Good morning, ladies and gentlemen, and welcome to the Alnylam Q2 2025 Earnings Conference Call. This call is being recorded on Thursday, July 31, 2025. I would now like to turn the conference over to the company. Please go ahead.

Good morning. I'm Christine Akinc, Chief Corporate Communications Officer at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Research and Development 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 on Slide 2, 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 our financials and guidance followed by a summary of our upcoming milestones before we open the call to your questions. I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. As shown in our Q2 results announced today, Alnylam is firing on all cylinders, and we're swiftly establishing ourselves as a top-tier biotech company. We're doing so by focusing on three core elements of the business that we believe will drive sustainable growth and value creation for years to come. The first is TTR leadership. As highlighted in today's press release, the launch is off to a very strong start. While it's still early days, we're encouraged by the pace, and we're deeply focused on laying the groundwork for long-term leadership in TTR. The next is growth through innovation, focused on the potential multibillion-dollar opportunities within our pipeline and an R&D engine set up to deliver sustainable innovation and value creation. To that end, I'd like to acknowledge the recent promotion of Pushkal Garg to Chief Research and Development Officer. Pushkal has been instrumental in progressing our pipeline, and in this role, he will oversee an integrated R&D organization to drive this exciting pipeline and platform into the future. Congratulations, Pushkal. The third element is strong financial performance with robust commercial execution and a disciplined capital allocation approach, providing us with the opportunity to sustain profitability going forward. As Tolga and Jeff will highlight later, the strong therapeutic profile of AMVUTTRA and ATTR-CM, combined with a large and underserved market, positioned this as a flagship commercial franchise with robust and durable long-term growth potential. Of course, all of this is underpinned by a best-in-class team and our award-winning culture. Our results this quarter fit within each of these strategic pillars and represent one of the most impactful quarters to date for Alnylam. Our commercial performance was driven by TTR franchise revenues of $544 million, 77% year-over-year growth, with growth largely attributable to the AMVUTTRA CM launch. This was just the first full quarter of the ATTR-CM launch. As of June 30, approximately 1,400 cardiomyopathy patients were receiving AMVUTTRA, which is a remarkable achievement. This performance reflects results from our cardiomyopathy launch in the U.S. only. International markets are coming online for AMVUTTRA for CM and are expected to begin to contribute to the CM launch in the second half of the year. Kudos to our teams for delivering these impressive early results. In addition to these commercial results, we continue to advance our leading pipeline of RNAi therapeutics. We initiated the TRITON-CM Phase III study of nucresiran, further establishing our commitment to leadership in TTR and are pleased to be announcing today that the FDA has granted Fast Track Designation for nucresiran for ATTR-CM. We also just shared encouraging Phase I multi-dose data for mivelsiran in Alzheimer's disease and kicked off a Phase I study for ALN-4324 in type 2 diabetes earlier in the quarter. Regarding financial performance, we're reporting our strongest quarter to date as a company with $672 million in total net product revenues or 64% growth year-over-year. As a result, we've increased our total net product revenues guidance for 2025 from a range of $2.05 billion to $2.25 billion to a revised range of $2.65 billion to $2.8 billion, representing an increase of $575 million or 27% at the midpoint, underscoring our confidence in the ATTR-CM launch and our other commercial products in the balance of the year. So zooming out from the success of Q2, this progress represents stellar execution towards our “Alnylam P5x25” goals, which we seek to achieve by the end of this year. Doing so will further establish Alnylam as a unique top-tier biotech company, delivering sustainable innovation to patients for many years to come. 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. I'm excited to share with you the results of our Q2 commercial performance. As Yvonne indicated, we are firing on all cylinders, and our Q2 performance was exceptional for the full portfolio. On a global basis, our commercial portfolio delivered $672 million in net product revenues, representing 64% year-over-year and 43% quarter-over-quarter growth. As you will see in a moment, the U.S. TTR performance was the major driver of growth given the ATTR-CM launch for AMVUTTRA. It is also encouraging that we saw very robust double-digit growth compared with Q1 across both our TTR and Rare franchises globally. All parts of our business are operating with focus and excellence. Let's quickly start with our Rare franchise. Our GIVLAARI and OXLUMO teams stayed focused and delivered $128 million in combined Q2 sales, up 24% versus last year. Growth was largely demand-driven with a tailwind from favorable GIVLAARI gross-to-net adjustments in the U.S. Now turning our attention to TTR franchise, where we delivered $544 million in global net product revenues during the quarter, representing a 77% increase compared with the second quarter of '24 and a robust 51% increase compared with the first quarter of 2025. In the U.S., combined Q2 sales of ONPATTRO and AMVUTTRA rose 80%, up roughly $170 million from Q1, driven primarily by AMVUTTRA's ATTR-CM launch. We closed the quarter with approximately 1,400 cardiomyopathy patients on therapy, contributing an estimated $150 million in revenue. This performance was fueled by strong execution and faster-than-anticipated access across payers and providers. Regarding the year-over-year dynamics, the U.S. TTR franchise grew 125% compared with the second quarter of 2024, primarily driven by the significant increase in demand from the ATTR-CM launch that I just highlighted. Turning to our international markets, we delivered 18% year-over-year growth, driven by continued strength in our hATTR-PN business, which remains a solid growth engine. Importantly, we have yet to recognize any ATTR-CM revenue internationally, as launches in Germany and Japan are slated to begin contributing in the third quarter. Now let me provide some additional perspectives on the U.S. TTR revenue dynamics, where the franchise achieved $383 million in the second quarter, representing a very robust 80% quarter-over-quarter growth. While we don't have the ability to report revenue by indication, the underlying trend is clear. From Q1 '24 through Q1 '25, the U.S. TTR franchise delivered steady growth of around $15 million to $20 million on average every quarter. In Q2 2025, we saw a pronounced step change, indicating an estimated $150 million contribution from ATTR cardiomyopathy. I will now provide some additional launch metrics to further contextualize AMVUTTRA's launch performance in ATTR cardiomyopathy. Our launch began on March 20, 2025, and Q2 marked our first full quarter post-approval. It is still early, and there is more work to do, but we're very encouraged by the strong momentum we're seeing. We've been focused on three key enablers around the U.S. launch of AMVUTTRA in ATTR cardiomyopathy. Health system setup, access, affordability, and treatment choice. The headlines are here, and I will go into more detail on each in the following slides. As we've shared on prior calls, there are approximately 170 priority health systems through which approximately 80% of ATTR cardiomyopathy patient volume flows. The majority of these provider accounts now have AMVUTTRA formulary, enabling therapy initiation throughout these health systems where ATTR-CM patients present. Moreover, nearly all of the priority health systems have already begun treating patients with AMVUTTRA for ATTR cardiomyopathy. This, together with the broad network of more than 2,000 alternate sites of care, has allowed us to achieve our aspiration. Roughly 90% of patients in the U.S. are able to receive AMVUTTRA treatment within about 10 miles of where they live. Bottom line, our priority was to enable broad provider account setup in our first year of launch. This has happened faster than we had initially anticipated. Since the end of our first quarter of launch, we are largely there. In addition, patients are getting first-line access to AMVUTTRA across all payer segments. Coverage is now confirmed by payers covering the majority of U.S. patient lives, inclusive of Medicare fee-for-service, Medicare Advantage, and commercial. Therefore, we can confirm that the majority of patients have access to AMVUTTRA as a first-line treatment, meaning without requiring patients to use another product first. Most patients are indeed paying zero in out-of-pocket costs. Consistent with what we've seen in polyneuropathy, there has been very limited use of our Quick Start Program, quite simply because patients are not experiencing delays in coverage. We're also seeing patient initiations flowing through all payer segments: Medicare fee-for-service, Medicare Advantage, and commercial. These access dynamics are consistent with what we've long seen in hATTR-PN, and we're encouraged to see them replicated in ATTR-CM. Most importantly, physicians and patients are choosing AMVUTTRA, a testament to its highly differentiated and compelling profile, including its rapid knockdown of the disease-causing protein. By the end of the second quarter, approximately 1,400 ATTR-CM patients had initiated treatment. While we don't plan to regularly report patient numbers going forward, we felt it was important to share this clear signal of early momentum in our first full quarter post-launch. This strong uptake also gives us early insight into utilization patterns, which so far have been broad and balanced. Initially, early uptake was more pronounced among stabilizer progressors. However, within just three short months, utilization has become relatively balanced between first-line new starts and stabilizer progressors. We're seeing steady growth across both sources of business, and we have a clear focus on making AMVUTTRA the first-line treatment of choice. Balanced utilization is also seen across academic and community settings. Lastly, physician adoption has been broad. Since launch, the total AMVUTTRA prescriber base has tripled quarter-over-quarter. This reflects growing awareness and confidence in AMVUTTRA across both cardiology and multidisciplinary practices. Bottom line, we're highly encouraged by the early progress post-launch. The trajectory supports sustainable growth and positions us for long-term leadership in TTR amyloidosis. In summary, access ramped faster than expected and the value proposition is resonating. We've seen rapid payer adoption and broad physician engagement. The clinical differentiator of AMVUTTRA is clearly being recognized. We're seeing robust growth in an underserved and expanding ATTR-CM population. This is a devastating disease, and we remain deeply committed to advancing care through real-world evidence generation and the development of our next-generation RNAi therapeutics, nucresiran. Finally, global expansion is underway. With regulatory approvals secured in Europe, Japan, and Brazil, we've now launched in Germany and Japan, unlocking access to more patients worldwide. We're also maintaining stable growth in the hATTR polyneuropathy business, both in the U.S. and globally. These drivers underpin our increased revenue guidance and reinforce our conviction in significant revenue growth going forward. We're just getting started, and we remain focused on disciplined execution anchored in patient and customer centricity and delivering long-term innovation-driven growth. I'll now turn it over to Pushkal to share more about our work to advance the science in ATTR and beyond. Pushkal?

Thank you, Tolga, and good morning, everyone. I'm delighted to see the early success of AMVUTTRA in these first few months of the launch. It is a true testament to the outstanding execution of our commercial and medical teams and to AMVUTTRA's unique and compelling profile established in HELIOS-B. To that end, we continue to generate evidence from the HELIOS-B study that further supports the long-term efficacy and safety of AMVUTTRA with the aim of cementing it as the first-line treatment of choice for patients with ATTR cardiomyopathy. This slide highlights some of the unique and profound benefits of AMVUTTRA's rapid knockdown mechanism of action that are emerging from HELIOS-B. In the left column, you can see the benefits on NT-proBNP and troponin I, important clinical biomarkers of cardiac stress and injury, respectively. Not only do you see a large effect in patients receiving the drug versus those on placebo, but it's interesting to see a reduction compared to baseline in troponin I, suggesting a potential disease-modifying effect on this biomarker. Further to that point, echocardiographic data in the middle column shows improvements in critical aspects of cardiac function, both diastolic and systolic. Ultimately, we saw this translate into substantial improvements in all-cause mortality as well as cardiovascular mortality of 33% to 36%. In addition to data coming from the HELIOS-B study, we are continuing to generate evidence to further support the safe and effective use of AMVUTTRA via numerous registry and real-world evidence-based studies and investigator-initiated studies. We look forward to sharing data from these sources over time. Further to our leadership and commitment to innovation in ATTR amyloidosis, we announced in June the initiation of the TRITON-CM Phase III study for nucresiran, which may offer greater knockdown, greater efficacy, and greater convenience for patients with ATTR cardiomyopathy. As a reminder, TRITON-CM is a randomized, double-blind, event-driven outcome study. Patients are allowed to be on background stabilizer therapy. Approximately 1,200 patients will be randomized and the primary endpoint is a composite of all-cause mortality and cardiovascular events. The primary analysis will be event-driven and will occur a minimum of 24 months after the last patient is enrolled. If successful, we target launching nucresiran in ATTR cardiomyopathy around 2030. Also, as Yvonne noted earlier, we've announced today that nucresiran has been granted Fast Track Designation by the FDA, which will enable a more streamlined review process. In parallel, we have the goal to bring nucresiran to patients as quickly as possible and see an opportunity to do so in hereditary ATTR-PN. Though we are not yet prepared to discuss full details for TRITON-PN, we remain on track to initiate a pivotal study for the polyneuropathy indication by the end of 2025 and anticipate the potential to launch in this indication several years ahead of cardiomyopathy. We look forward to sharing more details in due course. Moving on to another exciting program, just a few days ago, we presented new multi-dose data from the Phase I study of mivelsiran in patients with early-onset Alzheimer's disease. Recall previously that we observed marked reductions in Aß40 and Aß42, the pathogenic proteins implicated in cerebral amyloid angiopathy and Alzheimer's disease, respectively, with single doses of mivelsiran. We're pleased to see that continue with multiple doses administered every six months. In addition to the durable knockdown observed, the safety and tolerability profile also remains encouraging. The majority of adverse events observed were nonserious, mild-to-moderate, and deemed unrelated to the study drug. Importantly, we saw no evidence of changes in CSF white blood cells, protein, or neurofilament light chain, which bodes well for this program as well as our CNS platform. We look forward to further evaluating the profile of mivelsiran in the ongoing cAPPricorn Phase II study in CAA as well as a Phase II study in Alzheimer's that we expect to start by the end of the year. As Yvonne mentioned earlier, a key element of our journey towards becoming a top-tier biotech company is growth through innovation. Across what is one of the most robust pipelines in the industry, we are making great progress advancing promising programs across a range of therapeutic areas with multiple potential blockbuster opportunities. In addition to some of the highlights we've already discussed, in Q2, we also kicked off a Phase I trial for ALN-4324, targeting GRB14, an insulin sensitizer for the potential treatment of type 2 diabetes. We also remain on track to start a Phase II study of ALN-6400, targeting plasminogen in a bleeding disorder later this year. In summary, Alnylam continues to make remarkable progress and deliver unique innovation that puts us in a great position to have a deep, sustainable pipeline that can deliver meaningful impact to patients for many years to come. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q2 2025 financial results and discussing our full-year upgraded guidance. Let's begin with a summary of our P&L results for the second quarter compared with prior year. Total product revenues for the quarter were $672 million or 64% growth versus 2024, driven by 77% growth in our TTR franchise with particularly strong performance in the U.S. market, primarily related to an increase in demand associated with the launch of AMVUTTRA and ATTR cardiomyopathy. Collaboration revenue for the quarter was $61 million, representing a $166 million decrease when compared with last year. The decrease was primarily driven by the modification of our cemdisiran collaboration agreement with Regeneron, which resulted in approximately $185 million of revenue in Q2 2024. As a reminder, this amendment granted Regeneron an exclusive license to cemdisiran monotherapy. Royalty revenue for the quarter was $40 million, representing an $18 million increase compared with last year, driven by higher Leqvio sales. Gross margin on product sales was 79% for the quarter compared with 84% in the second quarter of 2024. The decrease in margin was primarily driven by increased royalties on AMVUTTRA as higher revenues in 2025 resulted in an increase in the royalty compared with last year. For the balance of the year, our gross margin on product sales is expected to decrease as the applicable AMVUTTRA royalty rates increase driven by higher sales of AMVUTTRA. Our non-GAAP R&D expenses of $274 million increased 11%, primarily due to increases in start-up clinical trial expenses associated with our cardiovascular outcomes trial for zilebesiran and the TRITON-CM Phase III study for nucresiran. Our non-GAAP SG&A expenses of $261 million increased 26% compared to last year, primarily driven by increased headcount and other investments in support of the AMVUTTRA-ATTR cardiomyopathy launch in the U.S. Our non-GAAP operating income for the quarter was $95 million, representing a $42 million decrease compared with last year, driven primarily by the recognition of collaboration revenue related to the modification of our Regeneron agreement in Q2 2024, as I previously highlighted. We continue to be pleased with the progress we are making towards achieving our non-GAAP profitability guidance in 2025. Finally, we ended the quarter with cash, cash equivalents, and marketable securities of $2.9 billion compared to $2.7 billion as of December 31, 2024, with the increase primarily driven by cash from operations and net proceeds from the issuance of common stock in connection with employee stock option exercises. Now I'd like to turn to our financial guidance for 2025, where we are substantially increasing our net product revenue guidance driven by the strong early launch performance of AMVUTTRA and ATTR cardiomyopathy with specific details as follows: we are increasing our net product revenue guidance from a range of $2.05 billion to $2.25 billion to a revised range of $2.65 billion to $2.8 billion, representing a $575 million or 27% increase from the midpoint of the prior guidance to the midpoint of the updated guidance. The combined full-year growth compared to 2024 is a 66% increase at the midpoint of the guidance range. On a franchise level, the guidance is broken down as follows: we are modestly increasing the midpoint of our total Rare franchise guidance by raising the bottom end of our prior guidance range by $25 million and leaving the top end of our guidance unchanged, resulting in revised Rare product sales guidance of $475 million to $525 million. We are materially increasing our total TTR guidance range from $1.6 billion to $1.725 billion to a revised range of $2.175 billion to $2.275 billion, representing a 34% increase or more than $550 million at the midpoint. Let me provide some additional context, which highlights the impact of the cardiomyopathy launch on our TTR franchise growth based on our upgraded guidance. During 2024, when we only marketed our TTR therapies for hATTR polyneuropathy, our TTR franchise delivered approximately $300 million in revenue growth compared with 2023. In 2025, with the ATTR franchise now including cardiomyopathy sales following the U.S. launch in Q2, the midpoint of our revised 2025 total TTR sales guidance of $2.23 billion represents an approximate $1 billion increase from 2024 total TTR sales of $1.2 billion. My last comment on our upgraded sales guidance assumes foreign exchange rates as of June 30 for the balance of the year, resulting in approximately $60 million of our $575 million guidance increase being attributed to changes in FX from our original guidance, which utilized December 31 FX rates. The remainder of our financial guidance, including collaboration and royalty revenue, combined non-GAAP R&D and SG&A expenses, and non-GAAP operating income remains unchanged. Let me now turn from financials and discuss some key goals and upcoming 2025 milestones. In the second half of 2025, we expect to achieve the following: initiate the Phase III CVOT of zilebesiran in hypertension. Note that we also announced today that we'll present KARDIA-3 Phase II this summer. TRITON-PN hATTR-PN will initiate Phase II studies for mivelsiran in Alzheimer's disease and AL-6400 in a bleeding disorder. 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 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.

Your first question comes from Richter Salveen with Goldman Sachs.

Congratulations here on the quarter. Could you give some details here on the patient profiles for AMVUTTRA with regard to the frontline patients and whether you're seeing mostly mixed phenotype patients or more of a broader population mix? And help us understand from here what the field force is most focused on.

Thanks, Salveen. I mean I'll start by saying, look, it's early days yet, but we're incredibly pleased with where the launch is going, particularly with broad and robust uptake because I think it also really shows is the data that we generated from HELIOS-B is really resonating with physicians. The rapid knockdown of TTR, all-cause mortality improvements, infrequent subcutaneous administration, which provides both convenience and security. So we're seeing broad uptake across first-line patients as well as patients that progress on stabilizers. We're seeing use across community physicians as well as academic physicians, as well as new prescribers and repeat prescribers. So the trends are really very supportive in suggesting continued growth. Now I think it's fair to say that the initial pickup has been faster in the stabilizer progressing patients because when you bring in a new therapy and the patients who've been progressing on stabilizers, it's not surprising that physicians are looking for an orthogonal treatment for these patients. But we're now achieving a really healthy share of first-line patients. So we have a good mix of first-line and stabilizer progressors. What we're going to be doing is really consolidating and building on the foundation of this very early picture. Tolga, you probably want to add a couple of comments.

Actually, you pretty much covered everything. What I would say is, again, we're just one quarter in and what we're already seeing, what you described is validating our clinical thesis and commercial strategy.

The next question comes from Tazeen Ahmad with Bank of America.

I just wanted to get a sense on how you're thinking about net price for AMVUTTRA and gross-to-net moving forward?

Yes. No, thanks for that question. Jeff, perhaps you'd like to start off answering that. And if there are any additional perspectives, Tolga and I can follow on from you.

Yes. Just a reminder of what we said back on the approval call in March. We said that we expected that we would reduce net price modestly and gradually over time. That does hold for our expectation for 2025. 2025 relative to 2024, I would expect a mid-single-digit reduction in net price for AMVUTTRA for the year.

Tolga?

Yes. I mean, look, one thing is also to importantly highlight is the fact that payer dynamics are moving very much as what we exactly expected. A lot of the payer policies are already out, both on Medicare Advantage as well as in commercial. What we're seeing is first-line access for those patients and patients actually paying minimal, in most cases, zero out-of-pocket costs. We will obviously manage that with early engagement with payers, and the impact of the gross-to-net is going to be, as Jeff highlighted, will evolve over time.

Thanks, Jeff and Tolga.

The next question comes from Maury Raycroft with Jefferies.

Congrats on the great quarter. Wondering if you can comment on whether there was any bolus effect in cardiomyopathy scripts in the second quarter? And could you also please clarify to what extent did stocking contribute to the growth of U.S. AMVUTTRA revenue in the second quarter?

That's a great question. Look, I think Tolga has touched on this. We've really demonstrated very solid commercial execution. That means that we've seen a little bit of faster progress than we expected, particularly around health system setup. I touched on this already, but it's meant that we had initial faster pickup with stabilizer progressors. As we went through the quarter, we now have this very healthy share of first-line. I think the key message number one for me is that the results we're sharing with you today are not just a flash in the pan. We expect continued sustainable growth, and that's the reason why we raised guidance today. The second key message is really just the durability of the franchise. We expect AMVUTTRA to deliver continued sustainable growth, but we'll be bringing nucresiran forward as well, as Pushkal highlighted, which gives us the potential to deliver franchise growth out into the 2040s.

I will address the second part of the question regarding inventory. In the U.S. for this quarter, we saw a $170 million growth in the TTR franchise from Q1 to Q2, largely driven by the demand for cardiomyopathy treatments. We estimate around 1,400 patients on therapy, resulting in $150 million in cardiomyopathy revenue for the quarter. On the inventory front, we experienced about a $25 million benefit in Q2 compared to Q1. This increase is not due to an increase in days on hand, which remained steady at around 20 days, aligning with our distributor agreements. The rise in inventory this quarter was a result of how we calculated the value of a day’s worth of demand, based on a 12-week moving average. The growth in inventory in the channel reflects a positive increase in channel stocking for the quarter. However, on the gross-to-net side, we faced a headwind that nearly offset the inventory benefit, underscoring that demand was the primary growth driver this quarter. We also observed an increase related to the Part D rebate, which is applicable to any drug under Part D, as well as a slight rise in 340B utilization. As a result, the net price from Q2 to Q1 decreased slightly, consistent with our earlier comments that we expect net price for AMVUTTRA in 2025 to decline by mid-single digits compared to 2024.

Thanks, Jeff. I think a very important question, and I think you've clarified that for our investors. So thank you.

The next question comes from Jessica Fye with JPMorgan.

Can you provide more detail on the assumptions behind the updated TTR franchise guidance regarding the pace of new starts? Can you also reassure us that the new guidance is not overly aggressive?

Okay. So two parts to that question. Maybe Tolga, if you start with the first part and then, Jeff, you can follow on from that.

Yes, absolutely. Hi, Jessica, I mean, look, at the end of the day, what we have already laid out is we're expecting steady growth in both first line as well as the second-line patient flow. As Yvonne indicated, let me also provide a little additional color. As expected, we initially saw uptake concentrated in patients who had progressed on stabilizers. Often, these are sicker patients. Physicians naturally look for an alternative therapy with a mechanism of action that's unique, accessible, and easy to administer. But what's been really particularly encouraging, and this is why the guidance we're providing is over $0.5 billion uptick from where we were is about a month into the quarter, we began seeing a very healthy and accelerating trend in first-line use, just as we had positioned from the outset. That makes a lot of sense. This is a progressive and fatal disease. Physicians want to hit the disease early and hit it hard and not hold back their best therapy for later, as they might in less serious conditions. Today, and this is where the guidance is really anchored in, we see both first-line and second-line segments are growing rapidly. Uptake is broad across first and second lines and academic and community. Importantly, we're seeing a good expansion of our prescriber base. We've just expanded it threefold, and that continues to move in the right direction. Our focus is clear: to continue reinforcing AMVUTTRA as the first-line treatment of choice, supported not only by our approved label, but also by growing evidence, as Pushkal highlighted, with new imaging data and emerging cardiac biomarker trends that suggest AMVUTTRA may even help reverse disease progress. Nonetheless, we're just one quarter in and already seeing that behavior that validates our clinical profile as well as our commercial ambitions. The current guidance really reflects that.

Yes. Look, I think I just want to emphasize that it's early days yet. We've only just achieved our first full quarter here. When we came up with the guidance, we've given guidance that we expected to achieve. We're going to be focusing our team on continued execution. As we progress, we will continue to update and share our perspective.

Yes. Maybe just a little bit more context on the guidance. Again, if you look at what I've highlighted in terms of the midpoint of the guidance and what it implies in terms of year-over-year growth for TTR, about $1 billion, right, is what I highlighted. Last year, the PN franchise grew $300 million and was growing at about 30%. If that's the growth that we're going to get from PN this year, that would imply $600 million plus from cardiomyopathy. We just did $150 million in the second quarter, and we feel really good about growth sustaining through the second half of the year. I do think we have a high level of confidence in the guidance that we've provided, Jess.

The next question comes from Paul Matteis with Stifel.

One for Tolga and the team. As it relates to stabilizer progressors, can you talk a little bit more about the criteria physicians are using? Now that you've been in the market, do you have a sense of what percent of patients who are on a stabilizer currently would be dictated to be a progressor and a good candidate for AMVUTTRA based on the clinical criteria that are being implemented?

Yes. So we'll start with Tolga, and then I'd like Pushkal to provide a clinical perspective.

Yes. Based on our research and published data, clinical evidence suggests that anywhere between one-third to half the patients on stabilizers at one point progress. We see that number continuing to grow. The only real option in terms of mechanism and clinical evidence suggests that it would be AMVUTTRA at this point. But let me turn it over to Pushkal, who can also provide some more clinical perspective about what we're seeing and how those guidelines are progressing.

Yes. Thanks, Tolga. Thanks, Paul. Look, I think it's really important, as we talk about ATTR cardiomyopathy, it has a clear cause, which is the accumulation of TTR protein in the myocardium. But as it clinically presents, it's a form of heart failure. Doctors have been treating heart failure for decades, and they know how to modify drug therapy for patients. They might add diuretics or SGLT2s or other agents as patients are progressing. They rely on a variety of factors. There isn’t any one specific indicator. Easy ways include looking at the European guidelines that were put out a couple of years ago, which had various considerations, including biomarkers, echocardiographic factors, exercise tolerance, patient ability to lie flat at night, and pedal edema. I think what we're seeing now in these early days is that doctors are applying that general clinical rubric of looking at a patient, how she or he presents, symptoms, signs, and other factors in terms of determining how patients will progress. More and more guidelines in this category will develop over time. There will not be one single factor that clinicians or payers will be able to rely upon to say specifically that the patient is progressing; rather, we rely on the constellation of factors that affect the patient's symptomatology.

The next question comes from Luca Issi with RBC Capital.

Congrats on the strong quarter. Maybe if I can circle back on the TTR guide, maybe, Jeff, if I assume $200 million in revenue for the year from ONPATTRO, that essentially means $550 million to $650 million in revenues for the next two quarters for AMVUTTRA, which is actually not dissimilar from the $492 million that you already printed today. I guess what I'm trying to say is that this guide has still a good degree of conservatism in it, especially given that you're going to start selling this drug in international markets like Brazil, Europe, U.K., Japan, et cetera. But I would love if you have a different view here. So any thoughts there, much appreciated.

Yes. Luca, I appreciate the question. I'll again reiterate what I said to the earlier question here. We're guiding to $1 billion of TTR growth year-over-year. Last year, the PN franchise grew $300 million and was growing at about 30%. If you just assume that's the growth that we're going to get from PN this year, that would imply $600 million plus from cardiomyopathy. We just did $150 million in Q2. I think we feel very confident about that. If you look at historical guidance and the consistency with which we either met or exceeded that, that's how we feel about the guidance that we're providing. I don't know if it's conservative at this point, honestly; we're one quarter into this. We certainly look forward to coming back at Q3 and reassessing things.

The next question comes from Ellie Merle with UBS.

Congratulations on the quarter. Just to drill into this a little bit more, how should we think about the rate of new patient starts per quarter from here? One thousand four hundred is obviously a phenomenal number. Should we think of this cadence of new starts continuing in Q3 and beyond? Also, in terms of the mix, you mentioned now seeing a more balanced starts mix between the new patients and the progressors, whereas initially, it was more with the progressors. How do you expect this mix to evolve over time from here?

Okay. So I think two questions. You can probably take both of them, Tolga.

Yes. Thank you. Look, at the end of the day, we're very pleased with 1,400 paid patients within a three-month period. And as you highlighted, while the patient starts initially were predominantly stabilizer progressors, very quickly that switched into a balanced and broad patient uptake. We certainly expect to see both categories continue to grow. In terms of the specific numbers, we kind of went out of our way to provide clarity on that. As you know, AMVUTTRA is a single SKU, so we can't really isolate CN patients with precision. We will continue to provide additional color, and those numbers, obviously, we expect to go up. The specific precision about reporting how it's going to go quarter after quarter is not going to be possible.

The next question comes from Kostas Biliouris with BMO Capital Markets.

Congrats on the impressive launch. One question on payers from us, although you already touched a little bit on that. We have seen some commercial payers requiring stabilizer use prior to AMVUTTRA treatment in cardiomyopathy. Can you comment on how common those requirements are across different plans? And what percentage of patients do these plans cover?

Yes. No, that's a great question. I mean I'll just start off by saying that as we look at this, access is just not a barrier. We're seeing broad coverage across Medicare fee-for-service, Medicare Advantage, commercial payers, and the vast majority of patients are getting first-line with no step. This is exactly what we predicted coming into the launch and what we've been working on for quite some time. I think it speaks to the AMVUTTRA profile as well as the nature of the disease. But Tolga, you might want to provide other perspectives.

The broad headline is really that as predicted, we're not facing a significant headwind in terms of payer coverage. What I'm really pleased to see was within a short three-month period, the majority of both Medicare Advantage and commercial payers published policies. In those policies, AMVUTTRA is covered first-line. We also flagged that there could be some commercial payers that could provide a step edit in their policies. We're seeing that, but it is incredibly minimal. It's in the single digits. We don't anticipate that to continue to grow, as most large commercial payers have already written policies that covers AMVUTTRA as first-line. When it comes to step edits, we have the tools and support systems that enables us basically to help patients and providers circumvent that or carefully manage it. We built a quiet engine driving real impact in our patient services. I'm really pleased to see how we've pulled through across all three segments. Patients are getting on treatment in fee-for-service, Medicare Advantage, and commercial payers, including those plans that have step edits. We don't see that as an issue for now. We will continue to monitor and engage with payers to ensure that these patients, dealing with a severe condition, are getting seamless access to our medicines.

That's great, Tolga. One data point that struck me was the minimal use we're seeing of our Quick Start Program. We introduced a Quick Start Program with all our launches to ensure patients have access. We're just not seeing much use, which I think is very encouraging.

The next question comes from Gena Wang with Barclays.

I also wanted to congratulate you on the outstanding quarter. Maybe, Yvonne, you mentioned that the vast majority will be the first-line patient. Is it fair to say that out of the 1,400 patients treated so far, over 50% are first-line patients? How many of them received free drug?

Tolga, you love breaking this down.

What we had said very thoughtfully is our uptake has been broad and balanced. That included, again, early on, some patients actually progressing on stabilizers. We're seeing a very strong trend of first-line indication. We're in the early innings. We just want to ensure that we continue this trend and educate both patients and prescribers about why AMVUTTRA has a compelling product profile to be a first-line treatment.

It was minimal, right? Very, very little used in the Quick Start Program.

The next question comes from Mike Ulz with Morgan Stanley.

Congrats on the strong launch as well. Maybe just a follow-up on TTR cardiomyopathy. You highlighted you're getting some nice broad use in the frontline as well as the stabilizer progressor patients. Just curious if you started to see any combination use early in the launch. I know you're not expecting it, but we've picked up some combination use.

Yes. Thank you for that question. Tolga, why don't you take that?

Yes. We certainly see a very small portion of those patients getting combination use. We would expect that as tafamidis goes generic, it could become more prominent. But right now, it's difficult to be very specific about looking at the specific combination use. Where it's allowed and where access is permissible, we do see some utilization of combo.

I think we've got time for one last question.

The next question comes from Ritu Baral with TD Cowen.

Congratulations on the quarter. A quick question on variants. You guys addressed the mixed phenotype. In your first-line access, what trends are you seeing in the V122I variant population? At least on my model, feedback suggests I'm underestimating that prevalence by about 6 times, but it is a more severe phenotypic presentation. Also, you mentioned step-through and step-edits. Are they the same thing as prior authorizations, or do you have a different set of prior authorizations?

Let me take your last part first. The step edit policies that we've seen are minimal; it's in the single digit and mostly in the commercial setting. There are no specific limitations other than patients needing to be on a stabilizer first. There's no time limit for that, and it’s really up to the physician if the patient is progressing. We don’t see specific hereditary or V122I indications in those guidelines. We’ve demonstrated early on that AMVUTTRA is well-positioned to be a first-line patient for all diagnosed ATTR-CM patients. We're not seeing that trend. Over time, we expect more guidelines to develop and become established.

I think you said it well. What we've seen in HELIOS-B is that AMVUTTRA works equally well in wild-type patients and in those with the V122I variant. As Tolga mentioned, our class of drugs has shown benefit in hereditary patients, which encompasses a wide range of mutations, and we've seen benefits across that. Therefore, we believe that this is an important and exciting treatment paradigm for first-line patients, regardless of their genetic subtype.

Thank you, Ritu. I think this brings our call to a close. Alnylam is continuing to execute strongly across all areas of the business, and we're very much looking forward to providing you further updates as we progress throughout the year. Thanks a lot.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.