Alnylam Pharmaceuticals Inc

NASDAQ:ALNY

Earnings Call Transcript 2020-Q1

[Operator]

Ladies and gentlemen, thank you for standing-by. Welcome to the Alnylam Pharmaceuticals First Quarter 2020 Conference Call. 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.

[Christine Lindenboom, VP, IR and Corporate Communications]

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 event section of the Investor page of our website at www.alnylam.com/event.

During today’s call, as outlined in 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 pre-clinical updates, Jeff will review our financials and Yvonne will provide a brief summary of upcoming milestones before opening the call for your questions.

I would like to remind you that this call will contain remarks concerning Alnylam’s future expectations, plans and prospects, which constitute forward-looking statements for the purposes of safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual report, quarterly report and 8-K current report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to provide such statements.

With that, I’ll turn the call over to John.

[John Maraganore, CEO]

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 ongoing public health crisis with the COVID-19 pandemic. Let me begin by acknowledging the tremendous impact that this disease has had on so many people including our communities, families, friends, and co-workers and also let me recognize the heroic efforts of our healthcare workers everywhere during this crisis.

I am 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 are 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 the 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 on activities including hospitals and clinics and reopening the businesses with precautionary measures. And then a new normal phase, potentially starting in the fourth quarter where we hope to see return toward normalcy.

You will hear us refer to these three phases throughout our presentation this morning.

Now rest assured that Alnylam is prepared to 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 on 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 spend 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 bring RNAi therapeutics to patients. ONPATTRO continues to demonstrate steady and continued growth globally with a very strong Q1 which we are very proud of. We're also pleased to have completed our first full quarter as a multi-product 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 three study of the vutrisiran and continuing enrollment in Apollo-B and the HELIOS-B Phase three studies of the vutrisiran and lumasiran 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 one 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 dose 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 towards this common goal. Our approach includes targeting the RNAi genome of 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 VIR for an accelerated filing of 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 the 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 multi-product 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 the 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 bio pharmaceutical company focused on advancing medicines with transformative potential to patients around the world.

So with that I'll turn the call over to Barry to review our commercial progress and medical affairs activities in more detail. Barry?

[Barry Greene, President]

Thanks John. Good morning everybody. I hope everybody is healthy and staying safe. I'll begin by reviewing our commercial performance in the first quarter. For ONPATTRO we achieved $66.7 million in global net product revenues representing nearly 20% quarter-on-quarter growth. As of March 31, we're delighted that over 950 patients were on commercial ONPATTRO treatments worldwide. In the United States, we continue to see progress with both repeat and new prescribers. In the first quarter, we had 22 new prescribers. As for the mix of these U.S. prescribers 57% of start forms submitted in the first quarter came from neurologists, 26% from cardiologists and 17% from other physician specialties. Fortunately for patients we're seeing the treatment is increasingly handled by multidisciplinary teams that include neurology, cardiology and other physician specialties and we expect this mix to continue to evolve.

In the United States, we also continue to see increased concomitant use of ONPATTRO with TTR stabilizers and recent market research suggests we got about 15% to 30% of patients with hATTR amyloidosis polyneuropathy are receiving the common treatment as we expect this pattern in the U.S. to grow. Overall adherence to therapy remains very strong at over 90% in the first quarter which we believe is an encouraging sign and consistent with the Apollo Phase 3 data. Regarding U.S. market access we continue to avoid any of the pair headwinds often reported with other orphan drug launches. Our VVA strategy continues to be very well received.

Now turning to the rest of the world, we're again very pleased with ONPATTRO performance. The plan delivered another very strong quarter of growth and we continue to anticipate it will be our second-largest country after the U.S. for ONPATTRO revenue and patients on therapy exiting 2020. In the CEMEA region we observed strength in France, Germany and the UK in the first quarter and continue to expand our footprint with recent launches in Italy, Sweden, Israel Turkey and Spain. Our team also remains 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 United States and Canada and now recently in Brazil.

As of April almost 25,000 samples have been submitted, out of which over 1,500 have tested positive for pathogenic TTR mutations. As we note, diagnostics and tests across therapeutic areas, we've seen some slowdown in testing as the pandemic phase set in, but we expect -- we expect sample numbers to return to near pandemic numbers as recovery phase in Q3 begins and beyond into the new normal.

Moving to the GIVLAARI, an acute hepatic porphyria or AHP, we achieve $5.3 million in U.S. net product revenues, the strong performance in our first full quarter of launch. We received over 60 start form of the United States with over 50 patients on commercial treatment from launch through March 31. We're pleased to see that patients are getting on drug within one to two weeks after the physician has submitted a start form.

We're also seeing patients initiate therapy outside of start forms a strong sign that providers appreciate the strong access environment Alnylam establishing for their patients. To that point similar to our experiences ONPATTRO we did not experience any major payer headwinds in the GIVLAARI in the United States to date again our VBA based approach is looking successful here and we're pleased to report we've already had one signed VBA GIVLAARI and our discussions with multiple payers interested in the VBA approach are progressing well.

Another highlight of patient access is that payers are adopting medical policies that are generally consistent with the approved GIVLAARI label without restrictions to a number of baseline attacks. Now outside the United States, we are pleased to announce approval in the GIVLAARI in the first quarter and we expect to open up key commercial geographies this year with our initial European launch underway in Germany in Q2 and named patient sales occurring elsewhere in the region.

Again our team is focused on improving awareness and diagnosis of AHP in the patient and physician communities. Through Alnylam, we can report 809 tests submitted in 84 patients with positive AHP mutations as of April representing about a 10% hit rate and samples tested.

Let me finish with more color around our supply chain and commercial activities in the phase of COVID-19. As John mentioned we expect 2020 to be comprised with pandemic periods through most of Q2, a recovery phase in Q3 and new normal starting in Q4. Our supply chain remains intact and we're confident we have sufficient inventory of commercial products, drug products, drug substance as well as raw materials from ONPATTRO and GIVLAARI and lumasiran as we begin to prepare for that launch.

We have comprehensive mitigation measures in place to reduce any potential supply chain exposure if needed. Our global field operations have largely shifted to virtual interactions with HCPs payers and patients. The exception of Japan where our field employees are still able to conduct in-person meetings subject to local restrictions. I want to note that for some time Alnylam has been developing digital and virtual tools, so we were well prepared for virtual interactions.

We expect these virtual interactions and engagements to continue through the pandemic phase of each recovery phase and while live face to face interactions are preferable in many cases, these new virtual tools will be part of the new normal. We believe some of the changes are actually very positive and we think they can improve the efficiency and effectiveness of HCP interactions for field force going forward.

Our teams also have been successful helping patients receive their ONPATTRO infusions or GIVLAARI injections at appropriate sites of care as determined with their physicians including home setting was particularly important during this pandemic period. For ONPATTRO home infusion has become broadly available in most countries thanks in part to the recognition of value by physicians, payers and regulators. In the U.S., in recent rule change by CMS created options for Medicare patients have coverage for home based administration.

Looking at the proportion of treatments received across academic centers, local centers and in the home we've seen a significant shift towards home care for Q4 2019 into Q1 2020 as a pandemic response expands globally. We believe particularly in United States we will continue to see patient shift to home care for local infusion centers in Q2 and beyond.

For ONPATTRO we believe adherence will likely decrease during the pandemic phase in Q2 and be in part to some skip doses or dose delays caused by patients moving to new care sites including home care. We will continue with site of care optimization through the recovery phase as patients regain comfort returning to hospitals and clinics for treatment or decides to continue with in-home administration if that's an option for them.

Finally, we also anticipate that the pace of new patient ensuing therapy will slow during Q2, even can reduce genetic testing and diagnosis and patients flow through the healthcare systems. Thus we expect some negative impact in Q2 with ONPATTRO revenues potentially decreasing by about 10% versus Q1 and then we expect improvement in growth in the second half of the year as health care systems return and recovery and into a new normal. Let me highlight here the midpoint of our ONPATTRO revenue guidance represents expected year-on-year growth greater than 70% and we remain highly confident in our growth trajectory in all regions. We're planning long game here and our goal is to continue to build an industry-leading two-tier franchise.

Now let me turn to GIVLAARI . AHP patients who experience debilitating porphyria attacks often require urgent care or hospitalization. So ____ patient starts and continuity of GIVLAARI treatment are particularly important given the impact of COVID-19 on urgent care and hospital sites. Given the envision results which are reduction in AHP attacks requiring urgent care visits or hospitalizations we expect less of an impact on GIVLAARI adherence the new patient starts during the pandemic phase relative to ONPATTRO.

In summary I'll reiterate that we are not simply waiting for the pandemic to pass we're taking numerous steps to do what's right for patients and to mitigate impact on our business during the pandemic phase. We're very confident about our growth and recovery phase and beyond and also continue to see a very bright long-term prospects for a broader ATTR franchise and other marketing products like the GIVLAARI . As you heard from us many times we're up for the ever changing environment and we'll be stronger for it. As John said challenge accepted.

With that I'll now turn over to Akshay through your recent R&D and pipeline progress. Akshay?

[Akshay Vaishnaw, President of R&D]

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 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 has been 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 BK 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 event. 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 toward SARS-CoV-2. Oral-based assays, ALN-COV were shown to block viral replication by up to three long 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 conserve region for virus that is likely to be maintained for the current pandemic and potentially future coronavirus outbreak.

Our plan is to advance inhalation administration of ALN-COV 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 analyses 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 issued 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 by being visited 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 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. In summary, while there are some disruptions in clinical development activities during the pandemic phase, we've successfully implemented many mitigation steps to minimize impacts on our programs, and we expect any shifts in our time line to be effectively managed shortly.

And with that, let me now turn it over to Jeff to review our financial results. Jeff?

[Jeff Poulton, Chief Financial Officer]

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 two 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 2019 primarily due to the current utilization of ONPATTRO full cost inventory while last year benefited from 0 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 and 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 spend 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 toward a self-sustainable financial profile without the need for future equity financings.

And with that, I'll now turn the call over to Yvonne to review our goals for the remainder of the year. Yvonne?

[Yvonne Greenstreet, Chief Operating Officer]

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?

[Christine Lindenboom, VP, IR and Corporate Communications]

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

[Operator]

[Operator Instructions] We will take our first question from Gena Wang with Barclays.

[Unidentified Analyst]

Hi, This is Peter Kim for Gena Wang. Congratulations on the update. 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 kind of new patients versus existing patients? And also, I think you mentioned that you're seeing some patterns of skipping dose among existing patients. And I was wondering if you had any sense on how this may continue in various different phases that you laid out.

[John Maraganore, CEO]

Yes, Peter, those are great questions. Let me I'm going to hand it over to Barry in just a second, but let me just start by saying again what we expect as part of our planning framework is to see impact in Q2 and then starting in Q3 and Q4 recovery back toward normalcy. So we do view the impact of all this to be short-lived. And of course, obviously, this short-lived effect that have to be put in the context of the broader efforts we have in advancing our TCR franchise, which, of course we view as a very significant and growing opportunity. So Barry, do you want to specifically talk to Peter's particular questions, which I thought were quite good?

[Barry Greene, President]

Yes. Peter, let me give you some color. And just to say that each country handles is handling the pandemic phase very differently. So this is broad color, but every country is a little bit different. The reason that we believe that Q2 will have impact is the site-of-care changes that were made by patients across the world. When a patient moved from an academic center to home care or a local infusion center, it requires that patients and their healthcare provider to help us activate that change.

And as you know, many of the healthcare providers were absorbed in fighting the pandemic itself. So we could see, instead of three weeks, it might have taken four or five weeks for a patient to change.

We're generally through all of those changes in countries where we've launched U.S., Germany, France. So I don't see much more change coming. Patients are where they're going to be. And I will note that many academic centers did stay open and patients continue to move to those centers. I think in the United States in Q2, we'll continue to see a move toward home infusion, because some academic centers are asking the patients to make that move. And just to give you a little bit more flavor, in the United States, we had about 9% home use, we moved about 16% in late April. And I see that percent moving up even more as we continue to move patients to home infusion. Hope that helps from a color perspective.

[Operator]

We'll move on to our next question from David Lebowitz with Morgan Stanley.

[David Lebowitz, Morgan Stanley]

Thank you very much for taking my question. 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?

[John Maraganore, CEO]

Yes. That's a great question, David. Obviously, we're very happy with our first full quarter of GIVLAARI performance in the U.S., and we're now looking forward to the launch that has initiated in Germany and also named patient sales that we have in Europe. So we're excited about where Q2 can take us with GIVLAARI as well. The straight answer to your question is these are all patients outside of our largely outside of our EAP program and largely outside of clinical studies. The patients that were in the clinical studies are still in the clinical studies in the open-label stage. And the EAP patients that we had in the U.S. by the time we launched was very, very small, low single digits, because of the fact that we achieved approval before ahead of schedule. So these are all brand-new patients.

[David Lebowitz, Morgan Stanley]

Thank you for that.

[John Maraganore, CEO]

Yes. Thank you.

[Operator]

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

[Tazeen Ahmad, Bank of America]

Good morning, thanks for taking my question. Maybe a quick one on your early data for hypertension. Can you give us some of the context of the competitive landscape or roughly 10-millimeter mercury reduction means? And how can you just define what the next steps are for that program?

[John Maraganore, CEO]

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?

[Akshay Vaishnaw, President of R&D]

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 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 plant 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 in 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 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.

[John Maraganore, CEO]

Yes. Thanks Akshay. We're very very excited about the regime. Yes.

[Tazeen Ahmad, Bank of America]

Thank you.

[Operator]

Next question comes from Paul Matteis with Stifel.

[Paul Matteis, Stifel]

Great. Thanks so much. 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 the, hopefully, an impact on mortality?

[John Maraganore, CEO]

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

[Akshay Vaishnaw, President of R&D]

Yes. So with respect to safety, Paul, patients were on a stable antihypertensive regimen, but they have to come off their drug to be in the study. So there was no combination use as such with background therapy with ALN- AGT on top. This was a clean hypothesis test of ALN-AGT alone in patients with essential hypertension. At the overall safety profile, as I mentioned during the formal part of the presentation, it's very encouraging. We saw no serious adverse events. And overall, we continue to be very, very encouraged by the safety so far.

With respect to the path forward, Dual Ras Blockade certainly has had some interesting data in the past, there are antihypertensive effects, but there are also some safety issues that people have wondered about, particularly with respect to renal function. One of the things that we are very excited about is the focused pharmacodynamic effect of the of our drug on the liver.

And one reason why previous combinations of ACE inhibitors and ARBs may have been nephrotoxic is are local effects in the kidney of those drugs.

And so with angiotensin ALN-AGT acting on liver alone, because of the GalNAc targeting system, will spare the kidney of any effects directly there. And so we are hopeful that they'll have an impressive safety profile as well as an impressive antihypertensive profiling combination. Of course, we're going to evaluate all these moving forward.

[Paul Matteis, Stifel]

Great. Thanks so much.

[John Maraganore, CEO]

Thanks Paul.

[Operator]

Next question comes from Maury Raycroft with Jefferies.

[Unidentified Analyst]

Hi, good morning. This is [indiscernible] on for 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.

[John Maraganore, CEO]

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

[Akshay Vaishnaw, President of R&D]

Sure. So as we've been in 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 sites are highly constrained. So hence my comment that we anticipate this drug will be highly applicable during this current crisis and likely future crisis, and it's not likely to be prone to mutation readily.

[Unidentified Analyst]

Okay. Thanks and just one follow-up on the HBV data that was recently

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

[John Maraganore, CEO]

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.

[Unidentified Analyst]

Okay. Thank you very much. Thanks for taking the questions.

[John Maraganore, CEO]

Yes. Thank you.

[Operator]

Next question comes from [indiscernible] with Cantor.

[Unidentified Analyst]

Hey guys, Thanks for taking my question. 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?

[Speaker]

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?

[Barry Greene, President]

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 healthcare 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 are 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 healthcare 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 Barry.

[Operator]

Next question is from Anupam Rama with JP Morgan.

[Anupam Rama, JP Morgan]

Hey, guys. Thanks so much for taking the question. 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?

[John Maraganore, CEO]

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?

[Akshay Vaishnaw, President of R&D]

Yes. I mean I think we'll present the full data set, obviously the primary endpoint, the change in for urinary and plasma parameters around oxalate study, say, in 24-hour safety, of course, will be very important. And the proportions of patients coming to near normal or normal, these are important parameters as well. So it's going to be a comprehensive data presentation, just as we did last year with the givosiran data where we had initial top line data.

[John Maraganore, CEO]

Yes. And I would just add to that, Anupam, that obviously, we have a lot of data that we can share and we will share it in a very completely transparent way as we always do. So we're looking forward to doing that. It's would have hoped to have done it in March with the OxalEurope Meeting, but that got shifted and then canceled once and twice. So the ERA-EDTA organizers have been kind enough to allow us to present there, and that's what we're going to do.

[Anupam Rama, JP Morgan]

Great. Thanks for taking the questions.

[Operator]

Thank you. Next question comes from Vincent Chen with Bernstein.

[Vincent Chen]

Congratulations on the progress and thanks for taking the question. Congratulations on the progress. One more just to revisit the question on rest of world ONPATTRO. In the geographies where you've launched, how much of the patients are coming from the EAP or from the pool of patients who are already have known to sites? I guess what portion of the patients who were previously known to sites got on to the EAP? And then how far are you through the process of transitioning both to EAP patients and the I guess patients who are known to sites on to commercial drug in some of the major geographies you outlined? And then one more, just in the guidance, do you anticipate any delays to the timing of OUS reimbursement decisions related to COVID?

[John Maraganore, CEO]

So those are two great questions. I think I'm going to have Barry answer them. I think the first one, you're going you're looking for a level of precision that I think we're not going to share. But Barry, maybe you can provide some color on that. And certainly on the payer question in other countries, you might want to comment on that, Barry, as well.

[Barry Greene, President]

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 launched in Europe, most of the European countries have rules that move patients very quickly from an EAP or free 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 has 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 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 site and 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 healthcare systems and the inability for patients to get into those academic centers. So that's reflected in the new guidance.

[Vincent Chen]

Right Barry. Thank you.

[John Maraganore, CEO]

Thank you.

[Operator]

We will take our next question from Ritu Baral with Cowen.

[Ritu Baral, Cowen]

Good morning everyone. Great to hear you all well and thank for taking the question. Can you –

[Speaker]

We can hear you as well.

[Ritu Baral, Cowen]

Good morning, everyone. So let's go first to the APOLLO-B and HELIOS-A study. 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 collection of those data 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 one to two weeks? Because I mean that's the goal of most orphan launches like six months out. So why is it so fast, so early? And could it stretch back out? Or it's just how it is going forward?

[John Maraganore, CEO]

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 on to 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?

[Akshay Vaishnaw, President of R&D]

Sure. Yes. So in terms of the endpoint structure, we don't see any changes anticipated in the primary endpoint of the overall strategy and the endpoint structure. So I think we feel secure there vis-a-vis APOLLO-B, as we mentioned today earlier that the main issues that at certain sites, there's been some slowdown in enrollments and we've shifted out the completion of enrollment to next year.

More details come on that from the end of this year. And with respect to the overall issue of maintaining study integrity and patient continuity, I would say the way we've been able to do that is widening assessment windows, getting patients on home administration, which we've done very successfully in the case of both drugs and allowing remote collection of both adverse events and labs.

So along with the showing some flexibility around visit windows. And by the way, all of these things that I'm mentioning are supported by regulators in various guidance documents. And so we feel comfortable there. We've documented it all very carefully as the rationale for that. And so I think, yes, certainly, some slowdown in enrollment for APOLLO-B, but overall endpoint integrity and study integrity, we are looking good.

[Ritu Baral, Cowen]

Sounds good. Thank you for the questions.

[Operator]

Next question comes from Salveen Richter with Goldman Sachs.

[Salveen Richter, Goldman Sachs]

Thanks for taking my question. 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 and 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.

[John Maraganore, CEO]

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 stabilizers being used or given to treat the cardiomyopathy. So that is what we appear to be saying. But your question, Barry, maybe you should answer the rest of the question.

[Barry Greene, President]

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 U.S., what we're seeing is cardiologists working with neurologists in these multi-disciplined 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 dynamic we see in it, it's both stabilizers, both tap and this 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.

[Salveen Richter, Goldman Sachs]

Thank you.

[John Maraganore, CEO]

Yes. thank you.

[Operator]

Next question comes from Ted Tenthoff with Piper Sandler.

[Ted Tenthoff, Piper Sandler]

Thanks for taking my question. 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 toward 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 Blackrock. I believe that's $100 million upfront. Did you take any debt down yet?

[Speaker]

Yes. Great question, 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 despite 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?

[Jeff Poulton, Chief Financial Officer]

Yes. Sure. The $600 million that's come in to date at close was $100 million in equity and $500 million for the first installment on the royalty monetization. We have not taken any debt down. We would expect to take the first $200 million down at the end of this year.

[John Maraganore, CEO]

Thanks, John. And just as a reminder, the first $500 million has not been is not in the Q1 numbers. It's been received, but it will be in Q2.

[Ted Tenthoff, Piper Sandler]

Awesome. Thanks.

[John Maraganore, CEO]

Okay.

[Operator]

Next question comes from Mani Foroohar with SVB Leerink.

[Mani Foroohar, SVB Leerink]

Hi guys, thanks for taking my question. I want to follow up on an earlier question on ALN-AGT. Paul obviously hit on some of the historical challenges around safety for oral therapies that are not targeted the way your GalNAc platform is. Can you give us a little bit of a sense of from a commercial perspective, how you think about the opportunity and what that means in terms of clinical trial design, should a comparator arm the ALN-AGT versus doublet with existing approved orals, ALN-AGT versus single therapy with something like, for example, losartan? And what does that mean in terms of where in the clinical algorithm ALN-AGT will fall in terms of after orals first line, like how does that clinical trial design interplay with your own commercial strategy and potential target population?

[John Maraganore, CEO]

Yes. Well, that's a great question, Mani. You should have been in our development review meeting yesterday to participate in the discussion, because it is still an evolving strategic question as to which angle we want to pursue. Of course, all that will be very much data-driven with our Phase I data that's obviously looking really exciting, but also with the Phase II data that emerges. So it probably would be too soon to say exactly where we will go, but we can certainly provide some context on sort of the range of opportunities. And so maybe I'll turn it over, first, to Akshay to comment, and then maybe Barry, you'll have some perspective as well to share. So Akshay?

[Akshay Vaishnaw, President of R&D]

Yes. With the preliminary data that we have to hand, we really think there's a very wide opportunity for this drug. So if we think about it even if we just start with the resistant hypertension segment, which is, in some sense, the apex of unmet need in hypertension. We're looking at probably hundreds of millions of people around the world, double-digit number of millions in the U.S. alone. And that number is consistently growing. And there, I think the approach would be that ALN-AGT would have to be developed in the context of background therapy to get proper control in those patients.

So you built that at one extreme. At the other end, you have patients with mild or moderate or even severe hypertension form who require a monotherapy, but and that's an even larger number than the resistance segment. But as we know, over 50% of them fall off therapy for one or more reasons. And there, an infrequent administration once every six months or something like that, like inclisiran would provide consistent control and a return on clinical benefit, both for patients, healthcare systems and payers. So there's another opportunity there.

And then ultimately, we know that the Ras blockers or Ras pathway agents are involved in providing cardiac benefit, not just from the direct effect on hypertension, but also via issues like cardiac remodeling. And so there are yet other opportunities in the long run to think about as well, cardiac remodeling and heart failure associated with hypertension and that there's. So there's just an enormous set of possibilities here, all in the face of a drug that could be administered very infrequently and would give tonic consistent plant control of the key pathogenic parameters in blood pressure. So that's just sort of painting the landscape. There's a lot more things you can do, and obviously, we'll share our forces peers and before.

[John Maraganore, CEO]

Yes. And before, Barry, you comment, just wanted to remind you, Mani, that we've shown preclinically some very impressive effects on cardiac function with knockdown of AGT in animal models. So that's very encouraging to see. Barry, any do you want to add any commentary on the commercial side?

[Barry Greene, President]

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, so 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 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.

[Operator]

Our next question comes from Do Kim with BMO Capital Markets.

[Unidentified Analyst]

Good morning, everyone. This is [indiscernible] 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 expenses are going to 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 with all the 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?

[John Maraganore, CEO]

Yes. I mean, listen, I mean for starters, and maybe, Yvonne, you want to comment on the partnering side of it. I mean we're very bullish on AGT as a product that we would take all the way. We're a company as we look out in the '25 and beyond period of time, we're going to want to have a potential blockbuster product like AGT, whether we complement our promotional efforts in some way with another type of company, something we could imagine contemplating in the future. Yvonne, do you want to comment any further on that for the AGT program?

[Yvonne Greenstreet, Chief Operating Officer]

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.

[John Maraganore, CEO]

Yes. That's great. And Barry do you want to comment on the really great question about access on GIVLAARI?

[Barry Greene, President]

Sure. Yes. Just one comment back on AGT. As you are aware, with the APOLLO-B, HELIOS-B studies, seeing success there. We'll have a very significant cardiovascular footprint, which positions us well to move into the world of AGT. So I'm excited about that. In terms of I think there was a question about what we're doing for lumasiran. So right now, in the stage of development, we're doing disease awareness, healthcare provider, patient advocacy group disease awareness.

We have virtual and digital setup for lumasiran. So patients, healthcare providers can get information on websites about understanding PH1 and its impact. Clearly, the regulatory discussion, that determines the label, will be important for other activities that we pursue and then the engagement with payers. We have talked to payers at a high level about the data and our value-based agreement approach, and they are very excited to work with us for PH1.

[Operator]

We'll take our next question from Alan Carr with Needham.

[Alan Carr, Needham]

Thank you. Coming back to your guidance, I'm just trying to get a better sense of whether or not this is based on actual pattern you see in the second quarter. Is it just an abundance of caution in terms of what you expect to happen? You've mentioned some reduction in patient visits and that sort of things with ONPATTRO, but can I have a little more detail about whether this is just cautious, something you're seeing? And then if you stick to opex, can you provide some more detail on exactly what you are coming back on spending?

[John Maraganore, CEO]

Yes. Well, let me just the guidance change, Alan, let me just start by saying, of course, this really reflects what we believe to be the impact of the pandemic phase in Q2. And obviously, we expect things in Q3 and Q4 to really come back to more to a normalcy. And obviously, we believe that our teams are really well equipped to navigate through even the Q2 period as well as we've demonstrated in performance in Q1. But Jeff, maybe you can comment on that and also the final question as well.

[Jeff Poulton, Chief Financial Officer]

Yes. Sure. As it relates to the reduction in ONPATTRO guidance, Barry, I think, very well highlighted the reasons for us reducing the guidance by 5%, and we have seen some of those impacts in April, and that's why we anticipate Q2 having the most impact for the year. As it relates to the spend guidance, I'd say there's really two drivers of the reduction. One is just natural savings as a result of the pandemic and the environment that we're operating in. Certainly, things like travel are significantly reduced.

But secondly, we have made some prioritization decisions to delay certain activities that we think are not going to have significant impact on the business, either in the short or the long term. The midpoint of the revised operating expense guidance reflects 8% growth versus 2019. So I do think it reflects very good discipline as we think about the move toward being a profitable company. We've consistently talked about the drivers for that being both top line growth and discipline in the way we manage our operating expenses. And so I'm proud of the organization, frankly, that we're sort of moving quickly toward that. And again, 8% growth year-over-year, I think, reflects very, very good discipline in managing in an uncertain environment.

[John Maraganore, CEO]

Yes. I am also proud of the organization Jeff as you know and pleased with your leadership in this regard for sure.

[Operator]

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

[John Maraganore, CEO]

Great. Well thank you everyone for joining us on this call and again I want to thank all of our Alnylam employees for their dedication and continued hard work. This is certainly a difficult time but we're really pleased with our ability to map to march forward and deliver R&D and commercial progress with the challenge accepted spirit that is in the Alnylam RNA. So we look forward to updating you on next, on our continued progress in the coming weeks and months and until then I hope that all of you stay safe and healthy. Bye-bye now.

[Operator]

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