Thank you for standing by and welcome to the Alnylam Pharmaceuticals First Quarter 2021 Earnings Conference Call. At this time, all participants are in listen-only mode. After the speakers' presentation, there will be a question-and-answer session. As a reminder today's program is being recorded. And now I'd like to introduce your host for today's program, Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications. Please go ahead.

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are John Maraganore, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Akshay Vaishnaw, President of R&D; Jeff Poulton, Chief Financial Officer; and Yvonne Greenstreet, President and Chief Operating Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website investor.alnylam.com/events. During today's call, as outlined in slide two, John will provide some introductory remarks and general context; Tolga will provide an update on our global commercial progress; Akshay will review recent clinical and preclinical updates; Jeff will review our financials; and Yvonne will provide a brief summary of upcoming milestones before opening the call to your questions. I'd like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors including those discussed in our most recent annual 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'd like to turn the call over to John. John?

Thanks, Christine, and thank you everyone for joining the call today. 2021 is off to a great start for Alnylam with four approved RNAi therapeutics now helping patients around the world and more in our pipeline poised to do the same in the coming years. To start, our teams delivered steady ongoing commercial execution and continued revenue growth including 13% quarterly growth for ONPATTRO, with our first triple-digit revenue quarter and an impressive initial uptake for OXLUMO in its first full quarter on the market. On the pipeline side, the full positive results from the HELIOS-A Phase 3 study of vutrisiran were presented last week and we announced that we have filed an NDA for vutrisiran with the FDA, bringing us a step closer to the potential approval of this important asset in our TTR franchise.

Thanks, John, and good morning everyone. Let's get started with a review of our commercial performance from the first quarter. In Q1, despite COVID headwinds, particularly in the US, we were able to achieve strong results. For ONPATTRO, we achieved $102 million in global net product revenues in the first quarter and we ended the quarter with over 1,500 patients on commercial treatment. In the US, we continue to see progress on many fronts including steady and continuous growth in patients as well as notable growth in new prescribers across specialties seeing patients with hATTR polyneuropathy. Adherence to treatment remains stable at pre-COVID levels and we continue to observe a trend of HCP choice in the concomitant use of ONPATTRO to treat polyneuropathy along with the use of a TTR stabilizer for cardiomyopathy in mixed phenotype hATTR amyloidosis patients. Much of our continuous growth in ONPATTRO revenue is driven by increased hATTR diagnosis rates, which, we believe, is due to wider availability of PYP scans. Access is another important highlight with confirmed access to ONPATTRO for over 98% of covered lives.

Thanks, Tolga, and good morning everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing our two product candidates patisiran and vutrisiran. With patisiran, we're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis patients. To this end, we're conducting the APOLLO-B Phase 3 study. We continue to enroll patients in APOLLO-B and expect to complete enrollment in early 2021, which would put us on track for a top-line readout in mid-2022. We're also advancing vutrisiran, delivered by quarterly subcutaneous injection. Here we're conducting two Phase 3 studies. The first is HELIOS-A, evaluating vutrisiran in amyloidosis patients with polyneuropathy, specifically in hATTR amyloidosis patients. Just over a week ago, at the American Academy of Neurology Conference, we presented our positive full nine-month results, which I'll briefly recap here. On the primary endpoint of change in mNIS+7 from baseline at nine months, vutrisiran treatment resulted in a 17-point mean treatment benefit relative to the external placebo group from the APOLLO Phase 3 study of patisiran. The effect was highly significant, indicating robustness of the treatment effect. Additionally, the mean change in mNIS+7 relative to baseline was a negative value, indicating improvement, providing evidence that like patisiran, vutrisiran not only halts neuropathy progression, but also achieves reversal of neuropathy symptoms relative to baseline in the majority of patients in this pivotal trial. Regarding the key secondary endpoint of change in Norfolk Quality of Life score at nine months relative to baseline, vutrisiran-treated patients demonstrated a mean improvement in quality of life compared to the external placebo arm.

Thanks, Akshay, and good morning everyone. I'm pleased to be presenting Alnylam's Q1 2021 financial results. As Tolga highlighted, it was another very strong quarter of commercial execution with excellent results. Turning to our results first for ONPATTRO. We generated $102 million in net revenue for the quarter, representing 13% growth from the fourth quarter of 2020 and 53% growth compared with Q1 2020. This marks the third consecutive quarter of double-digit quarter-on-quarter growth following one quarter of flattened growth we experienced during the onset of the pandemic in Q2 of last year. US ONPATTRO sales increased 15% versus Q4 2020 and were primarily impacted by the following: an approximate 4% increase in demand driven by the addition of new patients on therapy, an increase of inventory in the distribution channel with inventory increasing from approximately one week at the end of 2020 to approximately two weeks at the end of Q1. And a lower level of gross to net deductions in the third quarter compared with Q4 2020. Consistent with full year 2020, we expect gross to net deductions will remain in the mid-20s globally for ONPATTRO in 2021. In our international markets, ONPATTRO performance remained strong with growth of 11% versus Q4 2020, primarily driven by increased patient demand in our five major markets in Europe. Results in Japan were unfavorably impacted by a reduction of inventory at our distributor during Q1. Turning to our results for GIVLAARI. We generated $24.7 million in net revenue in Q1, representing 11% growth compared to the fourth quarter of 2020 driven by ongoing launches in the US and Europe. Reported results in the US were unfavorably impacted by an increase in gross to net sales deductions in Q1 compared with Q4. With OXLUMO, we had a strong first full quarter of sales generating $9.1 million in net revenue in the quarter. Turning now to a summary of our full P&L results for the quarter. Total combined product sales in the first quarter were $135.8 million, representing 89% growth versus Q1 2020. Net revenue from collaborations for the quarter was $41.8 million, a significant increase from Q1 last year, primarily due to revenue recognized from our Regeneron collaboration. Gross margin on total revenues was 83% for the quarter, down from 87% in Q1 2020, primarily due to lower margins on collaboration revenues in the quarter. Our combined non-GAAP, R&D and SG&A expenses for the quarter increased modestly at 6% versus Q1 2020. Key drivers of the increase were additional R&D investment in advancing our late-stage pipeline programs and increased SG&A investment to support the launch of OXLUMO. Our non-GAAP operating loss for the quarter decreased by approximately $45 million versus the same period in 2020, driven by strong top line growth and moderate growth in operating expenses. Q1 also represents the fifth consecutive quarter that we've delivered an improvement in our non-GAAP operating loss and clearly signals the path we're on towards profitability. Lastly, turning to our financial guidance. Following our strong Q1 results, we remain confident in our full year outlook and are reiterating the financial guidance we provided on our Q4 results call in February. Starting with net product revenues, we anticipate combined net product revenues for our three commercialized products will be between $610 million and $660 million. Our guidance for net revenue from collaborations and royalty is a range between $150 million and $200 million. And our guidance for combined non-GAAP R&D and SG&A expenses is a range between $1.175 billion and $1.275 billion. With that, I'll now turn the call over to Yvonne to review our upcoming milestones. Yvonne?

Thanks, Jeff, and hello everyone. We've already achieved important milestones in 2021. And as we look ahead, there are plenty of catalysts queued up for the next 12 to 24 months. Firstly, within our TTR franchise, we expect to complete enrollment in the Phase 3 APOLLO-B study of patisiran early this year, setting up top-line results in mid-2022. With vutrisiran, we're on track to initiate data generation for a biannual dosing regimen in mid-2021 followed later in 2021 by presentation of 18-month top-line results in HELIOS-A. And as we've announced today we can look forward to completion of enrollment in HELIOS-B later this year. For GIVLAARI, we look forward to an important regulatory milestone with its potential approval in Japan midyear. Turning to OXLUMO, we anticipate an approval in Brazil in mid-2021. Upcoming clinical milestones will also include top-line results in the Phase 3 ILLUMINATE-C study in mid-2021 as well as initiation of a Phase 2 study for recurrent renal stones in late 2021. This Phase 2 study will be important for lifecycle management of OXLUMO with the potential to significantly expand the overall opportunity. Our early and mid-stage pipeline has locked in store as well. For cemdisiran enrollment and dosing continues in the Phase II monotherapy study in IgA nephropathy. And dosing continues in the Phase I combo study with pozelimab in collaboration with Regeneron. Our partners at fair continue to enroll and dose ALN-HBV02 in the Phase II combo trial with pegylated interferon alpha. And at Dicerna, our partners continue to advance fitusiran for AAT deficiency liver disease. ALN-AGT is on track to enter Phase II midyear. With the start of the KARDIA program in hypertension and we're very excited about the planned filing in mid-2021 of our first CNS, CTA for ALN-APP. This sets us up for potential initial CNS proof-of-concept data in 2022. So needless to say, Alnylam has much to look forward to in the coming quarters as we execute on these key catalysts across our pipeline and platform and the first quarter marks a strong start with regard to our Alnylam P5x25 goals outlined in January. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Yvonne. Operator, we will now open the call for your questions. 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.

Our first question comes from the line of Tazeen Ahmad from Bank of America. Your question, please.

Hi, good morning, guys. Thanks so much for taking my question. Good news on the enrollment rate for HELIOS-B. I just wanted to get a little bit of color, if you could provide any on why you think it is enrolling faster than you previously anticipated. And does that give you a better sense of when we could see the data at least at the top line level readout? Thank you.

That's – thank you, Tazeen; and we're also very excited about the progress on HELIOS-B I think it really is supported by the enthusiasm in the community for Vutrisiran, as a once quarterly subcutaneous medicine for ATTR amyloidosis with cardiomyopathy, which is what we're evaluating in that Phase III study. So really, really good. And obviously there's an opportunity for biannual dosing as well pending those results. So let me turn it over to Akshay to comment on his perspectives on that. Akshay?

Yes. Just building on what you said, John, first and foremost, I'd say the outstanding work of our clinical operations team, particularly during this very stressful and remarkable COVID period. I think it's also a testament to our global reach in the TTR space through our work in hATTR amyloidosis with polyneuropathy. Many of the investigators, we know because they work in both diseases hATTR and ATTR cardiomyopathy. And I think they're very excited about the possibility of our drugs in wild-type TTR cardiomyopathy. And then of course, with our global reach we've gone to many sites where there's no access to approved drugs like tafamidis for example for wild-type TTR cardiomyopathy. And so people are very motivated to help study both ONPATTRO and Vutrisiran in that setting. So delighted with our own in-house efforts and I think there's a tremendous therapeutic rationale for our agents in those diseases and wonderful collaboration with the investigators in sites.

And Tazeen, to your question about timing for results, we're not giving any guidance at this point. It would be premature to do that. But we are planning an interim analysis and we are in planning and discussions with regulators to lockdown exactly what the design would be of that interim analysis. And when we have more clarity on that we can provide it to you at that time. Otherwise, you probably remember that the HELIOS-B study has a 30-month endpoint. So without the interim analysis, it would go 30 months past the point of enrollment being completed.

Okay. Thanks, John.

Thank you. Our next question comes from the line of Maury Raycroft from Jefferies. Your question, please.

Hi, good morning, everyone, and congratulations on the update today. Just wondering if you can provide a breakdown on how many ONPATTRO patients are on concurrent use with the stabilizers? And any specifics on switches as well?

Yes. Let me hand it over to Tolga on that and he can give you some framing around what we see in the US and what we see in the rest of the world, which is very important there. But just before I hand it over, obviously the use of ONPATTRO is for the treatment of polyneuropathy in the hereditary ATTR disease. So that's an important reminder as well. Tolga, do you want to go ahead and comment on some of these market dynamics that we observed?

Sure, John. Thank you and hi, Maury. As John mentioned, we are specifically indicated for polyneuropathy, which varies across different regions. ONPATTRO is one of the few treatments available for polyneuropathy, as there are no silencers or stabilizers approved for this condition in the US. Currently, we see that about 20% of our patients with hereditary ATTR have mixed phenotypes, along with the use of another stabilizer for cardiomyopathy treatment, even though it's not indicated. In Europe and Japan, we have approval for a stabilizer. We are encouraged by the transition of patients progressing to stabilizer treatments and observe the value of silencers and patient switches in Japan and key European markets, which significantly contribute to our growth. John?

Maury, does that answer your question?

Yes. Yes, very helpful. And maybe just as a follow-up, based on the combo use trend that you're seeing just checking if you're thinking about or having conversations with Pfizer to potentially collaborate on scanning or diagnosing or maybe even leveraging the combo commercially as you think about reaching the broader cardiomyopathy opportunity?

Yes, Tolga?

Yes, I mean look first of all having multiple players in this devastating condition is a very good thing for the patients. And even though we're not collaborating with Pfizer, I think if you look at the protocol development in major US centers with the advent of these treatments, it certainly is helping. We certainly believe those protocols should include genetic testing which then further establishes the condition for polyneuropathy and mix phenotype patients. So, while we're not in direct communication or collaboration I can tell you we're all aiming for those patients to get diagnosed as quickly as possible which we know it takes anywhere between five to 10 years and can cause mortality and morbidity. So, again, we're moving in the right direction in the same direction but there's no specific collaborative action between the two companies.

Got it. Very helpful. Thank you very much.

Thanks, Maury.

Thank you. Our next question comes from the line of Alethia Young from Cantor Fitzgerald. Your question please.

Congratulations on your progress. I want to focus particularly on GIVLAARI and the trends you're observing. From my understanding of this chart, it appears that you reported over $7 million in sales outside the US and $1.4 million within the US. I would like to discuss your thoughts on growth trends in the United States, especially regarding how they compare to international results. I noticed the APU in France regarding the timing; could you elaborate on that? Thank you.

Yes. I will pass it over to Tolga and perhaps Jeff will want to share some insights too, but I want to highlight our enthusiasm regarding GIVLAARI. The impact it has on patients suffering from acute hepatic porphyria is truly significant and impressive. We are very happy with the assistance we're providing to patients with this difficult condition. A key aspect of GIVLAARI's growth this year will come from expanding geographically, as we have achieved pricing and reimbursement in several European countries. Until now, growth has primarily been driven by Germany and our APU in France. We anticipate growth from geographic expansion, along with finding new patients. Tolga, would you like to elaborate further, and Jeff as well?

Absolutely.

I was actually asking about OXLUMO. I misspoke, sorry.

Okay. Sorry. Okay. All right. Well, thanks for the correction. Yes. No, look OXLUMO had a fantastic first quarter of launch. We're really, really pleased with that. And obviously it's approved in both Europe and the US and was first approved in Europe, which is terrific. And it's off to a great start. Tolga do you want to comment a little bit on some of that dynamic?

Yes. I was fully prepared for GIVLAARI. Now, let’s focus on OXLUMO, which is also addressing a serious condition. We gained valuable insights from early access patients in Europe, where most of our early access program participants were located. Consequently, the treating physicians chose to continue with the commercial therapy, which went quite smoothly, leading to a strong adoption in Europe. In the US, there have been fewer patients, making conversions less viable. However, with over 30 start forms in the US, we are confident that it will be a significant contributor to OXLUMO's growth. I'm also pleased to see that we are attracting patients across both pediatric and adult demographics, encompassing a wide eGFR category, which is very encouraging. Furthermore, we have successfully achieved two-thirds access in the US payer universe, and our value-based agreements are promoting smooth access. Therefore, it's too early for us to be concerned about the US market, and I am genuinely encouraged by the current patient start forms, which have already exceeded 30 in the last quarter.

Awesome. Thank you.

Thanks, Alethia.

Thank you. Our next question comes from the line Salveen Richter from Goldman Sachs.

Hi. Thank you so much for taking our question. This is Sonya on for Salveen. Could you help frame expectations into the APOLLO-B trial, in particular we're wondering what would be considered clinically meaningful? And how we should think about potential read-through to the HELIOS-B trial? Thank you.

Yes. Thanks Sonya. Just as a reminder, I'll hand it over to Akshay. But just as a reminder, APOLLO-B is our randomized double-blind placebo-controlled study of patisiran in wild-type and hereditary ATTR patients with cardiomyopathy. So this is the opportunity to potentially expand our patisiran opportunity into that broader segment. And so Akshay, do you want to comment a little bit on how we view success in that study?

Yes. The primary endpoint in APOLLO-B is the six-minute walk distance, which is a clinically validated measure in the disease and is intuitively clinically meaningful. Patients with cardiomyopathies, any form of heart failure, struggle with exercise and exercise tolerance. So being able to walk significantly better relative to the control arm is going to be very important to demonstrate that. And so, the primary endpoint, in and of itself, will be very clinically meaningful. Beyond that, we will get a lot of additional data from that study. Of course, we'll be looking at hospitalization rates and mortality. The study is not powered for that, but it will, of course, be important to see what trends we're seeing there. And in addition to that, a host of biomarkers and other endpoints such as BNP, such as echo cardiogram changes and technician and the like. Now, the reason why we feel excited about that whole package and the likelihood of success is that if you go back to the original APOLLO study with patisiran in hATTR with polyneuropathy and the cardiac patients within that study, or patients that had significant cardiac disease, I should say. We saw very encouraging findings. We saw the 10-meter walk test stabilized relative to placebo very deteriorated dramatically. We saw that BNP was favorable slightly down relative to placebo. In that study, BNP is an important cardiac biomarker. Echocardiogram showed reduction in the left ventricular wall thickness. And then subsequent to that other groups have demonstrated academic groups such as the Gilmore Group in London, and they published this. They see diminution on technician scans with evidence for regression of amyloid in the heart. They also saw that light cardiac MRI. They saw stabilization of six-minute walk distance in their ONPATTRO treated hATTR cardiopathy patients. These are all very encouraging findings to us that support the likelihood of success with APOLLO-B. And then, finally, with mortality and hospitalization itself, post hoc analysis from the original APOLLO study did demonstrate a significant difference. Now post hoc and we should be very mindful of that. But again, an encouraging finding. So in totality, I think the therapeutic rationale is very strong, both for APOLLO-B and also for vutrisiran in HELIOS-B where, of course, the study is larger and it's powered to detect mortality and hospitalization changes and that's the primary readout. And so, I think if APOLLO-B is positive, which I've given you the reasons why we're excited. We're then very encouraged by the implications for HELIOS-B as a result. And it should speed the interim analysis and so forth of HELIOS-B.

Yes, I would like to mention that we are anticipating data from APOLLO-B in the middle of 2022. We are on track to finish enrollment in early 2021, which is coming up soon. We expect to see the APOLLO-B data in mid-2022, making it a significant data release for us next year.

Thank you so much.

Thank you. Our next question comes from the line of David Lebowitz from Morgan Stanley. Your question, please.

Thank you for taking my question. When there is an interim analysis for APOLLO-B, what type of analysis will be conducted? Is there a possibility that this interim analysis could lead to an earlier regulatory submission, or should we assume that the only route to submission is the 30-month timeline?

Yes, David, thanks for that question. I'll hand it over to Akshay and maybe Yvonne wants to comment as well. But I mean, the purpose for doing the interim analysis would be to potentially bring vutrisiran to the market ahead of the final result, which would read out at 30 months. And so, that certainly is the intent of the interim analysis to shorten that time. So that is why we're doing it. Akshay, Yvonne, any more to add to that?

No, not really. I think you covered it, John. I think if APOLLO-B is positive, then that would certainly be very exciting for anticipating the results from HELIOS-B that would accelerate the interim analysis gives us great insight into the relevant interim analysis to do. And the motivation would be to get Vutrisiran to patients faster with that IA.

Yeah. Yvonne?

No, that's great. I think that's covered it.

I mean, the only thing I would say, David, is just bear in mind that we have not yet resolved the design of the interim analysis with the regulatory authorities. We have in the original protocol specified that there would be an interim analysis or there could be an interim analysis. But the final design of that would need to be aligned on with regulators, which is an important step.

Does that include the timing of the analysis?

Absolutely. The design and the timing and what the endpoint will exactly be, all those elements would be obtained in alignment with regulators, absolutely.

Helpful. Thank you for taking my question.

Thanks, David.

Thank you. Our next question comes from the line of Gena Wang from Barclays. Your question, please.

Thank you for taking my question. I have one regarding the value-based payment. Just wondering now you have three drugs or have a value-based reimbursement. So just wondering, what is the real-world implementation? And based on current experience, roughly what percentage of patients you need to actually adjust the payment or value due to lack of efficacy?

Yeah. Well, Gena, let me just start on that really important question and then maybe turn it over to Jeff to address how that's been handled in the real world. But let me start by saying that we're really proud of our proactive approach with value-based agreements with payers. Certainly in the U.S. commercial market, we've also done some element of that in Europe as well. And I think the results speak for themselves. I mean because the benefit of these shared arrangements with the payer community has been one, in which they view Alnylam as being proactive and open-minded about value. It has changed the dialogue away from price into discussion or recognition of value. We've been very innovative on that. And, of course, the result has been essentially no payer headwinds in the U.S. market and very broad access that we've been able to achieve for patients. So it is something which we're especially proud of and we hopefully can demonstrate the innovation on this from a commercial perspective similar to the innovation we've always had as an R&D organization. So with that, Jeff, do you want to comment on some of the real-world color on those VBAs?

Yeah, happy to. Gena, I'll speak to ONPATTRO. Obviously, that's the product that's been on the market the longest and that we have the most experience there. And I will say that the deductions that we're paying associated with the VBAs that have been signed with commercial payers are extremely modest at this point. And that's because the product is working well. So we're not having to make payments for patients that are discontinuing due to an unsatisfactory experience with the product. So, extremely modest again I would say in terms of the impact on the deductions that we're paying.

And I think the one index of that that we report out from time-to-time, Gena, as you know, is the adherence rate being so high with the product, which really speaks to how well the product is performing in the patient community. I think it's fair to say generally consistent with our clinical experience with patisiran in the APOLLO study.

And if I can add…

Tolga, anything to add?

Yeah, yeah. I mean, as you and Jeff mentioned the outcomes of our products and its efficacy is really a testament that these VBAs are working in favor of the patient and payers as well as us. So it's really a win-win-win situation. One should also keep in mind that as we design these VBAs, ASP risk is really minimized. And we're certainly not seeing that at this moment. And if it were to occur, it certainly is minimized in the way we formulate our VBAs. So we certainly don't now anticipate any long-term negative impact on our revenues.

Thank you very much.

Does that answer your question, Gena?

Yes. Very helpful. Thank you.

Thank you. Our next question comes from the line of Debjit Chattopadhyay from Guggenheim Securities. Your question please.

Are you on mute, Debjit?

Sorry, yes, I was on mute.

I thought so.

This is Aaron on for Debjit. So congrats on the progress, the ONPATTRO launch looks like it's going very well. Can you tell us what proportion of patients being treated in the U.S. also have concomitant cardiomyopathy versus polyneuropathy alone? And maybe elaborate on the ramp in diagnosed patients in ATTR? Thanks.

Sure. I mean we answered the first question earlier; you may not have heard the answer, but we can do it again, no problem. Tolga, do you want to handle both of those questions?

Our goal is to ensure that we can treat as many patients with polyneuropathy conditions as possible. Sometimes, physicians recognize these patients with a mixed phenotype, and in those cases, we support patients to ensure they have access to our medicine if they were previously receiving another treatment alongside it. We're satisfied with what we're observing. In Europe and Japan, this issue is not present, and we focus on building our business with these switches and naive patients, where we see significant progress. Can you please repeat the second question?

Just about the ramp in diagnosed patients in ATTR, how that's increasing?

Yes. Again I think a rising tide lifts all boats. So we do see a great expansion of protocol development in centers of excellence. We see a good referral network with community centers as you may know the PYP scintigraphy scans are really helping. And these scans are relatively cheap, inexpensive, and very accessible. So we see more and more centers diagnosing these patients. And then we do see a good uptake of our genetic testing program, Alnylam Act as well. And in fact, the last two, three months of the first quarter we've seen our highest in the number of genetic testing. So right now up to now we've tested about 36,000 patients that are suspected of hATTR and we received relatively high yield out of these we're about 6%. Over 2,000 patients were diagnosed with the genetic mutation. So that's going really well and we're very encouraged by both the increase in PYP scans, as well as systems taking advantage of genetic testing along with Alnylam Act. Did that answer your question?

Yes. That's great. Thank you.

Our next question comes from the line of Paul Matteis from Stifel. Your question, please.

Great. Thanks so much. I wanted to ask one more question about APOLLO-B. And that's really how do you think we could end up comparing these data to the tafamidis data? If we go back to APOLLO-A, I remember John, you're kind of talking about ahead of those data a goal that stabilized disease or even reversed it and that would be unequivocally better than tafamidis. Do you think the six-minute walk test data from APOLLO-B are going to be directly comparable to what we have from tafamidis in this population six-minute walk? And what would be the caveats any comparison? Thanks.

Well, Paul, I'll just start and then I'm sure Akshay will want to chime in. But in general, of course comparisons between studies is something that you have to always take with a grain of salt. There are formal ways of doing it which may be done by people. But ultimately it is fraught with caveats, to say the least. Akshay, do you want to comment a little bit on that further?

Yes. I mean, let me just reiterate because I think it's so important what you just said that Pfizer colleagues with their investigators did wonderful work and they should speak to the value of their results and the implication direct comparisons are not valid greatly. Now having said all of that, at a very high level I think what all of us would like to see in this space, patients investigators and all of this investigating drugs is we'd like to halt the course of this terrible disease cardiomyopathy in these patients. And looking at the published Pfizer data with tafamidis, I think it's fair to say that that drug obviously has a significant impact on mortality and hospitalization six-minute walk distance. But the overall feeling is that it's just slowing down the rate of deterioration. And what if we could just sort of hop the disease and extract stabilize these parameters like six-minute walk distance which is what we very much look forward to doing and showing with a policy, the work of Gilmore and tau which I cited earlier study of 20 companies hATTR amyloidosis patients where they looked at the cut in myopathy aspect showed stabilization compared to historic control. Now that's a single-arm study compared to historic control but that's encouraging. And everything keeps pointing to the idea that we could stabilize recently with Vutrisiran in HELIOS-A, we showed stabilization of BNP versus deterioration in the placebo. We've seen that previously with patisiran in the original APOLLO study. So I think direct comparisons are very fraud for all sorts of reasons. I think we'll have a similar population in APOLLO-B. So it will be a valid population to think about the value of the drug. And our goal is to show stabilization of the primary endpoint six-minute walk distance.

Does that answer your question, Paul?

Totally. Thank you.

Thanks, Paul.

Thank you. Our next question comes from the line of Ritu Baral from Cowen. Your question please.

Hi guys. Thanks for taking the question. A quick one on the timing of the potential HELIOS-B interim. Am I sort of reading between the lines right guys you have to meet with FDA before you decide on the interim to get their buy-in and that you want the top-line APOLLO-B data ahead of that discussion? Would that necessarily put that FDA discussion in the second half of 2022?

Well, okay. So first of all, it's the FDA and also other regulators that have an important input here on a matter like this like the EMA. So it's not just the FDA, but we certainly the timing of it will probably naturally occur the timing of that interim analysis will probably naturally occur after we have visibility on APOLLO-B results, right? But the design of the interim, our plan would be to try to focus on what that is sooner than we have the readout from APOLLO-B. Akshay, anything – anything to add Akshay from your perspective on that?

No, I just want to – with our announcement today of HELIOS-B enrollment completion by the end of the year looking very likely now. We didn't have that line of sight. We have that now. So the timing looks very conducive that will have the APOLLO-B data middle of May next year. And of course, by that time, the HELIOS-B study is fully enrolled, the patients have been on drug or placebo for a sufficient length of time, so it naturally leads to a very well-structured and planned IA after that fall for HELIOS-B.

Okay. And that would – if HELIOS-B enrolls on completion around end of 2022 most of those patients will have been on for 12 months or more do you think that that's adequate powering for an event-based trial based on your internal modeling of what TTR knockdown might result in?

Well, I think – go ahead, Akshay.

Yeah. No, I think Ritu said HELIOS-B enrollment of completion end of 2022. We're just saying today that, it should be by the end of 2021 based on our line of sight now. So, yeah, end of 2022 would be about 12 months yes, you're right. As for the exact details of that I think we're going to work through that and we'll share in due course, Ritu.

Okay. Fair enough. I'll keep bugging you about that. But last very quick question. Just as far as we think about ONPATTRO to the end of the year. What is your line of sight on potential roll-off of home administration allowances during the COVID pandemic that may be ending over the course of this year? And what impact could that have on ONPATTRO do you think?

Yeah. Tolga, do you want to answer that?

Yeah. Look at the end of the day a lot of payers and specialty pharmacies are offering home infusion services. Our payer – our patient services program, also does a phenomenal job with site of care and accommodating different routes of the way those patients will be administered. We've seen a good steady uptake even prior to the pandemic as well as during the pandemic. So those allowances, while they're good, weren't the main driver, I believe for our ability to be able to accommodate those patients in need. In Europe, we've seen an uptick from 9%, 10% all the way up to 30% home care. As well as in the US, we doubled the amount of patients, but it still represents about one-fifth of our patients that are getting home care. So we're not broadly exposed. The type of services we provide will continue. So we really don't see that as a detractor of the performance that we have in this business.

Got it. And as far as you know, there's no particular time that Medicaid home infusion is ending sometime in 2021 those temporary allowances?

That, I'm not aware, I wouldn't be able to speak to that.

We've not heard anything. We've not heard anything on that, Ritu.

Got it. Very helpful. Thank you.

Thank you.

Thank you. And our final question for today comes from the line of Navin Jacob from UBS. Your question please.

Hi, everyone. This is Jon on for Navin. We wanted to go back to HELIOS-A and we – that the severe AE rates were a lot lower for Vutri versus ONPATTRO and we were just curious, if there was any color you could provide on that?

Yeah. Akshay, do you want to answer that question? This is looking at the – and the comparison was to the small ONPATTRO arm in the study, I believe is what you're referring to. Akshay, do you want to comment on that?

Yeah. I mean, I think we're very happy about the encouraging safety data with Vutrisiran in HELIOS-A, as we are with GalNAc subcutaneous conjugates overall. As to direct comparison there, I think that the patisiran arm is very small. And really, it's not an apples-to-apples comparison when the data is so skewed that way in terms of sample size. So I don't think I'd overly conclude anything as we were discussing earlier. ONPATTRO, the overall safety profile relative to placebo, where the most robust test for that of course was the original APOLLO study. The data look very encouraging and favorable ONPATTRO in terms of safety. And in the real world, as evidenced by the retention on drug and the comfort investigators feel with it, patients feel with it. We're very encouraged that the real-world safety and experience is as good as it was in the original APOLLO study. So that's real testament to how it's serving patients.

And Jon, the lower SAE rate in the Vutrisiran arm relative to external placebo, we believe is related to the fact that patients on placebo are probably experiencing disease progression AEs that underscores that. So that's certainly, our belief based on those data.

Yeah. The – I mean, just from a mechanical viewpoint, if you see a patient every three weeks for an intravenous infusion, you're more likely to hear about a headache or whatever other intercurrent events going on in their lives as it does for all of us, and it may or may not be an adverse event; it may or may not be of relevance. So with the Vutrisiran being once quarterly, you're just not going to be asking the patient the same questions with the same frequency. But in either case, if something was of significance, it would emerge. And as you said, the overall safety profile for Vutrisiran does look very encouraging.

That's very helpful. Thank you.

Thank you, Jon. Well listen, thank you everyone for joining us on the call today. Obviously, we're really pleased with our first quarter results in 2021. It was a strong quarter for commercial execution. And we also had excellent progress across our pipeline programs and we're really pleased this quarter to have announced our P5x25 strategy, which we're obviously very, very excited about. So we look forward to talking to you in subsequent calls and wish everyone a wonderful rest of the day and hope everybody stays safe as well. Bye-bye now.

Thank you, ladies and gentlemen for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.