Alnylam Pharmaceuticals Inc (ALNY) 2022 Q1 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals First Quarter 2022 Earnings Conference Call. (Operator Instructions)

Please be advised today's conference may be recorded. (Operator Instructions)

I'd now like to hand the conference over to your host today, 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 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 provide some introductory remarks and 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 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 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 the date of this recording and should not be relied on 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. 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 continue to advance. With the TTR franchise, we presented positive 18-month results in the HELIOS-A Phase III study of vutrisiran. The NDA for vutrisiran is under review with a new PDUFA date of July 14, 2022, following the 3 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 2 Phase I studies. And today, we announced that the Phase I study of ALN-XDH in patients with gout has been initiated. Additionally, the first Alnylam RNAi therapeutic targeting a CNS disorder, ALN-APP, has entered Phase I, 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 3 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 the third key growth driver for the company comes from our sustainable innovation engine comprised of new platform enhancements, opportunities with extra hepatic delivery and our ability to find new genetically validated targets, which can drive further pipeline expansion to 2025 and beyond.

We believe all of this positions us well to deliver on our Alnylam P5x25 goal, 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?

Thank you, Yvonne, and good morning, everyone. The first quarter reflected steady progress as we increased the number of commercial patients on therapy across our 3 products by 9%. In spite of this increase, Q1 reported revenues decreased by 6% compared with Q4 2021 as Q4 benefited from a variety of nonrecurring stocking and gross-to-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 that have extended further into April.

And we're cautiously optimistic that COVID will have minimal impact on our commercial operations for the balance of the year, recognizing that the course of the pandemic remains uncertain. 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 with the fourth quarter and 34% growth compared with Q1 2021.

At the end of Q1, over 2,200 patients were on commercial ONPATTRO treatment worldwide, up from over 250 patients at year-end 2021, representing 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. 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-to-net deductions following Q4, which included several nonrecurring benefits, along with an unfavorable foreign exchange impact due to strengthening U.S. dollar in Q1, which impacted results across all 3 commercial products.

Moving to GIVLAARI. We achieved $35 million in global net product revenues in the first quarter, representing a 13% decrease compared with 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 350 at year-end '21, representing robust 14% quarterly patient growth. In the U.S., sales of GIVLAARI decreased 22% versus Q4 '21 and were primarily impacted by the following: 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, which negatively impacted reported growth by 15%; and an increase in gross to net deductions in the quarter, which negatively impacted reported growth by 7% following the fourth quarter, which included several nonrecurring gross-to-net benefits.

In our international markets, GIVLAARI delivered 11% growth in Q1 compared with Q4 '21, with the growth primarily driven by new patient adds across key markets and geographic expansion, including an initial contribution from the U.K. following Q1 commercial launch.

Moving now to OXLUMO, we achieved $15 million in global net product revenues in the first quarter, representing a 24% decrease compared with 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 and were primarily impacted by the following: a 6% increase in patient demand driven by an increase in patients on therapy, and an increase in gross-to-net deductions in the quarter, which more than offset the demand growth and negatively impacted reported growth by 11%.

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 nonrecurring benefits as well as the timing of order in partner 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 3 products, particularly our performance with ONPATTRO during the quarter. Additionally, even though we were disappointed by the 3-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 2 product candidates, patisiran and vutrisiran, across a number of clinical indications. While patisiran or ONPATTRO is currently approved in multiple markets around the world to treat 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 III 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 is also in development for ATTR amyloidosis as well as Stargardt disease. In ATTR amyloidosis, we're conducting 2 Phase III 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 showed 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 time line 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 plan 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 time frame for resolution. While our amendment resulted in a 3-month extension, we believe that this approach offers the fastest path to a 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 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 III study.

Further, at 18 months, vutrisiran also demonstrated improvement compared to external placebo in the exploratory cardiac endpoint, NT-proBNP, and trends 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. Vutrisiran also demonstrated an encouraging safety and tolerability profile, as shown by the data on this slide.

We're very pleased with the totality of the 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 hATTR amyloidosis with polyneuropathy.

In addition, I'll also remind you that we are seeking to further reduce the burden of treatment for patients by evaluating an every 6-month regimen of vutrisiran in the extension period of HELIOS-A, with data expected later this year. Of course, this is just the start for vutrisiran as we are also conducting another Phase III study, HELIOS-B, which is our ongoing Phase III cardiac outcome study with vutrisiran in hereditary and wild-type amyloidosis patients with cardiomyopathy.

HELIOS-B, which is fully enrolled, 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'll consider this after reviewing the results from 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 II KARDIA program. The first of these 2 studies, KARDIA I, 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 II, 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 I, in part due to impacts of 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 I in early 2023, with top line results expected in mid-2023. We are implementing similar measures in KARDIA II 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 2 to 4 new molecules into the clinic each year. Here, we achieved some notable progress in the first quarter. We announced this morning that the Phase I study of ALN-XDH in patients with gout has been initiated. This is an exciting program based on our work with the UK 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 I 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, and good morning, everyone. I'm pleased to be presenting 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 3 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 and given that approximately 50% of our product revenues are generated via 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 the year-over-year R&D expenses for the balance of the year, primarily driven by an increase in spend associated with our plans to increase enrollment in our zilebesiran KARDIA I and KARDIA II Phase II 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 with 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 3 commercial brands in Q1, we have decided to reduce our combined product revenue guidance for 2 primary reasons: First, as we announced earlier this month, our FDA PDUFA date for vutrisiran has been delayed by 3 months. And 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 have 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 billion to $1.450 billion 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 zilebesiran, where We plan to report Phase II 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 III study in mid-2022.

With vutrisiran, 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 midyear 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 I 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. (Operator Instructions)

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

When you look at the ONPATTRO performance in the quarter, did you happen to notice any different dynamics in the prescriber, a cardiologist versus a neurologist to start?

So thanks for that question, Dave. Look, 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.

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've also seen in April.

Got it. And when looking at the shift in guidance, as you cited, reduction relative to the vutrisiran PDUFA date being delayed. How are we supposed to look at it as a component of that change, the 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, as I said on the call, for 2 primary reasons. One is the FX, strengthening U.S. dollar, given the percentage of revenue that we generate from ex-U.S. markets. And secondly, because of the delay in the PDUFA date for vutrisiran. And the thinking there is that we've talked about vutrisiran being a growth driver overall for the TTR franchise for, I would say, for 3 primary reasons.

One is that we think it will be very attractively positioned for those mixed phenotype patients, we think, for potential switches from competitive products. And then lastly, for patients that have been diagnosed but not yet on treatment. We think vutrisiran will grow our overall franchise as a result of its profile. So the guidance just reflects the fact that we'll have -- assuming approval by July 14, that we'll have the product on the market for 1 less quarter than we originally anticipated when we guided in February.

Tolga, anything you'd like to add?

Yes. I mean, look, we're really excited about vutri. It clearly provides another growth opportunity for the TTR franchise. We built what we'd like to think a good strong growth engine within the TTR franchise across our key markets. And vutrisiran will be a great addition to that. What we've also seen is, although anecdotally, patients are excited about this. There is a group of patients that actually are going to be making an important decision. They're early in their disease progression. So they're not -- they may not be willing to get and start with the infusion, and it's going to be a really great treatment option for those patients who would then be able to take advantage of our subcutaneous quarterly injection.

Thanks, Tolga. And David, does that answer your question?

And I guess, just 1 more question on the delay in the PDUFA date itself. Could you just reiterate what information the FDA has asked for and versus what information you have elected to send them thus far? And you also spoke that there was no other areas of discussion. I expect that wouldn't change going forward.

Pushkal?

Yes. So I think, look, in terms of -- I'll probably have to reiterate a little bit of what I said on the call already. This is really all a result of a third-party secondary packaging and labeling facility that had a routine CGMP or current good manufacturing practice inspection. It's just a routine inspection. It was not related to vutrisiran. But this was a facility that we were going to -- we had proposed for -- to help with the launch of vutrisiran. But as a result of that, there were some inspection findings and the FDA has a time line by which they have to sort of classify that and determine what action is necessary.

That time line was beyond the PDUFA date, the April 14 PDUFA date for vutrisiran. And so as a result, if it wasn't classified, we ran a risk of getting a complete response letter. And the time line for resolution of that, as you know, can be somewhat uncertain. So based on that, we had discussions with the FDA, and we elected to file an amendment to bring on board a secondary, a different facility, and we were able to do that quickly and file an amendment to the existing NDA. That resulted in this 3-month clock extension in the PDUFA date.

But just to reiterate, there was no request for additional clinical data of any sort. There's no more safety or efficacy data that were asked for. There's no new clinical trials, et cetera. This really just came about because of this inspection finding at this facility unrelated to vutrisiran and our decision to really find the most expedited path to get vutrisiran approved into patients, and we think this was the best path to do that. So that's what this is all about.

Thanks, Pushkal. And we're absolutely ready to launch, assuming FDA approval by the July PDUFA date.

Our next question comes from Maury Raycroft with Jefferies.

I had a question about APOLLO-B. So 1 difference between Apollo-B versus BridgeBio's ATTRibute Phase III is 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.

Jeff, that's one for you.

Yes. Absolutely. Thanks, Maury, for your question. Look, I think -- we talked about this at some length over the last several months since the BridgeBio results. We remain quite confident about the design and the execution of the APOLLO-B study for a variety of reasons, both the criteria we're using to include patients with the disease, the clinical criteria that we require to show that they have disease that's likely to progress during the course of the study and likely to benefit from therapy, the sizing and powering of the study, the methods that we put in place in terms of the oversight and execution of the 6-minute walk test.

To your specific question, Maury, about the -- we do allow, in APOLLO-B, up to 30% of patients that have been previously on tafamidis. They -- assuming that they have been determined to progress based on the investigators' assessment, there's no formal criteria for that. That's really based on the investigators' assessment of the patient. And I think we powered very conservatively our study to allow for that. It's a global study. And so there was -- we knew there was going to be some background tafamidis use in the population. We certainly want to establish what the effect size of the drug is, both as a monotherapy and in combination, because we know that some of the reality of what's going to be happening in the marketplace. But we took very conservative powering assumptions.

And I'll remind you, we actually overenrolled by 20% in the study as well. So I think we're very well positioned for that. With regard to what gives us confidence, I think, ultimately, what gives us confidence is really the fact that we're targeting an upstream mechanism and in every data set that we've generated, both Apollo as well as with HELIOS-A as well as external data sets that have been generated through investigator studies, there's an accumulating amount of data that suggests the silencing may have an important effect on the cardiac aspects of this disease, whether it's measured by biomarkers, whether it's measured by echocardiographic parameters or even outcomes. So we look forward to the results in the middle of this year.

Good. That's a pretty good summary.

Our next question comes from Salveen Richter with Goldman Sachs.

Can you help us understand what the impact of COVID and the Ukraine are on the KARDIA-1 study on the latter? What proportion of the study is based in the Ukraine? And then just curious also on the lowered revenue guidance, I mean are you comfortable with the FX assumptions for the forward here?

Two great questions. Clearly, the KARDIA studies are incredibly important to us, and we are focused on inverting these as expeditiously as we can. Obviously, the Ukraine situation is devastating from a geopolitical and human perspective, it has 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 trying and ensure show enrollment into the study. And then we'll go to Jeff for the revenue guidance question.

Yes. And thanks, Salveen, for your questions. So look, with -- we've got these 2 studies that we've kicked off, as we said, for zilebesiran, which is a very exciting program for us that we think can actually transform the landscape for hypertension.

KARDIA-1 is a monotherapy study. It started in the middle of last year. And then KARDIA-2 is a study looking at combination therapy that started towards the end of last year. As is pretty common in diseases like in hypertension, other common diseases, we do have -- we did envision a geographic footprint for the study that was heavily reliant on Eastern European countries, and for KARDIA-1, specifically Ukraine. That was the first study -- the first country that was up and running, and we were expecting -- there was a lot of investigator interest in this study in the Ukraine.

Unfortunately, because of global -- the global events, that's been severely impacted. So while we were enrolling, we've actually had to stop -- curtail all our activities in the Ukraine, including interacting with investigators, being able to continue dosing patients, et cetera, and have had to put those activities on hold. There was also a headwind with COVID with regard to the sort of a prevalent condition that we were also facing.

So what we've done is we've actually expanded the geographic footprint of this study. We're bringing additional countries online, additional sites online as an important mitigation measure. And then the second thing is that we've had the opportunity to go back and look at our protocol and look for areas where we can actually just facilitate enrollment by streamlining certain activities reducing any burdens that may have been included in the protocol as originally conceived and streamline that, and we think that's going to help as well. So that's what's led to that change.

KARDIA-2 was not formally in the Ukraine, but it wasn't some -- it has been -- there are sites in Eastern European countries that may have some effect impact as well or feel some impact. And so we're also really employing similar measures there, broadening the footprint and have amended the protocol to sort of streamline some of the procedures in the study as well. So that's the story there.

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

Yes. Let me give you a little bit more detail, Salveen. So we -- in our guidance slide, updated guidance slide, we did a footnote at the bottom what the FX rates are that we've included in the updated guidance, which were as of April 18, and we also provided what we included in our original guidance on January 31. So you can see the strengthening of the dollar there. Just to make sure it's clear, the exposure that we've got to ex-U.S. revenue, based on our Q1 revenues, 49% of our revenues were in the U.S. dollar in Q1; 38% were in Europe, so primarily in the euro; and 13% were in ROW markets, primarily Japan. So those are -- the yen and the euro are our 2 biggest exposures.

If you use the revised rates that we have compared to what we used in the original guidance, that's about a $20 million headwind relative to the original guidance that we gave. And the dollar has actually further strengthened since April 18. Now in terms of the sensitivity to that, just as a rough estimate, sort of from this point going forward, each 1% strengthening of the dollar against ex-U.S. currencies is about a $3 million headwind for us. So the guidance range that we gave, hopefully, would accommodate additional movements in FX. But we're not -- obviously, we're not in the business of predicting which way the FX rates are going to move.

Our next question comes from Paul Matteis with Stifel.

Great. On vutrisiran, I just wanted to clarify 2 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 dosed products? 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?

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. Thanks for your question, Paul. I think -- look, I think what I will say is, again, this amendment was solely prompted by this inspection issue at the secondary packaging and labeling facility. We feel all other activities with regard to the review that the agency was conducting were on track, and we felt good about it. I can't comment specifically about the label. But I think we feel everything else is really going well and on track, and this is really solely about this one issue that needed to be -- as I've discussed.

Thanks, Pushkal. And Tolga, Perhaps you could take the second question with respect to whether there's a market opportunity to that population with respect to home dosing?

Yes. 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 quarterly dosing and subsequently 6-monthly 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.

So the home dosing, just to clarify, would be via a health care provider visiting the patient. Is that right?

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

Our next question comes from Matthew Harrison with Morgan Stanley.

Great. I guess just 1 quick follow-up. Can you -- there seems to be -- or I've gotten a lot of questions on the filing here. And just to make sure, was this a voluntary action by you or whether it's suggested by the FDA? If you could just clarify that? I think that would help a lot of people.

And then my sort of key question is just, can you talk a little bit about what you're doing in CNS more in depth, and in particular, sort of where you're starting in terms of dosing, how long you think it might take before we see some clear knockdown and what you see are some maybe of the key safety risk to watch out for?

Yes. So maybe 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've kicked off this program. We filed the CTA at the end of last year with ALN-APP, which is our first CNS-directed RNAi therapeutic. And we've 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.

And it is a very interesting upstream target that we think has applications for broadly Alzheimer's disease as well as for another indication, cerebral amyloid angiopathy, which is a devastating disease that results in cerebral hemorrhage. So both of those 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, lacks a lot of other confounding comorbidities, et cetera, so it should allow for a clean background for us to assess the safety and tolerability and knockdown of this first CNS therapeutic.

So we'll be looking closely in the single ascending dose cohort 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 in the study, other biomarkers that we'll be looking at in the context of the study to follow patients and look at 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 time frame, look, 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 a huge unmet medical need in patients with Alzheimer's as well as cerebral amyloid angiopathy. But if we're successful with these indications, it really does unlock the opportunity to be able to bring the power of our RNAi platform to many, many other CNS disease as well. As you know, there are huge medical need. So we're very focused on ensuring progress of this program and obviously delivering support data at around the end of the year.

Our next question comes from Ritu Baral with Cowen.

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 and 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 2 questions for you, Pushkal, with respect to label discussions and any indications around the potential for an inspection.

Yes. So Ritu, it's Pushkal. I think -- yes. I mean what I can say is that we've had a late cycle meeting, we -- label discussions, et cetera, is an ongoing process that happens in parallel with the regulatory review of the application. So all those activities were underway.

And as I said, this is really all about this unrelated inspection that happened at this packaging and labeling facility. And I actually -- I think we -- what I would say is that it's a compliment to our teams and the discussions that we're actually able to, with agility, put in an amendment quickly for the second facility and actually mitigate this risk quite substantially. So I think that's testament.

To your second question, which is somewhat related to that, the facility that we've amended to is one that we actually have experience with. It's a facility that we already use for ONPATTRO. We use it for GIVLAARI. We were actually -- plan could be using it for OXLUMO. And it's been, in fact, inspected by FDA and EMA in 2020 and 2021. So we have a lot of reasons to have confidence in sort of regulatory standing of that particular facility. It's always up to the FDA with an amendment to make their own determination as to whether inspection is necessary. And obviously, we defer to their judgment. But what we do feel is quite confident in the facility that we've supplemented or amended to in our application and the quality of what's done in that facility. So hopefully, that answers your question.

Got it. And if I can squeak in one very quick follow-up. Jeff and Tolga, you mentioned January, February compliance had headwind -- COVID headwinds. It's not something that you guys have previously talked about despite sort of definitely worse points in the pandemic. Was there something unique to the January, February Omicron wave that hit ONPATTRO versus the prior years?

So I think Tolga, that's a question for you. I mean, some more color on the COVID impacts absolutely, particularly with respect to 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 health care system, how the health care 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. I mean we're optimistic going forward. But as Tolga said, I think this virus has shown the potential to surprise us on multiple occasions. But we're cautious.

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

Just another point of clarification on your revised guidance. So it does include vutri, assuming that 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 who's already on ONPATTRO? And if you could give some color on that, that's great.

And then secondly, Ionis does have some data due soon as well for ATTR. And just wondering how you think that could potentially change the competitive dynamic in the marketplace with another entrant?

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

Right. So Tazeen, I think if you -- we should kind of maybe take a quick step back and look at the numbers that we're discussing here. I think from -- both from vutri opportunity as well as any new competitive entrants dynamic, we're still looking at 20,000 to 30,000 patients, PN and mixed phenotype patients. And being the market leader, we're now, as we announced this quarter, we moved from 1,525 in Q1 '21 to 2,200 patients in this past quarter. So we're adding a steady increase of patients for the treatment of this devastating condition. And vutri will certainly help us, I believe, to bring in some naive patients, especially those patients that are diagnosed early in their treatment.

We start seeing that dynamic already with ONPATTRO. We also certainly anticipate an acceleration of switches from the existing therapies that they may have been progressing or may not have found the best treatment regimen, which certainly provides that opportunity. And we do anticipate a number of ONPATTRO patients that might be interested in this new treatment regimen that they may prefer it. We're not guiding right now about the net and switch numbers, but we do overall anticipate growth to accelerate.

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 still lots of growth to come here. The second question, Tolga, I think it's also for you, how you're thinking about new entrants into the market, particularly from Ionis.

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 vutri's profile of subcutaneous injection every quarter, it certainly, we believe, is -- it will remain an 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. I believe more entrants like in the MS category will probably help further expansion of the category given what Yvonne indicated that there are still a lot of undiagnosed and untreated patients.

Our next question comes from Gena Wang with Barclays.

I have 2 clarification questions and 1 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 hypothetic questions, just say in the unfortunate event APOLLO-B missed a 6-minute walk test endpoint, what kind of a secondary endpoint data that will convince you HELIOS-B's outcome data will be positive?

So Pushkal, I think, yes, there are 3 questions for you there.

Yes. Absolutely. Gena. So look, on a couple of these blinded data, so as every sponsor does running a blinded clinical trial, we have folks in our clinical team, data management, et cetera, who are responsible for looking at blinded data over the course of the study. That's really to ensure that the study is being conducted properly to make sure that proper patients are being enrolled and they meet enrollment criteria, to look at outlying data points. If someone has a 2-meter walk at 6 -- in 6 minutes, or 2,000 meters to query the site and see if there was a data entry error, for instance, to see if there's patterns where sites are not conducting volume procedures properly. So that's all part of what's happening. So there are people who are looking at lines of data over the course of the study. It is all blinded. And so that's just part of the norms of the how a study is done and conducted to ensure that when we finally lock the database, that we have a clean data set that allows for interpretable data.

And so those activities are underway, as is done in every clinical trial that's done every sponsor. In terms of overlapping sites, we don't actually have the exact count, but we probably estimate that 20% to 25% of sites may be overlapping. I'd remind you that doesn't, a, reflect necessarily the number of patients that are overlapping between the 2 different studies; and three, where we do our study, it's all under the context of our protocol with the CROs that we work with. And our protocol has cleared trial procedures, training procedures, oversight, et cetera, that is all specific to APOLLO-B. I can't comment on the CROs that BridgeBio used. I actually don't know.

And then I think your third question was, which you called hypothetical, what I'll say is we'll be looking at the totality of data coming out of this study. As you know, the primary endpoint is around 6-minute walk test, but we'll be looking at KCCQ, which is an important secondary endpoint. We'll be looking at BNP. We'll be looking at echocardiographic parameters. And importantly, we'll be looking -- although it's a short study of 12 months, we will be looking at event rates with regard to mortality and importantly, hospitalization and be looking at the totality of those data to understand what we're seeing in terms of the impact of silencing in this patient population. And that will help us, a, interpret the data within APOLLO-B, but also help us think about the impact in this disease overall as it relates to HELIOS-B. So hopefully, that answers your questions.

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

Yes. Like regarding the secondary endpoint, like TCCQ, BNP event rates, any particular separation you'll be looking for that you think you'll be confident that HELIOS-B will be positive?

Gena, it's really -- it's impossible to answer that question. I think we'll be looking at the totality of the data to really make that assessment. So there's no single data point they'll be looking at, and there's no single number they'll be looking at.

Yes. Thanks. I think we've got time for 1 more question.

Our last question comes from Anupam Rama with JPMorgan.

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 and 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 2 metrics would be at a 12-month look?

Yes. So Anupam, we -- those are prespecified secondary endpoints. It's been our practice to -- when we report top line results to speak to P values with regard to primary and secondary endpoints. You can expect that to be provided on the top line, with additional color and detail, of course, will come at a medical conference subsequently. And I'm sorry, 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?

Yes. So what I would say is the study was not powered for those endpoints at all. So they are being captured, but they are not powered endpoints. And we -- as you can imagine, 12 months is a relatively short time to necessarily see effects on those. I'll remind you that tafamidis, it took 9 months to start to see a hospitalization separation, and roughly 12 to 18 months to see a mortality separation.

That said, our post-hoc data from APOLLO showed potentially a much earlier separation on those events, some of the data that have been published in circulation a few years ago. So there is some potential. And we've seen on other parameters effects of silencing potentially on echocardiographic parameters, technetium, et cetera, at earlier time points. So I think you're looking forward to seeing the results and seeing what that looks like. So there's -- and that's why we've captured these as important secondary endpoints to look at.

We are indeed. So look, thank you, everyone, for joining us on this call. 2022 is off to a steady start as we continue to advance our commercialization. We think, with all the exciting pipeline programs that we have in development, 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.