Earnings call transcript: Alnylam’s Q2 2025 results boost stock by 18%

Alnylam Pharmaceuticals Inc., a biotechnology company with a market capitalization of $52.3 billion, reported its second-quarter 2025 earnings, revealing a significant earnings per share (EPS) surprise and robust revenue growth, which led to an 18% surge in its stock price. The company posted an EPS of $0.32, vastly exceeding the forecasted -$0.59. Revenue reached $773.69 million, surpassing expectations by 20.29%. This performance is coupled with a positive market reaction, as seen in the pre-market price increase of 4.4%. According to InvestingPro, the company maintains an impressive gross profit margin of 86%.

Key Takeaways

• Alnylam’s Q2 2025 EPS of $0.32 beat the forecast of -$0.59.
• Revenue of $773.69 million exceeded expectations by 20.29%.
• Stock price surged by 18% following the earnings announcement.
• Raised 2025 total net product revenue guidance to $2.65-$2.80 billion.
• Strong performance in the TTR franchise with 77% year-over-year growth.

Company Performance

Alnylam Pharmaceuticals demonstrated strong performance in Q2 2025, driven by significant growth in its TTR franchise and rare disease products. The company reported a 64% year-over-year increase in total product revenues, reaching $672 million. The TTR franchise alone contributed $544 million, marking a 77% growth compared to the previous year. This growth aligns with the company’s strategic focus on expanding its presence in the ATTR cardiomyopathy market.

Financial Highlights

• Revenue: $773.69 million, up 20.29% from forecast
• Earnings per share: $0.32, beating forecast by $0.91
• Total product revenues: $672 million, 64% year-over-year growth
• TTR franchise revenues: $544 million, 77% year-over-year growth

Earnings vs. Forecast

Alnylam’s actual EPS of $0.32 significantly outperformed the forecast of -$0.59, resulting in a surprise of -154.24%. The revenue of $773.69 million also exceeded the forecast of $643.2 million, indicating a robust quarter for the company. This performance marks a notable improvement compared to previous quarters and highlights Alnylam’s effective execution of its strategic initiatives.

Market Reaction

Following the earnings announcement, Alnylam’s stock price surged by 18%, with pre-market trading showing a 4.4% increase. The stock reached a price of $354.75, moving closer to its 52-week high of $402.43. InvestingPro analysis indicates the stock is currently trading above its Fair Value, with a strong year-to-date return of 44.41%. This positive market reaction reflects investor confidence in the company’s strong financial performance and future growth prospects. For detailed valuation insights and 12 additional ProTips, visit InvestingPro.

Outlook & Guidance

Alnylam raised its 2025 total net product revenue guidance to a range of $2.65-$2.80 billion, reflecting a 27% increase. The company also expects TTR franchise revenues to be between $2.175 and $2.275 billion. These revisions underscore Alnylam’s optimistic outlook for continued growth, supported by international launches and new product developments. InvestingPro data shows five analysts have revised their earnings upward for the upcoming period, with analyst consensus indicating a "Buy" recommendation and price targets ranging from $212 to $500.

Executive Commentary

"We’re firing on all cylinders, and we’re swiftly establishing ourselves as a top-tier biotech company," stated Yvonne Greenstreet, CEO. This sentiment was echoed by Tolga, Chief Commercial Officer, who emphasized the importance of early intervention in treatment: "Physicians want to hit the disease early and not hold back their best therapy for later." Pushkar Garg, Chief R&D Officer, added, "We continue to generate evidence to further support the safe and effective use of ambutra."

Risks and Challenges

• Market Saturation: The growing competition in the biotech sector could impact market share.
• Regulatory Hurdles: Delays in product approvals could affect growth timelines.
• Economic Conditions: Macroeconomic pressures may influence healthcare spending.
• Supply Chain Issues: Potential disruptions could affect product availability.
• Currency Fluctuations: Exchange rate volatility may impact international revenues.

Q&A

During the earnings call, analysts inquired about the pricing strategy for Ambutra, with the company confirming a mid-single-digit net price reduction. Questions also focused on the broad patient uptake and minimal step edit policies from payers, highlighting the company’s effective market access strategies.

Full transcript - Alnylam Pharmaceuticals Inc (ALNY) Q2 2025:

Conference Operator: Good morning, ladies and gentlemen, and welcome to the Alnylam Q2 twenty twenty five Conference Call. At this time, all lines are in listen only mode. Following the presentation, we will conduct a question and answer session. This call is being recorded on Thursday, 07/31/2025. I would now like to turn the conference over to the company.

Please go ahead.

Christina Kinch, Chief Corporate Communications Officer, Alnylam: Good morning. I’m Christina Kinch, Chief Corporate Communications Officer at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer Bhuva Tangular, Chief Commercial Officer Pushpull Garg, Chief Research and Development Officer and Jeff Bolton, 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.

Tova will provide an update on our global commercial progress. Pushkar 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’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? Thanks, Christine, and thank

Yvonne Greenstreet, Chief Executive Officer, Alnylam: you everyone for joining the call today. As shown in our q two 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 multibillion dollar opportunities within our pipeline and an r and d engine set up to deliver sustainable innovation and value creation. To that end, I’d like to acknowledge the recent promotion of Pushkal Garg to chief research and development officer. Pushkal has been instrumental in progressing our pipeline. And in this role, Pushkal will oversee an integrated r and 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 and ATTR Centimeters 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. 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 $544,000,000, 77% year over year growth, with growth largely attributable to the Ambutra Centimeters launch. This was just the first full quarter of the ATTR Centimeters launch, and as of June 30, approximately a thousand four hundred cardiomyopathy patients were receiving Amphutra, 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 Centimeters and are expected to begin to contribute to the Centimeters launch in the second half of the year. Kudos to our team for delivering these impressive early results.

In addition to these commercial results, we continue to advance our leading pipeline of RNAi therapeutics. We initiated the Triton Centimeters phase three study of nucrusiran, 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 Centimeters. We also just shared encouraging phase one multidose data for mibelsiran in Alzheimer’s disease and kicked off a phase one study for ALN four three two four in type two diabetes earlier in the quarter. And with regard to financial performance, we’re reporting our strongest quarter to date as a company with $672,000,000 in total net product revenues or 64% growth year over year. As a result, we’ve increased our total net product revenues guidance for 2025 from a range of 2.05 to 2,250,000,000.00 to a revised range of 2,650,000,000.00 to $2,800,000,000, representing an increase of $575,000,000 or 27% at the midpoint, underscoring our confidence in the ATTR Centimeters launch and our other commercial products in the balance of the year.

So zooming out from the success of q two, 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

Tolga, Chief Commercial Officer, Alnylam: performance. Tolga? 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 $672,000,000 in net product revenues, representing 64% year over year and 43% quarter over quarter growth. As you will see in a moment, The U. S. TTR performance was the major driver of growth given the ATTR Centimeters launch for omburtamab. 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. Our GIVLAARI and OXLUMO teams stayed focused and delivered $128,000,000 in combined Q2 sales, up 24% versus last year. Growth was largely demand driven with a tailwind from favorable GIVLAARI gross to net adjustments in The U. S.

Now turning our attention to TTR franchise, where we delivered $544,000,000 in global net product revenues during the quarter, representing a 77% increase compared with the 2024 and a robust 51% increase compared with the 2025. In The U. S, combined Q2 sales of ONPATTRO and Ambutra rose 80%, up roughly $170,000,000 from Q1, driven primarily by Ambutra’s ATTR Centimeters launch. We closed the quarter with approximately fourteen hundred cardiomyopathy patients on therapy, contributing an estimated $150,000,000 in revenue. This performance was fueled by strong execution and faster than anticipated access across payers and providers.

Regarding the year over year dynamics, The U. S. TTR franchise grew 125% compared with the 2024, primarily driven by the significant increase in demand from the ATTR Centimeters launch that I just highlighted. Turning to our international markets. We delivered 18% year over year growth, driven by continued strength in our hATTR PM business, which remains a solid growth engine.

Importantly, we have yet to recognize any ATTR Centimeters 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 U. S. TTR revenue dynamics, where the franchise achieved $383,000,000 in the second quarter, representing a very robust 80% quarter over quarter growth. While we don’t have the ability to report revenue by indication, the underlying trend is clear.

From Q1 twenty twenty four through Q1 twenty twenty five, The U. S. TTR franchise delivered steady growth of around $15,000,000 to $20,000,000 on average every quarter. In Q2 twenty twenty five, we saw a pronounced step change indicating an estimated $150,000,000 contribution from ATTR cardiomyopathy. I will now provide some additional launch metrics to further contextualize Omvutra’s launch performance in ATTR cardiomyopathy.

Our launch began on 03/20/2025 and Q2 marked our first full quarter post approval. It is still early and there is more work to do, but we’re very encouraged by the strong momentum we’re seeing. As we’ve described on prior calls, we’ve been focused on three key enablers around The U. S. Launch of Almutra 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. As we’ve shared on prior calls, there are approximately 170 priority health systems through which approximately eighty percent 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 ATTR Centimeters patients present. What’s more, nearly all of the priority health systems have already begun treating patients with Almutra for ATTR cardiomyopathy. This together with the broad network of more than 2,000 alternate sites of care has allowed us to achieve our aspiration.

Roughly ninety percent of patients in The U. S. Are able to receive Omotrex 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. In addition, patients are getting first line access to Ambutra across all payer segments. Coverage is now confirmed by payers covering the majority of U. S. Patient lives, inclusive of Medicare fee for service, Medicare Advantage and commercial, which can therefore confirm that the large majority of patients have access to Omutra 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 programs, quite simply because patients are not experiencing delays in coverage. We’re also seeing patient initiations flowing through all payer segments, Medicare fee for service, Medicare Advantage and commercial. These access dynamics are consistent with what we’ve long seen in HATTR PM and we’re encouraged to see them replicated in ATTR Centimeters. 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 second quarter, approximately fourteen hundred ATTR Centimeters patients had initiated treatments. 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 amongst stabilizer progressors. However, within just three short months, utilization has become relatively balanced between first line, new starts and stabilizer progresses.

We’re seeing steady growth across both sources of business. And we have a clear focus on making Amutra 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 Almutra prescriber base has tripled quarter over quarter.

This reflects growing awareness and confidence in amputers 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 route 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 Centimeters 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 RNAi therapeutics, nucirisiran. 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 also maintaining stable growth in the hATTR polyneuropathy business both in The U. S. And The United States. These drivers underpin our increased revenue guidance and reinforce our conviction in significant revenue growth going forward. We’re just getting started and we remain focused on disciplined execution, anchored in patient and customer centricity and delivering long term innovation driven growth.

I’ll now turn it over to Pushkar to share more about our work to advance the science in ATTR and beyond. Pushkar?

Pushkar Garg, Chief Research and Development Officer, Alnylam: 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 VANVUTRA’s rapid knockdown mechanism of action that are emerging from HELIOS B.

In the left column, you can see the benefits on NT proBNP and troponin I, important clinical biomarkers of cardiac stress and injury respectively. Not only do you see a 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 thirty three percent to thirty six percent. 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. Further to our leadership and commitment to innovation in ATTR amyloidosis, we announced in June the initiation of the TRITON Centimeters Phase three study for nucresiran, which may offer greater knockdown, greater efficacy and greater convenience for patients with ATTR cardiomyopathy. As a reminder, TRITON Centimeters 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 twenty four months after the last patient is enrolled. If successful, we target launching NuCrisiran in ATTR cardiomyopathy around 02/1930. 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. In parallel, we have the goal to bring NUCRISERAN to patients as quickly as possible and see an opportunity to do so in hereditary ATTR PM. Though we are not yet prepared to discuss full details for TRITON PM, we remain on track to initiate a pivotal study for the polyneuropathy indication by the 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 one study of mevelsiran in patients with early onset Alzheimer’s disease. Recall previously that we observed market reductions in A beta-forty and A beta-forty two, the pathogenic proteins implicated in cerebral amyloid angiopathy and Alzheimer’s disease respectively with single doses of mavelsiran. 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 mirvelsiran in the ongoing CAPRICORN Phase II study in CAA as well as the Phase II study in Alzheimer’s that we expect to start by the end of the year. As Yvonne mentioned earlier, a key element of our journey towards becoming a top tier biotech company is growth through innovation. Across what is one of the most robust pipelines in the industry, we are making great progress advancing promising programs across a range of therapeutic areas with multiple potential blockbuster opportunities.

In addition to some of the highlights we’ve already discussed, in Q2, we also kicked off a Phase I trial for ALN-four thousand three hundred twenty four targeting GRB14 and insulin sensitizer for the treatment potential treatment of type two diabetes. We also remain on track to start a Phase II study of ALN-six thousand four hundred 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 Bolton, Chief Financial Officer, Alnylam: Jeff? Thanks, Pushkal, and good morning, everyone. I’m pleased to be presenting a summary of Alnylam’s Q2 twenty twenty five financial results and discussing our full year upgraded guidance. Let’s begin with a summary of our P and L results for the second quarter compared with prior year. Total product revenues for the quarter were $672,000,000 or 64% growth versus 2024, driven by 77% growth in our TTR franchise, with particularly strong performance in The U.

S. Market, primarily related to an increase in demand associated with the launch of Vimbutra and ATTR cardiomyopathy. Collaboration revenue for the quarter was $61,000,000 representing a $166,000,000 decrease when compared with last year. The decrease was primarily driven by the modification of our semdesiran collaboration agreement with Regeneron, which resulted in approximately $185,000,000 of revenue in Q2 twenty twenty four. As a reminder, this amendment granted Regeneron an exclusive license to semdesiran monotherapy.

Royalty revenue for the quarter was $40,000,000 representing an 18,000,000 increase compared with last year, driven by higher LECVIO sales. Gross margin on product sales was 79% for the quarter compared with 84% in the 2024. The decrease in margin was primarily driven by increased royalties on INVUTRA 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 and D expenses of $274,000,000 increased 11%, primarily due to increases in start up clinical trial expenses associated with our cardiovascular outcomes trial for zolvesiran and the TRITON Centimeters Phase III study for nucresiran.

Our non GAAP SG and A expenses of $261,000,000 increased 26% compared to last year, primarily driven by increased headcount and other investments in support of the Ambutra ATTR cardiomyopathy launch in The U. S. Our non GAAP operating income for the quarter was $95,000,000 representing a $42,000,000 decrease compared with last year, driven primarily by the recognition of collaboration revenue related to the modification of our Regeneron agreement in Q2 twenty twenty four, 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 $2,900,000,000 compared to $2,700,000,000 as of 12/31/2024, with the increase primarily driven by cash from operations and net proceeds from the issuance of common stock in connection with employee stock option exercises.

Now I’d like to turn to our financial guidance for 2025, where we are substantially increasing our net product revenue guidance, driven by the strong early launch performance of VANBUTRA and ATTR cardiomyopathy, with specific details as follows: We are increasing our net product revenue guidance from a range of 2,050,000,000.00 to $2,250,000,000 to a revised range of 2,650,000,000.00 to $2,800,000,000 representing a $575,000,000 or 27% increase from the midpoint of the prior guidance to the midpoint of the updated guidance. The combined full year growth compared to 2024 is a 66% increase at the midpoint of the guidance range. On a franchise level, the guidance is broken down as follows. We are modestly increasing the midpoint of our total rare franchise guidance by raising the bottom end of our prior guidance range by $25,000,000 and leaving the top end of our guidance unchanged, resulting in revised rare product sales guidance of $475,000,000 to $525,000,000 We are materially increasing our total TTR guidance range from 1,600,000,000.0 to $1,725,000,000 to a revised range of 2,175,000,000.000 to $2,275,000,000 representing a 34% increase or more than $550,000,000 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 market our TTR therapies for hATTR polyneuropathy, our TTR franchise delivered approximately $300,000,000 in revenue growth compared with 2023. In 2025, with the ATTR franchise now including cardiomyopathy sales following The U. S. Launch in Q2, the midpoint of our revised 2025 total TTR sales guidance of 2,230,000,000 represents an approximate $1,000,000,000 increase from 2024 total TTR sales of $1,200,000,000 And now my last comment on our upgraded sales guidance, which now assumes foreign exchange rates as of June 30 for the balance of the year, resulting in approximately $60,000,000 of our $575,000,000 guidance increase being attributed to changes in FX from our original guidance, which utilized December 31 FX rates. The remainder of our financial guidance, including collaboration and royalty revenue, combined non GAAP R and D and SG and A expenses and non GAAP operating income remains unchanged.

Let me now turn from financials and discuss some key goals and upcoming 2025 milestones. In the 2025, we expect to achieve the following: initiate the Phase III Cbot of zolbecerin in hypertension Note that we also announced today that we’ll present CARDI-three Phase II results at the European Society of Cardiology Congress later this summer. Initiate the TRITON PN Phase III study of nucresiran and hATTR PN and initiate Phase II studies for myvelsiran in Alzheimer’s disease and AL6400 in a bleeding disorder. Let me now turn it back to Christine to coordinate our Q and A session. Christine?

Christina Kinch, Chief Corporate Communications Officer, Alnylam: 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.

Conference Operator: Thank you. Ladies and gentlemen, we will now begin the question and answer Your first question comes from Richter Salvi with Goldman Sachs. Please go ahead.

Christina Kinch, Chief Corporate Communications Officer, Alnylam: Good morning. Thanks for taking my question and congratulations here on the quarter. Could you give some details here in 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 and help us understand from here what the what the field force is most focused on. Thank you.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Thanks, Sabine. I 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 PDSB is really resonating, you know, with physicians. You know, the rapid knockdown of TTR, all cause mortality improvements, infrequent subcutaneous administration, 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 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 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 stabilizer progressing patients because when you bring in a new therapy and, you know, the patients who’ve been progressing on stabilizers, it’s not surprising that, you know, physicians are are looking for an orthogonal treatment for these patients. But but we’re now achieving a really healthy share of first line patients. So we have a a good mix of a first line stabilizer progresses, and what we’re going to be doing is really, consolidating and building on the foundation, of this very early picture.

Torgi, do you wanna add a couple of comments?

Tolga, Chief Commercial Officer, Alnylam: Actually, pretty much covered everything. Mhmm. 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.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Thanks, Soda. Next question.

Conference Operator: Thank you. The next question comes from Tazeen Ahmad with Bank of America. Please go ahead. Hi. Good morning.

Thanks for taking my question. I just wanted to get a sense on how you’re thinking about net price for Ambutra and gross to net moving forward.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Yeah. No. Thanks for that question. Jeff, perhaps you’d like to start off answering that, and if there are any additional perspective. Tolga and I can can follow on from you.

Jeff Bolton, Chief Financial Officer, Alnylam: Yeah. Just a reminder of what we said back on the approval call in March. We said that we expected that we would reduce net price modestly and gradually over time, 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.

Tolga, Chief Commercial Officer, Alnylam: Okay. Yes. 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 to net is going to be as Jeff highlighted, will evolve over time.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Thanks. Thanks, Jeff. It’s all gone. Next question?

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

Speaker 6: 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 second quarter. And could you also please clarify to what extent did stocking contribute to the growth of US Ambulatory revenue in the second quarter?

Yvonne Greenstreet, Chief Executive Officer, Alnylam: So that’s a that’s a a great question. Look, you know, think, Togo has touched on this. You know, we’ve we’ve really demonstrated very solid commercial execution. And and that means that we’ve seen a little bit of, you know, faster progress than we expected, particularly around health 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 progresses.

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 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 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 Ambutra deliver continued sustainable growth, but we’ll be bringing new Creosiran forward as well as Prushkal highlighted, which which gives us the potential to deliver franchise growth out into the twenty forties.

Jeff Bolton, Chief Financial Officer, Alnylam: I’ll comment, on the second part of the question, which was about the inventory. I think the headline for the quarter is, again, in The US, Tolga, in his prepared remarks highlighted the $170,000,000 in growth in the TTR franchise in The U. S. Q2 versus Q1. Far and away the biggest driver of that was the cardiomyopathy demand, fourteen hundred patients on therapy, 150,000,000 in cardiomyopathy revenue for the quarter is what we’re estimating.

On the inventory side, we did see a $25,000,000 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 twenty days, which is at about the midpoint of the agreements that we’ve got in place with our distributors. 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 twelve week moving average of demand. And so it was demand that really drove the increase in inventory and the channel in the quarter, which is again a high quality increase in channel stocking in the quarter. Now on the gross to 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 to net side, a couple of things. One is that we had an increase associated with the Part D rebate that we’re paying like 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 twenty 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, Chief Executive Officer, Alnylam: Thanks, Jeff. I think a very important question and I think you’ve clarified that for our investors. Thank you. Next question, please.

Conference Operator: Thank you. The next question comes from Jessica Fye with JPMorgan. Please go ahead.

Speaker 7: 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 just reaffirm that the new guidance is not somehow aggressive?

Thank you.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Okay. So two parts to that question. Maybe, Talgo, if if you start with the first part, then, Jeff, you can follow on from that.

Tolga, Chief Commercial Officer, Alnylam: 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 Ivan indicated, let me also provide a little additional color. As expected, we initially saw uptake concentrated patients who had progressed on stabilizers. And these are often sicker patients, physicians actually 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 $500,000,000 uptick from where we were, is about a month into the quarter, we began seeing a very healthy and accelerating trend in first line use, just as we had positioned from the outset. And frankly, makes a lot of sense.

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 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’re 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 Evrutra as the first line treatment of choice, supported not only by our approved label, but also by growing evidence as Pushkar highlighted with new imaging data, emerging cardiac biomarker trends that suggests Amlutra may even help reverse disease progression. 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 reflect that.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Yeah. Look. I think I just want to emphasize that it’s it’s early days yet. We’re only we’ve only just achieved our our first full 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 achieve.

We’re gonna be focusing our team on continued execution. And as we progress, we will, you know, continue to update and and share our perspectives. But

Jeff Bolton, Chief Financial Officer, Alnylam: Yeah. Maybe just a just a little bit more context on on on the guidance. Again, you look at the 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 $1,000,000,000 right, is what I highlighted. Last year, the PN franchise grew 300,000,000 versus 23,000,000 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 PN this year, that would imply $600,000,000 plus from cardiomyopathy.

We just did 150,000,000 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.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Thanks, Jeff.

Conference Operator: Next question? Thank you. The next question comes from Paul Matteis with Stifel. Please go ahead.

Speaker 6: 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

Jeff Bolton, Chief Financial Officer, Alnylam: in the market, do you have

Speaker 6: 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 Invutra based on the clinical criteria that are being implemented? Thanks so much.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Yes. So we’ll start with Talgo and then, unlike Pushkar to provide a clinical perspective.

Tolga, Chief Commercial Officer, Alnylam: Yes. 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 what 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 a Butra at this point. But let me turn it over to Pushkar who can also provide some more clinical perspective about what we’re seeing and how those guidelines are actually progressing.

Pushkar Garg, Chief Research and Development Officer, Alnylam: Yeah, thanks Tolkien. Thanks Paul. Look, I think it’s really important. We talked about ATTR cardiomyopathy and the thing here is that it has a clear cause, which is accumulation of TTR protein in the 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. Frankly, you have to rely on a variety of factors. There’s not any one specific indicator.

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, patient’s 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. 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 rather have to look at the constellation of factors that affect the patient’s symptomatology.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Thanks, Pascal. Thank you. We’ll take the next question. Thank

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

Speaker 8: Great. Thanks so much for taking my question. Congrats on the strong quarter. Maybe if I can circle back on the TTR guide, maybe, Jeff, like if I assume $200,000,000 in revenue for the year from Patro, that essentially means 550 to $650,000,000 in revenues for the next two quarter for Butra, which is actually not dissimilar from the $492,000,000 that you already printed today. I guess what I’m trying to say, it feels to me that this guide has still a good degree of conservatism in it, especially given that you’re gonna start selling this drug in international markets like Brazil, Europe, UK, Japan, etcetera.

But would love if you have a different view here. So any thoughts there, much appreciated. Thanks so much.

Jeff Bolton, Chief Financial Officer, Alnylam: Yeah. Luca, I 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 300,000,000 and is growing at about 30%.

So that gets you to 600,000,000 plus for cardiomyopathy. We just did $150,000,000 in Q2. 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’ve either met that or exceeded that, that’s how we feel about the guidance that we’re providing. I don’t know if it’s conservative at this point.

Honestly, we’re one quarter into this. And certainly, we look forward to coming back at Q3 and reassessing things.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Thank you.

Speaker 9: Thanks so much.

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

Christina Kinch, Chief Corporate Communications Officer, Alnylam0: 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? Fourteen hundred 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 mix between the new patient 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.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Okay. So I think two questions, you can probably take both of them, Saldan.

Tolga, Chief Commercial Officer, Alnylam: 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 progresses very quickly that switch 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 our way to be able to provide that clarity. As you know, Ambutra is a single SKU, so we can’t really isolate CMP 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 is not going to be we’re not going to be able to report that.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Thank you.

Speaker 7: Next question.

Conference Operator: Thank you. The next question comes from Kostas Bouillaris with BMO Capital Markets. Please go ahead.

Speaker 9: 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 power 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, Chief Executive Officer, Alnylam: Yeah. No. 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 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 ambusha profile as well as the nature of the disease. But, Tolbert, you might want to You add another

Tolga, Chief Commercial Officer, Alnylam: got it, Ivan. I think the broad headline is really, as predicted, we’re not facing significant headwind in terms of payer coverage. What I’m really pleased to see was within a short three month period, majority of both Medicare Advantage as well as commercial payers have published policies. And in those policies, Almutra 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 separate 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 covers Almuthra’s first line. Now when it comes to STEP edits, we have the tools and the support systems that enables us to actually frankly to 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 separated. 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 that deal with the severe condition are getting a seamless access with our with our with our medicines.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Yeah. That looks great, Tal. And and one data point that that that that really struck me was actually just the minimal use we’re seeing of our quick start program. And we introduced the 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, is very encouraging. Next question, please.

Conference Operator: Thank you. The next question comes from Gena Wang with Barclays. Please go ahead. Thank you for taking my questions. I also wanted to congrats on the outstanding quarter.

So maybe, Yvonne, I think that you mentioned that the vast majority will be the first line patient. Is it fair to say that out of fourteen hundred patients treated so far, be over fifty percent of patient is a first line patient? And then out of this fourteen hundred patient, how many of them receive free drug?

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Toby, you love breaking this down.

Tolga, Chief Commercial Officer, Alnylam: 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 progressing on stabilizers. And then 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 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 why Albuterol has a compelling product profile to to be a first line patient. So I just wanted to reiterate that.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Yeah. It’s really important that we clarify exactly where we are. Jeff, I think

Jeff Bolton, Chief Financial Officer, Alnylam: She also had a question about the 1,400 patients and how many of them were in the quick start program. It was it was de minimis. Right? Was very, very low. It will be very minimal.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Next question.

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

Christina Kinch, Chief Corporate Communications Officer, Alnylam1: Good morning. Thanks for taking the question and congrats on the strong launch as well. Maybe just a follow-up on TTR cardiomyopathy. You highlighted you’re getting some nice broad use in the frontline as well as the stabilizer progressor patients. Just curious if you started to see any combination use early in the launch.

I know you’re not expecting it, but we’ve picked up some combination use in some of our KOL

Yvonne Greenstreet, Chief Executive Officer, Alnylam: calls as you’ve in Yeah. No. Thank you. Thank you for that question. Togo, why don’t you take that?

Tolga, Chief Commercial Officer, Alnylam: 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 generics over the years to become more prominent. But right now it’s really the specific 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.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Thank you. I think we’ve got time for one last question.

Conference Operator: Yes. The next question comes from Ritu Baral with TD Cowen. Please go ahead. Hi, guys. Thanks for squeezing me in and congratulations on the quarter.

A quick question on variance. You guys addressed the mixed phenotype, but in your first line and first line accent, what access, what trends are you seeing in the v one twenty two I variant population? As KOL feedback, at least on my model, has suggested I’m I’m underestimating that prevalence by about six x, but it is a more severe phenotypic presentation. And just a very quick follow-up. This is probably semantics, you guys, Toga, 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.

Tolga, Chief Commercial Officer, Alnylam: 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 no 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 indication. And frankly, we’re not surprised about that. We have, I think, while we’ve demonstrated early on with the polyneuropathy hereditary condition and then later with the broad cardiomyopathy label is that Albuterol is well positioned to be a first line patient for all diagnosed ATTR Centimeters patients.

And we’re really not seeing that trend. Now maybe I’ll turn it over to Pushkar if he has any specific commentary on the trial. I think

Pushkar Garg, Chief Research and Development Officer, Alnylam: you said it well. Look, think what we’ve seen in HELIOS B is that Kymbutra 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 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 one, two, three, whether it’s hereditary or wild type, think 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 to Ritu.

Yvonne Greenstreet, Chief Executive Officer, Alnylam: Thanks. Thank you, Ritu. I think this this brings our call to a close, and I just like to, you know, thank everybody for for joining us today on this call. Look. Online has continued 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.

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

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