Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call Q3 2020 Earnings Call. [Operator Instructions]. Please be advised that this call is being taped at the company's request. I'd now like to turn the call over to the company.

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; Andy Orth, Senior Vice President and Head of the U.S. business; 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, investors.alnylam.com/events. During today's call, as outlined on Slide 2, John will provide some introductory remarks and provide some general context. Andy 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 would like to remind you this call will contain certain 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 and quarterly reports and 8-Ks on file with the SEC. In addition, any forward-looking statements represent our views only of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaims any obligation to update such statements. With that, I'd like to turn the call over to John.

Thanks, Christine, and thank you, everyone, for joining the call today. We believe the third quarter and recent period highlight the tremendous progress Alnylam has made as a global commercial organization with a highly productive R&D platform. Starting with our commercial execution, we saw strong ONPATTRO and GIVLAARI performance in Q3, which Andy Orth will review momentarily. We have continued confidence for the rest of this year with another upward revision of our ONPATTRO revenue guidance range for 2020 and another beat for GIVLAARI relative to estimates. Akshay will review our recent R&D progress shortly, but the highlight in the recent period is the positive CHMP opinions recommending approval of OXLUMO or lumasiran and LEQVIO or inclisiran, which set us up with the potential to achieve 4 RNAi therapeutic approvals and launches in less than 3 years, a truly remarkable achievement. You'll also hear from Jeff, on our financial performance and our progress towards achieving a self-sustainable financial profile. We believe we're on our way. Indeed, at Alnylam, we're focused on continued global commercial execution on potentially transformational medicines, excellence in productivity from our organic R&D efforts while maintaining a clear line of sight towards financial self-sustainability. In fact, this is what we envisioned when we established our Alnylam 2020 goals back in 2015, that we'd be a multiproduct, global company with a deep clinical pipeline for future growth and an organic product engine for sustainable innovation. That moment is now upon us, and we couldn't be prouder of our achievements toward those variable goals, which we're on track to actually exceed. And we couldn't be more excited for the next phase of Alnylam's evolution. We will lay out our multiyear vision soon. And we look forward to delivering on our potential as a top-tier biopharmaceutical company focused on advancing medicines with transformative potential to patients around the world. Now before I hand it over to Andy, I'd like to mention that we plan to host a virtual R&D Day event on the mornings of December 15 and 16, where we'll be reviewing progress across our pipeline of investigational RNAi therapeutics. We hope you'll be able to join us online. So with that, let's now turn to a review of our commercial and medical affairs progress. Andy?

Thanks, John, and good morning, everyone. I'll begin by reviewing our commercial performance in the third quarter as well as our medical affairs progress. For ONPATTRO, we achieved $82.5 million in global net product revenue, delivering 24% growth versus Q2 primarily driven by increased patient demand. As of September 30, over 1,150 patients were on commercial ONPATTRO treatment worldwide. Turning to the U.S., we saw notable increases in demand and new patients starting therapy. Also, with many patients now having successfully transitioned to alternate sites of care, including home care, we benefited from strong patient compliance, which also contributed to the rebound in revenues. We continue to see progress with new prescribers in the U.S. with cardiologists making up more than half of new prescribing physicians. In the United States, we also continue to see a steady rate of concomitant use of ONPATTRO with TTR stabilizers and expect this trend to continue to grow. Turning to the rest of the world. We made very encouraging progress with ONPATTRO in the third quarter with $43.5 million in revenues from ex U.S. markets. As noted last quarter, we have secured access in all priority markets in Western Europe, including Portugal, following our Q3 launch. We are also pleased with the continued growth in Japan, a country of strength for ONPATTRO. An important dynamic observed in ex U.S. is patients switching to ONPATTRO from stabilizers for the potential to halt or reverse disease progression in hATTR patients with polyneuropathy. This dynamic represents greater than 50% of new ONPATTRO patients outside the U.S. Our medical affairs team also remains committed to addressing the challenge of raising disease awareness and improving diagnosis rates of hATTR amyloidosis, including with Alnylam Act, our third-party genetic screening initiative in the U.S., Canada and Brazil. As of October, greater…

Thanks, Andy, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing our 2 product candidates, patisiran and vutrisiran. Whilst ONPATTRO is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary ATTR amyloidosis, we 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 III study. We continue to enroll patients in APOLLO-B and continue to expect completion of enrollment in 2021 due to impacts from the COVID-19 pandemic. During Q3, we saw a pickup in the pace of enrollment and are still aiming to make up for lost time that we experienced during Q2 due to the pandemic. We're also advancing vutrisiran for the treatment of ATTR. Vutrisiran is delivered by a quarterly subcutaneous injection. Here, we're conducting 2 Phase III studies. The first Phase III study is HELIOS-A, which is evaluating patisiran in hATTR patients with polyneuropathy. Enrollment is complete in HELIOS-A, and we remain on track to report top line results early next year. The second Phase III study of vutrisiran is HELIOS-B, which has been conducted in hereditary and wild-type ATTR amyloidosis patients with cardiomyopathy, and this study is actively enrolling. On our ATTR roundtable in September, we shared modeling data suggesting the potential for a biannual dosing regimen for vutrisiran, which can further differentiate vutrisiran from other products currently approved or in development. We are actively advancing our efforts to bring a q6 monthly dose of the regimen to the market in parallel with our ongoing development of the q3 monthly regimen. Moving now to GIVLAARI, which is approved in the U.S., EU, Brazil and in Canada to treat acute hepatic porphyria, we're pleased with continued base…

Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting Alnylam's third quarter 2020 financial results. As Andy has already highlighted, it was a very strong quarter with outstanding results for both ONPATTRO and GIVLAARI. Turning to our results first for ONPATTRO. We generated $82.5 million in global net ONPATTRO revenue for the quarter, which represents a return to growth driven by strong commercial execution and improving market conditions following Q2 which was negatively impacted by the pandemic. Global sales increased 24% versus the second quarter of 2020 and 79% compared with Q3 2019. U.S. sales of ONPATTRO increased 21% versus Q2 2020 with primary sources of growth from the following: Patient demand increased 14% driven by an improvement in patient compliance which returned to prepandemic levels as well as the addition of new patients during the quarter. Modest inventory stocking during the quarter compared with destocking during Q2, offset by a slight increase in gross to net sales reductions, favorably impacted Q3 growth by 7%. We ended the quarter with less than 2 weeks of inventory in the channel. We are really pleased with the strength of the results in the U.S. in the quarter, with Q3 sales representing the highest level since launch. In our international markets, ONPATTRO performance remained strong with growth of 27% versus Q2 of 2020, with primary sources of growth from the following: an increase in patient demand contributed 19% growth and was primarily from major markets in Europe, where we achieved recent PNR outcomes, including from Portugal. We also saw continued excellence from Japan. Source of new patients in our international markets remains balanced between patient switches from a TTR stabilizer and new patients naive to treatment. Additionally, there were onetime benefits associated with finalizing our price in France and with completing…

Thanks, Jeff, and hello, everyone. As we look to close out 2020, we have a number of very important and exciting milestones lined up. For starters, we plan to continue our global commercialization of both ONPATTRO and GIVLAARI. We're also expecting 2 additional regulatory approvals by the end of the year for lumasiran and inclisiran in both the U.S. and Europe. We expect to launch OXLUMO in the U.S. by year-end. We plan to continue enrollment in our ATTR cardiomyopathy studies, specifically APOLLO-B with patisiran and HELIOS-B with vutrisiran. We look forward to presenting additional clinical results from the ongoing Phase I trial of ALN-AGT in hypertension at the AHA meeting on November 13. And our partner, Regeneron, plans to initiate a Phase I study for cemdisiran in combination with pozelimab as a potential therapeutic option for the treatment of complement-mediated diseases. We also look forward to updating you on overall pipeline progress and strategy at our virtual R&D day event in December. As John noted earlier, these are very exciting times for Alnylam as we expect to exceed our original Alnylam 2020 guidance, exiting this year as a global multiproduct commercial company with a robust clinical pipeline for continued growth and an organic product engine delivering sustainable innovation. 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 questions. [Operator Instructions]

[Operator Instructions] We'll take our first question from Gena Wang from Barclays.

And congrats on a very strong quarter. So one question regarding the commercial. First, for the ONPATTRO, do you expect for the 4Q, any thoughts on the inventory and where the major driver would be for the remaining of the year? And also for lumasiran, could you share with us the number of patients in early access program right now?

Yes. So thank you, Gena. Let's -- I'll go to Andy and Jeff on the ONPATTRO question specifically. Regarding the lumasiran EAP, we're not giving out specifics on patients that are in the program. But I will say at a high level that, obviously, we do have patients in our expanded access program. And obviously, as lumasiran gets approved, we will be transitioning those patients onto commercial product on a country-by-country basis based on [ E&R ] being achieved. So that's where we'll leave that question. Andy, do you want to start? And then maybe, Jeff, you can comment on impact of inventory. But I think, Andy, you can give a bigger picture, Q4 expectations for ONPATTRO.

Sure. Happy to. So as we noted, Q3, the growth was a mixture of both net new patient demand as well as a return to an increased compliance rate, specifically in the United States post that Q2 COVID impact. In Q4, we expect the growth to come primarily from that net new patient demand. And I'll turn it over to Jeff here on the inventory side.

Yes. In terms of where we are in inventory, Gena, at the end of the third quarter for ONPATTRO, we're less than 2 weeks. And based on the distribution agreements we have, that range is typically in the 1 to 3 weeks range. So again, we're right, maybe right in the middle of that at this point.

We'll now take our next question from Tazeen Ahmad from Bank of America.

So I wanted to get a sense of what information we should expect to see when the top line reads out from the HELIOS-A study early next year. And whatever that data does show, should we have any reason to think that there would be read-through into the population that you guys are studying in cardiomyopathy in the HELIOS-B study?

Yes, that's a great question, Tazeen, and I'll let Akshay handle it. Let me just start by saying we're very excited about vutrisiran because it is obviously going to enable a once-quarterly subcutaneous dose administration and potentially with additional work, we believe that we can introduce a biannual dosing regimen for patients with hATTR. Initially, it will be for the polyneuropathy setting with the HELIOS-A study. And then obviously, the focus will be in HELIOS-B and cardiomyopathy, both hereditary and wild-type. So Akshay, do you want to comment specifically on Tazeen's questions around what will be available at the top line and what potential read-through there will be on cardiomyopathy from HELIOS-A?

Yes. Thanks, John. So vis-à-vis HELIOS-A top line, we continue to believe that we'll have the data early next year. So that's very exciting. Our general habit when we present top line is to give the primary endpoint and relative secondaries and also, of course, the safety information on the study at a high level that's relevant to the report. We then report more fully on all the details at an upcoming scientific meeting after that. So those should be very informative as to how the study's done I think. And vis-à-vis the read-through into cardiomyopathy in HELIOS-B, if we harken back to APOLLO, the original APOLLO study with ONPATTRO, I think we learned a lot there about the impact on biomarkers, on the impact on [ echo ] findings in the heart in about 50% of the patients that had some evidence of cardiomyopathy within that study population for ONPATTRO. Now it remains to be determined exactly what proportion of patients have cardiac involvement here in HELIOS-A, but it will be exciting to see what the impacts have been on not just biomarkers, but other aspects of the disease in terms of the read-through, but very much dependent on the import population.

Thanks, Akshay. Does that -- Tazeen, does that answer your question?

Yes. And when you say early next year, can you -- is it possible that the data would be in January? Or are you not providing that level of granularity?

Yes. We're not going to provide that level of granularity, Tazeen. Our early period, as you know, is Q1 or Q2. But I think it's going to be early.

We'll now take our next question from Paul Matteis from Stifel.

Congrats on the quarter. Two questions. One, on vutrisiran, do you think you could bridge to the 6-month dose with just TTR lowering data and safety? And if so, what's the status of that clinical work? And then second, on lumasiran, on the Wall Street side, expectations of this drug are materially lower than that of givosiran, but I think some of the prevalence data for PH1 and 2, 3 that you've outlined are not that dissimilar to AHP's. So do you think givosiran is a realistic analogue for this? If so or if not, can you give any context?

Yes. Thanks, Paul, and great questions. I think for starters on the vutri q6 monthly, at a high level, it is certainly our belief that TTR lowering, combined with safety should support that approach. And we've been encouraged by engagement that we've had with regulators on that point. So I think that is certainly a path we would forward. And that would be consistent with other types of medicines and where dose regimens with a strong biomarker have been supported in future labeling. But obviously, that will require those data to be generated and then obviously submitted as part of an SNDA, and that would be the overall plan. Regarding OXLUMO and the market size, I'll let Andy comment a little bit on that further. But I think in general, when we look at the prevalence out there, we do believe that there are somewhere between 1,000 and 1,700 patients that are diagnosed and would be on label, if you will, patients that have mild to moderate PH1, which would be the initial label prior to then expanding it to include severe PH1. Andy, do you want to comment any further on the PH1 population and how we should think about lumasiran relative to GIVLAARI?

Sure, John. Thanks. And as you said here, we're at this point, expecting that number somewhere between 1,000 and 1,700 that would be addressable and on-label. And overall market opportunity, we do see luma becoming a $500 million brand as it launches globally. And furthermore, right, we're excited to get out there and continue to shape this market, which is largely, to this point, pretty underserved. So we'll be learning a lot as we go.

Perfect. Does that answer your question, Paul?

Yes, definitely.

We'll now take our next question from Anita (sic) [ Anvita ] Gupta from Cowen.

This is Anvita on for Ritu today. Congrats on the quarter. So 2 questions from my side. Do you expect the fourth quarter new lockdown impact to be better or worse than the second quarter lockdown impact? And then secondly, understood that it's unclear how many cardiomyopathy patients would be in HELIOS-A study, but if you do plan to provide a subgroup cardiac analysis, what would be the primary function outcome of such an analysis?

Great. Well, I'm going to have Akshay answer the second part -- second question. But regarding the first question, let me just give a high level and then, Andy, you can comment. Look, at a high level, it's our belief that the medical system is more adapted at this point than it was in Q2. This is -- I'm saying this globally from a global perspective. And for the most part, we have seen a return to medical procedures and diagnostic testing done in -- globally. And therefore, we believe that even with shutdown of countries that will occur -- could occur as we go into Q4 to deal with the second wave or third wave, depending on where you are, we do expect the medical system to stay relatively open, relative to what it was like in Q2. Andy, do you want to add any more color to that?

Yes. You've got it right, John. And furthermore, yes, the health care systems learned how to navigate and are showing that now with increased patient flows coming through maintenance of therapy for all levels of all patients continuing. But we have learned as well how to navigate this both on a promotional basis and continuity of care. So we're in a much better position here to weather what may come.

Fantastic. And Akshay, do you want to answer the HELIOS-A question?

Yes. Thanks, Anvita. We've got to remember that the primary goal of the study is to study the neuropathic aspects of the disease. So most of the endpoints are focused on that, certainly the primary endpoint and so forth. Now as I said before to a previous question, we will see how many cardiomyopathy patients or patients with true cardiomyopathy we have and report out all the data that we've collected, including biomarkers' echo. In terms of the primary functional outcome, as you put it, I guess the most important would be hospitalizations and deaths. But again, the study is not orientated towards kind of myopathy. So I don't know exactly how many of those events would have occurred, but we'll certainly be sharing them in due course.

Great. Does that answer your question?

Yes.

Moving on to our next question, it's from Alethia Young from Cantor Fitzgerald.

This is Emily on for Alethia. In light of some of the recent progress and challenges in AAT, we're curious to see how you're thinking about plans going forward with [ small cell ] for RNAi. And do you think that combination with [indiscernible] are some of the long-range goal here?

So I'm not sure I heard you clearly on the first part, Emily, could you repeat what area are you commenting on specifically?

For AAT. In light of the early...

Alpha 1 antitrypsin.

Yes.

Okay. Got it. Absolutely. Yes. Look, I mean, we are excited about the potential for RNAi therapeutics to treat the liver disease associated with alpha 1 antitrypsin deficiency and obviously have advanced a molecule alpha 1 -- ALN-AAT02 into development. Now earlier this year, we decided to partner that program together with Dicerna, who had their own independent effort as well. And so the combined effort between Alnylam and Dicerna now really is positioned to advance quite nicely and is in -- currently going to be -- is in a Phase I/II study. We'll be going into a Phase II/III in due course. So we're definitely excited about the opportunity, the way the partnership with Dicerna works is they will advance the program, 100% on their cost. We retain an opt-in right at the end of Phase III. So after all the risk is taken out, it's a free opt-in that we have to commercialize outside the U.S. market. So they'll keep the U.S., and we'll have the rest of world. So we are encouraging our colleagues at Dicerna to move swiftly with the program. And we do think that it becomes a very competitive opportunity to deal with the liver manifestations of the disease. Yvonne, anything else from your perspective to add as it relates to the Dicerna relationship?

No, John, I think you've covered it really well.

Right. Emily, does that answer your question?

Yes.

We'll now take our next question from Ted Tenthoff from Piper Sandler.

Just to congratulate you on continued excellent execution on the commercial side, especially going through difficult times. Really incredible to see just how, over the years, the vision to come together on how you're treating patients so effectively now. My question is related to fitusiran. A lot of the others were answered. But kind of what's the latest there? And we haven't really talked about that one as much recently just because there's been such a focus on the success with the other programs. But kind of how have you seen that market change a little bit over the last year? And where do you think that fits for Sanofi and for you guys going forward?

Yes. Thanks, Ted. Thanks -- first of all, for the comments, the congratulatory comments at the beginning. But on fitusiran, specifically, as you know, this is partnered, and as you mentioned, this is partnered with Sanofi. It's an RNAi therapeutic that targets antithrombin with the goal of increasing thrombin generation to improve hemostasis in patients with hemophilia A, hemophilia B with and without inhibitors. So it really is an attractive target product profile that we've constructed for the molecule. The program is in Phase III. It's being led by Sanofi. And we really rely on their continued execution of the program. So we hope to learn more in the next period. And so that's where it is. But I think for the most part, Sanofi really has been the driver of the program, and it's ultimately their call in terms of how they advance it. I don't know, Akshay or Yvonne, anything else to add to that from your perspectives?

I think the only thing I'd add is to put the hemophilia landscape continues to need innovation. The adoption of Hemlibra shows that people are keen to find therapies other than multiple times a week intravenous factor replacement. And so I'm -- we're excited about fitusiran. And hopefully, there's a great home for it both in hemophilia A and B with and without inhibitors. But as John said, Sanofi would guide you on further progress with the program.

Yes. Great. And can you just remind us your commercial interest there?

Yes. So we have -- a very important point. So we have reciprocal -- we have royalties on fitusiran that range from 15% to 30% tiered to sales. So we have a -- we do have a significant and attractive financial interest in the product success. No question about it.

Our next question comes from Anupam Rama from JPMorgan.

This is Tessa on the call, John. So for -- with the APOLLO-B trial enrolling in ATTR-CM, I think you noted that enrollment is expected to complete in 2021. Sort of -- when considering a potential for an internal analysis here, what are the factors that you're considering? And then a second quick one, on the ALN-AGT update next week at AHA, can you just give us a quick sense on the size and scope of the data we'll be seeing at the conference there next week?

Yes. Terrific. Great questions. Let me just first clarify with APOLLO-B, which is the patisiran study in both hereditary and wild-type ATTR cardiomyopathy. That's a 12-month study. There is no interim analysis. You certainly are right regarding an interim analysis on HELIOS-B. So I just want to clarify what trial.

Yes. I'm sorry, John, I meant HELIOS-B. I misspoke.

Okay. That's what I wanted to clarify. Okay. So Akshay, do you want to comment on HELIOS-B a little bit in interim analysis? Akshay, are you on mute?

The HELIOS-B interim analysis obviously is going to be very interesting to execute on. We've picked up enrollment very well this year after that slow Q2 with COVID. So as we further enroll in that study and also, importantly, completion of the APOLLO-B study, which will give important information on how our TTR reducing approaches impact cardiomyopathy. That information will be of strategic important, I think, in design of the interim analysis, which we're busy working on. And we'll share further details with you as enrollment picks up and we get more from APOLLO-B ultimately as the result reads out. With respect to your other question, Tessa, on ALN-AGT at American Heart next week. Yes, that's the first time we'll be sharing all the data that we have. There will be obviously safety. First and foremost, it's the first-in-human study. We'll also be sharing all the pharmacodynamic data on target knockdown and how that relates to change in blood pressure. We've reported that there are significant changes in blood pressure, but you'll see all the data in full, including dose dependence and the extent of change in systolic and diastolic, et cetera. And I think people will come away with the good insight into the frequency of dosing, and we obviously continue to believe that this will be an infrequently administered therapeutic for hypertension as we further develop it, which will give great advantage to this patient population where compliance is a huge, huge issue in about half the patients. So that's kind of a thumbnail on what's coming up next week.

We'll take our next question from Joel Beatty from Citi.

Great. For Alnylam HSD in NASH and that recently initiated study, could you discuss the potential to evaluate any efficacy or biomarker endpoints?

Absolutely. Akshay, do you want to talk about the HSD Phase I?

Yes. So that study is ongoing, will progress from healthy volunteers, dosing [ ascending ] fashion into a subset of patients with NASH itself. The target HSD, it doesn't circulate in the blood. So like a lot of our programs, we won't have direct biomarker data on the target itself, but there are a number of other downstream factors that we're looking at in terms of biomarkers, and we believe will be highly informative. We'll share more on that as the program progresses and the study progresses next year. And ultimately, I think what goes on in the liver in the NASH patients will be of great importance, both biochemically as well as radiological, and we'll share that as the study matures.

Yes, I'll just add to that, that we also have our upcoming R&D Day in December, and that will be an opportunity for us to do more of a deep dive on the HSD opportunity and the clinical plans for that program. But it is an exciting program because it is a genetically validated target for NASH. And we think it obviously holds great promise in that important indication.

We'll now take our next question from Maury Raycroft from Jefferies.

Congrats on the progress. First one is also on the ALN-AGT program. For the data next week, I'm just wondering if you're going to have some data from the additional exploratory cohorts, including obese patients, a soft control cohort and our combo cohort as well. And if not, I guess, what's the latest status with those cohorts? How meaningful are they? And then what are next steps with the program?

Okay. Great questions. I mean the simple answer is you won't see those cohorts next week because they haven't been dosed yet. But Akshay, do you want to comment a little bit on the next steps for those cohorts and just the completion of the Phase I?

Yes. So Maury, obviously, the study did get delayed in part through Q2 with COVID and so forth, which hit that study like so many others. We've picked up steam. We haven't commenced dosing as John said yet, but we're in place now to start dosing those cohorts and that will be ongoing through the rest of the year. And in due course, we'll report where we'll give a further update on the Phase I study early next year in terms of scientific meeting, where we can bring that information to everybody. But most importantly, next year, I think beyond the clear antipertensity effect, which we believe we've established and everyone will share in next week at AHA, the most important thing is to take that observation into the Phase II setting, and we're very busy aligning on the design of the Phase II effort and getting going with that next year. So that's the crucial next goal.

Yes. And I would just add, Maury, that again, our upcoming R&D Day, we will do a deep dive on the hypertension opportunity because we think it is obviously an exciting prospect for new innovation coming from the Alnylam pipeline.

Moving on to our next question, it comes from Salveen Richter from Goldman Sachs.

This is Sonya on for Salveen. So just really a quick question on the progress of your [ extrahep ] portfolio, particularly there with the ALN-APP. When can we expect first data there?

Yes. Thanks, Sonya. Well, I'm glad to get a question like this, and I'm sure Akshay is as well. Let me just say at the start and remind everybody that one of the exciting breakthroughs that we achieved over the last couple of years is the delivery, the efficient and highly durable delivery of RNAi therapeutics to the CNS and other tissues as well, including the eye and more recently the lung. So we are obviously quite excited about that because it opens up new prospects for our pipeline growth outside of the liver. And in the setting of the CNS itself, of course, it is really an opportunity to go after the many, many neurodegenerative diseases that are caused by gain-of-function mutations or gain-of-function expression of proteins in the CNS with a dose regimen that we think intrathecally can be given once every 6 months, if not less frequently. So it is a great opportunity for the company, and we've partnered with Regeneron on a 50-50 basis in that regard. Akshay, do you want to specifically talk about APP and the next steps?

Yes. So speaking of Regeneron and APP, it was great that they've partnered with us. We'll be taking the program with them into Phase I next year. We continue to guide that we'll enter Phase I in the middle of next year or so. And further guidance on when we'll actually see data will be given once we've gotten going with that Phase I study. And the other thing is, of course, this is a very interesting time with the aducanumab review ongoing, and there's a lot of excitement around what those data are showing. So it would be interesting to see the outcome of that on Friday. But we continue to believe in APP as a very important target for Alzheimer's disease and beyond. And not only can we tackle the a-beta deposits, we believe, in the extracellular space, but tackling the target outsource and turning off the tap, so to speak, and all the intraneuronal effects of a-beta will also be impacted. So we think this could have a really significant contribution to play. So excited to get into Phase I next year, and we'll update on data expectations after that.

And Yvonne, do you want to comment a little bit on how this works within our Regeneron relationship vis-à-vis our lead, et cetera? That might be a useful context.

Yes. No, that's great. I mean we were delighted that Regeneron have opted in. We're actually going to be leading the program, and we're very excited about that and obviously, share the economics with Regeneron, but we're very excited to be leading the first CNS program out of our platform.

We'll now out take -- our next questions comes from Alan Carr from Needham & Company.

Can you give a little more detail around the -- your COVID candidate? What exactly -- where things stand, what work you need to do around that? I'm kind of curious about where things stand. I believe you were looking at other candidates too and other targets around COVID-19. Can you give us a more comprehensive update around that program [indiscernible]?

Yes. Happy to, Alan. And let me start and then Akshay, you can comment as well. We're -- we continue to be committed to advancing our COVID program. Obviously, there's the opportunity of targeting the SARS-CoV-2 genome, which is an RNA genome, directly with an RNAi therapeutic is certainly an appropriate thing to do from a technology perspective and our recent advances in [ lung ] delivery obviously have come just in time to help us advance this program. We've done some work in the Syrian hamster model, which is an established model for SARS-CoV-2 infection. And we have seen antiviral activity in the model specifically. And we're encouraged by that. But we want to do more model work before we commit to specific IND timing and specific clinical development plan so that we can understand the best place to position this molecule in the context of emerging therapies for the treatment of COVID-19. And we're going to play the long game on this program as it relates to how it could play into the management of COVID-19 in the future, which we think will be an opportunity longer term for therapies, just like there is for diseases like flu. But that's how we're thinking about it, and those are the specific results. And we look forward to presenting those at some point in the future. Akshay, anything to add to that?

No, I think you covered it, John. That's exactly right.

We'll now take our next question from Patrick Trucchio from H.C. Wainwright.

With the understanding that the closure in the U.S. election may take some time, I'm wondering if you can comment how a potential change in the administration could impact health care policy and what impact, if any, this could have on Alnylam's R&D or commercial execution in the U.S. in 2021 and beyond.

Okay. Great. So yes, obviously, we are hoping that there is a completion and clarity on the election here in the coming days or coming weeks. And I think it's great to see our democracy going through the process of counting all the votes, which is the way democracies need to work. And so it's great to see that happening. And we certainly stand by to sort of see how it emerges overall. But I think that regardless of the outcome, whether Trump or Biden get elected, we believe that there's going to be a dialogue and continue to be a dialogue around drug pricing politically. But I think that Alnylam is very well positioned in that dialogue because of the type of innovation that we consistently deliver from our platform and I think the type of medicines that we bring forward, the type of ways that we've engaged with payers around sharing of risk and obviously, delivery of value ultimately. These are the types of approaches that we think will bode well for continued success and continued ability to get the value of our innovation recognized by governments and payers around the world. So we do think that we're in a good position to -- regardless of the outcome, regardless of the policies that emerge, to be able to continue to do what's right for patients first and foremost and obviously deliver on the value of that from our platform. So we think we're in a good place, Patrick, on that overall. We certainly have been active in helping different stakeholders in this discussion, and we will remain active as a company in this discussion. But we are generally optimistic, and maybe there will be some changes that come -- that occur, but we think we're very well equipped to do well through all of that.

We'll now take our next question from Leland Gershell from Oppenheimer.

I echo others' comments on the solid execution. Just a question on the reimbursement and progress with OXLUMO having been through the VBA discussions with others, on GIVLAARI recently, just wanted to ask if you have any comments on any differences you're seeing in that progress and if you would expect it to be -- basically be on pace with where you were with GIVLAARI as you execute on OXLUMO.

Yes, that's a great question, Leland. Let me just start by saying how proud I am of our access teams around the world with the great job they've done with ONPATTRO, the great job they're doing right now with GIVLAARI and right now, we have over 30, just about -- actually just about 30 value-based agreements that we signed with commercial payers in the U.S., and we continue to work with -- in global markets very effectively with the payer stakeholders. And we've shown a lot of -- we've demonstrated and brought a lot of innovation forward on these VBAs, both the general structure of them and how we share risk around performance of the product. But also on some of the new features that we've introduced, like the prevalence-based adjustment model that we've introduced on GIVLAARI. So with that as context, Andy, do you want to get more specific on OXLUMO? And obviously, we can't share all the details that we'll share when we launch the product, but maybe you can give some context on how our discussions are going.

Sure, sure. So similar to ONPATTRO and GIVLAARI, we will and are pursuing an aggressive value-based agenda with all payers globally. And feedback from early days on that front has been exceptionally positive. So we expect similar results in terms of open access for OXLUMO as we had with GIVLAARI and ONPATTRO, which are really, really strong. So we'll continue our industry leadership here.

Moving on to our next question, comes from Mani Foroohar from SVB Leerink.

A quick one, I guess, starting on for Jeff. Talk a little bit about the increasing compliance as a driver of ONPATTRO performance. I presume some of that is from patient hesitance that come in for their IV during the height of the pandemic. Has that compliance trend reversed entirely? Are there still a little bit of juice for next quarter and beyond? And then for Akshay, there's been a lot of talk about what HELIOS-A tells us about HELIOS-B. I'm inclined to agree that maybe APOLLO-B is the more useful leap forward. Can you give us a little detail on how you think about taking the option on HELIOS-B interim? Is the most appropriate approach to wait until you have APOLLO-B data to inform that? Or do you think that just data that you gather on a blinded basis from HELIOS-B itself as the study proceeds will provide you with the information you need to decide if and when to take that interim?

Okay. Those are great -- those are 2 great questions, Mani. Why don't we start with Jeff and then we'll have Akshay talk about the Cardi B, as we call them collectively strategery and how that relates to the interim. So Jeff, do you want to start first on the compliance question?

Yes, sure. So just to remind you on the results that Andy commented on earlier and I did as well, we grew 21% in Q3 in the U.S. for ONPATTRO versus Q2, 14% of that was demand related, and that was a mix of new patients coming on to therapy and the increased compliance that we saw in Q3. And that returned in the U.S. to prepandemic levels, Mani. So I don't see no -- sort of a big impact of that on growth going forward. And just a reminder, outside the U.S., we didn't see the same impact on compliance in Q2 that we saw in the U.S. So outside the U.S., the health care systems seem to do a better job of maintaining patients on therapy and compliance wasn't impacted. So again, I don't see a big impact of increased compliance going forward on our growth rates.

And just before I hand it over to Akshay, I would just add that the side of care adjustments that we made in Q2 have, I think, bolstered any potential downside of pandemic resurgence, the third wave that might happen in the U.S., et cetera. So I think that we're very -- we're better sheltered in Q4 and beyond to not -- if things get much worse, to not have any significant impact from what we saw like in Q2. Akshay, do you want to now handle the more complicated but interesting question that Mani has asked?

Would love to, John. The question, Mani, focused on APOLLO-B and the read-through to HELIOS-B. And I agree that that's a very important aspect of the work we're doing and the insights that we'll glean there will be very important for us. I'd also say that continuing work with patients from APOLLO itself and the open-label extension study gives us important insights into long-term outcomes on neuropathy and cardiomyopathy. We've had a number of studies ongoing out in the field and Dr. Gilmore from the U.K. group just published a paper in Jack imaging on reversal of amyloid deposition in TTR cardiomyopathy patients of the inherited type. And I think that says something important, and we continue to work with groups like that to understand what they're seeing and the outcomes that they're seeing both clinically and radiologically. HELIOS-A, as we discussed earlier, to your point, it's not as rich a data set for cardiomyopathy but there could be some important information there. And then APOLLO-B itself. And I think ultimately, we'll just have to see on the timings of all these data points and how they factor in. And as we get greater insight into the APOLLO-B readout, I think we can guide on what the exact HELIOS-B interim will be and use all these points of information to guide that. But I think we're fortunate because there's so much to teach us about what to expect ultimately from HELIOS-B and that should lead to a very informed structure around the interim.

Yes. Absolutely agree. Does that answer your question, Mani?

Yes. That's great.

We'll now take our next question from Navin Jacob from UBS.

This is Jon on for Navin. So with respect -- you've alluded to the COVID recovery across geographies. And we're curious if COVID has caused any shift in payer mix for your assets on GIVLAARI and ONPATTRO. We're also curious as to how -- as to which analogue might be better for us as we prepare for the OXLUMO launch. Would it be more like GIVLAARI with a bit more Medicaid or perhaps more like ONPATTRO? Any color would be appreciated.

Those are great questions. I'm going to hand them right over to Andy to answer.

Thanks. So let's start with the first one. So changes in payer mix. Specifically, in the United States, we're seeing little to no changes in payer mix. Remember that ONPATTRO is the vast majority Medicare. And at this point in time, GIVLAARI is pretty early days here, but largely commercial, and we're not seeing any material changes to those due to COVID. And then the second question, with OXLUMO, in terms of payer mix analogue, actually, neither are perfect but of the 2, it's certainly going to be less of a Medicare population, right? We think OXLUMO is more of a commercial and/or Medicaid insurance one. So that's, I guess, a little bit more similar to GIVLAARI, if that helps.

Moving on to our next question, comes from Vincent Chen from Bernstein.

Well, probably a little far out, but going over to CNS side of things for a moment. I was wondering if I could ask you for sort of your latest thoughts on ALN-HTT in Huntington's, and how that might offer advantages over competitive programs in this space, most notably Roche and Ionis' tominersen. Are there reasons to expect the ALN-HTT and the siRNA platform from CNS will outperform the Roche-Ionis program from a perspective of sort of the degree of knockdown achieved, the breadth or the -- ultimately the efficacy?

So let me hand it over to Akshay. Thanks for the question, Vincent. I'll just start by saying that, obviously, the -- what we've seen with our platform in the CNS has been pretty consistent with what we've seen in the platform with liver. And when you compare an RNAi therapeutic approach in the liver compared to an antisense oligo-based approach, what you see is you see deeper, better knockdown and much greater durability in the liver. We've seen that all the way through marketed products. And we see similar profiles in nonhuman primates between antisense oligos and RNAi therapeutics. So by all accounts, we expect a deeper knockdown potential with our platform and a much more durable approach that would allow for less frequent intrathecal administration, which, of course, is a important -- is a burden in the administration of oligos in the CNS. But there's some more to that -- there's more to the ACT opportunity that I'm going to leave to Akshay to comment on specifically on exon 1. Akshay?

Yes. And before I go to exon 1, the only thing I would add to what you said in terms of pharmacologic attributes shown on potency, durability, of course, but also just much better by distribution based on our preclinical findings. We think that the RNAi approach gives much better knockdown and deeper brain structures like the basal ganglia, which is very easy to get to for Huntington's predominantly. So those pharmacologic attributes and then there's the actual target strategy itself. And there's an abundance of literature now or significant literature suggesting that exon 1 itself has a very important role to play in the pathology of the disease and there are truncated transcripts that come off exon 1 that appear in and of themselves to be neurotoxic. And then there are protein aggregates made -- what protein made from the truncated exon 1 transcript that aggregates and causes pathology. So going for an exon 1 agnostic approach may not be the strongest, and we focused on a exon 1 approach so we can have the best approach to the target that the literature currently would support and the [indiscernible] support, and that along with the pharmacologic, actually, as we've discussed, I think, really sets us up for a very attractive profile. We look forward to going to the clinic.

Does that answer your question, Vincent?

Yes.

We'll now take our next question. It comes from Luca Issi from RBC.

Congrats on the commercial execution here. Maybe going back to Cardi B for a second, but maybe with a little bit more of a commercial angle here. Do you think that actually APOLLO-B would be sufficient for doc to change their prescribing habits from Vyndaqel to ONPATTRO? Or do you think the most doc will actually need to wait for HELIOS-B, given that again, APOLLO-B is just power for 6 minutes walking, you're still dealing with an IV drug? Any thoughts there would be helpful. Maybe second question. We've seen a few of your competitors actually going after ENaC for cystic fibrosis. Wondering if one, you have any thoughts on that approach? And two, what's your appetite to potentially enter that race?

Okay. Well, great questions. I think, obviously, the first one, Andy, I'd like you to answer. I'll just start by reminding everybody that, obviously, the APOLLO-B study is a study of patisiran, which is a nonbranded name for ONPATTRO, which is an investigational agent right now, and it's being studied in patients with both wild-type and hereditary ATTR amyloidosis with cardiomyopathy. And that study uses the 6-minute walk distance as the primary endpoint of 12 months. And then the HELIOS-B study with vutrisiran uses the -- uses CV hospitalization and mortality as a primary endpoint at 30 months treatment. And so that's an important distinction. But in general, and then Andy, you should comment, we do feel very encouraged that if APOLLO-B is positive and if we're able to get an approval with the FDA based on the study and other regulators, that this will be a very attractive alternative for the cardiology community to treat their patients with both hereditary and wild-type ATTR. And while the ultimate presentation of a TTR silencer with a quarterly or 6 monthly subcu approach will be certainly much more exciting in the future, in the meantime, ONPATTRO with its broader label will be an important treatment option for patients. Andy, do you want to comment a little bit on our perspective on that more -- in more detail?

Sure, John. Happy to. So we're very excited about the APOLLO-B potential here and the launch into hereditary and wild-type cardiomyopathy. To note, in the United States today, cardiologists are currently having very strong experience with ONPATTRO in treating the polyneuropathy. And upon approval, we do expect a meaningful amount of physicians to choose a TTR silencer versus a stabilizer. And furthermore, there also will be physicians who don't decide to choose. And frankly, they use both. And so reimbursement will be something we'll be proactively looking to solve on that front as well.

Terrific. And then, Akshay, do you -- or maybe, Yvonne, do you want to comment a little bit on, from a portfolio standpoint, how we think about programs and ENaC, for example, and is that -- and whether or not that's an area that we would consider?

Yes, sure, John. Look, I think what's been incredible about our platform is actually the kind of productivity that we've had. And we're increasingly demonstrating our ability to access tissues in addition to liver, CNS and ocular. And many of you may be aware that -- our [indiscernible] history with lung delivery as well with an RSV program many years ago. So we have a tremendous amount of opportunity in front of us. And clearly, we need to think how we prioritize the best opportunities for us. We have a lot on our plate to move forward from an execution perspective. But we remain open about continuing to explore the broad utility of our platform going forward. But nothing to share specifically on cystic fibrosis at this time. John, do you want to add anything?

No. I don't know, Akshay, anything you want to add to that?

No. I mean part of the ALN COVID assets, obviously, lung delivery has come front and center. We have that preliminary data set about a year ago now showing we've achieved lung delivery, which is very exciting. And just as we've done with many other settings and organs, the idea of genetically validated targets comes into the mix. And we have knowledge of a number of very interesting genetically validated targets beyond ENaC itself and cystic fibrosis. So this really is the new [ vista ] that's forming before us, and it will be exciting to take it on beyond the COVID effort itself.

We will now take our next question from Zhiqiang Shu.

Congrats on the strong quarter here. Quick question. Yes. Quick question on patisiran, I guess, on APOLLO-B. Have you guys looked at any, I guess, clinical or translational data in terms of the correlation between baseline disease severity and the potential response to the drug? 6 minutes walk or hospitalization, I recall, the -- stabilizer actually has a different trend when it comes to different patient population. And then second question quickly on AGT program, given the drug will be -- potentially target a large population, patient population, have you guys started to think about partnership opportunities there?

Right. Well, let me start with -- let me just -- Akshay, you should take the APOLLO-B, very interesting APOLLO-B question. But let me just -- on the AGT comment real quickly. Our intent with the AGT program is to advance it to the market. We certainly are a company that as we bring the medicine like AGT forward, we're going to have an opportunity to -- at that stage of our growth in company to commercialize a medicine like that. If we, at that point in the future, choose to bring on a promotional partner, we may do that. But our key goal is to retain the program and develop it ourselves, and that's how we're focused on it. And so that's what we're doing there. But Akshay, do you want to answer the APOLLO-B question that was asked?

Sure.

Actually John, maybe if I could just comment really quickly on the point you made. I think the other thing to remember is with our sort of TTR suite of opportunities. We are actually building up a very robust commercial footprint in the cardiovascular arena, so that's something else that we can consider as we plan for AGT.

Yes. Yes, absolutely. I agree completely. Thanks for jumping in on that, Yvonne. Akshay, do you want to then deal with the APOLLO-B question?

Yes. Zhiqiang, good question about APOLLO-B. Now of course, there's an ongoing blinded study. So we don't sort of look at all the data currently, and that's as it should be to maintain study integrity. So I can't comment on relationships between various parameters. I can tell you that there are very good associations between [ neuropath ] association stage and 6-minute walk distance. We know that from prior work, ours and other people's work. And we know how that relates to biomarkers, such as BNP and other imaging biomarkers. In terms of -- the other aspect to your question was outcomes with and without prior tafamidis. And there, we can look at older information from APOLLO itself, the original study for patisiran/ONPATTRO, the Phase III study. And what was very clear there actually is whether patients had previously been on a stabilizer, whether it was tafamidis or diflunisal or had never been on a stabilizer, their outcome was equivalent. And that is, on average, their mNIS+7, then your [ opti ] endpoint improved, their quality of life improved. So that's very encouraging for us that our mechanism of actions seems to be potent and whilst it wasn't a head-to-head study, everything pointed to ONPATTRO really having a profound impact and resulting in improvement of disease in the context of the APOLLO study. And we believe that's one of the very attractive features of the drug. We know from tafamidis, from the Phase III ATTRACT study that whilst clearly, there was benefit in terms of hospitalization and mortality, all the curves went down. It's just the curve for tafamidis didn't go down as much as it did for placebo, which is a good thing for patients. But sadly, disease progressed. It was quite clear whichever endpoint you looked at including 6-minute walk distance and walk distance declined over time in the active group as opposed to placebo. So if we can stabilize 6-minute walk distance, I think that's great. If we can actually improve 6-minute walk distance, even better. The recently published study by Professor Gilmore and others from the U.K. group in Jack imaging where they took a cohort of cardiomyopathy patients and they were given patisiran. At 1 year comparing to historic controls, they saw stabilization of 6-minute walk distance there and regression of amyloid, something that's -- neither of those things that have been seen with tafamidis up until now. So we think the fundamental mechanism of action to remove the pathogenic protein to a greater extent outcomes in neuropathy that we know well. And also some of the preliminary evidence emerging around the cardiomyopathy in use of ONPATTRO in investigational setting all suggest that we look forward to stabilizing disease and hopefully improving outcomes.

Zhiqiang, does that answer your question?

Yes.

At this time in moment, I would like to turn the conference back to the company for any additional or closing remarks.

Okay. Thank you, and thanks, everyone, for joining us on this call. Look, Alnylam is at a very exciting stage of its continued growth in development as a leading biotech. We're really pleased with our Q3 results and our execution from our commercial and R&D teams. We look forward to updating you on our continued progress at our R&D Day in December. Until then, I hope you all stay safe and healthy, and have a great day. Bye-bye now.

And that concludes today's call. Thank you for your participation. You may now disconnect.