Alnylam Pharmaceuticals, Inc.

Good day, and thank you for standing by. Welcome to the All-Islam Pharmaceuticals fourth quarter 2021 earnings conference call. At this time, all participants are in listen-only mode. After the presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star, then 1 on your telephone keypad. Please be advised, today's conference may be recorded. If you require operator assistance during the call, please press star, then 0. I'd now like to hand the conference over to Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications.

Good morning.

I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at El Nilem. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer, Tolga Tangler, Chief Commercial Officer, Akshay Vaishnav, 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.elnilam.com slash events. During today's call, as outlined in slide two, Yvonne will deliver introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Akshay will review our recent clinical and preclinical updates And Jeff will review our financials, including 2022 guidance, followed by a summary of our upcoming milestones before we open the call for your questions. I would like to remind you that this call will contain remarks concerning El Nilo'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 recently quarterly report on file at the SEC. In addition, any forward-looking statements represent our views only of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll now turn the call over to Yvonne.

Yvonne? Thanks, Christine, and thank you, everyone, for joining the call today. 2021 was another year of tremendous success at Alnylam, in which we delivered impressive commercial performance and made significant advancements across our broad pipeline of RNAi therapeutics. To start, our commercial products on PATRO, GIVLARI, and OXLUMO saw continued growth, primarily due to strong patient demand. In total, we achieved $662 million in net product revenue representing year-over-year growth of 83%, delivering at the upper end of our guidance range. We're also excited to have ended the year with the U.S. approval of the fourth RNAi therapeutic discovered by Alnylam, Lexio, which is partnered with Novartis. We also advanced our pipeline programs at all stages of development. This includes our TTR franchise, where we recently presented full 18-month results from the Helios A Phase 3 study of vitreous RAM. Akshay will review these shortly. We also completed enrollment in our two pivotal Phase 3 studies in ATTR amyloidosis with cardiomyopathy, Apollo B and Helios B. Furthermore, we advanced our B-SRAM into Phase 2 with the initiation of Cardio 1 and Cardio 2, representing what we believe be an opportunity to reimagine the treatment of hypertension. Additionally, we advanced two more prevalent disease programs towards the clinic, including our first CNS program. Looking toward 2022 and beyond, we view a few strategic goals as key potential growth drivers for our Nilem. First is the potential expansion of our TTR franchise. In the near term, with the potential approval of Vutrisram and the phase three readout of Apollo B with Patisram, and over time, as we aim to become the global leader in delivering impactful and highly differentiated medicines to patients. The second key growth driver is our expansion beyond rare diseases into prevalent diseases. And the third growth driver for the company comes from our sustainable innovation engine, comprised of new platform enhancements opportunities with extrahepatic delivery, and our ability to find new genetically validated targets, which offers the potential to drive further pipeline expansion to 2025 and beyond. Based on these opportunities, we believe we are well positioned to deliver on our Alnylam piece of fifth by 25 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 all best-in-class product candidates from our organic product engine, all while delivering excellent financial results. With that, let me now turn the call over to Tolga for a review of our commercial performance.

Tolga? Thanks, Yvonne, and good morning, everyone. We're very pleased with our fourth quarter performance. The ongoing pandemic had considerable impact on our ability to engage customers via face-to-face interactions. However, our ability to leverage data and analytics for our promotional efforts and improvements in our virtual interaction capabilities have enabled us to finish 21 with significant year-over-year growth. For OnPatro, we achieved $139 million in global net product revenues in the fourth quarter, representing 15% quarter-on-quarter growth compared with the third quarter, and 53% growth compared with Q4 2020. And we achieved $475 million in global on-patriot revenues for the full year. As of December 31st, over 2,050 patients were on commercial on-patriot treatment worldwide with patient compliance remaining consistent above 90%. In the U.S., Sales of OnPatro increased 17% versus Q3 and were primarily impacted by the following. Patient demand, which increased 4% driven by the addition of new patients on therapy with patient compliance remaining consistent above 90% as noted. Inventory stocking in the distribution channel during the fourth quarter. Compared with destocking in Q3, favorably impacted US reported growth by 15% during the quarter. This was expected given the low level of inventory in the channel at the end of the third quarter. We ended the year with approximately two weeks of inventory in the distribution channel, which is at the midpoint of our expectations. In our international markets, OnPatro fourth quarter performance remained strong with growth of 14% versus Q3 primarily driven by increased patient demand, broadly across Europe, Canada, and Japan, as well as favorability in gross net deductions, positively impacting net pricing for the quarter. We also continue to observe a good balance of first-line use and switches from stabilizers. Moving to Givlari, we achieved $41 million in global net product revenues in the fourth quarter, representing 28% quarter-on-quarter growth compared with Q3, and 84% growth versus Q4 2020. And we achieved $128 million in global GiveLari revenues for the full year. As of December 31st, over 350 patients were on commercial GiveLari treatment worldwide. We are pleased with the steady ongoing launch of GiveLari. In the U.S., sales of Givlari increased 35% versus Q3-21 and were primarily impacted by the following. Patient demand, which increased 8%, driven by an increase in patients on therapy, with patient treatment compliance at over 90%, and increase in inventory stocking in the quarter, which favorably impacted growth by approximately 20%. in addition to a decrease in gross to net sales deductions, which contributed an additional 6% growth. We also continue to make strong progress with value-based agreements with over 12 finalized to date with commercial payers. In our international markets, Givlari delivered 10% growth in the fourth quarter compared with Q3, with the growth primarily driven by new patient ads key Western European markets, notably Spain and Italy. In the UK, we received a positive opinion from NICE and look forward to a launch in the UK early this year. Moving now to Oxlumo. We achieved $19 million in global net product revenues in the fourth quarter, representing a 29% increase compared with Q3, and ended our first full year since launch with $60 million in global revenues. As of December 31st, over 140 patients were on commercial Oxlumo treatment worldwide. In the US, sales of Oxlumo increased 9% versus Q3 2021 and were primarily impacted by the following. Patient demand increase 15% driven by an increase in patients on therapy and patient treatment compliance at over 90%. Reported growth was unfavorably impacted by approximately 6% from a decrease in inventory stocking in the distribution channel during the quarter. Additionally, we have finalized 11 VBAs to date with commercial payers. Oxlumo growth in our international markets was 40% during the fourth quarter compared with Q3. Q4 growth benefited from an increase in patients on therapy in our established markets, progress in geographic expansion, and favorability in gross to net deductions positively impacting net pricing for the quarter. We also continue to be pleased by the broad utilization of Oxfamol across age groups and EGFR categories. In conclusion, despite the ongoing pandemic, particularly the effects of Omicron, since late November of last year, I'm proud of the performance our teams delivered. A strong fourth quarter and a strong year across all our three commercial brands with 83% revenue growth versus the prior year. Furthermore, we're excited about the potential upcoming launch of Boutry Saran, which has a PDUFA date of April 14th. If approved, we believe Boutry Saran will offer an important option for the treatment of the polyneuropathy of hereditary traceridin-mediated amlodiosis in adults with its quarterly sub-Q injection dosing regimen, and will further strengthen our franchise leadership in this important growth category. 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're advancing two late-stage clinical product candidates, paticeran and butriceran. While Sanpatro 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're conducting the Apollo B Phase III study, with which we expect to report top-line results in the middle of this year. We're also advancing Vutrisran, which is delivered by a quarterly subcutaneous injection and is also in development for ATTR amyloidosis, as well as a newly announced exciting opportunity in Stargardt disease. In ATTR, we're conducting two Phase III studies. The first is Helios A, evaluating butyric saran in HAT terambuloidosis with polyneuropsy. In 2021, we presented positive nine-month results from the study, which showed the study met its primary and secondary endpoints at nine months with an acceptable safety profile. These data formed the basis for our regulatory submissions to both the FDA and EMA, and we look forward to a potential U.S. approval with the upcoming PDUFA date of April 14, 2022. Additionally, just a few weeks ago, we presented the positive full results for the 18-month endpoints from the study. As a reminder, Helios A is a randomized open-label study in patients with hereditary ATT amyloidosis polyneuropathy. The study enrolled 164 patients who were randomized 3-to-1 to receive butyriceran at a dose of 25 milligrams administered subcutaneously once every three months or butyriceran administered intravenously once every three weeks. at a dose of 0.3 mg per kg as a reference comparator. To start, serum TTR reduction in the Vutriceran group was rapid and sustained over a period of 18 months. Specifically, Vutriceran achieved a mean steady-state serum TTR reduction from baseline of 88%. We're also very pleased to see low interpatient variability in TTR reduction over the time period. As expected, the TTR reduction achieved with futriceran was statistically non-inferior to that observed in the paticeran reference arm. This is important, as we would expect that a comparable level of TTR reduction by futriceran and paticeran should result in a comparable level of clinical impact. We're delighted that Helios A met all secondary endpoints measured at 18 months, including the statistically significant improvements in neuropathy as measured by the modified neuropathy impairment score, or MNIST plus 7, quality of life, gait speed, nutritional status, and overall disability relative to external placebo data from the Apollo Phase III study of PT-SRAN. Furthermore, at 18 months, PT-SRAN also demonstrated improvement compared to external placebo in the exploratory cardiac endpoint NT-proBNP and trend toward improvement in echocardiographic parameters as well as improvement compared to baseline in cardiac uptake of technetium on scintigraphy imaging collectively providing evidence to suggest that butyriceran treatment may potentially result in improvement of cardiac manifestations of disease. Looked at in aggregate and as expected, the treatment effect of butyriceran at 18 months across an array of endpoints is quite similar to that observed with butyriceran. These observations, including especially the exploratory cardiac data, underscore our confidence in the potential of both butyriceran and butyriceran in 80-ter amyloid doses with cardiomyopathy This, of course, is being evaluated in the ongoing Phase III studies, Apollo B with patriceran and Helios B with vitriceran. Let's now review the safety results at 18 months. Vitriceran demonstrated an encouraging safety and tolerability profile. By 18 months, three patients on the vitriceran arm, or 2.5%, discontinued the study due to adverse events. The single new discontinuation since month nine was an event of cardiac failure considered unrelated to study drug by the investigator. By month 18, there were two deaths, neither of which was considered related to study drug. There were two serious adverse events deemed related to which were surrounded by the study investigators, consisting of dyslipidemia and urinary tract infection. These deaths and related SAEs all occurred by month nine and had been previously reported. Treatment immersion adverse events occurring in 10% or more of patients included fall, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia, and dizziness. With the exception of pain in extremity and arthralgia, each of these events occurred at a similar or lower rate as compared with the external placebo. Injection site reactions were reported in five patients, or 4.1%, and were all mild and transient. There were no hepatic safety concerns. We're very pleased with the totality of the results and the profile of Vutriceran that continues to evolve. We believe that based on these data, Vutriceran, if approved, will present an exciting commercial opportunity, providing an attractive treatment option for patients with HAT-triomelidosis with polyneuropathy around the world. Of course, this is just the start for Vutriceran, and we're also conducting another Phase III study, Helios B, which is our ongoing Phase III cardiac outcome study with Vutriceran, in hereditary and wild type 80 teramyloidosis with cardiomyopathy. We were excited to complete enrollment in the third quarter of 2021 with over 600 patients well ahead of schedule due to strong enrollment. Helios-B has a 30-month endpoint of all-cause mortality and CV events, 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 the Apollo-B study and engagement with regulatory authorities. As I alluded to earlier, we also recently announced a promising new near-term opportunity for Vutriceran in Stargardt disease, providing the potential to expand the use of Vutriceran to treat an inherited and progressive ocular disease. This stems from our realization that the Vutriceran mechanism of action via reducing vitamin A can in turn potentially reduce the buildup of toxic metabolites in the eye that lead to vision loss in Stargardt disease. we believe this represents an important expansion opportunity for future SIRM in an area of high unmet medical need where no therapies exist today. We intend to start a Phase III study in late 2022. In addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. As we've highlighted for a bit now, a key growth driver for Alnylam is our expansion beyond rare diseases into prevalent disease, Our program for hypertension is a great example. Zolpizaran, formerly known as LNAGT, is our investigational RNAi therapeutic targeting the genetically validated target angiotensinogen in development for the treatment of hypertension. Zolpizaran is being evaluated in the Phase II cardio program. The first of the two studies, Cardio 1, is currently enrolling and is designed to evaluate the efficacy and safety of Zolpizaran as a monotherapy in patients with mild to moderate hypertension. The second of these studies, CARDI2, was initiated in the fourth quarter and is designed to evaluate the efficacy and safety of Zalbiceran as an add-on therapy in patients with hypertension despite treatment with standard of care. We also continue to gather data from the ongoing Phase I study and recently presented updated data at the American Heart Association Scientific Sessions. Here, single doses of investigation of Zalbiceran resulted in sustained AGT and blood pressure reductions through six months, supporting quarterly and potentially biannual dosing. We also observed that blood pressure response to low salt intake under the peak pharmacodynamic effect was consistent with augmented pharmacology with no hypotensive cardiac adverse events reported. Additionally, co-administration with erbosartan result in additional blood pressure lowering without signals of renal toxicity. Our BSRAN was generally well-tolerated with no treatment-related serious adverse events or study withdrawals, supporting continued development. Another key growth driver for Alnylam in the years to come will be our organic product engine driving sustainable innovation. Here, we made strong progress in the fourth quarter. We moved two programs towards clinic with recent CTA filings for LNXDH and GOUT, And very excitingly, our first CNS program, LNAPP, for the potential treatment of Alzheimer's disease and cerebral amyloid angiopathy. We're thrilled to announce today that the phase one study for LNAPP has now been initiated, and we look forward to starting the phase one trial for LNXDA early this year. There's just a few highlights amongst the many exciting programs being advanced by our organic research engine, and we look forward to updating you all on this progress throughout the year. With that, let me now turn the call over to Jeff to review our financial results and upcoming milestones. Jeff?

Thanks, Akshay. Good morning, everyone. I'm pleased to be presenting Alnylam's Q4 and full year 2021 financial results, which underscore Alnylam's strong commercial capabilities and operational excellence and reflect another impressive quarter of progress on our journey toward building a self-sustainable financial profile aligned with our P5 by 25 goals. After commenting on our fourth quarter and full year 2021 results, I will also provide our financial guidance for 2022. Turning now to a summary of our full P&L results for the quarter and full year. Total product revenues for 2021 were $662 million, or 83% growth versus 2020, with all three marketed products contributing material year-over-year growth. Net revenue from collaborations for the fourth quarter was approximately $60 million, which included recognition of a $25 million milestone due from Novartis following the December FDA approval of Lectio. Our non-GAAP R&D expenses increased 34% in the fourth quarter of 2021 compared to the same period in 2020, primarily due to an increase in expenses associated with our mid- and late-stage pipeline, including investment in our two Phase II studies for V-Ceran and hypertension, CARDIA-1 and CARDIA-2, and ongoing investment in our two ATTR Phase III studies in cardiomyopathy, Apollo B and Helios B. Our non-GAAP SG&A expenses increased 17% in the fourth quarter of 2021 compared to the same period in 2020, primarily due to increased investment in commercial and medical affairs activities to continue supporting OnPatro and GiveLawry and the first full year of Oxlumo commercialization. as well as legal expenses associated with the ongoing Department of Justice investigation. Our non-GAAP R&D and SG&A expenses were approximately $1.2 billion in 2021, representing 16 percent growth versus 2020, as we continue to advance our pipeline and deliver strong top-line growth while maintaining discipline in how we invest in our operations. Our non-GAAP operating loss for 2021 was $528 million, representing a $121 million improvement compared with 2020 as we continue to progress on our journey toward building a self-sustainable financial profile aligned with our P to the 5th by 25 goals. Finally, we ended the year with cash, cash equivalents, and marketable securities of $2.4 billion compared to $1.9 billion at the end of 2020. The increase was primarily due to receipt of the second $500 million payment from Blackstone associated with monetizing 50% of future sales of Lectio, $500 million from drawdown on our credit facility, and more than $200 million from the exercise of employee equity awards offset by cash used in our operations to support overall growth. We continue to believe that our current cash balance will bridge us to a financial self-sustainability profile an enviable position in today's market environment. Now turning to our financial guidance for 2022, which does reflect the potential impact of the ongoing pandemic, particularly during the first half of the year. Starting with net product revenues, we are providing combined net product revenue guidance for Onpatro, GiveLawry, Oxlumo, and Butresaran, assuming approval by the PDUCA date in April. We anticipate combined net product revenues for these four products will be between $900 million and $1 billion, with the midpoint of the range representing 44% growth compared to 2021. We also anticipate that our Q1-22 combined product revenues will be down modestly compared with Q4-2021. While we do expect an increase in patient demand during Q1, driven by an increase in patients on therapy across our products, We expect this will be more than offset by headwinds associated with the stocking, gross to net benefits that occurred in Q4, not recurring in Q1. Our guidance for net revenue from collaborations and royalties is a range between $175 and $225 million, with the midpoint of the range representing 10 percent growth from 2021. Growth in 2022 is expected to come primarily from our collaboration with Regeneron and royalties and milestones from Novartis based on Lectio sales. Our guidance for combined non-GAAP R&D and SG&A expenses is a range between 1.4 and 1.5 billion. The midpoint of the guidance range represents a projected 18 percent increase compared with 2021. We anticipate SG&A growth will be lower than our growth in R&D in 2022 as we seek to generate operating leverage from our existing commercial infrastructure to support our three current commercial products and a potential launch of Lutrisiran. We expect a higher rate of growth for R&D driven by increased investment in CARDIA-1 and CARDIA-2, our two ongoing Phase II Zolviziran studies in hypertension, plus increased investment in our preclinical portfolio as we continue to drive additional innovative organic growth opportunities. Let me now turn from financials and discuss some key goals and upcoming milestones in 2022. To start, we plan to continue commercializing our three existing marketed products on Patro, Kibari, and Oxlumo. We plan to continue advancing our ATTR franchise. With Patrice Rann, we look forward to the potential approval and U.S. launch of the fifth RNAi therapeutic with a PDUPA date of April 14th. Approval in the EU is anticipated mid-year, with subsequent launches in key markets to follow, pending finalization of pricing and reimbursement. With Petisiran, we look forward to top-line results from the Apollo B Phase III study in mid-2022. Next, we have an exciting readout coming up with Simdisiran, where we plan to report Phase II monotherapy results in IgA nephropathy in early 2022. For Zabisiran, the CAR-D1 trial is expected to complete enrollment in mid-2022. For ALN-HPVO2, partnered with VEER, and also known as VEER-2218, We look forward to Phase 2 combination results in the early part of the year. And for ALN-XDH, we're excited to get that Phase 1 study started shortly with top-line results for both this program and ALN-APP expected in 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 your questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have any additional questions.

Our first question comes from Ritu Baral with Cowan.

Hi, guys. Thanks for taking the question. I wanted to ask, as you think about the Vutrusaran approval and the Vutrusaran label, how should we be thinking about potential inclusion of cardiac subgroup data within the label, and should we expect any additional Helios A cardiac data sets presented at upcoming meetings that could either give us more insight into a potential Apollo B placebo, whether it's L-nylam data, whether it's third-party data, et cetera? Thanks.

Thanks for your question, Ritu. I'll just start off by saying that we're really excited about the potential launch of vitreous REM later this year, because we really believe that vitreous REM has a compelling proposition, really with its quarterly subcutaneous regimen allowing patients essentially freedom from their disease. And just one important point that I'd like to make, we do see the launch of vitreous you know, adding to our overall TTR franchise. We don't see it as a net zero-sum game. And we also recognize that we're still early with respect to accessing HA-TTR patients with polyneuropathy, given that Onpatro has been able to secure about 2,050 patients, and there are about 30,000 patients worldwide that are still awaiting treatment. you know, you probably are aware, I know this for you too, that, you know, what we feel so pleased about is that we've been able to essentially replicate with Helios A, both the nine-month and the 18-month data, what we found in Apollo. And I think this is an incredible achievement, actually, when you think about these studies being run at different times. And so the patient population was very similar and the results you know, as I said, were very consistent between Helios A and Apollo. But perhaps, actually, I'll ask you to comment on your views about the cardiac data and, you know, what we can expect there and, you know, what might be on the label.

Yeah, no, thanks, Yvonne. We were obviously very excited about the exploratory cardiac data, whether it's the BNP, the echocardiographic, and those essentially, as you said, were very similar to what we'd seen in Apollo. But most importantly, some new information on technetium scan showing the potential familoid mobilization with reduction in uptake in technetium. So that's really exciting new information and, again, adds to our confidence in our subsequent work in Apollo B and Helios B. So, you know, we continue to feel very good about the potential for both on Patro, T-strand, and Butrystrand in the cardiac context in those studies. As far as the label's concerned, whilst those exploratory data we believe are exciting and speak a lot about the potential for the drug, Helios A was designed and executed exactly as closely as possible to Apollo, and we expect a very similar label, frankly, read to the data that I'm talking about we've largely shared, but, you know, there'll be additional data coming out at meetings through the year, you know, further going into the Helios 8 dataset. But to your specific question, I don't know that those data will shed light on the natural history of the cardiomyopathy and the other features you're alluding to, as we look forward to the Apollo B data, which will be at hand all too soon in the middle of the year, actually. So, you know, I think that's where I'll leave it.

Got it. Thank you.

And, Richard, just as a reminder, you know, with respect to Helios A, of course, the patient population is HATTR with polyneuropathy.

Our next question comes from Gina Wang with Barclays.

Thank you for taking my questions. Just one question regarding the guidance assumption. I assume the main driver will be the ATTR franchise. Wondering if you can give a little bit more color regarding the assumption you have for Unpatro and the Vitruvian for 2022.

Yeah, that's a great question, Gina. You know, this is a very important part of, you know, our go-forward growth opportunity. TTR franchise, we believe that, you know, we will be the leaders in this area in terms of meeting the needs of all patients with TTR over time. Talca, perhaps you could speak specifically to how we're thinking about and on PATRO, I know that one of the things that we're really pleased about actually is the stickiness that we're seeing with on PATRO with a greater than 90% adherence, which actually is remarkable, you know, for therapy that's administered intravenously every three weeks. And as I said before, you know, I think the profile of vitreous saran is particularly compelling. And so I think, as I said, the important point here is that we see the launch of vitreous saran in polyneuropathy is growing the overall TTR franchise. And clearly, that will continue to grow over time, assuming, of course, positive data for both Ampatra and Vutrisran from Apollo B and Helios B, respectively. But perhaps, Tolga, you could provide some additional perspectives on how you see Ampatra and Vutrisran over the course of this year.

Sure, sure. Good morning, everyone. Listen, I mean, I think you really made the point around the fact that the guidance we have provided assumes an accelerated growth for our TTR franchise. That's our anchor franchise. Also, at the same time, our other, you know, ultra-rare disease products will certainly be contributing to that and punching above their weight. When it comes to Vutrisiran, Ivan is spot on. I mean, this is not going to be a zero-sum game. We do anticipate a number of patients that may not have been benefiting from Onpatro will certainly find the profile that we have very appealing, subcutaneous three months and then subsequently six months. We believe that's going to accelerate overall growth profile. And also, as she also pointed out, we are barely scratching the surface in terms of the the number of patients that are being diagnosed and treated. We have 30,000 patients across the world, and a very small number of those are being treated, despite the fact that there are three products available out there. So with the product profile, if approved for butyricinab and polyneuropathy indication, we certainly see an accelerated growth in the U.S. after the PDUFA date, April 14th. And then subsequently also we do anticipate two launches in Japan and Germany later in the fourth quarter, which probably will not contribute as much, but it's going to help the momentum.

Thank you. Our next question comes from Tazina Maag with Bank of America.

Hi, good morning, and thank you for taking my question. Could I ask one on Cartier One? You know, you do have your top-line results. Phase II that are due by this year end, as you mentioned. You know, what should we be looking for for what you would consider to be clinically meaningful data there? And, you know, what would be a good comp on the competitive landscape to kind of judge effectiveness against? Thanks.

Yeah, no, thank you for that question, Zineen. As I'm sure you all know, we are really very excited about the potential that Zalbisram has in addressing you know, patients with hypertension. You know, just to remind you, we've already demonstrated what we need to demonstrate from an efficacy perspective for an approval. In our phase one study, not just as a single dose, we're able to affect blood pressure lowering of, you know, between 10 and 20 millimeters of mercury, which is actually, you know, tremendous. Clearly, we need to deliver on the two phase two studies and then move forward into phase three. But I think from my perspective, what's really kind of exciting about Zarbisran is firstly the size of the opportunity in a very prevalent population, 1.2 billion people across the world with hypertension, but also the very straightforward path to regulatory approval here. And clearly, you know, CARDIA-1 is a key step along that journey. So I'll ask Akshay now to maybe speak a bit more specifically about, you know, what we're looking for with respect to outcomes from CARDIA-1. And then I will turn it over to Tolga to provide some views on the competitive landscape.

Yeah, great. So, as Yvonne said, I think we should once again recall really the very dramatic and impressive results from the Phase 1 study with over 20 mmHg drop in systolic blood pressure, the top dose, maintained out through six months. Now, the Cardio 1 study will hope to replicate the blood pressure results we saw in the Phase 1 study. Historically, anything above a five millimeter mercury drop in blood pressure seems to be notable and people would advance those kinds of drugs into further development. We would hope to do better than that based on what I just told you. Now whether we'll see exactly what we saw in the phase one study, I don't know. But I'm confident we can do better than that in cardio one than the five millimeter threshold I just said. You know, I think the other thing to remember about what's clinically meaningful with the angiotensinogen approach and why it may be sort of not entirely right to just compare it to a blood pressure reduction number is the way blood pressure is being reduced with angiotensin. So, yes, absolute reduction in blood pressure is important, but preventing, you know, fluctuations in blood pressure and having a smoother tonic control of blood pressure is important to patients, and we hope Zolpizaran can do that. We'll get insights into that from CardioOne. And, you know, restoring the physiological nighttime dipping that blood pressure patients often lose, that will be important. So there's so much more to Zarbisaran than just a stark blood pressure reduction number. It's the way it's done and the features I talked about, as well as the adherence advantages with having a potentially once every three or six month administration of the drug. So I'll stop there. Lots to look forward to, I think, in Cardio 1. But, Tolga, you want to say something about the landscape?

Sure. I mean, look, this is clearly a highly genericized class, but this is why I think Alnylam's underlying technology is so exciting. That allows us to really rethink the entire, you know, how to actually manage medicine. In this, despite the fact that there are easily accessible genericized products in this category, we still have 40 million Americans that are suffering hypertensive-related, you know, diseases. And the U.S. is spending about $100 billion, according to ACC, for that. So I believe, from a category perspective, this approach is going to be a tremendous benefit to the broader society. And we are obviously, when it comes to different therapy areas, we are obviously ahead of that curve right now in terms of providing an entirely new class of medicine.

That's great. Thanks, Akshay and Tolga. Sabine, did that answer your question?

Yeah. Thanks for the call, Yvonne.

Thank you. Our next question comes from Palmatits with Stiefel.

Great. Thanks so much, and congratulations on all the progress and getting close to a billion in product revenues, big milestone. I wanted to ask a question on Apollo B. I guess there's right or wrong debate in the investor community on the trial design and powering and how to make sense of the bridge buyer result. I guess now that you've digested their data, can you just point us to the one to two reasons why you're confident that on six-minute walk tests, you'll see decline for placebo and Apollo B, and that you're confident in your powering assumptions? Thanks so much.

Thank you, Paul. That's a great question. So, look, we're very confident, and, you know, we've reiterated, you know, this point about our track record in executing studies in the TTR space, and, you know, we believe that that we put all the mechanisms and we have the expertise in place to design studies, train the sites, work with vendors, et cetera, to make sure we have delivered the highest quality data. Now, you probably know as much about the BridgeBio data as we do, so we're not going to really speak to BridgeBio specifically, but I'll hand it over to Akshay to reprise, you know, our perspectives on Apollo B. Yeah, thanks, Siobhan.

So, Paul, I mean, I think, yes, you know the same data as us, but it's hardly, I think we'd all agree, a full explication of the data, right? We would love a full presentation. There's lots more to understand. So we have partial glimpses. I think a variety of different explanations over time have been offered. by BridgeBio colleagues, that's obviously for them to speak further to their study, but context, bias, training effects on six-minute walk distance, all of these have been mentioned by BridgeBio leaders. So, more for them to comment there. The one thing that struck us about their data, at least what's public, is that the six-minute walk distance didn't seem to perform, and yet other parameters, BNP and KCCQ, showed exactly or very similar to what happened in the ATTRACT study at 12 months. So, it's hard to reconcile that, and I think their explanations or putative explanations around training effects, context, bias, et cetera, it should be borne in mind because of the three parameters, BMP, KCCQ, and six-minute walk distance, the last one would be influenced by those kinds of features. And so, again, that's what we say to see and say from the outside, more for them to comment than I think us. For our part, we've worked in this area for over a decade. We have designed studies in the TTR spaces, significant phase three studies. We've replicated data across studies. I think the Helios A example, where we were just discussing earlier in the call, where the design of the study execution and the data delivery looks so similar to what happened in Apollo, you know, and Apollo was designed in 2013 or executed in 2013. So it shows that we, I think, we take great care and we know how to test hypotheses in this space. very diligently and rigorously. And so we continue to feel very confident in our Apollo B work and how we've designed it and powered it conservatively to hit the primary endpoint of 16 walk distance. And we'll have the data all too soon, middle of the year.

Our next question comes from Alethea Young with Cantor Fitzgerald.

Hey guys, thanks for my question and congrats on all the progress over your 2021. I guess just talking about maybe the trend lines between the T-SERAN and the T-SERAN potential approval and launch. I mean, do you expect kind of the ramp speed to be about the same or do you think the T-SERAN has the potential to have a faster ramp speed since it's already, you know, people kind of know about the class of drugs and it's a sub-Q things?

Thank you, Alicia. That's a great question. I mean, look, we've been really pleased with the performance of OnPatro. We've demonstrated, you know, steady and continuous growth since the launch in 2018. So we're delighted with the contribution that that has made to patients, but also to building our Nilem. You know, look, but, you know, but butreceran, you know, just has such a compelling profile given its quarterly sub-Q regimen. hopefully soon to become a six-monthly regimen. And, you know, we do believe that we have a real opportunity to grow the polyneuropathy market with retreats ran and then subsequently assuming positive results from Helios B, you know, cardiomyopathy as well. But Tolga, perhaps I'll hand this question over to you. I mean, how do you see Vitriceran and Onpatro performing in the market over the next year or so?

Right. Hi, Alethea. Thank you for that question, and thanks, Yvonne. Look, we're able to grow that franchise at 55% after third year of its launch, so clearly the progress we made in terms of growth has been good. Next year, we will continue to obviously grow on PATRO with three surroundings in the market. Based on the profile that Ivan indicated, we would anticipate the source of business we have is essentially mainly coming from academic centers. As is now, the business is evolving more into the community centers, and I think the profile that Butrisan has to offer will be very attractive to those physicians that are looking some different profile. And also, particularly in Europe, where the stabilizers are also indicated for polyneuropathy, a good portion of our growth has been coming from stabilizers, which are, as you know, daily oral tablets. Now, instead of having an infusion, without any premed and three months subcutaneous injection, clearly is a very attractive profile for those patients that may still be on the stabilizer. So overall, we certainly see a modest accelerated growth that we've been able to post versus last year, and we will see that in an accelerated fashion. That's the best way I would be able to describe it to you.

Yeah, Tolga, that's great. So, you know, very excited about the TTR franchise overall. Vitreceran affords the opportunity to, you know, for physicians and patients to start treatment earlier. You know, in patients with polyneuropathy and obviously in the U.S., you know, patients who have the mixed phenotype as well. And then, as Tolga said, you know, potential for earlier switch, just given the much reduced treatment burden of Vitreceran. So hopefully that's answered your question, Alicia.

It did. Thank you. Our next question comes from Anupam Rama with JP Morgan. Hey, guys. Thanks so much for taking the question.

I have a quick question on the net product guidance. So what is assumed specifically for OUS growth and sort of geographic expansion driving growth versus, say, deeper penetration in the US and some of your core countries that you've kind of outline in the slides for OnPatro, GiveLawry, and Oxaluma. Thanks so much.

Thanks, Anupam. That's a great question. Look, you know, if you think about the different products, you know, OnPatro has been on the market now for three years. you know, less opportunity for geographical expansion because we've actually managed to work our way through the various, you know, pricing reimbursement systems ex-U.S. very well, and we have incredibly good coverage in the U.S. as well. You know, Givlari, clearly earlier in its launch, and we see their, you know, continued geographic expansion. Just recently, the NICE approval in the U.K. speaks to that point. And Oxlumo, we're really, you know, 2021 was our first full year since launch. I think what we're particularly pleased about there is really broad utilization across all age groups, disease severity, and I think we're benefiting in Europe with respect to Oxlumo with the centers of excellence that you see there, which meant the patients already being diagnosed, as well as being able to transition patients from our expanded access program, and those were dynamics that we clearly didn't have in the U.S. And as we look forward, you know, I think, you know, we see continued geographical expansion for the more recently launched products, Givlaria and NoxLuber, as well as continued penetration. And from Petro, we see, you know, across the world, you know, increased patient demand, new prescribers, And so we expect to see continued penetration in the U.S. and outside the U.S. But what I'll do, maybe I'll hand it over to Jeff to provide a little bit more color on how we're thinking about the year ahead. Jeff?

Thanks, Yvonne. Good question, Anupam. We're not breaking out specific geographic detail, but I think Yvonne outlined sort of the key elements of what's going to drive our XUS growth. And it really depends on time on the market. The longer the products have been on the market, XUS, the more it's about naive patient funding. And in the case of our ATTR franchise, there's still a big switch element. Products that have been on the market a shorter amount of time still will benefit from additional geographic expansion. So in this case, Oxlumo will be the one that will benefit the most from that going forward. So hopefully that answers the question.

That's great. Thanks so much, guys. Yeah, thanks for the additional color.

Our next question comes from Salvine Richter with Goldman Sachs.

Good morning. Thanks for taking my question. So you have two data reads this year in tissue targets outside the liver. Could you just speak to the ALN, APP, and HSD readouts and whether you could establish a proof of concept with these reads and what you're specifically looking for clinically?

Yes, thank you for that question, Sabine. Look, I'm particularly excited about the opportunity extend the power of the RNAi platform outside the liver. I think this opens up a whole new horizon for our 9M as we think about our growth over the next several years. And as you said, you know, ALN-APP, you know, we're very excited to be moving that forward in patients with Alzheimer's disease. HSD is obviously a liver-directed target. I think what we're excited about with respect with HSD is the size of the NASH patient population, and therefore this is a much more prevalent disease opportunity. So I'm going to hand it over to to actually, first of all, just very briefly describe what we're expecting to see out of our ALN-APP proof of concept study. We'll be getting clinical data at the end of this year. And then also the ongoing phase one study with HSD and NASH. So actually, over to you to maybe address those two programs.

Yeah, thanks, Alvin. So with respect to... ALN-HSD, which in fact is a liver target therapeutic, and HSD is almost exclusively present in hepatocytes. So for NASH, you know, some of the key readouts beyond safety, of course, which is very important, will be you know, evidence for knockdown, and we're taking biopsies in this study, so you can't detect HSD in circulation, and hopefully the biopsies will support the kind of knockdown we're getting. We're obviously confident in that, given what we've seen with many other liver-directed therapeutics with our galnet conjugate system. And, you know, in addition to that, we would welcome seeing changes in transaminases. They're often abnormal in patients with NASH, and some improvements there would be encouraging, of course, as would changes in the biopsy because we won't get definitive biopsies. It's a small study and a definitive readout, but some changes in the histological parameters of NASH relating to inflammation and or fibrosis would be exciting to see. But again, you know, small study, short-term treatment, so it would be, frankly, very surprising if we see that, but we would love to see that if we could. So that's for HSP. For APP, CNS-directed therapeutic for Alzheimer's and for cerebral amyloid angiopathy. First and foremost, safety. This is our first foray into the central nervous system with our novel conjugate system. for neuronal tissues. And then beyond safety, we'll be looking for biomarker knockdown to show target engagement. And so APP, amyloid precursor protein, generates a host of fragments that are detected in the cerebrospinal fluid, and we'll be looking for changes in those fragments degradation fragments from the proteolytic breakdown of APP, one of which, most importantly, is A-beta itself. So that's what we look forward to from those two studies. But agreed, exciting times and great to see the power of RNAi going beyond the liver.

Thanks, actually. And, Fabian, of course, we announced today that our Phase I study has kicked off. with ALN APP. So, you know, we're looking forward to the data that, you know, actually describes at the end of this year. So terrific progress. We're very, very pleased.

Thank you.

Our last question comes from Maury Raycroft with Jefferies.

Hi, good morning. Congrats on the progress and thanks for taking my question. I have a question on Apollo B and For the study, you've got 14 sites in the U.S. and then 52 sites ex-U.S. listed. Just wondering if you can say what proportion of patients in Apollo B are going to be from the United States versus ex-U.S. And then as follow-up, can you talk about sites overlapping between your Apollo B sites and the BridgeBio sites?

Thanks, Maura. I think I'm going to pass that question right across to Akshay. Okay.

Yeah, so Maury, I mean, I think as we've shown before, the performance of our drugs, at least in our definitive experiences in HATTRPN, both in the shape of the original Apollo study with butyran and now with butyran, you know, in the context of HATTRPN, our drugs show very similar effects regardless of geography, frankly. And that's been published. You can go and look it up, etc., So that's important to bear in mind because of the centrality of TTR to these diseases, whether it's PN or other disorders like cardiomyopathy, as we believe. So we're looking forward to similar data, consistency of effect, regardless of geography in Apollo B and Helios B eventually, regardless of the site splits. And with regard to overlap of sites, we don't get into those details, but because largely we don't know if it's that relevant, frankly. Again, because of the strength of our hypothesis, we believe that TTR silencing approaches are the most potent way to address this disease, and the consistency of our prior data speak to that. And again, the encouraging exploratory cardiac data from Helios A just further attests to exciting information we're looking forward to from Apollo B later in the year, including, you know, I'd remind everybody the potential for cardiac mobilization that we saw with the technetium data in Heliopsy. But I'll leave it there. Thanks, Maureen. Thanks.

Do you have a follow-up question?

Well, maybe a quick follow-up. I guess if there are overlapping sites between the two studies, are you getting firsthand insight into the training effect and bias issues that you've discussed on six-minute walk tests, and have you been able to mitigate some of those issues?

Yeah, the bias issues and the training issues, we have reflected commentary from BridgeBio. We don't see any such issue in our studies, either historically or otherwise. And with respect to our studies, We take great care in understanding the natural history of these diseases, in carefully designing the study, in conservatively powering and designing the statistical approach to the study, and then selecting the right contract research organizations to work with who have experience with the kinds of endpoints and managing the kinds of sites we want to work with. And then during the study, diligently following up and making sure sites are performing per expectations. That's a sophisticated approach. That's one we've heard over a decade. We've done multiple phase three studies, all of which have been positive up until now across a range of drugs, including multiple drugs in the TTR space. You know, for BridgeBio, this was their first phase three study. And they would have to answer, you know, how many of those kinds of things were put in place. And they have made the commentary about context, bias, training effects, et cetera. So I'll leave it there, Maury. Thanks. Okay.

Very helpful. Thank you.

Thanks, Akshay. Look, and thank you, everyone, for joining us on this call. 2021 was a remarkable year for our nine, and we made significant progress both commercially and scientifically, and we're very excited about 2022, which is shaping up to build further on that as we continue to fire on all cylinders. Thank you, everybody, and have a great day.

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