Alnylam Pharmaceuticals, Inc. Q2 FY2023 Earnings Call

Good day and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Q2 2023 Earnings Conference Call. At this time, participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. Please be advised that today's conference is being recorded. I would now like to hand the conference over to the company.

Good morning. I am Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, our Chief Medical Officer; and Jeff Poulton, Chief Financial Officer. For those of you participating via conference call, the accompanied 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 two, Yvonne will offer some introductory remarks and provide general context, Tolga will provide an update on our global commercial progress, Pushkal will review pipeline update and clinical progress, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call to 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 under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this reporting 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 continued 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 included positive 18-month data from our APOLLO-B Phase 3 study, reaffirming the potential of patisiran in ATTR amyloidosis of cardiomyopathy. In July, we shared updated positive interim results from the Phase 1 study of ALN-APP in patients with early onset Alzheimer's disease, showing rapid and robust target engagement with a sustained effect of six 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 US Attorney's Office for the District of Massachusetts has now concluded and closed their case regarding the marketing and promotion of ONPATTRO in the US with no action. Operating with integrity has always been and will continue to be a call to our Alnylam and we will continue to hold our business conduct, and in particular our interactions with healthcare providers and patients, to 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 2 program, zilebesiran, and pending a successful AdCom and positive regulatory review, the potential launch of ONPATTRO and 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 with 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 US 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 or AMVUTTRA 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 the UK, UK being our most recent launch market. After more than six 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 US 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 US, 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. The robust demand was slightly offset by inventory dynamics, which decreased reported growth 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 US 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 were ONPATTRO at the time of AMVUTTRA launch. Now update on our Ultra-Rare franchise. We are proud to have developed and commercialized two 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 first quarter 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 the first quarter was driven by the following. In the US, 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 US 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 2023 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 two 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 13th. We also announced today that enrollment in a US expanded access protocol for patisiran that was open 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 pre-specified 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 six-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's typical for this disease. Similarly, in patients who received placebo during the double-blind period, initiation of patisiran in the OLE period was associated with initial evidence of stabilization in both the six-minute walk test and KCCQ relative to the double-blind period. Importantly, patisiran continued to demonstrate an encouraging safety profile through 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. Patients who rolled over from placebo to active treatment during the OLE saw slowing in relative 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 non-significant trends favoring patisiran treatment in these outcome endpoints, with extended follow-up during the OLE 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 1 study in patients with Early-Onset Alzheimer's disease. At the time of this interim look, 20 patients had been enrolled in three single dose cohorts in Part A of the ongoing Phase 1 study. To date, we've studied three dose levels, 25, 50, and 75 milligrams with four to six 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% and 90% respectively for soluble APP alpha and beta. At the highest dose tested, 75 milligrams, the median knockdown was greater than 55% for both biomarkers and sustained for at least six months. The safety of single doses 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 non-clinical chronic toxicology studies. In summary, I'm thrilled about these impressive human data that provide the first ever evidence that we may be able to use RNAi to silence disease-causing transcripts from 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're very excited to recently announce that Phase 1 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 and commercialization of zilebesiran on the basis of these impressive Phase 1 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 2 study, which aims to evaluate the safety and efficacy of zilebesiran in patients with uncontrolled hypertension when added on top of other anti-hypertensive 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 the 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 US 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, 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's sales of Leqvio, which launched in the US in the first quarter of 2022. Despite the modest growth for revenues from collaborations and royalties, we remain confident in achieving a full year result within 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 the KARDIA-1, KARDIA-2 Phase 2 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 a 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 four 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 has 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 four commercial products. With patisiran, we look forward to the upcoming meeting of the Cardiovascular and Renal Drugs Advisory Committee on September 13th with the PDUFA date shortly thereafter on October 8th. Later this quarter, we expect to report top line results from the KARDIA-1 Phase 2 study of zilebesiran. We also intend to report top line results from Phase 1 studies of ALN-TTRsc04, and development for the treatment of ATTR amyloidosis, and ALN-KHK, in development for the treatment of type 2 diabetes. Our partnered programs Sanofi expects to report additional results from the Phase 3 ATLAS program with patisiran, an investigational RNAi therapeutic and development for the treatment of hemophilia A or B with or without inhibitors. Additionally, Vir expects to report further results from Phase 2 combination trials of ALN-HBV02, in development for the treatment of chronic HPV infection. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Jeff. Operator, we'll now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question and then get back in the queue if you have additional questions.

Thank you. We'll now conduct the question-and-answer session. Our first question comes from Mike Ulz of Morgan Stanley. Your line is now open.

Hey, guys. Thanks for taking the question. Maybe just quickly, any updated thoughts on the upcoming AdCom ONPATTRO and ATTR CM in terms of why the FDA decided to host the panel and then where you expect the focus to be? Thanks.

So, 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 six-minute walk test and the KCCQ, particularly given the fairly recent FDA guidance around the utility of these endpoints in patients with heart failure. We really believe that we have compelling data for APOLLO-B study across a wide range of endpoints, supported by additional validation from the recent 18-month data that Pushkal described. We have submitted to the FDA. Pushkal, anything else to add?

I think you've really covered it, Yvonne. Our preparations are underway, and we feel confident about the data set generated with APOLLO-B. We are observing evidence of stabilization across several endpoints, which is critically important. Patients with this disease value their functional ability and quality of life. What we are seeing across multiple measures indicates that patisiran appears to support that, and this is further confirmed by the extended OE data we submitted. We look forward to presenting this to the advisory committee as they prepare for their review.

Thanks Pushkal. Next question?

One moment for the next question. Our next question comes from Luca Issi of RBC. Your line is now open.

Great. Thanks for taking our questions. This is Lisa on for Luca. I just wanted to dive into some specifics on the Roche deal first, 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 2. 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. Thanks.

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 in 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. The collaboration with Roche allows us to bring together our leadership in RNAi with their proven global commercial footprint and capabilities to help us maximize the resources and capabilities in order to be successful here. But I think it's important to be specific about the details of the milestones. So Jeff, maybe you could...

Yeah. 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 as $65 million for the initiation of KARDIA-3, which is the additional Phase 2 study that Pushkal talked about on the deal call. We expect that study to initiate next year. And then an additional $300 million for the first patient in on the CPOT, the Phase 3 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.

That's great, Jeff. Thank you. Next question?

One moment for our next question. Our next question comes from Citi with David Lebowitz. Your line is now open.

Thank you very much for taking my question. A 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 three months down the road? Or have they not exhibited any such intent at this point? And on franchise growth, while there's no 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?

Yeah. Two great questions. So, I'll take the question on the PDUFA date and then I'll hand over to Tolga to speak to your overall franchise question around the dynamics between ONPATTRO and AMVUTTRA. We're continuing to anticipate a PDUFA date of October 8th, 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 the PDUFA date of October 8th. Tolga, do you want to turn to the question on ONPATTRO dynamics?

Sure. Happy to. So, the way I think we should consider this is the US, and our newly launched AMVUTTRA markets and those markets that continue to have only ONPATTRO as an option in the franchise. As I indicated on the call, if you look at our US growth in the TTR categories, 70% quarter-over-quarter growth for the last four 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 US at the time of AMVUTTRA launch 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, and now we're starting to see in France with very creative AP2 program name patient program as was in the UK. We're getting accelerated approvals in those several key markets to make sure that we're providing AMVUTTRA as an option. 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 is still not yet available, we're seeing 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 good, strong growth, which positions us very nicely at the time of AMVUTTRA launch in these other markets. We'd like to see a good strong uptake of AMVUTTRA and subsequent switches from ONPATTRO to AMVUTTRA.

Thanks for taking the question.

Yeah, thanks. Let's turn to the next question.

One moment for our next question. Our next question comes from Paul Matteis of Stifel. Your line is now open.

Hey, thanks so much. 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 AdCom 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 or this announcement today. Thanks so much.

Thank you for your question. I am personally pleased that Akshay is stepping into the role of our first Chief Innovation Officer. In this role, he will concentrate on driving further success within our R&D organization. We have developed a strong capability in research and development, which enables Akshay to focus more on innovation as we strive to establish a leading biotech company. I believe this is a significant advancement for the company. There isn't a specific reason for the timing; Akshay feels we have built a solid foundation that allows him to take on a more concentrated role. He will remain involved in all key upcoming catalysts and milestones you mentioned. He is not on the call today as he is on vacation, but we may hear from him in the near future. Thank you for your question, Paul.

Okay. Thank you.

One moment for our next question. Our next question comes from Ritu Baral of TD Cowen. Your line is now open.

Good morning, everyone. I appreciate you taking my question. Yvonne and Pushkal, I would like to delve deeper into the preparation for the advisory committee, whether it pertains to your team, ours, or the FDA. Are you currently planning to discuss any additional data beyond 18 months from APOLLO-B or any information from the fully enrolled expanded access plan? Additionally, do you think there has been any change in the understanding of these endpoints, considering the recent BridgeBio data and the connections between these endpoints and others?

Thanks, Ritu. There are a few questions to address, so let's go through them. First, regarding our AdCom preparations, will we be providing any additional data to the FDA beyond the 18-month data we've already mentioned? Second, is there any change in our understanding concerning the endpoint selection? Pushkal, could you please address these two questions?

Thank you, Ritu. Regarding our AdCom preparations, we are in the process of consolidating our efforts. We feel confident about the team's readiness. This confidence is based on the robust data from APOLLO-B and further supported by the OLE data we previously discussed. The study has shown consistent results across various measures, particularly in functional ability and quality of life. The biomarker data suggest that patients on this drug experience a slower progression of decline. We also presented data at last year's R&D Day that highlighted positive effects on disease progression concerning NYHA Class and ATTR disease stage. Collectively, this indicates that patients starting treatment with this silencer experience delayed progression, which is crucial information we receive from clinicians. For patients in their seventies and eighties, improvements in functional ability and quality of life are particularly significant. The AdCom will compile these arguments, and we have garnered strong support from both the data and external key opinion leaders. We look forward to presenting these points at the advisory committee meeting and engaging with the agency and the panel. As for BridgeBio, I believe this news is promising for patients, as it appears there may be an additional treatment option being explored. Kudos to the patients, investigators, and the team at BridgeBio for their hard work during challenging times, resulting in a positive study outcome. Regarding our own franchise, we are excited about the profile of the silencer. While the emerging data from APOLLO-B shows trends that may not be statistically significant yet, they suggest promising outcomes in mortality and hospitalization. The main point is that even though we are diagnosing patients earlier, those patients still experience ongoing progression, which seems to be confirmed by the BridgeBio data. Effective therapies can provide benefits for this population, reinforcing the design elements of HELIOS-B, which we find very encouraging.

Great. Thanks.

One moment for our next question. Our next question is coming from Salveen Richter of Goldman Sachs. Your line is now open.

Thanks for taking our question. This is Tommy on for Salveen and congrats on all the progress. Our question is also on BridgeBio and HELIOS-B. So, we saw from BridgeBio that there is this imbalance in TAF drop-in rates between the two 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 be able to give physicians insight into potential additive benefit when you combine Alnylam insurance stabilizer?

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

Yeah. Look, I think, as it relates to TAF drop-in rates, as we’ve talked about in the past, we’ve got careful measures in place and the way 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 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. I think we will get interesting data emerging from that study in terms of how the drug functions as a monotherapy, as well as on top of background tafamidis.

Thanks. Next question please.

One moment for our next question. Our next question comes from Maury Raycroft of Jefferies. Your line is now open.

Hi, thanks for taking my question. For the 200-patient expanded access program study, can you talk about the types of patients you've enrolled, timeline to data, and how the data will be leveraged as it relates to regulatory or commercial plans?

Yeah. Pushkal, that’s a question for you around the EAP types of patients and then also thinking about how these data may be used going forward.

Thank you, Maury. When the APOLLO-B data was released, it highlighted the possibility of an alternative treatment option for patients with this condition. As we've mentioned several times during the call, these patients, despite having access to standard treatment with tafamidis, continue to show disease progression. In response, we established an expanded access program across 20 US centers, allowing patients who were experiencing worsening conditions or who could not tolerate the available treatment to access patisiran with support from their physicians. This program enrolled 200 patients fairly quickly, averaging about three new participants every two days. This situation underscores what we’ve been hearing from both clinical and patient communities: patients are still progressing with this disease and require further treatment options. This is an important consideration as we advance patisiran for this condition, and we hope to also see positive outcomes from the HELIOS-B study.

Yeah. Thanks Pushkal. I think the point about continued unmet medical need is really the important one here. We see the patients who are continuing to progress and patients that need alternative therapeutic approaches. Next question, please.

One moment for our next question. Our next question comes from Eliana Merle of UBS. Your line is now open.

Hey, guys. Thanks so much for taking the question. For HELIOS-B, can you elaborate on your rationale for using Andersen-Gill as a statistical method versus the Finkelstein–Schoenfeld pairwise analysis that was used in the stabilizing Phase 3, 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 visit as part of this endpoint definition? Thanks.

Pushkal, there may be two questions for you.

Sure. Ellie, I think there’s a multitude of approaches to conducting survival analysis and outcome analysis that take advantage of the fact that you’re looking at recurrent events and events over time. Our statisticians obviously spend a lot of time thinking about what’s the optimal way to demonstrate the clinical benefit. That’s highlighted in a statistical analysis plan that’s aligned with the agency. In this instance, one reason for preferring the Andersen-Gill is that we allow for variable follow-up in the context of the outcomes analysis. The Andersen-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. We think it gives us a little bit of an analytic or power advantage to do it that way. Regarding the various components of the endpoint, I think what’s really important, Ellie, is maybe just the larger picture. We’re trying to capture clinically relevant events that connote heart failure worsening and the need for care in patients with this disease. That said, care is increasingly provided in different geographies, in different places, including in hospitals and urgent care centers, et cetera. We look at the totality of all of that as indicating clinically relevant heart failure events that we may have an opportunity to affect with an effective therapy. That’s why we’ve captured that aspect in the endpoint structure.

Great. Thanks so much.

One moment for our next question. Our next question comes from William Pickering of Bernstein. Your line is now open.

Good morning. Thanks for taking my question. I was wondering what percent of AMVUTTRA patients are getting dosed at home so far. And yeah, as you look ahead to future competitive dynamics versus vutrisiran, 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? Thank you.

Tolga, there are two questions for you. The first relating to home infusion and the second, I think, relating to vutrisiran and how we're thinking about differentiation.

Yeah. 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 that’s dosed four times a year. And I think this really positions the product well from a convenience perspective. There are a number of important features that we believe will make AMVUTTRA incredibly competitive. Having a unique MOA, a robust and sustained disease reversal, obviously with a few doses, and we should also remember we have five years of experience now in this category, and now one full year in the US promoting AMVUTTRA. We have been able to establish numerous important patient and physician capabilities, starting from the fact that this is a Part B product where we have excellent coverage of reimbursement benefits. In addition to that, we facilitate various options in terms of site of care, not just in the home, but also in other different sites of care, whether it’s an infusion center or in hospital care. Moreover, we support the patient benefit. Since we launched ONPATTRO and now AMVUTTRA, we have nearly a third of our patients getting home care. What’s also important is to remember, almost all of our patients of over 90% stay on therapy. Not only do they get a good convenience access to these medicines, but also they have the ability to stay on therapy. We have very, very minimal dropouts. With all these other features that we offer, we believe this is going to remain a very significant benefit. Another important one is obviously to remember, unlike Part D until 2025, nearly 70% of our patients have zero copay. This will continue to be an important benefit. We feel very good about how AMVUTTRA is already being positioned in the market, first with the values that we bring to the table, as well as some of the services that we’ve set out there for the last five years.

Very helpful. Thank you so much.

One moment for our next question. Our next question comes from Genie Wang of Barclays. Your line is now open.

Thank you for taking my questions. I also have one question regarding HELIOS-B. I think, Pushkal, in the past, you commented on the dropping rate, I think early on was in the low single digit. I'm pretty sure now that it has increased. But do you think, so far, say if we're using a TRIBUTE study as a benchmark, that your dropping rate will be much lower than that, doing say, below 10%? And also do you see blinded events and how's that events tracking versus your initial assumption?

Thank you, Gena, for your questions. Regarding the drop-in rates, as you can imagine, over a study that lasts more than three years, those rates are likely to change. I can confirm that the rates are significantly lower than what we initially planned. We feel very positive about the overall powering of the study. Many factors influence how a study is powered and the eventual outcomes. Considering all of these factors, we feel confident about the study. As for event rates, we have an excellent clinical and statistical team dedicated to monitoring the study and ensuring data quality and integrity. Overall, we are quite optimistic about what we are observing. Our team has extensive experience in successfully designing and executing studies in this field, including APOLLO-B. Thus, we are very confident in our work with HELIOS-B.

Thanks for the question, Gena.

One moment for our next question. Our next question comes from Leland Gershell of Oppenheimer. Your line is now open.

Hey, thanks for taking the question. Just a question from me, as we look forward to the ALN-KHK data, obviously it's being looked at in type two 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, essentially NASH. Just wondering what your thoughts may be 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 two other programs in NASH, those are both partnered. Wondering if you have freedom to pursue NASH if you’d like for KHK. Thank you.

Yeah. That’s a great question. Just to remind everybody that KHK is a genetically validated target involving the 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 1 study on addressing target engagement and safety, and also looking at a range of relevant biomarkers with respect to glucose metabolism and insulin levels. However, I think you raised an interesting question, which is that the broad potential of KHK and metabolism in general. Pushkal, maybe you want to provide some perspective?

Yeah. Leland, I think it’s a really insightful question in the sense that we’ve seen epidemiologically that with a 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. It’s entirely possible that by perturbing this pathway with an RNAi mechanism, we may have beneficial effects in a number of these different domains. What’s exciting here is that we have what we think is a really potent and based on pre-clinical work a durable way to silence KHK, that we can elaborate upon. 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 and how to pursue them, et cetera. This is also then a proprietary target within Alnylam that we’re advancing. We have the freedom to operate across a full range of diseases, and take it where the science and the unmet need drives us. Look forward to sharing more data on that in the future.

Great, and thank you for highlighting, I think, another exciting opportunity in our pipeline and more to come towards the end of the year. Next question?

One moment for our next question. Our next question comes from Myles Minter of William Blair & Company. Your line is now open.

Hi. You've got Sarah on from Myles. Thanks for taking our question. Is there any clarity you can give on the timeline 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? Thank you.

The timelines for ALN-APP and any other programs using.

Yeah. So HTT. Thanks Sarah for the question. As I said in the remarks and as you’ve heard from us in a couple of recent calls, what we’ve seen in the CNS space with ALN-APP has been really, we think, groundbreaking. It 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. When you look at what we see there, we see with the levels of up to 84%, 90% lower of soluble APP alpha and beta that signify 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? That level of knockdown signifies that. The durability where we’re seeing knockdown pre-clinically is now translating clinically to what we saw in the liver. We think these drugs can be dosed six months a year, or every six months or even less frequently. That’s exciting. Third, most critically frankly, is the fact that so far, the solubility, safety, and tolerability is encouraging as well. This really opens up for us the opportunity to pursue multiple targets with our colleagues at Regeneron, with whom we’ve been working on this groundbreaking science. 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 a timeline for that, but you can imagine that we’re pursuing that rapidly. Our colleagues at Regeneron are advancing a molecule against SOD, also in preclinical development right now. We’ve additional targets behind that that we’re going to bring forward.

I think we have time for one last question.

One moment for our last question. Our last question comes from Mani Foroohar of Leerink. Your line is now open.

Hi. Good morning. This is Lily 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 generization, 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.

Yeah. I mean, first of all, thank you for that question. I guess the question specifically for tafamidis, for the cardiomyopathy indication, which we have yet to receive and obviously, how we're going to position the product is going to be dependent on HELIOS-B results. One thing to really remind everyone, if you look at our polyneuropathy experience where the product is different value in Europe and other markets, I wouldn’t say it has been a game-changer. We were able to accelerate growth and demand quite substantially in the markets that now AMVUTTRA is available versus tafamidis. We’ve seen an accelerated switch, particularly in Japan, where they have the polyneuropathy indication, unlike the US. Like any company that wants to continue to drive patient value and 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 a little too soon for us to consider that, and we will obviously keep you abreast of any important decision that we would 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. We look forward to sharing more progress in the coming months as we continue to deliver on our near and long-term goals. Thank you everybody, and have a great day.

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