Alnylam Pharmaceuticals - Q2 2024

Transcript

Operator (participant)

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 speaker's 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.

Christine Lindenboom (SVP of Investor Relations)

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 some general context. Tolga will provide an update on our global commercial progress. Pushkal will review pipeline updates and clinical progress, and Jeff will review financials and guidance, followed by a summary of upcoming milestones before we open the call for your questions.

I would like to remind you that this call will contain remarks concerning Alnylam future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor Provision of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statement represents our views only of the date of this recording and should not be relied upon as representing our views of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to Yvonne. Yvonne?

Yvonne Greenstreet (CEO)

Thanks, Christine, and thank you everyone for joining the call today. The second quarter of 2024 was a transformative one for Alnylam. Commercially, we achieved 34% year-over-year growth in global net product revenues, generating $410 million in net product revenues, which was primarily driven by 37% year-over-year growth in our TTR business. As such, we've raised our revenue guidance for the year by 11% as a 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 highlight of Q2 was our announcement of positive top-line results from the HELIOS-B phase III study of vutrisiran in ATTR cardiomyopathy, showing that vutrisiran improved cardiovascular outcomes, including a 35%-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 position 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 a 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 the 9th. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

Tolga Tanguler (CCO)

Thanks, Yvonne, and good morning, everyone. Q2 was another strong quarter for our commercial portfolio, delivering net product sales growth of 34% across our portfolio compared with the second quarter of 2023, as we continue to consistently increase the number of patients on therapy in both our TTR and rare franchises. Let me now turn to a summary of our second quarter TTR performance. Our TTR franchise achieved $307 million in global net product revenues, representing a 16% increase compared with the first quarter of 2024 and a 37% increase compared with the second quarter of 2023. This strong growth, now approaching 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 the 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 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 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 remained robust, including from our markets where we successfully launched AMVUTTRA in recent months. Finally, timing of orders in our partner markets, particularly Brazil, also contributed positively to the year-over-year growth. As shared previously, our team is looking forward to bringing vutrisiran to patients with ATTR amyloidosis with cardiomyopathy, assuming successful regulatory review and approval. We believe we have a tremendous opportunity to transform the treatment paradigm based on the product profile and recent HELIOS-B results, combined with the significant unmet patient needs in ATTR amyloidosis with cardiomyopathy, which is an estimated tenfold larger prevalence than hATTR-PN, where AMVUTTRA is the market leader.

We believe vutrisiran has the potential to address unmet patient needs and become the standard of care treatment of ATTR-CM with a first-line and market-leading profile in ATTR-CM, given its unique highly differentiated mechanism 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, an attractive quarterly dosing schedule with the site of care flexibility and favorable payer dynamics. We've been deeply committed to advancing treatment options in ATTR amyloidosis and understanding the unique needs of this community over the past decade and have built a strong foundation that will benefit our efforts to address the tremendous potential of ATTR-CM. At the same time, we recognize the critical importance of scaling our capabilities to establish vutrisiran as a standard of care in ATTR-CM.

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

The performance of GIVLAARI and OXLUMO, which delivered $103 million in global revenues combined product sales during the second quarter, remains solid as we continue to increase our patient base. The rare disease franchise grew 2% versus the first quarter of 2024 and 25% compared with the second quarter of 2023. For GIVLAARI, product sales increased by 7% in Q2 compared with the second quarter of 2023, with the following regional highlights: a 17% increase in the 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 continued robust growth in patients on therapy and revenue. Accordingly, we're pleased to be upgrading our full-year net product revenue guidance today by 11% at the midpoint of our guidance range. Jeff will share on that more later. With that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

Pushkal Garg (CMO)

Thanks, Tolga, and good morning, everyone. As Yvonne highlighted in her introduction, the major highlight of the second quarter was our announcement of the exciting and overwhelmingly positive top-line results from the HELIOS-B phase III study of vutrisiran in patients with ATTR cardiomyopathy. With these results, we now have the first clinical trial data that demonstrate the ability of an RNAi therapeutic 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 28% and 33% reductions in the risk of all-cause mortality and recurrent CV events in the overall and monotherapy populations, respectively, and 36% and 35% reductions in all-cause mortality in the overall and monotherapy populations, respectively. These outcome benefits were accompanied by clinically significant benefits on 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. 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 Hot Line 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 II study of zilebesiran, showing additive efficacy and good tolerability on top of standard of care antihypertensives in patients with inadequately controlled hypertension. KARDIA-3 is now underway, evaluating zilebesiran on top of two or more agents in patients who are at high cardiovascular risk.

Following that, we look forward to running a cardiovascular outcomes trial where our goal is to demonstrate the benefits of tonic blood pressure control in patients at high cardiovascular risk by showing reductions in cardiovascular morbidity and mortality. We're also excited to have initiated dosing in the caPPricorn-1 phase II study of mivelsiran, formerly ALN-APP, in patients with cerebral amyloid angiopathy. CAA is the second most common cause of intracerebral hemorrhage and remains highly underdiagnosed, with major unmet need. We've also advanced ALN-KHK, which is in development for the treatment of type 2 diabetes, with initiation of the Part B phase of the phase I study. Our partners continue to make great progress as well. Sanofi submitted regulatory filings for fitusiran for patients with hemophilia in China, Brazil, and the United States, where the FDA has set a target action date of March 28, 2025.

We've also announced today a pair of updates to our ongoing collaboration with Regeneron. First, we amended the license agreement for cemdisiran, an investigational RNAi therapeutic in development for the treatment of complement-mediated diseases, under which Regeneron gained exclusive rights to the asset as a monotherapy. In exchange, we received a $10 million upfront payment and are eligible to receive certain regulatory milestones and low double-digit royalties on sales, if approved. Additionally, as part of their regular portfolio review and prioritization efforts, Regeneron has decided to opt out of further co-development and co-commercialization of mivelsiran. As such, we now have full global development and commercialization rights to mivelsiran in all indications.

We're extremely excited about the potential of this program, our first in the CNS, to address the unmet needs of patients in two significant disease areas: CAA, where we've just initiated a phase II study, and Alzheimer's disease, where we plan to start a phase II study at or around the end of the year. So, in sum, we've made great progress in advancing our pipeline and platform, with much more to come. As a reminder, we plan to file proprietary INDs for 9 programs by the end of 2025 against targets in the liver, CNS, muscle, and adipose. If we include partnered programs, we anticipate 15 new INDs by the end of 2025, representing a doubling of our clinical pipeline by the end of next year.

This remarkable and unique pace of innovation puts us in a great position to have a robust, self-sustainable pipeline that can deliver 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?

Jeff Poulton (CFO)

Thanks, Pushkal. And good morning, everyone. I'm pleased to be presenting a summary of Alnylam Q2 2024 financial results and discussing our full-year guidance, starting with a summary of our P&L results for Q2 2024 compared with the same period in 2023. Total product revenue for the quarter was $410 million, or 34% growth versus 2023, with both our TTR and rare franchises reporting strong growth of 37% and 25%, respectively, primarily driven by continued strong demand, as Tolga previously highlighted. Net revenue from collaborations for the quarter was $227 million, representing a $221 million increase when compared with Q2 2023. The increase was primarily driven by the modification of our collaboration agreement with Regeneron, resulting in approximately $185 million of revenue, which was previously deferred. Royalty revenue for the quarter was $22 million, or more than three 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 startup activities for the zilebesiran and mivelsiran clinical studies, and increased employee compensation expenses.

Our non-GAAP SG&A expenses increased 21% in the second quarter compared to the same period in the prior year, primarily due to increased marketing investment associated with promotion of our TTR therapies and increased employee compensation expenses. Our non-GAAP operating income for the quarter was $138 million, representing a $292 million improvement compared with Q2 2023, primarily driven by strong top-line results, both in product sales as well as revenue from collaborations, as previously highlighted. We ended the second quarter with cash, cash equivalents, and marketable securities of $2.6 billion, compared with $2.4 billion as of December 31, 2023, with the increase primarily due to increased net product revenues and increased net proceeds from the issuance of common stock in connection with employee stock option exercises. We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile.

Now, I'd like to turn to our 2024 guidance, where we are updating all components of our full-year guidance with the specific details as follows. We are increasing our net product revenue guidance from a range of $1.4-$1.5 billion to a range of $1.575-$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-$425 million to a range of $575-$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-$1.775 billion to a range of $1.775-$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 our preparedness for an early 2025 launch in the U.S.

Given the strong momentum in our business underpinning these guidance changes, along with the strength of the HELIOS-B study results and our efforts to prepare for a highly successful ATTR cardiomyopathy launch next year, we are very confident in our ability to achieve both of the Alnylam P5x25 financial goals that we established three and a half years ago, which include achieving a 40%+ compounded annual growth rate in 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 30th, 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 I study of mivelsiran in patients with Alzheimer's disease. We expect three trial initiations by the end of 2024, including a phase III study of ALN-TTRsc04 in patients with ATTR cardiomyopathy at or around year-end, a phase II study for mivelsiran in patients with Alzheimer's disease at or around year-end, and a phase I study of ALN-BCAT in hepatocellular carcinoma.

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?

Christine Lindenboom (SVP of Investor Relations)

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)

At this time, if you would like to ask a question, please press the Star and 1 on your telephone keypad. You may remove yourself from the queue at any time by pressing Star 2. Once again, that is Star and 1 if you would like to ask a question. We'll take our first question from Eliana Merle with UBS. Your line is open.

Speaker 18

Hi, this is Jasmine on for Elly. Thank you so much for taking our question. 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 the Medicare Part B versus Part D affect this, especially given some of the IRA changes? Thank you.

Yvonne Greenstreet (CEO)

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

Tolga Tanguler (CCO)

Yeah, 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 copay as little as possible.

Given that we are actually physician-administered, which allows patients to be on Part B, we believe it's going to be a unique advantage in comparison to other available or future available products.

Yvonne Greenstreet (CEO)

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

Operator (participant)

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

Tazeen Ahmad (Analyst)

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 and first-line. Just based on the top-line results from HELIOS-B, which were impressive, it seems clear that there's 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.

Yvonne Greenstreet (CEO)

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

Tolga Tanguler (CCO)

Yeah, I mean, what we see with the physicians, and we know this from other therapy areas as well, in any progressive, debilitating, and essentially ultimately fatal disease, it really is imperative to start with the most potent treatment option first. And given the top-line HELIOS-B results, we believe vutrisiran is going to be well positioned to be the first-line agent. Look, I mean, at the end of the day, HELIOS-B is the most contemporary cardiomyopathy study completed to date, and patients had really aggressive backgrounds, background SGLT2s, tafamidis. And yet, against this incredibly high bar of contemporary backdrop, we showed a profound impact. I don't know, Pushkal, if you want to add anything else on this, but I believe this is going to be a key driver in physicians leveraging first-line treatment.

Pushkal Garg (CMO)

Yeah, I think building on Tolga, I totally agree with everything you said.

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

Yvonne Greenstreet (CEO)

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

Operator (participant)

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

Maury Raycroft (Analyst)

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

Yvonne Greenstreet (CEO)

Yeah, that's a great question, Maury, and clearly, we're working on finalizing the details as we speak. Pushkal?

Pushkal Garg (CMO)

Yeah, thanks, Maury. Look, we are working with the investigators and authors to sort of finalize the content, but we plan to go into pretty expansive detail on the endpoints in the study and the results that we presented at the top-line. If you think we're really excited to be able to share that now broadly with the community, both the clinical community and the investor community. So this will include, I anticipate, this will include baseline characteristics. You'll hear about sort of how this is a very contemporary population of patients that was heavily treated with other medications, effective agents. You'll see the results on the primary endpoint, including the components and all the secondaries. And we'll also be sharing curves for the primary endpoint and secondary endpoint of all-cause mortality.

You'll see that across the key you'll see the consistency of effect across a variety of subgroups, and specifically, we'll be sharing some curves in the overall and based on baseline tafamidis. I think you'll get a pretty fulsome view of the results. Of course, we'll have other opportunities to dive deeper into data at HFSA. We're limited in how much we can present at ESC, and there's a lot of rich data coming out of this incredible clinical trial that we'll be sharing in the weeks to come.

Yvonne Greenstreet (CEO)

Thanks, Pushkal. Next question.

Operator (participant)

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

Julian Pino (Analyst)

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, didn't see anything, unless I missed it, on the INHBE obesity program. Is that still ongoing? And I'm curious about the status of that as well. Thank you.

Yvonne Greenstreet (CEO)

Yeah, no, look, we're delighted with the progress of the ALN-APP program, now known as mivelsiran. I can't pronounce it, actually, Pushkal. mivelsiran. It's advancing well. We've been able to demonstrate rapid and robust and sustained reductions in sAPPβ for Aβ and 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 talk a little bit about where we're looking at the future.

Pushkal Garg (CMO)

Absolutely. So taking your two questions and building on what Ivan said, like APP, very exciting program. We just presented some data at AAIC, actually, that showed that we had consistent knockdown in both soluble APP, alpha, and beta, but also the downstream disease-related biomarkers of Aβ40 and 42 that are involved in CAA and Alzheimer's disease and continue to see very encouraging safety coming out of that program as well. So that program remains on track. We're very excited. As we talked about, we've recently kicked off a study in cerebral amyloid angiopathy, which is like the second leading cause of hemorrhage. And as you noted, we will be starting a study in Alzheimer's disease as well. We aren't ready to talk about the specifics of that. We're obviously working through our trial design, but we'll share that with you shortly. But we're very encouraged about this upstream mechanism.

Its potential to be very differentiated in this disease space and hopefully have a favorable impact on the disease of Alzheimer's disease, which I think we all know has a tremendous burden. With regard to your second question on inhibin E, look, I don't think there's any really specific updates I want to give on the early preclinical programs other than to say what you heard in the main comments was just we are pushing very aggressively in terms of our P5x25 strategy to move a multitude of programs forward based on the excitement that we have around the platform here. And so we are on track for 3+ INDs this year, 9 proprietary INDs by the end of 2025, and a doubling of our pipeline by the end of next year. But we'll give updates on those specific programs in due course and keep you posted.

Yvonne Greenstreet (CEO)

Perfect, Pushkal. Next question.

Operator (participant)

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

Kostas Biliouris (Analyst)

Good morning, everyone. Thanks for taking our question 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 patients under stabilizers progress very quickly, actually similar rate to natural history, and then switch to ONPATTRO, where the disease progression is almost halving. Any read-through from this study to cardiomyopathy? Would you expect similar dynamics with AMVUTTRA here? Thank you.

Yvonne Greenstreet (CEO)

Great question. Pushkal, I think this is for you.

Pushkal Garg (CMO)

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 then were put on ONPATTRO and actually seemed to have some stabilization of their disease. These were hereditary polyneuropathy patients. Look, I think it's very encouraging. We know that this is a complex disease. Patients do progress with polyneuropathy and with cardiomyopathy. So I don't think there's any question that there's an unmet need here for patients to have additional modes of therapy that can address what Tolga highlighted earlier is a very steadily progressive and fatal disease. So I think we all agree.

This is highlighted by the fact that even when we had the APOLLO data, APOLLO-B data, and we launched an EAP, there was tremendous need for patients who were on stabilizer therapy to get onto an additional orthogonal mechanism of action. That study enrolled very quickly. We are very excited about the opportunity. Our patients need additional therapies, and we'll be bringing that forward, we think, now for the CM patients as we have for the PN patients with AMVUTTRA.

Yvonne Greenstreet (CEO)

Great. Next question.

Operator (participant)

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

Jessica Fye (Analyst)

Hi, 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 of 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? Thank you.

Yvonne Greenstreet (CEO)

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 cerebral amyloid angiopathy and plan to start the study in Alzheimer's disease at or around year-end. So we couldn't be more pleased to have another wholly owned program in our pipeline and look forward to moving these programs forward ourselves.

Any other comment?

Pushkal Garg (CMO)

Yeah, just to comment on your questions. It's a little early to tell you about the specific venue where we'll be talking about the data, but I think what you'll see is starting to see some data with multiple doses in terms of, again, the primary purpose of the study is on safety and pharmacodynamics. And so what you'll be seeing is that with multiple dosing. But over time, we'll be able to share more and more data coming out of that. But I think, again, our confidence in this program is highlighted by the fact that we've kicked off a study of phase II in CAA, and we'll soon be kicking off a phase II in Alzheimer's disease. So we're very excited about the potential of this therapy and continue to investigate it.

Yvonne Greenstreet (CEO)

Huge potential, huge medical needs, and we're very, very pleased to be moving it forward. Next question.

Operator (participant)

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

Tolga Tanguler (CCO)

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?

Yvonne Greenstreet (CEO)

Great question. Tolga?

Tolga Tanguler (CCO)

Yeah. I mean, as we discussed before, this is a highly devastating disease, and there are 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. And I believe the nuances of the product start becoming a lot clearer. As you know, the product profile of AMVUTTRA is one that rapidly knocks down the disease-causing protein durably and with a good sustained quarterly injectable. That is becoming a good differentiator. And last but not least, of how patients get on the reimbursement and how they stay on the reimbursement.

And we're very pleased with the results that we've seen in Q2, and we expect to drive the momentum as such.

David Lebowitz (Analyst)

Excellent. Thank you for taking my question.

Operator (participant)

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

Gena Wang (Analyst)

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

Yvonne Greenstreet (CEO)

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

Tolga Tanguler (CCO)

Reimbursement?

Yvonne Greenstreet (CEO)

On reimbursement, yeah.

Tolga Tanguler (CCO)

Yeah. So I mean, I think one thing is really to keep in mind is we strictly adhere to the patient access philosophy that Alnylam has established over the years. And through that, what we really look at is the copay burden on the patients. Given that our product is reimbursed because it's a physician-administered product through Part B, what we've seen is nearly 70% of our patients have zero copay, and up to 80% of patients pay less than $2,000. This really puts us in an important position where the copay burden is either less or similar to those products that would be reimbursed in Part B with the new IRA redesign. So we believe this is a good mix of reimbursement.

When it comes to global, we've been able to compete in very price-sensitive markets across Europe and Japan in polyneuropathy in a very competitive way where we are driving about over 90% market share versus the stabilizer product that's in the market. Therefore, we really like where we are in terms of our reimbursement policy. Obviously, we're keeping an eye on it to make sure that patients get on this treatment if their physicians decide to do so.

Gena Wang (Analyst)

Thank you.

Yvonne Greenstreet (CEO)

Next question?

Operator (participant)

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

Ritu Baral (Analyst)

Hi, guys. Thanks for taking the question. I wanted to ask Tolga just how you are now sort of positioning, and it sounds like you've been positioning for a while, AMVUTTRA in TTR-CM as far as actual commercial strategies. Jeff mentioned a scale-up of the sales force. Can you talk about the magnitude of that, and are you changing the mix of targeting of the sales force? And then in our doc calls, our doc calls have mentioned that they do expect, despite the wealth of data, that this is going to be a commercially sensitive market. How are things like label language, KCCQ, New York Heart Association? 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.

Yvonne Greenstreet (CEO)

Tolga, straight to you. That's a terrific question.

Tolga Tanguler (CCO)

Sure. I mean, one thing I just want to make it clear, obviously, we're going to start off with a very strong foundation where this disease is being treated by multidisciplinary centers and where our organization is there. But when it comes to positioning, I want to make it very clear that we are strictly promoting our polyneuropathy indication, and we will adhere to that until, obviously, we receive the label expansion. So I just want to make that clear. Now, again, I think, as you highlighted, one of our great advantages is we have deep experience with TTR centers. We've been able to expand our polyneuropathy prescriber base by 50%. We have a well-integrated customer team. Now, we highlight the fact that the prevalence of this disease obviously tenfold. Having said that, the number of prescribers is not tenfold. It's a lesser magnitude of prescriber base.

Therefore, we believe we can actually scale this up in the appropriate way. And then when it comes to, in rare diseases, having an integrated customer-facing team where you have good coverage of reimbursement support, you have good coverage of medical and field organization support is going to be key. We have that. And the last piece, I think, of the puzzle is a very good, strong established patient support services where we are actually quite pleased with time to treatment from patient start forms into patients getting reimbursed and starting on therapy. Now, those are obviously some of the capabilities where we're keeping an eye on. We're going to scale that up.

Now, when it comes to your second part of your question in terms of labeling, how we're going to be positioning the product, obviously, that's going to be depending on the FDA, and we don't comment given the label discussions that we have. I think what you will see at ESC is going to give you a further color about the robustness of this data and how we can actually be able to communicate effectively both primary, composite, and secondary endpoints, as well as the all-cause mortality. We believe there's going to be a clear differentiation for our product. Last but not least is the product profile itself. I mean, given that this is a swiftly progressing, irreversible disease, to be able to demonstrate a rapid knockdown that really knocks down the disease-causing pathogen as quickly as possible is going to be important.

Given the convenience of quarterly dosing is going to be important. Given that how patients actually quickly get on access to this treatment is going to be very critical. So combining all this with the data that we have with HELIOS-B and the product profile, we really do strongly believe physicians will choose AMVUTTRA if approved as a first-line product given where the disease is, given what the product is, and given where we have the data.

Yvonne Greenstreet (CEO)

Thanks, Tolga. Next question.

Operator (participant)

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

Speaker 19

Hi. Thanks for taking my question and congrats on the results. This is Tommy 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 tafamidis that would be considered meaningful in HELIOS-B? And just to follow up on the commercial questions, over the longer term, what's your strategy here for growing the market beyond standard of care or adding on top of tafamidis? Thank you so much.

Pushkal Garg (CMO)

Yeah. So maybe I can take the first part of your question in terms of is there some numerical target in terms of benefit on top of tafamidis? I think really what I would say is the feedback that we've gotten all along, and I think has only been accentuated since we've shared the top-line results with KOLs, is just the enthusiasm for a new medicine to help these patients first and foremost. Second of all, what they're seeing from the top-line results is an opportunity for this drug to actually access the broad spectrum of patients with this disease.

We saw strong efficacy as a monotherapy across all the endpoints, but we saw equally strong efficacy in the overall population, which, I'll remind you, includes 40% of patients who started on background taf and a good proportion of people who actually added on taf and added on SGLT2 inhibitors, had diuretic intensification. And so I think, as some have noticed from the top-line results, there is, if you just look at the mortality numbers, the strength of the data in the overall population, both in terms of the actual magnitude of effect as well as the p-value, are somewhat stronger, which implies a pretty substantial effect in the add-on population. Now, that's encouraging because it wasn't powered or designed to show an effect in that population. But to see what we're seeing is consistent evidence of additive efficacy, I think, is encouraging.

There's no numerical target, but I think what people are seeing is a picture of a drug that's emerging to them that looks to be quite effective for this disease.

Yvonne Greenstreet (CEO)

I think, Tolga, a few words about the market. We've talked about how we think about the market pre-taf, loss of exclusivity, and post-taf, loss of exclusivity. Perhaps you could make a few comments on thinking there.

Tolga Tanguler (CCO)

Yeah. I mean, we believe, given that this is a rare disease, it's unusual for a combination therapy to be used given some of the access challenges. However, I think we believe, given the dataset, we believe there's going to be some combination use early on prior to the taf 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, there's easy access for patients to get diagnosed early. I think having an 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 diagnosis and treatment rates. And we believe those patients deserve many options to be treated.

Yvonne Greenstreet (CEO)

Jeff, anything you want to add?

Jeff Poulton (CFO)

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

Yvonne Greenstreet (CEO)

Great. Thank you. Thank you. Thanks, Tolga.

Operator (participant)

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

Mike Ulz (Analyst)

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? Thanks.

Yvonne Greenstreet (CEO)

Tolga, I think another one for you.

Tolga Tanguler (CCO)

Yeah. Look, this is a disease, especially in the 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 few multidisciplinary centers. What we've seen is those multidisciplinary centers start expanding more, and the awareness of how 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 see in 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 it needs more education, more disease awareness.

And we believe having more voices articulating how disease manifests itself and helping 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?

Pushkal Garg (CMO)

Yeah. No, Tolga, you said it very well. I mean, I think the only things 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 heart failure with preserved ejection fraction.

And I think, to Tolga's point, now we have a therapy, hopefully soon multiple therapies for these patients. We've now, over just the last few years, had the proliferation of non-invasive diagnostic methods to identify these patients. And we're starting to understand more how to identify these patients based on red flag symptoms such as polyneuropathy or spinal stenosis or carpal tunnel syndrome, things like that. So I think there is just a heavy, heavy need for more disease education awareness because we now have, we believe, hopefully multiple therapies for these patients that can actually stem the progression of this ultimate otherwise progressive and fatal disease. So I think there is a lot of growth here in terms of patients to treat.

Mike Ulz (Analyst)

Helpful. Thank you.

Operator (participant)

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

William Pickering (Analyst)

Yes. Hi. Thank you so much for taking my question and congrats on the great results. Looking ahead to ESC, there seems to be a lot of investor interest in comparing the vutri monotherapy arm with the 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 vutri versus placebo in the background taf subgroup? Thank you.

Pushkal Garg (CMO)

Yeah. Thanks, Will. Look, I think what we have here with HELIOS-B is really a very, very rich study, right? This was a study done in 655 patients in the modern era. These were patients who were diagnosed with non-invasive means, as we've talked about, and we'll share more at ESC. It was a pretty rigorous test. These were patients, 40%, who were already on an effective therapy, a good proportion of the monotherapy arm who 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 this study was not was a head-to-head study with tafamidis. That is the one thing it was not. It was not designed for that purpose. And so the comparison that you're referring to really is a non-randomized comparison.

As you can imagine, the patients who entered in on taf were different because they'd been on the drug for a while. Obviously, there were geographic differences in those patients. The majority of the taf patients came from the U.S. Comparing that then to the vutri patients who were 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 vutri appears to have really encouraging efficacy on every parameter we've 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.

Yvonne Greenstreet (CEO)

Next question.

Operator (participant)

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

Miles Minter (Analyst)

Hey. Thanks for taking the question. Just with ICER releasing that draft guidance on TTR-CM 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 2024? And if you are, are you going to be presenting something on cost-effectiveness of vutrisiran and TTR-CM? Thanks very much.

Tolga Tanguler (CCO)

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

Yvonne Greenstreet (CEO)

Okay. I think we have time for one more question. The last question, please.

Operator (participant)

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

Luca Issi (Analyst)

Oh, great. Thanks so much for squeezing me in. 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 III. Do you basically need to run another HELIOS-B, or you can maybe get away with a smaller PKPD 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. Thanks so much.

Yvonne Greenstreet (CEO)

Okay. Well, we're going to come back to that question because, as I said, we're not ready really to get into details of what the next detailed step is in our clinical plan. 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 just want to thank everybody for joining. I mean, really, the second quarter of 2024 has marked an inflection point in our Alnylam journey, and we really are proud of our progress. As Tolga has described, we're driving 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.

Operator (participant)

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