Alnylam Pharmaceuticals, Inc. Q1 FY2020 Earnings Call

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals First Quarter 2020 Conference Call. Please be advised that this call is being taped at the company's request.

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; Barry Greene, President; Akshay Vaishnaw, President of R&D; Jeff Poulton, Chief Financial Officer; and Yvonne Greenstreet, 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, on alnylam.com/events. During today's call, as outlined on Slide 2, John will provide some introductory remarks and general context; Barry will provide an update on our commercial and medical affairs 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 for your questions. I'd like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as well as various other important factors, including those discussed in our most recent annual report, quarterly report and 8-K current reports on file with the SEC. In addition, any forward-looking statements represent our views only as 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 provide such statements. With that, I'll now turn the call over to John.

Thanks, Christine, and thank you, everyone, for joining us on the call today. I think it goes without saying that the first quarter of 2020 has been unlike any that we have faced as a company, as individuals or as a society. We find ourselves in an unprecedented situation as the world confronts its ongoing public health crisis with the COVID-19 pandemic. Let me begin by acknowledging the tremendous impact this disease has had on so many people, including our communities, families, friends and coworkers. And also, let me recognize the heroic efforts of our health care workers everywhere during this crisis. I'm also especially proud of the amazing work by our Alnylam team and their ongoing efforts to bring medicines to patients around the world, including our work on potential RNAi therapeutics for COVID-19. Together, we are in the fight against this virus. With that, let me start this morning's call with our COVID-19 planning framework. Later, Barry will discuss commercial and supply chain implications of the COVID-19 pandemic and Akshay will discuss the pandemic's impact on our clinical trials and the steps we're taking to mitigate this. As you know, the COVID-19 pandemic represents a very fluid global crisis that changes almost daily. There is significant uncertainty about how this situation will unfold, but for now, our Alnylam planning framework is based on the following three phases. First, the current pandemic phase, which we believe will likely encompass most of the second quarter. Second, a recovery phase, which we believe will likely encompass most of the third quarter, where we will see a gradual resumption of activities, including at hospitals and clinics, and reopening of businesses with precautionary measures. And then a new normal phase, potentially starting in the fourth quarter, where we hope to see a return toward normalcy. You'll hear us refer to these three phases throughout our presentation this morning. Now rest assured that Alnylam is prepared for times like this; 'Challenge Accepted' is part of our RNA. And we are making adjustments as needed across our operations for the benefit of the patients and communities we serve and also for the safety of our employees. Now in light of the current situation, despite our strong conviction for Alnylam's prospects in 2020 and beyond, we have decided to lower our 2020 guidance for ONPATTRO by 5%. We believe that this is a prudent decision, not because of any underlying lack of confidence in ONPATTRO's growth and long-term prospects, but simply due to the near-term uncertainties that we're all facing. We also intend to moderate our spending this year and are lowering our expense guidance as well, and Jeff will talk about this in just a minute. Now amid all of this unprecedented public health crisis, Alnylam continues to fire on all cylinders, advancing our pipeline and bringing RNAi therapeutics to patients. ONPATTRO continues to demonstrate steady and continued growth globally with a very strong Q1, which we're very proud of. We're also pleased to have completed our first full quarter as a multiproduct, global commercial company with GIVLAARI showing impressive performance in the U.S. And then with lumasiran, we've submitted regulatory filings in the U.S. and Europe with approval anticipated later this year. We also made significant progress across our TTR franchise expansion opportunity, completing enrollment in the HELIOS-A Phase III study of vutrisiran and continuing enrollment in APOLLO-B and the HELIOS-B Phase III studies of patisiran and vutrisiran, respectively. In addition to these achievements across our late-stage pipeline, our early-stage programs continue to advance. For example, we're announcing positive top-line results this morning from our ongoing Phase I study of ALN-AGT, an investigational RNAi therapeutic targeting angiotensinogen for the treatment of hypertension. We're very excited about the potential of ALN-AGT, as hypertension is the number one modifiable risk factor for cardiovascular disease and a safe and effective infrequently dosed therapy could provide much-needed innovation in a highly prevalent condition. We are also doing our part to help address the COVID-19 pandemic, and we're proud to be part of an entire industry advancing science and innovation toward this common goal. Our approach includes targeting the RNA genome with SARS-CoV-2, the virus that causes COVID-19. And earlier this week, we announced the selection of a development candidate, ALN-COV, also referred to as VIR-2703, with potent and highly cross-reactive activity. And also we announced plans, together with our partners at Vir, for an accelerated filing of an IND at or around year-end 2020. This would break all records from time from program initiation to filing of an IND. Finally, let me finish with a bigger picture for Alnylam as we look forward to the rest of the year and beyond. Alnylam continues to lead advancement of RNAi therapeutics as a whole new class of medicines, and we're very much on track to achieving, and in fact exceeding, our Alnylam 2020 strategic goals that we originally announced in early 2015. Indeed, we believe we're on track to exit 2020 as a multiproduct, global commercial company with a deep clinical pipeline for future growth and a robust and organic product engine for sustainable innovation. A few weeks ago, we announced a landmark strategic financing collaboration with Blackstone worth up to $2 billion. This deal, one of the largest-ever financings in biotech history, provides Alnylam with very significant capital that we believe secures our bridge towards achieving a self-sustainable financial profile without the need to access the equity markets ever in the future. With a significantly strengthened cash position, along with the multiple drivers for potential top-line revenue growth and disciplined expense management, we are more confident than ever that we can build a top-tier biopharmaceutical company focused on advancing medicines with transformative potential to patients around the world. So with that, I'll now turn the call over to Barry to review our commercial progress and medical affairs activities in more detail. Barry?

Thanks, John. Good morning, everyone. I hope you are all doing well and staying safe. I will start by discussing our commercial performance for the first quarter. For ONPATTRO, we recorded $66.7 million in global net product revenues, reflecting nearly 20% growth from the previous quarter. As of March 31, we are pleased to report that over 950 patients are undergoing ONPATTRO treatments globally. In the U.S., we continue to see advancements with both returning and new prescribers, having added 22 new prescribers in the first quarter. The breakdown of these U.S. prescribers shows that 57% of start forms came from neurologists, 26% from cardiologists, and 17% from other specialties. It’s encouraging that treatment is being managed by multidisciplinary teams, which we expect to continue evolving. We are also observing increased combined use of ONPATTRO with TTR stabilizers in the U.S., with market research indicating that 15% to 30% of patients with hATTR amyloidosis polyneuropathy are receiving this common treatment, a trend we expect to grow. Adherence to therapy remains robust at over 90% in the first quarter, which aligns with the encouraging APOLLO Phase III data. Concerning U.S. market access, we are pleased to avoid the payer challenges often seen with new orphan drug launches, and our value-based arrangement strategy has been well received. Turning to the international market, we are again very satisfied with ONPATTRO's performance. Japan has shown strong growth and we anticipate it will rank as our second-largest market for ONPATTRO revenue and patients following the U.S. In the CEMEA region, we witnessed strong performance in France, Germany, and the U.K. this quarter and are expanding our reach with recent launches in Italy, Sweden, Israel, Turkey, and Spain. Our team is committed to raising awareness and improving diagnoses of hATTR amyloidosis through initiatives like Alnylam Act, which is our third-party genetic screening program initiated in the U.S., Canada, and now Brazil. As of April, nearly 25,000 samples have been submitted, with over 1,500 testing positive for a pathogenic TTR mutation. Although we’ve seen a slowdown in testing due to the pandemic, we anticipate a return to near pre-pandemic levels by the third quarter as things stabilize. Regarding GIVLAARI for acute hepatic porphyria, we generated $5.3 million in U.S. net product revenues in our first full quarter. We received over 60 start forms in the U.S., with more than 50 patients on treatment since launch through March 31. We are encouraged that patients are starting treatment within 1 to 2 weeks after their physician submits the necessary forms. Additionally, some patients are starting therapy outside of formal requests, indicating that providers value the improved access we’re offering. Like ONPATTRO, we have not faced significant payer challenges for GIVLAARI in the U.S. so far, and our value-based approach appears to be effective. We are also pleased to have secured one signed value-based arrangement for GIVLAARI and are advancing discussions with multiple payers interested in this model. Another positive aspect is that payers are implementing medical policies that align closely with the approved GIVLAARI label, without limitations on the number of baseline attacks. Internationally, we are excited to announce that GIVLAARI was approved in the EU in the first quarter, and we expect to make significant commercial strides this year, starting with our launch in Germany in the second quarter and initiating patient sales in other regions. Our team remains focused on increasing awareness and diagnosis of AHP. Through Alnylam Act, we have received 809 tests, with 84 patients identified as having positive AHP mutations, yielding a 10% success rate in samples tested. In terms of our supply chain and commercial activities amid COVID-19, we expect 2020 to be marked by the pandemic through much of the second quarter, followed by a recovery phase in the third quarter and then a new normal starting in the fourth quarter. Our supply chain is sound, and we are confident in our inventory levels of ONPATTRO and GIVLAARI as well as the raw materials for lumasiran as we prepare for its launch. We have implemented measures to mitigate potential supply chain risks. Our global field operations have mainly transitioned to virtual formats, except in Japan, where field employees can still conduct in-person meetings as local guidelines permit. Alnylam has been developing digital and virtual engagement tools for some time, enabling us to adapt effectively for remote interactions. We expect this approach to continue through the pandemic and into the recovery phase. While in-person meetings are preferred, these virtual tools can enhance our engagement with healthcare providers. Our teams have also successfully assisted patients in receiving their ONPATTRO infusions or GIVLAARI injections at appropriate care sites, including home settings, which is crucial during the pandemic. Home infusion for ONPATTRO is now widely available in many countries, thanks to recognition from physicians, payers, and regulators. A recent change in U.S. rules allows Medicare patients coverage for home-based treatments. We’ve observed a significant shift toward home care for treatments since the pandemic began. We expect that more patients may prefer home care for infusions in the upcoming months. However, we anticipate that adherence to ONPATTRO may dip during the pandemic due to potential skipped doses or delays caused by patients transitioning to new care settings, including home care. We will focus on optimizing site-of-care strategies during the recovery phase as patients adjust to returning to hospitals and clinics or choose in-home treatments. We also foresee that the flow of new patients beginning therapy will slow in the second quarter due to reduced genetic testing, diagnosis, and patient movement through healthcare systems. As a result, we expect a decline in ONPATTRO revenues for Q2, possibly by around 10% compared to Q1. We anticipate recovery and growth in the latter half of the year as healthcare systems stabilize into a new normal. The midpoint of our ONPATTRO revenue guidance indicates expected year-over-year growth of over 70%, and we are optimistic about our growth trajectory across all regions. We are committed to building a leading TTR franchise. Regarding GIVLAARI, patients experiencing debilitating porphyria attacks often rely on urgent care or hospitalization. Therefore, maintaining new GIVLAARI patient starts and continuity of treatment is critical, especially considering COVID-19’s impact on urgent care and hospital facilities. Based on ENVISION results showing a reduction in AHP attacks requiring urgent care or hospitalizations, we expect to face fewer challenges with GIVLAARI adherence and new patient starts during the pandemic compared to ONPATTRO. In summary, we are proactively addressing patient needs and mitigating business impacts during this pandemic, and we are confident in our growth during the recovery phase and beyond, as well as our strong long-term prospects for our broader ATTR franchise and other marketed products like GIVLAARI. We are prepared for the changing environment and believe we will emerge stronger, embracing the challenges ahead.

Thanks, Barry, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we are working diligently to advance our two product candidates, patisiran and vutrisiran. While ONPATTRO is currently approved in multiple markets around the world to treat polyneuropathy associated with hATTR amyloidosis, we're committed to expanding the product's label for the treatment of cardiomyopathy in both inherited and wild-type ATTR amyloidosis patients. To this end, we are conducting the APOLLO-B Phase III study. While we continue to enroll patients in APOLLO-B, we have announced today that due to the impact of the COVID-19 pandemic, we expect completion of enrollment to shift into 2021. But rest assured, we'll work very hard to make up any lost time as we enter the recovery and new normal phases in Q3 and Q4 of this year. We're also advancing vutrisiran, which is delivered by a quarterly subcutaneous injection and is also in development for ATTR amyloidosis. Here, we are conducting two Phase III studies. The first is HELIOS-A, which is evaluating vutrisiran in hATTR amyloidosis patients with polyneuropathy. Enrollment is now complete in HELIOS-A, and we remain on track to report top-line results early next year. Second Phase III study of vutrisiran is HELIOS-B, which is being conducted in inherited wild-type ATTR amyloidosis patients with cardiomyopathy. Enrollment is ongoing in the study, which is still in relatively early stages, having just initiated in December of last year. We do expect some enrollment delays here as well in the pandemic phase during Q2. I'll now turn to recent progress with lumasiran, an investigational RNAi therapeutic that we are developing for the treatment of primary hyperoxaluria Type 1, or PH1, in the ILLUMINATE development program. This includes ILLUMINATE-A, our pivotal study in adult and adolescent patients with mild to moderate renal impairment, where we reported positive top-line results in December. We now plan to present full results from the ILLUMINATE-A study in June as the OxalEurope Meeting has been postponed once again. Our lumasiran Phase III program also includes our ILLUMINATE-B study in pediatric patients under six years of age. Enrollment is complete, and we remain on track to report top-line results in mid-2020. We're continuing enrollment in the ILLUMINATE-C study in patients with advanced PH1 disease across all age groups. We recently completed the rolling submission of our NDA and submitted our MAA for lumasiran. This was our first NDA and MAA submitted with our staff working virtually, and I'm proud that our teams were able to do this in less than four months after our top-line results. We expect a regulatory decision on lumasiran approval by the end of 2020. As you know, we have two additional late-stage programs that are in development with partners. It includes inclisiran in development for hypercholesterolemia, now partnered with Novartis, which is in registration in the U.S. and EU, where both NDA and MAA filing has been accepted, and where we expect initial approval in late 2020. We also included fitusiran in development for hemophilia A or B with or without inhibitors, partnered with Sanofi. Sanofi has recently disclosed that two of the ATLAS Phase III trials have now completed enrollment. So we can expect top-line results from the ATLAS Phase III trials in the first half of 2021 as Sanofi has guided. In addition to our late-stage clinical programs, we believe we have also been making great progress in our early and mid-stage programs. This includes ALN-AGT in development for hypertension, resistant hypertension, blood pressure that is not adequately controlled with three or more antihypertensive drugs, affects an estimated 11 million people in the United States alone. These patients are at substantially high risk of stroke, heart failure, renal failure and other tissue damage. Hypertension is the number one modifiable risk factor for cardiovascular disease, and we believe ALN-AGT has the potential to offer significant benefit to patients by addressing the need for improved blood pressure control. In our press release this morning, we announced positive initial top-line ALN-AGT results from 48 patients with essential hypertension in the ongoing Phase I study. ALN-AGT was administered as a single subcutaneous dose and achieved an over 90% knockdown of angiotensinogen, or AGT. In addition, ALN-AGT was associated with an over 10 millimeters of mercury reduction of mean 24-hour systolic blood pressure at baseline relative to placebo. The durability of AGT knockdown and blood pressure effects appears to be supportive of our once-quarterly and perhaps a biannual dose regimen, similar to the results we achieved in the initial Phase I study of inclisiran. The safety and tolerability profile of ALN-AGT is also encouraging, with no drug-related serious adverse events. We plan on presenting these data at the medical meeting in the second half of 2020. In the meantime, we're very excited about these initial top-line results that support further development of ALN-AGT in Phase II studies that we expect to start next year. Turning to our COVID-19 RNAi therapeutics effort in collaboration with our partners at Vir, we've now selected a development candidate, ALN-COV or VIR-2703, with potent and highly cross-reactive activity towards SARS-CoV-2. In oral-based assays, ALN-COV was shown to block viral replication by up to three logs order with the picomolar EC50. To our knowledge, this is the most potent direct antiviral for SARS-CoV-2 reported to date, high cross-reactivity toward over 4,300 viral isolates, including the 2003 SARS virus, shows that we are targeting a highly conserved region for the virus that is likely to be maintained for the current pandemic and potentially future coronavirus outbreaks. Our plan is to advance inhalational administration of ALN-COV for treatment and/or prevention of COVID-19. We plan to soon discuss this program with the FDA and other regulators, and we expect to file an IND at or around year-end 2020. Finally, I'd like to wrap up by addressing the potential impacts of COVID-19 on our clinical operations activities and the steps we are taking to mitigate it. Of course, the top priority here is ensuring patients' safety while continuing to conduct our trials in a vigorous way, since these investigational trials are supporting the advancement of potentially life-saving or life-transforming therapies. All of our protocols and statistical analysis plans include measures to account for missing data, and we continue to work with sites and CRO partners to minimize missing data and ensure studies continue with as little interruption as possible. We're pleased to see regulatory agencies issue pragmatic guidance acknowledging possibility for protocol deviations, missing data, etc. As such, we're capturing the impact of COVID-19 on these parameters, which we will incorporate into our study documentation. We're also taking steps in all of our studies to minimize patient exposure to the virus and keep patients on study. We've done this by expanding our efforts around home care, widening visit windows, collecting labs locally or at home and doing remote collection of adverse events. During the pandemic phase, we expect to continue to see an impact on new patient enrollment and, to a lesser degree, delayed or missed doses in some of our studies. As we have said, we'll do everything we can to minimize these impacts and make up for any lost time as we enter the recovery and new normal phases.

Thanks, Akshay, and good morning, everyone. I'm pleased to be presenting Alnylam's Q1 2020 results. As Barry has already highlighted, it was a very strong quarter of commercial execution with outstanding results for both ONPATTRO and GIVLAARI. I will focus my comments on three topics today: Q1 product sales results for ONPATTRO and GIVLAARI, summary of our full P&L results for the quarter and comments on our guidance for 2020. Turning to our results first for ONPATTRO, where we had another quarter of continued and steady global growth. We generated $66.7 million in net revenue for the quarter, representing 19% growth in the fourth quarter of 2019 and 154% growth compared with Q1 2019. U.S. growth during the quarter was negatively impacted by modest destocking in Q1 2020 compared with modest stocking in Q4 2019. Inventory in the distribution channel in the U.S. is between 2 and 2.5 weeks at the end of Q1. U.S. growth during the quarter benefited from a lower level of gross to net deductions following the increase in Q4 2019 that we highlighted on our year-end earnings call. We continue to expect gross to net deductions will remain in the mid-20s as a percentage of global gross sales for ONPATTRO in 2020. Growth in our international markets was very strong during the quarter and was broadly driven across many markets in Europe as well as strength in Japan. We think this clearly reflects the benefit of having a strong and growing global brand. Turning to our results for GIVLAARI. We had a strong first full quarter of sales, generating $5.3 million in net revenue in Q1 following a late 2019 launch in the U.S., as covered in Barry's prior remarks. We anticipate seeing a contribution from our international markets in the second quarter with a launch in Germany. It is worth noting that we believe the impact of the COVID-19 pandemic on our Q1 product sales results for ONPATTRO and GIVLAARI was minimal. Turning now to a summary of our full P&L results for the quarter. Net revenue from collaborations for the quarter was $27.5 million, a significant increase from last year primarily due to revenue recognized from our Regeneron collaboration. Gross margin was 82% for the quarter, down from 87% in Q1 '19 primarily due to the current utilization of ONPATTRO full-cost inventory while last year benefited from zero-cost ONPATTRO inventory. Our combined non-GAAP R&D and SG&A expenses for the quarter increased 40% versus the prior year. Key drivers were the increased investment in advancing our late-stage pipeline programs and increased investment in SG&A to support ongoing launches of ONPATTRO and GIVLAARI. Our non-GAAP net operating loss for the quarter increased by 12% versus the same period in 2019. However, we remain confident that 2019 represents our peak non-GAAP net operating loss year, as we expect more moderate operating expense growth for the balance of the year and strong top-line growth in the second half of 2020. We ended the quarter with cash and investments of approximately $1.4 billion. We expect to see an increase in our cash balance in Q2 as we received $600 million in cash in early April following the close of the Blackstone strategic financing collaboration. Now turning to our financial guidance. We believe our results for the first quarter demonstrate the strength of our commercial teams in challenging circumstances. However, as Barry noted earlier, we do expect an impact from the COVID-19 pandemic. So we have decided to lower our 2020 ONPATTRO revenue guidance from $285 million to $315 million to $270 million to $300 million. This represents a 5% decrease at the midpoint of the guidance range but still represents more than 70% planned growth versus 2019. In parallel, we are implementing further discipline in our operations to moderate our spending and are lowering our guidance range for combined non-GAAP R&D and SG&A expenses to $1 billion to $1.075 billion from $1.025 billion to $1.125 billion. Our guidance for net revenue from collaborations remains unchanged at $100 million to $150 million. Regarding cash, we believe our $2 billion strategic financing collaboration with Blackstone secures Alnylam's bridge towards a self-sustainable financial profile without the need for future equity financings.

Thanks, Jeff, and hello, everyone. While 2020 presents challenges related to the COVID-19 pandemic, it promises to be an important and exciting year in Alnylam's efforts to build a top-tier biopharma company. For starters, we plan to continue our global commercialization of ONPATTRO as well as the global launch of GIVLAARI, including in Europe following our recent EMA approval. We are also expecting two additional regulatory approvals by the end of the year for lumasiran and inclisiran. We're also executing on six late-stage programs in nine distinct clinical trials. We plan to continue enrollment in our ATTR cardiomyopathy study, specifically APOLLO-B with patisiran and HELIOS-B with vutrisiran. With lumasiran, we look forward to presenting four results from the ILLUMINATE-A Phase III study and top-line results from the ILLUMINATE-B Phase III study. And of course, we'll also continue advancing the rest of our pipeline as well as exciting preclinical efforts, and we'll highlight these milestones throughout the year as they occur. Notably, we aim to deliver two new IND filings in 2020, namely ALN-HSD for NASH and very, very importantly, ALN-COV for COVID-19 from our product engine. 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.

This is Peter Kim for Gena Wang. Congratulations on the uptake. For your revised ONPATTRO guidance, I know you gave a lot of color, but I was still wondering how much of that do you expect is coming from, I guess, new patients, like break new patients versus existing patients? And also, I think you mentioned that you're seeing some patterns of skipping doses among existing patients. And I was wondering if you have any sense on how this may continue in various different phases that you laid out.

Yes, Peter, those are great questions. I’m going to hand it over to Barry in just a second, but I want to start by saying that in our planning framework, we expect to see an impact in Q2, followed by a recovery towards normalcy starting in Q3 and Q4. We believe that this impact will be short-lived. Additionally, this short-term effect should be viewed in the context of our ongoing efforts to advance our TTR franchise, which we see as a significant and growing opportunity. Barry, would you like to address Peter's specific questions, which I thought were quite insightful?

Yes, Peter, let me provide some insights. Each country is managing the pandemic phase in its own way, so the situation varies from one to another. We believe that the second quarter will be affected by the changes in where patients receive care worldwide. When a patient transitions from an academic center to home care or a local infusion center, it requires the patient and their healthcare provider to facilitate that change. Many healthcare providers were focused on addressing the pandemic, which may have extended the time required for a patient to make the switch from three weeks to four or five weeks. We are generally past those changes in the countries where we have launched, such as the U.S., Germany, and France. I don’t anticipate much more change. Patients are settling into their new care locations. It’s worth noting that many academic centers remained operational, and patients continued to seek treatment there. In the U.S., we expect to see an ongoing shift toward home infusion in Q2 as some academic centers encourage patients to transition to home care. To provide further detail, about 9% of treatment was at home in the U.S., which increased to 16% in late April, and I expect that percentage will continue to grow as we move more patients to home infusion. I hope this provides clarity.

With respect to GIVLAARI, are the patients that are, I guess, now on drug, are these mostly for patients that were on prior trials or have transitioned over from EAP programs? Or are these new patients that were found in other genetic efforts?

Yes, that's a great question, David. We're very pleased with our first full quarter of GIVLAARI performance in the U.S. and are looking forward to the launch that has started in Germany, along with named patient sales we have in Europe. We're excited about the potential of Q2 for GIVLAARI as well. To directly answer your question, these patients are primarily outside of our EAP program and mostly outside of clinical studies. The patients involved in the clinical studies are still participating in the open-label phase. By the time we launched, the EAP patients we had in the U.S. were very few, in low single digits, due to achieving approval ahead of schedule. Therefore, these are all new patients.

Could you provide some insights on your early data for hypertension? In terms of the competitive landscape, what does a reduction of approximately 10 millimeters of mercury signify? Additionally, could you outline the next steps for that program?

Yes. Great, Tazeen. We're obviously very excited about the potential for ALN-AGT in hypertension. This is an area that is crying for innovation that's been lacking for decades. Akshay, do you want to answer the question specifically?

Sure. With respect to the first one, the greater than 10-millimeter drop that we described, frankly, is a very impressive result relative to most of the drugs at this stage of development. So we are very excited about that. But the impact and the contribution, I think, is not just from the change in the degree of blood pressure change that we've described, but it's also this infrequent administration, which increasingly looks to us like it could be quarterly or every six months or beyond. And the whole pattern seems to be repeating the vutrisiran profile in terms of durability of effect. So that's very exciting. That's clearly important given that 50% of patients come off their meds within months to years of starting antihypertensive treatment. And then finally, the other issues that, of course, with clamped control of angiotensinogen, we would get tonic and control of blood pressure. And current medications do not give that. You tend to get cyclical effects as you take your tablets and then as the tablet wears off, the blood pressure changes back to the pathological range again, and then you take your tablet again and then it improves. And that kind of seesawing pharmacology is not desirable and puts patients at risk. So it's certainly the millimeters of mercury is impressive. But beyond that, there are other factors that we're also very pleased about. In terms of next steps, we're busy planning Phase II. And obviously, we are heavily engaged with regulators in making sure we do that in a way that is both important for the development of the drug but also where regulators are supportive of the path ahead. So we see a lot of good potential for this drug moving forward.

Great. Again, a couple of questions in AGT, if you don't mind. Were these patients on ACE inhibitors or ARBs? And I guess, can you just tell us a little bit more about safety? There's historically been some concerns with Dual Ras Blockade, hyperkalemia, things like that. And then second, with drugs like aliskiren and also I think ACE and ARB combination studies, Dual Ras Blockade has a history of showing a blood pressure benefit but not necessarily a benefit on outcome. So maybe you can comment on biologically why you think this early POC data is going to translate ultimately to hopefully an impact on mortality?

Yes. Great questions, Paul. Akshay, you get them.

Yes. Regarding safety, patients were on a stable antihypertensive regimen but needed to discontinue their medication to participate in the study. Therefore, there was no combination use of ALN-AGT alongside their background therapy. This was a straightforward test of ALN-AGT alone in patients with essential hypertension. As I mentioned earlier in the presentation, the overall safety profile is very encouraging. We did not observe any serious adverse events, and we remain very optimistic about the safety thus far. Looking ahead, Dual Ras Blockade has shown some intriguing data in the past with antihypertensive effects, but there have also been concerns about safety, especially regarding renal function. We are particularly excited about the specific pharmacodynamic effect of our drug on the liver. One reason previous combinations of ACE inhibitors and ARBs may have caused nephrotoxicity is due to their local effects in the kidney. Since ALN-AGT acts solely on the liver through the GalNAc targeting system, it should avoid direct effects on the kidney. We are hopeful it will demonstrate a strong safety profile as well as effective antihypertensive properties in combination. Naturally, we will evaluate all these factors moving forward.

This is Swapnil on Maury. Congratulations on a very successful quarter. Just a couple of questions on early stage. So for the 2703 program, where you say 99.9% active in 4,300 genomes. Can you talk a little bit about the applicability of this drug in now and different mutated forms of the virus? And then I have a follow-on.

Yes, great. Akshay, do you want to handle that with our COVID program?

Sure. So as we've been in the discovery phase with the COVID program, of course, we've tracked the viral genomes as the sequences have come online, and with over 4,300 sequences available now and studying our target site against those sequences, we're very, very confident that this site appears to be highly constrained, not prone to mutation, and we have a match in almost all of those genomes, as reflected in the 99.99% number. Equally, the cross-reactivity to the previous SARS virus from the early 2000 SARS-CoV-1, it also suggests that the target site's highly constrained. So hence my comment that we anticipate this drug will be highly applicable during this current crisis and likely future crises, and it's not likely to be prone to mutation readily.

Okay. And just one follow-up on the HBV data that was recently presented, like is there like any ongoing work or strategies from a combination perspective with Vir?

Yes. No, absolutely, I mean, as Vir has guided, the next step with the HBV program is further Phase II studies in combination with interferon, which is the initial focus. But then additional agents will be explored as well, including proprietary agents that are in the Vir pipeline. So we're quite excited about the data that Vir recently presented with the HBV molecule, 2218 as they call it. And obviously, it represents a significant opportunity for Alnylam because we have the right to opt in for 50-50 at the end of Phase II just prior to Phase III. So it gives us a way for free up until then to see how the data mature and to be able to come in with what could be a very attractive asset for the future of the company.

My question is on ONPATTRO and rest of world. The trends look pretty strong on certainly a dollar-denominated growth basis. So I guess I wonder if you could talk a little bit more about whether the U.K. or what specific markets are driving that? And when you think about the mix of kind of the potential slowing that's in your guidance now, do you think it's kind of evenly balanced between the U.S. and ex U.S.?

Yes, that's a great question, Alethia. And yes, we're really pleased with the rest of world performance that we've seen with ONPATTRO, and it just is a real testament to our commercial team's execution in those parts of the world. Barry, do you want to answer the specifics for Alethia?

Yes. Yes. Thanks. And I agree with John completely. So Alethia, I'll remind you that when we think about hereditary TTR amyloidosis patients and where they come from, we've communicated previously that they really come from three different streams. There's patients on drug via EAP or free groups program, there's patients known to sites and then there's pure new patient finding, which requires patients to flow through the health care system obviously to get diagnosed. Somewhere between 10% and 15% of patients with preserved injection fracture, heart failure patients are due to TTR. So those patients have to show up to be appropriately diagnosed. So when we think about outside the United States, we have the benefit in U.K., Italy and others for patients coming from all three buckets. Those patients can be naive patients where ONPATTRO is given front line. Those patients can also be patients that move from free of goods, the EAP or others to commercial goods or patients that get switched from stabilizer. We saw a lot of that in France, for example. France has a lot of experience with patients progressing on stabilizers and has the opposite experience with ONPATTRO. And then, of course, Japan is also a market where patients are coming from patients known to site and then new de novo found patients. Really in the United States, since it was the first launch in 2018, we've largely worked through those first two buckets. In the U.S., the market is dependent on patients flowing through our health care systems so that they can be appropriately diagnosed. So we feel good about the growth across all four regions as Brazil is getting up online as well. So you can see that in the United States, the dynamic is find new patients, put them on ONPATTRO, add to a previously prescribed stabilizer, whereas all other parts of the world are still benefiting from all three of those streams of patients. Hope that helps.

Thanks for all the color on how you guys are thinking about managing through the COVID-19 pandemic, and I hope everyone at the company is doing well. Just a quick question from us on the full data for ILLUMINATE-A at ERA-EDTA, what potential new analyses should we be expecting sort of beyond the top line that we already know?

Yes. Thanks, Anupam. And thanks for your kind words at the beginning. I really appreciate that. Akshay, do you want to comment on the ILLUMINATE-A top line?

Yes. I believe we will present the complete data set, including the primary endpoint related to the changes in urinary and plasma parameters from the oxalate study and the 24-hour safety results, which will be very significant. The proportions of patients approaching near normal or normal levels are also crucial. Therefore, we will have a detailed data presentation, similar to what we did last year with the givosiran data, where we provided initial top-line results and then followed up.

Congratulations on the progress. I would like to revisit the question about the rest of the world regarding ONPATTRO. In the regions where you have launched, what percentage of patients are coming from the Expanded Access Program or from the pool of patients who were already known to the sites? Specifically, what portion of the patients previously known to the sites are now part of the EAP? Additionally, how far along are you in transitioning both EAP patients and those known to the sites to the commercial drug in the major geographies you mentioned? Lastly, do you expect any delays in the timing of international reimbursement decisions related to COVID?

Those are two important questions. I think Barry can provide some insight on them. Regarding the first question, you're seeking a level of precision that we're not going to disclose. Barry, could you also comment on the payer situation in other countries?

Yes, absolutely. Thanks, John. And great question. So as I mentioned, in the United States, it's pure new patient finding. That's the stage that the United States is in. As we launch in Europe, most of the European countries have rules that move patients very quickly from an EAP or free of charge program on to a paid program. So that happens quickly in most countries across Europe. And we are getting patients from all three buckets, all three work streams of patients. Now I will highlight, and as you know, Europe had significant experience with stabilizers and saw patients progress with stabilizers in the polyneuropathy frame but also in the cardiomyopathy side. So the desire to move a patient on to a drug like ONPATTRO that has an opportunity of stopping disease progression, in many cases reversing things like polyneuropathy, has a highly attractive profile. So in Europe, patients are coming from all three of those streams. In Japan, where we did not have an EAP, patients are coming from patients known to the site and then newly found patients. So both of those are coming. Again, many patients are being switched off of stabilizers, but there are new patients being found in the endemic regions of Japan and we're benefiting from finding those patients and getting them on ONPATTRO. In terms of payer, for ONPATTRO, we haven't seen any significant delays. In the United States, there's really been no delays in the GIVLAARI VBA. And there have been slight, call it a week or two, delays and rescheduling of P&R discussions across countries in Europe, but nothing significant that leads to any of the change to guidance we're providing. The change really is the impact to our health care systems and the inability for patients to get into those academic centers. So that's reflected in the new guidance.

So let's go first to the APOLLO-B and HELIOS-A studies. Since those are more mature studies, what should we be thinking about as far as lost data, anything that can be recouped on telemedicine and how that might impact powering? Or any flexibility around the collection of those datas as we think about the integrity of the data set? And then my quick follow-up is can you explain the GIVLAARI time to fill, this 1 to 2 weeks? Because I mean that's the goal of most orphan launches like 6 months out. So why is it so fast, so early? And could it stretch back out, or is this just how it is going forward?

Well, let me quickly answer your second question, and then Akshay can prepare to answer your first question. Basically, our teams have gotten better and better from the ONPATTRO experience to being able to do this much more rapidly with GIVLAARI. I think it also reflects the confidence around reimbursement that we have built within the system. So we're really happy with that. We see no reason why it should stretch out at this point. We're very much really operating and using our patient hub effectively to get patients onto treatment as soon as those start forms come in within just a couple of weeks. So very happy about that. Don't see that changing. So Akshay, do you want to handle the question on the clinical trials, which I thought was very good?

In terms of the endpoint structure, we do not expect any changes in the primary endpoint of the overall strategy and the endpoint structure, so we feel secure there. Regarding APOLLO-B, as we mentioned earlier, there has been some slowdown in enrollments at certain sites, which has pushed back the completion of enrollment to next year. We will provide more details on that by the end of this year. To maintain study integrity and patient continuity, we have widened assessment windows, transitioned patients to home administration successfully for both drugs, and allowed for remote collection of adverse events and labs. We have also shown flexibility around visit windows, all of which are supported by regulators in guidance documents. We have carefully documented the rationale for these adjustments. While we have observed a slowdown in enrollment for APOLLO-B, we are confident in the overall integrity of the endpoints and the study.

A few here. So how is ONPATTRO being prescribed in the mixed phenotype right now, given some increased evidence with combination use with Pfizer's VYNDAQEL? And then just secondly, if you can talk to any numbers around the contribution of cardiologists in the prescriber mix and some of the Q-over-Q trends you're seeing, just given some competitors and noted some declines in new diagnostics.

Yes. Those are great questions. Let me just start by saying that, of course, ONPATTRO is being prescribed for treating the polyneuropathy that's present in patients. Where we see combination use, we believe it's because ONPATTRO is being given for the polyneuropathy appropriately and that the stabilizer's being used or given to treat the cardiomyopathy. So that is what we appear to be seeing. But your question, Barry, maybe you should answer the rest of the question.

Yes. Absolutely. So I agree with John completely. What John just described is the U.S. dynamic, not the rest of the world dynamic. In the U.S., what we're seeing is cardiologists working with neurologists in these multi-discipline teams and amyloid centers popping up. And we see this as very good news that the neurologists have a renewed sense of urgency to prescribe ONPATTRO for the polyneuropathy of hATTR amyloidosis. The dynamics we see, and it's both stabilizers, both tafamidis and diflunisal, depending on insurance and ability to pay, so we're seeing ONPATTRO added in the United States to a patient with a stabilizer that's seeing maybe a new care center. They understand the mixed phenotype nature of the disease and are adding ONPATTRO. For other parts of the world, we are seeing mostly patients switched off of the stabilizer for the treatment of polyneuropathy for hATTR amyloidosis.

Congrats on a really good quarter. Two questions, if I may, real quickly. Firstly, I appreciate all the hard work you guys are doing with Vir to combat SARS-CoV-2 and COVID-19. In addition to this antiviral program, which is advancing towards the clinic, what other efforts are you doing with Vir? I think the partnership is a little bit more expansive. If you could explain that. And then one real quick one for Jeff. I think you mentioned that you've taken down $600 million from Blackstone. I believe that's $100 million upfront. Did you take any debt down yet?

Yes. Great questions, Ted. Let me just quickly answer your first one and then give it over to Jeff. In addition to the work we're doing targeting the SARS-CoV-2 genome directly, which is the ALN-COV program that's now aiming for an IND by the end of the year, we also are targeting, and this is still preclinical, we're targeting ACE2, which is the known receptor for SARS-CoV-2 and other coronaviruses, as well as TMPRSS2, which is a protease that cleaves to the spike protein and activates it for binding to ACE2. So we do have these host factor programs going on in addition to the direct antiviral strategy that we're developing. Those are further back, we're obviously going to explore them appropriately. When you target a host factor, you have to think about the safety of the on-target effect and what does that mean. But obviously, we do think that these are important things to explore preclinically. And if the data supports it, we'll take them into development. So Jeff, do you want to answer the Blackstone question on the debt?

Yes. The $600 million received to date includes $100 million in equity and $500 million for the first installment on the royalty monetization. We have not drawn any debt so far. We anticipate taking the first $200 million at the end of this year. Additionally, please note that the first $500 million is not included in the Q1 numbers. While it has been received, it will be accounted for in Q2.

This is D.K. on for Do. Congratulations on the Q1 update. I just have two quick questions. First one, I just want to piggyback off the AGT in terms of the long-term strategy there? Is it reasonable to think that a partnership, possibly ex-U.S., could transpire in the future given how capital intensive it can be to kind of commercialize for such a large population? And my second question has to do with lumasiran. Given that there could be an end of the year launch, similar to GIVLAARI, can you give us a sense of how the pre-commercial efforts have been going? How have your market access discussions been going with payers? Do you foresee a similar ease of somewhat what you saw with GIVLAARI in terms of converting patients into the commercial product? Or are there some gating steps that we should be thinking about?

Yes. For starters, we're very optimistic about AGT as a product that we intend to fully develop. As we look toward 2025 and beyond, we aim to have a potential blockbuster product like AGT, and we may consider complementing our promotional efforts with another company in the future. Yvonne, would you like to add anything further about the AGT program?

No, John, you've covered it. I mean we really think it's a very exciting program for us. And we have time to think it through. As we look out to the 2025 period, this could be a really nice additional growth driver for Alnylam. And we'll enjoy being able to progress that most likely within Alnylam, but it gives us the optionality to consider partnering approaches at the right point in time. But for now, thinking about it very much as an Alnylam opportunity.

Yes. Just the only thing I'd add, and I think you and Akshay covered the opportunities incredibly well, we will approach the commercialization with the innovation that we've shown for at least our first two launches. And we've got some time to develop this drug of course, we have to get into Phase II and then Phase III. But we will launch with that value-based agreement concept around the world. And I would argue that if you have an efficacious safe and infrequently administered drug that clamps blood pressure to the numbers we've suggested, it's a drug that has an opportunity to lower catastrophic risk at a population level, and that's something I'm confident we can get paid for.

That concludes today's question-and-answer session. I will hand it over to the speakers for additional or closing remarks.

Thank you, everyone, for joining us on this call. I want to express my gratitude to all of our Alnylam employees for their dedication and hard work. This is certainly a challenging time, but we are pleased with our ability to move forward and achieve R&D and commercial progress with the spirit of 'Challenge Accepted' that is in the Alnylam RNA. We look forward to updating you on our ongoing progress in the coming weeks and months. Until then, I hope you all stay safe and healthy. Bye-bye now.

That concludes today's presentation. Thank you for your participation. You may now disconnect.