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

Ladies and gentlemen, thank you for standing by, and welcome to the Alnylam Pharmaceuticals conference call to discuss top line HELIOS-A Phase III results. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your speakers today, the company. Thank you. Please go ahead.

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, our Chief Executive Officer; Akshay Vaishnaw, President of R&D; and Yvonne Greenstreet, President and Chief Operating Officer. Also on the line and available for Q&A are Pushkal Garg, Chief Medical Officer; Tolga Tanguler, Chief Commercial Officer; and Rena Denoncourt, Senior Director, Program Leader for vutrisiran. For those of you participating via conference call, the slides we made available via webcast can also be accessed by going to the Events section of the Investors page of our website at www.alnylam.com/events. During today's call, as outlined in Slide 2, John will provide some opening comments, Akshay will discuss the HELIOS-A study and top line results in more detail, Yvonne will give an update on next steps with vutrisiran, and we'll then open the call for your questions. Before we begin, I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to John.

Thanks, Christine. And to everyone listening, happy New Year, and thank you for joining us this morning. I want to start with a comment. As I tweeted last night, we strongly condemn the insurrection of our Capitol, obstruction of our democratic process and needless violence. During this pandemic that is claiming countless lives, we need the best from us, our scientists, health care and frontline workers, not deluded, hateful, and fractured acts of division. We are, of course, grateful that Congress is able to complete their certification of President-elect Biden. And we look forward to a peaceful -- hopefully, a peaceful transition of power, which is a cornerstone of our democracy. So now turning to our news today. As you saw in our press release, we are announcing positive top line results from the HELIOS-A Phase III trial of vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis. Akshay will go through the results in just a minute, but let me start by saying we think that these results in patients with hereditary ATTR amyloidosis with polyneuropathy are about as picture perfect as we could have hoped for. Vutrisiran hit on the primary endpoint with a large treatment effect and a very robust p-value with 11 zeros after the decimal point. Vutrisiran also hit on both 9 months secondary endpoints, including the key quality of life endpoint, which also showed a large and robust treatment effect. Of note, the mean values for mNIS+7 and QOL change from baseline at 9 months were both negative values, indicating an actual improvement and evidence -- and further evidence for reversal of polyneuropathy manifestations of the disease, just like we observed for patisiran in the APOLLO study. On safety, vutrisiran showed an encouraging safety and tolerability profile with discontinuations, deaths and adverse events generally higher in the historical placebo arm. Given these data, we believe that vutrisiran has the potential to become a best-in-class therapeutic option for patients with ATTR amyloidosis, initially for hereditary patients with polyneuropathy, but ultimately, we believe for patients with all forms of ATTR amyloidosis. As you know, in December of 2018, we launched ONPATTRO, the first-ever approved RNAi therapeutic, bringing a transformative medicine to adult patients with hATTR amyloidosis polyneuropathy. Today, ONPATTRO is the market-leading medicine for the treatment of these patients, and we could not be more proud of the impact this medicine has had on patients and their families. Now with the positive HELIOS-A data we are -- that we are announcing today, we believe that vutrisiran can soon become an additional attractive therapeutic option for patients with polyneuropathy as a once quarterly subcutaneous injection. In addition, we will start setting a biannual subcu dosing regimen for vutrisiran early this year, potentially enabling introduction of an even more convenient and disruptive treatment option for patients. These positive HELIOS-A data laid the foundation for the planned expansion of our ATTR franchise into what we believe represents a multibillion-dollar opportunity for Alnylam. If approved, we expect the launch of vutrisiran based on the current study will drive significant growth of our overall ATTR opportunity. Specifically, we believe, and this is important, that vutrisiran will drive increased penetration into the mixed phenotype population for treating the polyneuropathy in those patients, either as monotherapy or in combination with TTR stabilizers, going above and beyond where ONPATTRO is even today. Then additional clinical studies with both vutrisiran and patisiran in cardiomyopathy will help us continue to grow the ATTR amyloidosis opportunity overall for Alnylam. Of course, this includes the APOLLO-B Phase III study of patisiran, which is expected to complete enrollment in early '21 and read out top line data in mid '22, followed by the HELIOS-B Phase III study of vutrisiran, which is actively enrolling and doing quite well in enrollment throughout '21. It is also notable that vutrisiran now becomes the fifth RNAi therapeutic program developed at Alnylam to report positive Phase III results, all in a span of just over 3 years. This is a remarkable accomplishment, one we are proud of and one that we believe underscores the power of an organic, reproducible and modular platform and an R&D strategy anchored on human genetics. As we've discussed before, these elements combine to create an overall probability of clinical success for our programs that greatly exceeds historical industry norms, and we believe that this is sustainable. In addition, the new study highlights our deep understanding of the science and pharmacology of RNAi therapeutics, allowing us to successfully predict target knockdown, thereby accelerating development as well. In the instance of vutrisiran, for example, we were able to progress from a relatively small Phase I study in healthy volunteers directly to a pivotal trial in patients with only 3.5 years from first-in-human to pivotal trial readout, a truly remarkable achievement. With strong ongoing global commercialization of ONPATTRO and GIVLAARI and the launch of OXLUMO now underway, vutrisiran is one step closer to becoming yet another program in the Alnylam portfolio to reach the market, assuming regulatory approval, meaningfully increasing the number of revenue-generating assets for our company, all of which are in a growth phase for the foreseeable future. Frankly, we believe this profile of organic growth and organic generation of commercial products is nearly unprecedented in biotech history. The positive HELIOS-A results with vutrisiran further strengthen our position toward building a top 5 biotech company with the ability to deliver transformative medicines and sustainable innovation for hundreds of thousands of patients around the world. Now before turning it over to Akshay, I'd like to take a moment to acknowledge the patients and their families, caregivers and the investigators and study staff across the globe who participated in HELIOS-A and made this important medical advance possible. And it should not go unmentioned that a significant amount of the study results we were reporting today were generated during the COVID-19 pandemic, where our entire development organization and especially our clinical operations team, our CRO partners and study sites successfully enabled study continuity and integrity. Of course, we are particularly indebted to all the patients participating in HELIOS-A and other vutrisiran studies. Without their participation, we could never have generated the evidence needed to seek approval for this important new medicine. And if approved, bringing a [indiscernible] treatment option to the ATTR community. With that, I'll now turn it over to Akshay to review the results in more detail. Akshay?

Thanks, John, and welcome, everybody. We are indeed thrilled with these top line results from our HELIOS-A Phase III study, and I will now review the program and the results with you in more detail. As most of you are aware, hereditary ATTR amyloidosis is a multisystem orphan disease caused by mutations in the transthyretin or TTR gene that leads to aggregation of misfolded TTR monomers into amyloid fibrils. The amyloid deposits in nerves, heart, gut and kidney, causing damage to these tissues. The disease predominantly manifests as either a polyneuropathy due to amyloid deposition in nerves or cardiomyopathy due to deposition in the heart, although a significant proportion of patients exhibit signs of a mix phenotype. The neuropathy itself is also typically mixed in that all classes of nerves can be affected, leading to disabling sensory, motor and autonomic symptoms. Regardless of the clinical presentation, hATTR amyloidosis is a progressive debilitating disease that is generally fatal. ATTR amyloidosis is a common pathogenic mechanism related to wild-type or mutant TTR production and deposition of amyloid in a range of tissues. It's a single disease caused by TTR that results in a spectrum of clinical manifestations, including both cardiomyopathy and polyneuropathy. Alnylam's RNAi therapeutics reduced the production of the disease-causing TTR protein in the liver, thereby reducing continued amyloid deposition, allowing the body to remove existing amyloid deposits, thus holding or improving the manifestations of disease. Across our TTR franchise, we are developing 2 complementary products; ONPATTRO, the first RNAi therapeutic ever approved, is administered every 3 weeks by IV infusion and is currently approved in over 30 countries for the treatment of the polyneuropathy of hereditary ATTR amyloidosis in adults. It's also currently under development for the treatment of ATTR cardiomyopathy, including in wild-type patients, in the APOLLO-B Phase III trial. Vutrisiran, the focus of today's call, is an investigational RNAi therapeutic that utilizes the same RNAi mechanism as ONPATTRO. It is administered as a quarterly subcutaneous injection via prefilled syringe. Vutrisiran utilizes our enhanced stabilization chemistry or ESC-GalNAc-conjugate delivery technology. Vutrisiran is now the fourth ESC-GalNAc-conjugate to yield positive Phase III results, further validating Alnylam's GalNAc-conjugate delivery platform. We believe that vutrisiran, as a low dose infrequent subcutaneously administered therapeutic, capable of reducing serum TTR by 80% to 90%, could potentially be a very attractive therapeutic option for patients. In addition to HELIOS-A, the efficacy and safety of vutrisiran are being evaluated in patients with ATTR amyloidosis with cardiomyopathy, both hereditary and wild-type forms, in the HELIOS-B Phase III study. As John mentioned, we're also exploring the potential for an additional dosing regimen that would allow the treatment of this disease with only 2 small volume subcutaneous injections of vutrisiran per year. Let me turn specifically to the HELIOS-A study and begin by reviewing the study design. HELIOS-A is a randomized open-label study in patients with hereditary ATTR amyloidosis with polyneuropathy. The study enrolled 164 patients who were randomized 3:1 to receive vutrisiran at a dose of 25 milligrams administered subcu once every 3 months or patisiran administered intravenously once every 3 weeks at a dose of 0.3 mg per kg. This study has a 9-month primary endpoint where the results in vutrisiran treated patients are compared with the results in the placebo arm from the APOLLO trial of patisiran in a similar patient population. This design was aligned on with the FDA and EMA. A small patisiran arm was included as a reference comparator, but not for formal statistical comparison. The primary endpoint is the change from baseline in the modified neuropathy impairment score or mNIS+7. This is a 304 point score, where 0 indicates absence of disease and 304 points corresponds to end-stage disease. The mNIS+7 score assesses a sensory, motor and autonomic function. In addition, we included 2 secondary endpoints at month 9, encompassing clinically meaningful readouts to further assess the impact of vutrisiran on disease symptoms. These secondary endpoints were the Norfolk Quality of Life diabetic neuropathy questionnaire, which is a validated instrument to measure quality of life and the 10-meter walk test, which assesses gait speed. At the 9-month time point, we also included an exploratory cardiac endpoint of NT-proBNP, a well-known cardiac biomarker of cardiac stress, to evaluate potential effects of vutrisiran on cardiomyopathy. There are additional secondary endpoints, which will be assessed at 18 months, including modified body mass index or mBMI and the Rasch-built Overall Disability Scale or RODS. We have also included a number of additional exploratory cardiac endpoints at month 18, including biomarker and echocardiographic data as well as cardiac imaging data. We expect to announce top line results for the 18-month endpoints later this year. I'll now turn to the 9-month top line results we announced today. As a reminder, we plan to present the complete results in early 2021, likely at the American Academy of Neurology or AAN meeting in April, pending abstract acceptance. As such, we're going to limit our discussion today to top line results. Vutrisiran hit on the primary and both secondary endpoints. Patients who received vutrisiran showed a statistically significant and clinically meaningful difference in the mean change from baseline in the mNIS+7 score relative to the placebo arm from APOLLO. This result was highly statistically significant with a p-value of less than 10 to the power negative 11. The mean change in mNIS+7 relative to baseline from vutrisiran treated patients was a negative value, indicating an improvement in the overall score on average and in a binary analysis, the majority of patients showed improvements in measures of neuropathy impairment relative to baseline. This provides compelling evidence that like patisiran, vutrisiran not only halts neuropathy progression but achieved reversal of neurological impairment in the majority of patients in its pivotal trial. Vutrisiran treated patients also demonstrated a mean improvement in quality of life relative to the APOLLO placebo arm as measured by the Norfolk Quality of Life diabetic neuropathy questionnaire. This result was also highly statistically significant with a p-value of less than 10 to the power negative 8. The mean change in Norfolk-QOL for vutrisiran was also a negative value indicating the improvement in the overall score on average. The other secondary endpoint, the 10-meter walk test also achieved statistical significance with a p-value of less than 10 to the power negative 4. Across the primary and both secondary endpoints, the patisiran reference arm also showed results consistent with those observed in the APOLLO study. In addition, at 9 months, we analyzed the exploratory endpoint of NT-proBNP, which is a marker of cardiac stress. Vutrisiran treatment led to statistically significant results on this endpoint as well, providing initial evidence suggesting that vutrisiran treatment may potentially result in improvement in the cardiac manifestations of disease. As I mentioned earlier, we look forward to seeing additional exploratory cardiac endpoint data as part of the 18-month results readout expected in late '21. Now let's turn to top line safety results. Vutrisiran demonstrated an encouraging safety and tolerability profile. There were 2 study discontinuations, 0.6% due to adverse events that led to death in the vutrisiran arm by month 9, neither of which was considered related to study drug. One death was due to COVID-19 unfortunately, and one was due to an iliac artery occlusion during a hospitalization for pneumonia in a patient with preexisting congestive heart failure. There were 2 serious adverse events deemed related to vutrisiran by the study investigator consisting of dyslipidemia and an E. coli urinary tract infection. Treatment emergent adverse events occurring in 10% or more of patients receiving vutrisiran included diarrhea, pain in extremity, fall and urinary tract infections. These events are common in the disease itself and occur at a similar or lower rate than that observed in historical placebo comparator group. Injection site reactions were reported in 5 patients, 4.1%, and were mild and transient. There were no clinically significant changes in liver function tests or LFTs. In summary, we're thrilled with these top line results from HELIOS-A. And as John mentioned, we look forward to sharing our complete 9-month results at a medical meeting in the coming months. With positive 9-month data now in hand, we are very focused on our goal of filing our NDA for vutrisiran in early '21 with a potential impact -- potential approval in early 2022. In the meantime, patients continue to be treated in the study, and we look forward to reporting results from the 18-month analysis in late 2021, including more data on exploratory cardiac endpoints. With that, let me now turn the call over to Yvonne. Yvonne?

Thanks, Akshay. Let me add that I too am thrilled to be at this stage in vutrisiran's journey. As Akshay mentioned and consistent with our previous guidance, we now plan to submit an NDA filing for vutrisiran in early 2021. In other words, in the first half of 2021. And assuming regulatory approval, we expect to launch vutrisiran in early 2022. We also expect to be able to introduce a biannual dosing regimen for vutrisiran shortly thereafter. We're extremely excited about the positive data that we're seeing from HELIOS-A for hATTR amyloidosis patients with polyneuropathy. And believe that upon approval, vutrisiran will present an extremely exciting commercial opportunity. Based on these data, we believe that vutrisiran could provide an attractive treatment option for patients with hATTR amyloidosis with polyneuropathy around the world. Through its initial markets of opportunity, we believe that vutrisiran could address unmet needs for the 20,000 to 30,000 hATTR amyloidosis patients with polyneuropathy, including those with some degree of cardiomyopathy or the so-called mixed phenotype patients. As a once quarterly subcutaneous injection, we expect to see strong uptake across both polyneuropathy and mixed phenotype patients. And as John mentioned, we believe that vutrisiran, based on HELIOS-A alone, will significantly expand our opportunity beyond ONPATTRO, especially by achieving greater penetration in the mixed phenotype segment, either as monotherapy or in combination with TTR stabilizer drugs. Ultimately, assuming we achieve positive results through the ongoing HELIOS-B study in ATTR patients with cardiomyopathy, we expect that vutrisiran will potentially be able to address the full spectrum of both hereditary and wild-type ATTR amyloidosis, addressing 300,000 and possibly more patients worldwide. To that end, the exploratory cardiac biomarker data that we're reporting today are particularly encouraging. Regarding our commercial infrastructure, the progress we've made executing on the commercial launch of ONPATTRO has laid the groundwork, we believe, for a successful vutrisiran launch. We've been engaging with the ATTR amyloidosis community for over a decade, including the physicians, patients, patient advocacy groups and caregivers, to improve the awareness of this disease and to aid speed and accuracy of diagnosis. And on the access front, we've engaged with payer groups to facilitate access for our 3 wholly owned commercial brands. And with around 30 value-based agreements with commercial payers in place in the U.S. as well as a commercial presence either directly or through distributor partnerships in over 50 markets worldwide, we can leverage the successful commercial track record to facilitate the launch of vutrisiran. Finally, we plan to extend our established and highly regarded Alnylam Assist patient services hub to support U.S. patients as they initiate treatment with vutrisiran. In summary, we're extremely excited by the prospect of bringing vutrisiran to the market, assuming approval, and plan to fully leverage the commercial infrastructure in place for ONPATTRO, GIVLAARI and OXLUMO. In closing, I'd also like to thank the patients, caregivers, patient advocacy groups and study investigators and the staff that continue to work extraordinarily hard for the ATTR community. With that, I will now turn the call back to Christine to coordinate Q&A. Christine?

Thanks, Yvonne. Operator, we will now open the call for questions. [Operator Instructions]

[Operator Instructions] Our first question comes from Alethia Young with Cantor.

Congrats, as always, on all this progress and clinical development and success here. But -- yes. So I just wanted to ask a little bit about -- kind of thinking about like market positioning and do you think that vutrisiran will be something that potentially patients switch from? Or is it something that drives share from other competitors in the market? Just kind of how do you think about kind of over the next 12 to 18 months, vutrisiran taking share with a more convenient dosing? Or is it possibly something more about the cardiac profile that would help it be positioned a little bit better in the market as well?

Yes, Alethia, great question. And I'm going to start by making some comments, and then we have Andy Orth on the call who can comment as well, but also Tolga Tanguler, who is our new Chief Commercial Officer, may want to chime in as well. So regarding the positioning, we think this is very important. We are very confident that a once quarterly subcu profile for vutrisiran will clearly be a very welcome option for patients. Obviously, there is no premedication. It's really very well suited for an HCP administered therapy. It will be a Part B drug. We would obviously expect several benefits of that as well. And we are quite confident that this will be used increasingly above and beyond even where ONPATTRO is today in the mixed phenotype patients for the treatment of polyneuropathy, either alone, which happens very frequently, or in combination with TTR stabilizers. And it's really that mixed phenotype segment that is the greatest growth opportunity for the current label of our products in the hereditary ATTR polyneuropathy space. So we're quite confident that this will significantly go above and beyond where ONPATTRO has been able to go and will continue to go. But once it gets introduced, we expect an expansion. Andy, do you have any other comments you want to add to that?

John, actually, Andy isn't on the call today.

Oh, I forgot. Tolga do you want to -- and Tolga, welcome to your first call.

No, thank you. First of all, let me say, I'm incredibly excited to be part of Alnylam. This is day 3 for me, therefore, I will simply concur with what John said. One of my prior experiences was to lead Pfizer's rare disease business for North America. So I completely agree with John's positioning on how we would move forward with vutrisiran.

Yes. Thanks, Tolga. And does that answer your question, Alethia?

Yes, that's helpful.

Our next question comes from Ritu Baral with Cowen.

I wanted to ask a question about the cardiac subgroup and the data. At this point, can you tell us how big the cardiac subgroup of APOLLO-A is? And any additional, even directional, color you can give us on the 10-minute walk and the BNP levels that you mentioned?

Right. So let me just -- I'll hand it over to Akshay in a second, but just remind you, Ritu, that this is top line, so we're not going to get into any detailed numbers. But Akshay, do you want to just provide a general sense for Ritu?

Yes, sure. As you saw running through my report of the date through the entirety of the data set that the results are very, very similar to what we saw in APOLLO, the original Phase III study with ONPATTRO, in terms of mNIS+7, in terms of the Norfolk Quality of Life. Of great interest, I think we saw improvement, just as we did in that study, with the majority of patients showing improvements in those measures and the overall scores improving. And I can assure everybody that the BNP data set at month 9, the cardiac subgroup, these are all very, very similar. And directionally, I think -- as well as the 10-meter walk test. Directionally, I think this is lined up to be at least as good as what we saw in APOLLO, if not better. So I think, overall, very, very encouraging, both from the overall viewpoint of the neuropathy and these preliminary exploratory data with respect to the cardiac aspects.

Yes. And I would just add one thing, Ritu, which is at the 18-month time point, we have quite a bit more cardiac data that we'll be collecting, and we'll look forward to providing top line on that by the end of the year. But that also includes pre- and post-cardiac imaging. So just like we've seen in some recent case series reports for patisiran evidence for cardiac amyloid regression, it will be of great interest to see how those results look in a more robust study for vutrisiran. So that's going to be an important readout, but that will be at the 18-month endpoint.

Great. And of course, I meant HELIOS-A. Any chance that, that 18-month will give us any tell on event rates, John?

Well, we certainly collect those data, if you mean, clinical outcomes. We certainly collect those data, and we'll certainly look at those data. But I don't know, Akshay, do you want to comment any further? It's not -- we've got to keep in mind that we're comparing to a historical placebo here as well. Akshay, anything to comment there?

Yes. The historical placebo, there are always going to be small variations between studies. I also think the sample sizes to make firm interpretations from events like hospitalization or death, this is a much smaller sample size than the [ cardi B ] studies. So of course, we have -- we will have all that information, but we'll have to interpret it with all the due caveats. But preliminarily, everything looks very encouraging.

Our next question comes from Anupam Rama with JPMorgan.

Congratulations on the data and thanks for not dropping this Monday morning of my investor conference that happens next week. Can you remind us why the EU wanted an 18-month analysis from HELIOS-A versus 9 months? And can you remind us, I can't remember if this was the same for patisiran as well?

Yes. Well, let me just pass that over to Akshay, and Pushkal may want to comment as well. Do you guys want to triage it between the 2 of you?

Yes. No. I'll just say it wasn't the case for patisiran ONPATTRO, but Pushkal actually led the negotiations for all this. So Pushkal, why don't you elaborate?

Yes. No -- as Akshay said for APOLLO, it was at 18 months across both territories. And this was just really variation in terms of how the regulators looked at the data or the study and what they wanted in terms of an approval package in the total package. So it's just variation there. So we're going to be using the 9-month data to file in the U.S. as well as in Brazil and Japan. And as Akshay mentioned, we will have the 18-month data very shortly later this year, and then we'll use that to file in Europe.

Our next question comes from Gena Wang with Barclays.

Also add my congrats on the great data. So just wondering, one was how the UTI was deemed as drug-related? When we look at the APOLLO study, actually, in the placebo arm, you have a higher UTI. And my second question is, how is vutrisiran compared to ONPATTRO just directionally? I know you cannot disclose the details.

Yes. I'll turn it over to Akshay, but I'll just start by saying that overall adverse events that can occur in this population include UTI. And overall, those were actually similar or lower in the vutrisiran arm compared to the placebo arm from APOLLO. But Akshay, do you want to comment as to why it was deemed related?

Well, I can't really, because that's the judgment of the investigator. But Gena, this happens all the time in trials that you get relatedness assignments that on the surface don't entirely make sense and generally cannot be clarified. So it's the judgment of the investigator. I think it's very important when we look at adverse events to look at the overall safety, look at the biologic mechanism of action, look at the toxicology data and all the rest of it. And I can, frankly, have no reason to believe that this was related to the drug, but that's the assignment of the investigator. And of course, we respect that. And we don't see a similar pattern of other renal events or urinary events. And as John said, importantly, UTIs occur in these patients. So maybe this investigator was being conservative, I don't know. So it's a little bit mysterious, but I don't think there's anything of concern there for us. And certainly, we're very encouraged by the overall fact that many of these events like UTIs and diarrhea and other things that occur in association with this disease, falls, extremity pain, all of them are actually lower in vutrisiran than in the placebo arm in APOLLO. So I think we tend to be encouraged by the overall safety profile very much so.

Does that answer your question, Gena?

Yes. And how is vutrisiran compared to ONPATTRO, just big picture wise?

Yes.

Go ahead, John.

No, go ahead, Akshay.

Yes. I think as you saw from the top line data, and we're going to be very excited to share the full data set at the upcoming meeting later in the spring, but net-net, I think these data are at least as good as ONPATTRO, if not better. Some of the key findings that lead us to conclude that are that the majority of patients improved, just as they did in APOLLO. The key clinical endpoints, the mNIS+7, the quality of life, improved relative to baseline for the overall population. These are all very, very strong data. And I think lead us to conclude, along with the knockdown and the exciting exploratory cardiac endpoint data, that these data are at least as good as if not better.

Including the safety.

And the safety, of course.

And our next question comes from Paul Matteis with Stifel.

Let me add my congratulations. On NT-proBNP, I think if I remember, there was a difference in how the reviewers at FDA and EMA look at this endpoint and the importance of it and also how they analyze it. I guess, can you maybe speak to that? I think in the FDA review, there was talk about skew and variability? And how did that kind of inform your statistical analysis of these data and your kind of overarching interpretation?

Yes. Akshay, do you want to take that?

Yes. Yes. So Paul, I think the important thing to say straight off is that the FDA doesn't currently recognize NT-proBNP as a validated surrogate biomarker for conditions like heart failure or cardiomyopathy. So it's not the LDL effectively of these conditions. However, I think the field recognizes that directionally, these data tend to be very important because they are a measure of cardiac stress, they can be measured routinely clinically. And we obviously respect that the agency doesn't recognize this as a validated surrogate, but everyone is very -- knows these data, knows their significance and understands that directionally they point to something important. In the case of APOLLO, as you know, when we saw similar data, that was then associated with improvements in echocardiographic findings, including LV strain, including cardiac thickness, which saw a reduction likely due to amyloid mobilization, and an improvement in 10-meter walk test. And then in post hoc analysis, we saw that it was associated with improvements in hospitalization and mortality. So directionally, I think they're very, very important. But we obviously acknowledge that it's not the LDL of cardiomyopathy, and I don't think we're saying it is. But certainly, the track record in our hands in these patients, it's an important biomarker to take note of. And we obviously want to show the full 18-month data where we'll get more BNP data, we'll get echo data, we'll get technetium scan data. We will obviously have overall hospitalization and mortality as well, for what it's worth. And then that will be followed by good [ cardi B ] studies, the APOLLO-B data set and the HELIOS-B data set. So that's how we think about it, and I hope that's helpful. In terms of the statistical analysis, I think we're very confident. Whichever way you cut these data, I don't think our conclusions will change, that we saw what we saw and it is very encouraging. But the regulatory backdrop is as I discussed.

Our next question comes from Salveen Richter with Goldman Sachs.

This is Sonya on for Salveen. Could you -- how should we think about like the vutrisiran data in the context of the emerging gene editing landscape?

Yes. I mean, look, the gene editing landscape, of course, is very early. We're obviously excited about where gene editing can go. But obviously, it's very, very early compared to a proven technology like RNAi with multiple products on the market and many, many Phase III readouts and safety and so forth. So we'll certainly share them on from where we are, but they've got a long way to go, Sonya. Now in terms of competition, though, I think it's worth noting vutrisiran is a once quarterly subcu injection based on this initial study. And then if we're successful, and we expect that we will be, in advancing a biannual treatment regimen, I sort of scratch my head on the benefits of a potential gene editing approach to be honest. 2 injections a year, it's almost like a vaccine as opposed to the uncertainties of gene editing. So I think we feel very good about it competitively. I don't know, Akshay or Pushkal, if you'd like to comment further on that.

Pushkal, why don't you give us your thoughts?

No, I really don't have much to add. I think John really summarized it well. I think it's exciting with the advancements that are happening in the field, and we're going to watch carefully. But I think when you have something that looks, with the evolving efficacy and safety profile of something like vutrisiran, I think this provides a really incredibly valuable treatment option for patients. And when you get to quarterly or subcu dosing or even biannual as we expect to get to, I think that's going to be an important treatment option. And frankly, it's not entirely clear what advantage necessarily gene editing would have in that context.

Yes. I think maybe putting it a different way, Sonya, we do think that a biannual dosing regimen shuts the category down from a targeting silencing approach.

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

Maybe, John, can you remind us of how big you think the mixed phenotype population is, at least in the U.S.? And then secondly, is there any kind of additional color you could provide on the observation of dyslipidemia? Is that something that is of any concern? It was just one patient. I'm sure we'll see additional color on that, as you said, later in the year, but wanted your initial thoughts.

Yes. Well, thanks, Tazeen. We -- the mixed population -- well, let's put it this way, the polyneuropathy and mix population together represent anywhere from 25,000 to 30,000 patients worldwide. That's the overall prevalence. Now the diagnosed -- as we know, the diagnosed prevalence is smaller than that, although that's increasing over time with improved disease awareness through the benefit of medical education and frankly, the promotional efforts of not only Alnylam but also other players in the field. So that is growing. The diagnosed prevalence is growing as well. But it -- really, in the U.S. market, it represents the vast majority of the patients that we see. As a reminder, the predominant U.S. genotype is the V122I genotype, and that is because of the African-American population and the migration, unfortunately, of the slave trade from Western Africa. And that population, over 50%, Martha Grogan published a study of 56% of that population are patients that have clinical polyneuropathy as assessed. So it is really the lion's share of the hereditary ATTR market in the U.S. It's a little bit different in the rest of world where you have other genotypes like Val30Met, but there's still quite a bit of cardiac presentation in even V30Met and other genotypes as well. So the mixed population really is quite significant. It's -- for the hereditary segment, it is the lion's share. I don't know, Akshay or Pushkal, do you want to comment on the dyslipidemia?

Yes. And my perspectives are very similar to the UTI discussion we just had as a one-off SAE that doesn't seem to have much direct causality or biologic plausibility. But Pushkal, why don't you give us your perspective?

Yes. No, it's quite similar. I think, Tazeen, just as Akshay said earlier, I mean we really rely on the investigator judgment and defer to the investigator judgment ultimately in terms of causality. And so that's what's reflected here. This was an [indiscernible] heart disease and the investigator deemed this as a potentially related event. Importantly, that patient stayed on therapy. And second of all, as we look broadly across the data set and -- no evidence of biologic plausibility and no evidence or concern about a signal with regard to dyslipidemia. So I would just leave it at that.

John, if I could just add with respect to the mixed phenotype. I think the inexpensive and widespread availability of PYP scanning is really driving diagnosis in this patient population, and we expect that to continue. So I think it is a population that we expect will continue to see increased diagnosis. And clearly, the profile of vutrisiran is particularly applicable to helping to treat this patient population.

Yes, absolutely. Yes, that's a really important point, Yvonne. And Tazeen, as a reminder, the vast majority of patients that are being diagnosed, new patient finding that's happening in the U.S., happens through cardiac imaging and with technetium scans, now that, that technique has now been widely adopted across the U.S. And then those patients, if they have a mutation, which genetic testing is part of the usual triage, then they're assessed for polyneuropathy. And then if they're a mixed patient, then they become somebody who a physician may want to treat with ONPATTRO today and then potentially in the future for vutrisiran. But we do see vutrisiran as a once quarterly subcu injection, potentially in the future biannual, as really significantly expanding that mixed phenotype population for our TTR franchise, even before the cardiomyopathy trials readout, of course, only for the treatment of neuropathy, but that mixed phenotype is an important population for us.

Okay, John. And if I could just follow-up really quickly. Based on what you said, would you then see ONPATTRO on a go-forward basis as limited mostly to pure polyneuropathy patients?

Well, I think ONPATTRO, obviously, has been a great drug. Many patients who have been on ONPATTRO will continue to take ONPATTRO because they're receiving -- they're happy with their care. They're happy with their setup and why change if things are working well? And so I think clearly, new patients, we can expect many of the new patients coming into vutrisiran. But I think ONPATTRO will continue to be an important therapy that's out there for patients that are receiving it today. So we'll see how that evolves. And obviously, we'll share more as we get closer to market on how this transition will occur.

John, if I could just add in. I think with vutrisiran coming onstream, we'll really begin to see the power of a franchise as we provide multiple products for patients with TTR amyloidosis. So with both ONPATTRO and vutrisiran being available to patients, I think there'll be a reinforcing effect as the franchise delivers value.

Absolutely.

Our next question comes from Joel Beatty with Citi.

Congrats on the data. Based on the results today, is there any potential to resize or otherwise change the design of the Phase III TTR cardiomyopathy trials?

Thanks, Joel. That's a good question. I will hand it over to Akshay for his thoughts.

Yes. Joel, the APOLLO-B and HELIOS-B studies are well-designed, robust approaches. They're agreed to in terms of sample size with regulators. They're enrolling well after a hiccup during the earlier COVID period. So we're committed to completing those studies and are making excellent progress towards that. And by the time one starts thinking about altering design, I think the focus really should be on getting them completed. And that's important from an efficacy viewpoint, it's important from a safety viewpoint, and that's the path we're going to go down.

The only thing I would add, Joel, is obviously, we do our planning and interim analysis on HELIOS-B. And we are planning on, obviously, settling and identifying the exact assessments that will be done in that interim analysis. And certainly, the HELIOS-A data assist in that consideration from an overall safety perspective as well. So I think that's certainly helpful in terms of how we think about the interim analysis and the design of that, which still needs to be settled and agreed upon as well with regulatory authorities. But that might be one area where there's some important benefits from all this.

Our next question comes from Mani Foroohar with SVB Leerink.

Congrats on the data again, a really great outcome for patients. So one of the things that's been a very useful sort of selling point and product attribute or whatever phrase you want to use for ONPATTRO has been being able to present patients the opportunity for disease reversal and improvement as opposed to simply slowing the curve of decline. As we look at the admittedly limited cardiac data across this 9-month profile, is there an avenue to discuss improvement in NT-proBNP from baseline? Or is there no evidence of that quite yet, and we're still talking about slower decline versus placebo? Just trying to get a sense of where we are in terms of building that product profile.

Yes. Mani, that's a great question. Let me start and maybe Akshay could chime in. What we're reporting today, again, is top line and what we've said quite clearly is that we do see -- in the mNIS+7 and the quality of life endpoints, we do see negative values at 9 months, which means an improvement from baseline. And we think that's really quite notable, very similar to what we reported in -- with APOLLO when you see the data presented later in the spring. With NT-proBNP, I think we can also say that it is quite similar to what we have generated historically with ONPATTRO, patisiran, both in the setting of our APOLLO study, but also in the setting of other recently published case series as well. So we're quite encouraged by that. And we clearly believe strongly that the benefit of a TTR silencer mechanism of action is to halt or reverse all manifestations of disease unlike the TTR stabilizers that, while they do provide benefit, only slow progression, and many patients do ultimately progress from TTR stabilizers. So does that make sense, Mani?

Yes. That makes a lot of sense to me. That's helpful.

Yes. No. Akshay, anything you want to add to that?

I think you covered it, John, yes.

Thank you.

Maybe, John, this is Pushkal. If I could just add, to Mani's question, I think the other piece of evidence that supports what you said is the recent publication by Fontana and Gilmore et al that really does show broadly in the cardiovascular -- in a population of cardiovascular patients that with -- ONPATTRO treatment was associated with improvements in extracellular volume based on cardiac MRI, regression of technetium uptake in the heart and improvements in 6-minute walk test. So I think the totality supports what you're saying, which is this mechanism of action has the potential to reverse both -- ultimately reverse both the neuropathy and the cardiovascular aspects of the disease.

Yes. And as Philip Hawkins at our R&D Day said, as it relates to the activity of TTR stabilizers with cardiac imaging, those are not associated with reversal of cardiac amyloid, like what we've observed with patisiran in the case series study that was presented and published.

Our next question comes from Luca Issi with RBC Capital.

Congrats on the data. Can you remind us what you need to show to get the biannual dosing over the finish line? And then wondering if you have any high-level update on inclisiran.

Yes. No. Thanks, Luca. So we've had engagement with regulators on the 6-minute regimen, and we're confident that showing TTR knockdown and safety in a patient population is going to be a package that will be acceptable to them. And so that's the plan very specifically. And there are many ways we can generate those data, and we plan on starting the data generation efforts in early '21. So obviously, this will be something which we expect to happen quickly, and it can be introduced relatively quickly. So it's not a new -- very importantly, it's not a new efficacy study that's required. It's really based on the well-established PK and PD of this approach, combined with, obviously, safety in the population. Anything else, Pushkal, to add to that or Akshay?

No, I think you covered it, John.

Okay. Terrific. And then regarding inclisiran, obviously, inclisiran was approved by the EMA last year, which is very exciting. It becomes our fourth RNAi therapeutic. But it did receive a CRL from the U.S. FDA related to an inspection of a site in Italy where inspectors have been unable to get access to a physical inspection due to the COVID-19 pandemic. Novartis has obviously been working closely with the FDA. I think the goal here is to quickly address the FDA's needs, and we'll look forward to being able to update you sometime soon on the path forward there. But I think, importantly, we do not expect this to be any protracted period whatsoever, but we'll await further clarification of all this on timing from our partners at Novartis.

Our Next question comes from Alan Carr with Needham & Company.

This is Joey on for Alan. Congrats on the data. I just had a quick one on the biannual of vutrisiran here. It sounds like from your comments, you would just need to show TTR knockdown and some safety. But how -- from your experience, would you be looking to sort of unlock a significant amount of patients going from the quarterly shot to a biannual shot? Or what's the thinking around that?

Yes. I mean the quarterly dosing of 25 milligrams per quarter, when we do modeling 50 milligrams per quarter, so twice the dose -- I'm sorry, 50 milligrams every 6 months, so twice the dose every 6 months, provides similar PK/PD. So we believe that, that is the right approach. And obviously, it will become an option for patients to go once a quarter -- from once a quarter to once every 6 months. And it will obviously be an option for the entire patient population to have a once every 6 monthly dose option initially for polyneuropathy patients, but then with the APOLLO-B and HELIOS-B studies; HELIOS-B, in this case, for the cardiomyopathy patients as well. And we think that, that, biannual dosing regimen is really going to be the game changer in the whole space. It provides an inclisiran-like dynamic in the whole competitive landscape. So we're quite excited about that.

Our next question comes from Patrick Trucchio with H.C. Wainwright.

Congrats again on the data. Can you tell us what proportion of patients in HELIOS-A study had prior tetramer stabilizer use and how this proportion compared to APOLLO study? And how it impacted the data set, if at all, or if there are any learnings in HELIOS-A based on prior stabilizer use?

Yes. That's a great question. And again, this is top line, so we're not going to get into patient baseline demographics. I can say that there were a very significant number of patients that had prior TTR stabilizer use and presumably entered the study because they weren't doing that well on their TTR stabilizer because they did need to discontinue stabilizer therapy to come on to the study. But we can't -- we won't get into the specifics right now, but what I'll tell you is that it's very similar to what we observed in the APOLLO study with patisiran where we also had patients that had been on prior TTR stabilizer. Pushkal, anything else to add other than what I just said?

No, I think you've covered it.

Great. Is that helpful?

I would just add, John, that in APOLLO where we've shared all those data, it was clear that patients who had been on tafamidis and had come off and come into APOLLO showed an equally beneficial outcome in APOLLO with patisiran as those that never had tafamidis and, in fact, showed the same improvements that we saw in the overall population. So really, patisiran stood out in that regard in either tafamidis naive patients or tafamidis experienced patients.

Yes, absolutely.

Our last question is from Vincent Chen with Bernstein.

This is Brian on for Vincent. Just a quick one on the safety. So thinking back to the APOLLO data, I recall that there were some signs of AV block in 4 patients in the drug arm. And the FDA reviewer noted that this could be due to remodeling of the interventricular septum. I guess just asking, did we see any evidence of this in the vutrisiran data? And how are you guys thinking about this?

Yes. No, that's a great question. I'll hand it over to Pushkal. Again, I'll just do the overall reminder that this is top line, and we'll present the more fulsome data, hopefully, in the spring in April at the AAN meeting, pending abstract acceptance. And the other caveat I'll add is that, obviously, overall, the safety profile that we've seen for vutrisiran in the study is very encouraging and is comparable to the type of safety profile that was also very encouraging relative to placebo in the APOLLO study. So Akshay or Pushkal, anything else to add to that?

Nothing from me.

Yes. It's Pushkal. Maybe I'll just add a couple of things. I mean, Brian, first of all, just a reminder that these patients come in with fairly extensive cardiac involvement, many of them, right? And so cardiac arrhythmias and conduction defects is a pretty common aspect of this disease. So that's an important thing just to remember at baseline. Obviously, we look at this very carefully. We've been encouraged by the post-marketing safety profile of ONPATTRO as it's gone into a broader number of patients with regard to cardiac events, et cetera. And as we -- and as mentioned earlier, even seeing evidence of a cardiac benefit potentially in a post hoc analysis coming out of APOLLO. We've looked at this data, and we'll certainly share more, hopefully, at the upcoming AAN meeting. But we are very encouraged by the overall safety profile, including the cardiac safety profile of vutrisiran.

Does that answer your question, Brian?

Yes. And congrats on all the progress.

This concludes the question-and-answer session. I'd now like to turn the call back over to the company for any closing remarks.

Well, thanks again, everyone, for joining us today. Obviously, we'll be talking to many of you next week as well. We do look forward to sharing more of these 9-month data from HELIOS-A. I think you're going to be very pleased with what you see. And we also obviously look forward to seeing the 18-month data top line -- full results or top line results by the end of the year, including, importantly, a lot more cardiac data. Look, we can't be -- we couldn't be more excited about bringing this new investigational medicine forward for patients. We think this is going to be a great treatment option for the patient community, and we are thrilled for them as well. So please have a great day, and we look forward to talking to you very soon. Bye-bye now.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.