Alnylam Pharmaceuticals - Q3 2023

Transcript

Operator (participant)

Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Q3 2023 earnings conference call. At this time, participants are in a listen-only mode. After the speaker's 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 call over to the company.

Christine Lindenboom (SVP of Investor Relations and Corporate Communications)

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 in slide two, Yvonne will offer introductory remarks and provide 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 to your questions.

I would 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 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?

Yvonne Greenstreet (CEO)

Thanks, Christine, and thank you everyone for joining the call today. In the third quarter of 2023, we continued to make great progress across our business while also experiencing a disappointment. As we announced last month, the U.S. Food and Drug Administration declined to approve the supplemental new drug application for patisiran, an investigational RNAi therapeutic that was in development for the treatment of the cardiomyopathy of ATTR amyloidosis. As we have conveyed, we are extremely disappointed with this outcome, particularly with regard to the needs of patients, many of whom spoke at the advisory committee meeting in September. We have been steadfastly committed to this underserved population for over a decade and remain confident in our long-term strategy to building a leading TTR franchise, with patisiran and the HELIOS-B study serving as a very important next step in this journey.

We look forward to sharing those top-line results, which remain on track for early 2024. As we continue to progress our plans in ATTR cardiomyopathy, our commercial strength in the third quarter was driven by the ongoing successful launch of AMVUTTRA in patients with hereditary ATTR amyloidosis with polyneuropathy. This contributed to a 35% year-over-year growth in total net product revenues compared to the third quarter of 2022. We also delivered important clinical updates from key pipeline programs in the third quarter. In September, we announced positive top-line results from the KARDIA-1 phase II dose-ranging study of zilebesiran, which demonstrated greater than 15 mm Hg reduction of systolic blood pressure at 3 months of treatment compared to placebo, as well as an encouraging safety and tolerability profile in adult patients with mild to moderate hypertension.

Additionally, the results also reflected sustained reductions in systolic blood pressure at 6 months, supporting the potential for quarterly or biannual dosing. We also shared updated positive interim results from the phase I study of ALN-APP in patients with early-onset Alzheimer's disease, which showed rapid and robust target engagement with sustained effects out to 10 months with a single dose and an encouraging clinical safety and tolerability profile. Additionally, we presented data from the APOLLO-B study of patisiran at HFSA, showing that the effects of patisiran treatment on 6-minute walk tests and KCCQ were maintained through 24 months of treatment. This type of relative stabilization in what is otherwise a steadily progressive disease is very encouraging and further bolsters our confidence in HELIOS-B.

We're thrilled to have had these results published in the New England Journal of Medicine just a few weeks ago, which is accompanied by a favorable editorial highlighting the step forward represented by RNAi therapeutics in this disease. Lastly, we're excited to have achieved a third-place ranking in Science Magazine's Top Employer Survey for 2023. This marks the fifth year that Alnylam was featured as one of the top three companies in their annual survey of industry professionals. We are poised to deliver a couple more pipeline updates by the end of the year, including top-line phase I results for ALN-TTRsc04, as well as ALN-KHK, our investigational RNAi therapeutic for type 2 diabetes.

I encourage you all to save the date and tune in to our annual R&D Day, which will be held virtually on December 13, where we will discuss all of the exciting progress across our pipeline and platform.... We believe all of this puts us on track with our Alnylam P5x25 goals, making Alnylam a top-tier biotech, developing and commercializing transformative medicines for patients around the world with rare diseases and beyond, driven by a high-yielding pipeline of first and or best-in-class product candidates from our organic product engine, all while delivering exceptional financial results. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

Tolga Tanguler (Chief Commercial Officer)

Thanks, Yvonne, and good morning, everyone. Q3 was another strong quarter for our commercial portfolio, with both our TTR franchise, driven by another robust quarter of ONPATTRO performance in the U.S. market, and our ultra-rare franchise delivering growth in excess of 30% compared with the prior year, as we continue to steadily increase the number of patients on all of our therapies. Total net product revenues grew 35% year-over-year for the third quarter, or 33% at a constant exchange rate. Let me now turn to a summary of our third quarter TTR performance. Our TTR franchise achieved $230 million in global net product revenues for ONPATTRO and AMVUTTRA, representing a 3% increase compared with the second quarter and 35% growth compared with the third quarter of 2022.

At the end of the third quarter, more than 3,790 patients were on commercial ONPATTRO or AMVUTTRA treatment worldwide, up from over 3,490 patients at the end of the second quarter, representing 8% quarterly patient growth. Now, let me provide highlights of our U.S. and international TTR performance. In the U.S., combined sales of ONPATTRO and AMVUTTRA increased by 11% compared with the second quarter and a robust 47% year-over-year, driven by AMVUTTRA's launch. The U.S. growth was primarily driven by the following: a 6% increase in demand, which was driven by the strength of ongoing AMVUTTRA patient uptake, more than offsetting a decrease in ONPATTRO patients that switched to AMVUTTRA.

At the end of the third quarter, more than 80% of Alnylam U.S. TTR patients are now on AMVUTTRA, a positive sign indicating how well the product profile has been received by both prescribing physicians and patients. In addition to the demand growth, reported growth was also favorably impacted by approximately 5% due to an increase in AMVUTTRA inventory in the distribution channel. Now, let me turn to our international markets, where TTR franchise growth decreased by 7% compared with the second quarter. Although there was growth in patients on therapy during the quarter, this growth was offset by a variety of factors, including price adjustments in Germany following the end of the 6-month free pricing period, inventory destocking in Japan, and the timing of orders in emerging and partner markets.

It is worth noting that we have now launched AMVUTTRA in all major international markets following recent launches in Spain and Italy. I'm proud of the efforts of our market access team as we have made AMVUTTRA available to patients and secured reimbursements significantly faster than industry benchmarks. Now, moving to our ultra-rare products and the performance of GIVLAARI and OXLUMO, which delivered $83 million in combined product sales during the third quarter, representing a 1% increase compared with the second quarter and a solid 33% growth compared with the third quarter of 2022.

We ended the quarter with more than 1,000 patients on our two ultra-rare products, an exciting milestone with more than 625 patients on GIVLAARI commercial therapy and more than 375 patients on OXLUMO commercial therapy, representing 8% combined quarterly growth in patients on our ultra-rare products compared with the second quarter 2023. For GIVLAARI, product sales declined 6% in Q3 compared with the second quarter, with the following regional dynamics: a 5% increase in demand in the U.S. market, driven by an increase in patients on therapy. A 25% decrease in our international markets, driven by the timing of orders in emerging and partner markets. Whereas we previously indicated Q2 results benefited from a large order and higher gross to net deductions.

For OXLUMO, we delivered a robust 19% increase in product sales compared with the second quarter, which was driven by the following: a 10% increase in the U.S., driven by 16% demand growth, partially offset by a reduction of inventory in the distribution channel. A 23% increase in our international markets, driven by increased demand and the timing of orders in our emerging and partner markets. We were pleased with the results in the quarter, particularly the strong patient growth with both our TTR and ultra-rare franchises, delivering an 8% increase in patients on therapy during the quarter, as well as delivering robust year-over-year growth in revenues, with both franchises growing in excess of 30%.

As we look ahead to the end of the year, we anticipate a strong fourth quarter, positioning us to end the year at the approximate midpoint of our net product revenue guidance range. With that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

Pushkal Garg (Chief Medical Officer)

Thanks, Tolga, and good morning, everyone. Let me start with our TTR franchise. As you know, we have two products approved for the polyneuropathy of hereditary ATTR amyloidosis, ONPATTRO and AMVUTTRA. We've also been pursuing expansion into ATTR cardiomyopathy through two large studies, APOLLO-B for patisiran and HELIOS-B for vutrisiran. As previously announced, while APOLLO-B delivered positive results, not just on the primary endpoint, but consistently across additional secondary and exploratory endpoints as well, all with a positive safety profile, the FDA declined to approve the sNDA for patisiran, citing insufficient evidence of clinical meaningfulness. As a result of this decision, and with the top-line readout from HELIOS-B expected in early 2024, we have elected not to invest further into additional development to secure approval for patisiran in ATTR cardiomyopathy in the United States.

The positive data on multiple aspects of ATTR cardiomyopathy coming out of the APOLLO-B study reaffirm our confidence in the success of vutrisiran. In particular, the 24-month data show that both six-minute walk test and KCCQ were relatively stable over the entire period, in contrast to the large expected decline expected in this disease and suggest the potential that RNAi-mediated TTR silencing may result in a differentiated efficacy profile in this disease. The HELIOS-B study is designed and powered to demonstrate a benefit of vutrisiran in patients very similar to those studied in APOLLO-B on the composite outcome of all-cause mortality and recurrent cardiovascular events over a 30- to 36-month period.

The study is on track to read out in early 2024, and assuming positive data, we then plan to seek a label expansion for AMVUTTRA, and if approved, ultimately launch that medicine into the growing market of patients around the world with wild type or hereditary ATTR amyloidosis with cardiomyopathy. We believe that the convenient quarterly subcutaneous dosing regimen with a therapeutic profile that includes cardiovascular outcomes data in its label, could potentially position AMVUTTRA as a transformative therapy with a market-leading profile for patients with this disease. Moving on, following announcement of initial human proof-of-concept data on ALN-APP, our first RNAi therapeutic design for CNS delivery, which is in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy, we are excited by the positive results we've seen from the phase one study to date.

At the Clinical Trials on Alzheimer's disease conference a few weeks ago, we presented additional 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 mg, 50 mg, and 75 mg, with 4-6 patients dosed in each cohort. Excitingly, ALN-APP treatment resulted in rapid, dose-dependent, and sustained reductions in both soluble APP alpha and beta, biomarkers of target engagement in the CSF. We saw rapid knockdown as early as day 15 and observed peak mean reduction of 69% and 82%, respectively, for soluble APP alpha and soluble APP beta.

Reduction was sustained with a mean reduction of 33% and 39%, respectively, for soluble APP alpha and beta, 10 months after a single 75 mg dose. We also presented clinical data that for the first time, showed marked reductions in Aβ42 and Aβ40, the soluble forms of the amyloidogenic peptides that aggregate into amyloid deposits in Alzheimer's disease and CAA. Specifically, at two months after a single dose of 75 mg of ALN-APP, mean reductions of CSF Aβ42 and Aβ40 were 49% and 71%, respectively. Given that these peptides are directly implicated in disease pathogenesis, these findings are encouraging, as they suggest that treatment with an RNAi therapeutic can potentially interrupt relentless progression of these two devastating diseases. 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 and has now also received all required approvals to proceed in the United Kingdom and the Netherlands. 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 sum, I'm thrilled about these impressive human data showing the potential for RNAi to silence 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 have reported positive top-line results from the KARDIA-1 phase II dose-ranging study. In KARDIA-1, zilebesiran met the primary endpoint, demonstrating a dose-dependent, clinically significant reduction in 24-hour mean systolic blood pressure, measured by ambulatory blood pressure monitoring at month 3, achieving a placebo-subtracted reduction greater than 15 mm Hg, with both 300 mg and 600 mg doses. The study also met key secondary endpoints, including significant change in 24-hour mean systolic blood pressure, as measured by ABPM at month 6, as well as significant change in office systolic blood pressure at months 3 and 6 for all zilebesiran arms compared to placebo. The study results indicate zilebesiran was associated with dose-dependent, potent, and durable knockdown of serum AGT levels through month 6. Importantly, zilebesiran demonstrated an encouraging safety and tolerability profile.

We look forward to sharing complete results for KARDIA-1 at the upcoming AHA Scientific Sessions this month, and we remain on track to deliver top-line results from the KARDIA-2 phase II combination study of zilebesiran in early 2024. Before I wrap up, I'd like to briefly update on one of our partnered programs, fitusiran, which is in development for the treatment of hemophilia A or B, with or without inhibitors. Sanofi just reported encouraging safety and efficacy data for the antithrombin-based dosing regimen in a phase 3 study and indicated they are currently in discussions with the FDA regarding filing an NDA in 2024. These are just a few highlights from a broad and innovative pipeline, driven by our underlying organic product engine, that we expect will deliver sustainable innovation and represents a key growth driver 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?

Jeff Poulton (CFO)

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q3 2023 financial results and discussing our full-year guidance. Starting with a summary of our P&L results for Q3 2023. Total product revenues for the quarter were $313 million, or 35% growth, versus Q3 2022. As Tolga previously mentioned, the increase was driven by strong growth from our TTR and ultra-rare franchises, with both reporting growth greater than 30% during the quarter compared with the prior year. Our reported results in the quarter benefited modestly from foreign exchange, as constant exchange rate product sales growth was 2% lower at 33%.

Net revenue from collaborations for the third quarter was $427 million, representing nearly a $400 million increase from Q3 2022, primarily due to increases in revenue from our zilebesiran co-development and co-commercialization collaboration with Roche, which included full recognition of the $310 million upfront payment received in the third quarter, as well as $65 million in revenue in connection with our Regeneron collaboration. The $65 million represents the portion of revenue recognized from a $100 million milestone earned from achieving certain criteria during early clinical development for our CNS program, ALN-APP. Royalty revenue during the quarter was $10 million, which was driven by Novartis' sales of LEQVIO, which continued to increase following launch in the U.S. in the first quarter of 2022.

Gross margin on product sales was 75% in Q3, representing a 10% decrease compared with the third quarter of 2022, primarily due to a Q3 write-off of ONPATTRO inventory that had been manufactured for future demand associated with the ATTR cardiomyopathy indication for patisiran, for which we did not receive regulatory approval. Recall that I mentioned on our ONPATTRO CRL investor call on October 9th, that we expect ONPATTRO demand to decrease on a go-forward basis as AMVUTTRA continues to cannibalize existing ONPATTRO polyneuropathy business in markets where AMVUTTRA has launched. As a result, for 2024, we anticipate ONPATTRO product sales will be in the $200-$225 million range.

Our non-GAAP R&D expenses increased 16% in the third quarter compared to the same period in 2022, primarily due to higher costs related to clinical activities and increased headcount to support our R&D pipeline and an expense for achievement of certain milestones payable to a partner. Our non-GAAP SG&A expenses increased 2% in the third 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. For the first time in Q3, we generated non-GAAP operating profit during the quarter equal to $278 million, driven by the significant revenue recognized during the quarter from our collaborations with Roche and Regeneron. We anticipate that in future quarters, we will revert to a non-GAAP operating loss, as we have not yet achieved sustainable profitability.

Finally, we ended the quarter with cash, cash equivalents, and marketable securities of $2.4 billion, compared to $2.2 billion at the end of 2022, with the increase primarily related to the $310 million upfront payment from Roche, offset by 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. We are increasing our collaboration and royalty revenue guidance from $100 million-$175 million to $575 million-$625 million. The substantial increase is primarily attributable to two factors that were not included in our previous guidance.

First, recognition of the full $310 million upfront payment received from Roche in the third quarter in conjunction with our zilebesiran collaboration.

I would also like to note that our accounting conclusions associated with the Roche collaboration are summarized on slide 27 in the appendix of today's presentation. Secondly, achievement of the $100 million ALN-TTRsc04 milestone from Regeneron during the third quarter, the majority of which will be recognized as revenue during 2023. All other elements of our 2023 financial guidance remain unchanged. Let me now turn from financials and discuss some key goals and upcoming milestones slated for the remainder of 2023. We will, of course, be executing on global commercialization of our products, ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. We intend to report top-line results from phase 1 studies of ALN-TTRsc04 in development for the treatment of ATTR amyloidosis, and ALN-KHK, in development for the treatment of type 2 diabetes.

With our partnered programs, Vir expects to report further results from phase II combination trials of ALN-HBV02 in development for the treatment of chronic hepatitis B. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Christine Lindenboom (SVP of Investor Relations and Corporate Communications)

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

Operator (participant)

Thank you. At this time, we will conduct the question-answer session. As a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from Ritu Baral of TD Cowen. Your line is now open.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Good morning, guys. Thanks for taking the question. I wanted to ask a little bit about the HELIOS-B statistical plan. I understand that you're using the Andersen-Gill method, in which our statistical consultant anyway said that any kind of CV event would be analyzed as a recurring event, and would count, versus what has been used by other developers where they had ranks of... They had to rank events. Within this Andersen-Gill, are events of different types in the composite weighted equally, or are certain events, you know, like death and hospitalization, weighted more, such that the analysis may be more meaningful to doctors for serious events and regulators as well? Thank you.

Yvonne Greenstreet (CEO)

Thanks, Ritu, and good morning. Kind of a great question, and as you know, we're laser-focused on delivering a successful HELIOS-B study and feel confident, just given, you know, our track record in the area and all the studies that we've delivered that have been positive to date. But regards to your specific question around, you know, how we're thinking about the statistical analysis, Pushkal, maybe you could provide a few perspectives.

Pushkal Garg (Chief Medical Officer)

Yeah. Thanks, Ritu. You know, look, I think there's lots of ways that people look at these types of data. As you mentioned, our focus is really on death and recurrent hospitalizations. And both Finkelstein-Schoenfeld and Andersen-Gill can do that. I think one of the unique aspects of the study that we've done to sort of increase and maximize power is actually have differential follow-up for patients. So we have follow-up that can range from 30-36 months. And the Andersen-Gill allows us to actually incorporate that variable follow-up, whereas in the Finkelstein-Schoenfeld, that follow path to sort of be aligned to the lowest common denominator. So it actually gives us some additional power, and that's why our statisticians and our team is, you know, we've prioritized that in the statistical analysis plan.

So certainly, you know, it weighs deaths, but we look at all of those deaths and the hospitalization events, as well as recurrent events that you talked about. So we think that really optimizes the power for the study.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Great. Thank you.

Pushkal Garg (Chief Medical Officer)

Thanks, Ritu.

Operator (participant)

Thank you, and one moment for our next question. Paul Matteis of Stifel, your line is now open.

Paul Matteis (Managing Director and Head of Therapeutics Research)

Great. Thanks so much for taking the question. I appreciate it. You know, we've been trying to think about what, if any, learnings there are from the recent advisory committee to HELIOS-B, and, you know, we fully understand, right, that HELIOS-B is generating outcomes data and the issues with APOLLO-B at the FDA level are related to a lack of that to some extent. That said, I was curious if you think from a regulatory perspective, it's important that you show some level of added outcomes benefit on top of tafamidis. And I, I'm assuming the study is not really powered for a p-value, but how would you kind of delineate what the line is on a clinically meaningful effect in the combo therapy subset of HELIOS-B? Thanks so much.

Yvonne Greenstreet (CEO)

Pushkal, that's probably a question that goes straight to you.

Pushkal Garg (Chief Medical Officer)

Yeah. Thanks, Paul. Look, I think maybe a couple points. You know, as reflected previously, obviously, we're disappointed in the decision that was made. But as we look at the APOLLO-B results with regard to TAP and non-TAP, you know, the add-on TAP group was a very small group, only 91 patients. The study wasn't designed to characterize that subgroup. But we are encouraged, and when we looked at the data that were presented at the Adcomm and at various congresses, that the outcomes data in both groups actually are trending favorably for the patisiran arm, and that bodes well for HELIOS-B. You know, the other point I would just make around that is that we've.

We have an experience now in that study, as we've mentioned, that we targeted operationally about 50% of patients. We've come in somewhat less than that, which certainly adds in the overall powering of the study, while we over-enrolled as well by 10%. I think with regard to the add-on factor that you were mentioning from a regulatory perspective, I think, you know, one of the points that probably is worth noting is that I think that point was raised in particular, because tafamidis has a mortality claim, and what APOLLO-B, what ONPATTRO was coming forward with, was with a functional claim in terms of six-minute walk test in KCCQ. And so that raises questions about how these drugs are going to be used in combination or in sequence, et cetera.

You know, in contrast, as you've just highlighted, HELIOS-B is going to deliver outcomes results, and so that issue becomes much less of an issue. The other point is that we have a much larger experience in this study and much longer follow-up. So I do think that we're going to be able to look at the consistency of effect across both the monotherapy and the baseline Taf group, and that's really what we'll be focusing on as we look at that subgroup, as well as a number of other subgroups in the study.

Yvonne Greenstreet (CEO)

Excellent. Thank you.

Paul Matteis (Managing Director and Head of Therapeutics Research)

Makes sense. Thank you.

Operator (participant)

Thank you, and one moment for our next question. Our next question comes from Luca Issi of RBC. Your line is now open.

Speaker 15

Oh, great, thanks for taking our questions. This is Lisa on for Luca. I just want to touch base on HELIOS-B. Is it possible that you will elevate NT-proBNP and six-minute walk test as part of the composite primary endpoint? You obviously have shown promising results from both of those endpoints in APOLLO-B, and in that way, if they're elevated, you would have a primary endpoint that ends up replicating BridgeBio. So you could, in theory, use that as a regulatory precedent to facilitate your conversation with Norman Stockbridge. Would that be a fair way to think about it? Any color there would be much appreciated. Thanks.

Pushkal Garg (Chief Medical Officer)

Thanks, Lisa, for your question. Look, I think, you know, what you're pointing out and raising is the fact that when we looked at the APOLLO-B data, we did see really pretty much every endpoint lining up in favor of TTR lowering, whether it was functional, like six-minute walk test or quality of life, echocardiographic parameters and biomarkers like NT-proBNP. And so, I appreciate the point that you're raising. And, certainly as, Yvonne highlighted, we're laser-focused on delivering a successful study. We're very confident in the overall design of the study, the execution of the study.

I think, you know, to your point about the BridgeBio results, I think they point to the fact that in the modern era, that this is still a progressive disease, despite patients being caught earlier in their disease process, and that an effective therapy can show a benefit, on top of that, and so in that setting. So, we're overall really encouraged by what the study is and how it's designing out. And as we've mentioned, look, we're laser-focused on this. If there are any tweaks, adjustments that we make to the statistical analysis plan, we'll follow up in due course.

Yvonne Greenstreet (CEO)

Thanks, Lisa.

Speaker 15

Uh, thanks.

Operator (participant)

Thank you. One moment for our next question. Ellie Merle of UBS, your line is now open.

Ellie Merle (Senior Biotech Equity Research Analyst)

Hey, guys. Thanks so much for taking the question. Just again, kind of on potential for combination. Just commercially, how are you thinking about the proportion of ATTR cardiomyopathy patients that will be treated with, say, monotherapy versus, say, a combination with tafamidis, assuming the success of HELIOS-B? And then just from a commercial perspective, what do you think payers want to see in terms of the benefit of vutrisiran on top of tafamidis, say, in terms of mortality, hospitalization, sort of anything coming out of any kind of initial conversations there? And then just a second quick question. What data can we expect from the phase I ALN-KHK data this year, and will the readout include weight loss data? Thanks.

Yvonne Greenstreet (CEO)

All right. So maybe we'll take your first question. Look, you know, we believe that AMVUTTRA is going to be a really important option for patients with the potential for a differentiated profile, given its infrequent administration, you know, minimal copays. And if you look at, you know, the progress that Tolga highlighted earlier with respect to the growth in patient demand for AMVUTTRA, the patients with polyneuropathy, you know, we believe that this is going to be a really important addition to the treatment armamentarium for physicians. Tolga, maybe you could speak specifically to how we're thinking about use with tafamidis.

Tolga Tanguler (Chief Commercial Officer)

Yeah, I mean, I think one of the points that we really need to make it clear is innovation really rules the day. And AMVUTTRA has been a game changer already in polyneuropathy, and I believe, we believe very strongly based on our research, AMVUTTRA's availability in cardiomyopathy is going to be important, especially if you look at our track records. In price-sensitive markets where actually tafamidis is available, in Europe for polyneuropathy, we've been able to actually build an attractive business, tablets versus infusion, tablets versus then subcutaneous, and be able to build that business not just by net patients, but also with switches. Now, in the U.S., which is similar to sort of the-...

The profile that you've alluded to in terms of how we would actually think about in combination, is, our business is already built about with the mixed phenotype patients. About 30% of our patients are already on tafamidis. Granted, we're indicated for cardiomyopathy, and tafamidis is now indicated for cardiomyopathy. We're obviously, for us to be able to really elucidate how the positioning is gonna work out, we need the HELIOS-B data. That's gonna be really important. And that will obviously inform the best way we're gonna position this and the best way we're gonna engage with the payers.

But again, just to give you a sense about the unmet medical needs, if you look at the early access program that we have, we've already been able to enroll 200 patients, because patients do progress, and we believe this is gonna be an important alternative.

Yvonne Greenstreet (CEO)

Thanks, Tolga. That was a kind of great answer. With respect to your final question about KHK, we're obviously, you know, trying to avoid taking, you know, multipart questions on the call to give everybody a chance to ask the question and respect to KHK. You know, we look forward to seeing more data, as Pascal explained at the end of the year. Next question, please.

Operator (participant)

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

David Lebowitz (Senior Research Analyst)

Thank you very much for taking my question. You spoke earlier about talking that HELIOS-B can allow for a very differentiated profile versus the other therapies in the space. And my question is regarding, to some extent, linked to some of the earlier questions. Given the trial differences, they have different populations with different levels of severity. Their endpoints are slightly different from each other, with slightly modified statistical analyses. How easy is it gonna be to actually demonstrate to physicians that a profile is actually differentiated? And what aspects of the data would you focus upon?

Yvonne Greenstreet (CEO)

Pushkal, I think maybe you can start off by, you know, maybe also reflecting on some of the data that we've seen already from APOLLO-B and.

Pushkal Garg (Chief Medical Officer)

Yeah.

Yvonne Greenstreet (CEO)

The 24-month data that demonstrated actually sort of stabilization of disease in many patients.

Pushkal Garg (Chief Medical Officer)

Yeah, absolutely. Thanks, Yvonne, and thanks, Dave, for your question. Look, I think, you know, it's important to acknowledge, first of all, there aren't any head-to-head data in this field, right? So, what we're looking at, though, is a field that's evolving fairly rapidly, right? With, because of the growing recognition of the unmet need, and you have, you know, for the benefit of patients, multiple therapies coming forward. And you're right to point out that everyone is using, you know, there are some variations, for example, in the way that endpoints and statistical analyses are done. But I think what you have to do is think about it from the way that the clinician thinks about it. When they step back and they look at a patient who's coming in and, you know, they're progressing, with this...

They present with this disease at the various stages. It's marked by dyspnea, by exercise fatigue, poor quality of life, and you're seeing a decline over time. Their echocardiographic parameters are worsening, their heart is thickening, their NT-proBNP is rising, they may develop arrhythmias, et cetera. That's what clinicians are looking at. When they look at clinical data, I think what they're looking at then is, I believe, looking at all of the data that are coming forward in terms of how is this drug, how are these various drugs affecting the disease process. And I think, you know, as Yvonne was alluding to, I think what we're starting to see coming out of APOLLO-B really indicates the potential for a very unique profile when you silence TTR upstream using an RNAi mechanism of action.

Where we are seeing really favorable effects across all of these different parameters that we've looked at, whether it's functional, quality of life, whether it's echocardiographic, whether it's biomarker-based. And that, you know, in a disease that's otherwise steadily progressive, to see stability out to two years on both six-minute walk tests and KCCQ, stands out. And I think that's what's quite remarkable. So look, I think over time, as clinicians will get experienced, and I think this is again, where clinicians are having experiences Tolga highlighted with AMVUTTRA, both ONPATTRO and now AMVUTTRA, for now many years, taking care of PN patients and mixed phenotype patients. I think, they're also getting accustomed to the, the, the efficacy profile, the tolerability, the safety profile of these medicines.

So all of that helps, I think, in terms of physicians' understanding of how to use medicines for their patients.

Yvonne Greenstreet (CEO)

Great. Thank you, Pushkal. Next question.

Operator (participant)

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

Speaker 14

Thanks for taking our question. This is Tommy on for Salveen. So on HELIOS-B, how similar do you expect the APOLLO-B and HELIOS-B patient populations to be in terms of genotype and baseline characteristics? And besides the higher cap on HELIOS-B for baseline taf use, are there any other notable differences? And do you have the flexibility to potentially push back top-line data from HELIOS-B until all patients get to 36 months of follow-up, if that was seen as necessary? Thank you.

Yvonne Greenstreet (CEO)

Great question. Thank you. Pushkal?

Pushkal Garg (Chief Medical Officer)

Yeah, Tommy, I think what I'd say is that in general, I would think about the patient populations in APOLLO-B and HELIOS-B as being fairly similar, right? They, we started these studies around the same time. The entry criteria in general are the same. As you talked about, the one exception is that we allowed for a higher baseline portion of patients to come in on tafamidis. But by and large, I would think about these similar, and I think that's, you know, again...

Yvonne Greenstreet (CEO)

Mm.

Pushkal Garg (Chief Medical Officer)

What helps us here is the fact that we've seen the positive results out of APOLLO-B across all the different measures that we've talked about. But this study has the benefit of being, you know, twice as large, and three times as long. The follow-up, as you know, is designed to allow for differential follow-up and really to maximize the follow-up that we have on the patients. So, I think that, you know, as was asked earlier as well, I think this really, you know, maximize or optimizes the power that we can sort of gain on some of the endpoints. So, we're looking forward to presenting the results in early 2024.

Operator (participant)

Thank you, and one moment for our next question. Jessica Fye of JPMorgan Chase, your line is now open.

Na Sun (VP)

Hey, guys, this is Na Sun on for Jessica Fye. Assuming HELIOS-B is positive, do you envision the net price of AMVUTTRA changing from the current polyneuropathy, right, which is cardiomyopathy? Why or why not? Thank you.

Yvonne Greenstreet (CEO)

Right. So it's pretty early days yet. As Pushkal said, we're expecting top-line results from HELIOS-B in early 2024. And really, at this point in time, you know, I don't think it's appropriate for us to make any specific comments about pricing other than to say, obviously, you know, we want to provide value to patients, physicians, and the ecosystem in general, according to our, you know, patient access principles. So I think that's about all we can say at this point in time. Thank you for the question.

Operator (participant)

Thank you, and one moment for the next question. Maury Raycroft of Jefferies, your line is now open.

Maury Raycroft (Equity Research Analyst)

Hi, good morning. Thank you for taking my question. I think it was mentioned on our recent conference call that you have the opportunity to make tweaks to the HELIOS-B statistical analysis plan up until the database locks. Can you elaborate more on what that could entail? Would it require FDA buy-in, and how this flexibility factors into your chances of success for HELIOS-B?

Yvonne Greenstreet (CEO)

Yeah, I know that's a great question. Pushkal, any comments you'd like to make on the question?

Pushkal Garg (Chief Medical Officer)

Yeah, Maury, I think I'm gonna probably, you know, restate what we've talked about previously, which is, you know, Our teams are looking obviously at data in the study. We're looking at external datasets, et cetera. And as is normal in the industry, has been normal practice here at Alnylam, there are tweaks that can be made. You know, in past instances, we've looked and changed from parametric to nonparametric statistical tests, et cetera. We've added subgroups, et cetera. So there are things that can be done that can help either the primary analysis or the overall data set that are being done in terms of maybe, you know, in terms of pre-specified analyses or methodologies that are applied.

I'm not going to speculate or hypothesize about, you know, what's going to be aligned with agencies or not. So, I think, but, you know, if there's material information there, we'll certainly share that with you in due course.

Yvonne Greenstreet (CEO)

Thank you. Next question.

Operator (participant)

Our next question. Give us one moment. Gena Wang of Barclays, your line is now open.

Gena Wang (Managing Director and Biotech Equity Research Analyst)

Thank you. Maybe just follow Maury's question. So are you planning to add, say, any additional follow-up time, flexibility regarding...? Because right now, when I look at your slides, it's still saying the last patient, follow-up reach month 30. And, do you have a flexibility and the willingness or plan to, extend to 36 months? And then another very quick question regarding tafamidis. Just wanted to make sure I heard correctly, Pushkal, I think you mentioned 50% of patients on baseline tafamidis. Was that correct, or was it close to 50%? And also, regarding the tafamidis drop-in, is BridgeBio below 14%, is a good benchmark, for HELIOS-B?

Pushkal Garg (Chief Medical Officer)

Yeah, thanks, Gena. Maybe a couple of points just to clarify. So look, in terms of the study design, the study design has variable follow-up of 30-36 months. And so we will be following you know the majority of the patients out to the 36 months because of the way that enrollment occurred. But there is variable follow-up in the context of the study during the blinded portion of the study. In terms of baseline tafamidis, we had an operational target of 50%, but as we've stated previously, we came in under that under that number. And then with regard to drop-ins, you know, what we said is that the drop-in rate remains below the assumptions that we had when we designed the study.

So again, all of these offer tailwinds in terms of what we believe in the overall powering of the study. So hopefully that helps.

Gena Wang (Managing Director and Biotech Equity Research Analyst)

Thank you.

Yvonne Greenstreet (CEO)

Great. Any other questions?

Operator (participant)

Yes. Our next question. Give me one moment. Our next question comes from Mike Yee of Morgan Stanley. Your line is now open.

Mike Yee (Managing Director and Senior Biotechnology Analyst)

Good morning, and thanks for taking the question. Maybe just another follow-up on HELIOS-B. When you share the data early next year, can you give us a sense of what level of detail and, and data that you will include in the top-line results? You know, for example, will we see the tafamidis combo subgroup analysis? Thanks.

Pushkal Garg (Chief Medical Officer)

Yeah, thanks for the question, Mike. Look, I think as is our norm, during a top-line results, we will present the pre-specified hierarchical endpoints, along with p-values, along with an update on safety, and then with subsequent data presented at a scientific congress.

Yvonne Greenstreet (CEO)

Great. Next question?

Operator (participant)

This concludes the question and answer session. I'd like to now turn it back to the company for closing remarks.

Yvonne Greenstreet (CEO)

Great. Thank you, everyone, for joining us on this call. We're very pleased with our progress in the third quarter of 2023 across the business, and look forward to sharing more progress with you in the coming months as we deliver on our goals. Thank you so much, and have a good day.

Christine Lindenboom (SVP of Investor Relations and Corporate Communications)

Goodbye.

Operator (participant)

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.