Alnylam Pharmaceuticals, Inc. Q1 FY2022 Earnings Call

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; Pushkal Garg, Chief Medical Officer; and Jeff Poulton, Chief Financial Officer. Akshay Vaishnaw, President is unable to join the call today due to a personal conflict. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today’s call, as outlined on Slide 2, Yvonne will deliver introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Pushkal will review recent clinical and preclinical updates; and Jeff will review our financials, 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 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 recently quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only as 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 will now turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. The first quarter of 2022 was another quarter of continued progress at Alnylam across our commercial and pipeline portfolios. First, despite an expected quarter-on-quarter decrease in combined product revenues from our commercial portfolio of ONPATTRO, GIVLAARI and OXLUMO, we observed a steady increase in patients on therapy. Alongside that commercial progress, our RNAi therapeutic pipeline programs continued to advance. With the TTR franchise, we present positive 18-month results from the HELIOS-A Phase 3 study of vutrisiran. The NDA for vutrisiran is under review, with a new PDUFA date of July 14, 2022, following the three months delay we announced earlier in April to allow for the review of newly added information related to a new secondary packaging and labeling facility. We also brought new programs into the clinic with the initiation of two Phase 1 studies. And today, we announced that the Phase 1 study of ALN-XDH in patients with gout has been initiated. Additionally, the first on Alnylam, RNAi therapeutic targeting a CNS disorder, ALN-APP, has entered Phase 1, a very exciting milestone for our platform. And initial top line results from both of these programs are expected in late 2022. Looking further out, we believe Alnylam is poised for significant growth based on three key drivers. First is the potential near-term expansion of our TTR franchise, where we aim to become the global leader in delivering impactful and highly differentiated medicines to patients. Second, is our expansion beyond rare diseases into prevalent diseases. And a third key 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 can drive further pipeline expansion to 2025 and beyond. We believe all of this positions us well to deliver on our Alnylam P5x25 goals, making Alnylam a top biotech company developing and commercializing transformative medicines for rare and common diseases for patients around the world, driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine, all while delivering exceptional 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. The first quarter reflected steady progress as we increased the number of commercial patients on therapy across our three products by 9%. In spite of this increase, Q1 reported revenues decreased by 6% compared to Q4 2021, as Q4 benefited from a variety of non-recurring stocking and gross net benefits. Additionally, we did experience some headwinds from COVID in the early part of Q1, particularly in the U.S., where we saw a decrease in patient compliance across our portfolio in January and February, when Omicron cases were at their peak. We are encouraged by improved market conditions that developed in March and extended further into April. We're cautiously optimistic that COVID will have minimal impact on our commercial operations for the balance of the year. I will now provide details on the performance of each of our products. For ONPATTRO, we achieved $137 million in global net product revenues in the first quarter, representing a 1% decrease compared to the fourth quarter and 34% growth compared to Q1 2021. At the end of Q1, over 2,200 patients were on commercial ONPATTRO treatment worldwide, up from over 2,050 patients at year-end 2021, representing a steady 7% quarterly patient growth. In the U.S., sales of ONPATTRO increased 4% versus Q4 2021 and were primarily impacted by the following: a 7% increase in demand driven by an increase in patients on therapy, which was negatively impacted by a decrease in patient compliance, primarily in January and February when Omicron cases were at their peak along with inventory stocking dynamics, which contributed to a 6% decrease in reported growth and a modest decrease in gross to net deductions in the quarter, contributing to a 3% increase in reported growth. In our international markets, ONPATTRO Q1 product sales declined 5% versus Q4, despite an increase in patients on therapy due to an increase in gross net deductions following Q4, which included several non-recurring benefits, along with an unfavorable foreign exchange impact due to the strengthening U.S dollar in Q1, which impacted results across all three commercial products. Moving to GIVLAARI, we achieved $35 million in global net product revenues in the first quarter, representing a 13% decrease compared to Q4 2021 and 43% growth versus Q1 2021. At the end of Q1, over 400 patients were on commercial GIVLAARI treatment worldwide, up from over 250 at year-end '21 representing robust 14% quarterly patient growth. In the U.S., sales of GIVLAARI decreased 22% versus Q4 '21, primarily impacted by flat patient demand despite a 5% increase in patients on therapy due to reduced patient compliance, which was negatively impacted by COVID in January and February; inventory stocking dynamics negatively impacted reported growth by 15%; and an increase in gross to net deductions in the quarter negatively impacted reported growth by 7% following the fourth quarter, which included several non-recurring gross to net benefits. In our international markets, GIVLAARI delivered 11% growth in Q1 compared with Q4 '21, primarily driven by new patient adds across key markets and geographic expansion, including an initial contribution from the U.K., following the Q1 commercial launch. Moving now to OXLUMO, we achieved $50 million in global net product revenues in the first quarter, representing a 24% decrease compared to Q4 '21 and 59% growth versus Q1 2021. At the end of Q1, over 160 patients were on commercial OXLUMO treatment worldwide, up from over 140 at year-end '21, representing 14% quarterly patient growth. In the U.S., sales of OXLUMO decreased by 5% versus Q4 2021, primarily impacted by a 6% increase in patient demand, driven by an increase in patients on therapy, which more than offset the demand growth and negatively impacted reported growth by 11% due to an increase in gross to net deductions in the quarter. OXLUMO sales decreased in our international markets by 32% during the first quarter compared with Q4, despite an increase in patients on therapy during the quarter, primarily due to an increase in gross to net deductions following Q4, which included several non-recurring benefits, as well as the timing of orders from partners in emerging markets. In conclusion, as expected, despite the reduction in reported revenue growth during the quarter, and challenges from COVID in the early part of the quarter, we remain encouraged by the steady growth in patients we achieved across all three products, particularly our performance with ONPATTRO during the quarter. Additionally, even though we were disappointed by the three-month PDUFA delay for vutrisiran in the U.S., we are poised to launch the product upon potential FDA approval by the new July 14 PDUFA date, and we remain confident that this will continue to represent an attractive option for TTR polyneuropathy patients and an incremental growth opportunity for our TTR franchise. With that, I will now turn it over to Pushkal, to review our recent R&D and pipeline progress. Pushkal?

Thanks, Tolga, and good morning, everyone. Let me begin by updating you on our efforts in ATTR amyloidosis, where we are advancing two product candidates, patisiran and vutrisiran across a number of clinical indications. While patisiran or ONPATTRO is currently approved in multiple markets around the world for the polyneuropathy associated with hereditary ATTR amyloidosis, we are committed to expanding the product's label to the treatment of cardiomyopathy, in both hereditary and wild-type ATTR amyloidosis patients. To this end, we're conducting the APOLLO-B Phase 3 study, and we remain on track to report top line results in the middle of this year. We're also advancing vutrisiran, which is delivered by a quarterly subcutaneous injection, and it's also in development for ATTR amyloidosis, as well as Stargardt disease. In ATTR amyloidosis, we're conducting two Phase 3 studies. The first is HELIOS-A, which is evaluating vutrisiran in hereditary ATTR amyloidosis patients with polyneuropathy. In April 2021, we presented positive results from the study at the AAN meeting, which shows the study met its primary and secondary endpoints at 9 months. Those data form the basis for our regulatory submissions to both the FDA and EMA, which are currently under review. As we announced a few weeks ago, the FDA has extended the review timeline of the NDA to allow for the review of newly added information related to a new secondary packaging and labeling facility. Specifically, we submitted an amendment to our NDA upon learning that the original third-party secondary packaging and labeling facility we planned to use for the vutrisiran launch was recently inspected as part of a routine cGMP inspection. This inspection was unrelated to the vutrisiran application, but as its outcome was unknown, it nevertheless could have resulted in vutrisiran receiving a complete response letter with uncertainty regarding the timeframe for resolution. While our amendment resulted in a three-month extension, we believe that this approach offers the fastest path to potential approval. The updated PDUFA goal date to allow for this review is July 14, 2022. I'd like to reiterate that the inspection issues raised at the original facility were not specifically related to vutrisiran; there have been no questions with regard to the safety or efficacy of the product, and there have been no additional clinical data or trials requested. In addition to these 9-month results, we have also presented positive data from the 18-month analysis of the study in January of this year at the SFNP meeting in France. We're delighted that HELIOS-A met all secondary endpoints measured at 18 months including statistically significant improvements in neuropathy, as measured by the modified neuropathy impairment score or mNIS+7, quality of life, gait speed, nutritional status, and overall disability relative to external placebo data from the APOLLO Phase 3 study. Furthermore, at 18 months, vutrisiran also demonstrated improvement compared to external placebo, and the exploratory cardiac endpoint NT-proBNP showed a trend towards improvement in echocardiographic parameters as well as improvement compared to baseline in cardiac uptake of technetium on scintigraphy imaging. We believe that taken together, these data, along with the exploratory cardiac data from the original APOLLO study, provide evidence to suggest that TTR silencing by patisiran and vutrisiran treatment may potentially improve the cardiac manifestations of this disease. Patisiran also demonstrated an encouraging safety and tolerability profile, as shown by the data on this slide. We're very pleased with the totality of these results and the profile of vutrisiran that continues to evolve. We believe that based on these data, vutrisiran, if approved, will present an exciting commercial opportunity, providing an attractive treatment option for patients with ATTR amyloidosis with polyneuropathy. In addition, I'll also remind you that we are seeking to further reduce the treatment burden for patients by evaluating a six-month regimen of vutrisiran and the extension period of HELIOS-A, with data expected later this year. This is just the start for vutrisiran, as we're also conducting another Phase 3 study, HELIOS-B, which is our ongoing Phase 3 cardiac outcome study with vutrisiran in hereditary and wild-type amyloidosis patients with cardiomyopathy. HELIOS-B, which is fully enrolled with a 30-month endpoint of all-cause mortality and cardiovascular 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 after reviewing the results from the APOLLO-B and engaging with regulatory authorities. In addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. As we've highlighted for some time, a key growth driver for Alnylam is our expansion beyond rare diseases into prevalent conditions. A great example is our program in hypertension. Zilebesiran is our investigational RNAi therapeutic targeting angiotensinogen or AGT, which is in development for the treatment of hypertension. Zilebesiran is being evaluated in the Phase 2 KARDIA program. The first of these two studies, KARDIA-1, is designed to evaluate the efficacy and safety of zilebesiran as a monotherapy in patients with mild-to-moderate hypertension. The second of these studies, KARDIA-2, was initiated late last year and is designed to evaluate the efficacy and safety of zilebesiran as an add-on therapy in patients with hypertension despite treatment with standard of care agents. We've announced this morning that we are experiencing enrollment delays in KARDIA-1 due in part to impacts from the situation in Ukraine, as well as the ongoing pandemic. We're expanding the geographic footprint of the study and are also streamlining certain aspects of the protocol to facilitate enrollment. As a result, we now expect to complete enrollment in KARDIA-1 in early 2023 with top line results expected in mid-2023. We are implementing similar measures in KARDIA-2 as well, so as to complete enrollment at or around year-end. Another key growth driver for Alnylam in the years to come will be our organic product engine driving sustainable innovation, with the goal of bringing two to four new molecules into the clinic each year. Here we achieved some notable progress in the first quarter. We recently announced that the Phase 1 study of ALN-XDH in patients with gout has been initiated. This is an exciting program based on our work with the U.K. Biobank, where we found that heterozygous loss of function of XDH was associated with significantly reduced serum urate and a lower risk of gout. We expect top line results in late 2022. We also achieved a major milestone with the initiation of our Phase 1 study of ALN-APP, our first RNAi therapeutic targeting a CNS disorder. ALN-APP is an innovative program with the potential to address both Alzheimer's disease and cerebral amyloid angiopathy. Initiating this program is a key step towards expanding our pipeline into extrahepatic tissues, and we look forward to top line results in late 2022 here as well. These are just a few highlights among the many exciting programs we're advancing to address important unmet needs for patients. And we look forward to updating you on our progress throughout the year. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

Thanks, Pushkal, good morning, everyone. I'm pleased to be presenting on Alnylam's Q1 2022 financial results and I will also provide an update on our 2022 financial guidance. Turning now to a summary of our full P&L results for Q1 2022. Total product revenues for the quarter were $187 million, or 38% growth versus Q1 2021, with all three marketed products contributing more than 30% year-over-year growth. It is also worth highlighting that year-over-year growth in combined product revenue was held back by approximately 5% due to the foreign exchange impact of a strengthening U.S. dollar, given that approximately 50% of our product revenues are generated from sales in international markets. Net revenue from collaborations for the first quarter was approximately $26 million, representing a 38% decrease compared with Q1 2021, primarily due to a reduction in revenue from our Regeneron collaboration, which is subject to quarter-to-quarter variability dependent on a variety of factors including the level of work completed during the quarter, which is reimbursed by Regeneron. Our non-GAAP R&D expenses decreased 2% in the first quarter of 2022 compared to the same period in 2021, primarily due to modestly reduced clinical trial expenses across the portfolio. However, we do expect an increase in year-over-year R&D expenses for the balance of the year, primarily driven by an increase in spending associated with our plans to increase enrollment in our zilebesiran KARDIA-1 and KARDIA-2 Phase 2 studies. Our non-GAAP SG&A expenses increased 18% in the first quarter of 2022 compared to the same period in 2021, primarily due to increased legal expenses, charitable contributions, and other expenses to support our strategic growth. Our combined non-GAAP R&D and SG&A expenses were approximately $295 million in Q1 2022, representing 6% growth versus Q1 2021 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 Q1 2022 was $117 million, representing a $13 million improvement compared to Q1 2021 as we continue to progress on our journey towards building a self-sustainable financial profile, aligned with our P5x25 goals. Finally, we ended the quarter with cash, cash equivalents, and marketable securities of $2.2 billion, compared to $2.4 billion at the end of 2021. Now turning to our financial guidance. Despite steady progress in adding patients across our three commercial brands in Q1, we have decided to reduce our combined product revenue guidance for two primary reasons. First, as we announced earlier this month, our FDA PDUFA date for vutrisiran has been delayed by three months. Secondly, a strengthening U.S. dollar has created a foreign exchange headwind for our international operations, which today comprise approximately 50% of our global sales. As a result, we have reduced our full year combined product revenue guidance from an original range of $900 million to $1 billion to a revised range of $870 million to $930 million, representing a 5% reduction at the midpoint of the ranges. This updated guidance assumes approval of vutrisiran in the U.S by the revised PDUFA date of July 14, as well as foreign exchange rates as of April 18, that are footnoted at the bottom of our guidance slide. Additionally, we've also reduced our non-GAAP combined R&D and SG&A expense guidance from an original range of $1.4 billion to $1.5 billion to a revised range of $1,390 million to $1,450 million as we seek to partially offset the reduction in our top line guidance. Let me now turn from financials and discuss some key goals and upcoming milestones on deck through mid-2022. To start, we will continue executing on our global commercialization of ONPATTRO, GIVLAARI, and OXLUMO. On the R&D side, we have an exciting clinical readout coming up with cemdisiran, where we plan to report Phase 2 monotherapy results in IgA nephropathy in early 2022. We plan to continue advancing our TTR franchise with patisiran. We look forward to top line results from the APOLLO-B Phase 3 study in mid-2022. With patisiran, we look forward to the potential approval and U.S. launch of our fifth RNAi therapeutic with a new PDUFA date of July 14. Approval in the EU is anticipated mid-year with subsequent launches in key markets to follow, pending finalization of pricing and reimbursement. With ALN-HSD, we expect to report top line results from Part B of the Phase 1 study in patients with NASH in mid-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 additional questions.

Thank you very much for taking my question. When you look at the ONPATTRO performance in the quarter, did you happen to notice any different dynamics in the prescriber, a cardiologist versus neurologist at the start?

So, thanks for that question, David. Real quick, we're pleased with the growth that we're seeing with respect to patient demand with ONPATTRO. But I'll turn it over to Tolga to answer your specific question.

Yes. Hi, good morning. Look, at the end of the day, this is a multisystem disease and we do know that both neurologists and cardiologists play a very important role in the treatment. We have not really seen any change in the way the product is prescribed across the globe. We certainly had seen some, as we indicated on the call, some softness in January and February, particularly in the adherence compliance rate. But we are very encouraged by what we've seen in March. And the Omicron impact obviously is dissipating as we also seen in April.

Got it. And when looking at the shift in guidance as you've cited, the reduction relative to the vutrisiran PDUFA date being put or delayed. How are we supposed to look at it as a component of that change that vutrisiran delay for the overall guidance change? And I guess I'm trying to level in on how should we view expectations for the drug for this year?

Yes, this is Jeff. We updated our guidance for two main reasons. First, the strengthening U.S. dollar affects our revenue from international markets. Second, there is a delay in the PDUFA date for vutrisiran. We believe that vutrisiran will be a key growth driver for the TTR franchise for three main reasons. It is well-positioned for mixed phenotype patients, it may attract switches from competitive products, and it will likely help patients who have been diagnosed but are not yet in treatment. This guidance reflects our expectation that, assuming approval by July 14, we will have the product in the market for one less quarter than we initially expected when we announced it in February.

Tolga, anything you'd like to add?

We are truly enthusiastic about vutrisiran as it offers an exciting growth opportunity for the TTR franchise. We believe we have established a strong growth engine within this franchise across our primary markets, and vutrisiran will significantly enhance that. Additionally, while we have observed that patients are generally excited about the treatment, there is a specific group currently early in their disease progression who will face a critical choice. They may not be ready to begin with the infusion, making this subcutaneous quarterly injection an excellent treatment option for them.

Thanks, Tolga. Does that answer your question?

Thank you very much. And I guess just one more question. On the delay in the PDUFA date itself, can you just reiterate what information the FDA has asked for versus what information you have elected to send them thus far? And you also spoke that there was no other areas of discussion, I expected that Type 1 change going forward?

Pushkal?

Yes, I need to reiterate some of what I've already mentioned on the call. This situation stems from a routine inspection at a third-party secondary packaging and labeling facility. It was a standard Current Good Manufacturing Practice inspection that was not directly related to vutrisiran. We had intended for this facility to assist with the launch of vutrisiran. However, due to some findings from the inspection, the FDA has a timeline to determine the necessary actions, which extended beyond the PDUFA date of April 14 for vutrisiran. If it wasn't classified in time, we risked receiving a complete response letter. The timeline for resolving this can be uncertain, so after discussions with the FDA, we decided to file an amendment to involve a different facility. We accomplished this swiftly and submitted an amendment to the existing NDA, which led to a three-month extension of the PDUFA date. Importantly, there was no request for additional clinical data, safety or efficacy information, or new clinical trials. This situation arose solely from the inspection finding at the facility, which was unrelated to vutrisiran, and our goal was to find the quickest route to secure approval for vutrisiran for patients. We believe this was the best course of action.

That was going to be absolutely ready to launch, assuming FDA approval by the July PDUFA date. Thank you, David. Next question.

Thank you so much.

Hi, good morning. Thanks for taking my question. I had a question about APOLLO-B. So, one difference between APOLLO-B versus BridgeBio's ATTRibute Phase 3 is the inclusion of up to 30% stabilizer progressors. Can you elaborate on the criteria to classify patients as stabilizer progressors for the trial? Maybe talk about what gives you confidence the RNAi mechanism is going to work in these patients?

Yes, absolutely. Thank you, Maury, for your question. We have discussed this at length over the past several months since the BridgeBio results. We remain very confident in the design and execution of the APOLLO-B study. We have specific criteria for including patients with the disease, which require that they have a form of the disease likely to progress during the study and that they could benefit from treatment. We carefully considered the size and power of the study and the methods for oversight and execution of the 6-minute walk test. Regarding your specific question about APOLLO-B allowing up to 30% of patients who have previously been on tafamidis, this is contingent on the investigator's assessment of their progression. There are no formal criteria; it's based on the evaluator's judgment. We were conservative in our study's design to accommodate this. It's a global study, and we anticipated some background of tafamidis usage in this population. We aim to identify the drug's effect size, both as a standalone treatment and in combination, reflecting the reality we expect in the marketplace. We used conservative power assumptions, and I should note that we actually over-enrolled the study by 20%. We believe we are well-positioned for success. What gives us confidence is that we are targeting an upstream mechanism. The data we have generated from APOLLO and HELIOS-A, along with external datasets from investigator studies, shows accumulating evidence suggesting that silencing may significantly impact the cardiac aspects of this disease, as evidenced by biomarkers, echocardiographic parameters, and outcomes. We look forward to the results later this year.

Great.

That's a summary.

Good morning. Thanks for taking my question. Can you help us understand what the impact of COVID in the Ukraine are on the KARDIA-1 study on the ladder? What proportion of the study is based in the Ukraine? And then just curious also on the lowered revenue guidance. Are you comfortable with the FX assumptions for the here?

Great questions. Clearly, the KARDIA studies are incredibly important to us. And we're focused on enrolling these as expeditiously as we can. Obviously, the Ukraine situation is devastating from a geopolitical and human perspective, but it's had an impact on enrollment in KARDIA-1. But perhaps, Pushkal, you can address that, and also some of the approaches that we're taking to try and assure enrollment into the study.

Thank you, Yvonne. I'll address the revenue guidance question. We have initiated two studies for zilebesiran, which is a promising program that we believe can change the landscape for hypertension. KARDIA-1 is a monotherapy study that started in the middle of last year, while KARDIA-2 focuses on combination therapy and began towards the end of last year. Commonly in hypertension and other prevalent diseases, we aimed to conduct the study largely in Eastern European countries, with Ukraine being the first country to begin enrollment. Unfortunately, due to global events, this has been significantly impacted, and we have had to halt all activities in Ukraine, including interactions with investigators and patient outreach. Additionally, we faced challenges from COVID that affected the condition's prevalence. To address these issues, we are expanding the study's geographic footprint by adding more countries and sites. We have also reviewed our protocol to identify ways to simplify enrollment by reducing burdens that were part of the original design. We believe these measures will be beneficial. Although KARDIA-2 was not formally in Ukraine, it does include sites in Eastern Europe that may also feel some effects, so we are applying similar strategies there by broadening the footprint and streamlining protocols to facilitate enrollment. That's the update on our situation.

Yes, and just to remind everybody that we expect to complete enrollment of KARDIA-1 in early 2023 with the top line data expected mid-2023. For KARDIA-2, we're expecting completion of enrollment at around year-end 2022. So, the data will be forthcoming in due course, which we are looking forward to. So, Jeff, I think a question for you in terms of how we thought about FX.

Yes, let me provide more details, Salveen. In our updated guidance slide, we included the foreign exchange rates as of April 18 and also referenced what we used in our original guidance on January 31. You can see the strengthening of the dollar there. To clarify, regarding our exposure to revenue outside the U.S., 49% of our Q1 revenues were in U.S. dollars, 38% were in Europe, primarily in euros, and 13% were from other markets, mainly Japan. The yen and the euro are our largest exposures. Using the revised rates compared to our original guidance, there is about a $20 million headwind. The dollar has further strengthened since April 18. As a rough estimate, each 1% strengthening of the dollar against currencies outside the U.S. results in about a $3 million headwind for us. We hope that the guidance range we provided will accommodate additional fluctuations in foreign exchange, but we do not predict how the rates will move.

Helpful. Thank you.

Great. Thanks so much for taking my question. On vutrisiran, I just wanted to clarify two things. One, I don't know how much detail you go into. But given the proximity of this amendment to the PDUFA, how deep were you in labeling discussions? And I guess, how confident are you that all other aspects of the review were kind of largely resolved and more in the check-the-box phase? And then just second on vutrisiran, can you just clarify, is this going to be in 100% in-office dose product? And are you comfortable that from a market opportunity perspective, there isn't some meaningful subpopulation of patients that really might prefer the independence of home dosing? Thanks so much.

So, I think first question, Pushkal, I think is for you. How confident are we in achieving approval by the new PDUFA date, given the proximity to putting in the amendment?

Yes, thank you for your question, Paul. What I want to emphasize is that this amendment was prompted solely by the inspection issue at the secondary packaging and labeling facility. We believe that all other activities related to the agency's review are on track, and we feel positive about that. I can't comment specifically on the label, but we believe everything else is progressing well. This situation is specifically about the one issue that needed to be addressed as I've mentioned.

Thanks, Pushkal. And Tolga, actually you could take the second question with respect to whether there's a market opportunity or subpopulation with respect to home dosing for people?

Yes. Yes. Hi, Paul. So, this study was obviously designed with physician-administered routing. Therefore, we are eligible for Part B in the U.S. Through the Omicron and COVID, we actually were able to build a pretty substantial site of care and home injection capabilities. Therefore, we believe these capabilities will be nicely applied to a quarterly dosing and subsequently six-month dosing. And given the severity of these patients, we still believe these patients are being monitored by the physician and quarterly or biannual checkups of these patients are actually very much parallel to the regimen that the doctors would like to see. So, in either way, we have the right capabilities that we'll be able to accommodate what the patient needs are.

Okay. So, the whole dosing, just to clarify would be via a healthcare provider visiting the patient. Is that right?

That's exactly right. And right now, at the moment, we actually serve about 20% of our patients through home infusion.

Good morning. Thank you very much. I have a quick follow-up question. I've received several inquiries about the filing. Can you clarify whether this was a voluntary action on your part or if it was suggested by the FDA? I believe that clarification would be helpful for many. Additionally, could you provide more detail about your activities in CNS? Specifically, I would like to know about your starting point regarding dosing, how long you anticipate it will take before we see a clear response, and what you consider to be the key safety risks to monitor. Thank you.

Yes, so maybe with the first question with respect to the filing. Yes, it was a voluntary action that we decided in close consultation with the FDA. So, I think that's another factor that gives us confidence in actually achieving an approval by the PDUFA date. Maybe Pushkal, you could take the question on the CNS opportunity where we are with ALN-APP.

Absolutely. So, as we announced today, we're very excited that we kicked off this program; we found the CTA at the end of last year with ALN-APP, which is our first CNS-directed RNAi therapeutics. We kicked off the initial study in patients with early-onset Alzheimer's disease, we're going directly into patients with this therapeutic, first with some single doses and ultimately with some multiple doses in the context of the study. It is a very interesting upstream target that we think has applications for broadly Alzheimer's disease as well as for other indications, including cerebral amyloid angiopathy, which is a devastating disease that results in cerebral hemorrhage. So, both of these are part of the development plan. The initial study, as I said, goes into EOAD patients as a population that we think has a tremendous unmet need, lacking a lot of other confounding comorbidities that allows for a clean background for us to assess the safety and tolerability and knockdown of this of CNS therapeutics. So, we'll be looking closely in the single ascending dose cohorts for safety and tolerability. And then important biomarkers that we'll be looking at, particularly soluble APP alpha and beta in the CSF, that's going to help us understand knockdown. There are also imaging modalities that are incorporated into the study and other biomarkers that we'll be looking at in the context of the study to follow patients and look at clinical pharmacologic activity. But the main thing we'll be looking at will be soluble APP alpha and beta in the CSF. In terms of the exact timeframe that we're actively conducting the study at multiple sites, and as we've said, assuming enrollment goes as predicted, we expect to be able to report out some proof-of-concept data at the end of the year.

And just to add, one of the reasons why we're so excited about this program is obviously there's huge unmet medical needs in patients with Alzheimer's as well as cerebral amyloid angiopathy. But if we're successful with these indications that we do have the opportunity to bring the power of the RNAi platform to many, many other CNS diseases where it represents huge medical needs. So, we're very focused on ensuring progress with this program and hope to deliver data.

Good morning. Thanks for taking the question. Just a quick follow-up to Paul's question. Can you comment on whether you guys have started labeling discussions before the vutrisiran PDUFA delay? And also, has there been any indication that the new Fill & Finish plant requires an inspection at this point after I guess, the FDA has had a chance to review the additional CMC package submitted?

So, I think there's a few questions for you, Pushkal, discussions and indications around the potential for an inspection.

Yes, this is Pushkal. We have had a late cycle meeting, and discussions about labeling are ongoing alongside the regulatory review of the application. All these activities are in progress. I want to emphasize that the recent unrelated inspection at our packaging and labeling facility has been managed well. Our team was able to swiftly amend our application for the second facility, significantly reducing the associated risk. To address your second question, the facility we amended to is one we are familiar with as we already use it for ONPATTRO and GIVLAARI, and we planned to use it for OXLUMO as well. It has been inspected by the FDA and EMA in 2020 and 2021, which gives us a strong level of confidence in its regulatory standing. The decision on whether an inspection is necessary rests with the FDA, and we respect their judgment. However, we are confident in the quality and capabilities of the facility we added to our application. I hope that answers your question.

Got it. If I can ask a quick follow-up, Jeff and Tolga, you mentioned compliance headwinds in January and February due to COVID. This is something you haven't really discussed before, despite some challenging times during the pandemic. Was there something specific about the Omicron wave in January and February that impacted ONPATTRO compared to previous years? I think, Tolga, that's a question for you. I mean, some more color because it impacts specifically with ONPATTRO.

Absolutely. I mean, look, each variant humbles us. We always learn new things about how the health system impacts. We have actually anticipated and I think shared some of our insights early on, particularly with the AHP patient when it comes to GIVLAARI. With ONPATTRO, given the elderly patient population and given the healthcare system, the healthcare system reacted across the world. We certainly had seen that. Some skipped dosing, but it has nicely recovered in March. So, we're rather comfortable where the direction is going.

Yes, that's great, Tolga. So, I mean, we're optimistic with you going forward. But as Tolga said, I think this virus has shown the potential for surprises on multiple occasions.

Understood, Yvonne.

Thank you. Next question.

Hi, good morning. Thanks for taking my question. Just another point of clarification on your revised guidance. So, it does include vutri as it gets approved. But how are you thinking about the early days of the launch for vutri and PN? And specifically, its interaction with ONPATTRO, do you expect cannibalization to be part of the early launch metrics there? Or are you assuming a different patient population will start on vutri versus on ONPATTRO? I think if you could give some color on that, that's great. And then secondly, I have some data too soon as well for ACTR. And just wondering how you think that could potentially change the competitive dynamic in the marketplace with another entrant? Thank you.

Tolga, I think you can answer the first question around the interplay with respect to vutri and ONPATTRO, how are we thinking about the early days of the launch?

I believe we should take a moment to review the numbers we are discussing. From the vutri opportunity and the dynamics of new competitors, we are still looking at 20,000 to 30,000 patients for PN and identified mixed patients. As the market leader, we have increased our patient count from 1,525 in Q1 '21 to 2,200 this past quarter. This steady increase reflects our commitment to treating this serious condition. I am confident that vutrisiran will help us attract more newly diagnosed patients, particularly those diagnosed early in their treatment. We are already observing this trend with ONPATTRO. Additionally, we expect to see more patients switching from existing therapies that may not have been effective for them, which will create further opportunities. While we are not currently providing guidance on the exact numbers of new and switched patients, we do expect overall growth to pick up speed.

Yes, that's a great answer, Tolga. And maybe just to add that we really are still in the early stages of building the TTR franchise. We're currently addressing the needs of 2,200 patients with ONPATTRO. But there are another 30,000 or 40,000 patients there who are addressable by ONPATTRO. So, there's still lots of growth to come here. The second question, Tolga, I think is also for you. How are you thinking about new entrants into the market, particularly for ACTR?

Yes, I mean, specifically with the PN category, we see an accelerated growth also in diagnosis. And I think, more share of voice, increased share of voice, I think, is going to certainly help that pattern. If you think of the vutrisiran profile of subcutaneous injection every quarter is certainly we believe will remain attractive and will continue to help us be the market leader. But I think again, we shouldn't think of this category as a zero-sum game. More entrants, like in the MS category, will probably help further the expansion of the category and given what Yvonne indicated that there are still a lot of undiagnosed or untreated patients.

Thanks.

Next question?

Thank you for taking my questions. I have two clarification questions. And one hypothetical question. So, for APOLLO-B, do you see data on the blinded base? And then for overlapping sites, do you use the same CRO versus BridgeBio's ATTRibute study? And for the hypothetical question, just say in the unfortunate event, APOLLO-B missed the 6-minute walk test endpoint, what kind of secondary endpoint data that will convince you HELIOS-B outcome data will be positive?

Pushkal, I think three questions for you there.

Yes, absolutely. Hi, Gena. Regarding the blinded data, as is standard in running a blinded clinical trial, we have team members in our clinical department and data management who monitor the blinded data throughout the study. This is to ensure proper conduct of the trial, verify that the correct patients are enrolled according to the enrollment criteria, and investigate any outlying data points. For example, if someone records a 2-meter walk in six minutes or 2,000 meters, we would query the site to check for potential data entry errors or identify any patterns indicating that sites may not be following procedures correctly. These activities are typical of how a study is conducted to ensure we have a clean and interpretable data set when we lock the database. Regarding overlapping sites, we estimate that about 20% to 25% of the sites may overlap. However, this does not necessarily represent the number of patients who may be participating in both studies. Our study is conducted within the framework of our protocol with the CROs involved, which includes clear trial procedures, training, and oversight specifically for APOLLO-B. I cannot comment on the CROs that BridgeBio used. In response to your third question, which you termed hypothetical, we will review the complete data from this study. The primary endpoint focuses on the 6-minute walk test, but we will also consider other important secondary endpoints like KCCQ, BNP, and echocardiographic parameters. Although the study is relatively short at 12 months, we will examine event rates related to mortality and hospitalization to gauge the effects of silencing in this patient population. This analysis will inform our understanding of APOLLO-B while also providing insights into the broader implications for the disease in relation to HELIOS-B. I hope that answers your questions.

Thanks, Pushkal. Gena, does that answer your question?

Yes. Regarding the secondary endpoint, TCCQBnT event rates, what specific separation are you looking for that would give you confidence that HELIOS-B will be positive?

Gena, it's really impossible to answer that question. I think we'll be looking at the totality of the data to make that assessment. There's no single data point or number that we'll be focusing on.

Our last question comes from Anupam Rama with JPMorgan.

Hey, guys. Thanks so much for taking the question. Maybe I had a follow-up on Gena's question. But I just wanted to confirm that you'll have some of that mortality, CV hospitalizations in the top line results versus waiting for a full presentation at a medical conference or something like that. And specifically, what your expectations on those two metrics would be at a 12-month look? Thanks so much.

Yes. Anupam, those are predefined secondary endpoints. As is our practice when reporting top-line results, we will discuss P values related to both primary and secondary endpoints. You can expect that information in the top-line results, but we will provide additional details at a medical conference later. I apologize, I think I missed the second part of your question.

Like, what would be your expectations at a 12-month look on CV hospitalizations and mortality?

Oh, yes. The study was not designed to focus on those endpoints at all. They are being recorded, but they are not primary endpoints, and as you can imagine, 12 months is a relatively short time to see effects on those. I want to remind you that with tafamidis, it took 9 months to start seeing a difference in hospitalizations and about 12 to 18 months to see a difference in mortality. However, our post-hoc data from APOLLO showed potentially much earlier differences in those events based on some data published a few years ago. There is potential, and we have observed effects of silencing on echocardiographic parameters at earlier time points. I believe you are looking forward to seeing the results and understanding what they entail. That’s why we have highlighted these as important secondary endpoints to examine.

We are indeed. Thank you, everyone, for joining us on this call. 2022 is off to a steady start as we continue to advance our systems. We did with all the exciting pipeline programs that we have in development. There are a lot of exciting and important upcoming milestones over the course of the year, and we look forward to updating you on these. So, thank you to everybody for joining our call today and have a great day.

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