Alnylam Pharmaceuticals Inc

NASDAQ:ALNY

Earnings Call Transcript 2023-Q1

[Operator]

Thank you for standing by, and welcome to the Alnylam Pharmaceuticals First Quarter 2023 Financial Results Conference Call. As a reminder, today's conference call is being recorded.

I would now like to turn the conference over to the company. Please go ahead.

[Christine Lindenboom, executive]

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 Jeffrey Poulton, Chief Financial Officer. Also in the room and available for Q&A is Pushkal Garg, our Chief Medical Officer.

For those of you participating via conference call, the 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 2, Yvonne will offer some introductory remarks and provide general context. Tolga will provide an update on our global commercial progress. Akshay 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 for 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 reports on file with the SEC. In addition, any forward-looking statements represent our views only 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 will turn the call over to Yvonne. Yvonne?

[Yvonne Greenstreet, executive]

Thanks, Christine, and thank you, everyone, for joining the call today. 2023 is off to a great start with AMVUTTRA launch continuing with its strong growth with Q1 delivering 48% growth in total product sales compared to the first quarter of 2022. We've also made great strides in our pipeline, including the recent exciting announcement of positive interim results from the Phase I study of ALN-APP, our investigational RNAi therapeutic in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy.

These results mark a significant milestone for Alnylam as we believe they establish human proof of concept for RNAi therapeutics in the CNS, and potentially unlock many additional opportunities where we may be able to address significant unmet medical needs.

We also have a number of exciting upcoming milestones that highlight the depth and breadth of our pipeline, which includes the presentation of 18-month results from the APOLLO-B Phase III study of patisiran, at ESC-HF later this month and top line results in the KARDIA-1 Phase II study of zilebesiran in patients with hypertension expected in mid-2023.

This execution is in line with our focus on the following 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 for patients. Second is our expansion beyond rare diseases to also address more common disease areas. And the third growth driver for the company comes from our sustainable innovation engine comprised of new platform enhancements, opportunities with extra hepatic 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 puts us on track with our Alnylam P5x25 goals, making Alnylam a top-tier biotech developing and commercializing transformative medicines for rare diseases and beyond 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 delivering exceptional financial results.

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

[Tolga Tanguler, executive]

Thanks, Yvonne, and good morning, everyone. Q1 was a strong quarter for our commercial portfolio, driven by our TTR franchise and the strength of our ongoing launch of AMVUTTRA as we delivered 48% total product sales growth or 52% on a constant exchange rate basis compared with the first quarter of 2022.

Let me now turn to a summary of our first quarter TTR performance. Our TTR franchise achieved $204 million in global net product revenues for ONPATTRO and AMVUTTRA, representing a 7% increase compared with the fourth quarter and a solid 49% growth compared with the first quarter of 2022. With the U.S. market year-over-year growth standing out at a robust 75%, driven by the ongoing launch of AMVUTTRA. At the end of the first quarter, over 3,160 patients were on commercial ONPATTRO or AMVUTTRA treatment worldwide, up from over 2,975 patients at the end of the fourth quarter, representing 6% quarterly patient growth.

In the U.S., combined sales of ONPATTRO and AMVUTTRA increased 5% versus the fourth quarter and were primarily impacted by the following: a 7% increase in demand, which was driven by the strength of ongoing AMVUTTRA patient uptake, more than offsetting the decrease in patients on ONPATTRO that switched to AMVUTTRA. Inventory dynamics decreased reported growth by approximately 3% as AMVUTTRA inventory in the channel continues to decrease with ongoing patients switching to AMVUTTRA.

Overall, in the U.S., we continue to be very pleased with the impact we're seeing from AMVUTTRA in expanding the opportunity for our TTR franchise as reflected by the robust 75% year-over-year quarterly growth that we achieved in Q1, representing the third consecutive quarter of achieving TTR growth in excess of 70% on a year-over-year basis in the U.S. following AMVUTTRA's launch in the third quarter of 2022.

Additionally, key operating metrics continue to trend favorably, including growth in new patient start forms, the switch rate from ONPATTRO, patient compliance rates and the expansion of our prescriber base.

In our international markets, total TTR Q1 product sales increased 9% versus the fourth quarter, driven by strong demand in Japan following the fourth quarter launch of AMVUTTRA offset by inventory destocking in Japan. The AMVUTTRA demand growth in Japan is particularly encouraging with the new patient growth being driven by a mix of switches from tafamidis as well as patients naive to therapy.

Additionally and importantly, ONPATTRO continues to deliver steady growth in markets where AMVUTTRA is not yet launched, positioning these markets for the upcoming AMVUTTRA launch. ONPATTRO also benefited from the timing of orders in our distributor markets. Our global results continue to be challenged by foreign exchange headwinds, with total TTR year-over-year reported growth of 49% held back 5 percentage points due to changes in FX rates.

Now moving to our ultra-rare products and the performance of GIVLAARI and OXLUMO, which delivered $72 million in combined product sales during the first quarter, representing a 2% increase compared with the fourth quarter and a more robust 45% growth compared with the first quarter of 2022. We ended the quarter with more than 550 patients on GIVLAARI commercial therapy, and more than 300 patients on OXLUMO commercial therapy, representing 6% and 7% quarterly growth compared with the year-end '22 for GIVLAARI and OXLUMO, respectively.

For GIVLAARI, global growth of 2% in Q1 compared with the fourth quarter was impacted by the following: a decline in U.S. growth of 3%, primarily due to reduced patient compliance associated with the seasonal impact from the annual preauthorization required by payers during the first quarter that we expect will recover in subsequent quarters. Growth in our international markets increased 11% as demand increase in European markets and also benefited from the timing of orders in our distributor markets.

For OXLUMO, global growth of 1% in Q1 compared with the fourth quarter was impacted by the following: U.S. reported growth increased 3%, driven by an increase in patient demand. Growth in international markets was flat with a demand increase in European markets offset by the timing of orders in our distributor markets.

Additionally, changes in year-over-year foreign exchange rates negatively impacted Q1, GIVLAARI and OXLUMO reported growth by 3 and 4 percentage points, respectively.

In conclusion, we are pleased with the growth in revenues, particularly with the ongoing signs of strong performance associated with the AMVUTTRA launch, which we believe represents an important therapy option for hATTR amyloidosis patients with polyneuropathy, an accelerated growth opportunity for our TTR franchise.

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

[Akshay Vaishnaw, executive]

Thanks, Tolga, and good morning, everyone. I'd like to start today with a recap of recent news that marks a very important milestone for Alnylam and the broader field of RNAi therapeutics, which is our progress with ALN-APP, an investigational RNAi therapeutics in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy.

As announced last week, we reported the first-ever clinical results with an RNAi therapeutics directed to the CNS. Given the importance of the positive data and the intense interest in the study from all parties concerned, not least patients and physicians, I think it's worthwhile to further discuss the interim findings from our ALN-APP program. ALN-APP targets amyloid precursor protein, or APP, which we're investigating as a potential treatment for Alzheimer's disease and cerebral amyloid angiopathy or CAA. Human genetics have shown that certain mutations or duplications in the APP gene can cause early-onset Alzheimer's disease for amyloid plaques form in brain tissue and are associated with neurodegeneration. Other mutations in the same gene can cause CAA, where (ab)2 fragments distinct from those that aggregate to form Alzheimer's plaque deposit within the walls of blood vessels in the brain and results bleeds.

CAA is, in fact, the second leading cause of intracerebral hemorrhage. So this one parent protein APP can be harmful into distinct pathophysiological processes.

In animal studies, we've shown that targeting APP with an siRNA showed great promise with broad CNS biodistribution after a single intrathecal injection as shown on the left here. With knockdown in all major CNS cell types, which is the neuron, oligodendrocyte, microglia and astrocytes.

On the right, we can see that a single 60-milligram intrathecal dose in nonhuman primates resulted in significant and sustained target knockdown with durability after 6 months at which time the experiment was terminated, but APP suppression was still ongoing. These pharmacologic findings, which were reliable, reproducible and appeared safe, increased our excitement around the therapeutic hypothesis, specifically that by lowering APP protein production in the CNS via RNAi mechanism, we could reduce the downstream fragments that aggregate and deposit in tissues and, therefore, hopefully ultimate disease cause.

To support advancement to clinical testing, we conducted short-term IND-enabling GLP toxicology studies in the rat and nonhuman primate where 2 low, medium and high doses were given them on the part, i.e., where we greatly exaggerated dose and regimen relative to that expected in the clinic. These studies demonstrated the supportive safety profile and no significant CNS histopathology and thereby enabled the ALN-APP Phase I study.

The Phase I trial is designed as a 2-part study, a single ascending dose part A, followed by multiple dose Part B. Part A was enabled by the GLP toxicology studies I've just mentioned. The Phase I is being conducted in patients with early onset Alzheimer's disease. The primary endpoint of this study is safety and tolerability of ALN-APP.

Secondary objectives are focused on characterizing the pharmacology of ALN-APP. The study also includes a variety of exploratory biomarkers, which will allow us to assess whether ALN-APP is showing any impact on other biomarkers of disease progression. Interim data shared of initial single ascending dose cohorts and we continue enrolling in Part A as we explore further doses.

At the time of this interim look, 20 patients with early onset Alzheimer's disease have been enrolled in 3 single dose cohorts in Part A of the ongoing Phase I study. Today, ALN-APP has been well tolerated with no study dropouts, and all adverse events being mild or moderate in parity.

Available CSF data from white blood cells and protein appear similar to placebo. Neurofilament light chain, or NfL, which is a marker of neuronal damage and which may be elevated in drug-induced neurotoxicity was also monitored. Reassuringly, early data for NfL, which are currently available from 2 out of the 3 cohort study to date, also look comparable to placebo.

Now let's look at the pharmacodynamic results after single intrathecal doses. To date, we've studied 3 dose levels, 25 milligrams, 50 milligrams and 75 milligrams, all available data to are -- all available data to the 3-month time point are shown. Excitingly, we observed that unlike placebo, ALN-APP treatment resulted in rapid, dose-dependent and sustained reductions of both sAPP alpha and soluble APP beta, both biomarkers of target engagement in the CSF. We saw rapid knockdown as early as day 15 and observed maximum knockdown of up to 84% and 90%, respectively, for APP alpha and APP beta. At the highest dose tested, 75 milligrams, the median knockdown was greater than 70% for both biomarkers and sustained for at least 3 months.

Initially, per protocol, we intended to dose escalate from 75 milligrams to 225 milligrams. However, given that the knockdown observed at 75 milligrams substantially exceeded our initial target of 50% biomarker knockdown, we chose to de-escalate to 50 milligrams. As you can see at 50 milligrams, while we have more limited data set, it appears equally promising and similar to the 75 milligram dose with substantial knockdown for both APP alpha and beta.

Now notably, the durability we see in humans reflects what we saw in nonhuman primate studies where single doses gave similar profound durable knockdown extending to 6 months or beyond. Accordingly, we anticipate that the responses we see here in Part A will continue. Indeed, for the data available beyond 3 months in this human study, we see continued target suppression. This durability of effect is important for ALN-APP as well as our overall CNS assays as it suggests the potential for infrequent dosing. We look forward to seeing with longer follow-up. Indeed, how long this knockdown effect is sustained, we believe these dates suggest that the drug will be able to be dosed quarterly at most and based on animal data and the translation of our platform in humans, we believe that's the potential treatment dose every 6 months or less frequently.

Enrollment in the single ascending dose portion of the Phase I study is ongoing in Canada, the Netherlands, the U.K. and United States. Additional enrollment in Part A will allow us to continue to explore single-dose PK and PD and characterize the durability and effect longer -- and long-term safety.

Results from Part A will also inform the doses and regimens to be put forward into Part B and multiple dose portion of the study, which will include patients from part A. In parallel to Part A of the Phase I study, we conducted chronic GLP toxicology studies in animals to support the multi-dose Part B of the Phase I. These chronic GLP tox studies were conducted without knowledge of the impressive knockdown and durability we see today at low doses of ALN-APP, we've seen this Phase I study. So for standard practice, we exaggerated doses and dosing frequency relative to any dose and regimen that would ultimately be used in clinical testing.

Specifically, we administered low, medium and high intrathecal doses, monthly for 6 months in the rat and every other month for 9 months in the nonhuman primate. The data from the chronic studies will be shared with regulatory authorities. The board -- we have already received regulatory approval to begin Part B in Canada, where, in fact, the majority of the Part A patients have been enrolled to date and approval is pending in the U.K. and Netherlands.

In the U.S., the FDA has currently placed partial clinical hold on the multidose Part B of the Phase I study due to findings observed in chronic toxicology studies. Of course, given the high exposure that we achieved with frequent administration of high doses, it's not unexpected that we would observe findings in these chronic toxicology studies. However, it's important to contextualize exposures by relative CSF volumes between toxicology species and humans.

For example, relative to a potential clinical dosing regimen of 75 milligrams given every 6 months, there's a more than tenfold greater annualized exposure at all doses tested in the rat and nonhuman primate. And at the top doses evaluated in those chronic tox studies, there's a 75- and 50-fold greater annualized exposure in rat and nonhuman primates, respectively, relative to the same potential human dose. And if we scale based on organ way, then these annualized exposures would be even greater in the chronic tox studies.

I want to nevertheless acknowledge that the FDA will be the ultimate arbiter of the data, and we look forward to getting further guidance from them. Accordingly, we plan to engage with them to discuss all preclinical information as well as these new interim Phase I clinical data, which provides important context to support potential initiation of Part B in the U.S.

To close this part of the discussion, I'm absolutely thrilled about these incredible human data that provide the first ever evidence that we may be able to use RNAi to find these disease-causing transcripts in the CNS.

In animal studies, we've already demonstrated the reproducible and modular nature of our CNS platform with the knockdown against the diverse range of targets and hope that we can address disease-causing genes, not just for Alzheimer's, CAA, ALS and Huntington's, but also many other disorders.

We look forward to presenting these interim data from Part A of the Phase I ALN-APP study at an upcoming medical congress.

With that, let me turn to our efforts in hATTR amyloidosis where we're advancing 3 clinical-stage product candidates, namely patisiran, vutrisiran and ALN-TTRsc04. As you know, ONPATTRO is currently approved in multiple markets around the world, to treat hereditary ATTR amyloidosis with polyneuropathy, and we're committed to expanding the product's label for the treatment of cardiomyopathy in both the hereditary and wild-type ATTR amyloidosis patients.

As announced in February, we're delighted that our supplemental new drug application, patisiran for cardiomyopathy of ATTR amyloidosis has been accepted by the FDA with a standard review and a PDUFA date of October 8. In the file acceptance letter, the FDA stated that they've not identified any review issues. And as you also noted that they're planning to hold an advisory committee meeting to discuss the application.

Currently, we have no further details from the FDA regarding the timing of the outcome or the specific topics they wish to discuss. When we learn more, we will communicate that information in due course. If the sNDA is approved, this will allow us to extend the potential benefits of patisiran to many patients with wild-type hereditary ATTR amyloidosis with cardiomyopathy. This filing is based on the pivotal APOLLO-B study, which demonstrated improved functional status and quality of life in patients with ATTR amyloidosis with cardiomyopathy given patisiran for 12 months relative to placebo.

The global profile of patisiran is supported by an encouraging safety profile and exploratory data that favored patisiran treatment relative to placebo on various biomarkers of disease progression at month 12. We've announced this morning that 18-month data from the APOLLO-B study have been submitted to the FDA as part of the sNDA review, and we'll be presenting these results at the ESC Heart Failure meeting at the end of May.

Now similar to ONPATTRO growth, we're also committed to expanding the label for AMVUTTRA to include the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis. This is being done with HELIOS-B Phase III study of investigational vutrisiran. HELIOS-B, which is fully enrolled, as an end point of all-cause mortality and CV events assessed after at least 30 and up to 36 months, and we remain on track to share top line results in early 2024.

Wrapping up with TTR, ALN-TTRsc04 is an investigational RNAi therapeutic based on our IKARIA platform and offers the potential for more durable and potent TTR silencing with the possibility for annual dosing, a potentially transformative profile. TTRsc04 entered the clinic and began dosing in the Phase I study, and we expect top line results in late 2023.

In addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. A notable highlight includes zilebesiran, our investigational RNAi therapeutic for hypertension, which we believe could transform the treatment of the disease and offer a highly differentiated profile from all existing antihypertensives, including oral RAAS inhibitors. We look forward to the important upcoming milestones from the Phase II program and remain on track to deliver top line results from KARDIA-I in mid-2023 and top line results from KARDIA-II at or around year-end '23. These are just a few of the highlights from our broad and innovative pipeline driven by our underlying organic product engine and that -- where we expect to deliver sustainable innovation representing a key growth driver for Alnylam in the years to come.

To wrap up these highlights, we're excited to have initiated dosing in the Phase I study of ALN-KHK for the potential treatment of type 2 diabetes with Regeneron as announced initiation of Phase III study of ALN-HSD in patients with NASH.

Now with that, let me now turn it over to Jeff to review you our financials and upcoming milestones. Jeff?

[Jeffrey Poulton, executive]

Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q1 2023 financial results and discussing our full year guidance. Starting with a summary of our P&L results for the first quarter.

Total product revenues for the quarter were $276 million or 48% growth versus Q1 2022. As Tolga previously indicated, the increase is primarily related to growth in TTR product revenues driven by the launch of AMVUTTRA in the U.S. in the third quarter of 2022 as well as increased patients on GIVLAARI and OXLUMO therapies. It's also worth noting that year-over-year growth in combined product revenues was held back by approximately 4 percentage points due to impact of changes in foreign exchange rates.

Net revenue from collaborations for the first quarter was approximately $36 million, representing a 41% increase compared with Q1 2022, primarily due to an increase in revenue from our collaboration arrangements with Regeneron attributed to an increase in reimbursable activities under our research services arrangement in addition to an increase in revenue recognized associated with license programs within the collaboration.

Royalty revenue during the quarter was $7 million, which was driven by Novartis' sales of Leqvio, which launched in the U.S. in the first quarter of 2022.

Gross margin on product sales was 85% in Q1, representing a 2% decrease compared with the first quarter of 2022. The decrease was primarily driven by increased royalties due to Sanofi on sales of AMVUTTRA, which was partially offset by lower manufacturing costs for AMVUTTRA compared with ONPATTRO.

Our non-GAAP R&D expenses increased 35% in the first quarter compared to the same period in 2022, primarily due to increases in headcount to support our R&D pipeline, development expenses associated with the APOLLO-B, HELIOS-B and KARDIA-1, KARDIA-2 clinical studies and manufacturing-related expenses with our preclinical activities. Q1 2022 non-GAAP R&D OpEx was disproportionately lower than all other quarters during 2022. Thus, we expect lower year-over-year quarterly growth rates for R&D in the remaining quarters of 2023.

Our non-GAAP SG&A expenses increased 17% in the first quarter compared to the same period in 2022, primarily due to increased headcount and other investments supporting our strategic growth, including the global launch of AMVUTTRA. Our non-GAAP operating loss for Q1 2023 was $110 million, representing a $7 million improvement compared with Q1 2022 and driven by strong top line growth, offset by more moderate growth in operating expenses.

Finally, we ended the quarter with cash, cash equivalents and marketable securities of $2.1 billion compared to $2.2 billion at the end of 2022 with the decrease primarily due to our operating loss in the quarter. We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile.

Now I'd like to turn to our full year 2023 financial guidance. We are reiterating the financial guidance we provided on our year-end results call in February. Starting with net product revenues, we continue to anticipate combined net product revenues for our 4 commercialized products will be between $1.2 billion and $1.285 billion. Our guidance for net revenue from collaborations and royalties remains in range between $100 million and $175 million. And our guidance for combined non-GAAP R&D and SG&A expenses remains unchanged and is a range between $1.575 billion and $1.65 billion.

Let me now turn from financials and discuss some key goals and upcoming milestones slated for early and mid-2023. We will, of course, be executing on global commercialization of our products ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. From our TTR programs, we have a couple of upcoming data presentations. 18-month results from APOLLO-B will be presented at the ESC Heart Failure Meeting later this month and the HELIOS-A randomized treatment extension results looking at a biannual dose regimen for vutrisiran will be presented at ASNP also at the end of May.

We expect to report top line results from the KARDIA-1 Phase II study of zilebesiran and also intend to complete enrollment in the KARDIA-2 Phase II study. With our partner programs, we expect additional results from Phase II combination trials of ALN-HBV02.

Let me now turn it back to Christine to coordinate our Q&A session. Christine?

[Christine Lindenboom, executive]

Thank you, Jeff. Operator, we will now open the call for questions. [Operator Instructions]

[Operator]

[Operator Instructions] And our first question comes from Ritu Baral from TD Cowen.

[Ritu Baral, analyst]

I know I'm only allowed one, so I'm going to try and stick to it as much as I can. The 18-month data that work that's coming up from APOLLO-B, can you talk a little bit more about what will be presented? Maybe how many patients are in continued follow-up at 18 months? Will we have key secondary endpoints like the Kansas City? And additional safety follow-up as well.

[Yvonne Greenstreet, executive]

So as a reminder, to everybody on the call, APOLLO-B is double-line randomized study for 12 months. And at this point, patients who are on placebo were given the option to switch to patisiran for continuation of dosing. These data corroborate really what we saw in the 12-month portion of the study. And as we noted on the call, we've submitted these data to the FDA and we'll be presenting these data at the ESC-HF in Prague in May.

Pushkal, do you want to add any other comments about the data and engagement with the agency?

[Pushkal Garg, executive]

Yes, absolutely. Thanks, Yvonne. Thanks, Ritu, for the question. As Yvonne said, we're really excited about these data. You asked, Ritu, about ongoing follow-up, right? All patients were randomized out to 12 months and then all patients were offered the opportunity to be an active drug from 12 months and beyond. And this is a cut of data out to 18 months, and we've had very high retention on the study, which is important and corroborates the profile. And I think it's going to be an opportunity to look at sort of the continued profile of what we've seen on patients on active drug, which was -- we saw evidence of stabilization across key endpoints, particularly the 6-minute walk test, sort of where it was associated with around the age-related decline that's seen in that parameter as well as stabilization in the key secondary endpoint of the Kansas City Cardiomyopathy Questionnaire.

So that's important. It's an opportunity to look at the placebo patients as they cross over to active drug and look at ongoing safety. Net-net, as Akshay and Yvonne commented, Ritu, we're really -- feel quite confident and good about the data that we've seen and then it corroborates the profile of patisiran and its potential role in this disease.

[Yvonne Greenstreet, executive]

Yes. And as a reminder, we've submitted a 120-day safety update as is routine in the submission process.

[Operator]

Our next question comes from Tazeen Ahmad from BofA.

[Tazeen Ahmad, analyst]

Maybe just one on AMVUTTRA sales. It looks like you're off to a good start on the ramp. Just wondering what your internal data is saying about any kind of market share being taken from ONPATTRO and whether or not if that is the trend, you'd expect that to be the case going forward as well.

[Yvonne Greenstreet, executive]

Tolga, I think that's one that goes to you.

[Tolga Tanguler, executive]

Thank you, Yvonne. Tazeen, look, first of all, we're incredibly excited to the fact that we have been able to build a category and essentially grow our business quarter-over-quarter by over 70%, 3 subsequent quarters in the U.S. And what we see in terms of the dynamic with ONPATTRO is a very healthy switch rate while we're adding net naive patients in a very robust manner. So what our internal data really suggests is that there is lesser and lesser patients that are stable on ONPATTRO as we expect those patient numbers to remain in small double digit or single digits over time.

[Yvonne Greenstreet, executive]

Yes, really just I think kind of emphasize how pleased we are with the launch metrics for AMVUTTRA in terms of the balance of new patients as well as switches and really the expansion of the prescriber base, which is very encouraging for continued growth in the trajectory of our TTR franchise. So thanks for that question, Tazeen.

[Operator]

Our next question comes from Ellie Merle from UBS.

[Sarah Krupp, analyst]

This is Sarah on for Ellie. On your CAA program, I guess, can you talk about some of the time line there and maybe the prioritization of that versus Alzheimer's and how we should think about the size of the CAA market opportunity?

[Yvonne Greenstreet, executive]

Thanks for that question. I guess that question has been stimulated actually by the incredible results that we've shown are quite remarkable results that we've shown in our Phase I interim study. And clearly, that's the first step in the journey of bringing RNAi therapeutics to patients with CNS diseases in general. We're clearly starting off with early onset Alzheimer's disease. But Pushkal, I think cerebral amyloid angiopathy get another important opportunity, potentially for ALN-APP given the genetics, but could you say a few words about how we're thinking about the opportunity here?

[Pushkal Garg, executive]

Absolutely. Thanks, Yvonne. Thanks, Sarah. Look, as it has been highlighted by both Akshay and Yvonne. CAA is really devastating disease. It's the second leading cause of intracerebral hemorrhage only behind hypertension and there's really no available therapies for these patients. And so it's something where the genetics and the biology really strongly suggest that APP lowering, may be a benefit to these patients.

In some ways, you can think about it, is very comparable to the hypothesis we've been pursuing with our TTR program by reducing amyloid we can reduce downstream tissue damage in nerves and heart in this case, in the parenchyma of the brain in Alzheimer's disease and the vasculature of the brain in CAA. So these initial data that we've shared today really give us promise that we can advance ALN-APP towards both of these diseases, frankly, in parallel.

We've not announced specifically what the time lines for that are. We're obviously working through and continuing the Part A of the study to do further dose exploration and really establish what we're seeing in terms of the magnitude of knockdown, but also the durability so that we can identify multi-dose regimens, et cetera, characterize safety and then we want to be pursuing Phase II studies in both of these indications in due course and we'll update.

[Yvonne Greenstreet, executive]

Akshay, anything to that?

[Akshay Vaishnaw, executive]

No. All good. Good answer Pushkal.

[Operator]

Our next question comes from Salveen Richter with Goldman Sachs.

[Tommie Reerink, analyst]

This is Tommie on for Salveen. Congrats on the progress. So for zilebesiran, can you frame what you're hoping to see in this upcoming Phase II monotherapy and combo data, the path to registration here given supportive data? And any updates on the Reversir platform?

[Yvonne Greenstreet, executive]

Yes. I think your question was referring to zilebesiran. Is that correct? I just wanted to make sure. As you know, we're very excited about the opportunity for zilebesiran in hypertension -- a condition that impacts 100 million or more people and only 70% are able to achieve the goal in blood pressure reduction. So we think it's a really important area that we believe our platform has a real opportunity to completely transform how these patients are treated and hopefully lead to a better outcomes with respect to morbidity and mortality.

And we've got 2 Phase II studies ongoing KARDIA-1 and KARDIA-2. Clearly, we need to wait for those results before we speak more specifically about plans beyond that. But Pushkal, do you want to talk a little bit maybe around the current status of our studies and how we're thinking about future development?

[Pushkal Garg, executive]

Sure. Yes. So look, zilebesiran has the potential to be an incredibly transformative medicine for high blood pressure. What we saw in the Phase I study that we've already reported was opportunity to realize almost 20 millimeters of systolic blood pressure lowering with 24-hour ABPM lasting -- and durability lasting out to 6 months with a single injection. We think as Yvonne highlighted that, that can actually address a multitude of the issues that lead to hypertension being the #1 addressable cause of cardiovascular morbidity and mortality around the world.

We've got 2 studies. The KARDIA-1 study is a monotherapy study. I think that was the first study you asked about. And that study completed enrollment at the end of last year. And so we're looking forward to data in the middle of this year. And that's really going to allow us to establish the dose and the regimen for ongoing pivotal studies. We're looking at a range of doses from 150 milligrams to 600 milligrams and q 3- and q 6-month dosing. And so coming out of that study, we'll hopefully be able to establish what that pivotal dosing regimen is.

The second study that we're doing is KARDIA-2 as you're probably familiar, in hypertension, combination therapy is sort of standard of care. And so what we're doing in KARDIA-2 is looking at combining zilebesiran with 3 common classes of medicines, diuretics, calcium-channel blockers and angiotensin-receptor blockers. And what we want to be seeing there is the additive efficacy and safety, and that will help us design ongoing studies for our registrational program.

I'm really excited that their enrollment has really been picking up in that study, and we are on track with enrollment early this year and report out data towards the at or around year-end. So with those data together, we think we'll be able to provide more guidance on what the pivotal registrational program will look like.

[Yvonne Greenstreet, executive]

Yes, perhaps important to add that actually from a regulated perspective, to achieve an approval -- a medicine for hypertension have to demonstrate a 5-millimeter of mercury lowering of systolic blood pressure. And of course, we've actually already demonstrated more than that in our Phase I studies as is highlighted. So as we deliver the Phase II data and hopefully move to larger numbers in the Phase III and deliver similar efficacy and also robust safety, we feel that it's a fairly straightforward answer and approval here. Thank you for the question.

[Operator]

Our next question comes from Paul Matteis from Stifel.

[Paul Matteis, analyst]

Congrats on the quarter and the recent CNS data. I wanted to ask just a commercial question. It looks like you saw this really nice jump in the sequential net patient add rate when AMVUTTRA became available. It looks like that kind of step back down to more than normal rate we were observing throughout 2022. Is that kind of how you're thinking about the likely cadence going forward that maybe there was this bolus of patients that were interested in a much more convenient product and now the growth rate from here is probably steadier?

[Yvonne Greenstreet, executive]

Tolga?

[Tolga Tanguler, executive]

Yes. Thank you, Paul. I mean, look, first of all, I just want to reiterate the fact that we're incredibly pleased with how AMVUTTRA performance is taking shape in the U.S. and now in Japan and other European markets. What's really important to highlight is -- the product profile is very compelling that this category growth not only address the pent-up demand that we were anticipating, but it's also continuing to actually help us expand this franchise, mostly noted by the fact that we have -- we are seeing an expanding prescriber base.

Our start form rates are continuing to go up. And what we see is also our ability to get naive patients, not just ONPATTRO switches are continuing to be at the stated rate. The results that you see in Q1, Paul, is mostly -- it's a bit diluted because given the insurance renewals that we see in this Q1, tends to impact the net sales impact in the U.S. We're actually very encouraged with some of those internal metrics that I just shared with you, making us quite confident that in subsequent quarters, we see the uptake continue to be at the similar rates that we see in the prior quarters.

[Yvonne Greenstreet, executive]

Thank you so much, Tolga.

[Operator]

Our next question comes from Jessica Fye from JPMorgan.

[Jialiang Liang, analyst]

This is JL for Jess. So we have a question on reimbursement around AMVUTTRA. So from a cost-benefit perspective for payers and recognizing the, HELIOS-B data has yet to come out, how would you compare AMVUTTRA to tafamidis for cardiomyopathy? And also curious, how are you thinking about this for ONPATTRO where you already have your positive pivotal data?

And then moving to Medicare patients specifically, can you remind us what the out-of-pocket cost is like for AMVUTTRA per year for the Medicare patients? And how does it compare to the out-of-pocket cost for tafamidis, again, for the Medicare patients? And with the upcoming IRA changes to Medicare, how do you see this change potentially -- how do you see the difference can change potentially?

[Yvonne Greenstreet, executive]

So there's a lot of questions here. We'll -- we try to remember them and pass them at. I mean Tolga, I maybe start with the last question first, [indiscernible] and talk a little bit about how we're seeing out-of-pocket patient's cost [indiscernible] study and the sort of Medicare context.

[Tolga Tanguler, executive]

So that's also kind of, let's say, straight in the record. So we have about 70% of our patients on Medicare and Medicaid. And those are patients that are on Part B. And right now, if you look at our current cost burden on those patients, about 70% of our patients pay zero co-pay in the Part B program, and it's consistent with both ONPATTRO as well as AMVUTTRA.

As you all know, we have very limited value-based agreements that actually really unburdens the patients to be able to have access and what we really see, that's probably the most important marker is if you look at are these patients that are put on therapy with a start form, do they actually end up getting the therapy? And are they staying on therapy? And what's really encouraging is both -- and we can say that now with AMVUTTRA 3 quarters in the market. We see very similar exceptionally high compliance rates, which also suggests that those patients that may have sub-copay burden are continuing to be able to access, thanks to our value-based agreements and other ways that we support those patients. What was the other question?

[Yvonne Greenstreet, executive]

I think you've actually answered 2 answer out of 3 questions. And the third is how we're thinking about pricing in cardiomyopathy, particularly with respect to tafamidis. I mean given that we're still awaiting a label for ONPATTRO and we're waiting HELIOS-B results for vutrisiran. I think it's probably too early to speak to that detail.

So thank you for your questions and let's go on for next question.

[Operator]

Our next question comes from Gena Wang with Barclays.

[Huidong Wang, analyst]

Thank you for sharing your APP data. Indeed, a very impressive knockdown profile. I had one question on the data, but with regards and hopefully can cover all 3 questions. So when we look at the natural -- nature of biotechnology paper, 60 milligrams from nonhuman primate data was only showing similar knockdown when we look at compared to the 75 milligram in human, so will let to almost nearly tenfold better translation to human. And then my second question is that you showed median percentage in knockdown, so what is the mean and the standard deviation look like if we're only focusing on 75 milligram profile. And then lastly, do you need to run another nonhuman primate study in order to satisfy FDA to remove the partial clinical hold?

[Yvonne Greenstreet, executive]

Okay. So 3 questions there. And I think I would say, they're kind of all for you. I think one was about the translation from the preclinical testing to clinical setting. Second was with respect to the percentage knockdown that we're seeing and the third, our plans to address the clinical hold. I think before I actually answer the questions on the clinical hold, I think it's really important to emphasize that Part A is ongoing in a number of countries, including the U.S. And in fact, we have approval to progress with Part B from Health Canada. In fact, it's actually said in its remarks, most of the patients actually in Part A come from Canada. So it's really important to note that we're able to progress with Part B. But clearly, still a lot to learn from Part A in terms of PK, PD, durability, et cetera, before we define our plans for the next [indiscernible] study.

Akshay, maybe you want to talk a little bit more about how we're thinking about addressing the clinical hold with the FDA and then the other 2 questions that relates to the data.

[Akshay Vaishnaw, executive]

Yes. Thanks, Yvonne. Thanks, Gena. Let me just go in order. So I think your first question, Gene, if I got it right, the 60 milligram in the monkey expectations in that in terms of translation. I think, I mean, even without doing a lot of calculations, if you think about the size of the monkey brain and the CSF volume, and you have to administer 60 milligrams to get something like the knockdown curves we're seeing at 50 milligrams here in humans and 75 milligrams. It just shows the gain in potency, and we believe we'll also see durability in humans relative to nonclinical species.

You've watched us for a long time. And if you're talking back to the [ liver ] data, that's exactly what we see in the liver setting. So these human Phase I data are really rather exciting and I think solid product profile where we hope that low doses rather than to the animal, we see very important significant knockdown or highly durable intervals that would allow in a treatment dosing, hopefully, every 6 months, maybe even annually. So that was question one.

Your second question was we showed the medians what about the mean and standard deviations at 75. Again, we haven't shown the patient-by-patient data. We'll share more data at the upcoming meeting. But I can reassure you that as you go from low to high dose, the kind of variability you see patient-to-patient at high dose, you now see a track of the track for each patient is following the same curve. So the data will be very tight in terms of means and standard deviation. [indiscernible] we've looked at them at 50 and 75, but we haven't shown them today.

So again, that conforms exactly to what we see with RNAi and other tissues, where at low doses, some pharmacologic doses you see variability between individuals just as you see in placebo. But once you're at an [indiscernible] pharmacologic doses, you get very tight knockdown and little intra-individual variability. Again, these are all small numbers, but very encouraging data.

And finally, do we need a nonhuman primate trying to get off hold? I mean I think I shared today our impressions of the clinical data, the situation with the chronic tox studies, exaggerations and exposures we have. We want to discuss all this with the FDA and get their guidance. Obviously, they have a very important voice in this. We want to benefit from their input. So let's go and do that. And from that, we'll learn whether we need to do more studies or not. But if we can administer low doses and get up to a year of knockdown, who knows what we'll see, but certainly very exciting times.

[Operator]

Our next question comes from David Lebowitz with Citi.

[Unknown Analyst]

This is [indiscernible] on for David. So we wanted to ask that the ATTR space appears likely to have an additional TTR silencer entry, how does the competition shake out between your offerings and eventual competitors?

And maybe one more if you have time, that assuming ONPATTRO approval for ATTR-CM is going to be based on functional endpoints, how do you see the therapy getting utilized after that approval?

[Yvonne Greenstreet, executive]

Yes. Actually, it would be really helpful if you could repeat your question and maybe just kind of hold yourself to kind of one question. So maybe you can just repeat the one key question you'd like us to address?

[Unknown Analyst]

Sure. Okay. So my first question was that the ATTR space appears to likely have an additional TTR silencer entry. How does the competition shake out between your offerings and eventual competitors?

[Yvonne Greenstreet, executive]

Okay. So let's start off with Tolga and then Pushkal will also add some remarks. Tolga?

[Tolga Tanguler, executive]

Yes. So as you know, AMVUTTRA has really been the game changer and it's been transforming the market and building the category growth. And frankly, the potential availability of more treatment options is really good for patients. This is a highly devastating disease. Patients are still either undiagnosed or under-treated. So similar to other competitive markets, it will increase disease awareness, spot early diagnosis, enable earlier treatment initiations, which in turn supports a significant category growth that we already see and we expect to see.

Now in terms of the product profiles, obviously, what we see is, and I'll have Pushkal come back a little bit on our clinical profile. But what we're really pleased to see is, first of all, the rapid offset is very important for patient outcomes. Disease reversal is important. I am confident -- and we're obviously very confident of our product profile, only 4 times a year in registration and also given the fact that strong uptake is a clear signal of our [indiscernible] profile is -- and our customer-facing profile and how we're competing in the market. So with that, maybe I'll turn it over to Pushkal to comment on the product profile at clinical level.

[Pushkal Garg, executive]

Yes. I mean I think, Tolga, I think you hit actually most of the key points. I mean I think it's important to state that there's really no head-to-head studies between [ patisiran ] and - we've just seen some early data here, and we look forward to learning more about it, but there's no head-to-head data between [ patisiran ] and vutrisiran.

I think as we've been in the marketplace, as we've talked to clinicians, as we've talked to patients, what we've learned about what's important to them, obviously, they're looking for strong efficacy and a good safety profile. And as you dive deeper into that, speed of onset of action is quite important. We've been very pleased by the rapidity of knockdown, TTR knockdown that we see with our agent and that seems to translate actually to patients feeling better.

We've noticed that with the VMI data and nutritional status, and we get reports of patients anecdotally feeling a lot better very early on therapy. And likewise, ultimately, people want to regain function as much as possible. They want to be able to live their lives basically as free of this disease as humanly possible. And what's this concept of disease reversal, that Tolga mentioned, becomes very important. And we've been encouraged when you look across key parameters like the mNIS, when you look at the Norfolk Quality of Life, et cetera, in the PN space, that we have 50% or upwards of patients who are sort of reaching that reversal threshold.

And so again, we're really excited about the profile that we have with AMVUTTRA, how it's been received and the feedback that we've been hearing. And so I think we're very encouraged. And again, it's great that there'll be another agent out there, as Tolga said, but we're very confident about the profile of AMVUTTRA and what it offers.

[Yvonne Greenstreet, executive]

No, that's great. And I think having sort of 5 years of experience, marketing TTR medicines, I think, gives us the opportunity to really understood this market and extract insights that are helpful in terms of educating patients and physicians. So thank you for that question.

[Operator]

Our next question is from Michael Ulz from Morgan Stanley.

[Michael Ulz, analyst]

For ALN-TTRsc04, assuming you get some supportive data later this year, can you talk about the potential path forward there? And if there's opportunity to maybe shorten that time frame? And would you be looking to move forward in both polyneuropathy and cardiomyopathy?

[Yvonne Greenstreet, executive]

Thanks for that question. We're really excited about progressing ALN-TTRsc04 for a number of reasons. Importantly, the potential for increased knockdown greater than 90% and frequency perhaps annual dosing. So we think this is a real step forward for our platform in general. And Pushkal, maybe you can talk a little bit about how we're thinking about developing this program going forward.

[Pushkal Garg, executive]

Yes, absolutely. Ye sc04, I think, really represents sort of the next generation of innovation in the TTR space where we want to bring best possible offering to patients. And we believe the deeper knockdown and greater durability are the 2 things that will make a huge difference for patients.

And obviously, from a business perspective, it's also valuable to us because it doesn't -- it freezes some of the royalties, et cetera, that we have around AMVUTTRA. So we're obviously motivated and excited to bring this forward to patients as quickly as we can. So to your point, we will be looking for ways to speed up the development program. And while it's early to speak to exactly what the details of that are, this first Phase I study is going to allow us to look at both the magnitude of knockdown, the durability of knockdown as well as safety.

And with that, maybe one way to think about this to look back at what we did with the AMVUTTRA program, where we went directly from Phase I studies into Phase III pivotal trials.

And moreover, when we have patient-level data across a number of studies, it allows us to pursue some very innovative development approaches. For example, with HELIOS-A, we did not have a placebo control group. We were able to use patient-level data and do a historical control against the APOLLO-placebo data. And see you can imagine that we will be moving this forward and trying to use similar approaches to speed up development, both in polyneuropathy and particularly in cardiomyopathy. So we'll have more to say about that as we advance our development plans.

[Yvonne Greenstreet, executive]

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

[Operator]

Our final question of the day comes from Kostas Biliouris from BMO Capital Markets.

[Konstantinos Biliouris, analyst]

Congrats on the progress. One quick question on the ONPATTRO filing. I'm wondering whether you have already submitted data to the FDA as part of the format-safety update? And if so, whether you can elaborate on the type of additional safety data that you have submitted?

[Pushkal Garg, executive]

Sure. Kostas, thanks for the question. So the review of the ONPATTRO sNDA for cardiomyopathy is ongoing, and we have submitted both the day 120 safety update, which really just corroborates with additional safety across adverse events, laboratory data, et cetera, with some extended follow-up beyond what we've submitted in the initial NDA. And we also as announced today, have submitted the month 18 efficacy update across primary and secondary endpoints to the agency as well, which we also think corroborates the efficacy that we saw, the clinical importance of those data and a favorable benefit risk profile of the product in this disease population. So we look forward to the agency's ongoing review.

[Yvonne Greenstreet, executive]

Great. So -- thank you for the question. And thanks to everyone for joining this call. We're really happy with the strong start that we've made in 2023. We've got strong commercial execution, significant pipeline and platform development, which really underscore the power of RNAi therapeutics and addressing major unmet needs for patients. And we look forward to sharing more progress with you in the coming months as we continue to deliver on both our near- and long-term goals. Thank you, everybody.

[Christine Lindenboom, executive]

Goodbye.

[Operator]

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.