Alnylam Pharmaceuticals, Inc.

Ladies and gentlemen, thank you for standing by. And welcome to the Alnylam Pharmaceuticals conference call to discuss fourth quarter and full year 2020 financial results. There will be a question and answer session to follow. Please be advised that this call is being taped at the company's request. I would 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 El Nilem. With me today on the phone are John Merriganori, Chief Executive Officer, Tolga Tangular, Chief Commercial Officer, Akshay Vaishnav, President of R&D, Jeff Fulton, Chief Financial Officer, and Yvonne Greenstreet, President and Chief Operating Officer. In addition, Andy Wirth, Senior Vice President, Head of the U.S. Business, is on the line and available for Q&A. For those of you participating via conference call, the accompanying slides can be accessed by going to the events section of the investor page of our website, investors.elnilam.com slash events. During today's call, as outlined in slide two, John will provide some introductory remarks and provide general context. Togo 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 that this call will contain remarks concerning L9M'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 recently quarterly report on file of 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 disclaim any obligation to update such statements. With that, I'd like to turn the call over to John. John?

Thanks, Christine, and thank you, everyone, for joining the call today. Despite the challenges we all faced in 2020 with the COVID-19 pandemic, Al Milam had one of its strongest years ever as a successful global commercial organization with a highly productive R&D platform. We delivered on our commercial expansion, growing top-line product revenues by over 100%, driven by strong continued execution for Ampatro and Givlari. We continue to advance the pipeline, which includes programs across both rare and common disease populations. And we remain focused on financial discipline to help us reach our goal of achieving a self-sustainable financial profile. Underscoring the success of 2020, We started the year with two products, six approvals, and access in 14 countries. We then ended 2020 with four products, 15 approvals, and access in 41 countries. This includes the approvals of Oxlumo in the EU and the US, and together with our partners at Novartis, Lectio in the EU. We are very proud to have ended 2020 exceeding our Al Milam 2020 goals that we boldly set forth back in 2015. We're now excited to have announced our new five-year strategy and goals with Alnylam P to the fifth by 25. Alnylam P to the fifth by 25 is aimed at fulfilling Alnylam's aspirations and potential of becoming one of the most successful biotech companies ever with transformative medicines in both rare and common diseases for patients around the world supported by additional growth through LIFL expansion, a robust and high-yielding pipeline of first and or best-in-class product candidates from our organic product engine, an exceptional financial performance with over 40% revenue CAGR through year-end 2025, and sustainable profitability achieved within the period. Without a doubt, this is an exciting new chapter for El Nile. Akshay will review our recent R&D progress in just a moment, but an important highlight in the recent period is the positive pipeline results from our Heli-OSA phase 3 study of futriceran. Importantly, we believe that futriceran can significantly expand our opportunity in HATTR amyloidosis with polyneuropathy, positioning L-myelin with continued growth in our ATTR franchise even before our expected expansion in the wild-type ATTR cardiomyopathy setting, assuming favorable clinical results and approvals. Now, for a review of our commercial and medical affairs progress, it's my pleasure to welcome Tolga Tanguilar to his first Alnylam earnings call. Tolga joined Alnylam recently as our chief commercial officer, following roles at Alexion and Pfizer in both rare and common disease franchises, and we're excited about the future of our global commercial efforts under his leadership. With that, let me turn the call over to Tolga. Tolga?

Thanks, John, and good morning, everyone. I appreciate the warm welcome and couldn't be more excited to join the Alnylam team. Let's get started with a review of our commercial performance. For Ampatro, we achieved $90.4 million in global net product revenues in the fourth quarter, representing approximately 10% quarter-on-quarter growth compared with Q3, and we achieved $306 million in global on-patro revenues for the full year 2020. As of December 31st, approximately 1,350 patients were on commercial on-patro treatment worldwide. In the U.S., we continue to see strength in demand with just over 10% growth, and we saw patient compliance remain at pre-COVID levels. In the US, we also continue to see a steady rate of concomitant use of Onpatro to treat HA-TTR polyneuropathy along with the use of TTR stabilizers in mixed phenotype patients as the HA-TTR diagnosis rates continue to increase due to, we believe, wider availability of PYP scans. We believe our leadership with regard to access is also notable. with over 98% of US lives covered. Turning to the rest of the world, we made very encouraging progress with OnPatro in the fourth quarter, with $47.3 million in revenue from ex-US markets. Market access has now been achieved in over 20 countries, and we recently received regulatory approval in Taiwan. As we have noted, an important ongoing dynamic observed ex-US is patient switching from stabilizers, which we believe is attributable to the potential to halt or reverse polyneuropathy manifestations of the disease with Ompetro. And this represents more than 50% of new Ompetro patients outside the US. Our customer facing medical affairs team also remain committed to addressing the challenge of raising disease awareness and improving diagnosis of HATTR amyloidosis, including with Alnylam Act, our third-party genetic screening initiative in the US, Canada, and Brazil. As of January, 33,912 samples have been submitted, out of which 1,952 have tested positive for a pathogenic TTR mutation. We are encouraged by the recovery in testing volumes we've seen in recent months, and we believe this trend will continue. We have also seen continued strength in PYP scans being performed, another leading indicator for new patient growth. In 2021, we expect steady and continued growth for Onpatro, driven mostly by new patient findings with some additional geographic expansions. Moving on to GiveLawry, we achieved $22.1 million in global net product revenues in the fourth quarter, representing 33% quarter-on-quarter growth compared to Q3. And we achieved $55.1 million in global GiveLawry revenues for the full year 2020. As of December 31st, approximately 200 patients were on commercial GiveLari treatment worldwide. Our progress with patient access in the U.S. has been strong, having now finalized over 10 value-based agreements or VBAs, including first state-level VBA with MassHealth for Medicaid. We now have confirmed access for 94% of covered U.S. lives. We have not experienced any payer headwinds with GiveLari to date. And we're pleased to see the majority of plans adopt medical policies without restrictions to the number of baseline attacks. The CMEA region saw great progress as well, with notable strength from our launch in Germany, as well as ATU supply in France, finalization of reimbursement in Italy, and name patient sales in other countries. We also look forward to completion of the ongoing review of our NDA in Japan, which was submitted in September and is expected to be launched in mid-2021. In 2021, we expect steady and continued growth for Givlari, driven by geographic expansion, along with new patient findings. Finally, We're excited with the progress of our third launch, Oxlumo, the brand name for Lumens Seren. 2021 will be the first full year of launch for this new medicine from our island, and we're pleased to see strong early demand. Since receiving approval in the US and EU in November 2020 and launching in December, we have received eight start forms as of year end, and achieved global net product revenues for the fourth quarter of approximately $0.3 million, representing encouraging early patient demand in Europe. As with our other launches and guided by our patient access philosophy, we are hard at work making sure the patients who need Oxlumo are able to access it. We're pleased with progress being made with payers in the US and EU, in establishing VBAs, including patient need adjustment and prevalence-based adjustment features. Our teams are now actively engaged with the physician and patient advocacy communities, leveraging capabilities we've strengthened over the past year, delivering success even in the challenging virtual environment of an ongoing pandemic. In conclusion, The fourth quarter highlighted the broad capabilities of our operations, which supported the continued growth of OnPatro, the ongoing adoption of Givlari, and the initial launch for Oxlumo. And looking back at the full year, I'm so impressed by the team's resilience in the face of unprecedented challenges to meet the needs of patients and continued driving awareness, uptake, and growth. With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress. Akshay?

Thanks, Tolga, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing our two product candidates, Patisran and Butrisran. While Donpattro is currently approved in multiple markets around the world to treat the polyneuropathy associated with HER3 ATTR amyloidosis, We're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type AT-tramyloidosis 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 early 2021, which would put us on track for a top-line readout in mid-22. We're also advancing Vutriceran, which is delivered by a quarterly subcutaneous injection and is also in development for AT-tramyloidosis. Here, we're conducting two Phase III studies. The first Phase III study is Helios A, which is evaluating butrycerin in HAT thromboidosis patients with polyneuropathy. Just last month, we announced positive top-line nine-month results from the study, demonstrating very impressive efficacy and encouraging safety with a once-quarterly subcutaneous injection of butrycerin. Specifically, butrycerin met the primary and both secondary endpoints measured at nine months. As compared with the historical placebo control from the Apollos study, butryceran achieved a highly significant improvement in neuropathy impairment as measured by the MNIST plus 7 assessment. Also, butryceran showed improvements in the Norfolk QOL and Gates feed secondary endpoints compared with historical placebo. Additionally, butryceran demonstrated improvements in neuropathy impairment and quality of life relative to baselines. confirming that RNAi therapeutics can achieve reversible polyneuropathy disease manifestations commensurate with what we've observed with Patisaran in the APOLIS study. We also observed significant effects on the nine-month cardiac endpoint of NT-proBNP and additional cardiac data being collected as part of the 18-month endpoint, which we plan to report later in the year. Patisaran demonstrated an encouraging safety and tolerability profile. There were two study discontinuations, or 1.6%, due to adverse events that led to death in the vitreous saran arm by month nine, neither of which was considered related to study drug. There were two SAEs deemed related to vitreous saran, dyslipidemia, and an E. coli UTI. AEs occurring in more than 10% of patients receiving vitreous saran include diarrhea, pain in the extremities, fall, and urinary tract infections. These events are common in the disease itself and occurred at a similar rate or lower than observed in the historical placebo comparator group. Injection site reactions were reported in five patients, or 4.1%, and were all mild and transient. There were no clinically significant changes in liver function tests. With these positive results in hand, we plan to file our NDA in early 2021 and aim to bring our fifth RNAi therapeutic to market in early 2022, assuming regulatory approval. And, as we've mentioned, what's exciting about VutrisRAN is the opportunity of expanding our overall market share, particularly to treat polyneuropathy in mixed phenotype patients. The second phase 3 VutrisRAN study is Helios B, which has been conducted in heritory and wild-type AT-tramloidosis patients with cardiomyopathy, and this study is actively enrolling. Finally, in addition to Helios A and B, we're also evaluating a once-every-six-month dosing regimen for VutrisRAN we expect to initiate our study of this regimen in early 2021. Also, later in 2021, we plan to start the Helios-C study of uterine SRAM for the prevention of manifestations of AT2 amyloidosis. I'll now turn to progress with Oxaluma, our RNAi therapeutic recently approved in the EU and US as the first treatment for primary hyperoxalurea type 1, or PH1. We continue to evaluate the safety and efficacy of VoxLumino in the ongoing Luminate C Phase III clinical trial in PH1 patients of all ages with more severe renal impairment, including patients on dialysis. Enrollment has been completed, and we expect data in 2021. Together, the Luminate studies comprise a comprehensive clinical development program intended to demonstrate safety and efficacy of VoxLumino across the full spectrum of patients diagnosed with PH1. We're also excited to initiate a Phase II study later in the year, evaluating Lumaceran for the treatment of recurrent renal stones, which could really expand the overall opportunity. As you know, we have two additional late-stage programs that are in development with partners. These include Lecvio or Inclisiran partnered with Novartis, which was approved last year in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. Lecvio marks the first RNAi therapeutic approved for a common disease and has the potential to be a blockbuster product for our partner Novartis. On top of approval in the EU, Novartis has completed 10 additional filings globally. As has been communicated previously, Novartis received a CRL from the FDA due to unresolved facility inspection-related conditions at a third-party manufacturing facility in Europe. The FDA has not raised any concerns related to the efficacy or safety of Inclisiran, and Novartis plans to submit its response in Q2 or Q3 2021. We're confident Novartis will do everything it can to accelerate this process. Our late-stage programs also include Fetuceran in development for hemophilia A or B with or without inhibitors partnered with Sanofi. Fetuceran is under evaluation in the Phase III Atlas program. We're pleased to report that dosing has been resumed in the ATLAS phase three studies and that previous reports of thromboembolic events were associated with a high level of antithrombin reduction to less than 10% of normal. Sanofi will now evaluate a once every two monthly 50 milligram dosing regimen for fitusiran that can be titrated up in frequency to once monthly and in dose to 80 milligrams depending on antithrombin levels achieved. We believe this tailored approach will optimize patient safety and will also provide further differentiation versus other subcutaneous options, which are given once weekly. Excitingly, Sanofi has announced that Fituzaran recently received fast-track designation. Now, in addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. One of the exciting parts of our story now is the expansion of RNAi therapeutics beyond rare diseases into prevalent disease opportunities, We believe now is the time to address many unmet needs in common disease settings such as hypertension, NASH, gout, and diabetes, amongst others, and that the pharmacological properties of RNAi therapeutics provide the foundation for success. Our program for hypertension is a great example. LNAGT is our investigational RNAi therapeutic targeting the genetically validated target angiotensinogen for the treatment of hypertension. We're now transitioning to the start of our Cardio 1 and Cardio 2 Phase 2 studies, which will start in mid-2021. And these studies will evaluate ALN-AGT as monotherapy and also in combination with RAS inhibitors in about 1,000 patients with uncontrolled hypertension. We also have a promising development program, ALN-HSD, for the treatment of NASH in Phase 1 in partnership with Regeneron. In addition, we continue to make strong progress on our many preclinical RNAi therapeutic opportunities beyond the liver. Today, we're advancing over 25 preclinical programs with delivery in four tissues, liver, CNS, eye, and lung. These programs span rare and common diseases, are supported by human genetics, and are poised to be first and or best in class medicines. Notably, we continue to advance our CNS and ocular efforts with Regeneron, And our LNAPP program remains on track for a CTA filing in mid-2021. Overall, we expect to deliver two to four new INDs per annum in the near term and aim to achieve four plus INDs per annum by the end of 2025. In summary, we see this as a truly remarkable time for alnylam and RNAi. I couldn't be more excited about our continued progress in bringing transformative medicines to patients. And our Alnylam P to the fifth times 25 strategy highlights the impact we're now positioned to make for the future of medicine. With that, let me now turn it over to Jeff to review our financial results.

Jeff. Thanks Akshay and good morning, everyone. 2020 was an unprecedented year that underscores Alnylam's strong commercial capabilities and operational excellence as we delivered robust top line growth while managing disciplined investment across our business. After commenting on our fourth quarter and full year 2020 results, I will also provide our financial guidance for 2021. As Tolga highlighted, U.S. sales of OnPatro increased 10% versus Q3 2020 and were impacted by the following. Patient demand increased 13% driven by the addition of new patients on therapy with patient compliance remaining consistent with Q3 when we return to pre-pandemic levels. Inventory destocking during the quarter, compared with modest stocking in Q3, reduced reported growth during the quarter. We ended the quarter with just over one week of inventory in the channel in the U.S. We're really pleased with the continued strength in our U.S. results, with two consecutive quarters of double-digit growth following a pandemic-challenged Q2, and with Q4 sales representing the highest level since launch. In our international markets, on PATRO performance remained strong, with growth of 9% versus Q3 2020, primarily driven by increased patient demand broadly across Europe and Japan. Additionally, there was a modest benefit from inventory stocking in Japan at year end. Turning to our results for Giblari, we had a strong fourth quarter, generating $22.1 million in global net revenue, representing 33% growth compared to the third quarter of 2020. Revenue in Europe during 2020, as expected, was primarily generated from two markets, Germany and France. As we saw with OnPatro in year two of its commercialization, as we secure pricing and reimbursement, we anticipate additional markets for GiveLawry coming online across Europe and Asia in 2021. Turning now to a summary of our full P&L results for the quarter and full year. Total product sales for 2020 were approximately $362 million, which were more than double 2019, with Unpatro delivering more than 80% growth versus 2019, and Gablari contributing $55 million in its initial launch year. Net revenue from collaborations for the fourth quarter was $50.7 million, primarily due to revenue recognized from Arvir and Regeneron collaborations, and a $15 million increase around milestone from Novartis following the December EU approval of Lectio. Gross margin as a percentage of total revenue was 86% for the quarter, up from 83% in Q4 2019, primarily due to an on-patro inventory write-off that occurred in Q4 2019. Our non-GAAP R&D expenses in the fourth quarter 2020 decreased compared to the same period in 2019, primarily due to Q4 2019 having a high level of expense associated with clinical material manufactured for future clinical trials. Our non-GAAP SG&A expenses increased in the fourth quarter of 2020 compared to the same period in 2019, primarily due to increased investment in commercial and medical affairs activities to support the ongoing launches of Unpatro and GiveLawry and the launch preparation activities for ExLumo. Our combined non-GAAP R&D and SG&A expenses were $1,063,000,000 in 2020, representing 11% growth versus 2019. which was significantly lower than the growth and combined at non-GAAP R&D and SG&A expense in 2019, which was 31%. As I've noted on several occasions over the last year, this more moderate level of OpEx growth is one of the key levers supporting our path towards profitability. Our non-GAAP operating loss for the quarter decreased by approximately $82 million compared to the same period in 2019, driven by strong top-line growth and flat non-GAAP combined R&D and SG&A expense. The full year non-GAAP operating loss ended at approximately $649 million, which is $116 million favorable to our full year 2019 non-GAAP operating loss, consistent with our past guidance that 2019 would be our peak loss year. We ended the year with cash, cash equivalents, and marketable securities of approximately $1.9 billion, up from $1.5 billion at the end of 2019. Cash was favorably impacted in 2020 by the $2 billion Blackstone strategic financing collaboration that we announced in Q2, which contributed approximately $800 million in financing this year, including $200 million in Q4 related to the initial drawdown of the debt facility with GSO, Blackstone's credit arm. Now turning to our financial guidance for 2021. Starting with net product revenues, We are now transitioning to providing combined net product revenue guidance for Onpatro, GiveLawry, and Oxlumo. We anticipate combined net product revenues for these three products will be between $610 and $660 million, with the midpoint representing more than 75% growth compared to 2020. Retriever and approval is not expected until early 2022, so it's not factored into our guidance for product revenues this year. It is also worth noting that our guidance reflects the uncertainty related to the COVID-19 pandemic, which should decrease over time as the vaccine rollout progresses around the world. Our guidance for net revenue from collaborations and royalties is a range between 150 and 200 million, with the midpoint of the range representing more than 30% growth from 2020. Growth in 2021 is expected to come primarily from our collaboration with Regeneron and royalties and milestones from LECVIOs. Our guidance for combined non-GAAP R&D and SG&A expense is a range between $1,175,000,000 and $1,275,000,000. The midpoint of the guidance range represents a projected 15% increase compared with 2020. We anticipate SG&A growth will be modest as we generate operating leverage from our existing commercial infrastructure to support our three commercial products. We expect a higher rate of growth for R&D driven by investments in our two Phase III ATTR cardiomyopathy studies, Apollo B and Helios B, as well as initiation of two robust Phase II studies in our AGT program for hypertension. Finally, achievement of the top-line and non-GAAP operating expense guidance we have provided today for 2021 will deliver another year of improvement in our non-GAAP operating loss. as we continue to make progress on our path to delivering sustainable profitability. With that, I'll now turn the call over to Yvonne to review our goals for 2021. Yvonne?

Thanks, Jeff, and hello, everyone. 2021 is shaping up to be a productive year for Arnylam, as we embark on a new five-year chapter of our journey, outlined in our Arnylam piece of 5x25 Guidance. For starters, we plan to continue our global commercialization of Onpatro, Givlari, and Oxlumo. We look forward to major market approvals in Japan for Givlari and Brazil for Oxlumo. We plan to continue advancing our TTR franchise program through the ongoing ATTR cardiomyopathy studies. For Patriceran, we expect to complete enrollment in the Apollo B study early this year. For Patriceran, enrollment is ongoing in the Helios B study And following the HEDIS-A positive top-line results, we look forward to filing an NDA and presenting nine-month results at AAN in April. In 2021, we also plan to report additional data on the 18-month endpoints, which include a larger number of exploratory cardiac endpoint measures. We expect to start studying our biannual dose regimen for vitreous REM in early 2021. For Lumaceran, the Illuminate-C Phase III study is expected to have top-line results mid-year, and we look forward to initiating the Cardia I and II Phase II studies for ALN, AGT, and hypertension. And, of course, we're excited about what our partners have in store this year. Novartis will be executing on the initial launch for Leclerc and aiming for U.S. approval, and Sanofi will be advancing for Tuceran in the Atlas Phase III programs. Finally, you can expect additional data readouts from our pipeline during the course of the year. 2021 marks the start of the next chapter for Alnylam, with sights set on our new five-year goals to become one of the most successful companies in the industry. We're eager to deliver on this ambition and look forward to updating you throughout the year. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Yvonne. Operator, we will now open the call for your questions. To those dialed in, we'd like to ask you to limit yourself to one question each and then get back in the queue if you have any additional questions.

As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from the line of David. Levowitz from Morgan Stanley. Your line is now open.

Thank you for taking my question. When you look at Givlaria performance thus far, it seems to be doing quite well. Has this caused you to, number one, reevaluate what the size of the market is for Givlaria in general? And has it changed the way you look at markets for Givlaria? these types of diseases and what you think of what the ultimate opportunity for these types, for PH1, prophyria, and other diseases of this nature might be?

Thank you, David. I think that was you, David. It's a good question. Obviously, GIVLARI was really off to a good start. It had a very strong year, its first full year of launch last year, and we look forward to to its continued launch in 2021. And we do expect continued growth in 2021 driven not only by new patient finding but significant geographic expansion that will be occurring by virtue of P&R and also approvals we expect in major markets like Japan in 2021. Let me turn it over to Tolga and Andy Orth maybe to comment further. Let's start with Toga. Anything to add to that?

Thanks, John. And hi, David. Good morning. No, John, essentially, I mean, it's good to be recognized with a good, strong performance of Givlaria, especially during a pandemic era. That says a lot about the capabilities of the organization and how we've been able to launch this, both in the U.S. and ex-U.S. And to your point, we do anticipate an approval in Japan, but So overall, I think the trends are good. It's also a good sign of the value of the medicine that provides to these patients that have not been properly treated. Andy, anything to add to that?

Yeah, I would just add that we continue to be really excited about the opportunity. We still think this is a half-billion-dollar opportunity for the company globally, and And the learnings we're gaining here as we go through 2020 will hopefully allow us to accelerate that as we get into 21 and 22.

Right. Thank you. David, does that answer your question?

Thank you. Thanks for taking my question. Great.

Thank you. Our next question comes from the line of Joel Beatty from Citi. Your line is now open.

Hi. Thanks for taking the question. I'm curious, could you share any insight into the ability to have combination therapy and TTR with any competing drugs in the U.S. and how that compares with ex-U.S. markets?

Yeah, that's a great question, a very important one, and one that defines an important part of the dynamics of the PATRO execution and market dynamics in the U.S. and the rest of the world. So why don't we go to Tolga to add some more color on that question.

Yeah, would you be able to repeat the question again? I wasn't quite sure if you were asking about the sort of the concomitant use.

Yeah, concomitant use of OnPetro with computing TTR agents. Is that different in the U.S. versus ex-U.S.?

Right. No, it is. It is different. What we see in the U.S. in particular is that there's about 20-25% of the utilization of current on PATRO patients are actually also on tefamidus. We do see that. In XUS, we tend to see a much rapid switch from TTR stabilizers to silencers. That's what we've experienced. However, in some markets, we also see some minor level of concomitant use as well. when it comes to both using a stabilizer and a silencer.

And just to emphasize the point, you know, obviously the use of Onpatro is for the treatment of the polyneuropathy that exists in these patients, which is where it's indicated. So these are hereditary ATTR patients that have polyneuropathy and likely have a mixed phenotype, which is why they may be getting both drugs. Absolutely, yes.

Great. Thank you.

Thank you. Our next question comes from the line of Salveen Richter from Goldman Sachs. Your line is now open. Good morning.

Thanks for taking my question. I'm just curious if we're going to see an interim analysis here on Helios B and when we can expect that and what we should expect to see.

Yeah, great question, Sabine. So just as a reminder, and I'm going to hand this over to Akshay in a second, but as a reminder, Helios B is our randomized double-blind placebo-controlled study of butreceran compared to placebo on top of standard of care for the treatment of ATTR amyloidosis with cardiomyopathy. So that includes both hereditary as well as wild-type disease. The study is enrolling quite well. You know, we are going to be enrolling throughout 21, but we're really pleased with how well the enrollment is going. But your point about interim analysis, let's turn it over to Akshay.

Yeah, thanks, Sylvain. So, you know, I think we have a wonderful opportunity to do an interim analysis in Helios B. There are a number of, you know, approaches we can consider, but importantly, we want to use all data elements to inform that interim analysis. And We have data from the original Patisran Apollo study itself. We now have data from Helios A, nine-month data in patients with mixed HATTR disease with cardiomyopathy. Those were exploratory data on BNP, which we've shared, showing improvement in BNP. And we're going to get 18-month data later in the year that will encompass not just BNP and echo data, but some technician scan data. and also 10-meter walk tests and other elements. So there are a lot of data sets coming that continue to inform us about the potential for RNA-based approaches for ATTR cardiomyopathy. And most importantly, next year, as we've just guided, we'll get Apollo B data on the six-minute walk distance. And so these are the elements that will go into our thinking. There are lots of options. We're excited about it, and we will update you when we have finalized the approaches.

Great. Does that answer your question, Sylvain?

Yes, thank you.

Excellent.

Thank you. Our next question comes from the line of Paul Matisse from Stiefel. Your line is now open.

Great. Thanks so much for taking my question. I wanted to ask just a broader pipeline one. You know, last year AGT really came into the forefront. If you had to pick one of your earlier programs that you featured at R&D Day or or in the CNS pipeline that you don't think is discussed right now but might be at the forefront of the conversation by the end of this year or early next, which would you pick? And then one piece of that, you know, I'm a little surprised you guys don't have anything in neuromuscular, given the amount of funding that's gone into conjugation approaches there. Is that at all of interest of you with RNAi? Thanks a lot.

Okay, great questions, Paul. So I'm going to give you my view, and then we'll go to Akshay, and then we'll go to Yvonne. So you get three different perspectives on it. And then we'll come back, and Akshay will address the question on neuromuscular. Look, from my perspective, a program in our pipeline that I think will get a lot of attention this year is ALN-APP. That's our RNAi therapeutic targeting amyloid precursor protein. It's our first CNS program. It's really going to be a defining moment for extrahepatic delivery of RNAi therapeutics, and we're leading the way on the translation of this program. remarkable technology for the treatment of neurodegenerative diseases where there's just enormous unmet need. And so I think that's going to be a landmark program for the field and for El Nilem and for the future of our pipeline. So that's my pick. Let's go to Akshay next.

I was going to pick that. Okay, I'll pick something. Okay. I think we, Paul, we have the benefit of many, many interesting targets we're addressing to address high unmet medical need. You know, I trained as a rheumatologist. The XDH program, which we featured at R&D Day, will address gout. Gout is a hugely prevalent global disorder. Not only is it a rheumatologic disorder, but it can impact kidneys and kidney function. So very, very important disease. and one that's rapidly increasing in incidence, by the way. So we would love to make a dent there. The animal data are very encouraging. We can get over 95% knockdown of the target XTH with over 50% reduction in peripheral blood urate levels. It'll be interesting, you know, based on the phase one, which I think will be very informative, and we can achieve a lot with that phase one to figure out how to position exactly and help the most patients. But As part of our, you know, broadening into common disease, that's another element beyond AGT and the NASH programs like HSD. John's talked about APP and Alzheimer's. So I'd pick the XDH program. Yvonne. Yvonne. Okay.

Well, I'm going to pick the HPV program for three reasons. You know, one, HPV is an enormous opportunity. It's a disease that afflicts. you know, close to 300 million people around the world. So incredibly important. Second reason is I think the encouraging data that we've had from our phase two study with a one and a half log reduction in HB surface antigen. And obviously in partnership with VEAR, that's now being studied in combination. And I think has the opportunity to affect functional cure for these patients, which would be absolutely tremendous. And then the third reason is the fact that we have a 50-50 free opt-in and right prior to Phase 3. So I think this could start to become a program that we spend a little bit more time talking about as the year goes on.

Absolutely. And, you know, we're encouraged by the progress that VEER has been making, and I'm sure there will be quite a bit of new data this year on that program. So, Akshay, do you want to handle the neuromuscular question?

Yeah, Paul, so, I mean, I think we are doing a good amount of work, actually, in neuromuscular disease, actually. You know, if we think about it, the front and center, we've got all our work in HHTG amyloidosis. The polyneuropathy there is a peripheral neuropathy, and so it's squarely a neuromuscular disorder. Of course, it's impactful in the hereditary situation. Increasingly, we hear about neuropathy in wild type, and I think that will be an important area to think about as well. on PATROS approved, of course, for the hereditary polyneuropathy in ATTR. So that's one area. We're going to do a study of Helios C, which we intend to kick off later in the year with butryceram to prevent the onset of this syndrome, HAT tramloidosis, more to come on that. And separately, we've got programs in ALS. There are a number of genetically validated targets in ALS that people are familiar with, SOD1, C9-NORF, and others. And that's under the basket of programs with Regeneron, where we collaborate. So that's another neuromuscular disorder course with Regeneron. We're also pursuing myasthenia gravis with some Disran and C5 antibody prozolimab. So more details on those Regeneron collaborative programs to come, I'm sure, later in the year, actually. And beyond that, we are doing work in lots of additional neuromuscular disorders at a research and preclinical stage that we don't necessarily share until the data are mature enough to discuss. But I can assure you there are programs ongoing in other disorders, including common inherited peripheral neuropathy, for example, we're interested in. Lots going on in neuromuscular disease, and I think we're pretty excited about the progress we've made, and certainly the dent we've made in HAT2 amyloidosis polyneuropathy.

Thanks, Akshay. Paul, does that answer your question?

Yep. Thank you.

All right. Great.

Thank you. Our next question comes from the line of Tazina Mott from Bank of America. Your line is now open. Hi, guys.

Good morning. Thank you for taking my question. Wanted to get your thoughts on how you think the ATTR market in general is developing. Do you have a better sense of how much of these addressable patients have been diagnosed and how the stabilizers are helping to develop that market? Thanks.

Well, that's a great question, Tazine. And let me kick it off by saying that we have a multi-product, multi-year perspective on the broader ATTR franchise at El Nile, a franchise where we aim to be the leader across the industry, helping patients with the medicines and the innovation we bring forward. Obviously, today we are approved with one product, for the treatment of the polyneuropathy of hereditary ATTR amyloidosis. Onpatro is off to a terrific start. It is the market-leading product for treating polyneuropathy with this disease, and we're really pleased with the performance that we've seen. We expect continued growth in the polyneuropathy segment for Onpatro alone. At the same time, we just recently reported positive phase 3 data with Heliosea, which will open up the opportunity for Vutriceran, a once-quarterly sub-Q drug, which with additional work we believe we can make it a once-every-six-monthly sub-Q drug. And we should expect approval next year in HATTR polyneuropathy, which we believe will expand the polyneuropathy opportunity beyond even on PATRO. And then, of course, as Akshay mentioned a minute ago, we opened up the door with the Apollo B study mid-next year, assuming positive data, with cardiomyopathy, both wild-type and hereditary. So this is really a multi-year growth opportunity for the innovation that we're bringing forward for the treatment of this disease. Tolga, do you want to comment a little bit further? Andy, you as well, in terms of how we see this evolving over time?

No, I think, John, you said it very nicely. We certainly see this category evolving as the time goes by. And as John indicated, obviously, we now have one indication with Onpatro that is the leader in the silencer market for polyneuropathy. But we know that there are a tale of two cities almost. You have The polyneuropathy, that's more of a rare disease with lesser prevalence given the hereditary condition. And then obviously there's the wild type that we certainly don't have the indication yet with cardiomyopathy. But the diagnostics of that is probably going through the same route, which is really an inexpensive PYP scan. That access, having that access, has significantly increased our ability to be able to diagnose more polyneuropathy patients. And if Helios A as well as Apollo B, if they were to succeed, we certainly will be able to take advantage of much larger cardiomyopathy segments. So from an alliance perspective, what we're already demonstrating with OnPatro and its leadership in polyneuropathy I think it's a great signal for us to be able to actually define how we're going to be able to play in this current segment as well as be able to provide the right medicine for other segments if our products were to be approved. Andy?

Yeah, and just to add, the hereditary and the wild-type markets are in the very early stages of their growth for what we expect them to be. and that's going to happen over the next, you know, one, two, five to ten years. And as John and Tolga highlighted, our portfolio that we're going to bring to bear here puts us in an excellent position, so we're really pretty excited about it.

And, you know, to Zane, I agree with everything that Tolga and Andy just said. I have often made the analogy of where the ATTR marketplace will go over time, to what happened with multiple sclerosis and with many products, many mechanisms of action, and obviously major patient impact at the end of the day. along with obviously significant revenue and overall value of that market. So I think you will see that materializing in a way that will accommodate multiple opportunities for patients at the end of the day, and Alnylam is going to be a major leader in this space.

Okay, thank you.

Thank you.

Thank you. Our next question comes from the line of Ritu Baral from Cowan. Your line is now open.

Hey, guys. Thanks for taking the question. I'm going to be up front. It does have a couple different parts, but it's all on capture performance, which continues to be really strong. One, you know, how much does home infusion present a tailwind to what we've seen, especially over Q4 and long-term? Can you maintain coverage of home infusion. Are you planning on potentially expanding the sales effort with the Vitru-Saran approval in early 2022? And then lastly, just any color on Apollo C. Akshay, you sort of threw it out there, prevention of symptoms, but anything else you can say about that?

Okay, so let's – why don't we – Akshay, why don't you quickly answer the Helios C question, and then we'll go – we'll give Toga and Andy some time to reflect on the Alpatra questions, and we'll go to them. So, Akshay.

Sure. You know, Ritu, when we looked at the original Apollo data, it was very clear that – Potent, significant reduction of TTR, 80% or so, you know, was associated with remarkable outcomes for the polyneuropathy and for the cardiac aspects in those with mixed disease, we think. And, you know, the drug was labeled for the treatment of the polyneuropathy of HATTR, which is right and proper. But as we looked at the detailed data, patients with very early disease, with lesser disease burden, you know, did very well, and all their MNIST scores went down to single digits or very close to zero, and that led to the hypothesis that what if we could give the drug even before the overt onset of disease in patients with, you know, very low or maybe no evident polyneuropathy, and can we prevent the onset of symptomatic disease? And I think we feel very optimistic about that. Similarly, you know, we now know that patients are being diagnosed or being identified as having TTR deposits in their heart before the onset, by technician scan, before the onset of clinical disease. And so, you know, it's a very reasonable hypothesis, and I think one with a high likelihood of success, that if we can turn the tap off and substantially reduce TTR levels, that we can substantially reduce the occurrence of this disease and prevent its onset. So that's What we're working on now, we intend to start that study, which we'll call Helio-C with Vutriceran later in the year, the subcutaneous injectable, once every six months or so, and more details to follow. But I think it's a very, very exciting hypothesis, and how often in a rare disease do we get a chance to try and help patients by preventing the onset of disease.

Great. And let's go to Tolga first on the commercial questions on Ampatro and then Vutriceran and the sales effort. Tolga.

Sure. Thanks, John. A great question, and you're right. We are very pleased with the growth of MPATRO quarter over quarter, and certainly it will be driven by continuous patient finding and, if appropriate, the switch outs from the patient's current treatments. Now, in regards to patient access, obviously, With the pandemic, what we've seen is a good steady increase of patients being able to access home infusion, particularly in the United States and Europe. Those rates have gone up, but we also believe that patients have been actually able to, as well as the healthcare systems, been able to quickly pivot and provide alternative care sites for patients, as well as providing easy access to infusion clinics. So we're pleased that we have the ability to be able to either redirect those patients to alternative site cares or provide the home infusion network that we have available, particularly in the U.S. and Europe. That's certainly a tailwind, and we actually, frankly, have not seen any impact on our compliance rates. Therefore, you know, the pandemic didn't really impact the current patient retention and compliance rates at all. And again, we have those services available. The second part of your question in regards to how would we see the expansion, obviously, when the cardiomyopathy indication is received, obviously, that's something we are always exploring and making sure that we have the ability to be able to to communicate effectively to healthcare professionals about earlier indications, but that's something, obviously, we need to continue to plan for. Let me turn it over to Andy if he has anything to add.

Yep, thanks. Thanks, Tolga. And I think you got it right on the home infusion, Ritu. We've got that essentially, quote, unquote, running smoothly and maxed out on our commercially insured patients and where they choose. Many are taking advantage of that. And then on the Medicare side, obviously, you know, the rule that was passed last year isn't exactly the favorite of hospitals in some physicians, but we've been able to take advantage of that where we can. I will say our ability to get folks infused at, you know, the common locations, infusion centers, hospitals, et cetera, is great. And many patients, frankly, choose that as a route of preference for the social dynamic, or they just don't want somebody in their house. And on the second one, Rita, was your question on Helios A in neuropathy or Helios B in cardiomyopathy?

No. Yeah, it actually was for Helios A. I'm just wondering if you're planning any commercial expansion just for vitriceran and FAP even before your cardiomyopathy labels might come online.

Got it, got it. And as you know, right, overlapping labels with Onpatro, and while we're not exactly releasing any plans on that front, You know, we love the promotional efforts we've got out there today and are really excited about what Helios A is going to bring to our portfolio.

Great. Okay, good. Thank you, Ritu. We should move on to the next question, I think.

Thank you. Our next question comes from the line of Anupam Rama from J.P. Morgan. Your line is now open. Okay.

Good morning. This is Tess on the call for Anupam. Thanks for taking our question. As you consider launch dynamics between GovLARI and OxLUMA, what are the similarities and differences worth considering here? And then second part of the question is on GovLARI, anything more granular you can provide on your assumptions around 2021 U.S. versus the rest of world? growth in 2021 versus 2020? Thanks so much, guys.

Okay. Thank you, Tess. Those are great questions. Obviously, I think we covered Givlaria as an introduction earlier. You know, we're excited about this year as being the second full year of launch for that important medicine. And then in the case of Oxlumo, which only got approved in November of last year for the treatment of primary hyperoxaluria, this will be the first full year of launch. So that's an exciting year. So let's go to Tolga to answer this great question.

Sure. Thanks, John. Yeah, I mean, look, if you look at both of those products and what they're really addressing, both diseases are highly rare and both diseases are highly devastating. And as John indicated, we had an excellent full year of launch with Givlari during a pandemic. And we've been able to capitalize on a lot of patients that have been waiting for this therapy. And we're probably going to be looking at the same type of dynamic with Oxlumo, with obviously relevant, prevalent number of patients across the world. Therefore, from a business model perspective, the condition that those patients are in, we expect a very similar uptake when it comes to Oxlumo.

Great, and Andy?

John, if I would just, oh, let Andy go, but I was just going to add, I guess one of the main differences here is that, you know, Oxlube is going to be treating a lot of pediatric patients, and it obviously brings a different population that needs to be addressed. But sorry, Andy, over to you.

Yeah, the only thing I would add here is the level of excitement we are seeing right now in the PH1 communities, physicians, patients, patient advocacy groups, et cetera, is just incredible and frankly matches that that we saw with Givlari a year ago. So we're off to a really, really good start. And as Yvonne mentioned here, this is a more so pediatric population than we saw with Givlari, clearly.

Terrific. So I think we have time for one more question.

Thank you. Our next question comes on the line of Gina Wang from Barclays. Your line is now open.

Thank you for taking my questions. So I have one big picture question. For Alnalen, we know no doubt, you know, Alnalen is a clear leader on AI space, and you've done so much work identifying the best targets and the candidates, and some already come to fruition. Will you be willing to leverage this knowledge to the other technology platforms, such as gene editing space, and since we could see some synergy there?

Yeah, thanks, Gina. I mean, look, we are excited about the many, many prospects we have with RNAi for the foreseeable future. We have a ton of wood to chop with this science and this technology, and the type of innovation that we can bring forward really is boundless. Now, you know, we're always going to look at, you know, other types of technologies and how they might complement what we're doing, especially in areas where we have a commercial presence, where we might want to, you know, obviously think about ways to strengthen and expand our leadership beyond maybe just an R&AI-based approach. So we'll certainly look at that. But in terms of, you know, product engines to speak of, you know, what we have in front of us right now is just boundless from the number of opportunities and you know, we're very flush with things. Let me turn it over to Yvonne also to provide some additional color on that question as well. Yvonne?

Yeah, no, that's great, John. And, yes, no, we do keep a, you know, careful watch on what's going on outside our 9M as well for sure. You know, I think one additional point to make on gene editing, because that's probably where you were going, you know, I think whilst, you know, this approach has a lot of potential for patients. I think, you know, it is still in the very early stages of clinical development. There's a lot that we need to learn about, you know, long-term durability and efficacy and safety, et cetera. So, you know, we continue to stay engaged and be aware of what's going on. But as John says, we have an awful lot to do with, you know, what we have in our hands at the moment.

Terrific. Thank you, Yvonne. Agree. So I think that's the last question, right, Christine?

Correct.

Okay, good. All right, so let me then just close. I want to thank everybody for joining us on the call. We're obviously very pleased with our results for the fourth quarter and what we did in 2020. It was a remarkable year despite the headwinds from COVID-19. But we're now on a new chapter with Alnylam P to the 5th by 25th. aiming to build the top five company in market capitalization over the next five years with remarkable science and technology and innovation. So thank you all, and have a great day. Bye-bye now.

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