Q2 2025 Alnylam Pharmaceuticals Inc Earnings Call

Operator: Good morning, ladies and gentlemen, and welcome to the Alnylam Q2 2025 conference call. At this time, all lines are in listen-only mode. Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. This call is being recorded on Thursday, July 31st, 2025. I would now like to turn the conference over to the company. Please go ahead.

Good morning, ladies and gentlemen, and welcome to the enum Q2, 2025 conference call at this time. All lines are in listen-only mode. Following the presentation, we will conduct a question and answer session. If at any time during this, call, you require immediate assistance, please press star zero for the operator. This call is being recorded on Thursday July 31st 2025. I would now like to turn the conference over to the company. Please go ahead.

Christine Lindenboom: Good morning. I'm Christine Lindenboom, 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 in slide two, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Pushkal will review pipeline updates and clinical progress, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call to your questions.

Good morning, I'm Christina. Kent Chief, corporate Communications officer at Long Island, with me today are Avon Breen, Street chief executive officer, poet angular, Chief commercial officer, which will guard Chief research and development officer, and Jeff Bolton Chief Financial Officer. For those of you participating via conference calls the accompanying slides can be accessed by going to the event section of the investors page of our website investors out on nylon.com vents.

Christine Lindenboom: I'd 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 as of the date of this reporting 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?

During today's call is outlined in slide 2 of annual offer introductory remarks and provide some general contacts. Total will provide an update on our global commercial progress, which will review pipeline updates and clinical progress, and Jeff will review our financials and guidance followed by a summary of upcoming Milestones before we open the call to your questions.

I would like to remind you that this call will contain remarks concerning our online 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 as of the date of this reporting and should not be relied upon as representing our views as of any subsequent date.

Yvonne Greenstreet: 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. And whilst 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 multi-billion-dollar opportunities within our pipeline and an R&D engine set up to deliver sustainable innovation and value creation.

We specifically disclaim any obligation to update such statements. I'd like to turn the call over to Avon Navon.

Thanks, Christine, and thank you everyone, for joining the call today.

As shown in our Q2 results announced today. Our nanom is firing on all cylinders and we're swiftly establishing ourselves as a top. Tier bar tech company we're doing. So by focusing on 3 core elements of the business that we believe will drive sustainable growth and value creation for years to come.

The first is TTI leadership.

It's highlighted in today's press release. The launch is off to a very strong start.

And whilst it's still early days, we’re at the pace, and we’re deeply focused on laying the groundwork for long-term leadership in TTR.

Yvonne Greenstreet: 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, Pushkal 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 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 Ambutra in ATTR CM, combined with a large and underserved market, position this as a flagship commercial franchise with robust and durable long-term growth potential. And of course, all of this is underpinned by a best-in-class team and our award-winning culture.

The next is growth through innovation, focusing on the potential multi-billion dollar opportunities within our pipeline and an R&D engine set up to deliver sustainable innovation and value creation.

To that end, I would like to acknowledge the recent promotion of Pushkal Garg to Chief Research and Development Officer.

Push call has been instrumental in progressing, our Pipeline and in this role pushkar will oversee an integrated R&D organization to drive this exciting Pipeline and platform into the future.

Congratulations, push call.

Unity to sustain profitability going forward.

A stronger and Jeff will highlight later. The strong therapeutic, profile of ambra in attr-cm combined with a large and underserved Market positioned this as a flagship commercial franchise, with robust and durable long-term, growth potential. And of course, all of this is underpinned by a best-in-class team and our award-winning culture

Yvonne Greenstreet: 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 percent year-over-year growth, with growth largely attributable to the Ambutra CM launch. This was just the first full quarter of the ATTR CM launch, and as of June 30th, approximately 1,400 cardiomyopathy patients were receiving Ambutra, and this is a remarkable achievement. This performance reflects results from our cardiomyopathy launch in the US only. International markets are coming online for Ambutra 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 RAI therapeutics.

our results this quarter fit within each of these strategic pillars and represent 1 of the most impactful quarters to date for our NM.

Our commercial performance was driven by TTR franchise revenues of 544 million. 77% year-over-year growth

With growth largely attributable to the amp CM launch.

This was just the first 4 quarter of the attr-cm launch and as of June 30th, approximately 1,400 cardiac patients were receiving ample and this is a remarkable achievement.

this performance reflects results from our cardiomyopathy launched in the US, only

International markets are coming online from Futura for cm and are expected to begin to contribute to the CM launch in the second half of the year.

Hos to our teams for delivering these impressive early results.

Yvonne Greenstreet: We initiated the Triton CM Phase III study of Nucrisiran, further establishing our commitment to leadership in TTR, and are pleased to be announcing today that the FDA has granted fast-track designation to Nucrisiran 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 AON-4324 in Type 2 diabetes earlier in the quarter. And with regard to financial performance, we're reporting our strongest quarter to date as a company, with $672 million in total net product revenues, or 64 percent growth year over year.

In addition to these commercial results, we continue to advance our leading pipeline of rnai Therapeutics. We initiated the Triton CM phase 3. Study of an increase around further establishing our commitment to leadership in TTR and are pleased to be announcing today that the FDA has granted Fast Track, designation to increase ran for attr-cm.

We also just shared encouraging Phase 1. Multi-dose data for myver and in Alzheimer's disease and kicked off a phase 1 study for aln 4324 in type 2, diabetes earlier in the quarter.

Yvonne Greenstreet: As a result, we've increased our total net product revenues guidance for 2025 from a range of $2.05 to $2.25 billion to a revised range of $2.65 billion to $2.8 billion, representing an increase of $575 million, or 27 percent 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 Pizza Fit by 25 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 view of our commercial performance. Tolga?

And with regard to financial performance, we're reporting our strongest quarter to date as a company. The $672 million in total net product revenues represents 64% growth year-over-year.

As a result, we've increased our total net product revenues guidance for 2025 from the 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 ATTRc, CM launch and our other.

Commercial products from the balance of the year.

So zooming out from the success of, Q2, this progress represents Stellar execution towards our nylon Pizza fist by 25 goals, which we seek to achieve by the end of this year.

Doing so will further establish our Island as a unique, top, tier biotech company, delivering sustainable Innovation to patients for many years to come.

Tolga Tanguler: 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 percent year over year and 43 percent quarter over quarter growth. As you will see in a moment, the US TTR performance was the major driver of growth given the ATTR CM launch for Ambutra. It is also encouraging that we saw very robust double-digit growth compared with Q1 across both our TTR and rare franchises across the globe. All parts of our business are operating with focus and excellence. Let's quickly start with our rare franchise.

With that, let me now turn the call over to Tolga for review of our commercial performance Toler.

Thanks Ivan and good morning, everyone.

I'm excited to share with you the results of our Q2 commercial performance.

As Ivan 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

If you, as you will see in a moment, the US TTR performance was the major driver of growth given the attr-cm launched Forum Woodrum.

It is also encouraging that we saw very robust, double digit growth, compared with q1 across both our TTR and rare franchises across the globe.

All parts of our business are operating with focus and excellence.

Tolga Tanguler: Our Ghivlari and Opsilomo teams stayed focused and delivered $128 million in combined Q2 sales, up 24 percent versus last year. Growth was largely demand-driven, with a tailwind from favorable Ghivlari growth-to-net adjustment in the US. Now, turning our attention to TTR franchise, where we delivered $544 million in global net product revenues during the quarter, representing a 77 percent increase compared with the second quarter of 2024 and a robust 51 percent increase compared with the first quarter of 2025. In the US, combined Q2 sales of Ompatro and Ambutra rose 80 percent, up roughly $170 million from Q1, driven primarily by Ambutra'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.

Let's quickly start with our rare franchise, arguably and obso 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. Gilar gross, net adjustments in the US.

1% increase compared with the first quarter of 2025.

In the US combined, Q2 sales of on patrol and on buitre, Rose 80% up, roughly 170 million dollars from q1 driven, primarily by AMU, trust attr-cm launch.

We closed the quarter with approximately 1400 cardium, myopathy, patients on therapy.

Contributing an estimated 150 million dollars in Revenue.

This performance was fueled by strong execution and faster than anticipated access across payers and providers.

Tolga Tanguler: Regarding the year-over-year dynamics, the US TTR franchise grew 125 percent 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 percent 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 US TTR revenue dynamics, where the franchise achieved $383 million in the second quarter, representing a very robust 80 percent quarter over quarter growth. While we don't have the ability to report revenue by indication, the underlying trend is clear.

Regarding the year-over-year Dynamics, the US 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 hatr PN business which remains a solid growth engine importantly, we have yet to recognize any attrc, CM Revenue internationally as launches in Germany and Japan are slated to begin contributing in third quarter.

Now, let me provide some additional perspectives on the US TTR, Revenue Dynamics, where the franchise achieved 383 million. In the second quarter, representing a very robust.

80% quarter over quarter growth.

Tolga Tanguler: From Q1 '24 through Q1 '25, the US 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 Ambutra's launch performance in ATTR cardiomyopathy. Our launch began on March 20th, 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. As we've described on prior calls, we've been focused on three key enablers around the US launch of Ambutra in ATTR cardiomyopathy: health system setup, access and affordability, and treatment choice. The headlines are here, and I will go into more detail on each in the following slides.

While we don't have the ability to report revenue by indication, the underlying trend is clear.

From q1 24 through q125. The US TTR, franchise delivered, steady growth of around 15 to 20 million dollars.

On average every quarter.

In Q2 2025 we saw we saw a pronounced step change indicating an estimated 150 million dollar contribution from attr cardiomyopathy.

I will now provide some additional launch metrics to further contextualize on what trans launch performance in attr cardiomyopathy.

Our wants began on March 20th, 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

As we've described on prior calls, we've been focused on 3 key enablers around the US. Launch of ARA in attr cardiomyopathy.

Health Systems set up.

Access and affordability.

And treatment choice.

The headlines are here and I will go into more detail on each in the following slides.

Tolga Tanguler: As we've shared on prior calls, there are approximately 170 priority health systems through which approximately 80 percent of ATTR cardiomyopathy patient volume flows. The majority of these provider accounts now have Ambutra on formulary, enabling therapy initiation throughout these health systems where ATTR CM patients present. What's more, nearly all of the priority health systems have already begun treating patients with Ambutra for ATTR cardiomyopathy. This, together with the broad network of more than 2,000 alternative sites of care, has allowed us to achieve our aspiration. Roughly 90 percent of patients in the US are able to receive Ambutra 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 now, at the end of our first quarter of launch, we are largely there.

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 a withdrawal, formulary enabling therapy initiation throughout these Health Systems, where attrc and patients present.

What's more nearly all of the Priority Health Systems have already begun treating patients with down with utra for attr cardiomyopathy?

This together with the broad network of more than 2,000 alternative sites of care has allowed us.

To achieve our aspiration roughly, 90% of patients in the US are able to receive our motor treatment within about 10 miles of where they live.

Bottom line, our priority was to enable broad provider accounts set up in our first year of launch.

This has happened faster than we had initially anticipated since. Now at the end of our first quarter of launch, we are largely there.

Tolga Tanguler: In addition, patients are getting first-line access to Ambutra across all payer segments. Coverage is now confirmed by payers covering the majority of US patient lives, inclusive of Medicare fee-for-service, Medicare Advantage, and commercial. We can therefore confirm that the large majority of patients have access to Ambutra as a first-line treatment, meaning without requiring patients to step through another product first. Most patients are indeed paying zero in out-of-pocket costs, and 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 initiation 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.

In addition, patients are getting first line, access to ambula across all payer segments.

Coverage is now confirmed by payers covering the majority of us patient lives. Inclusive of Medicare fee for service, Medicare Advantage.

And Commercial.

Step through another product first.

Most patients.

Are indeed paying zero in out-of-pocket costs?

And consistent with what we've seen in polar opportunity. There has been very limited use of our Quick Start programs.

Quite simply, because patients are not experiencing delays in coverage.

We 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 had rpn, and we're encouraged to see them replicated in attr. Cm.

Tolga Tanguler: This reflects our deep experience engaging with payers and the advantage of our fully integrated in-house patient support services. Now, most importantly, physicians and patients are choosing Ambutra, 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. More specifically, very early initial 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.

This reflects our deep experience, engaging with payers and the advantage of our fully integrated in-house patient Support Services.

Now most importantly, Physicians and patients are choosing amutan a testament to its highly differentiated and compelling profile including its rapid knockdown of the disease-causing protein.

By the end of second quarter.

Approximately 1,480, trcm 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.

More specifically.

Tolga Tanguler: We're seeing steady growth across both sources of business, and we have a clear focus on making Ambutra the first-line treatment of choice. We also see balanced utilization across academic and community settings. And lastly, physician adoption has been broad. Since launch, the total Ambutra prescriber base has tripled quarter over quarter. This reflects growing awareness and confidence in Ambutra 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 ramps faster than expected, and the value proposition is resonating. We've seen rapid payer adoption and broad physician engagement. The clinical differentiator of Ambutra is clearly being recognized. We're seeing robust growth in an underserved and expanding ATTR CM population.

Very early initial update was more pronounced among stabilizer progressors. However, within just 3, short months, you 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 our mutra the first line treatment of choice.

We also see balance utilization across academic and Community settings.

And lastly physician adoption has been brought since launch. The total amount of prescriber Base has tripled quarter over quarter, this reflects growing awareness and confidence in our Mas across both Cardiology and multi-disciplinary practices.

Bottom line.

We're highly encouraged by the early progress plus launched. The trajectory support sustainable growth and positions us for long-term leadership in TTR radios in summary.

Access ramp faster than expected, and the value proposition is resonating.

We've seen rapid pay adoption and Broad physician engagement.

The clinical differentiator of our is clearly being recognized.

Tolga Tanguler: Look, this is a devastating disease, and we remain deeply committed to advancing care through real-world evidence generation and development of our next-generation RNAi therapeutics, Nucrisiran. 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 US 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 discipline 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.

We're seeing robust growth in an underserved and expanding attr-cm population.

Look, this is a devastating disease and we remain deeply committed to advancing care through real world, evidence generation and development of our next Generation. Rni Therapeutics nuclear

Finally.

Global expansion is underway.

With the regulatory approvals secured in Europe, Japan, and Brazil. We've now launched in Germany and Japan unlocking access to more patients worldwide.

We're ALS maintaining stable growth in the hatr poly operative business.

both in the US and

These drivers underpin, our increased Revenue guidance and reinforce our reinforced, our conviction in significant Revenue, growth going forward.

We're just getting started and we remain focused on discipline execution, anchored in patient and customer centricity.

And delivering long-term innovation-driven growth.

Pushkal Garg: Thank you, Tolga, and good morning, everyone. I'm delighted to see the early success of Ambutra 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 Ambutra'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 Ambutra 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 Ambutra'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.

All now, turn it over to pushkar to share more about our work to advance the science in attr and Beyond pushka.

Thank you, toga. And good morning everyone. Uh, I'm delighted to see the early success of ambra in these first few months of the launch. It is a true Testament to the outstanding execution of our commercial and Medical Teams and TVs unique and compelling profile established in Helios B.

Long-term efficacy and safety of ambra 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 vutra, Rapid knockdown mechanism of action that are emerging from Helios B.

Pushkal Garg: Not only do you see a larger effect, a large effect in patients receiving 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. And 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 Ambutra by numerous registry and real-world evidence-based studies and investigator-initiated studies. We look forward to sharing data from these sources over time.

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 larger effect, a larger effect in patients receiving drugs versus those on placebo, but it's interesting to see a reduction compared to baseline and troponin. I'm suggesting a potential disease-modifying effect on this biomarker.

Further to that point, echocardiographic data in the middle column show improvements in critical aspects of cardiac function, both diastolic and systolic.

and 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 Ambra through numerous registry and real-world evidence-based studies, as well as investigator-initiated studies. We look forward to sharing data from these sources over time.

Pushkal Garg: 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 Nucrisiran, 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 Nucrisiran in ATTR cardiomyopathy around 2030. Also, as Yvonne noted earlier, we've announced today that Nucrisiran has been granted fast-track designation by the FDA, which will enable a more streamlined review process.

Further to our leadership and commitment to innovation and ATR Moly dosis, we announced in June the initiation of tritonia of the Triton CM Phase 3 study for new Crease Ran, which may offer greater knockdown, greater efficacy, and greater convenience for patients with ATR cardiomyopathy.

As a reminder Trident cm is a randomized, double blind. Event-driven outcome studies, patients are allowed to be on background stabilizer therapy. Approximately 12200 patients will be randomized, and the primary endpoint is a composite of all cos 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 new creature around and attr cardiomyopathy around 2030.

Also, as Ivon noted earlier, we've announced today that new creature and has been granted Fast Track, designation by the FDA which will enable a more streamlined review process.

Pushkal Garg: In parallel, we have the goal to bring Nucrisiran 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 A-beta 40 and A-beta 42, the pathogenic proteins implicated in cerebral amyloid angiopathy and Alzheimer's disease, respectively, with single doses of Mivelsiran.

In parallel, we have the goal to bring new creature into 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 PM. We remain on track to initiate a pivotal study for the poly neuropathy 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 1 study of Naval surround in patients with early onset Alzheimer's disease.

Pushkal Garg: 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 AEs observed were non-serious, mild to moderate, and deemed unrelated to 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 Capricorn 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.

Recall previously that we observed Market reductions in a betta 40 and a beta 42. The pathogenic proteins implicated in cerebral amloid, and geopath, and Alzheimer's disease respectively, with single doses of the VIN, we're pleased to see that continue with multiple doses administered every 6 months.

In addition to the durable knockdown observed, the safety and tolerability profile also remains encouraging, the majority of AES observed were non serious mild to moderate and deemed unrelated to study drugs.

Importantly, we saw no evidence of changes in CSF. White blood cells, protein or neurofilament light chain, which bod well for this program, as well as our CNS platform.

We look forward to further evaluating the profile of elrond in the ongoing Capricorn. Phase 2 study in CIA as well as a phase 2 study in Alzheimer's that we expect to start by the end of the year.

Pushkal Garg: 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 AON-4324 targeting GRB-14, an insulin sensitizer for the treatment, potential treatment of Type 2 diabetes. We also remain on track to start a Phase II study of AON-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?

As Ivonne mentioned earlier, a key element of our journey towards becoming a top, tier biotech company is growth through innovation.

Crosswood is 1 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 1 trial for aln 4324 targeting grb, 14 and insulin sensitizer for the treatment potential treatment of type 2 diabetes.

We also remain on track to start a phase 2 study of aliens. 6400 Target targeting plasminogen in a bleeding disorder later this year.

In summary, Al NM 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.

Jeff Poulton: 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 percent growth versus 2024, driven by 77 percent growth in our TTR franchise, with particularly strong performance in the US market, primarily related to an increase in demand associated with the launch of Ambutra 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 Symdisiran 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 Symdisiran monotherapy.

Jeff.

Thanks for push calling. Good morning, everyone. I'm pleased to be presenting a summary of Al nemes, Q2 2025 Financial results and discussing our full year upgraded guidance.

Let's begin with the 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 US market. Primarily related to an increase in demand associated with the launch of in 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 SMD deran collaboration agreement with regeneron, which resulted in an approximately 185 million of Revenue in Q2 2024.

Jeff Poulton: Royalty revenue for the quarter was $40 million, representing an $18 million increase compared with last year, driven by higher Lekvio sales. Gross margin on product sales was 79 percent for the quarter, compared with 84 percent in the second quarter of 2024. The decrease in margin was primarily driven by increased royalties on Ambutra, 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 Ambutra royalty rates increase, driven by higher sales of Ambutra. Our non-GAAP R&D expenses of $274 million increased 11 percent, primarily due to increases in startup clinical trial expenses associated with our cardiovascular outcomes trial for Zavisiran and the Triton CM Phase III study for Nucrisiran.

As a reminder, this amendment granted regeneron on an exclusive license to send the Saran monotherapy.

Royalty revenue for the quarter was 40, million representing, an 18 million increase compared with last year, driven by higher like vo 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 ion bootra1n.

But the balance of the Year our gross margin on product sales is expected to decrease as the applicable and voucher royalty rates, increase driven by higher sales of inbra.

Jeff Poulton: Our non-GAAP SG&A expenses of $261 million increased 26 percent compared to last year, primarily driven by increased headcount and other investments in support of the Ambutra ATTR cardiomyopathy launch in the US. 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 31st, 2024, with the increase primarily driven by cash from operations and that proceeds from the issuance of common stock in connection with employee stock option exercises.

Our non-gaap R&D expenses of 274 million increased 11% primarily due to increases in startup clinical trial. Expenses associated with our cardiovascular outcomes trial for zombie Saran and the Triton CM phase 3 study for new crease around.

Our non-gaap sgna expenses of 261 million increased 26% compared to last year.

Primarily driven by increased headcount and other investments in support of the ambua, attr, cardiomyopathy launched in the US.

Our non-gaap operating income for the quarter was 95 million represented in 42 million, decreased compared with last year, driven primarily by the recognition of collaboration Revenue related to the modification of our, our regeneron agreement and 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 the proceeds from the issuance of common stock in connection with employee stock option exercises.

Jeff Poulton: 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 Ambutra and ATTR cardiomyopathy, with specific details as follows. We are increasing our net product revenue guidance from a range of $2.05 to $2.25 billion to a revised range of $2.65 to $2.8 billion, representing a $575 million, or 27 percent 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 percent increase at the midpoint of the guidance range. On a franchise level, the guidance is broken down as follows.

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 bamburgh 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.

Jeff Poulton: 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 to $525 million. We are materially increasing our total TTR guidance range from $1.6 to $1.725 billion to a revised range of $2.175 to $2.275 billion, representing a 34 percent 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.

On a franchise level. The guidance is broken down as follows.

there 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 to 525 million,

We are materially increasing our total TTR guidance range from 1.6 to 1.725 billion to a revised range of 2.175 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 Cardinal lap be launched on our TTR franchise growth, based on our upgraded guidance.

during 2024, when we only marketed our rttr therapies for h8 todr poly our TTR franchise delivered, approximately 300 million in Revenue growth compared with 2023

Jeff Poulton: In 2025, with the ATTR franchise now including cardiomyopathy sales following the US 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. And now my last comment on our upgraded sales guidance, which now assumes foreign exchange rates as of June 30th 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 31st 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 2025, with the attr.

Calling the US 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.

And now my last comment on our upgraded sales guidance, which now assumes foreign exchange rates as of June 30th 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, 31st FX rates

The remainder of our of our financial guidance, including collaboration and royalty Revenue combined non-gaap bar and DNS, G&A expenses and non-gaap operating income remains unchanged.

Jeff Poulton: In the second half of 2025, we expect to achieve the following: initiate the Phase III seed lot of Zavisiran and hypertension. Note that we also announced today that we'll present CARDIA3 Phase II results at the European Society of Cardiology Congress later this summer. Initiate the Triton PN Phase III study of Nucrisiran and HATTR PN, and 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?

Let me now turn from financials and discuss some key goals and upcoming 2025 milestones.

And the second half of 2025, we expect achieve, achieve the following.

Initiate, the phase 3 cbot of of zombies and hypertension.

Note that we also announced today that we'll present cardio, 3 phase 2 results at the European Society of Cardiology Congress later this summer.

Initiate. The Triton PN phase 3 study of Nan and had trpn and initiate Phase 2. Studies for my Velar and Alzheimer's disease, and Al 6400 in a bleeding disorder.

Christine Lindenboom: 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.

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 1 question, each and then get back in the queue if you have additional questions.

Operator: Thank you. Ladies and gentlemen, we will now begin the question and answer session. Should you have a question, please press the star followed by the number one on your touchstone phone. You will hear a prompt that your hand has been raised. Should you wish to decline from the polling process, please press the star followed by the number two. If you are using a speakerphone, please leave the handset before pressing any keys. One moment, please, for your first question. Your first question comes from Richter Salvi with Goldman Sachs. Please go ahead.

Thank you, ladies and gentlemen. We will now begin the question and answer session. Should you have a question, please press the star, followed by the number 1 on your touchtone phone. You will hear a prompt that your hand has been raised. Should you wish to decline from the Q&A process, please press the star, followed by the number 2. If you are using a speakerphone, please lift the handset before pressing any keys. One moment, please, for your first question.

Your first question comes from Richard salvi with Goldman Sachs, please go ahead.

Richter Salvi: Good morning. Thanks for taking my question and congratulations here on the quarter. Could you give some details here on the patient profiles for Ambutra 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. Thank you.

Good morning. Thanks for taking my question and congratulations here on the quarter. Um could you give some details here on the patient profiles for friend vutra with regard to the Frontline patients and whether you're seeing um mostly mixed phenotype patients or more of a a broader population mix and and help us understand from here, what the, what the field force is

Yvonne Greenstreet: Thanks, Pavilion. I mean, I'll start by saying, look, you know, it's early days yet, but we're incredibly pleased with where the launch is going, particularly with, you know, broad and robust uptake. Because I think it also really shows that the data that we generated from Helios B is really resonating, you know, with physicians. You know, the rapid knockdown of TTR, all-court mortality improvements, infrequent subcutaneous administration, which provides both convenience and security. So, you know, we're seeing broad uptake across, you know, first-line patients as well as patients that progress on stabilizers. We're seeing use across the community of physicians, as well as academic physicians, as well as new prescribers, as well as repeat prescribers. So the trends are really very supportive in suggesting continued growth.

Most focused on thank you.

Yvonne Greenstreet: Now, I think it's fair to say that the initial pickup has been faster in the stabilizer progressing patients because you bring in a new therapy and, you know, there are patients who've been progressing on stabilizers. It's not surprising that, you know, 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, stabilizer progressors, and 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?

Thanks for being. I, I mean, I'll start by saying look, um, you know, it's early days yet but we're incredibly pleased with, um, where the launch is going particularly with um, you know, Broad and robust uptake because I think it was was really shows as the data that we generated from Helio speed is really resonating. Um you know with um Physicians um you know the rapid knockdown of PTR uh all cause mortality improvements uh infrequent subcutaneous industrial which provides both convenience and security so you know we're seeing we're seeing broad uptake across you know first-line patients as well as patients that progress on um stabilizers we're seeing use across the community physicians as well as academic Physicians, as well as new prescribers as well as repeat prescribers. So the trends are really very supportive um in in in suggesting continued growth now, I think it's it's fair to say that the initial pickup has been faster in the uh stabilizer progressing, uh patience because you bring in a

new therapy and um you know that patients who've been progressing on stabilizers. It's not surprising. Um that uh, you know, Physicians are looking for um, an orthogonal treatment for these patients but but we're now achieving a really healthy share of um, first line patients. So we have a good mix of of first line, stabilizer progresses and what we're going to be doing is really, um, consolidating and building on the foundation. Um,

Is very early picture.

Pushkal Garg: 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 validates our clinical thesis and commercial strategy.

Talking, you probably want to add a couple of comments, actually, you pretty much covered everything. What I would say is again, we're just 1 quarter in and what we're already seeing, what you described is validates, our clinical pieces and Commercial strategy.

Yvonne Greenstreet: Thanks, Tolga. Next question.

Thanks essay. Next question.

Operator: Thank you. The next question comes from Tizine Ahmad with Bank of America. Please go ahead.

Thank you.

The next question comes from tazeen. Ahmad with back of America. Please go ahead.

Tazeen Ahmad: Hi, good morning. Thanks for taking my question. I just wanted to get a sense on how you're thinking about net price per Ambutra and growth to net moving forward.

Yvonne Greenstreet: Yvonne, 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.

Jeff Poulton: Yeah, just a reminder of what we said back on the approval call in March. You know, we said that we expected that we would reduce net price modestly and gradually over time, and that does hold for our expectation for 2025. 2025 relative to 2024, I would expect mid-single-digit reduction in net price for Ambutra for the year.

Yeah, thanks for that. Uh question. Um Jeff perhaps you'd like to start off answering that and if there are any additional uh perspective tool and I can can follow on from you.

Yeah, uh, just a reminder of of what we said back on the approval, call in March, you know, we said that we expected that we would reduce net price modestly, and gradually over time. And I, and I, I, that does hold for our expectation for 2025 2025 relative to 2024, I would expect mid single digit reduction in in net, price Ram, buitre for the year.

Yvonne Greenstreet: Okay.

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

Okay. Yeah, I mean look I

1 thing is also to, to importantly, highlight, is the fact that

Yvonne Greenstreet: Thanks, Jeff and Tolga. Next question.

Peridynamics are are moving very much in as what we exactly expected. A lot of. The payer policies are already out, uh, both on Medicare Advantage as well as in commercial. And what we're seeing is a a a a firstline access to those patients and and and patients actually paying minimal in most cases, zero uh, out of pocket, uh costs. So uh, we'll obviously manage that with early engagement with payers. Uh and and and the impact of the gross net is going to be as as as Jeff highlighted will will evolve over time.

Thanks, thanks. Chad. Next question.

Operator: Thank you. The next question comes from Murray Raycroft with Jeffrey. Please go ahead.

Thank you. The next question comes from. Murray Ray Croft with the Jeffreys. Please go ahead.

Paul Matteis: Hi, good morning, and congrats on the great quarter, and thank you for taking our question. I'm 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 US Ambutra revenue in the second quarter?

Yvonne Greenstreet: So that's a great question. Look, you know, I think Tolga's touched on this. You know, we've really demonstrated very solid commercial execution, and that means that we've seen a little bit of faster progress than we expected, particularly around health system setup. So, you know, I touched on this already, but you know, it's meant that we had initial faster pickup with stabilizer progressors, but as we went through the queue, we now have this very healthy share of first-line, and we're just in the first quarter of launch. So I think the key message, number one, for me is that the results that 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. And I think the second key message is really just the durability of the franchise.

Hi, good morning and uh, congrats on the great quarter and thank you for taking our question. Um, wondering if uh, if you can comment on whether there was any bolus effect in cardiomyopathy scripts in second quarter and uh, could you also please clarify to what, what extent did stocking contribute to the growth of us on Bluetooth revenues? Second quarter? So that's a that's a a great question. Look, you know, I think talk has touched on this, you know, we've we've really demonstrated very solid, um, commercial execution. And, and that means that we've seen a little bit of, um, you know, faster progress than we expected a particularly around Health, um, health system setup, um,

Yvonne Greenstreet: You know, we expect to see Ambutra deliver continued sustainable growth, but we'll be bringing Nucrisiran forward as well, as Pushkal highlighted, which gives us the potential to deliver franchise growth out into the 2040s.

So, you know, I touched on this already, but, you know, it's meant that we had initial faster pickup with stabilizer progressors. Um, but as we went through the queue, um, we now have this very healthy share of, um, first line, um, and with just in the first quarter of launch. So I think, I think the key message number 1 for me, is that the results that we're sharing with you today are not just the flash in the pan. We expect continued sustainable growth and and that's the reason why we, we raised guidance today. And I think the second key message is really just the durability of the franchise, you know?

We expect to see ambra. Deliver continued sustainable growth but we'll be bringing new crease around forward as well as pushkar highlighted which which gives us a potential to deliver franchise growth out into the 2040s.

Jeff Poulton: I'll comment on the second part of the question, which was about inventory. I think the headline for the quarter is, again, in the US, Tolga in his prepared remarks highlighted the $170 million in growth in the TTR franchise in the US Q2 versus Q1. Far and away, the biggest driver of that was the cardiomyopathy demand: 1,400 patients on therapy, $150 million in cardiomyopathy revenue for the quarter is what we're estimating. On the inventory side, we did see a $25 million benefit in Q2 compared to Q1. That's not actually because days on hand increased between Q1 and Q2, as it actually stayed constant at around 20 days, which is at about the midpoint of the agreements that we've got in place with our distributors.

I'll comment, uh, on the second part of the question which was about uh, inventory. Um, I think the headline for the quarter is again in the US Togo in his prepared. Remarks highlighted, the 170 million in growth in the TTR franchise in the US Q2 versus q1 Far. And Away the biggest driver of that was the cardi myopathy demand, 1400 patients on therapy. 150 million in in cardiomyopathy revenue. For the quarter is what we're estimating.

Jeff Poulton: What drove the increase in inventory in the quarter was the calculation of what a day of demand is, or a day of inventory is worth, which is based on a 12-week moving average of demand. And so it was demand that really drove the increase in inventory in the channel in the quarter, which is, again, a high-quality increase in channel stocking in the quarter. Now, on the gross net side, we had an opposite movement, so a headwind that roughly offset the benefit that we had in inventory, which is why we're highlighting demand was the key driver of growth in the quarter. On the gross net side, a couple of things. One is that we had an increase associated with the Part D rebate that we're paying.

On the inventory side, we did see a 20 about 25 million benefit in Q2 compared to q1. That's not actually, because days on hand, increase between q1 and Q2 as it actually stayed constant at around 20 days, which is at about the midpoint of the agreements that we've got in place with our, with our Distributors, uh, what drove the increase in inventory, in the quarter, was the calculation of what a day of demand is, or a day of inventory is worth, which is based on a 12-week, moving average of demand. And so it was demand that really drove the increase in inventory and, and the channel, and the quarter, which is again, a high quality increase in in, uh, in Channel stocking in a quarter. Now on the gross. Can that side? We had an opposite movement. Uh so a, a headwind that that roughly offset the benefit.

Jeff Poulton: Like, you know, anybody that's got a Part D drug at this point is paying rebates on the IRA Medicare redesign. We do have a small portion of our TTR sales that go through the Part D channel, and that's the home care part of the business. Historically, that's been about 20 percent in polyneuropathy, so there is an increased rebate that we're paying there, which was in line with our expectations. We also saw modestly higher 340B utilization in the quarter. So on price, net price Q2 to Q1 was down slightly, which is consistent with what I said on the earlier question, that we do expect net price $25 versus $24 for Ambutra to be down mid-single digits.

Yvonne Greenstreet: Thanks, Jeff. I think a very important question, and I think you've clarified that for our investors, so thank you. Next question, please.

We also saw modestly higher 340b utilization in the quarter. So on price net price Q2 to q1 was down slightly, which is consistent with. What I I said on the earlier, question that we do expect net price, 25 versus 24 frame, vutra to be down mid single digits,

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

Operator: Thank you. The next question comes from Jessica Five with JP Morgan. Please go ahead.

Thank you. The next question comes from Jessica 5 with JP Morgan. Please go ahead.

Tazeen Ahmad: Hey, guys, good morning. Thanks for taking our question. Can you speak a little more in a little more detail to the assumptions underpinning the updated TTR franchise guidance as it relates to, like, the pace of new starts? And I guess just in general, can you just maybe provide a little assurance or reaffirm that the new guidance is not somehow aggressive? Thank you.

Hey guys. Good morning. Thanks for taking our question. Um, can you speak a little more in a little more detail to the assumptions? Underpinning. The updated TTR franchise guidance as it relates to like the pace of new starts and I guess just in general can you just maybe provide a little Assurance or reaffirm that the new guidance is not somehow aggressive. Thank you.

Yvonne Greenstreet: 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.

Okay so it's 2 parts that question. Maybe talk if if you start with the first part and then Jeff

Pushkal Garg: Yeah, absolutely. Hi, Jessica. I mean, look, at the end of the day, what we've already laid out is we're expecting a 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. And these are often sicker patients. Physicians naturally look for an alternative therapy with a mechanism of action that's unique, that's accessible, easy to administer, and so forth. But what's been really particularly encouraging, and this is why the guidance we're providing is over half a billion dollars uptake 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. And frankly, that makes a lot of sense.

Um, you can follow on from that.

Yeah. Absolutely. Hi Jessica. I mean, look at the end of the day. Uh, what we've already laid out is we're expecting a steady growth in both first line, as well, as the second line. Uh, second line. Uh, patient flow, um, is Ivonne indicated. Let me also provide a little additional color is expected. We initially saw optic, concentrated patients. Who had progressed on stabilizers? Uh, and

These are often sicker patients Physicians naturally. Look for a, an alternative therapy, uh, with a mechanism of action. That's Unique, that's accessible, easy to administer um, and so forth. But what's been really particularly encouraging? And this is why the guidance we're providing is uh over half a billion dollars optic from where we were.

Pushkal Garg: This is a progressive and fatal disease. Physicians want to hit the disease early, and it is hard, and not hold back their best therapy for later, as they might in less serious conditions. So today, and this is where the guidance is really, you know, anchored in, we see both first-line and second-line segments are growing. They're growing rapidly. Uptake is broad across first and second-line and academic and community. And more importantly, we are seeing a good expansion of our prescriber base. We've just expanded by threefold, and that continues to move in the right direction. So as we move forward, our focus is clear: to continue reinforcing Ambutra 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, emerging cardiac biomarker trends, that suggest Ambutra may even help reverse disease progression.

Is, uh, about a month into the quarter with regards, to seeing a very healthy and accelerating Trend in first line. Use, uh, just as we had positioned from the outset, and frankly, that makes a lot of sense. Uh, this is a progressive and fatal disease. Physicians want to hit the disease early, and it is hard and not, hold back, their best therapy for later as they might in less serious conditions. So today, uh, and this is where the guidance is really, uh, you know, anchored in, uh, we see both first line and second line segments are growing, they're growing rapidly. Uptake is Broad across first and second line, and academic, and community. And more importantly, we are seeing a good expansion of our prescriber base. Uh, we've just expanded by 3-fold and that continues to, uh, move in the right direction. So, as we move forward, uh, our focus is clear, um, to continue reinforcing and mutra as the first night treatment of choice.

Pushkal Garg: So nonetheless, we're just one quarter in and already seeing that behavior that validates our clinical profile as well as our commercial ambitions. And I think the current guidance really reflects that.

Yvonne Greenstreet: Yeah, look, I think I just want to emphasize that it's early days yet. We've only just achieved our first full quarter here. And you know, when we came up with the guidance, we've given guidance that we expect to achieve. We're going to be focusing our team on continued execution. And as we progress, we will, you know, continue to update and share our perspectives. But.

Jeff Poulton: Yeah, maybe just a little bit more context on the guidance. Again, if you look at the, you know, what I highlighted in terms of the midpoint of the guidance and what it implies in terms of year-over-year growth for TTR, about a billion dollars, right, is what I highlighted. Last year, the PN franchise grew $300 million versus $23 and was growing at about 30 percent, right? So if you just sort of assume that 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. So I do think we have a high level of confidence in the guidance that we provided, Jeff.

Supported not only by our approved labels but also by growing evidence as as push call highlighted with new Imaging data, emerging cardiac biomarker, test trans that suggests amra may even help reverse disease progression. So, nonetheless, we're just 1 quarter in and already seeing that behavior that well, validates on our, uh, clinical profile as well as our commercial Ambitions. Uh, and I think, uh, the, the current guidance really reflect that. Yeah, look, I think I just want to emphasize that it's. It's, uh, it's early days yet. Um, we're only we've only just achieved our our first 4 quarter here. And, you know, when, when we came up with the guidance, we we've given guidance that, that, that, that we, that we expect to, um, achieve. We're going to be focusing on team on continued execution. And as we progress, we will, um, you know, Continue to update and, and share our perspectives, but yeah, maybe just a, just a little bit more context on on, on the guidance. Um, again, if you look at the

The, you know what I highlighted in terms of the midpoint of the guidance and what it implies in terms of year-over-year growth for TTR about a billion dollars, right? Is what, what I highlighted last year? The PN franchise group, 300 million versus 23 and was growing at about 30%, right? So if you just sort of assume that that's the growth that we're going to get from PM this year, that would imply 600 million plus from cardiomyopathy. We just did a 150 million in the second quarter and we feel really good about growth sustaining.

Yvonne Greenstreet: Thanks, Jeff. Next question.

Through the second half of the year. So I do think we have a high level of confidence in the guidance that we provided Jess.

Thanks Jeff. Next question.

Operator: Thank you. The next question comes from Paul Mattis with Stifel. Please go ahead.

Thank you. The next question comes from Paul Mattis with stifel, please go ahead.

Paul Matteis: Hey, great. Thanks so much for taking my question. 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? And I guess 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 Ambutra based on the clinical criteria that are being implemented? Thanks so much.

Be a progressor and a good candidate for a voucher based on the clinical criteria that are being implemented. Thanks so much.

Yvonne Greenstreet: Yeah, so we'll start with Tolga and then, unlike Pushkal's provider, clinical perspective.

Pushkal Garg: Yeah, so Paul, I mean, look, based on our research and obviously published data, clinical evidence suggests that anywhere between third to half the patients on stabilizer at one point progresses. And while we see that number is continuing to grow, and then obviously the only real option in terms of mechanistically and the clinical evidence suggests that, you know, it would be Ambutra at this point. But let me turn it over to Pushkal, who can also provide some more, you know, clinical perspective about what we're seeing and how those guidelines are actually progressing.

yes, we start with Togo and then um, unlike Push Girls provider, clinical perspective,

Paul Matteis: Yeah, thanks, Tolga. Thanks, Paul. Look, I think it's really important. This is a, you know, we talk about ATTR cardiomyopathy and the thing here is that it has a clear cause, which is the accumulation of TTR protein in the, you know, misfolded protein in the myocardium. But as it clinically presents, it's a form of heart failure. And 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. And so I think they're well accustomed to actually looking at a variety of factors. And frankly, you have to rely on a variety of factors. There's not any one specific indicator.

Yeah. Uh, so Paul, I mean look based on our research and and obviously published data clinical evidence suggests that anywhere between 3 to half the patients on stabilizer at 1 Point progresses. Uh, and what we see that number is continuing to grow and then obviously the, the only, uh, real option in terms of mechanistically and the clinical evidence suggests that, you know, it would be on utra at this point. But uh, let me turn it over to to pushkar who can also provide some more, you know, uh, clinical uh, perspective about what we're seeing and how those guidelines are actually. Uh, progressing. Yeah, thanks to. Thanks Paul. Uh, look, I think it's really important. This is a, you know, we talked about attr cardiomyopathy in, in the, the thing here is that its it has a clear cause which is accumulation of TTR protein in the, in the, you know, misfolded protein in The myocardium, but as a clinically presents, it's a form of heart, failure, and doctors have been treating heart failure for decades. And they know how

Paul Matteis: An easy way to think about that is when you look at the European guidelines that were put out a couple of years ago, and they had a variety of considerations, including biomarkers, echocardiographic factors, exercise tolerance, patients' ability to lie flat at night, different things, pedal edema. And so 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 they present, their symptoms, their signs, and other factors in terms of determining how patients will progress.

Paul Matteis: You know, we do think that over time, more and more guidelines in this category will develop over time, but our expectation is that there will not be some one single factor that clinicians or payers will be able to rely upon to say specifically that a patient's progressing, but we'll rather have to look at the constellation of factors that affect a patient's symptomatology.

How to modify drug therapy for patients. They might add diuretics or sglt2s or other agents uh as patients are progressing. And so I think they're well accustomed to actually looking at a variety of factors and frankly you have to rely on a variety of factors. There's not any 1 specific indicator. Um, an easy way to think about that is when you look at the European guidelines that were put out a couple of years ago, and they had a variety of considerations, including biomarkers echocardiographic factors. Exercise tolerance, patients, ability to lie flat at night, um, different things, pedal edema. And so I think what we're seeing. Um, now in these early days is that doctors are applying that General clinical rubric of looking at a patient, how they present their symptoms, their signs and other factors in terms of determining how how patients will progress, you know, we do think that over time more and more guidelines in this category will develop over time. Uh but our expectation is that there will not be some 1 single factor that clinicians or payers will.

Yvonne Greenstreet: Thanks, Pushkal.

Paul Matteis: Thank you.

Yvonne Greenstreet: We'll take the next question. Take the next question.

Thanks for call. Thank you. We'll take the next question. We'll take the next question.

Operator: Thank you. The next question comes from Luca Izzi with RBC Capital. Please go ahead.

Yvonne Greenstreet: Oh, great. Thanks so much for taking my question. Congrats on this strong quarter. Maybe if I can circle back on the TTR guide, maybe Jeff, like, if I assume $200 million in revenue for the year from Petro, that essentially means $550 to $650 million in revenues for the next two quarters for Ambutra, which is actually not dissimilar from the $492 million that you already printed today. I guess what I'm trying to say is it feels to me 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, UK, Japan, et cetera. But we'd love if you have a different view here. So any thoughts there? Much appreciated. Thanks so much.

Thank you. The next question comes from Luca Easy with RBC Capital. Please go ahead.

Oh great, thanks so much for taking my question. Congrats on the strong quarter. Maybe if I can Circle back on the TTR guys, maybe Jeff like.

If I assumed $200 million in revenue for the year from Pro, that essentially means $550 million to $650 million in revenues for the next two quarters from Buitre, which is actually not similar to the $4.092 billion that you already printed today.

And guess what I'm trying to say. It feels to me that this guy 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, UK Japan, Etc. But would love if you have a different view here, so, um, any thoughts there? Much appreciate it. Thanks so much.

Jeff Poulton: Yeah, Luca, I appreciate the question. I'll again reiterate what I said to the earlier question here. We're guiding to a billion dollars of TTR growth year over year. Last year, PN grew $300 and is growing at about 30 percent. So that gets you to $600 plus for cardiomyopathy. We just did $150 million in Q2. You know, I think we feel very confident about that. If you look at historically the guidance that we've given and the consistency with which we either met that or exceeded that, you know, that's how we feel about the guidance that we're providing. I don't know if it's conservative, you know, at this point. Honestly, we're one quarter into this, and certainly we look forward to coming back at Q3 and reassessing things.

Yeah, Luca appreciate the the question. I'll I'll again reiterate what I what I said to the to the earlier question here, we're we're guiding to a billion dollars of of TTR growth.

Year-over-year last year, PN grew, 300 and is growing at about 30%, so that that gets you to a 600 plus for for cardiomyopathy. We just did 150 million in in Q2. Uh, you know, I think we feel very confident about that. If you look at historically the, you know, guidance that we've given and and the consistency with with, with we've either,

Yvonne Greenstreet: Thank you.

Paul Matteis: Thanks so much.

Metadata or exceeded that, you know, that's how we feel about the, the guidance that we're providing, I don't know if it's conservative. Uh, you know, at this point honestly, we're 1 quarter into this. And certainly we we look forward to to coming back at Q3 and and reassessing things. Thank you.

Yvonne Greenstreet: Next question.

Thanks so much.

Operator: Thank you. The next question comes from Ellie Merle with UBS. Thank you.

Next question, thank you.

The next question comes from Ellie. Merl with you UBS, thank you.

Tazeen Ahmad: Hey, guys, congratulations on the quarter, and thanks so much for taking the question. Just to drill into this a little bit more, how should we think about the rate of new patient starts per quarter from here? $1,400 is obviously a phenomenal number. Should we think of this cadence of new starts continuing in 3Q and beyond? And second, in terms of the mix, you mentioned now seeing more balanced starts mixed between the new patients, newly diagnosed, and the progressors, whereas initially it was more of the progressors. How do you expect this mix to evolve over time from here? Thank you.

To expect this mix to evolve over time from here. Thank you.

Yvonne Greenstreet: Okay, so I think two questions, so you can probably take both of them, Tolga?

Pushkal Garg: Yeah, so thank you. Look, at the end of the day, we're very pleased, obviously, with $1,400 paid patients within a three-month period. And as you had highlighted, while the patient starts initially was more predominantly stabilizer progressors very quickly, that switched into a balanced and broad patient uptake. We certainly expect to see both of those categories continue to grow. Now, in terms of the specific numbers, we kind of went out of our way to be able to provide that clarity. As you know, Ambutra is a single SKU, so we can't really isolate CM patients with precision. So we're going to continue to provide additional color, and those numbers, obviously, we expect to go up. But in terms of the specific precision about how it's going to go quarter after quarter, it's not going to be, we're not going to be able to report that.

Okay, so I think 2 questions that you can probably take both of them told them. Yeah so uh thank you look at the end of the day we're very pleased obviously with uh 1400 paid patients uh within a, a 3 month period. And as you had highlighted um while while the um

The the patient starts initially was more predominantly. Uh stabilizer program is very quickly that switched into a balance and Broad uh patient uptake. We certainly expect to see both of those categories continue to grow. Now in terms of the specific numbers, we kind of go went on our way to be able to provide that uh Clarity uh is you know amb is a single uh SKU so we can really isolate uh CM Pace the patients with Precision. So we're going to uh continue to provide additional color and those numbers obviously we expect to to go up uh but but in terms of the specific Precision about how it's going to go quarter off to quarter is not going to be uh we're not going to be able to report that.

Yvonne Greenstreet: Thank you. Next question.

Thank you.

Next question.

Operator: Thank you. The next question comes from Costas Bullaries with BMO Capital Market. Please go ahead.

Thank you. The next question comes from, Costas bulerias with BMO Capital Market, please go ahead.

Paul Matteis: Thanks for taking our question and 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 Ambutra treatment in cardiomyopathy. Can you comment on how common those requirements are across the different plans and what percentage of patients do these plans cover? Thank you.

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

Thank you for taking our question, and congrats on the impressive launch. I have 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 Ambrx treatment in cardiomyopathy. Can you comment on how common those requirements are across the different plans, and what percentage of patients do these plans cover? Thank you.

Pushkal Garg: You got it, Yvonne. I think the broad headline is really, 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 as well as commercial payers have published policies. And in those policies, Ambutra in broad strokes are covered first-line. Now, we also had actually flagged that there could be some commercial payers that could actually provide a step edit in their policies. We're seeing that, but it is incredibly minimal. It's in the single digits, and frankly, we don't anticipate that to continue to grow as most other large commercial payers have already written policies that cover Ambutra as first-line.

Yeah, I know. That's a great question. I mean I just start off by saying that as we look at this you know access is just not the barrier and we're seeing bone coverage across, you know, Medicare FIFA service Medicare advances commercial payers and the vast majority of patients are getting first line with with no steps exactly what, uh, we predicted coming into the launch and what we've been, you know, working on for uh, you know, quite some time I think it really speaks to the ambulatory profile, as well as the, um, nature of the disease. Um, but told that you might want to, I mean, I don't know that perspective, you you got it. Ivonne.

Pushkal Garg: Now, when it comes to step edits, we have the tools and the support systems that enable us to actually, frankly, help patients and providers to circumvent that or make sure that it's managed very, very carefully. This is, we've actually built over the years a quiet engine driving real impact in terms of our patient services, and I'm really pleased to see how we've been able to pull through on all three segments. Patients are already getting on treatment, whether it's fee-for-service, whether it's Medicare Advantage, also on commercial payers, including those plans that have actually step edit. So we don't see that for now, and obviously, we're going to close the monitor and continue to engage with payers to make sure that these patients that deal with the severe condition are getting a seamless access with our medicines.

I think the broad headline is really as predicted. Uh we're not facing uh a significant headwind in terms of of payer coverage. What I'm really pleased to see was within a short 3-month period majority of both Medicare Advantage as well as commercial payers, have published policies and in those policies on mutra in in Broad Strokes are covered first line. Now, we also had actually flagged that there could be some uh, commercial payers that could actually provide uh, a separate it, uh, in their policies. We're seeing that. But it is incredibly minimal. Uh, it's in the single digits, and frankly, we don't anticipate that to, to, to continue to grow as most other large commercial payers have already written policies that covers on with tra first line. Now, when it comes to to, to step edits, uh, we have the tools and, uh, and the support system.

Systems that enables us to actually, frankly, to help patients and, and providers to circumvent that or or make sure that they it's managed. Uh, very very carefully. This is, uh, it's a we we've actually built over the years, a quiet engine uh, driving real impact in terms of our patient services. And I'm really pleased to see how we've been able to pull through uh, on all. All 3 segments, uh, patients are already getting on treatment, whether it's C4 service, whether it's Medicare.

Yvonne Greenstreet: Yeah, that's great to hear. And one data point that really struck me was actually just the minimal use we're seeing of our Quick Start program. We introduced a Quick Start program with all of our launches to make sure that we can, you know, help patients with access, and we're just not seeing much use, which I think, again, is very encouraging. Next question, please.

Advantage also on Commercial payers, including those plans that have actually separated. So we don't see that uh, for now and obviously we're going to close the Monitor and continue to engage with payers to make sure that uh these patients that that deal with the severe condition are getting a seamless access with our with our with our medicines. Yeah, it looks great. So and and 1 data point that, that that, that really struck me was actually just the minimal use. We're seeing of our Quick Start program. We introduced a Quick Start program with with all, with all of our launches to make sure that we can, you know, help patients with access. And we're just not seeing much use which I think again. Um, is very encouraging.

Uh, next question, please.

Operator: Thank you. The next question comes from Gina Wang with Barclays. Please go ahead.

Thank you. The next question comes from Gina white with Barclays. Please go ahead.

Paul Matteis: Thank you for taking my questions. I also wanted to congrats on the outstanding quarter. So maybe, Yvonne, I think you mentioned that the vast majority would be the first-line patient. Is it fair to say that out of 1,400 patients treated so far, would be over 50 percent of patients is a first-line patient? And then out of this 1,400 patients, how many of them receive free drug?

The vast majority will be the first line. Uh, patient is a fair to say that out of a 1,400 patient treated so far, uh will be over. 50% of patient is the first line patient and then out of this 1,400 patient. How many of them receive free drug?

Yvonne Greenstreet: Tolga, you love breaking this down.

Pushkal Garg: Yeah, yeah. Look, Gina, good to hear from you. I think what we had said very thoughtfully, I would say, is our uptake has been broad and balanced. So that included, again, early on, some patients that were actually, you know, progressing on stabilizers. And then what we're seeing is a very, very strong trend of first-line indication. We're in the early innings, and I think the job is to, and we're getting, I would say, our fair share of first-line patients, but the job is not done yet. What we want to make sure is that we continue to this trend and make sure that we continue to educate both patients as well as prescribers on why Ambutra has a compelling product profile to be a first-line patient. So I just wanted to reiterate that.

Yvonne Greenstreet: Yeah, it's really important that we clarify exactly where we are. Jeff, you can?

Paul Matteis: I think she also had a question about the 1,400 patients and how many of them were in the Quick Start program. It was de minimis, right? It was very, very low.

Well, do you love breaking this? Uh, down? Yeah, I uh, that look, look look, uh, Gina good. Good to hear from you. Um, I think what we had said, very uh, thoughtfully I would say is our update has been Broad and balanced. Uh, so that included again, early on, uh, some patients that were actually, uh, you know, progressing on stabilizers. And then, uh, what we're seeing a very, very strong trend of first, line indication, we're in the early Innings and I think the job is to and we're getting, I would say, our fair share of first-time patients, but the the job is not done yet. Uh, what we want to make sure is that we continue to this trend and make sure that we continue to educate both patients as well as uh prescribers and why on router has a compelling product profile to to be a first-time patient. So I just wanted to, uh, reiterate that. Yeah, it's really important that we clarify exactly where we are addressing. I think there was, she also had a question about the 1400 patients and how many of

Pushkal Garg: It was absolutely very minimal.

We're in the Quick Start program. It was the Minimus, right? It was very, very low; it will be very minimal.

Yvonne Greenstreet: Next question.

Next. Next question.

Operator: Thank you. The next question comes from Mike Oath with Morgan Stanley. Please go ahead.

Thank you. The next question comes from Michaels with Morgan Stanley. Please go ahead.

Paul Matteis: Good morning. Thanks for taking the question, and congrats on the strong launch as well. Maybe just to follow up on TTR cardiomyopathy, you highlighted you're getting some nice broad use in the front-line 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 in some of our KOL clinics.

Uh, good morning. Thanks for taking the question and, uh, congrats on the strong launch as well. Uh, maybe just to follow up on uh, TTR cardiomyopathy. You highlighted, you're getting some nice. Uh, broad use in the front line as well as the stabilizer progressor patients, just curious if you started to see any combination use early in the launch.

Yvonne Greenstreet: Yeah, no, that's it.

Paul Matteis: As you've seen it here.

Yvonne Greenstreet: That's it. Yeah, no, thank you. Thank you for that question. Tolga, why don't you take that?

Pushkal Garg: Yeah, look, we certainly do see a very small portion of those patients getting a combination use. We would certainly expect that as tafamidis goes generic over the years to become more prominent. But right now, it's really difficult to be very specific about looking at the specific combination use, but I think in where it's allowed and where access is permissible, we do some utilization of combo.

I know you're not expecting it. Uh, but we've we've picked up uh, some combination use and some of our KO. Yeah, no, that's true. That's, that's a yeah, no. Thank you. Thank you for that. For that question. Talk about it. Why? Why don't you take that? Yeah, look uh, we certainly do, see a very uh, a small portion of those patients getting a a combination used. Uh, we would certainly expect that as uh, to family, this goes generics over the years to, to become, uh, more prominent. But right now, uh, it's really uh,

Be specific to be very specific about looking at the, the specific combination used. But I think uh, in where it's allowed and where access is is is permissible uh we do some, some utilization of combo

Yvonne Greenstreet: Thank you.

Paul Matteis: Thank you.

Yvonne Greenstreet: I think we've got time. We've got time for one last question.

Thank you. Thank you. I think we've got time. We've got time for 1 for 1, last for 1 last question.

Operator: Yes. The next question comes from Ritu Burrell with Titi Cohen. Please go ahead.

Paul Matteis: Hi, guys. Thanks for squeezing me in, and congratulations on the quarter. A question on variants. You guys addressed the mixed phenotype, but in your first-line and first-line access, what trends are you seeing in the V122i variant population? As KOL feedback, at least on my model, suggests I'm underestimating that prevalence by about 6X, but it is a more severe phenotypic presentation. And just a very quick follow-up, and this is probably semantics, but you guys, Tolga, you've mentioned step through and step edits. Are they the same thing as prior authorizations, or do you have a different set of prior authorizations? Thanks.

Yes, the next question comes from Rell with JD Cohen. Please go ahead.

Hi guys. Thanks for squeezing me in and congratulations on the quarter. Um, a quick question on variance. Um, you guys might address the mixed phenotype but in your first line, um, and first line accent what? Um access what trends are you seeing in the V1? 122? I variant population. Um as kol feedback at least on my model has suggested. I'm I'm under estimating that prevalence by about 6X but it is a more severe um phenotypic presentation and just a very quick follow-up and this is probably semantics but you guys told us you've mentioned step through and step edits. Are they the same thing as prior authorizations or do you have a different

Set of Prior authorizations, thanks.

Pushkal Garg: Yeah, so let me take your last part first. The step-edit policies that we've seen, again, it's incredibly small. It's in the single digit, and it's mostly predominantly in the commercial setting. There are no real specific limitations other than patients putting on a stabilizer first, and frankly, there's not even a time limit or duration, and it's really up to the physician if the patient is progressing. So we find these policies relatively easy to manage for the patients. And there are no specific hereditary or V122i indications. And frankly, we're not surprised about that. We have, I think, what we've demonstrated early on with the polyneuropathy hereditary condition, and then later with the broad cardiomyopathy label, is that Ambutra is well-positioned to be a first-line patient for all diagnosed ATTR CM patients. And we're really not seeing that trend.

Pushkal Garg: Now, maybe I'll turn it over to Pushkal if he has any specific commentary on the thrust.

Yeah, so let me take your last part first. Uh, the step edit policies, that we've seen again. It's incredibly uh, small. It's, it's in the single digit and it's mostly, uh, uh, predominantly in the commercial setting it. There are no real specific limitations other than, uh, patience, uh, putting on a stabilizer first. And frankly, there's not even a time limit or duration, and it's really up to the physician if the patient is progressing. So we find these policies relatively easy to manage, uh, for the patients. Um, and there are no specific hereditary or uh, V1, 22i indication. And frankly, we're not surprised about that. We have, I think what we've demonstrated early on with the polar opy, hereditary condition, and then later with the broad cardiomyopathy label is that on wood tray is well, positioned to be a first-time patient. Uh, for all all all uh, diagnosed attr-cm patients, uh, and we're really not seeing that trend.

Paul Matteis: Yeah, I think you said it well. Look, I think, you know, what we've seen in Helios B is that Ambutra works equally well in wild-type patients and in V122i patients. And as Tolga mentioned, this is the one class of drugs that's shown to actually benefit in hereditary patients, which constitutes the wide range of mutations, and we've seen benefits across that. So across, I think, all ranges of severity, whether it's NYHA class 1, 2, 3, whether it's hereditary or wild-type, I think, you know, that's, I think, what really cements our belief that this is really, and what we're hearing from prescribers in terms of the opportunity to treat patients with this drug as a first-line agent.

Yvonne Greenstreet: Thank you. Ritu, I think this brings our call to a close, and I'd just like to, you know, thank everybody for joining us today on this call. Look, our line has continued 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.

I think you you said it? Well look I think you know what we've seen in Helios B is that in butcher Works equally well and wild type patients and in b122. I patients and as toga mentioned uh this is the 1 class of drugs. That's shown actually a benefit in hereditary patients, which constitutes the wide range of mutations and we've seen benefits across that. So across, I think all ranges of severity, whether it's nyha class, 1 2 3, whether it's hereditary or wild type. Uh, I think, you know, that's I think what really cements our belief, that this is really and, and what we're hearing from prescribers in terms of the opportunity to treat patients, uh, with this drug as a first-line agent to

Thank, thank you.

Number 2, I think this this brings our call to close and I'd just like to, you know, thank everybody for for joining us today on this call. Um,

Look online was continuing to execute strongly across all areas of the business. And, and we're very much looking forward to providing you further updates as we progress throughout the year,

Thanks a lot.

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

Ladies and gentlemen.

This concludes today's conference call. Thank you for your participation. You may now disconnect