Alnylam Pharmaceuticals Inc (ALNY) 2022 Q2 法說會逐字稿

Hello. Thank you for standing by, and welcome to the Alnylam Pharmaceuticals Second Quarter 2022 Earnings Conference Call. (Operator Instructions) Please be advised that today's conference may be recorded.

I would now like to hand the conference over to the company. Please go head.

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Akshay Vaishnaw, President; and Jeff Poulton, Chief Financial Officer.

For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events.

During today's call, as outlined on Slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress, Akshay will review recent clinical and preclinical updates, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call for your questions.

Please note, we are in a quiet period with regard to the upcoming of APOLLO-B results and therefore, will not be addressing any questions on that matter.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans 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 quarterly report on file with the SEC. In addition, any filing statements represent our views only as of the date of this recording and should not be relied upon as representing our views of any subsequent date. We specifically disclaim any obligation to update such statements.

With that, I'd like to turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. We're very pleased with our second quarter results and the progress we've made towards our near- and long-term goals. Commercially, we achieved 14% product sales growth compared with the first quarter as we continue to drive a steady increase in patients on therapy across our portfolio of marketed products, including ONPATTRO, GIVLAARI and OXLUMO. And we're excited to have expanded that portfolio with the recent U.S. approval and positive opinion for AMVUTTRA for hATTR amyloidosis patients with polyneuropathy. And we're looking forward to executing on AMVUTTRA launch and the potential for further global expansion.

5 RNAi therapeutics from our organic platform approved in under 4 years is truly remarkable.

In addition to our growing commercial portfolio, we continue to make great strides with our RNAi therapeutic pipeline programs. This includes our progress in establishing our TTR franchise, where we are tracking towards plan and are on the cusp of seeing results from the APOLLO-B Phase III study of patisiran in patients with ATTR amyloidosis with cardiomyopathy. We've announced today that we expect to share top line data within the next 3 weeks with full data to be released thereafter at a medical congress.

In addition to these highly anticipated results,we also continued to make exciting progress across numerous other programs within our pipeline. We have and continue to innovate upon what we believe to be one of the most productive, organic and self-sustainable platforms in biotech, which has the potential to deliver meaningful value-creating therapies for rare and prevalent diseases in the years to come.

To that end, there are many recent and upcoming milestones that underscore the breadth and scope of our pipeline. For cemdisiran, we reported positive top line Phase II results in patients with IgA nephropathy, a kidney disease with significant unmet medical needs. We're now working with Regeneron to finalize Phase III plans and potentially initiate a program by the end of this year.

We were also excited to see positive data presented by Sanofi from the Phase III ATLAS-PPX study of fitusiran in patients with hemophilia, which met its primary endpoint and demonstrated that fitusiran prophylaxis significantly reduced bleeding episodes compared to prior factor or bypassing agent prophylaxis.

Looking through to the end of this year, we expect to have updates across our pipeline, including the potential for top line results from early studies of ALN-HSD in NASH, ALN-XDH in gout and ALN-APP in early onset Alzheimer's disease, our first CNS endeavor. Taken together, this all highlights our focus on these 3 key drivers for Alnylam's growth over the next several years.

First is the potential near-term expansion of our TTR franchise opportunity, where we aim to become a global leader in delivering impactful and highly differentiated medicines to patients. The second key growth driver is our expansion beyond rare diseases to prevalent diseases. And the third growth driver for the company comes from our sustainable innovation engine, comprised of new platform advancements; opportunities with extrahepatic delivery; and our ability to find new genetically validated targets, which can drive further pipeline expansion to 2025 and beyond.

We believe all of this positions us well to deliver on our Alnylam P5x25 goals, making Alnylam a top biotech company, developing and commercializing transformative medicines for rare and common diseases for patients around the world driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine, all while life exceptional financial results.

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

Thanks, Yvonne, and good morning, everyone. Q2 was a strong quarter for our commercial portfolio with 14% quarter-over-quarter growth, as Yvonne highlighted. Both excited about the FDA approval and launch of AMVUTTRA in June, and we're encouraged by early promising size of our (inaudible). I'll have more detail to share on that shortly.

As anticipated, we are also experiencing improved market conditions following COVID impact in Q1, as we saw increased promotional activities, improved patient flows, healthy demand and improved patient compliance across our portfolio.

I'll now provide details on the performance of each of our products. We continue to see growth for ONPATTRO, achieving $153 million in global net product revenues in the second quarter, representing a 12% increase compared with the first quarter and 35% growth compared with Q2 '21. At the end of Q2, over 2,400 patients were on commercial ONPATTRO treatment worldwide, up from over 2,200 patients at the end of the first quarter, representing a steady 9% quarterly patient growth.

In the U.S., sales of ONPATTRO increased 14% and versus the first quarter and were primarily impacted by an increase in patients on therapy and improved patient compliance following Q1, which was negatively impacted by COVID. In our international markets, ONPATTRO Q2 product sales increased 10% versus Q1 202, primarily due to an increase in patients on therapy and the timing of orders in distributor and partner markets. Important to note, our global results continue to be challenged by foreign exchange headwinds, with ONPATTRO year-over-year reported growth of 35% being called back 7 percentage points by the strengthening U.S. dollar.

As you are aware, we received U.S. approval for AMVUTTRA at the end of the second quarter, and we're very pleased with the initial launch so far as our teams continue to execute in line with our clients. We received 133 start forms from launch through July 22, and keeping demand generation on track with approximately 1/3 of start forms generated from patients new to Alnylam and 2/3 from switches from ONPATTRO. Over 20% of those start forms came from new prescribers, which we believe is an encouraging early sign of potential market growth.

We hit the ground running, reaching over 61,000 key stakeholders within 48 hours of launch, serving as a catalyst for field engagement. We have also been engaging with health systems and the formulary processes has been started in over 60% of the priority delivery networks.

Further from an access standpoint, our teams have been engaged, and feedback has been posted today. In fact, there is one national policy published with a large national payer covering 24 million lives. The first (inaudible) has also been treated, and we're looking forward to continuing this rollout and updating you further on our Q3 call.

Moving to our ultrarare disease franchise. First, with GIVLAARI. We received $45 million in global net product revenues in the second quarter, representing a 28% increase compared with Q1 '22 and 47% growth versus Q2 '21. At the end of Q2, over 420 patients were on commercial GIVLAARI treatment worldwide, up from over 400 at the end of the first quarter, representing a 5% quarterly patient growth.

In the U.S., sales of GIVLAARI increased 25% versus the first quarter and were primarily a result of the following: A healthy demand growth of 12%, driven by an increase in patients on therapy and improved patient compliance following a soft Q1, primarily impacted by COVID; inventory stocking dynamics, which favorably impacted reported growth by 8%; and a decrease in gross net deductions in the quarter, which favorably impacted reported growth by approximately 5%.

In our international markets, GIVLAARI delivered 34% growth compared with the first quarter, with the growth primarily driven by new patient adds, including a strong launch in the U.K. and favorability in gross-to-net deductions.

Finally, Global GIVLAARI year-over-year reported growth of 47% was also held back by 6 percentage points due to unfavorable foreign exchange rates.

Moving now to our second ultra-rare disease product, OXLUMO. We achieved $15 million in global net product revenues in the second quarter, representing a 2% increase compared with the first quarter. At the end of '22 over 200 patients were on commercial OXLUMO treatment worldwide, up from over 160 at the end of the first quarter, representing 25% quarterly patient growth.

In the U.S., sales of OXLUMO increased 32% versus the first quarter and were primarily impacted by an increase in patient demand as well as inventory stocking dynamics and a decrease in gross-to-net deductions during the quarter. In our international business, despite an increase in patients on therapy during the quarter, Q2 OXLUMO sales decreased by 15% compared with Q1, primarily due to an increase in gross-to-net deductions during the quarter and the timing of orders in our distributor and partner markets.

On a year-over-year basis, global OXLUMO sales decreased 9% despite an approximately doubling of patients on therapy. The decrease was primarily due to a higher proportion of patients on the monthly loading dose portion of their treatment, as well as lower net pricing in our international markets in Q2 '22.

Additionally, as with ONPATTRO and GIVLAARI, changes in foreign exchange rates also negatively impacted OXLUMO Q2 '22 results, with reported year-over-year growth of minus 9%, held back by 5 percentage points due to the strengthening U.S. dollar.

In conclusion, we are pleased with the growth in revenues and patient demand achieved in Q2 and look forward to our Q3 results, which will include the first full quarter of AMVUTTRA launch.

With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress. Akshay?

Thanks, Tolga, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we are advancing 2 clinical stage product candidates, patisiran and vutrisiran. While patisiran, or ONPATTRO, is currently approved in multiple markets around the world, to treat the polyneuropathy associated with hereditary ATTR amyloidosis, we're committed to expanding the product's label for the treatment of cardiomyopathy in both Hereditary and wild-type ATTR amyloidosis patients. To this end, we are conducting the APOLLO-B Phase III study. And as announced this morning, we expect to report top line results within the next 3 weeks.

We're also advancing vutrisiran, which is delivered by a quarterly subcutaneous injection and was recently approved in the U.S. under the brand name AMVUTTRA, to treat the polyneuropathy of hATTR amyloidosis in addition to receiving a positive CHMP opinion in the EU. Here too, we're committed to expanding the label for the treatment of cardiomyopathy in hereditary and wild-type patients. Patisiran is also in development for Stargardt disease.

HELIOS-A evaluating vutrisiran in hATTR amyloidosis patients with polyneuropathy form the basis for our regulatory submissions and recent U.S. approval of AMVUTTRA. In April 2021, we presented positive results from the study at the AAN meeting, which showed the study met its primary and secondary end points at 9 months. We continue to pool results from the study and recently presented new 18-month results from exploratory cardiac endpoints at the ESC HF meeting. These findings show that in a variety of predefined -- shows that in a predefined cardiac subpopulation of hATTR amyloidosis patients with polyneuropathy, treatment with vutrisiran was associated with improvements in exploratory cardiac endpoints relative to external placebo, including levels of NT-proBNP and a trend towards improvement in echocardiographic parameters.

These findings in the cardiac population were consistent with the previously reported results in the mITT population. Additionally, in a planned cohort of patients from the MITT population, vutrisiran treatment reduced cardiac uptake of technetium on scintigraphy imaginging relative to baseline in the majority of assessable patients, including those with Perugini greater than and equal to 2 at baseline, suggesting that patients highest degree of cardiac amyloid burden may recognize benefit from RNAi therapeutics. Vutrisiran also continued to demonstrate an encouraging safety and tolerability profile.

As mentioned, this is just the start for vutrisiran as is also being evaluated in the HELIOS-B Phase III study for the treatment of patients with AT amyloidosis with mild cardiomyopathy, including both Hereditary and wild-type ATTR amyloidosis. HELIOS-B, which is fully enrolled, has a 30-month endpoint of all-cause mortality and CV events with many patients followed up to 36 months. And we expect the full results in early 2024.

The study design includes the potential for an interim analysis, and we will consider this following results from APOLLO-B and engagement with regulatory authorities.

In addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. Notable highlights in the second quarter was an announcement of positive top line results from our Phase II study of cemdisiran, an investigational RNAi therapeutics targeting the C5 component -- the complement pathway, and is in development in collaboration with Regeneron for the treatment of IgA nephropathy, or IgAN.

In the study, at week 32, treatment with cemdisiran resulted in a 37% mean reduction from baseline in the 24-hour urine protein to creatinine ratio relative to placebo. This was the primary endpoint of the study and an important prognostic marker of disease progression. The results of secondary endpoints were also consistent with the therapeutic benefit of cemdisiran in IgAN. There were no significant drug-related safety signals and we believe these collective efficacy and safety data support continued clinical development of cemdisiran monotherapy in patients with IgAN. We now look forward to gaining alignment with Regeneron to finalize plans for Phase III and hope to initiate a program by the end of this year pending regulatory agency feedback.

Moving on, a key growth driver for Alnylam in the years to come will be our organic product engine driving sustainable innovation. The second quarter featured a new highlights in this regard. In Nature Biotechnology, we published data from preclinical research on the delivery of lipophilic sRNA conjugates to extrahepatic tissues, including the CNS. These data provide early evidence of a potential role for 2'-O-hexadecyl C16 conjugated siRNA in treating diseases of the CNS, eye and lung.

We're further exploring the potential for lipid conjugate to help the delivery to other organs.

In another publication in Nature Communications this time, we published research findings by identifying mutations in the Inhibin EG associated with protection against abdominal obesity and metabolic syndrome, a condition impacting more than 20% of adults worldwide. Finding support the potential of inhibit E, which was previously referred to as gene x to be evaluated as a novel target treatment for the treatment of cardiometabolic disease since inhibit e loss of function improves waist-to-hip ratio and is associated with an improved lipid profile.

We plan to pursue a development candidate for inhibit e and x gene product Activin E, leveraging our IKARIA platform.

As you can appreciate, we have an incredibly broad and innovative platform that continues to advance and these are just a few recent highlights. We look forward to updating you on a number of these programs in the coming months.

With that, let me now turn the call over to Jeff to review our financials and upcoming milestones. Jeff.

Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q2 2022 financial results and an update to our full year guidance.

Starting with a summary of our P&L results for Q2 2022. Total product revenues for the quarter were $214 million or 33% growth versus Q2 2021. It's also worth noting that year-over-year growth in combined product revenues was held back by approximately 7% and due to the foreign exchange impact of a strengthening U.S. dollar, which reached a 20-year high recently, and given that approximately 50% of our product revenues are generated via sales in international markets.

Net revenue from collaborations for the second quarter was approximately $9 million, representing an 85% decrease compared with Q2 2021 and primarily due to a reduction in revenue from our Regeneron collaboration, which is subject to quarter-to-quarter variability depending on a variety of factors, including the level of work completed during the quarter, which is reimbursed by Regeneron. We do expect an increase in collaboration revenue and royalties in the second half of the year, primarily driven by increased activity across our Regeneron programs as well as from an increase associated with Leqvio royalties and sales milestones as Novartis' U.S. launch progresses.

Our non-GAAP R&D expenses increased 15% in the second quarter compared to the same period in 2021, primarily due to increased spend on early development activities and increased headcount to support the growth of our pipeline.

Our non-GAAP SG&A expenses increased 19% in the second quarter compared to the same period in 2021, primarily due to increased headcount and other expenses to support the growth of our commercial portfolio.

Our non-GAAP operating loss for Q2 2022 was $161 million, representing a $47 million higher loss compared with Q2 2021, which was primarily impacted by the reduction in collaboration revenue during the quarter.

Finally, we ended the quarter with cash, cash equivalents and marketable securities of $2.1 billion compared to $2.4 billion at the end of 2021. We continue to believe our current cash balance is sufficient to bridge to a self-sustainable financial profile.

Now I'd like to turn to our full year 2022 financial guidance. Following the strength of our operating results in Q2, we are reiterating the financial guidance we provided on our Q1 results call in April.

Starting with net product revenues. We anticipate combined net product revenues for our 4 commercialized products will be between $870 million and $930 million. However, given the continued strengthening of the U.S. dollar since we issued our guidance in April and the fact that approximately 50% of our global product sales are generated in international markets, we are currently trending towards the lower half of our $870 million to $930 million guidance range.

Our guidance for net revenue from collaborations and royalties is a range between $175 million and $225 million. And our guidance for combined non-GAAP R&D and SG&A expenses is a range between $1.390 billion and $1.450 billion.

Let me now turn from financials and discuss some key goals and upcoming milestones on deck through the end of 2022. We'll continue executing on our global commercialization of ONPATTRO, GIVLAARI and OXLUMO as well as the launch of AMVUTTRA.

Next, our TTR franchise will have important updates. With patisiran, top line results from the APOLLO Phase III study are expected within the next 3 weeks. With vutrisiran, we plan to report results on a biannual dose regimen and initiate a Phase III study in Stargardt disease, both in late 2022. Lastly, we plan to file an IND and initiate a Phase I study for ALN-TTRsc04 in healthy volunteers by the end of the year.

In our mid-stage portfolio, we are looking forward to milestones that include: Completion of enrollment in the Phase II study of lumasiran in patients with recurrent renal stones by year-end; completion of enrollment in our Phase II KARDIA-2 study of zilebesiran at or around year-end; and results from the Phase II study of ALN-HBV02 in combination to monoclonal antibody, VIR-3434, which our partners at -- we are expect to report later this year.

Wrapping up, we have a few early stage readouts coming as well. These include top line results from Part B of the Phase I study of ALN-HSD in patients with NASH expected in mid-2022. Preliminary top line results from the Phase I study of ALN-APP in patients with early onset Alzheimer's disease expected in late 2022. And preliminary top line results from the Phase I study of ALN-XDH in patients with gout also expected for late 2022.

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. (Operator Instructions) As a reminder, we are in a quiet period with regard to our APOLLO-B study and will not be responding to questions on that topic.

(Operator Instructions) Our first question comes from Paul Matteis with Stifel.

Just on vutrisiran, just a 2-part question, the commercial dynamics. I guess one, can you talk about the initial prescribing for patients new to a silencer? And how much of that is coming from cardiologists?

And then just curious on the economics of in-office dosing for vutrisiran. And how does that compare for a physician versus ONPATTRO as an infusion?

Thanks, Paul, for that question. I'd just like to start off by saying that we really are delighted to have (inaudible) therapeutic provides for the 4 years with AMVUTTRA. It's great to have a additional option for patients here. And as Tolga said on the call, the initial signs of launch are very, very encouraging.

But Tolga, I'd like to hand over this question to you. So it's around is the commercial dynamics with respect to the initial launch. How much from cardiology? And then any commentary on the economics with respect to ONPATTRO compared to patisiran from a physician perspective. Thanks, Tolga.

Absolutely. Paul, this is really an exciting time. We launched the product and reporting the information that's available to us within the 5 weeks -- in that 5 weeks, we were able to received over 130 start forms. And of those, 1/3 of those were actually naive patients. They are new to Alnylam. And that's actually a very good robust number.

It's early for us, and these are only start forms. Patients need to go through the system and make sure that they actually get the product in. But it's an early sign, 1/3 as new -- naive patient dynamic is very encouraging.

In terms of the economics, essentially, the product is Part B, therefore it is still a buy and bill. And those patients that are going to be looking at a very similar dynamics as we see in ONPATTRO.

What we're also excited about is frankly, 20% of our prescribers in this very short period our new prescribers of TTR and new prescribers of AMVUTTRA. So that's also a very exciting dynamic that I like to underline.

(Operator Instructions) Our next question comes from David Lebowitz with Citi.

First on vitrusiran. This is not with respect to any details on the data. I just want to -- as far as presentation, I know historically in the past, for top line releases, you put out P values. I just want to confirm that we would likely see P value certainly on the primary endpoint, but also the secondary endpoints as well.

And one little add-on here. As far as pricing goes, could you at least give us a perspective on what type of shift we might see once cardiomyopathy gets added to the label?

Great. David, thanks for that question. I think the first one, Akshay, is for you.

Yes. Just clarifying, David, that you said vutrisiran, but I suspect you meant patisiran with respect to the APOLLO-B results, am I correct?

Indeed, of course.

Yes. And you're right, we'll present top line results in the form of a PR with P values as we test the primary and secondaries in a hierarchical order. So that's as much as I can say on that at the present time.

Thanks, Akshay. Maybe Tolga, you could take the second question with respect to pricing. And any shift as we hopefully enter the cardiomyopathy.

Well, we're excited about the portfolio of serving Cardiomyopathy patients. But as you can appreciate, it's a little too soon for us to share any information because it's a little too soon. But we will obviously update appropriately when we make those decisions.

Our next question comes from Salveen Richter with Goldman Sachs.

Could you just speak to the dynamics with regard to switching and combination that's playing out between your TTR franchise and Pfizer's tafamidis?

I think Tolga, that question straight over to you.

Yes. I mean, switching-wise, obviously in the U.S., we're indicators for polyneuropathy and tafamidis indicated for cardiomyopathy. Therefore, we do not see any switching dynamics.

In terms of concomitant views, we see similar rates that we've seen in the past. It's about anywhere between 15% to 20%. And what we see, what we're excited about switching dynamics is in ex U.S., particularly in Europe and Japan, where both of those products and available the polyneuropathy, we've seen a significant source of our business is really built by the switches.

Obviously, we continue to add new naive patients both in Europe and Japan. But early on, we've seen a good strong dynamic, which alludes to us that the physicians believe that there is actually probably more opportunity to use ONPATTRO as a silencer in the earlier part of the disease to get adequate treatment.

Our next question comes from Ritu Baral with Cowen.

I was hoping for -- just to follow-up to Paul and Salveen. Just a little more detail on the new patients. Tolga, you mentioned the prescribers, but are you seeing less severe patients? Is -- are you seeing more mixed phenotype patients? And does this sort of bolus imply that there's some other sort of warehoused patients to work through as we look at the new patient question for AMVUTTRA.

Yes, it's a great question. Thank you. As I indicated before, it's little too soon for us to really give a lot of specific dynamics. It's an area where we're obviously closely monitoring. What we're encouraged about is the early signs indicate that we do see some a little younger patients. But again, it's difficult to generalize at this point. We're only 5 weeks into the launch.

What we're, again, excited about is the fact that we are seeing a broad range of patients quickly either switched or naive to being treated. Part of it, I'm sure, is going to be a little bit of the warehousing. But it's important to highlight that in Q1, we had a great, strong, robust ONPATTRO growth. What we originally thought was probably the patients -- physicians will be waiting and warehousing some of those patients for AMVUTTRA. That didn't exactly happen. But I'm certain that part of the uptake that we see in the first 5 weeks might be contributed to that warehousing dynamic.

Yes. Thanks, Tolga. It really does look at the introduction of AMVUTTRA helping us -- will help us grow the overall TTR franchise going forward, which I think is very encouraging.

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

Mine's on HELIOS-B. So you've reiterated your confidence that the early 2024 target for data readout is something that you feel confident about. I'm just wondering, is there at all a scenario in which you would opt to extend the observation period though to allow for a higher chance of seeing a significant improvement in mortality benefit?

Maybe I'll start by reiterating our confidence in an early 2024 data readout from HELIOS-B. And Akshay, any perspectives on how we might think about that study going forward?

Yes. We've revisited the study designs and thoroughly assessed how robust is the study? Will it -- is it structured and powered a way to help us meet the primary endpoint and the secondary endpoints? And we are comfortable with the study design. And so the study designs are altered. The only thing we'll consider is the interim analysis, of course, in due course.

And the other thing I would say, by the way, is that as you -- patients come in over a long period in the study, and in a large study like that. So many of them will have gone to 36 months, and that provides additional coverage in terms of the robustness of the study. So we're comfortable and we'd reiterate data early '24, and looking forward to positive results.

Our next question comes from Joseph Stringer with Needham.

Our question was for AMVUTTRA. I know it's early days. But how do you anticipate the time from start form to getting patients on drug? How do you think this compares relative to your experience with ONPATTRO?

Yes, that's a great question, Joey. And clearly, with AMVUTTRA being our second product in the TTR franchise, we're really building on what's a very robust commercial operation that we have under Tolga's leadership.

But Tolga, perhaps you could talk a little bit about that. Sorry to have that all speaking.

Thanks, Yvonne.

Obviously, we're very well positioned to be able to maximize the opportunity for AMVUTTRA given our experiences in a ONPATTRO and AMVUTTRA's really attractive profile, being subcutaneous injectable every 3 months.

In regards to the -- how the timing is going to work is, look, I mean, at the end of the day, we do have the right capabilities, right patient services, benefit verification and so forth already in place within this category. And what we've so far done is working very closely with not only with major national and regional payers, but also with integrated delivery networks and other health providers to make sure that formularies are in place.

Given the fact that we actually also set the price, despite its very attractive profile, at parity with ONPATTRO, we have not so far seen any significant headwinds. Nevertheless, like any new product, it does take time for the health care system to absorb and make sure the P&T committees and so forth are in place to get the product group.

We're very pleased with the early signs of what we've so far done and how the health care systems are reacting. But I'm sure we're going to see some delays early on and eventually get to a place where I think it's going to be a payment in ONPATTRO, even maybe a little faster approval dynamic. But it's a little too soon for us to share where we are now with that.

Thanks, Tolga. I think good progress thus far. We're very pleased.

Our next question comes from Maury Raycroft with Jefferies.

I was going to ask a question on zilebesiran for hypertension. Just wondering if you can elaborate on steps you've taken to streamline the protocol to speed up enrollment. And what the status is on that?

Yes. Just for everybody, as a reminder. We unfortunately experienced some delays with our KARDIA-1 studies of zilebesiran with primarily due to the fact that you selected sites in the Ukraine. And obviously, with the ongoing war, and you noticed the sites were unable to move forward. We've expanded our site footprint and are very pleased with progress that far. We also took the opportunity to just refine the protocol to make it an easier study to execute for physicians.

I don't know, Akshay, if you want to add any.

No, I think you covered it, Yvonne. The only other thing more specifically on the streamlining notably, Maury, in these protocols, one tries to capture is more scientific information as one can. But given the needs of the program, we were able to move some of the assessment that don't take anything away from the core issue of and hypertensive effects and safety and so forth and yet maintain 2 large robust cohorts, which will be easier to approve, one in monotherapy and one in culmination therapy. So between the site expansion and these change the controls, we are optimistic about readouts next year.

Great. And just to add that we're expecting to complete enrollment in KARDIA-2 at the end of this year. So that's right. Looking to that.

Our next question comes from Luca Issi with RBC Capital.

Great. Maybe one on TTR polyneuropathy, how are you thinking about the competitive landscape here? Obviously, Yvonne's have reported successful Phase III and they seem very confident they can compete commercially given the AstraZeneca global footprint? I know we don't have the full data at this point, but how are you thinking about implications of that launch for your franchise?

Thanks,. Look, I think there was a primary question about how we believe that we're going to compete in the TTR PN space, particularly with potential new competitors coming on stream with AstraZeneca.

Yes. Thank you, Yvonne. Look, first of all, we are always excited to bring new modes of medication, different alternative treatments to patients because -- there's a lot of wood to chop when it comes to TTR-PN prevalence and what the patients that are currently being treated. We anticipate the prevalence number's around 25,000 to 30,000 patients worldwide, and we are a very small fraction of that, that we've been able to deliver. So what we've seen in similar categories, a good expansion of diagnosis and treatment rates going on.

In regards to where we are. Look, at the end of the day, we have been able to actually establish ourselves in the last 4 years as the major driver, including in Europe and Japan, against tafamidis that is also being promoted by an important company. One of the important, I think, drivers of our growth is going to be, obviously, the making AMVUTTRA available worldwide, and we are well positioned to do that. We have Europe and Japan, a geographic footprint and available in over 50 markets through other partners and distributors.

Given the fact that we're going to be a year ahead already of that competition, and plus, again, a very attractive profile that AMVUTTRA offers for the patients with a subcutaneous injectable over 3 months, and soon with 6 months, if those trials work, I -- we really like our chances in terms of how we're well positioned to be able to make this product available and continue to be a leader, as a portfolio leader.

But again, I just want to reiterate, having said that, there are going to be products available, and that's good for patients, and we're excited about that.

Thanks. Tolga. Akshay, do you want to say anything about the profile?

Yes. No, I'll just add to what Tolga said, which makes a lot of sense. But in terms of the data themselves, I think we've got a very comprehensive base (inaudible) Patisiran around AMVUTTRA in hATTR. Of course, the primary showing improvement in neuropathy, which is deciding. And in terms of the other end points or the secondaries, it's not just the exploratory cardiac and with the impact on the heart and the point, but still notable particularly with the new observation of reducing technician scan uptake. And that's very exciting for patients and physicians.

And so along with the convenience Q-3 and then hopefully soon Q-6 monthly dosing, this is a very differentiated product in a market that Tolga explained, we've been leaders in.

And ultimately, I will add that whilst patients need good options in this space. We'll want to see the full data package associated with first, recalling that the first time around with (inaudible), and there were some safety issues of note, including renal effects, injection site reactions, platelet effects. And I'm sure they and everybody is keen to know that the safety is good. So let's see. But I think we're off to a great start with AMVUTTRA.

Our next question comes from Gary Nachman with BMO.

Okay. Great. So back to AMVUTTRA and the start forms and the 2/3 switches from ONPATTRO. What's the profile of initial patients that are switching from ONPATTRO? Are you getting a sense if it's more patient- or physician-driven? Do they stay on ONPATTRO up until they get AMVUTTRA? If that takes some time? And how do you expect that split between new and switches to shift over the next couple of quarters?

Tolga I think that one's do lots of interest in the AMVUTTRA early dynamics.

Again, I mean, look, at the end of the day, what we're really excited about is AMVUTTRA's profile is giving the stability and physicians the ability to be able to actually treat -- diagnose and treat more patients. And what we've so far seen the early signs is, in terms of initiations, it's both when it comes to switches as well as naive patients. We have a good, robust patient services and our patients have been informed about the availability, and some of those patients proactively reached out to their physicians.

What we've also seen is, as I indicated earlier, a good, new prescribers coming into the treatment of this condition and excited to be actually providing this medicine to those patients that probably were on the fence, given that it's an infusion with ONPATTRO's earlier profile. And AMVUTTRA tends to offer a very convenient option with great safety and efficacy data.

Therefore, we do, what we so far seen in the 133 start forms is a good, broad range of both patient prescriber base as well as patient demographics that ranges across younger as well as more traditional demographics.

Our next question comes from the Anupam Rama with JPMorgan.

Maybe following on the last question on AMVUTTRA on switching dynamics. What does your market research suggest on the time frame in which you would expect switching to kind of peak, or where most patients that are going to switch, have made the switch? I think that's what we're trying to understand, many of us.

Anupam, that's a great question, and thank you for putting it forward very precisely. So I think Tolga, that's a specific question here around what our market research is setting up, right, about the time to sort of peak switching.

What we're really interested at this point is really to make sure that the overall category is growing. So our focus is actually right now, is really to make sure that we are bringing as many as new patients as possible given this new option. The switch is what we believe is going to play out a little more organically, and we'll obviously update The Street for about a year about the switch and naive patients.

What we expect that to organically happen is most patients will end up with on what's regiments profile. However, we also know that in rare diseases, there are patients who are pleased with their existing treatment. Some of these patients never had any new treatment before AMVUTTRA -- sorry, ONPATTRO was available. So we do expect some patients to remain on therapy.

But in similar dynamics that we've seen in other categories, patients tend to gravitate towards a more better option, which we believe AMVUTTRA is. But I also wanted to take the opportunity to remind everyone that we're going to be updating on the start form dynamics for 2 to 3 quarters.

Just one other comment, Anupam. From a modeling perspective, it doesn't matter if you're on ONPATTRO or AMVUTTRA. They're the same price, same value per patient per year. So just a reminder on that point.

Great point.

Our next question comes from Tom Lu with Barclays.

Actually, can you hear me?

Yes, we can hear you.

This is Gena Wang from Barclays. So I have a question, but maybe follow-up the start form 133 start form. You said 34 new to Alnylam. Just if you can give a little bit more clarity, what percentage of these are the switcher from TEGSEDI versus truly naive patients?

And then quickly on HELIOS-B. I just wanted to, is a maintenance check. Last time, we discussed the tafamidis dropping rate maintained at a low single digit. Any change in the dropping rate?

Okay. Let's start with Tolga. So the answer to your question on that. And then to Akshay on the HELIOS-B question.

We really appreciate the excitement around the strong launch of AMVUTTRA, yet it's only 5 weeks of data. So we wanted to make sure that we all recognize that the of the data we're providing is as good as we possibly can at this point. Those 34 new patients are naive to us.

And in terms of your own modeling, one should also remember that the TEGSEDI is -- remains a very small portion of the overall category. So we wouldn't necessarily index our naive patients just only on switches from an alternative treatment one.

Good opportunity to grow exactly new patients coming into AMVUTTRA fit.

So Akshay, HELIOS-B has dropped in rates?

Yes. Thanks, Gena. I can reiterate that the drop in rates remain well within expectations. And I think as discussed before, we obviously had put in a buffer in the sample size to account for tap drop. We're well within those estimates. We're comfortable with it, this time, Gena.

Our next question comes from Ellie Merle with UBS.

I guess not an ATTR question, but on the pipeline for lumasiran and recurrent renal stones, I guess maybe just with the Phase III finishing enrolling here this year, thinking about Phase II data next year. I mean, how should we think about what you're looking to see here? It's obviously a much broader population.

I guess, what could we learn in terms of the relationship between oxalate reduction and reduction in stone formation in this broader population, and your confidence in the biology there?

And then, I guess, thinking about sort of the regulatory pathway from there, like what a potential Phase III could look like? And any types of like patient segmentation in terms of accessing this much larger population.

Akshay, I'm not sure if you caught all of that. I think it's around the recurring stone study, what we're looking to see from the Phase II data, how we're thinking about oxalate reduction. And then I think plans for moving forward that study.

Yes. So thanks for the question. So the LUMA recurrence stone formation study is ongoing. It's also a very large population globally, numbering in the millions probably. And what we want to see is a reduction in oxalate. Now in the PH1 population, of course, we saw very substantial reduction in oxalate. They have an enzymatic defect in the liver and the targeting of GO1 leads to 70-plus percent reduction in oxalate.

This is a hypothesis we're testing. One of the interesting things is we may not need to achieve levels like that, to see a reduction in stone events. And so let's look at the data as it comes out next year and see. And I say that because the important thing is, once oxalates becomes at saturating levels, in the urine, that's when stone formation occurs. So you may not need to take it all the way back down to normal, you might just need to get it out of that super-saturation range by some relatively modest margin to prevent some formation.

And so a lot more work to do here, and we'll update you as we get data. But this is a very exciting opportunity with an approved drug that looks very safe in the PH1 population. And that just reminds me to say of course safety will also be important to see in the RFS population. But we're optimistic with what we've seen so far with LUMA in PH1.

Thanks, Akshay. And another program in our pipeline which is orientated around patients with much more common to diseases, I think an exciting potential development for Alnylam.

Our next question comes from Myles Minter with William Blair.

Just on cemdisiran and the IgA nephropathy data. Can you sort of discuss where you see like the complement inhibitor methodology sitting in the lines of therapy and I guess, how it relates to the data that we've seen from the endothelin receptor-1 antagonist.

And I guess, is that a key consideration for Regeneron and how they would potentially design a pivotal study and the types of patients that you would enroll in that pivotal study?

So quite a few questions there. I mean, really just, I think, start off by reiterating that we were really pleased with the Phase II results with a patients with IgA nephropathy, very common condition and 37% reduction in growth scenario. I think this is great. And I think -- and it's another potential Phase III program for Alnylam. So we're very pleased to be working with our partners Regeneron moving forward the next steps.

Akshay, I think there were a number of questions in there that I think are much more specific around how we're thinking about that.

Yes. We're very excited about the Phase II results with a 37% reduction in urine proteinuria. Busy working with Regeneron right now, we take the lead in this program in the, I guess, (inaudible). And we're sort of very busily looking forward to engaging regulatory authorities and hopefully kicking off the study by the year-end.

The specifics of where complement or anticomplement approach is set. The interesting thing is the fundamental underlying pathology here, IgA immune complex is that deposit is the males and activate complement. That activated complement then damages the glomerular basement membrane, and proteinuria results.

An additional aspect of the disease, I don't think anyone really understands how the, is hyperfiltration is the kidney and so blood flow dynamics change through the glomerulus.

So we have the opportunity here more formally to impact 2 key pathogenic factors. With anticomplement approaches, we can get at the fundamental underlying immunopathology, and we've seen the preliminary results we've shared. So this will have a foundational role, I believe, in the future, in what will end up being a polypharmacy situation where there will be anti-inflammatory like anticomplement. Cemdisiran would be a great fit for that. It could be a once a month, once every 3-month type injection.

And then in addition to that, things that alter blood flow, endothelin antagonists ACE inhibitors, ARBs, et cetera. And so you'll see drugs from both classes, the antihypertensive type drug and anti-complement drugs being combined. And we'll see if steroids will also become part of the picture, but there's more work to do there, although they are rather general nonspecific agents held potential side effects.

And just to add up, of course, these favorable results open up the potential for cemdisiran get the need of patients with other glomerular diseases. So we're enthusiastic moving forward there.

One more question. I think we have one more question before we close. Last question, please.

Our last question comes from Olivia Brayer with Cantor.

I know you're in a quiet period with respect to APOLLO-B, but I wanted to ask if there are any monitoring requirements after patients reach that 12-month mark that are built in this study?

And then I've got a follow-up on sequencing for mixed phenotype patients. Is there anything you can do to improve access for patients that could move on to ONPATTRO and AMVUTTRA after tafamidis?

So I just want to say, you pointed out, we are in a quiet period, so we're not going to be taking any questions on APOLLO-B.

But I didn't actually quite catch your second question. I think it was something to do with AMVUTTRA, but I didn't hear it probably. Could you repeat the question, second -- the second part of the question?

Yes, sure. It's just about mixed phenotype patients, right? And whether there's anything you guys can do to improve payer access there for patients that could sequence on to ONPATTRO and AMVUTTRA after tafamidis?

You mean polyneuropathy mixed phenotype patients?

Yes.

Yes. I mean, look, we certainly have the right capabilities to support those patients. The fact that we've been able to position this at parity pricing we'll certainly believe help increase access. So far, we haven't really heard any headwind around the access piece. But we are indicated for polyneuropathy, and in the U.S., tafamidis is indicated for cardiomyopathy. So in terms of providing any bridge strategy for Access would not be something we would consider.

Like any of our new patients, we have great support of benefit verification and patient access support which those patients will certainly be eligible if they go through our patient services.

Thanks, Tolga. Okay. So thank you, everyone, for joining us on this call. We're very happy with the progress that we've made in the second quarter and first half of 2022. We've delivered strong commercial results. We've advanced our diversify programs and development. And we've got a number of exciting catalysts on deck in the coming months. We look forward to updating you along the way while we continue to deliver on our near and long term goals.

Thanks, everyone, and have a great day.

Goodbye. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.