Alnylam Pharmaceuticals, Inc.

And thank you for standing by. Welcome to the Al Nilem 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.

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Al Nilem. With me today are Yvonne Greenstreet, Chief Executive Officer, Tova Tangular, 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.onilam.com slash events. During today's call, as outlined in slide two, Yvonne will offer introductory remarks and provide some general context. Togo will provide an update on our global commercial progress, Pusha will review pipeline updates and clinical progress, and Jeff will review financial 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 El Nilo's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe River 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 recently periodic report on file of the SEC. In addition, any forward-looking statements represent our views only of the date of this reporting 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?

Thanks, Christine, and thank you, everyone, for joining the call today. The second quarter of 2024 was a transformative one for our nylon. 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. And 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 in the Helios B phase 3 study of Vutriceran in ATTR cardiomyopathy, showing that Vutriceran 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 Futrisram as the new standard of care in ATTR cardiomyopathy, assuming regulatory approval. Moreover, we believe these positive results can establish Futrisram as an anchor commercial franchise for our nylon, driving robust top-line growth and value creation for many years to come. With an eye towards our nylon pizza fest by 25 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 all 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 the 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 Ambutra in ATTR cardiomyopathy. You'll hear from several of my Arnylam 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?

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 HAT-TRPN. We are approaching 5,000 patients on treatment with Onpatra or Ambutra 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 HAT-TRPN performance. In the U.S., combined sales of Onpatro and Ambutra increased by 16% compared with the first quarter, and by a robust 40% year-over-year as momentum in new patient ads continued 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 Ambutra patient uptake, more than offsetting the decrease in patients on Onpatro that have switched to Ambutra. It is worth noting that at the end of the Q2, approximately 90% of our US TTR are on Ambutra. 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 Ambutra as patient uptake remained robust, including from our markets where we successfully launched Ambutra 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 Butrisiran 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 Ambutro is the market leader. We believe which has the potential to address unmet patient needs and become the standard of care treatment of ATTR-CN with a first-line and market-leading profile in ATTR-CN, 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 severe 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 Mutrisran as a standard of care in ATTR-CM. To this end, we are seriously 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 team that delivers 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 on-item 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 Givlari and Oxluma, 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 Givlari, 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 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?

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 Vutrisran 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 butresaran meeting an extraordinarily high bar for efficacy, with statistical significance on all five pre-specified primary and secondary endpoints in both of the study populations, highlighting the powerful impact of butresaran 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 tests, KCCQ, and NYHA class. all of which are key measures of disease progression. We observe consistent effects in all key subgroups, including patients who are on baseline defamitis. And finally, Lutrisiran 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 Cardia 2 Phase 2 study of Zalbesaran, showing additive efficacy and good tolerability on top of standard of care antihypertensives in patients with inadequately controlled hypertension. Cardio 3 is now underway, evaluating Zalvisran 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 of tonic 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 Mivalciran, formerly ALNAPP, 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 ALNKHK, which is in development for the treatment of type 2 diabetes with 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 Fetuceran 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 Semdesiran, 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 MyVelserant. As such, we now have full global development and commercialization rights to MyValceran 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 two study, and Alzheimer's disease, where we plan to start a phase two 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 partner 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? Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Al Milam'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, 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. That 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 Lectio sales as Novartis continues to grow demand for Lectio 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 from Patro 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 Ambutra as Ambutra 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 Zalbeceran and Myvelisaran 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 31st, 2023, with the increase primarily due to increased net product revenues and increased net proceeds from the issuance of common stock 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 to 1.5 billion to a range of 1.575 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 to $425 million to a range of $575 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 to 1.775 billion to a range of 1.775 to 1.875 billion. There are two primary drivers of the increase. First, the opt-out of Mivalceran by Regeneron will result in increased R&D investment as the program is now wholly owned by L-Nylon. Second, given the strong Helios V 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 were very confident in our ability to achieve both of the Alnylin P to the fifth by 25 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 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 Al Nilem, 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 Butresoran to the FDA using a priority review voucher. We plan to report interim results from Part B of the Phase 1 study of Malvesoran in patients with Alzheimer's disease. We expect three trial initiations by the end of 2024, including a Phase III study of ALN TTRF-CO4 in patients with ATTR cardiomyopathy at or around year end, a Phase II study for Mabelsiran in patients with Alzheimer's disease at or around year end, and a Phase I study of ALN-BCAT into pedicellular 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. 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.

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 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 Ambutra? And how could the difference in Medicare Part B versus Part D affect this, especially given some of the IRA changes? Thank you.

Okay, I think that's, that's a question for you to talk, 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 that is we to include patients with cardiomyopathy assuming positive regulatory approval. But Tolga, you may want to respond to a specific question.

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, you know, 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. And 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 compared to other available or future available products. Thanks, Salda. That's great.

Next question, please.

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

Hi, good morning. Thank you for taking my question. Mine is on the triceram. 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.

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

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 which 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 SGL2s, defamitis, And yet, against this incredibly high bar of contemporary backdrop, we showed a profound impact. I don't know, Pushkar, if you want to add anything else on this, but I believe this is going to be a key driver in physicians leveraging a first-line treatment.

Yeah, I think, building Toga, I totally agree with everything you said. And I think, you know, to Zina'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, you know, the investigators and authors for the ESE presentations 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.

Of course, more to come at ESE, and we look forward to that. Next question, please.

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

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.

That's a great question, Maury, and clearly we're working on finalizing the details as we speak. Pushkar.

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, you know, I anticipate this will include baseline characteristics. You'll hear about, you know, 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. And you'll see that across the key, you know, 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 tefamidase. So I think you'll get a pretty fulsome view of the results. And 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. Thanks, Pushkar. Next question?

Thank you. We'll take our next question from Paul Matias 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 two 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 HBNE obesity program. Is that still ongoing? And I'm curious the status of that as well. Thank you.

Yeah, no, look, we're delighted with the progress of the LNATC program. I don't know if my views, I can't pronounce it actually, but Scott, I'll be saran. You know, it's advancing well. You know, we've been able to demonstrate rapid and robust and sustained reductions in SAPP alpha and beta, you know, 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. Pushkar, maybe talk a little bit about where we're looking at the future.

Absolutely. So, you know, taking your two questions and building on what Yvonne said, like APP, very exciting program. We just presented some data. at AIC actually that showed that we had consistent knockdown in both, you know, soluble AVP alpha and beta, but also the downstream disease-related biomarkers of A beta 40 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 a 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 we all know has a tremendous burden. With regard to your second question on inhibin E, Look, I think, I don't think there's any really specific updates I want to give on the early preclinical programs other than to say, you know, what you heard in the main comments was just we are pushing very aggressively in terms of our 225 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 three plus INDs this year, nine proprietary INDs by the end of 25, and a doubling of our pipeline by the end of next year um but we will uh we'll give updates uh on those specific programs in due course and uh and then keep you posted perfect next question thank you we'll take our next question from costas bill horace with bmo capital markets your line is open good morning everyone thanks for taking our question and congrats on the tremendous progress the

A quick question from us on real-world data that recently was published on ATTR polyneuropathy. This study showed that patients understabilized progress very quickly, actually similar rate to national history, and then switched to on part where the disease progression is almost halting. Any read-through from this study to cardiomyopathy, And would you expect similar dynamics with Sambutra here? Thank you.

Great question. First of all, 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 tefamidus and progressed in proportion to those patients. then were put on PATRO and actually seemed to have some stabilization in their 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, do progress 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, you know, what Tolga highlighted earlier, is a very steadily progressive and fatal disease. And so I think we all agree. And, you know, this is highlighted by the fact that, you know, even when we had the Apollo data, Apollo B data, and we launched an EAP, there was tremendous need for patients who are on stabilizer therapy to get onto an additional orthogonal mechanism of action, and that study enrolled very quickly. So 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 mFutro.

Great.

Next question. Thank you. We'll take our next question from Jessica Fry with JP Morgan. 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 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.

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

Yeah. Any other comments? Yeah, just as a 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, you know, I think what you'll see is starting to see some data with multiple doses in terms of, you know, again, the primary purpose of the study is on safety and pharmacodynamics. And so what you'll be seeing is that with multiple dosing. Um, but you know, over time we'll be able to share more and more data coming out of that. But I think, you know, again, our confidence in this program is highlighted by the fact that we've kicked off a study of phase two in CAA, and we'll soon be kicking off a phase two in Alzheimer's disease. So we couldn't, you know, we're very excited about the potential therapy and continue to investigate it.

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

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

Thank you very much for taking my question. I'm curious, certainly since Epon-Tersen has been on the market for a couple 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.

Soga?

Yeah, 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, you know, 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 Ambutra 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. Thank you for taking my question.

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

Thank you. I will also ask another question regarding M-Rutro. Given this Part B coverage, have you seen any pattern in terms of, you know, the patient population regarding, sorry, you know, the pattern from ATTR part in neuropsy patient regarding patient population and the geographic locations? And quickly on the TTR-SCO4, any latest thoughts on Phase III trial design?

Yeah, maybe I'll start with the TTR SEO4 question. I mean, clearly, this is a, you know, an opportunity to really build a durable franchise in TTR for R9. And we've seen rapid knockdown, very durable knockdown. And, you know, we're looking at a program that potentially has, you know, improved knockdown. with, you know, six-monthly or annual dosing. So we're really, really excited about moving forward TTI-CO4. 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 reimbursement? On reimbursement, yeah.

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 remain, 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 D with the new IRA redesign. So we believe this is a good mix of reimbursement. And when it comes to global, we've been able to compete in very price sensitive markets across Europe and Japan. in a very, you know, 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, and obviously we're keeping an eye on it to make sure that patients get on this treatment if their physicians decide to do so.

Thank you. Next question. Thank you. We'll take our next question from Ritu Barel with TD Cal. Your line is open.

Hi, guys. Thanks for taking the question. I wanted to ask to Tolga just how you are now sort of positioning, and it sounds like you've been positioning for a while, Ambutra in TTRCM, you know, as far as actual commercial strategies. Jeff mentioned a scale up of the Salesforce. Can you talk about the magnitude of that? And are you changing the mix of targeting of the Salesforce? 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, 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.

I'll go straight to you. That's a terrific question. 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, you know, 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, you know, 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 the 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 where we don't comment given the, you know, 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. And 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, you know, 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 V and the product profile, we really do strongly believe physicians will choose Almutra if approved. as a first-line product, given where the disease is, given what the product is, and given where we have the data.

Thanks, Volker.

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

Hi. Thanks for taking my question, and congrats on the results. This is Tommy on for Salvine. Just a question on your discussions with KOLs and cardiologists. Have you heard a number or range for the additive benefit on top of TAF that would be considered meaningful in heliopsy? And just to follow up on the commercial questions, over the longer term, what's your strategy here for growing the market beyond taking care or adding on top of disaminase? Thank you so much.

Yeah, so maybe I can take the first part of your question in terms of is there some numerical target in terms of on top of tefamidase. I think really what I would say is, you know, 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, you know, 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. We saw equally strong efficacy in the overall population, which I'll remind you includes 40% of patients who start on background TAP and a good proportion of people who actually added on TAP and added on SGLT2 inhibitors had diuretic intensification. And so, you know, and I think as some have noticed from the top line results, there is, you know, 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. So 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.

I think a few words about the market. We've talked about how we think about the market pre-TAF loss of excessivity and post-TAF loss of excessivity. Perhaps you could make a few comments on. Yeah, I've been thinking that.

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, you know, given the data set, 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, you know, diagnostic tools have advanced over the last six years, there's easy access for patients to get diagnosed early. I think, you know, having increased share of voice and promotional awareness of this category is going to help. You know, the only available treatment has actually done a phenomenal job of, you know, expanding the diagnosis rates. And with added voices in this category is only going to, you know, accelerate the diagnosis and treatment rates. And we believe, you know, 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. Thank you. Thank you. You're welcome.

Thank you. We'll take our next question from Mike Oates 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 TTRCM. 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.

Dr. I think another one for you.

Yeah. Look, this is a disease, especially in the wild-type cardiomyopathy, patients don't, you know, 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. 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 needs more education, more disease awareness. And we believe having more voices articulating how disease manifests itself and help the 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 start 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, Pushkar, do you have anything?

Yeah, no, Toby, you said it very well. I mean, I think the only things I would just add is just a reminder that, you know, until about five years ago, there was no therapy for these patients at all that was specific, right? And so they were treated as sort of, you know, art there with preserved ejection fraction. And I think to Toby's point, now we have a therapy, hopefully soon multiple therapies for these patients. We've now, over just the last few years, the proliferation of non-invasive diagnostic methods to identify these patients. And we're starting to understand more where, you know, 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, you know, hopefully multiple therapies for these patients that can actually stem the progression of this result from otherwise progressive and fatal disease. 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. 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 the Voutri 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 Voutri plus, Voutri versus placebo in the background TAF subgroup? Thank you.

Yeah, thanks, Will. Look, I think what we have here with HealUSB is really a very, very rich study, right? This was a study done 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, you know, the results, we believe, are very, very encouraging. The one thing this study was not was a head-to-head study with tefamidus. 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. And 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 TAP patients came from the U.S. So comparing that then to the Butry 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 Butry appears to have know really encouraging efficacy on every parameter we've measured both as a monotherapy and evidence of additive efficacy on top of defamitis and consistent results across the whole series of endpoints that we looked at next question thank you we'll take our next question from miles minter with william blair your line is open

Hey, thanks for taking the question. Just with ISA releasing their draft guidance on TTR-CM pricing, I know that was in relevance to Defamitus, but there's also some commentary about Futriceran in that as well. Is El Nile intending to be at that public hearing in September 20? And if you are, are you going to be presenting something on cost effectiveness of Futriceran and TTR-CM? Thanks very much.

Yeah, thank you for that question. As ISA, 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, you know, health outcomes authority and will continue to engage with ICER and others. We haven't, you know, disclosed whether we would be part of the hearing.

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

Yes, that last question will come from Luca Issy with RBC Capital. Your line is open.

Oh, great. Thank you so much for squeezing me in. Congrats on all the progress. Maybe circling back on Gina's question here, Pushkal, for TTR-SC04, which is obviously super important as we think about the royalty to Santa Fe on the Phase III, do you basically need to run another Heliospeed, 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.

Okay. Well, you know, 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. 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 Nile Islands journey, and we really are proud of our progress. you know, as Torges describes, a living robust commercial growth, you know, Pushkar has gone through some of the incredible advancements in our pipeline. And, you know, 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 this program. Thank you for your participation. You may disconnect at any time.