Alnylam Pharmaceuticals Inc

NASDAQ:ALNY

Earnings Call Transcript 2019-Q1

[Operator]

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call First Quarter Earnings. [Operator Instructions]. Please be advised that the 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 & Communications]

Good morning. I'm Christine Lindenboom, 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; Manmeet Soni, Chief Financial Officer; and Yvonne Greenstreet, Chief Operating Officer. For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the Investor page of our website, www.alnylam.com.

During today's call as outlined in Slide 2, John will provide some introductory remarks and provide general context. Akshay will review recent clinical updates. Barry will provide an update on our commercial progress. Manmeet will review our financial results for the first quarter and updated 2019 expense guidance, and Yvonne will provide a brief summary of upcoming milestones before opening the call to your questions.

I would like to remind you that today's call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purpose of the safe harbor provision under the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual report on file with the SEC.

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. Please also note that the press release and related financial tables, including a reconciliation of GAAP to non-GAAP measures that we will discuss today, can also be found on the Investor page of our website. We believe non-GAAP measures provide useful information to management and investors regarding our financial conditions and results of our operation.

With that, I'd like to turn the call over to John.

[John Maraganore, CEO & Executive Director]

Thanks, Christine, and thank you, everyone, for joining the call this morning. 2019 is off to a great start for Alnylam as we execute on both the commercial and R&D fronts. Before we dive into the details, I'd like to provide some overall context by highlighting four key points. First, as Barry will describe later in the call, we believe that the ONPATTRO launch is going very well. We're reporting $26.3 million in Q1 global net product revenues. And with over 400 patients receiving treatment with commercial ONPATTRO worldwide as of the end of Q1, the patient and physician experience is expanding quickly, supported by very strong execution by our U.S. and European commercial teams. ONPATTRO is now available in over 10 countries around the world, and we expect this to continue to expand by year-end 2019.

As we noted in yesterday's press release, a highlight of our commercial execution has been our success in achieving access for patients and recognition of the value of ONPATTRO, something we're very pleased with in this otherwise challenging pricing environment. The second point I'd like to make is that amid our commercial progress in Q1, our R&D engine continues to be very productive. Akshay will go into this in further detail, but a notable highlight for the quarter and recent period was our positive Phase III ENVISION results for givosiran, our investigational RNAi therapeutic for the treatment of acute hepatic porphyria. We are extremely pleased with the overall result, showing what we believe to be a very robust treatment effect and an encouraging safety profile in this high unmet-need disease.

We also made strong progress in the rest of our clinical programs, and as a reminder, we expect two more Phase III data readouts in 2019, namely, inclisiran starting in mid-2019 in collaboration with The Medicines Company; and lumasiran in late 2019. The third point I'd like to make is that while we're excited about our commercial and R&D execution, we're also focused on future growth. Having recently cracked the code of CNS and ocular delivery of RNAi therapeutics in rodents and nonhuman primates, we now look forward to pursuing RNAi programs in a broad range of neurodegenerative and ocular diseases where there are limited treatment options available today and where RNAi therapeutics can potentially emerge from the clinic as transformative medicines. We believe our new strategic alliance with Regeneron, the largest collaboration Alnylam has ever formed, can help us realize significant value creation in these future growth areas with an industry-leading effort, potentially bringing novel medicines to patients in need.

My fourth point is that with our success in raising new equity capital through a follow-on offering that we did in January and with the substantial funding from our Regeneron alliance, which is expected to close in Q2, along with growing product revenues, we believe our balance sheet now has the strength to support a multiyear horizon for business execution. As Manmeet will highlight, our financial results position Alnylam well for appropriate investment in our commercial and R&D objectives, delivering what we believe will be significant value creation both in the near term and also in the long term.

Finally, and to sum up, we couldn't be more excited about where we are in our efforts toward achieving our Alnylam 2020 goals of becoming a global multiproduct commercial biopharma company with a deep clinical pipeline for future growth and a robust product engine for sustainable innovation, a profile rarely, if ever, achieved in biotech history.

With that, I will turn it over to Akshay to review our latest pipeline progress in more detail. Akshay?

[Akshay Vaishnaw, President, Research & Development]

Thanks, John, and good morning, everyone. Let me dive right in and start with patisiran, which, as a reminder, is the nonproprietary name for ONPATTRO. We continue to work toward our goal of expanding the patisiran label to include cardiomyopathy in both hereditary and wild-type ATTR amyloidosis patients. Based on the positive exploratory cardiac endpoint data from APOLLO highlighting the potential for patisiran to favorably impact certain cardiac manifestations of ATTR amyloidosis, we have obtained alignment with the FDA on APOLLO-B.

Specifically, APOLLO-B is designed as a randomized, double-blind, placebo-controlled Phase III study of patisiran with six minute walk distance as a primary endpoint after 12 months of treatment. The study is planned for about 300 patients with either wild-type or hereditary ATTR with cardiomyopathy. We're also going to include patients who are either naïve to TTR stabilizers or progressing while receiving TTR stabilizers. We're on track to start this study in the middle of the year. And if positive, it should support an expanded label for patisiran in the '21 to '22 time frame.

We're also advancing vutrisiran, our investigational subcutaneously delivered TTR silencer, as a potentially best-in-class therapeutic for ATTR amyloidosis. We believe that a once-quarterly low dose low-volume subcutaneous injection that can achieve approximately an 80% to 90% knockdown of TTR can present a very attractive option for patients. We continue to enroll the HELIOS-A study, HELIOS-A Phase III study of vutrisiran in hATTR patients with polyneuropathy, which is aimed at bringing vutrisiran to the market as rapidly as possible. Later in 2019, we also plan to initiate an outcome study for vutrisiran, which we called HELIOS-B. And if successful, should allow vutrisiran to enter the very large wild-type ATTR market opportunity with supportive mortality and speedy hospitalization data.

Let's now move on to givosiran, our investigational RNAi therapeutic in development for the treatment of acute hepatic porphyrias. At EASL last month, we presented the complete positive results from the ENVISION Phase III study. Givosiran demonstrates a robust treatment effect in significantly reducing the annualized rate of composite attacks in AHP patients relative to placebo. Specifically, givosiran met the primary efficacy endpoint with a 74% mean and 90% median reduction relative to placebo in the annualized rate composite porphyria attacks in patients with AIP over six months. 50% of givosiran-treated patients were attack-free during the six month period as compared to 16.3% of patients in the placebo-treated group.

In addition, the annualized attack rate, or AAR, in those who have one or more attacks in the study period was 50% lower in the givosiran arm relative to placebo, same patient benefits even when they don't yet go to zero attacks.

Turning to safety and tolerability results. AEs were reported in 89.6% of givosiran patients and 80.4% of placebo patients. SAEs were reported in 20.8% of givosiran patients and 8.7% of the placebo group. One patient in the givosiran arm, as previously mentioned, discontinued treatment due to an AE. There were no deaths in this study. Three SAEs in the givosiran group were reported as related to study drug, a single case of pyrexia, abnormal liver function test and CKD. Adverse events reported in greater than 10% of givosiran patients and seen more frequently compared to placebo with nausea, injection site reactions, CKD and fatigue.

We look forward to performing deeper analysis of our Phase III results, including on the long-term impact of givosiran in AHP patients, and we expect to have additional data from ENVISION presented at the International Congress on porphyrias or ICPP, meeting in Milan in September.

As for next steps in the program, we're very focused on completing our regulatory submissions to the FDA and EMA, which we expect to complete in mid-2019 and then working closely with the authorities towards potential approval.

I'll now turn to recent progress in lumasiran, the investigational RNAi therapeutic we're developing both primary hyperoxaluria type 1 or PH1. As you know, we're conducting the ILLUMINATE-A Phase III study of lumasiran where we continue to enroll patients. This is a randomized, double-blind, placebo-controlled study in approximately 30 patients with PH1 aged 6 or older with mild to moderate renal impairment. We expect to report top line results from ILLUMINATE-A in late 2019 and if positive, to submit regulatory filings beginning in early 2020.

In addition to this pivotal trial, we're also planning - we're also advancing the ILLUMINATE-B and ILLUMINATE-C studies in pediatric and severe renal impairment patients, respectively. We're very excited about lumasiran as a potentially transformative medicine for patients with PH1, a devastating disease. And we believe our most recent results presented just last month at the International Society of Nephrology continue to highlight the strong potential for this investigational RNAi therapeutic.

In closing, let me just touch on three key additional R&D highlights. First, another important Phase III program for Alnylam is inclisiran, a PCSK9 program with The Medicines Company. Last week, Medco provided a key update regarding the ORION-9, -10 and -11 trials with Independent Data Monitoring Committee, which reviews unblinded Phase III data recommended continued study conduct without alteration. This is very encouraging and now provides us with over 3,000 patient years of safety data for RNAi therapeutics.

Second, while we continue to execute either alone or without partners on our six Phase III programs, we're pleased with our progress in our early and mid-stage clinical pipeline, notably with advance of Cemdisiran, our C5 RNAi therapeutic program, into a Phase II study for IgA nephropathy. We advanced ALN-AAT02 and with our partners VIR ALN-HBV02 in ongoing Phase I studies with data expected later this year. And we added an exciting new program ALN-AGT for the treatment of refractory-resistant hypertension into Phase I. Of note, the last three programs I mentioned all utilize our ESC+ platforms. So these data will be important for continued optimization of GalNAc-conjugated RNAi therapeutics.

Finally, we're thrilled with the progress we made at Alnylam in the delivery of RNAi therapeutics for the CNS and the eye. Our scientists presented an update on our studies with articles, there had been a harbor meeting a few weeks ago, including the first comparative results for RNAi versus an ASO approach with favorable results for RNAi therapeutics. And now with our new alliance with Regeneron, we're positioned to build what we believe could be the industry-leading effort. Notably, we believe this new alliance will allow us to expand our overall R&D productivity from 1 to 2 new INDs per annum to 3 to 4 new INDs annually increasing our prospects for ensuring that Alnylam can deliver important medicines to patients for many years to come.

And with that, let me now turn it over to Barry to review our commercial progress. Barry?

[Barry Greene, President]

Thanks, Akshay. As both Akshay and John highlighted, we're at a very exciting stage in building fully integrated global biopharmaceutical company, and the capabilities we've built from ONPATTRO lay the groundwork for the launches of future products that Akshay highlighted. We're very pleased with the ONPATTRO launch progress this quarter in which we achieved $26.3 million in global net product revenues. As of March 31, we estimate that over 400 patients worldwide were receiving commercial ONPATTRO compared to the 200-plus receiving commercial ONPATTRO estimated at the end of 2018, representing over 100% quarter-on-quarter growth.

We're also very pleased with the overall and continued global demand this quarter even with competition from recent market entrants and the availability of investigational drugs through a very large expanded access program and clinical trials. We believe that our disease education and patient- finding programs are working, and our commercial messages are resonating. We believe that we continue to present physicians and patients with a differentiated treatment option for the polyneuropathy with hereditary ATTR amyloidosis even as the competitive landscape intensifies in coming months. That said, we're still at the relatively early stages of this launch.

Let's start with a discussion of U.S. performance, and here, I'll turn to start forms, which as a remember can be likened to prescriptions for ONPATTRO that we receive at our Alnylam Assist patient hub. Start forms are a good but incomplete indicator of new patient demand.

In the very first quarter, we received a total of 77 start forms in the U.S., taking us now to over 325 start forms that we've received since launch. Encouragingly, over 90% of these Q1 start forms came from newly identified patients who've not been treated previously in the ONPATTRO expanded access program or EAP. This compares to Q4 2018 where the mix of start forms was about 50-50 between EAP and non-EAP patients.

The mix of prescribing physician specialties submitting Q1 start forms is also very informative, showing continued uptake across a broad range of specialties. Of note, 55% of start forms in Q1 came from cardiologists, which we believe reflects the mixed phenotype patient population and continued recognition of polyneuropathy as a major disease manifestation even in patients who may initially present with cardiac manifestations and therefore, be under the care of a cardiologist for their disease.

We're also very encouraged by the number of new prescribing physicians and the number of physicians who have submitted multiple prescriptions. Since launch, we've had over 150 prescribing physicians, and we're now receiving start forms from about two new prescribers every week. In summary, we're pleased with the demand in both depth and scope and the overall growth we're seeing in the U.S. market. As I previously mentioned, it's important to remind you also that start forms are an incomplete picture of our U.S. demand, since we're seeing U.S. vial demand of 20% to 25% outside of Alnylam Assist.

As treating institutions continue to gain comfort with reimbursement, this number may further increase. For these reasons, we're going to shift away from reporting start form metrics in future quarters. But of course, we'll continue to provide you with continued color on U.S. ONPATTRO demand and overall market dynamics. As highlighted in the update we released yesterday, we now have confirmed access to ONPATTRO as prescribed for more than 90% of U.S. lives under commercial, Medicare, Medicaid and other government payer categories. 65% of our U.S. patients are covered by Medicare.

We're also very pleased with how well the value-based agreements, or VBAs, are going with 10 commercial U.S. payers and plan to have most commercial patients covered by VBAs by year-end. So we believe the U.S. market access picture has been excellent for ONPATTRO, and we're pleased that physicians can prescribe and patients can receive this potentially life-saving medicine with support from the payer community.

Now let's turn to our commercial efforts and performance in our Canadian, European, Middle East and Africa region or CEMEA. Outside of EAP, ONPATTRO is now available to many European countries, including Germany, France, Spain, the Netherlands, Luxembourg, Portugal, Sweden, Switzerland and Austria. We're very pleased with overall performance in the region. In addition to naive patients, we are observing patients with physicians switching to ONPATTRO from other products, which is approved in the EU and reimbursed in many countries. We're also pleased with the progress we've been making on market access in the region. As we noted in yesterday's release, we've received favorable and, in many cases, differentiating health technology or HTA ratings from authorities in several important countries, including France and Germany. We're also preparing for a launch in Canada following regulatory approval.

Finally, in the rest of the world, we're preparing for a launch in Japan. We expect this year following regulatory approval, and we're also advancing our plans to make ONPATTRO available to patients in Latin America starting in Brazil. Our health economics and access teams are doing an outstanding job getting access for patients and are being met with positive reception by payers around the world. While we execute on our global launch of ONPATTRO, our medical affairs and commercial teams also remain committed to addressing the challenge of raising disease awareness and improving diagnosis in hATTR amyloidosis. We continue to believe that hATTR amyloidosis is an under-diagnosed disease where improved medical education and diagnosis will help patients reach treatment options faster.

As we've highlighted previously, our Alnylam Act program is a third-party genetic screening initiative aimed at facilitating diagnosis of patients suspected of having hereditary ATTR amyloidosis. As of April, over 13,000 samples have been submitted, which over 850 have tested positive for pathogenic TTR mutation. We're also pleased to now partner with 23andMe, supporting the addition of a new genetic health risk report for TTR amyloidosis, which will help 23andMe customers who've opted in to receive such reports, learn about their genetic risk for the three most common TTR variance in the United States.

We also believe these medical education diagnostic efforts will be enhanced by the evolving competitive landscape in hATTR amyloidosis. As new agents near approval and become available, which we expect this summer, if not sooner, we believe overall awareness will continue to accelerate, and we're enthusiastic about the benefits this will confer to patients. Furthermore, we believe that the distinctive clinical profile we've demonstrated for ONPATTRO with regards to neurologic impairment, including reversal of Neuropathy Impairment from baseline in majority of patients in APOLLO study, will continue to be recognized these patients and physicians. We believe these physician and patient experiences will be critical for choice of therapy in the future.

Finally, let me briefly turn to givosiran, which we expect will become our second commercial product. As we work towards completing our U.S. and EU regulatory submissions for givosiran, our medical and commercial teams are focused on efforts to continue to improve the awareness and the diagnosis for acute hepatic porphyria, both in the health care physician and patient communities and worldwide.

We've partnered with the American Porphyria Foundation to help drive engagement and awareness. We have now also launched our patient- and physician-facing Internet micro sites to give patients resources and education materials about their disease, to provide HCPs with content to help them recognize the signs and symptoms of AHP and help them navigate with the appropriate diagnostic tests to arrive at an accurate diagnosis.

We've expanded our Alnylam Act genetic testing and counseling service to support patient diagnosis in AHP. In addition, we continue to leverage the broad reach of social media to connect with people living with the burden of frequent abdominal pain with the goal of learning about their symptoms and educating them on porphyria as a potential diagnosis.

We're excited about the commercial opportunity for givosiran and look forward to launching the potentially transformative medicine in approximately 12 months if approved by regulators.

With that, I'll now turn the call over to Manmeet to review our first quarter financial performance. Manmeet?

[Manmeet Soni, SVP, CFO & Principal Accounting Officer]

Thanks, Barry, and good morning, everyone. Please refer to our press release issued earlier today for a summary of our financial results for the first quarter of 2019. I would like to take this opportunity to provide a brief overview of three key areas: our cash position, our first quarter of 2019 results and our updated 2019 financial guidance. Let me start with our cash balance. We ended the first quarter with a strong balance sheet of approximately $1.29 billion in cash, cash equivalents, marketable debt securities and restricted investments. Just as a reminder, this cash balance is as of first quarter end and excludes proceeds of $800 million that we will receive upon closing of the Regeneron collaboration, which was announced on April 8 and is expected to close during the second quarter of this year.

Moving now to our revenues. We recorded $26.3 million of ONPATTRO net product global revenue during the first quarter of 2019, which represents a significant growth from the fourth quarter net product revenues of $12.1 million. The majority of product revenues came from the sale of ONPATTRO in the United States. As of first quarter end, our channel inventory with the specialty pharmacies and distributors in the U.S. remained at approximately one week. Our gross-to-net, or GTN, percentage during the first quarter of 2019 was in the mid-20s. In the U.S., most of the GTN relates to mandatory discounts for 340B entities, Medicaid patients and reserves for VBAs. Similarly, in Europe, GTN discount is related to reserves for mandatory discounts and expected final pricing in European countries.

Cost of goods sold, or COGS, was $3.3 million for the first quarter, which is approximately 13% as a percentage of net product revenues. Subsequent to the utilization of our zero cost inventory, we expect COGS will be in mid- to high teens, including royalties paid to third parties. We recognized $7 million of collaboration revenue during the first quarter of 2019 as compared to $21.9 million during the first quarter of 2018. Our total first quarter revenues were $33.3 million. As expected, the decrease in the collaboration revenues is due to recognition of onetime milestone revenue from Sanofi Genzyme during the first quarter of 2018.

Moving to other operating costs and expenses. GAAP R&D expenses were $129.1 million for the first quarter of 2019 as compared to $96.9 million for the first quarter of 2018. Non-GAAP R&D expenses were $113 million as compared to $86.7 million for the first quarter of 2018. The increase in non-GAAP R&D expenses was due to increased compensation expenses and facility expenses with growth in the number of our late-stage programs and higher headcounts during the period as we continue to expand and advance our development pipeline.

Turning to SG&A. GAAP SG&A expenses were $89.6 million as compared to $72.4 million for the first quarter of 2018. Non-GAAP SG&A expenses were $73.7 million as compared to $63 million for the first quarter of 2018. The increase in non-GAAP SG&A was due primarily to an increase in commercial and medical affairs head count in connection with the ongoing launch of ONPATTRO. Both non-GAAP R&D and SG&A expenses exclude stock-based compensation expense. Our stock-based compensation expenses also increased to $32 million during the first quarter of 2019 as compared to $19.6 million during the first quarter of 2018 due to increased head count and due to accounting for the probabliity of vesting of performance-based stock awards as a result of the commercial launch of ONPATTRO and clinical achievements with respect to our givosiran Phase III study.

As mentioned in our press release, we expect the Regeneron collaboration to close during the second quarter, and we have updated our 2019 annual non-GAAP R&D expenses guidance to be in the range of $550 million to $590 million compared to our previously guidance range of $520 million to $560 million due primarily to third-party payment obligations resulting from the Regeneron collaboration. We also tightened our 2019 annual non-GAAP SG&A expense guidance to be in the range of $390 million to $410 million as compared to our previously guided range of $390 million to $420 million.

I will now hand it over to Yvonne to review our 2019 goals. Yvonne?

[Yvonne Greenstreet, EVP & COO]

Thanks, Manmeet. 2019 is shaping up to be another transformative year for Alnylam following the notable progress made in Q1 and the recent period. Starting with ONPATTRO. While we continue our global commercial execution, we also look forward to initiating the APOLLO-B Phase III study in mid-2019, aimed at securing an expanded label to include wild-type and hereditary cardiac amyloidosis.

With vutrisiran, we plan to enroll the HELIOS-A Phase III trials throughout the year and expect to initiate HELIOS-B, an outcome study, in late 2019. Moving to givosiran. With our Phase III data now in hand, we plan to complete our rolling NDA submission as well as file an MAA in mid-2019. With lumasiran, we expect to complete enrollment to the ILLUMINATE-A study in mid-2019 and to report top line results from that study in late 2019. We expect to begin enrolling pediatric patients in ILLUMINATE-B and also plan to start the ILLUMINATE-C study in patients with severe renal impairment in mid-2019.

With inclisiran, our partners at The Medicines Company have guided to have top line results, the ORION-9, -10 and -11 studies in the third quarter of 2019 and assuming positive data to submit an NDA for inclisiran by the end of the year. They also guided recently that they will present new data from the ORION-3 Phase II open-label extension study in the next two weeks and then more data from other ORION trials later in May. Of course, we'll continue advancing our pipeline of earlier-stage clinical efforts as well as exciting preclinical efforts, and we'll highlight those milestones throughout the year as they occur. In particular, you should expect data readouts for a number of our early and mid-stage clinical programs, including ALN-AATO2 ALN-HBV02 and ALN-AGT, our ESC+ program during the course of the year.

Let me now turn it back to Christine to coordinate our Q&A session. Christine?

[Christine Lindenboom, VP, IR & Communications]

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

[Operator]

[Operator Instructions]. We will now take our first question from Maury Raycroft with Jefferies.

[Maurice Raycroft, Jefferies]

Congrats on the update today. First question is just if you could provide any new perspective gained by the prescriber mix, 55% cardiologist; 35%, neurologist and for the types of patients you're getting under treatment. Are there any other trends you can discuss based on that for ONPATTRO.

[John Maraganore, CEO & Executive Director]

Okay. Thanks, Maury. Barry, do you want to answer that?

[Barry Greene, President]

Maury, thanks for that. I think the biggest thing, and when we highlighted this on the call, is that people are recognizing that the manifestation of TTR is one disease and is a multisystem disease. The history of being either a polyneuropathy or cardiomyopathy is moving by us. So we now see that this is a mixed phenotype disease. Importantly, cardiologists have the tools to recognize TTR amyloidosis, not just hereditary but wild-type and a significant number of patients in the heart failure clinics, in fact, have amyloidosis. So we are raising the tools are out there. So many of these patients passed by cardiology and again as we highlighted, most of these patients out there with hereditary TTR amyloidosis have a mixed phenotype, including polyneuropathy, which is perfect for ONPATTRO.

[Operator]

We will now take our next question from Ritu Baral of Cowen.

[Ritu Baral, Cowen and Company]

Mine is on apparent assumptions around APOLLO-B and HELIOS-B or maybe focus on APOLLO-B because that's closer. What are your treatment effect assumptions and powering assumptions and what sort of data sets are they based on? And if you can address enrollment time line estimates at this point for both these trials.

[John Maraganore, CEO & Executive Director]

Thank you, Ritu. I'm going to hand it over to Akshay. I'll just start by saying that we get into the details of the specific trial designs typically along with statistical considerations when we formally announce the start of those studies. So some of the details you may be looking for are immature. But Akshay, maybe you could provide some color.

[Akshay Vaishnaw, President, Research & Development]

Yes, I mean, just at a high level, Ritu, for APOLLO-B, of course, we have a wealth of data from the literature now, on sites of network business data. We also have our own experience from enrolling the ENDEAVOUR study in the placebo arm and how that behaved. And then of course, there's the experience from ATTR-ACT itself which is now published, and we can analyze for both the natural history of this in the placebo arm there as well as the impact of tafamidis. Given the totality of that data, we could do a pretty robust sampling effort. And we think 300 is adequate to show a significant treatment effect on what is an important cardiorespiratory outcome in six minute walk distance. As John said, we have a lot more detail to follow. The study kicks off midyear, APOLLO-B and as it gets going, we'll give you more idea of enrollment time lines and so forth. But as noted this morning, we anticipate hopefully approval and label changes in the '21 or '22 time frame but more details to follow. In HELIOS-B, we intend to kick off later this year. So as we approach that date, we'll certainly share more details about that thinking around design there.

[Ritu Baral, Cowen and Company]

Is it fair to say that APOLLO-B - I'm sorry, the APOLLO substudy is more important than the ENDEAVOUR data that you will generate from lumisiran?

[John Maraganore, CEO & Executive Director]

Yes. I think the APOLLO cardiac subpopulation data are very helpful. We didn't measure six minute walk in that study, but we did have 10-meter walk time. So we have some data regarding functional ability to walk. So I think that's may be very helpful as well, Ritu.

[Operator]

Our next question comes from Alethia Young of Cantor Fitzgerald.

[Alethia Young, Cantor Fitzgerald & Co.]

Congrats on the quarter. I just wanted to explore this comment that you made around tafamidis patients switching in Europe, and I guess one part is just what's the feedback from that switch? And do you think there is a rate to be had or something to think about in the United States around what that may mean for tafamidis likely to be approved in the United States later this year?

[John Maraganore, CEO & Executive Director]

Sure. Barry, do you want to maybe start and maybe Akshay will want to comment as well.

[Barry Greene, President]

Yes. Thanks for the question. So as you know, despite a failed Phase III in polyneuropathy, tafamidis was approved in many European countries and access was provided, not in all, and it was approved for Fast stage one. And as patients progress, while on stabilizer, and we know that while stabilizer slow the progression of disease, we're not seeing halting or reversal in majority of patients, patients continue to progress and it's physician's choice at this point in recognizing progression and understanding whether they want to add or switch patients to another agent. So as we highlighted, a number of patients in Europe, specifically France and Germany, are patients that a physician has deemed progressing on tafamidis and need to add or switch ONPATTRO.

[Akshay Vaishnaw, President, Research & Development]

Yes, Alethia just following up. We have important information APOLLO in this regard where about half the patients had the nonstabilizers previously, tafamidis and diflunisal. And they did very well in APOLLO in terms of their outcomes relative to both that were naïve to stabilizers. They did equally well, and so this theme of ONPATTRO to help stabilize or improve neuropathy outcomes was being consistent whether you had been on stabilizers or not. And that's encouraging, and I'm sure that plays into people's assessment of what's the right drug for their patients whether they are naïve or showing signs of progression on the stabilizer.

[Operator]

And our next question comes from Paul Matteis of Stifel.

[Paul Matteis, Stifel, Nicolaus & Company]

Great. Congrats on all the progress. On the start forms, I think you said previously that over 80% of start forms were leading to an actual patient start. Is that continuing to trend in that similar manner as more of the start forms come from non-EAP patients? And then just secondarily, Barry, I was wondering if you could just quickly comment on how you're thinking about EU pricing. Of course, the goal is to get the best price possible. But as you go into the Netherlands, France with the progress you've made on the evaluation of a drug, do you remain confident that you're going to be able to keep a tight band around the U.S. price as you diversify into more countries?

[John Maraganore, CEO & Executive Director]

Yes, those are two great questions, Paul. Barry, you should cover both.

[Barry Greene, President]

Okay. Thanks, Paul. So in terms of start forms, yes. Over 80% of start forms result in patients getting drug. It's probably about between 80% to 90% at this point. So that's looking very, very favorable, and we continue to improve the time from start form to patients getting on drugs under five weeks. Many patients, 2 to 3 weeks. So that's really progressing well. In terms of Europe, our goal is to keep entirely very, very tight vial price band around the world. Of course, the per patient per year cost will vary depending on weight, but our goal is to keep a very tight vial price.

[John Maraganore, CEO & Executive Director]

I would just add one piece of color, Paul, that Barry knows and we're sharing - we actually see the time from start form to the start of infusion to be quicker now with the non-EAP patients than it had been before with the EAP patients. Part of that is just getting the system improved over time to do that, but also just time period appears to be quicker for the non-EAP patients actually.

[Operator]

Our next question comes from Vincent Chen of Bernstein.

[Vincent Chen, Sanford C. Bernstein & Co.]

I heard you comment really on the competitive dynamics that you've seen in the TTR space with respect to ONPATTRO and Tegsedi now that they're on market in the U.S. Have you seen patients switching or Tegsedi or go from Tegsedi to ONPATTRO? Or any other color you could provide there would be quite helpful.

[John Maraganore, CEO & Executive Director]

Well, again Barry should comment. I think in general as we reflect on the competitive landscape, there is now obviously Tegsedi approved in the U.S. and Europe, and there's also a large expanded access program for tafamidis in the U.S. as well. So we now have a full quarter with a competitive landscape that is where we expect it to be for the rest of the year. Barry, do you want to comment specifically on what we're seeing with the Tegsedi specifically?

[Barry Greene, President]

Yes. Frankly, we're just not hearing that much. We are hearing, in some cases, that a patient may choose a subcu alternative. But, for the most part, the patient and physician experiences with ONPATTRO have been outstanding, and we're seeing more patients flowing, patients with polyneuropathy clearly flowing to ONPATTRO.

[John Maraganore, CEO & Executive Director]

Including patients that were previously on Tegsedi.

[Barry Greene, President]

Correct.

[Operator]

Our next question will come from Gena Wang of Barclays.

[Gena Wang, Barclays Bank]

So I also had one regarding the start form. So when we look at the non-EAP patient this quarter compared to the last quarter, it seems there's a drop if we calculate 90% of this quarter start forms versus 50% over the last quarter. So just wondering if any additional color you can provide. I know, Barry, you also mentioned that we should not just look at start forms. What additional metrics we should look at going forward?

[John Maraganore, CEO & Executive Director]

Barry, you want to handle that?

[Barry Greene, President]

Yes, Gena. So as we highlighted the last two quarters, we believe that, particularly in the United States, all patients would transition from EAP to commercial drug by the end of this quarter - by the end of Q1. We've largely achieved in that. So the reason that 90% are non-EAP is that the EAP patients have moved previously to commercial drug. We find that the majority are now non-EAP are more reflective of a future run rate. So that's actually very good in terms of patient finding and new prescribers coming on and understanding disease diagnosis and understanding ability to use ONPATTRO.

[John Maraganore, CEO & Executive Director]

I would just add to that, Barry, that the other thing to look at, which I think is very important is on the - when we look at the first quarter and a half of the launch, these were patients that were largely in the EAP or patients that were known to sites, in some cases patients that were out in the EAP as well. So this is a different quarter, and we think it's more reflective. I think the other thing, too, to keep in mind on the patient funding side is that we're consistently saying about 100, plus or minus, new patients every quarter from Alnylam Act that are coming out with positive TTR mutation. We get a couple thousand samples every quarter now that are being tested, and we're staying about at 100 or so, sometimes a little bit more patients with positive TTR mutations per quarter. So the patient finding work is really working, and we don't - we obviously don't know if those patients are eligible for ONPATTRO. That's a physician decision at the end of the day, but it's important that we're helping improve diagnosis out there to increase the pool of diagnosed patients.

[Operator]

Our next question comes from Whitney Ijem of Guggenheim.

[Whitney Ijem, Guggenheim Securities]

I'm just curious, is there any special or different outreach or patient education sort of targeting the mixed phenotype populations versus the neuropathy population?

[John Maraganore, CEO & Executive Director]

Good question. Barry, do you want to handle that?

[Barry Greene, President]

Yes. That's a very good question. So we have broad patient education across health care providers and patients, of course. There are specific mutations of people that live in certain dense areas. So the V30M mutation is of people in Portuguese descent. So there are communities that are largely people of Portuguese descent with special programs there. We're piloting a number of programs for the V122I, patients of those of African or Western African descent. That is a patient group that requires some specific touch because of their experience with the pharmaceutical and government industries. So we're piloting programs to help appropriately educate. And of course, the T60G, the other most prevalent mutation, are heavily Appalachia driven. So we've got programs there. So we've got broad programs across all mutations but where appropriate, specific programs targeting specific people of certain mutations.

[Operator]

We will now take our next question from Dave Lebowitz of Morgan Stanley.

[David Lebowitz, Morgan Stanley]

I guess to this point, has the preliminary presence of Pfizer with respect to tafamidis had a positive impact? How is it affected in the cardiomyopathy space with respect to, I guess, affecting ONPATTRO?

[John Maraganore, CEO & Executive Director]

Barry, do you want to handle that?

[Barry Greene, President]

Yes. David, it's a great question, and we highlighted this in the call. The issue, as we think about TTR amyloidosis over the next several years, is not who has which part of the pie. It's identifying patients early, getting them the appropriate diagnosis and getting them on the right therapy. The longer - the earlier we can diagnose patients, the better opportunity we have to have transformative impact on their lives rather than trying to treat them at the very end of the disease. So having other commercial voices educating the cardiology community to look at their heart failure clinics or to look at patients differently than they had before we believe will lead to earlier and more accurate diagnosis. That can only help the overall patient community. And of course, for patients with polyneuropathy, hereditary patients with polyneuropathy, we believe the data are very clear on ONPATTRO being a very good choice for those patients.

[John Maraganore, CEO & Executive Director]

I would just add to that and David, one of the things that I've seen a little bit, I've done several field trips now with our team, what's encouraging to see is how the physician community is getting increasingly more organized around the management of amyloidosis. In several of the meetings that I had, I encountered cardiologists, neurologists that are linking up, working together, really thinking about their institution being an amyloidosis center of excellence at least in the local region. So I think that's really happening because of the availability of new therapies and the increased effort that's going on not just from Alnylam but also pre-commercially from Pfizer and others around this disease and the unmet needs. So I think it's going to be a positive thing as we highlighted in our prepared remarks to see this improved education and diagnosis coming from multiple commercial efforts.

[Barry Greene, President]

Yes. I'd add that the increase in centers of excellence was a really important point, John. It's happening not just in the United States but in many countries around the world.

[Operator]

Our next question comes from Ted Tenthoff of Piper Jaffray.

[Edward Tenthoff, Piper Jaffray Companies]

Great, and my congrats on the really nice quarter. I'm trying to get a sense of sort of what revenues are maybe between North America and Germany either on a dollar basis or on a patient basis. Any color you can give us along those lines?

[John Maraganore, CEO & Executive Director]

Yes. Manmeet, do you want to provide?

[Manmeet Soni, SVP, CFO & Principal Accounting Officer]

Yes. As we've discussed, right, earlier, majority of the revenues came from the United States, right? Apparently, I think we're not providing any further color based on competitive reasons.

[John Maraganore, CEO & Executive Director]

Yes, for competitive reasons, Ted, we're going to hold off on giving you a lot more detail on that. Obviously, in the quarters to come, we'll provide more visibility on it, but I think for right now, clearly, the majority is in the U.S. But Europe is strong. We're very pleased with Europe.

[Edward Tenthoff, Piper Jaffray Companies]

Excellent. And congrats again on a good launch.

[John Maraganore, CEO & Executive Director]

Thank you.

[Operator]

Our next question will come from Anupam Rama of JPMorgan.

[Anupam Rama, JPMorgan Chase & Co.]

Congrats on the quarter. Maybe following up on some of the tafamidis questions. What have you heard about capacity for tafamidis EAPs? And with a couple of trials, including the cardiomyopathy population on the horizon as well as the tafamidis approval coming here in the U.S., how do you think about maximizing enrollment here in the U.S. for the cardiomyopathy population?

[John Maraganore, CEO & Executive Director]

All right. So when you say enrollment, I assume you're talking about our studies that we're planning. But maybe, Barry, you want to start first with the commercial intel and insights?

[Barry Greene, President]

Yes. That's a great question. So we've heard that most of the tafamidis expanded access studies are full largely driven by better recognition of the wild-type population. And in fact, what many of the cardiologists that are amyloidosis experts are saying is that about 15% of patients with heart failure preserved ejection fraction are driven by TTR amyloidosis. And obviously, most of those are wild-type. So the EAPs rapidly accrued, and we see that as a very good sign as we think about cardiac manifestations enrolling our trials, both hereditary and TTR, but number of wild-type patient seems to be increasing dramatically.

[John Maraganore, CEO & Executive Director]

Anything to add on the clinical trial side?

[Akshay Vaishnaw, President, Research & Development]

Yes. I mean just following up on Barry's comments what is clear is the prevalence of wild-type obviously enables a significant number of studies to operate in parallel in conjunction with the fact that currently, there is no approved drug for wild-type and the EAP via Pfizer seems to be saturated currently. So we've launched APOLLO-B. The majority of patients in APOLLO-B will be wild-type much as in ATTR-ACT with the Pfizer stat study. And we're confident that due to the prevalence and the need for access to therapies for these folks, we'll be enrolling in the U.S., in Europe and elsewhere. And so we'll supply more details and time lines around the trial in the months to come, but we think we're in a good place.

[Operator]

Our next question will come from Alan Carr of Needham & Company.

[Alan Carr, Needham & Company]

I was wondering if you can comment on what might be behind so many patients coming to you from outside the Alnylam Assist program, what you think the dynamics are there and can you go over a bit more about if you have a slide on givosiran and the patient population. I'm wondering if you can give us any more resolution on how many patients specifically have been identified there.

[John Maraganore, CEO & Executive Director]

Right. Thanks, Alan. Barry, I think you can handle both of those.

[Barry Greene, President]

Yes. So outside of Alnylam Assist. So Alnylam Assist is a hub to benefit patients and walk them through what can be very complicated process for some patients. As institutions are getting more comfortable with the access and as we highlighted in our call, we have outstanding access, and we really partnered with payers in the United States and now across the world, the institutions are not having a rough time getting reimbursed for the purchasing of vials that they then give to their patients. So as they get more and more comfortable that they get paid for the purchase of vials and patients are comfortable they can go directly to institutions, that's what we see now. We prefer patients to come through our hub because of all the other services that get offered, and we want to make sure the patients get all the support they need. But institution can optimize how they conduct their business, and that's the 20% to 25% we're seeing outside the hub.

[Alan Carr, Needham & Company]

To what extent is that growing? Is that stable? Or do you think that'll keep expanding? That number 20% to 25%?

[Barry Greene, President]

It's been fairly stable, but that's not something that we have specific control over. But as institutions gain comfort and gain more patients, they can conduct their business and purchase vials directly. As long as patients are getting the right support and getting drugs clearly and staying on drug, it's okay with us.

[John Maraganore, CEO & Executive Director]

And Barry, do you want to answer the question on givosiran patient size, patient numbers?

[Barry Greene, President]

We've been pretty consistent, Alan, that there's about 1,000 patients that have recurrent attack and about 5,000 that are risk at attack. These are patients that physicians report are under their care. Of course, we get closer to launch, we'll get more granular on how many patients we see attractable for givosiran.

[John Maraganore, CEO & Executive Director]

Yes, I'll just add that we have very active patient - go ahead, Alan, sorry.

[Alan Carr, Needham & Company]

I'll let you finish.

[John Maraganore, CEO & Executive Director]

Yes, I was going to say we have very active patient finding efforts that are going on as we speak, and we have an Alnylam Act program in porphyria, which continues, it's still at the early stages, but it continues. So we're encouraged by the number of patients that we're finding now as we get ready for a potential launch this time next year.

[Operator]

Our next question comes from Mani Foroohar of SVB Leerink.

[Mani Foroohar, SVB Leerink]

Congrats on the quarter. A couple of little ones. Quickly for Manmeet, do said gross-to-net in the U.S. is in the mid-20s, correct?

[Manmeet Soni, SVP, CFO & Principal Accounting Officer]

The global one was mid-20s. That's what we said on the call.

[Mani Foroohar, SVB Leerink]

Okay. With more VBAs coming on, something like 10 are on board now, I presume some element of that is an accounting for potential impact of VBAs. Help give us a feel how much of that is based upon the at-risk component of VBAs, which is cash that could come back to you guys if patients continue to perform in line with the APOLLO study. Just scale how much of that you guys could potentially get back in the out-years of all these patients.

[Manmeet Soni, SVP, CFO & Principal Accounting Officer]

So Mani, let me start with how we account to give a little bit of color, right? We account for our estimation on currently how many patients are on VBAs and how much potential rebate could go to them. So we've already reserved. When we book revenues, we proportionally book a reserve for them. Every quarter, we true-up our reserves if needed if we see a change in our estimate. Currently, I would say, on the U.S. side, we are on low 20s as a GTN which will provide you color, which includes even the VBA impact as we have guided previously, right? U.S. was always in low 20s and combined global is in mid-20s. Does that help you provide with answers on the VBA and the overall split of GTN?

[Mani Foroohar, SVB Leerink]

Yes. That's helpful. And moving on to the pipeline, thinking of APOLLO-B and HELIOS both from the case of cardiomyopathy. Given what you've seen, it's from the rapid saturation of the tafamidis EAP, does this change your expectations into the potential enrollment curve? Could you see fast enrollment than you had previously thought about? And to take advantage of this, would you need to start enrolling prior to tafamidis being commercially available? Or do you think this volume tailwind will persist even in the face of tafamidis commercial approval?

[John Maraganore, CEO & Executive Director]

Yes. Akshay?

[Akshay Vaishnaw, President, Research & Development]

Yes. We are proceeding as quickly as we can with APOLLO-B and HELIOS-B, and the exact timing of approval of tafamidis is not clear. It's upcoming I imagine, but we're going to attempt to enroll as many patients as we can in these studies, both in U.S., Europe and elsewhere before the approval of tafamidis. But given the staggered approvals and reimbursement that will occur with tafamidis in U.S. and around the world, there will still be a large pool of accessible patients for trials. And so again, we're confident that we can enroll studies like APOLLO-B, HELIOS-B later in the year and access these patients. And as far as time lines are concerned, more details to follow later in the year.

[Yvonne Greenstreet, EVP & COO]

We've discussed the studies with clinical trial investigators, I mean, they've demonstrated real enthusiasm for engaging in our studies despite other studies ongoing and the advent of the tafamidis approval. But we feel confident actually there's a large population here, and we'll be able to enroll the studies fairly rapidly.

[Operator]

Our final question from today's question-and-answer session will come from Terence Flynn of Goldman Sachs.

[Unidentified Analyst]

This is Gavin on for Terence. Apologize if you answered this already. We are just curious on the percentage of patients identified in Alnylam Act. How many of those transitioned ultimately to the hub and started therapy? And then any color on in-home infusion versus the hospital setting would be great.

[John Maraganore, CEO & Executive Director]

All right. Let me quickly answer the first one. The answer is we don't know and, the reason for that is that we provide this service for free. Physicians can submit their samples. But we don't use that information or give that information to our sales team and so forth. So it is something which we don't know by design. It's important that we keep it that way from an execution perspective. But ultimately, we feel good about the fact that we have a medicine that we think has strong value for patients with polyneuropathy in this disease. And if a physician diagnoses a patient and then observes disease with polyneuropathy, we believe that we've got a therapy that's the right choice for them. It's ultimately their decision, but we believe that we have the right therapy. So we're just trying to improve diagnosis rates with that approach overall. Barry, do you want to handle the in-home infusion questions?

[Barry Greene, President]

Yes, just a little bit more to make a point. Alnylam Act is one of the genetic testing services out there. There other genetic testing services as well as physicians using commercial insurance to genetically test. So it's really represents a sampling of the increased genetic testing that's going on out there. And again, as John highlighted, overall improvement of diagnosis helps the patient community. In terms of infusion. So home infusion has been available since we launched ONPATTRO in the United States and many countries. We highlighted this in the previous quarter. It's been interesting that most patients actually are reporting, this is anecdotal, but are reporting back through our patient hub that they're enjoying their local infusion centers, and we've actually had patients who went to home infusion and went back to the local infusion center where they enjoy the camaraderie and the care of an infusion center. So the infusion center experience is actually going quite well.

[Operator]

This concludes today's question-and-answer session. I would now like to turn the conference back to the company.

[John Maraganore, CEO & Executive Director]

All right. Well, thank you, everyone, for joining us this morning. We're obviously very pleased with the progress we're making on the commercial side and of course, the continued progress we're making on R&D. We look forward to updating you on this progress in the months to come, and we hope you have a terrific rest of the day. Bye, bye now.

[Operator]

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