Alnylam Pharmaceuticals, Inc. Q2 FY2024 Earnings Call

Good day and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Second Quarter 2024 Conference Call. At this time, all participants are in a listen-only mode. After the speakers’ presentation, there will be a Q&A session. Please be advised that today’s conference is being recorded. And I would now like to hand the conference over to the company for their remarks. Please go ahead.

Good morning. I’m Christine Lindenboom, Senior Vice President, 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 2, 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 this call will contain remarks concerning Alnylam’s future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I will turn the call over to Yvonne. Yvonne?

Thanks Christine and thank you everyone for joining the call today. The second quarter of 2024 was a transformative one for Alnylam. Commercially, we achieved a 34% year-over-year growth in global net product revenues, generating $410 million in net product revenues, which was primarily driven by 37% year-over-year growth in our TTR business. And as such, we’ve raised our revenue guidance for the year by 11% at the midpoint. The commercial capability that we’ve established over the last five years will continue to drive significant growth for our current business and will be a key to our success as we prepare for a potential launch next year in ATTR cardiomyopathy. To that end, the major highlights of Q2 was our announcement of positive top line results from the HELIOS-B Phase 3 study of vutrisiran in ATTR cardiomyopathy, showing that vutrisiran improved cardiovascular outcomes, including a 35% to 36% mortality benefit compared to placebo and demonstrated encouraging safety. These results reflect the true power of the RNAi mechanism of action, supporting what we believe to be a highly differentiated therapeutic profile and positioned vutrisiran as the new standard of care in ATTR cardiomyopathy, assuming regulatory approval. Moreover, we believe these positive results can establish vutrisiran as an anchor commercial franchise for Alnylam, driving robust top line growth and value creation for many years to come. With an eye towards our Alnylam P5x25 goals, we are firm in our belief that we are on track to become a top-tier biotech, developing and commercializing transformative medicines for patients around the world with rare and prevalent diseases driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine, all while delivering exceptional financial results. Before I turn it over to Tolga, I’m excited to tell you about the TTR Investor Day that we will be hosting in New York City on Wednesday, October 9th. This event, which will be webcast live, will focus on our leadership in ATTR amyloidosis, including the efforts that we are undertaking to optimize the success of the launch of AMVUTTRA in ATTR cardiomyopathy. You’ll hear from several of my Alnylam colleagues as well as external experts. We’ll be sharing more details about this event shortly, and I hope that you can join us in New York on October 9th. 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 our commercial portfolio, delivering net product sales growth of 34% across our portfolio compared with the second quarter of 2023 as we continue to consistently increase the number of patients on Tenke in both our TTR and rare franchises. Let me now turn to a summary of our second quarter TTR performance. Our TTR franchise achieved $307 million in global net product revenues, representing a 16% increase compared with the first quarter of 2024 and a 37% increase compared with the second quarter of 2023. This strong growth, now approaching six years from our initial commercial launch supports our belief that there remains a significant opportunity in hATTR-PN. We are approaching 5,000 patients on treatment with ONPATTRO or AMVUTTRA globally, still a small percentage of the estimated tens of thousands of patients that suffer from this devastating disease. Now let me provide highlights of our U.S. and rest of world hATTR-PN performance. In the U.S., combined sales of ONPATTRO and AMVUTTRA increased by 16% compared with the first quarter and by a robust 40% year-over-year as momentum in new patient adds continue to drive strong growth. The U.S. year-over-year growth was primarily driven by the following: a 34% increase in demand driven by the strength of our ongoing AMVUTTRA patient uptake, more than offsetting the decrease in patients on ONPATTRO that have switched to AMVUTTRA. It is worth noting that at the end of the Q2, approximately 90% of our U.S. TTR are on AMVUTTRA. Now, let me turn to our international markets, where the TTR franchise growth also increased by 16% compared with the first quarter and 35% year-over-year. The strong year-over-year growth was primarily driven by increased demand for AMVUTTRA as patient uptake remains robust, including from our markets where we successfully launched our product in recent months. Finally, timing of orders in our partner markets, particularly Brazil, also contributed positively to the year-over-year growth. As shared previously, our team is looking forward to bringing vutrisiran to patients with ATTR amyloidosis with cardiomyopathy, assuming successful regulatory review and approval. We believe we have a tremendous opportunity to transform the treatment paradigm based on the product profile and recent HELIOS-B results, combined with the significant unmet patient needs in ATTR amyloidosis with cardiomyopathy, which is an estimated tenfold larger prevalence than hATTR-PN, where AMVUTTRA is the market leader. We believe vutrisiran has the potential to address unmet patient needs and become the standard of care treatment of ATTR-CM with a first line and market-leading profile in ATTR-CM, given its unique highly differentiated mechanism of action, enabling rapid knockdown of TTR at the source that is deep and durable, reduction in mortality and CV hospitalization events, as well as substantial impact on measures of disease progression and attractive quarterly dosing schedule with the site of care flexibility and favorable payer dynamics. We’ve been deeply committed to advancing treatment options in ATTR amyloidosis and understanding the unique needs of this community over the past decade and have built a strong foundation that will benefit our efforts to address the tremendous potential of ATTR-CM. At the same time, we recognize the critical importance of scaling our capabilities to establish vutrisiran as a standard of care in ATTR-CM. To this end, we are serially advancing our launch preparation and expanding our capabilities, leveraging our strong foundation, including our deep and credible relations with TTR centers, a global and highly specialized and integrated customer-facing teams that deliver a seamless experience for patients and physicians, our track record of creating strong payer and health system partnerships that supports exceptional patient access, not only in the U.S., but also across all major global markets, including Canada, Europe and Japan, and our award-winning patient support services team that have enabled us to help patients access their online treatments quickly with one of the fastest timelines in the industry transitioning from start form to therapy and also support patient adherence. We're also proud to have established a sustainable rare disease business that addresses a significant unmet patient need. The performance of GIVLAARI and OXLUMO, which delivered $13 million in global revenues, combined product sales during the second quarter remains solid as we continue to increase our patient base. The rare disease franchise grew 2% versus the first quarter of 2024 and 25% compared with the second quarter of 2023. For GIVLAARI, product sales increased by 7% in Q2 compared with the second quarter of 2023, with the following regional highlights, a 17% increase in U.S., primarily driven by growth in new patients on therapy, an 8% decrease in our rest of world markets, primarily driven by the timing of orders in our partner markets, which offset demand growth across European markets. For OXLUMO, we delivered a robust 68% year-over-year growth with the following regional dynamics, a 79% increase in the U.S., primarily driven by demand growth, a 61% growth from our rest of world markets, driven by increased demand in both our European and partner markets. In conclusion, we delivered strong results in the second quarter and first half of the year with both our TTR and rare franchises, delivering continuous robust growth in patients on therapy and revenue. Accordingly, we’re pleased to be upgrading our full year net product revenue guidance today by 11% at the midpoint of our guidance range. Jeff will share on that more later. With that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

Thanks, Tolga and good morning, everyone. As Yvonne highlighted in her introduction, the major highlight of the second quarter was our announcement of the exciting and overwhelmingly positive top line results from the HELIOS-B Phase 3 study of vutrisiran in patients with ATTR cardiomyopathy. With these results, we now have the first clinical trial data that demonstrate the ability of an RNAi therapeutic to improve cardiovascular outcomes. We observed truly outstanding results in this study with vutrisiran meeting an extraordinarily high bar for efficacy with statistical significance on all five prespecified primary and secondary endpoints in both of the study populations, highlighting the powerful impact of vutrisiran and its mechanism of action on this disease. Specifically, we observed a 28% and 33% reduction in the risk of all-cause mortality and recurrent CV events in the overall and monotherapy populations, respectively, and a 36% and 35% reductions in all-cause mortality in the overall and monotherapy populations respectively. These outcome benefits were accompanied by clinically significant benefits on the six-minute walk test, KCCQ, and NYHA class, all of which are key measures of disease progression. We observed consistent effects in all key subgroups, including patients who are on baseline tafamidis. And finally, vutrisiran demonstrated encouraging safety and tolerability consistent with its established profile. We're announcing this morning that the detailed results from the HELIOS-B study will be presented as a hotline oral presentation at the European Society of Cardiology Congress on Friday, August 30th, 2024, in London. We will also host a conference call and webcast during the Congress to discuss these detailed results with investors. We're also hard at work engaging with regulators as we work towards a supplemental NDA filing in the United States in late 2024 with additional global regulatory filings thereafter. As a reminder, we will be using our priority review voucher to accelerate the U.S. regulatory review in hopes of bringing this medicine to patients as quickly as possible. In addition to HELIOS-B, we made progress across a number of other pipeline programs, highlighting the breadth of opportunity we have with our RNAi platform. As we discussed on the last earnings call, we recently reported positive results from our KARDIA-2 Phase 2 study of zilebesiran, showing additive efficacy and good tolerability on top of standard of care antihypertensives in patients with inadequately controlled hypertension. KARDIA-3 is now underway, evaluating zilebesiran on top of two or more agents in patients who are at high cardiovascular risk. And following that, we look forward to running a cardiovascular outcomes trial, where our goal is to demonstrate the benefits, photonic blood pressure control in patients with high cardiovascular risk by showing reductions in cardiovascular morbidity and mortality. We're also excited to have initiated dosing in the Capricorn 1 Phase 2 study of mivelsiran, formerly ALN-APP in patients with cerebral amyloid angiopathy. CAA is the second most common cause of intracerebral hemorrhage and remains highly underdiagnosed with major unmet need. We've also advanced ALN-KHK, which is in development for the treatment of type 2 diabetes with the initiation of the Part B phase of the Phase 1 study. Our partners continue to make great progress as well. Sanofi submitted regulatory filings for vutrisiran for patients with hemophilia in China, Brazil, and the United States, where the FDA has set a target action date of March 28, 2025. We've also announced today a pair of updates to our ongoing collaboration with Regeneron. First, we amended the license agreement for cemdisiran, an investigational RNA therapeutic in development for the treatment of complement-mediated diseases under which Regeneron gained exclusive rights to the asset as a monotherapy. In exchange, we received a $10 million upfront payment and are eligible to receive certain regulatory milestones and low double-digit royalties on sales, if approved. Additionally, as part of their regular portfolio review and prioritization efforts, Regeneron has decided to opt out of further co-development and co-commercialization of mivelsiran. As such, we now have full global development and commercialization rights to mivelsiran in all indications. We’re extremely excited about the potential of this program, our first in the CNS to address the unmet needs of patients in two significant disease areas. CAA, where we’ve just initiated a Phase 2 study in Alzheimer's disease, where we plan to start a Phase 2 study at or around the end of the year. So in sum, we’ve made great progress advancing our pipeline and platform with much more to come. As a reminder, we plan to file proprietary INDs for nine programs by the end of 2025 against targets in the liver, CNS, muscle and adipose. If we include partnered programs, we anticipate 15 new INDs by the end of 2025, representing a doubling of our clinical pipeline by the end of next year. This remarkable and unique pace of innovation puts us in a great position to have a robust, self-sustainable pipeline that can deliver a meaningful impact to patients across multiple disease areas. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

Thanks, Pushkal and good morning everyone. I’m pleased to be presenting a summary of Alnylam's Q2 2024 financial results and discussing our full year guidance. Starting with a summary of our P&L results for Q2 2024 compared with the same period in 2023. Total product revenue for the quarter was $410 million, a 34% growth versus 2023, with both our TTR and rare franchises reporting strong growth of 37% and 25%, respectively, primarily driven by continued strong demand, as Tolga previously highlighted. Net revenue from collaborations for the quarter was $227 million, representing a $221 million increase when compared with Q2 2023. The increase was primarily driven by the modification of our collaboration agreement with Regeneron resulting in approximately $185 million of revenue, which was previously deferred. Royalty revenue for the quarter was $22 million or more than 3 times what was recognized in the second quarter of 2023. The increase was driven by higher Leqvio sales as Novartis continues to grow demand for Leqvio worldwide. Gross margin on product sales was 84% for the quarter compared with 75% in the second quarter of 2023. The improvement in margin is primarily due to higher costs in 2023 associated with canceled manufacturing commitments for ONPATTRO and other adjustments to inventory for which similar expenses were not realized in 2024. I expect our gross margin on product sales will be lower for the balance of the year, driven by higher royalties paid on AMVUTTRA as AMVUTTRA growth continues at a brisk pace. Our non-GAAP R&D expenses increased 14% in the second quarter compared to the same period in the prior year, primarily due to increased costs associated with our preclinical activities, increased development expenses associated with start-up activities for the zilebesiran and mivelsiran clinical studies, and increased employee compensation expenses. Our non-GAAP SG&A expenses increased 21% in the second quarter compared to the same period in the prior year, primarily due to increased marketing investment associated with promotion of our TTR therapies and increased employee compensation expenses. Our non-GAAP operating income for the quarter was $138 million, representing a $292 million improvement compared with Q2 2023, primarily driven by strong top line results, both in product sales and collaboration revenue, as previously highlighted. We ended the second quarter with cash, cash equivalents and marketable securities of $2.6 billion compared with $2.4 billion as of December 31st, 2023, with the increase primarily due to increased net product revenues and increased net proceeds from the issuance of common stock in connection with employee stock option exercises. We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile. Now, I’d like to turn to our 2024 guidance where we are updating all components of our full year guidance with the specific details as follows: we are increasing our net product revenue guidance from a range of $1.4 billion to $1.5 billion to a range of $1.575 billion to $1.65 billion, representing an 11% increase from the midpoint of the prior to the updated guidance. The primary driver of the increased guidance is the ongoing strength of performance in our hereditary ATTR polyneuropathy franchise. We are increasing our collaboration and royalty revenue guidance from a range of $325 million to $425 million to a range of $575 million to $650 million. The primary driver of the increase is the modification of our collaboration agreement with Regeneron, which resulted in the recognition of approximately $185 million of previously deferred revenue this quarter. And lastly, we are increasing our guidance for combined non-GAAP R&D and SG&A expenses from a range of $1.675 billion to $1.775 billion to a range of $1.775 billion to $1.875 billion. There are two primary drivers of the increase. First, the opt out of mivelsiran by Regeneron will result in increased R&D investment as the program is now wholly owned by Alnylam. Second, given the strong HELIOS-B top line results, we are increasing our planned ATTR cardiomyopathy launch prep efforts to optimize their preparedness for an early 2025 launch in the U.S. Given the strong momentum in our business, underpinning these guidance changes, along with the strength of the HELIOS-B study results and our efforts to prepare for a highly successful ATTR cardiomyopathy launch next year, we are very confident in our ability to achieve both of the Alnylam P5x25 financial goals that we established three and a half years ago, which include achieving a 40% plus compounded annual growth rate and total revenues across the five-year period and achieving sustainable non-GAAP operating income within the period. Let me now turn from financials and discuss some key goals and upcoming milestones slated for mid and late 2024. As was mentioned earlier, we will be presenting detailed results from HELIOS-B at the ESC Congress on Friday, August 30 in London. We will also be hosting a conference call and webcast to discuss the data. We've also announced today that we plan to host a TTR Investor Day on October 9th in New York City. At this event, we will feature senior leaders from Alnylam as well as external experts to highlight the potential of our TTR business. This will be webcast as well. We will be submitting a supplemental new drug application for vutrisiran to the FDA using a priority review voucher. We plan to report interim results from Part B of the Phase 1 study of mivelsiran in patients with Alzheimer's disease. We expect three trial initiations by the end of 2024, including a Phase 3 study of ALN-TTRsc04 in patients with ATTR cardiomyopathy at or around year-end, a Phase 2 study for mivelsiran in patients with Alzheimer's disease at or around year-end and a Phase 1 study of ALN-BCAT and hepatocellular carcinoma. And we remain on track to file three investigational new drug applications by year-end. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Jeff. We will now open the call for your questions.

We'll take our first question from Ellie Merle with UBS. Your line is open.

Hi, this is Jasmine on for Ellie. Thank you so much for taking our question. So, can you discuss the reimbursement landscape in ATTR cardiomyopathy? And how you're thinking about the potential difference in pricing between polyneuropathy and cardiomyopathy for AMVUTTRA? And how could the difference in Medicare Part B versus Part D affect this, especially given some of the IRA changes? Thank you.

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

Yes. Specific to the PN, I think it's actually a testament of the growth that we've been able to deliver this quarter and the prior quarters where patients get on therapy seamlessly. Thanks to our patient support services and preferable position that we have in terms of our access, and patients actually stay on therapy. And that, again, has a lot to do with our profile of the product and quarterly injectables as well as our ability to continue to secure access for those patients. When it comes to CM, we'll be leveraging a similar level of principles, meaning we will obviously make sure that patients have seamless access and they stay on therapy without the burden of co-pay as little as possible. And given that we are physician administered, which allows patients to be on Part B, we believe is going to be a unique advantage in comparison to other available or future available products.

Thanks, Tolga. That's great. Next question please.

Thank you. We'll take our next question from Tazeen Ahmad with Bank of America. Your line is open.

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

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

Yes, I mean, what we see with the physicians, and we know this from other therapy areas as well, in any progressive debilitating and ultimately fatal disease, it really is imperative to start with the most potent treatment option first. And given the top line HELIOS-B results, we believe vutrisiran is going to be well positioned to be the first line agent. Look, I mean, at the end of the day, HELIOS-B is the most contemporary cardiomyopathy study completed to date and patients had real aggressive backgrounds around SGL2, tafamidis. Yet against this incredibly high bar of contemporary backdrop, we showed a profound impact. I don't know, Pushkal, if you want to add anything else on this. But I believe this is going to be a key driver for physicians leveraging the first-line treatment.

Yes, I think that building on Tolga, I totally agree with everything you said. And I think, Tazeen, it's early days obviously, but as I think what we've heard repeatedly from clinicians is that they're looking for an orthogonal mechanism of action that can have an impact on this disease. And the investigators and authors for the ESC presentation said that we've shared the data deeply with are incredibly excited. And so we’re looking forward to being able to roll those data out. But I think we're seeing a lot of enthusiasm based on the data that we've shared so far.

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

Thank you. We'll take our next question from Maury Raycroft with Jefferies. Please go ahead, your line is open.

Hi. Good morning. Congratulations on the quarter. Thank you for taking my question. I would like to ask about ESC and the upcoming data. Will you be reporting KM curves and time to events kinetics for the different mono versus combo subgroups in the study? Also, could you provide more information on what details you plan to disclose at the conference?

That's a great question, Maury. Clearly, we're working on finalizing the details as we speak. Pushkal?

Yes, thanks, Maury. We are currently collaborating with the investigators and authors to finalize the content. We plan to provide extensive details on the study's endpoints and the results we presented initially, and we are excited to share that with both the clinical and investor communities. This will include baseline characteristics, highlighting that the patient population was contemporary and heavily treated with effective medications. You will see the results for the primary endpoint along with its components and all secondary endpoints. We will also present curves for both the primary and secondary endpoints related to all-cause mortality. You’ll observe the consistency of the effects across various subgroups, and specifically, we will share some curves based on baseline tafamidis. I believe you will receive a comprehensive view of the results. Additionally, we will have more opportunities to delve deeper into the data at HFSA, as we are limited in what we can present at ESC. There is a wealth of valuable data emerging from this remarkable clinical trial that we will share in the coming weeks.

Thanks, Pushkal. Next question.

Thank you. We'll take our next question from Paul Matteis with Stifel. Your line is open.

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

Yes. No. Look, we're delighted with the progress of the ALN-APP program. It’s progressing well and we've been able to demonstrate rapid and robust and sustained reductions in APP, going very well, and we feel there's tremendous potential in the two indications that we are progressing both Alzheimer's disease and cerebral amyloid angiopathy. Pushkal, maybe you can look at the future.

Absolutely. Addressing your questions regarding the APP program, we recently presented data that demonstrated consistent reductions in both soluble APP alpha and beta, along with downstream disease-related biomarkers related to CAA and Alzheimer's disease. We continue to observe encouraging safety outcomes from this program, which remains on track. We're excited to have recently initiated a study on cerebral amyloid angiopathy, a major cause of hemorrhage, and we will also be starting a study focused on Alzheimer's disease. While we aren't prepared to discuss the specifics yet, we are actively working on the trial design and will share that information soon. We are optimistic about the upstream mechanism's potential to be uniquely beneficial in this area and to positively affect Alzheimer's disease, which carries a significant burden. Regarding your second question on HBM, I don’t have specific updates on the early preclinical programs to share, except to reiterate our commitment to advancing multiple programs due to our enthusiasm for this platform. We are on schedule for more than three INDs this year and aim to have proprietary INDs by the end of 2025, along with a doubling of our pipeline by the end of next year. We will provide updates on those specific programs in due course.

We'll take our next question from Kostas Biliouris with BMO Capital Markets. Your line is open.

Good morning. Thanks for taking our questions and congrats on the tremendous progress here. A quick question from us on real world data that recently was published on ATTR polyneuropathy. This study showed that a patient under stabilizes progress ONPATTRO very quickly, actually similar rate to national history and then switch to on where the disease progression is almost halting any read-through from this study to cardiomyopathy? And would you expect similar dynamics with some good years.

Great question. Pushkal, I think...

Yeah. Thanks, Kostas. I think you were citing a paper that was recently published coming out of a European experience that looked at a cohort of patients who had been on tafamidis and progressed, and a proportion of those patients that were put on ONPATTRO actually seem to have some stabilization of the disease. These were hereditary polyneuropathy patients. Look, I think it's very encouraging. We know that this is a complex disease. Patients do have a progressive course with polyneuropathy and with cardiomyopathy. And so I don't think there's any question that there's an unmet need here for patients to have additional modes of therapy that can address what Tolga highlighted earlier, which is a very steadily progressive and fatal disease. We are very excited about the opportunity where patients need additional therapies and will be bringing that forward, we think, now for the CM patients as we have for the PN patients with ONPATTRO.

Great. Next question.

Thank you. We'll take our next question from Jessica Fye with JPMorgan. Your line is open.

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

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

Yes, just to address your question, it's a bit early to discuss the specific venue for the data presentation. However, you can expect to see some data regarding multiple doses, as the primary focus of the study is on safety and pharmacodynamics. Over time, we will be able to share more detailed data. Our confidence in this program is evident as we have initiated a Phase II study in CAA and will soon begin a Phase II study in Alzheimer's disease. We are very excited about the potential of this therapy and are committed to further investigation.

Each potential huge medical need, we're very, very pleased to be moving forward. Next question.

Thank you. I'll take our next question from David Lebowitz with Citi. Your line is open.

Thank you very much for taking my question. I'm curious, certainly, since Eplontersen has been on the market for a couple of quarters now. Have the nature of the discussions with physicians changed since the drug's launch at all? And can you make any commentary on how the market is evolving relative to a new competitive therapy?

Great question. Tolga?

Yes. I mean, as we discussed before, this is a highly devastating disease, and there's still tens of thousands of patients that are expecting to get diagnosed and treated. Therefore, any addition in the market with increased promotional share of voice is a good thing. In respect to how the conversations are shaping up, as you can see from our Q2 results, now this is a two-player market in the U.S., where we continue to grow very rapidly. I believe the nuances of the products start becoming a lot clearer. As you know, the product profile on vutrisiran is one that rapidly knocks down the disease-causing protein durably and with good sustained quarterly injectables. That is becoming a good differentiator. And last but not least, the way patients get on reimbursement and how they stay on the reimbursement. We’re very pleased with the results that we’ve seen in Q2, and we expect to drive the momentum as such.

Excellent. Thank you for taking my question.

Thank you. We'll take our next question from Gena Wang with Barclays. Your line is open.

Thank you. I have another question regarding metro. With the Part B coverage, have you noticed any trends in the patient population related to ATTR neuropathy, particularly concerning geographic locations? Also, what are your current thoughts on the Phase III trial design for TTRsc04?

Yes. Maybe I'll start with the TTRsc04 question. I mean clearly, this is an opportunity to really build a durable franchise in TTR for Alnylam, we've seen rapid knockdown, very durable knockdown. And we're looking at a program that potentially has improved knockdown with six months of yearly dosing. So we're really excited about moving forward with TTRsc04. It's too early to comment on the specifics of the clinical program at this point in time, but there will be more to come as we get to the end of this year. Tolga, do you want to take the question on reimbursement?

Yes. It’s important to remember that we strictly follow the patient access philosophy that Alnylam has developed over the years. We focus on the co-pay burden that patients face. Since our product is reimbursed as a physician-administered product through Part B, we have observed that nearly 70% of our patients have no co-pay, and up to 80% of patients pay less than $2,000. This positions us favorably, as the co-pay burden is either lower or comparable to those products reimbursed partially with the new IR redesign. We are pleased with our reimbursement policy and are monitoring it closely to ensure patients can access this treatment if their physicians choose to recommend it.

Great. Next question.

Thank you. We'll take our next question from Ritu Baral with TD Cowen. Your line is open.

Hi, guys. Thanks for taking the question. I wanted to ask Tolga just how you are now sort of positioning AMVUTTRA in TTR-CM, as far as actual commercial strategies, Jeff mentioned a scale-up of the sales force. Can you talk about the magnitude of that? And are you changing the mix of targeting of the sales force? And then in our docs, do calls have mentioned that they do expect despite the wealth of data that this is going to be a commercially sensitive market. How are things like label language, KCCQ, New York Card Association like those are real endpoints in your study. How are they going to factor into your marketing message? How important are they? Or is it going to be mortality driven all the way? Thanks.

Tolga. Straight to you, a terrific question.

Sure. I want to clarify that we are starting with a solid foundation where this disease is treated by multidisciplinary centers with our organization involved. However, in terms of positioning, I want to emphasize that we are only promoting our polyneuropathy indication and will stick to that until we receive any label expansion. It's important to note that we have strong ties with TTR centers and have increased our polyneuropathy prescriber base by 50%. Our customer team is well-integrated, and the prevalence of this disease is indeed significant, though the number of prescribers is not proportional to that prevalence. Therefore, we believe we can appropriately scale this. In the realm of rare diseases, having a customer-facing team with solid reimbursement support and effective medical and field organization support is essential, and we have established that. Additionally, we are pleased with the efficiency of patient support services, specifically the timeline from when patients start forms to when they are reimbursed and begin therapy. These are capabilities we will continue to enhance. Regarding your second question about product positioning and labeling, we rely on the FDA for guidance and won't comment on label discussions. However, I believe the upcoming ESC presentation will provide more insight into the robustness of our data, including details on primary and secondary endpoints as well as all-cause mortality. We expect clear differentiation for our products. Lastly, the product profile is crucial; we need to show a rapid reduction of the disease-causing protein, especially since this disease progresses swiftly and can be reversed. The convenience of quarterly dosing is also key for quick patient access to treatment. Combining this with our HELIOS-B data and product profile, we are confident that physicians will choose AMVUTTRA as a first-line option if approved, given the disease context, the product, and the supporting data we have.

Thanks, Tolga. Next question.

Thank you. We'll take our next question from Salveen Richter with Goldman Sachs. Your line is open.

Hi. Thanks for taking my question and congrats on the results. This is Tom on for Salveen. Just a question on your discussions with KOLs and cardiologists. Have you heard a number or range for the additive benefit on top of TA that would be considered meaningful in that context? And just a follow-up on the commercial questions. Over the longer term, what's your strategy here for growing the market beyond taking share or adding on top of tafamidis? Thank you so much.

Yes. I can address the first part of your question regarding any numerical target for the benefit beyond tafamidis. The feedback we've received has been very positive, especially after sharing the top-line results with key opinion leaders. There is a strong enthusiasm for a new medication that can assist these patients. Moreover, the top-line results indicate that this drug could potentially reach a wide range of patients with this condition. We observed strong efficacy as a standalone treatment across all endpoints. Additionally, the overall population showed equally strong efficacy, which includes 40% of patients starting on background tafamidis and a significant number who added SGLT2 inhibitors and experienced diuretic intensification. It's noteworthy that the strength of the data in the overall population, in terms of both effect magnitude and p-value, was quite robust, suggesting a substantial effect in the add-on group. This is encouraging since the study wasn't designed to specifically demonstrate an effect in that cohort, but the consistent evidence of additive efficacy is a positive sign. There isn't a specific numerical target, but the emerging image of this drug appears to be quite effective for this disease.

I think to add a few words about the market. We've talked about how we think about the market pre-tamofidine loss of exclusivity and post-loss of exclusivity. Perhaps you could make a few comments on that.

Yeah, I mean, thinking about that, we believe, given that this is an area of disease, it’s unusual for a combination therapy to be used given some of the access challenges. However, I think we believe given the data set, there’s going to be some combination use early on prior to the tafamidis exclusivity. But to your point, what's really important is the category growth. What we've seen is given that the diagnostic tools have advanced over the last six years, patients have easy access for get diagnosed early. I think having increased share of voice and promotional awareness of this category is going to help. The only available treatment has actually done a phenomenal job of expanding the diagnosis rates. And with added voices in this category, it’s only going to accelerate the treat diagnosis and treatment rates. And we believe those patients deserve many options to be treated to.

Jeff, anything you want to add?

I don't have anything further to add, no.

Great. Thank you. Thanks, Tolga.

Thank you. We'll take our next question from Mike Ulz with Morgan Stanley. Your line is open.

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

I think another one for you.

Yes. Look, this is a disease, especially in wild-type cardiomyopathy. Patients don't start having these symptoms until sometimes it's too late. So that's one of the key drivers. The second thing is there are only a few multi-disciplinary centers. What we've seen is those multi-discipline centers start expanding more and the awareness of how the disease actually manifests itself is being picked up by authorities. As much as we say, it's tenfold of the polyneuropathy, it's still a rare disease. In the U.S., it's less than 200,000 patients. Therefore, it is not as common as what doctors used to seeing, cardiologists or neurologists or even in some cases, orthopedic surgeons where they see bilateral carpal tunnel syndrome or spinal stenosis. It's an area where needs more education, more disease awareness. And we believe having more voices articulating how this disease manifests itself and helps patients to get treated early is going to be key. One of the things we're doing, and I believe others will be doing as well, is to engage with a lot of centers to make sure that on electronic medical records, patients get flagged early. I think these are some of the initiatives that the industry is going to be making to make sure those patients get quickly flagged. I don't know, Pushkal, do you have anything?

Yes. No, Tolga, you said it very well. I mean, I think the only thing I would just add is just a reminder that until five years ago, there was no therapy for these patients at all that was specific, right? And so they were treated as sort of with heart failure and reduced ejection fraction. And I think to point now, we have a therapy, hopefully assuming multiple therapies for these patients. We’ve had the proliferation of noninvasive diagnostic methods to identify these patients. We’re starting to understand more where how to identify these patients based on red flag symptoms such as polyneuropathy or spinal stenosis or carpal tunnel syndrome, things like that. So I think there is just a heavy, heavy need for more disease education awareness because we now have what we believe, hopefully, multiple therapies for these patients that can actually stem the progression of this otherwise progressive and fatal disease. So I think there is a lot of growth here in terms of patients to treat.

Helpful. Thank you.

Thank you. We'll take our next question from William Pickering with Bernstein. Your line is open.

Yes. Thank you so much for taking my question. Congrats on the great results. Looking ahead to ESC, there seems to be a lot of investor interest in comparing the vutrisiran monotherapy arm with the TAF plus placebo arm. Could you talk about the extent to which you think that is a helpful comparison and any limitations relative to just looking at Q3 versus placebo and the background TAF? Thank you.

Yes. Thanks, Will. Look, I think what we have here with USB is really a very, very rich study, right? This was a study done with 655 patients in the modern era. These were patients who were diagnosed with noninvasive means. As we've talked about, and we'll share more at ESC, it was a pretty rigorous test. These are patients, 40% who are already on an effective therapy, a good proportion of the monotherapy arm. We started another effective therapy. In the midst of the study, patients started SGLT2s, other things. So it was a pretty rigorous test and the results, we believe, are very, very encouraging. The one thing the study was not was a head-to-head study with tafamidis. That is the one thing it was not designed for that purpose. And so the comparison that you’re referring to really is a non-randomized comparison. And as you can imagine, the patients who entered in on TAF were different because they’ve been on the drug for a while. Obviously, there were geographic differences in those patients. The minority of the TAF patients came from the U.S. So comparing that then to the vutrisiran patients who are on monotherapy, it’s really unfortunately a flawed analysis. I think what we’ll see, as we highlighted in the top line results, is that vutrisiran appears to have really encouraging efficacy on every parameter we measured both as a monotherapy and evidence of additive efficacy on top of tafamidis and consistent results across the whole series of endpoints that we’ve looked at.

Next question.

Thank you. We'll take our next question from Myles Minter with William Blair. Your line is open.

Hi. Thanks for taking the question. Just with as releasing that draft guidance on TCICM pricing. I know that was in relevance to tafamidis, but there’s also some commentary about vutrisiran in that as well. Is Alnylam intending to be at that public hearing in September 20? And if you are, are you going to be presenting something on the cost-effectiveness of future drugs? Thanks very much.

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

Okay. I think we have time for one more question. Last question please.

Yes. The last question will come from Luca Issi with RBC Capital. Your line is open.

Great. Thanks so much for squeezing me in and congrats on all the progress. Maybe circling back on Gena's question here Pushkal, for TTRsc04, which is obviously super important as we think about the royalty to Sanofi on the Phase 3. Do you basically need to run another HELIOS speed or can you maybe get away with a smaller PK/PD trial? And maybe related, what's the dose that you're going to pursue? I think the sad portion of the trial, you went all the way to 600 milligrams. So just wondering if that is the go-forward dose.

Okay. Well, we're going to come back to that question because as I said, we're not ready really to get into the details of what the next detailed steps in our clinical plans. So we'll come back and share more on that later, but thanks for your interest. We're also very excited about the program. Thanks, Luca. Okay. I think that brings our call to a close. And I just want to thank everybody for joining. I mean really the second quarter of 2024 has marked an inflection point in our items journey. And we really are proud of our progress. As Tolga described, the being robust commercial growth. Pushkal has gone through some of the incredible advancements in our pipeline. And now more than ever, we believe that we're firmly on a path to becoming a top-tier biotech company. So thank you, everybody, and have a great day.

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