborations and royalties, we remain confident in achieving the full year result with our $100 million to $175 million guidance range, primarily driven by our Regeneron collaboration and Leqvio royalties and milestones.

Gross margin on product sales was 75% in the quarter, representing a 9% decrease compared with the second quarter of 2022. The decrease was primarily due to fees incurred associated with canceling manufacturing commitments for ONPATTRO and other adjustments to inventory as demand for ONPATTRO continues to decrease, driven by ongoing patients switching to AMVUTTRA.

Our non-GAAP R&D expenses increased 11% in the second quarter compared to the same period in 2022, primarily due to increases in headcount to support our R&D pipeline and development expenses associated with KARDIA-1, KARDIA-2 Phase II clinical studies.

Our non-GAAP SG&A expenses increased 14% in the second quarter compared to the same period in 2022, primarily due to increased headcount and other investments supporting our strategic growth, including the global launch of AMVUTTRA. Our non-GAAP operating loss for the quarter was $154 million, representing a $7 million improvement compared with Q2 2022, driven by strong top line growth, offset by more moderate growth in operating expenses.

Finally, we ended the quarter with cash, cash equivalents and marketable securities of $2.1 billion compared to $2.2 billion at the end of 2022 with the decrease primarily due to our operating loss year-to-date. 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 full year 2023 financial guidance where we are reiterating our previously issued guidance. Starting with net product revenues, we continue to anticipate combined net product revenues for our 4 commercialized products will be between $1.2 billion and $1.285 billion.

Our guidance for net revenue from collaborations and royalties remains a range between $100 million and $175 million. And our guidance for combined non-GAAP R&D and SG&A expenses remains unchanged and is a range between $1.575 billion and $1.65 billion.

Let me now turn from financials and discuss some key goals and upcoming milestones slated for mid and late 2023. We will, of course, be executing on global commercialization of our 4 commercial products. With patisiran, we look forward to the upcoming meeting of the Cardiovascular and Renal Drugs Advisory Committee on September 13 with the PDUFA date shortly thereafter on October 8.

Later this quarter, we expect to report top line results from the KARDIA-1 Phase II study of zilebesiran. We also intend to report top line results from Phase I studies of ALN-TTRsc04 in development for the treatment of ATTR amyloidosis and ALN-KHK and development for the treatment of type 2 diabetes.

Our partner programs, Sanofi expects to report additional results from the Phase III ATLAS program with patisiran, an investigational RNAi therapeutic in development for the treatment of hemophilia A or B with or without inhibitors. Additionally, Vir expects to report further results from Phase II combination trials of ALN-HBV02 and development for the treatment of chronic HBV infection. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

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

(Operator Instructions)

Our first question comes from Mike Ulz of Morgan Stanley.

Maybe just quickly, any updated thoughts on the upcoming Ad Comm for ONPATTRO in ATTR-CM in terms of why the FDA decided to host the panel and then where you expect the focus to be?

Thank you for that question. Clearly, we're actively preparing for the advisory committee. We're really looking forward to presenting the data that we have from APOLLO-B.

Whilst there are no specific questions at this time, we believe that the topics are going to be focused on the clinical meaningfulness of changes in the 6-minute walk test and the KCCQ, particularly given the fairly recent FDA guidance around the utility of these endpoints and in patients with heart failure. We really believe that we have compelling data for our APOLLO-B study across a wide range of endpoints and supported by additional validation in the recent 18-month data that, as Pushkal described, we have submitted to the FDA. Pushkal, anything else to add?

I think you've really covered it, Yvonne. I think it really is -- our preparations are underway. We feel really good about the data set that's been generated with APOLLO-B, and what we're seeing as evidence of stabilization across a series of endpoints, which is really critically important.

Patients with this disease revalue their functionality and their quality of life. And what we're seeing across multiple measures is that patisiran appears to enable that, and that's reconfirmed with the extended OLE data that we submitted. And we look forward to presenting that to the Advisory Committee as they do their review.

Our next question comes from Luca Issi of RBC.

Great. This is Lisa, on for Luca. I just wanted to dive into some specifics on the Roche deal for zilebesiran. We know the deal entails $310 million upfront plus substantial near-term milestones. Your partner, Roche, has said that they expect to invest another $275 million to get to the end of Phase II.

So just wondering if you can add any clarity on the $275 million? And if this is part of the substantial near-term milestones that you're expecting?

That's a great question and a good opportunity for clarification. I'll pass it on to Jeff in a moment. But I just wanted to remind everybody that really what we feel that we have here within our hands with zilebesiran is a game-changing therapy for patients with hypertension, really to maximize the value and drive a successful global product launch. We want to come to the market with cardiovascular outcomes data to help inform the various stakeholders.

And obviously, that's a significant endeavor. And the collaboration with Roche allows us to bring together our leadership in RNAis, what is their proven global commercial footprint and capabilities and help us maximize the resources and capabilities in order to be successful here. And I think it is important to be specific about some of the details of the milestone. So Jeff, maybe you could...

Yes. Let me just clarify that. So the substantial near-term development milestones that we had referenced when we announced the deal are -- there's actually $365 million in potential development milestones that we could earn.

And that's broken down $65 million for the initiation of KARDIA-3, which is the additional Phase II study that Pushkal talked about on the deal call, and we expect that study to initiate next year. And then an additional $300 million for the first patient in on the CVOT, the Phase III study. So taken together, that's the $365 million.

When you look at that in combination with the development cost sharing where Roche will put 60% of the bill and Alnylam will put 40% of the bill, really from an out-of-pocket perspective for Alnylam to take this drug forward to the market really minimizes the financial burden for us, which allows us to then reallocate capital across our pipeline and hopefully drive additional growth.

Our next question comes from Citi with David Lebowitz.

Question on the submission of the 18-month data for ONPATTRO inclusion. I know the PDUFA date stands in October. Is there any consideration by the FDA to consider this a major amendment and move the PDUFA date 3 months down the road?

Or have they not exhibited any such intent at this point? And on franchise growth, while -- nothing else question, the overall franchise is growing quite well. How is ONPATTRO maintaining as much share as it is to this point given how well AMVUTTRA is doing?

Yes, 2 great questions. I'll take the question on the PDUFA date, and then I'll hand over to Tolga for speak to your overall franchise question around -- is the dynamics between ONPATTRO and AMVUTTRA.

We're continuing to anticipate a PDUFA date of October 8, and we're working towards that. If that changes, of course, we'll communicate any new information. But as of this moment, we are continuing to expect a PDUFA date of October 8. Tolga, do you want to turn to the question on dynamics?

Happy to. So the way I think we should think about this is U.S. and our newly recently AMVUTTRA launch markets and those markets that are continuing to have only ONPATTRO as an option within the franchise. As I indicated on the call, if you look at our U.S. growth in the TTR category, 70% quarter-over growth for the last 4 consecutive quarters, which is quite substantial.

And that's really primarily driven by AMVUTTRA. In fact, the number of ONPATTRO patients that remains in the U.S. at the time when we launched AMVUTTRA is getting smaller and smaller. So we're very pleased with how patients are switching over to AMVUTTRA.

And we've also seen in other markets like Japan, now we start seeing in France with a very creative AP2 program, the main patient program, as well as in the U.K. We're getting accelerated approvals in those several key markets to make sure that we're providing AMVUTTRA as an option.

Now the reason why you see a good persistent growth on ONPATTRO, albeit a smaller portion of our business, is because markets like Italy and Spain, where AMVUTTRA still not yet available. We're seeing a good, robust growth. And that's, again, a testament to the need of an option in this market in polyneuropathy as well as our commercial abilities that we've been able to drive a good, strong, robust growth. which obviously positions us very nicely at the time of AMVUTTRA launch in these other markets. We're going to start seeing -- we'd like to see a good strong uptake of AMVUTTRA and subsequent switches from ONPATTRO to AMVUTTRA.

Our next question comes from Paul Matteis of Stifel.

I wanted to ask about the timing and any reason behind Akshay's role change. I think Akshay became President just 18 months ago, and it's such a pivotal time for Alnylam with the Ad Comm coming up, the HELIOS-B data.

I haven't heard him at all on this call. So I was just curious if you could expound upon this a little bit and clarify if there's anything else behind the decision with this announcement today.

Thank you for that question. Look, I'm personally delighted that Akshay is going to take on this opportunity to become our first Chief Innovation Officer, and in that capacity, continue to focus on helping to deliver continued success with respect to our R&D organization.

We're also delighted that we've built a really strong robust capability across the research and development organization. And that's allowed actually to be able to focus more specifically on innovation as we build a top-tier biotech company. So I think this is a terrific step forward for the company. There's no specific reason for this timing other than the fact that I actually felt that we're now in a position where we have a really strong capability, which allows them to take on a much more focused role for the company.

And he'll continue to be involved in all the important upcoming catalysts and milestones that you just described. He's not on the call today because he's actually on vacation, but I'm sure we may well here on an upcoming call in the future. So thanks for that question, Paul.

Our next question comes from Ritu Baral of TD Cowen.

Yvonne and Pushkal, I wanted to dig down a little bit more on the preparation into the Advisory Committee, whether it's yours or ours or FDA's.

Right now, are you planning to be able to discuss any additional data cuts later than 18 months from APOLLO-B or any data out of that fully enrolled expanded access plan? And do you believe that there's any shift in understanding around these endpoints given the recent BridgeBio data and how all of these endpoints and other endpoints like outcomes sort of link together?

Thanks, Ritu. There are kind of a few questions there and we sort of maybe sort of unpick them. So -- in terms of our Ad Comm preparations, any additional data that we're providing with the FDA beyond the 18-month data that we've already referenced. And then secondly, kind of any shift in understanding with respect to the endpoint selection. So I mean, Pushkal, maybe you could take those 2 questions?

Yes, absolutely. Thanks, Ritu. Look, in terms of the Ad Comm preparations, we're getting into the period where trying to -- we're really pulling together aspects of our preparation.

We feel very good about how the team is prepared for this. And it's all based on incredibly strong data coming out of APOLLO-B and reaffirmed by the OLE data that we talked about earlier. And really, it's the fact that across multiple measures within the study, looking at endpoints like functional ability and quality of life. The biomarker data that are predictive of longer-term outcomes, we're seeing evidence of relevant stability of patients who get on this drug appear to have less progressive decline.

And we shared data last year at R&D Day, showing favorable impacts on progression on NYHA class and ATTR disease stage. So all of this really paint a picture of delayed progression when patients are put on a silence or with this disease. And that's really important. We keep hearing from clinicians in the field that, that's really important to patients.

These are patients in their 70s and 80s. They value their functional ability and their quality of life. And so these changes are meaningful to them. And I think what I can say is that the Ad Comm we'll be pulling together those various arguments. We've received a lot of support both from the data side, but also from external key opinion leaders, et cetera.

And so we look forward to making those points at the Advisory Committee and interacting with the agency and the panel there. Vis-a-vis BridgeBio, look, I think what I would say is, first of all, it's great news for patients. It looks like there may be potentially an additional medicine as we kind of learn more about this data and additional stabilizer for patients with this disease.

And I think hats off to the patients, the investigators and the colleagues at BridgeBio because it was -- it's been a challenging time, and it's great to see that they've pulled out what looks to be a very positive study in that regard. I think as it relates to our franchise, we really remain excited about what the silencer profile looks to be, again, building on what I just said about APOLLO-B, the emerging data that we're seeing, again, not statistically significant, but emerging trends with regard to outcomes coming out of APOLLO-B, both on mortality and hospitalization.

But I think the key will be looking for more data at the ESC meeting. But I think what the results highlight is that in -- while we are diagnosing patients earlier with this disease, and that's been a big question in the field, these patients still endure ongoing progression. So that APOLLO-B looks like that's reaffirmed in the BridgeBio data and an effective therapy can show a benefit in that population. And I think that reaffirms the design elements of HELIOS-B. So we're very excited about that as well.

Our next question is coming from Salveen Richter of Goldman Sachs.

This is Tommie on for Salveen. And congrats on all the progress. Our question is also on BridgeBio and HELIOS-B. So you saw from BridgeBio that there is this imbalance in taf drop-in rates between the 2 arms that have this impact on separation.

How are you thinking about the risk there to HELIOS-B, given the drop in allowance? And kind of on the other hand, would HELIOS-B able to give physicians insight into potential additive benefit when you combine a [zilebesiran] stabilizer?

Okay. So 2 questions there. So you -- Pushkal, maybe I'll just start off by saying that we're actually really pleased to see the BridgeBio results because it really reaffirms that even if patients are diagnosed earlier in the disease, they continue to have disease progression, where an effective therapy is able to demonstrate benefits in these early-stage patients. So I think we're actually really kind of pleased that this gives us increased confidence actually in delivering a successful HELIOS-B. But Pushkal, maybe you can talk specifically about the taf imbalance and taf drop-in rates, potential impact on HELIOS-B and also thinking about combination approaches, stabilizers (inaudible)?

Yes. Look, I think as it relates to taf drop-in rate, I think as we've talked about in the past, we've got careful measures in place in the way that the study was designed. And we feel good about the drop in rate that's there.

It's substantially below our internal assumptions as we design the study. We're not going to provide any more specific updates on that, but we're very encouraged by what we're seeing with regard to that and about the overall design of the study.

The study allows for a proportion of patients to be on background tafamidis entering into the study, just like we did in the APOLLO-B study. As we've said, our targets were around 50%, but we've operationally come in below that. And so I think we will get interesting data emerging from that study in terms of how the drug functions as a monotherapy, but as well as on top of background tafamidis.

Our next question comes from Maurice Raycroft of Jefferies.

For the 200-patient Expanded Access Program study, can you talk about the types of patients you've enrolled time line to data and how the data will be leveraged as it relates to regulatory or commercial plans?

Yes. Pushkal, that's a question for you around the EAP, types of patients and then also thinking about how do you think it may be used going forward?

Yes, Maurice, thanks. When the APOLLO-B data came out, it posed it -- brought forward the potential for an alternative mechanism for patients with this disease, as we've talked about multiple times during the call. These patients despite available standard of care therapy with tafamidis, continue to progress.

And so what we did was establish an Expanded Access Program at 20 U.S. centers that enable patients who were experiencing progression or otherwise intolerant of available therapy to avail themselves of patisiran with their physician support. So that was open at 20 centers. And as I mentioned, that enrolled actually relatively rapidly.

We had 200 patients, that was actually in the order of about 3 patients every 2 days that was enrolled -- 2 patients every 3 days, sorry, that was enrolled in this EAP program, and it really highlights, I think, what we've been saying and what we've been hearing a lot from the clinical community and the patient communities that patients continue to progress with this disease and they need additional therapies.

And so I think that's important as we think about bringing forward patisiran in this disease and then hopefully, vutrisiran as well based on the results of HELIOS-B.

Yes. Thanks, Pushkal. I think the point about competing unmet medical need is really the important one here for the patients who are continuing to progress, in patients that need alternative therapeutic approaches.

Our next question comes from Eliana Merle of UBS.

For HELIOS-B, can you elaborate on your rationale for using Anderson-Gill as a statistical method versus the (inaudible) pairwise analysis that was used in the [stabilizer] Phase III such as the recent BridgeBio data?

And then second, just in terms of the event rate, how are you thinking about the proportion of cardiovascular hospitalizations that will come from the urgent heart failure visit component and the importance of including the urgent heart failure as part of this endpoint definition?

Pushkal, there's 2 questions for you.

Sure. So Ellie, I think there's a multitude of approaches in conducting survival analysis and outcome analyses that take advantage of the fact that you're looking at recurring events and events over time and our statisticians obviously spend a lot of time thinking about what's the optimal way to demonstrate the clinical benefit, and that's highlighted in the statistical analysis plan that's aligned with the agency.

In this instance, one of the reasons for preferring the Anderson-Gill is the fact that they're -- we allow for variable follow-up in the context of the outcomes analysis. And the Anderson-Gill really allows us to fully leverage that, whereas other approaches would allow us to use a fixed time of follow-up and frankly, the shortest amount of follow-up.

So we think it gives us a little bit of an analytic or power advantage to do it that way. With regard to the various components of the endpoint, I think what's really important, Ellie, is maybe just in a larger picture, we're trying to capture clinically relevant events that could out to heart failure worsening and the need for care in patients with this disease.

And so that's why care is increasingly provided in different geographies in different places, including in hospitals and urgent care centers, et cetera. And so we look at the totality of all of that -- indicating clinically relevant heart failure events that we may have an opportunity to affect with an effective therapy. And that's why we've kind of captured that aspect in the endpoint structure.

Our next question comes from William Pickering of Bernstein.

I was wondering what percent of AMVUTTRA patients are getting dosed at home so far? And as you look ahead to future competitive dynamics versus Eplontersen? What does your market research tell you about how patients are thinking about the trade-offs between physician-delivered therapy quarterly versus monthly self-injection?

Tolga, those are 2 questions for you. The first relating to home infusion and the second, I think, related to Eplontersen. How we're thinking about differentiation?

Yes. No, thank you. Great question. Look, I think the way we should be thinking about this is AMVUTTRA will be the only disease-reversing treatment for polyneuropathy, dosed 4 times a year. And not only I think this really positions the product well from a convenience perspective, but -- there are a number of important features that we believe will make AMVUTTRA incredibly competitive.

Having a unique MOA, a rapid and sustained disease reversal. Obviously, with infused dose -- and we should also remember, we have 5 years of experience now in this category and now 1 full year in the U.S. promoting AMVUTTRA, that we really have been able to establish a number of important patients and physician capabilities.

Starting from the fact that this is a Part B product and where we have excellent coverage of reimbursement benefits. And then going into the patients, whether it's site of care and providing various options, not just in the home but also in other different sites of care, whether it's an infusion center or in a hospital care.

And more importantly, that supporting the patient benefit. So one of the question that you asked is since we've launched ONPATTRO and now AMVUTTRA, we have over -- nearly 1/3 of our patients are getting home care. And what's really also important is to remember that almost all of our patients, over 90% stays on therapy. Not only get a good convenient access to these medicines, but also has the ability to stay on therapy.

We have a very, very minimal dropout. So with all these other features that we offer, we believe this is going to remain a very significant benefit. And another important one is, obviously, to remember, unlike Part D until 2025, our patients, nearly 70% of them has zero co-pay, and this will continue to be an important benefit.

So we are very -- we feel very good about how AMVUTTRA is already being positioned in the market. First, with the values that we bring on the table as well as some of the services that we've set out there for the last 5 years.

Our next question comes from Gena Yang of Barclays.

I also have 1 question regarding HELIOS-B. I think Pushkal, in the past, you commented on tafamidis drop-in rate. I think, early on was in the low single digit. I don't -- I'm pretty sure now increased. But do you think so far, say, if we're using a [TRIBUTE] study as a benchmark, with your dropping rate, it will be much lower than that, it's doing, say, below 10%? And also, do you see blinded events? And how that event's tracking versus your initial assumption?

Yes. Thanks, Gena, for your questions. Look, I think in terms of the drop-in rates, as you can imagine, is over the course of a 3-year plus study, you're going to see those rates are going to evolve over time. What I can say is that the rates are -- the drop-in rates are significantly below our planning assumptions.

And so we feel very good about the overall powering of the study. There's a multitude of factors that contribute to how a study is powered, et cetera, and how that's going to turn out. And again, when we look at all of those elements, we feel good about the study. In terms of event rates, of course, you have a crackerjack clinical and statistical team. They're responsible for monitoring the study and ensuring the quality of the data that come in and the integrative study.

And we feel, again, really positive about what we're seeing overall. And we have a long history of people and those teams who've designed and executed really successfully team studies in this field, including APOLLO-B. And so again, we feel very good about what we're doing here with HELIOS-B.

Our next question comes from Leland Gershell of Oppenheimer.

Just a question for me as we look forward to the ALN-KHK data, obviously, being -- looked at type 2 diabetes and you'll be looking at glycemic indices, so we'll see presumably data there. But just wondering where that target sits could be useful for other related conditions, weight loss obesity, potentially NASH?

Just wondering what your thoughts maybe with respect to taking that candidate in one of those directions as you will be looking at overweight, obese patients in the study. And even though you may have 2 other programs in NASH, those are both partnered. Wondering if you have freedom to pursue NASH, if you like, for KHK?

Yes, that's a great question. And just remind everybody that KHK is a genetically validated target involved in metabolism of fructose. And that's relevant to the development of diabetes, and as you point out, obesity as well.

Clearly, we're focused in our Phase I study, addressing target engagement and safety and also looking at a range of relevant biomarkers with respect to glucose metabolism and insulin levels. But I think you raise an interesting question, which is the broad potential of KHK in metabolism in general. Pushkal, maybe you want to provide some perspective?

Yes. Yvonne, I think it's a really insightful question in the sense that we've seen epidemiologically that with rise in fructose consumption, we've seen parallel increases both in diabetes, overweight, NASH and a number of metabolic syndrome type diseases that all travel together.

And it's entirely possible that by perturbing this pathway with an RNAi mechanism that we actually may have beneficial effects in a number of these different domains. So what's exciting here is that we have what we think is a really potent and based on preclinically durable way to silence KHK, that we can elaborate and we have a number of biomarkers that we can measure in the clinic that will help guide us along the path in terms of which of these indications to pursue, how to pursue them, et cetera.

And so -- and this has also been a proprietary target within Alnylam that we're advancing. And so we have really freedom to operate across a full range of diseases and take it where the science and the unmet need drives us. So look forward to sharing more data on that in the future.

Highlighting, I think, another exciting opportunity in our pipeline and more to come towards the end of the year.

Our next question comes from Myles Minter of William Blair & Company.

You've got [Sarah], on for Myles. Is there any clarity you can give on the time line of advancing ALN-HTT into the clinic or any other assets that are using C16 conjugate technology? And how has this been informed by the clinical ALN-APP data thus far?

So time lines for ALN-APP and any other programs using -- sorry?

HTT.

Yes. So thanks, Sarah, for the question. I think, look, as I said in the remarks and as you've heard from us in a couple of recent calls, I think what we've seen in the CNS space with ALN-APP has been really, we think, groundbreaking. It really opens up a whole new vista where we can take RNAi therapeutics to affect a wide variety of neurodegenerative diseases and beyond in the CNS.

Now when you look at what we see there? We see with the levels of up to 84%, 90% lowering of soluble APP alkaline beta, that really signifies that we're getting deep brain penetration. That's always a big question as you're trying to think about additional targets that you can pursue can you get into the deeper brain structures.

And that level of knockdown signifies that. And then you have durability where we're seeing knockdown preclinically, that's now translating clinically and comparable to what we saw in the liver. And we think these drugs can be dosed 6 months a year or every 6 months or even less frequently. And so that's exciting.

And then the third and most critically, frankly, is the fact that so far the solubility -- safety and tolerability is really encouraging as well. And so this really opens up for us the opportunity to pursue multiple targets with our colleagues at Regeneron, who we've been working on in terms of this groundbreaking science.

And so to your point, HTT is another molecule that we recently announced as a development candidate. We're doing preclinical work now, IND-enabling work, to bring that into the clinic. We haven't formally announced the time line for that. But you can imagine that we're pursuing that rapidly.

Our colleagues at Regeneron are advancing a molecule against -- for ALS. Again, (inaudible) also in preclinical development right now. And we have additional targets behind that, that we're going to bring forward.

Our last question comes from Mani Foroohar of Leerink.

This is [Lili], on for Mani. We had a question in terms of the commercial positioning for vutrisiran. What will be your strategy to protect the assets from the upcoming tafamidis genericization? And do you expect the need for a potential post-approval head-to-head study?

Tolga, I'm going to hand that question straight over to you.

Yes. I mean, first of all, thank you for that question. I guess the question specifically for tafamidis for cardiomyopathy indication, which we have yet to receive. And obviously, how we're going to position the product is going to be dependent on the HELIOS-B results.

But 1 thing to really remind everyone. If you look at our polyneuropathy experience where the product is a different value in Europe and other markets, AMVUTTRA has been a game-changer. And we've been able to accelerate growth and demand quite substantially in the markets that now AMVUTTRA is available versus tafamidis and where we've seen an accelerated switch.

Particularly in Japan, where they have the polyneuropathy indication, unlike the U.S. Like any company that wants to continue to drive patient value and patient growth, we will, of course, be looking into the post genericization, and we will subsequently consider any alternative in terms of clinical trial and other options.

But it's -- I would say it's a little too soon for us to consider that, and we will obviously keep you abreast of any important decision that we will make eventually.

I'm now showing no further questions at this time. I would like to turn the conference back to Alnylam for closing remarks.

Thank you, and thanks, everybody, for joining us on this call. We're clearly very happy with the continued execution that we've seen in 2023 across multiple elements of our business: commercial, R&D and business development. And we look forward to showing more progress in the coming months as we continue to deliver on our near- and long-term goals. So thank you, everybody, and have a great day.

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