Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

Great. Good morning, everyone, and welcome to the 44th Goldman Sachs Conference. Really happy that everyone is here to join us. Before we start, I'm just going to read a disclaimer. We are required to make certain disclosures in public appearances about Goldman Sachs' relationships with companies that we discuss. The disclosures relate to investment banking relationships, compensation received or 1% or more ownership. We are prepared to read aloud disclosures for any issuer during the sessions upon your request. However, these disclosures are available in our most recent reports available to you as clients in our firm portal. In addition, updates to these disclosures are available by ticker on the public website. Goldman Sachs agrees to host this conference on the basis that no third-party speaker will provide confidential or material nonpublic information. In addition, by attending the conference, you provide Goldman Sachs the right to record and redistribute the conference information. So these or third-party speakers do not necessarily reflect those of Goldman Sachs. With that, I'm Salveen Richter. I cover the biotechnology sector here at Goldman Sachs. We're really pleased to kick the conference off with Alnylam. So with us, we have Jeff Poulton, CFO; and Eric Green, Head of Development. Thank you both for joining us this morning.

Pleasure.

Nice to be here.

So to start here, perhaps we can talk about the big upcoming event and program here in the context of ONPATTRO with ATTR cardiomyopathy, where you've been notified of an FDA AdCom, and you have an October 8 PDUFA. So to start, do you have any indication to date on the content and timing of the AdCom? And what do you -- when do you think this could become more clear? And what are your thoughts on the topic for discussion?

You want me to start, Jeff?

Go ahead, Eric.

Yes. We, obviously, had announced the APOLLO-B data late last year, filed the submission to the FDA late last year. And as you noted, the PDUFA is in October. At the time of the acceptance of the sNDA, we were notified that the FDA does plan to hold an AdCom. At that time, they had noted no issues. Review issues have been noted but that was back in February. We have not yet been notified of when the official date will be for the AdCom. We await that to being posted to the Federal Register. We expect that sometime this summer, which will then make it official and everybody will know exactly when that meeting is. We believe that the topics could be focused around the efficacies that was seen in the APOLLO-B study. Recall, our study was a 12-month study, double-blind, placebo versus patisiran. The primary endpoint was a change in 6-minute walk distance at 12 months versus placebo. A key secondary was a change in quality of life measure, KCCQ. The study was positive on both of those endpoints, statistically positive results and we believe clinically meaningful results. But it's quite possible, the FDA would want to get some advice on the meaningfulness of those data. In particular, we recognize and have acknowledged that there's a new heart failure guidelines, draft guidelines that were put out by the FDA in 2019, that talks specifically to be able to use these types of measures, how patients function or how they feel as endpoints that could support full approval, not requiring outcomes such as mortality or hospitalization. So we believe to our knowledge that this ONPATTRO patisiran could be the first product reviewed since those draft guidelines were published. So it's quite possible, the FDA was also looking for insight into a data package such as ours that could be approved under these new guidelines.

Great. Just following on that thought of understanding the meaningfulness of 6-minute walk test and KCCQ, how focused are they on the p-value in the context of the trial and what they would want to see as a bar? And then also just in terms of addressing the unmet need versus tafamidis, how do those factors come into play?

I believe most -- all regulatory agencies are really looking at the benefit risk they see in any given drug with APOLLO-B and somewhere with HELIOS-B with vutrisiran. We had interactions with all health authorities on the design of the study. So with the FDA, we had interactions with them as we finalized the design for APOLLO-B. And there was agreement that 6-minute walk, as a primary endpoint, could be supportive of approval. We feel that with the statistical and we believe clinically meaningful results that we have shown, where they're almost 15-meter difference versus placebo at 12 months. And indeed, the patisiran arm declined in 6-minute walk as approaching that of age-matched normal healthy adults aging and the decline you would see over about a year. In addition to seeing the quality of life, which was essentially stable over the 12 months and now that we've had the 18-month APOLLO-B OLE data, we're showing that stability continues in quality of life. We think, now we've shown how patients function with a 6-minute walk and how they feel with KCCQ, that is, we hope, quite supportive. So it really does then come down to the regulatory review and how they feel looking at one well-controlled study and the data that came out of it. I think you mentioned the other one was the unmet need potentially versus tafamidis. In the U.S., obviously, the only drug approved currently for the treatment of ATTR amyloidosis is tafamidis. In the ATTRACT study, they showed that patients did continue to progress. Their 6-minute walk continued to decline despite treatment with tafamidis. They did see obviously a benefit in their composite endpoint at 30 months. But it did take a while for the 2 arms, the curves to separate mortality and on hospitalization. So there was still some unmet need we feel there. From what we see in the market and from market research, there are patients that aren't doing well on tafamidis, are probably looking for another option. And with nothing else available, that could be a very challenging place for a patient with this type of a progressive disease. In addition, there may not -- there may be some patients that are unable to afford or have access to tafamidis given some of the out-of-pocket burdens that they may experience even with Part D on Medicare, for instance. So we do believe there is a need for another treatment -- or ideally even another treatment modality, completely separate from TTR stabilization. And hopefully, that's taken into account by the FDA.

Maybe just a little bit of evidence on demand for another treatment. We have an early access program that we've opened up for ONPATTRO for cardiomyopathy in the U.S. And there's actually been really good demand to get into that access program despite the fact that tafamidis obviously is available commercially on the market. So as Eric suggests, I mean this is a fatal progressive disease. And if patients are not doing well on the existing therapy in the market, there's going to be a desire, frankly, desperation to try something else. So there's a real unmet need here.

And how do you think about the trends on outcomes in the context of those new guidelines where I believe you'll be setting precedent here?

So for the APOLLO-B, I presume we're talking about -- yes, so in the original data set, in the 12-month double-blind portion, we had secondary endpoints looking at composites, and we shared those. And probably too early, so the study was never designed. It wasn't big enough and we didn't expect really to have an effect of that quickly. So even the trends that we saw in the original 12-month data were encouraging. Now with the 18-month data, the open-label extension data where patients that were on patisiran continue to receive patisiran, you have that 18 months of experience. Importantly, though, you saw the placebo patients that started receiving that patisiran at the end of the 12 months and now have 6 months of treatment, you start to see a change in some of the slopes, 6-minute walk, on the KCCQ, even in some of the biomarker data. And then we also shared, essentially as exploratory, can be statistically compared, what the composite looks like for hospitalizations and mortality and separately, what the mortality curves look like between patients that were on patisiran the entire time versus patients who were on placebo that switched to patisiran. And we think it's encouraging, right? We do see a -- start to see a separation of those curves. Despite starting patisiran treatment, they've already accumulated the detriment of 1-year worth of placebo treatment. That said, it's a progressive disease. You really want to find and treat these patients earlier and hopefully, arrest the progression of the disease. So we think that those data continue to gain support for APOLLO-B, for ONPATTRO in its review but also probably foreshows a little bit what we might think for HELIOS-B also.

Maybe jumping over to HELIOS-B here. Help us understand the confidence that you have regarding the trial design, the powering and all the aspects, given the changes that we've seen competitors make in the field here. And then any read through that could play out from BridgeBio when you look to seeing that trial play out?

Yes. So we were designing both APOLLO-B and HELIOS-B at around the same time a number of years ago. We had the ATTRACT data -- had been published. We kind of knew how various different patient segments did. We had nice 6-minute walk curves. We know the hospitalization and mortality curves. We took all that information in. We intentionally were excluding some of the worst of the worst patients, kind of NYHA Class III patients that didn't meet a minimum for a 6-minute walk or had too high of an NT-proBNP for a biomarker. So we knew we're looking for a slightly healthier patient population. However, we did and do require patients have to a confirmed diagnosis of cardiomyopathy due to ATTR amyloidosis and have a medical history of symptomatic heart failure. So while there's some thought that maybe patients with the broader ecosystem, knowing about this disease, having an option to treat this disease, if there is a diagnosis, maybe the population generally is getting healthier, that isn't necessarily what we were enrolling in our study. So having that in the requirement of a symptomatic heart failure does give us, I think, an appropriate patient population, more similar to ATTRACT. We then took into account what we expected the market to be, if you will, as we're trying to enroll this. We anticipated the potential for patients coming into the study already on tafamidis and operational cap of 50%. We said we actually have come in below that. So that gives us a little bit more conservative [indiscernible] there. We also enrolled -- overenrolled by about 10% in the study. So that automatically gets you a little bit more power. And then the way we're doing our analysis is, a little bit different than ATTRACT where we're going to complete the analysis at 30 months from when the last patient enrolled, double-blind portion. However, patients before that can be in the double blind up to 36 months. So for a lot of really early patients, they'll have a full 3 years on the double-blind portion and we're able to count any events that occur in those additional 6 months roughly for all patients. So that also increases the power relative to the number of patients enrolled. So I think that -- and then we just obviously talked about the APOLLO-B data, which gives us insight into the similar -- very similar patient population that we see. So all of that is, I think, kind of comes together with -- we're confident in what we have designed and executed for HELIOS-B. I think you did mention versus what are we going to expect to see when parameters come out in late July?

Yes.

Well, we obviously focused primarily on the placebo arm, right? What does that patient look like? See what the demographics were in that -- the patient population. Frankly, how and how many patients stayed in that study when they read up the part A of their study, that 12-month results. It's unclear to me anyway. I don't think they've publicly shared as how many patients have stayed in that study? How many dropped off? How many, I believe, had the option to start with tafamidis? So how many patients dropped in with tafamidis treatment? And how might that confound the results? So it will be obviously important for patients potentially to have another option. But for us, we'll be focusing primarily on that placebo.

If there were any aspects that you saw that you think have read through to your trial, can you make changes at this point?

I presume technically, we probably could but we've been very confident in the design. We completed enrollment nearly 2 years ago. We expect the results here in early 2024. So any window for any potential change is closing but we remain confident in all the reasons I mentioned earlier. So no changes at this point to announce.

And then can you speak to where you stand with the biannual dosing and the annual dosing under the ICARIA program? And when we might understand those profiles?

Yes. So the biennial dosing -- I believe, you're talking about vutrisiran, we had talked in the original HELIOS-A study. So in patients with hereditary ATTR amyloidosis with polyneuropathy, we created a randomized treatment extension program where we randomized patients to either receive -- continue to receive the quarterly 25-milligram dose or a semi-annual, every 6 month, 50-milligram dose. We had top line results we talked about earlier this year, where despite seeing good safety, no impact on efficacy. We did see a little bit of a return towards baseline with a [ 60-minute ] -- month, every 6-month dosing. And just enough to make us think that maybe that's not an optimal profile and then contrasted with the great uptake we'd seen with AMVUTTRA already in the market and the efficacy we have seen in the original part of the HELIOS-A. So at this point, we don't have plans to submit those q6M dosing data for any label change. The ICARIA program you mentioned is our next product, ALN-TTRsc04. This product is currently in Phase I in healthy volunteers, similar to what we've done with our other TTR programs and we're expecting data from that later this year. It will help us understand the depth of TTR reduction as well as the duration of the effect that we could see, both directly in time but also with modeling to see if we can actually indeed get to potentially an annual dose, which was supported by nonhuman primate data and modeling that shows that we could have a product possibly with deeper TTR reduction than we see with vutrisiran and less frequent dosing. So that could be quite a step forward for patients, for the product profile with the same, if not better efficacy, with even more convenience, could be great. And on the business side, it actually potentially would avoid any third-party royalties that we currently have with vutrisiran. I don't know if you want to clarify anymore on that.

Yes. The royalties that we pay on AMVUTTRA to Sanofi are between 15% and 30% and that's tiered based on different sales levels. So as Eric just suggested, that would be a significant benefit of a [ c04 ] not to have that royalty burden. And also the intellectual property will extend the life of the franchise further as well.

Coming over to competitive positioning here of both your drugs, ONPATTRO and AMVUTTRA, in cardiomyopathy versus Pfizer's drug here, how might that play out when you look at reimbursement dynamics, right, out-of-pocket costs but also the oral versus -- sorry, the -- yes, the oral versus IV component?

I'll start with the question on -- I think first on ONPATTRO, ultimately AMVUTTRA, some of the reimbursement dynamics. I think starting first with the opportunity that we see first with ONPATTRO in the marketplace based on the market research that we've done suggests that there's 2 real opportunities. One is for patients and we talked about this earlier, that are on tafamidis, that are not responding adequately, right? There's going to be demand for them to try something else. Again, I commented about the early access program that we're already seeing some of that demand. And then the second segment that we see as an opportunity based on the market research is for patients that are not able to access the therapy due to out-of-pocket co-pay burden. And that's a real issue, probably certainly more significant today than it will be over time as the IRA kicks in and the Part D redesign has some benefits for patients where out-of-pocket expenses will be capped for Part D meds at $2,000. Today, there's patients that face tens of thousands of dollars of expenses out of pocket, which is why there's a challenge for patients to get on therapy even with that transition from a reimbursement perspective to the out-of-pocket cap for patients on Part D. We feel good about the positioning of a Part B medicine in terms of out-of-pocket burden for patients for our ATTR franchise today. So for either ONPATTRO or AMVUTTRA in the U.S., we're at about 70% of the patients that have a zero -- $0 out-of-pocket impact. And for those that have an impact, it's a high percentage, if it's $2,000 or less. So even as we transition to the Part D cap, I think we feel good. The second question was about...

The administration difference.

Yes. I mean I think for ONPATTRO, look, I think we've had the product in the market for 5 years. And despite the fact that it's got a pretty significant burden on the patients for an every 3-week IV-infused drug, we've seen greater than 90% adherence and compliance to therapy, which is really remarkable in my experience with a therapy like that. I think it speaks to, frankly, the seriousness of the disease and the motivation of the patients but likely also speaks to the fact that the experience that they're having with the product from an [indiscernible] and safety perspective is pretty good. So that really hasn't been a significant burden to us when we get patients on therapy. With that being said, obviously, relative to an oral, I already talked about the 2 segments that would probably drive ONPATTRO uptake but longer term, the expectation is with a positive HELIOS-B result that -- the sort of the burden difference between ONPATTRO, which is every 3-week IV; AMVUTTRA, which is a pretty convenient once-a-quarter subcu, that we're not going to have those same challenges relative to a daily oral.

Could you touch on IRA and the impact here in the future, potentially on Part D out-of-pocket cost?

Yes. I mean I think it's -- this is one of the really great benefits of the IRA, is the fact that from a patient perspective for Part D meds, that the burden is going to be significantly reduced and capped at $2,000. If you look at high-priced meds like tafamidis, there are patients that today have out-of-pocket burdens north of $20,000 a year. So really beneficial, I think, for patients that this is going to go into effect. It's going to be about a 2-year transition. I think the cap in 2024 will be $3,250 and then it will get to $2,000 in 2025. Again, as that compares to our meds, which are Part B, I commented earlier that we still feel really good about Part B where majority of the patients that we have on therapy today have a $0 out-of-pocket cap.

Let's turn to the pipeline here. And you have recently shown us early data in -- outside of liver-targeted programs and we saw data from ALN APP and in early Alzheimer's disease. What was exciting to you about this data set? And how does it translate to other CNS programs?

Exciting program for us. Obviously, we've been looking to get beyond the liver, if you will, for quite some time. We announced this product for ALN APP targeting amyloid precursor protein a while ago. So we were very excited to enroll the patients last year in a single-ascending dose portion of Part A of this Phase I study and then just announced the top line results from 3 different dose cohorts, 25, 50 and 75 milligrams dosed by [ IT ] infusion and seeing now the knockdown, the reduction of APP, as measured by a biomarker in the CSF, soluble APP alpha and beta. So we went into this non -- we had nonclinical data, obviously, nonhuman primate data with knockdown, we saw a broad distribution of reduction of target proteins and significant and durable reductions. But we weren't sure yet how that was going to translate to humans. We have a great database in the liver side. We're just now starting to build it on CNS. So we're very excited, maybe even a touch surprised to see at these relatively very low doses, seeing the durability, rapid reduction and durable reduction of APP, especially at the highest dose out to 3 months of greater than 70% reduction. Going into this, because no other modalities have been able to target so upstream in this disease, nobody has been able to go after APP itself, we weren't quite sure what a target knockdown or reduction would be appropriate or necessary. We still don't really but we are thinking, based on human genetics, around 50% reduction would be something reasonable to aim for. We were quite happy to see this type of reduction already at these relatively low doses. What it helps hopefully and not only are we excited about what it could mean for these early Alzheimer's patients, perhaps a broader sporadic Alzheimer's patients, there's also cerebral amyloid angiopathy disease, CAA, that could also be applicable or treated potentially by this reduction of APP. But it also gives us a lot of insight on what could be now a new platform pillar for us. So utilizing a C16 ligand internal to our siRNA, we're now seeing human translation of reduction of a target protein. Our second program, ALN-SOD1, is being led by our partners at Regeneron but we've opted into that as a CoCo program. That now is an IND-enabling work. We recently announced a Huntington's program also in IND-enabling work. And at the top line results call, we actually talked about 2 other targets that we're also working on in research, alpha-synuclein and MAPT or tau. So hopefully, these very first data will continue to follow-up these patients. Actually really excited to announce today, we're going to have more detailed data from this Phase I Part A data at the AAIC conference, so the Alzheimer's Association International Conference in Amsterdam in July, July 17. Happy to announce that the abstract was accepted and we will be putting more data out from this Phase I. So a little bit longer follow-up. So we're excited for this program but also the potential for now -- open up a whole another part of our platform.

Great. Could you also walk through just where you stand with the clinical hold on the multiple dose programs?

Yes. So Part A, as I mentioned, is a single-ascending dose portion, currently open in 4 countries: U.S., Canada, U.K. and Netherlands. Part B is a essentially an open-label extension portion where patients enrolled in Part A, at appropriate time can move over to Part B and receive additional doses of ALN APP. That Part B has already been cleared by regulatory authorities in Canada, under review by the U.K. and Netherlands. But in the U.S., as you know, there is a partial clinical hold for the Part B portion, only in the U.S., as they have some questions about our chronic toxicology studies. So we're still in dialogue with the FDA but we will hopefully be able to work with them to eventually open up the Part B here in the U.S. also. I think important to note, though, most of the patients in Part A were enrolled just by operational happenstance in some ways in Canada. So we still have a way to move this forward program, even with the multi-dose portion at least in Canada and potentially in the U.K. and Netherlands also.

You might want to comment on the dose difference between what we did in the clinic versus what we're studying in the chronic tox portion.

Yes. That's a great point. So as I mentioned earlier, we had no idea of translatability from what we saw in nonhuman primates to what we would see in humans. So without any of that knowledge, we designed these chronic tox studies in both rodents and in nonhuman primates, what turned out to be very exaggerated doses and very exaggerated dosing frequency. So the margins, it depends how you -- upwards of 50x higher in each of those studies than what we think we would need clinically and even higher in some cases, at the highest doses. So we feel there's significant margins from what we've shown in the tox studies, which are designed to elicit responses -- are designed to elicit some type of a safety signal. So we kind of know where the outer edges are. So we hope with discussions with FDA and any other agencies in the future, what our clinical data are, now that, that's now new, we understand the translatability and the dose is much lower than we expected as well as these exaggerated doses of frequency for the tox.

So moving forward with your portfolio, you do have zilebesiran in hypertension that's being studied. You have 2 ongoing Phase II trials. Could you just talk about the expectations we should have for this data set that's coming up this year? And then how you think about the regulatory path on that forward?

So zilebesiran, we think is a very exciting program in hypertension targeting angiotensinogen at the top of the [indiscernible], a well-known path for affecting blood pressure. We have Phase II study, we call KARDIA-1. It's actually a monotherapy dose exploration study. We announced that, that study had completed enrollment at the late part of last year and we expect data in the middle of this year. It's a monotherapy study. So patients, if they come in the study on any other antihypertensive, have to wash out of that and then are randomized to either zilebesiran, 1 of 3 different doses and 2 different regimens or a placebo. So this is really going to be a much bigger data set compared to what we had in our Phase I, similar patient population, just much larger patient population to really help us understand go-forward dose and regimen or regimens that take into later development. KARDIA-2 is a combination study. So this is probably more interesting data set. We're -- continue to enroll that study but we expect the data to be at the end of this year -- at or around the end of this year. And patients are, again, washed out of anything they're on before they come into the study and then are randomized to 1 of 3 standard agents. And they're protocol-defined doses and products. But there's an ARB, a calcium channel blocker and a diuretic. Once patients are randomized in 1 of those 3 groups, they are on that for 1 month. If at the end of that 1 month, they're still not to target, blood pressure still uncontrolled, then they're randomized to receive either zilebesiran or placebo. So we'll be looking for additive efficacy, blood pressure reduction on top of standard agents that generally maxed label doses as well as any safety of the combination. In particular, in that ARB arm, we'll be looking for what the impact may be on additional blood pressure reduction relative to the safety you've seen. There's generally class effect labels that disparage or don't recommend dual RAS inhibition. And in general, because of -- in the past, some large [indiscernible] analysis, you see a slight increase on the risk side but with no benefit, no additional blood pressure reduction. So we're trying to understand that. Still a relatively small sample size but that will be a very important data set for us.

And how are you thinking about the commercial opportunity in the context of the competitive dynamics but also with Novartis having just some challenges with building this buy-and-bill model in the cardiovascular space for Leqvio?

Maybe I'll talk about Leqvio first and then you can talk a little bit about how we're thinking about maybe the commercial opportunity and narrowing just a bit. So I think with Leqvio, they've been at it in the U.S. for a little over a year, really focused on opening up a buy-and-bill channel into the cardiology space, which has taken some work and some effort. I think they pointed to Entresto maybe as a good comp. And I think if you overlay the 2 curves, it's pretty close. I think our hope is, based on the work that they're doing right, to open up that channel for Leqvio that, that's something that we'll be able to benefit from in the future, assuming that we get zilebesiran through the Phase II studies and then a pivotal study and get it to launch that would also be a buy-and-bill Part B Med. Again, I think if they've opened up that space with the cardiology offices, gotten them comfortable with how that works, then we'll hopefully benefit from that. Eric, do you want to talk about the potential for how we're thinking about Phase III here?

Exactly. Obviously, the data from the KARDIA-1, KARDIA-2 will tell us a lot and then help us think where we're going. Well, we've talked a lot about in the past about identifying a patient population with uncontrolled hypertension at high cardiovascular risk. Perhaps they've already had a stroke or other CV event, perhaps they have other comorbidities that put them at elevated risk for stroke or other CV events. So we think that these types of patients are probably on another 1, 2 or 3 other antihypertensive agents and which then maybe be is obvious, trying to be added on top. What's really exciting about this product, about this profile, we believe that this ability to have with infrequent dosing, quarterly, maybe even every 6 months, a tonic control of blood pressure. And we have some really exciting data from the Phase I, where we looked at 24-hour ambulatory blood pressure monitoring. And you see even, I think, the data we're at 6 or 8 weeks after a single injection of zilebesiran, you saw a tonic control blood pressure, reduction relative to placebo for the entire 24-hour period. And this compares very favorably, we believe, versus daily oral that, one, most people forget to take. They don't take consistently. They may not get their refills. There's just lots of issues of compliance and adherence. But even if they do, by nature of an oral product, they tend to wane. The effect tends to wane over that 24-hour period. And if people, at least like me, take their dose in the morning, by the time they're waking up 20, 22 hours later, just as a physiologically, you have a blood -- morning blood pressure surge and your blood pressure medication is wearing off, that's why you have a lot of these CV events occur in the early morning hours. So the tonic control of blood pressure with very infrequent dosing, we think, could be a very attractive profile. And with this type of a high-risk patient population, we think we could have a very nice...

Yes and even though high risk in sort of a segment, it's still a really large opportunity.

Millions and millions of the patients, unfortunately. And then high blood pressure is the #1 preventable cause of morbidity and mortality almost around the world.

Before we open it up to the audience, could you just touch on anything you're -- or what you're really excited about in your portfolio of partnered programs with Regeneron and also looking at target tissues outside of the liver and CNS?

There's so many to choose from. So I think we're very fortunate. Alnylam's, I think, done a great job of discovering a lot of interesting molecules in our labs and then working with a lot of different partners to be able to move a lot of them forward, far more than we would probably choose or be able to do ourselves. So you mentioned Regeneron partnership that we signed back in 2019. We are CoCo with them on CNS programs. We have the chance to alternate leadership. We're leading ALN APP but they've opted in as a CoCo, so they're helping with about half of the cost. There are ocular programs that could come out of that relationship at which Regeneron would take a lead on, given their experience in that space, obviously. And select liver targets could also be part of that agreement. Regeneron has a combination with their anti-C5 antibody, pozelimab, along with our cemdisiran, an anti-C5 siRNA. They're studying that in MG and PNH. They have a couple of NASH programs, ALN-HSD and ALN-PNP. HSD is in Phase II. Now, they're enrolling NASH patients. PNP is still in Phase I but they're really excited about how we can build out a NASH portfolio, potential for combination use in the future. Sanofi is still taking the lead on fitusiran, our drug in hemophilia. I think they're expecting more pivotal data later this year in a potential filing. So that could be a really exciting innovation for hemophilia patients. We're taking the lead on our ALN-HBV program in hepatitis B and hepatitis D infection now. So we have essentially a free opt-in before Phase III on that program. So for us, I think it's great to see all this innovation coming out of our labs, other folks who are helping to develop it and take it to patients without having the burden on our P&L as well.

Any questions from the audience? I'll ask you one more, Jeff. Could you just speak where -- speak as to where you stand on FX impact? And then how you're thinking about capital allocation in the context of your goal towards profitability?

Yes. Sure. Happy to talk about FX. FX was a pretty significant headwind for the company throughout '22 on the top line, I think it's about a 10% headwind on growth over the course of the year. As we've entered 2023, the dollar has moderated, weakened just a bit. When we announced our Q1 results, we announced 48% product sales growth, which was 52% on a constant currency basis. So a little more moderate impact on the top line. We don't explicitly hedge the top line of our P&L. We do have a natural hedge given that we have a pretty significant part of our operations outside the U.S. So we've got expenses outside the U.S. as well. So from a true economic exposure perspective, we offset about 50% of that top line exposure. We did give our guidance this year on a constant currency basis. So hopefully, that will provide a bit more transparency and clarity of the impact of FX, ultimately on the results that we deliver. We're still really confident in our ability to get to profitability. That was one of the goals that we established with [indiscernible] that we would get to non-GAAP profitability by the end of the period. I think the fact that we've established that as a goal, has been really helpful because it creates the need to make choices, right? We've probably got more opportunities in front of us than we can actually afford to prosecute. So we have to make very thoughtful decisions about what we're going to advance and what we're going to not advance. On the R&D side, typically, there's 2 or 3 things that we look for. We look for genetically validated targets. We look for programs that have a biomarker that will get us -- give us an early read on the potential efficacy profile. And then lastly, we're looking at therapeutic options that would have pretty significant unmet need. So those are the things that we're thinking about. We've obviously started to invest more in prevalent disease programs and new tissue type. I would expect more of the same as we progress towards profitability.

Great. Well, on that note, thank you so much. Pleasure speaking this morning.

Thank you.

Pleasure. Thanks. Thank you.