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Alnylam Pharmaceuticals Inc (ALNY) Q1 2019 Earnings Call Transcript

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Alnylam Pharmaceuticals Inc  (NASDAQ: ALNY)
Q1 2019 Earnings Call
May. 01, 2019, 8:30 a.m. ET

Contents:

  • Prepared Remarks
  • Questions and Answers
  • Call Participants

Prepared Remarks:

Operator

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call First Quarter Earnings. There will be a question-and-answer session to follow. 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 -- Vice President of Investor Relations and Corporate Communications

Good morning. I am 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 on Slide 2, John will provide some introductory remarks and provide general contacts, Akshay will review recent clinical update, 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 for 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, PhD -- Chief Executive Officer

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 US 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 results 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 the lumasiran in late 2019.

The third point I'd like to make is that while we are 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 non-human 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 our 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 multi-year horizon for business execution.

As Manmeet will highlight, our financial results position Alnylam well for appropriate investments 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 multi-product 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, MD, PhD -- President, Research and Development

Thanks, John and good morning everyone. Let me dive right in and start with patisiran, which as a reminder is the non-proprietary 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 HAP to 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 (inaudible) as the 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 naive to TTR stabilizers or progressing while receiving TTR stabilizers. We are on track to start the study in the middle of the year and, if positive, it should support an expanded label for patisiran in the '21 to '22 timeframe.

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, and present a very attractive option for patients. We continue to enroll the HELIOS-A Phase III study of vutrisiran in hATTR patients with polyneuropathy which is aimed at bringing vutrisiran to 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 supported mortality and (inaudible) hospitalization data.

Next, I 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 the 74% mean and 90% median reduction relative to placebo in the annualized rate of composite porphyria attacks in patients with AIP over 6 months. 50% of givosiran treated patients were attack-free during the 6-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 had one or more attacks in the study period was 50% lower in the givosiran arm relative to placebo change (ph) for patient benefits even when they don't get the go to zero attacks (ph).

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, but no death in this study. Three SAEs in the givosiran group were reported as related to study drugs, a single case of pyrexia, abnormal liver function tests, and CKD. Adverse events reported in greater than 10% of givosiran patients and see (ph) more frequently compared to placebo were nausea, injection site reactions, CKD and fatigue.

Adverse events reported in greater than 10% of givosiran patients and see more frequently compared to placebo were 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 Porphyrins and Porphyrias or ICPP meeting in Milan in September. As for next steps in the program, we are 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 authorities toward potential approval.

I'll now turn to recent progress in lumasiran, the investigation RNAi therapeutic we're developing for primary hyperoxaluria type 1 or PH1. As you know, we are 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 age six 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 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 safety data, recommended continue study conduct without alterations. 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 with our partners on our six Phase III programs, we are pleased with our progress in our early and mid-stage clinical pipeline. Notably, we've advanced cemdisiran, our C5 RNAi therapeutic program, into Phase II study for IgA nephropathy, we advanced ALN-AAT02 and with our partners at 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 plus platform, so these data will be important for continued optimization of GalNAc conjugated RNAi therapeutics.

Finally, we're thrilled with the progress we've made at Alnylam in the delivery of RNAi therapeutics in the CNS and the eye. Our scientists presented an update on our studies at Cold Spring 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 are positioned to build what we believe could be the industry leading asset. Notably, we believe this new alliance will allow us to expand our overall R&D productivity from one to two new INDs per annum to three to four 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 are at a very exciting stage in building a fully integrated global biopharmaceutical company and the capabilities we've built from ONPATTRO laid the groundwork for the launches of future products that Akshay highlighted. We are 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 in 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 the patient finding programs are working and our commercial messages are resonating. We believe that we continue to present physicians and patients with differentiated treatment options for the polyneuropathy, the hereditary ATTR amyloidosis even as the competitive landscape intensifies in coming months. That said, we are still at the relatively early stages of this launch.

Now, let's start with the discussion of US performance, and here I'll turn to Start Forms, which as a reminder, can be likened to prescriptions from 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 US 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 are 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 US market. As I previously mentioned, it is important to remind you also that start forms are an incomplete picture of our US demand since we're seeing US 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 US ONPATTRO demand and overall market dynamics. As highlighted in the update we released yesterday, we now confirmed access to ONPATTRO if prescribed for more than 90% of US lives under commercial, Medicare, Medicaid and other government payer categories. 65% of our US states are covered by Medicare. We're also very pleased with how well the value based agreements or VBAs are going with 10 commercial US payers and plan to have most commercial patients covered by VBAs by year-end. So we believe the US market access picture has been excellent for ONPATTRO and we're pleased that physicians can prescribe and patients can receive this potentially lifesaving 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 in 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 and physicians switching to ONPATTRO from other products including tafamidis, 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 received favorable and in many cases differentiating Health Technology or HTA ratings from authorities in several important countries, including France and Germany. We are also preparing for a launch in Canada following regulatory approval. Finally, in the rest of the world, we're preparing for launch in Japan. We expect this year following regulatory approval and we are also advancing our plants 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 of 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 of 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 hATTR amyloidosis, which will help 23andMe customers who have opted in to receive such reports learn about their genetic risk for the three most common TTR variants in the United States.

23andMe customers who have opted in to receive such reports learn about their genetic risk for the three most common TTR variants in the United States. We also believe these medical education diagnostic efforts will be enhanced by the evolving competitive landscape in ATTR amyloidosis. As new agents near approval and become available which we expect this summer, not sooner, we believe overall awareness will continue to accelerate and we are enthusiastic about the benefits this will confer to patients. Furthermore, we believe that the distinctive clinical profile we've demonstrated for ONPATTRO with regard to neurologic impairment including reversal of neuropathy impairment from baseline in majority of patients in APOLLO study will continue to be recognized by patients and physicians. We believe the 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 toward completing our US and EU regulatory submissions for givosiran, our medical and commercial teams are focused on efforts to continue to improve the awareness and diagnosis of acute hepatic porphyria, both in the healthcare physician and patient communities and worldwide. We partnered with the American Porphyria Foundation to help drive engagement and awareness. We have now also launched our patient and physician facing Internet microsites 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 to the appropriate diagnostic test to arrive at an accurate diagnosis.

We have 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 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 this 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 S. Soni -- Chief Financial 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 3 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 specialty pharmacies and distributors in the US remained at approximately one week (ph). Our gross to net or GTN percentage during the first quarter of 2019 was in the mid 20s. in the US, 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 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.

Total first quarter revenues were $33.3 million. As expected, the decrease in the collaboration revenues is due to recognition of one-time 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 headcount 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 headcounts 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 with $32 million during the first quarter of 2019 as compared to $19.6 million during the first quarter of 2018 due to increased headcount and due to accounting for the probability 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 guided 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, MBChB, MBA -- Chief Operating Officer

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, aim to secure an expanded label to include wild-type and hereditary cardiac amyloidosis. With vutrisiran, we plan to involve the HELIOS-A Phase III trial 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 report topline 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 from 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 have also guided recently that they will present new data from the ORION 3 Phase II open label extension study in the next 2 weeks and then more data from other ORION trials later in May.

Of course, we will 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-AAT02, ALN-HBV02 and ALN-AGT, our ESC plus programs during the course of the year. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Christine Lindenboom -- Vice President of Investor Relations and Corporate Communications

Thank you, Yvonne. Operator, we'll now open the call for questions. To 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.

Questions and Answers:

Operator

(Operator Instructions) We will now take our first question from Maury Raycroft of Jefferies. Please go ahead.

Maury Raycroft -- Jefferies -- Analyst

Hi, everyone. Good morning and congrats on the update today. First question is just if you could provide any new perspective gained by the prescriber mix of 55% cardiologists and 35% neurologists and for the types of patients you're getting under treatment, are there any trends you can discuss based on that for ONPATTRO?

John Maraganore, PhD -- Chief Executive Officer

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

Barry Greene -- President

Yes. Hey 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 as one disease -- and as a multi-system disease. The history of being either a polyneuropathy or cardiomyopathy is moving by us and we now see that this is a mixed phenotypes disease. Importantly, cardiologists have the tools to recognize ATTR amyloidosis, not just hereditary, but wild-type, and a significant number of patients in their heart failure clinics in fact have amyloidosis. So awareness is raising the tools are out there, so many of these patients pass by cardiology and again, as we highlighted, most of these patients out there with hereditary ATTR amyloidosis have a mixed phenotype including polyneuropathy which is a perfect for ONPATTRO.

Maury Raycroft -- Jefferies -- Analyst

Great, thank you very much.

Operator

Thank you. We will now take our next question from Ritu Baral of Cowen. Please go ahead.

Ritu Baral -- Cowen -- Analyst

Hey guys, thanks for taking the question. Mine is on powering assumptions around APOLLO-B and HELIOS-B and maybe focus on APOLLO-B, that's closer, but where, 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 timeline estimates at this point for both these trials? Thanks.

John Maraganore, PhD -- Chief Executive Officer

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 announced the start of those studies. So some of the details you may be looking for are premature, but Akshay, maybe you can provide some color?

Akshay Vaishnaw, MD, PhD -- President, Research and 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 6-minute walk distance data. We also have our own experience from enrolling the ENDEAVOR study and the placebo arm and how that behaved. And then of course, there is the experience from ATTR-ACT itself, which is now published and we can analyze for both the natural history of the 6-minute walk distance from the placebo arm there as well as the impact of tafamidis. Given the totality of that data, I think 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 outcomes with 6-minute walk distance. As John said, a lot more detail to follow, the study kicks off mid-year, APOLLO-B, and as it gets going we will give you more idea of enrollment timelines and so forth, but as noted this morning, we anticipate hopefully approval and label changes in the '21, '22 timeframe, 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 (inaudible) there.

Ritu Baral -- Cowen -- Analyst

Is it fair to say the APOLLO sub-study is more important than the ENDEAVOR data that you generate from of revusiran?

Barry Greene -- President

Yes, I think this, the APOLLO cardiac sub population data are very helpful. We didn't measure 6-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 going to be very helpful as well, Ritu.

Ritu Baral -- Cowen -- Analyst

Got it. Thanks for taking my questions.

Operator

Thank you. Our next question comes from Alethia Young of Cantor Fitzgerald. Please go ahead.

Alethia Young -- Cantor Fitzgerald -- Analyst

Hey guys, thanks for taking my question and congrats on the quarter. Sorry, I'm losing my voice. 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 then do you think there is a read to be had or something to think about in the United States around what that may mean as tafamidis is likely to be approved in the United States later this year? Thanks.

John Maraganore, PhD -- Chief Executive Officer

Sure. Barry, do you want to 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 (ph) stage 1 and as patients progress while on stabilizer and we know that while stabilizers slow the progression of disease, we're not seeing halting the reversal in majority of patients, patients continue to progress and it is a physicians' choice at this point in recognizing progression and understanding where 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 to ONPATTRO.

Akshay Vaishnaw, MD, PhD -- President, Research and Development

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

Operator

Thank you. Our next question comes from Paul Matteis of Stifel. Please go ahead.

Paul Matteis -- Stifel -- Analyst

Great, thanks so much and 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 the drug, do you remain confident that you're going to be able to keep a tight band around the US prices you are diversifying to more countries? Thanks.

John Maraganore, PhD -- Chief Executive Officer

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

Barry Greene -- President

Okay. Yes, thanks, Paul. So in terms of start forms, yes, over 80% of start forms result in patients getting drug, it's probably about -- is between 80% and 90% at this point. So that's working very, very favorable and we continue to improve the time from start form to patients getting on drug under five weeks; many patients in two to three weeks. So that's really progressing well. In terms of Europe, our goal is to keeping it entirely a very, very tight vial price band around the world. Of course, the per patient per year costs will vary depending on weight, but our goal is to keep a very tight vial price.

John Maraganore, PhD -- Chief Executive Officer

It is John, I would just add one piece of color of Paul that Barry knows and we're sharing, which is we actually see the time from start form to the start of infusion to be quicker with -- 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 the time period appears to be quicker for the non-EAP patients actually.

Paul Matteis -- Stifel -- Analyst

Thanks for the color, John.

John Maraganore, PhD -- Chief Executive Officer

Thank you.

Operator

Our next question comes from Vincent Chen of Bernstein. Please go ahead.

Vincent Chen -- Bernstein -- Analyst

Thanks for taking the question. I saw you comment briefly on the competitive dynamics that you've seen in the TTR space with respect to ONPATTRO and TEGSEDI now that they are on market in the US, have you seen patients switching to TEGSEDI or go from TEGSEDI to ONPATTRO and any other color you could provide there would be quite helpful?

John Maraganore, PhD -- Chief Executive Officer

Well again Barry should comment. I think in general, as we reflect on the competitive landscape, there is now obviously TEGSEDI approved in the US and Europe. And there's also a large expanded access program for tafamidis in the US 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 and what we're seeing with 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 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 are seeing more patients flowing -- patients with polyneuropathy clearly following to ONPATTRO.

John Maraganore, PhD -- Chief Executive Officer

Including patients that were previously on TEGSEDI.

Barry Greene -- President

Correct.

Vincent Chen -- Bernstein -- Analyst

Thank you.

Operator

Our next question will come from Gena Wang of Barclays. Please go ahead.

Gena Wang -- Barclays Bank -- Analyst

Thank you for taking my questions. So I also had one regarding the Start Form. So when we look at the non-EAP patients this quarter compared to the last quarter, it seems there is a drop if we calculate 90% of this quarter start form versus with 50% of last quarter. So, just wondering if any additional color you can provide. I know, Barry, you also mentioned that we shouldn't not just look at the start form, what additional metrics we should look at going forward?

John Maraganore, PhD -- Chief Executive Officer

Yeah. Barry, you want to handle that?

Barry Greene -- President

Yeah, Gena. So, as we highlighted the last two quarters, we believe that particularly in the United States all patients who transitioned from EAP to commercial drug by the end of this quarter by the end of Q1, we've largely achieved 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.

Akshay Vaishnaw, MD, PhD -- President, Research and Development

Yes, I would just -- 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, patients -- in some case patients that were queued up to be 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 finding side is that we are consistently seeing about 100 plus or minus new patients every quarter from Alnylam Act that are coming out with positive TTR mutations. We got a couple of thousand samples every quarter now that are being tested and we're seeing about a 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.

Gena Wang -- Barclays Bank -- Analyst

Thank you.

Operator

Our next question comes from Whitney Ijem of Guggenheim. Please go ahead.

Whitney Ijem -- Guggenheim Securities -- Analyst

Hey guys, thanks for taking the question. I'm just curious, is there any special or different outreach or patient education sort of targeting the mixed phenotypes populations versus the neuropathy population?

John Maraganore, PhD -- Chief Executive Officer

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

Barry Greene -- President

Yeah, Whitney that's a very good question. So we have broad patient education across healthcare 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 Portuguese descent with special programs there and we're piloting a number of programs for the V122I patients, those of African -- or Western African descent. That is a patient group that requires a 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, (ph) the other most prevalent mutations are heavily Appalachia driven. So we've got programs there. So we've got broad programs across all mutations, but were appropriate specific programs targeting specific people of certain mutations.

Operator

We will now take our next question from David Lebowitz of Morgan Stanley. Please go ahead.

David Lebowitz -- Morgan Stanley -- Analyst

Thank you very much for taking my question. I guess, to this point has the preliminary presence of Pfizer, with respect to tafamidis had a positive impact. How has it affected in the cardiomyopathy space with respect to I guess affecting ONPATTRO?

John Maraganore, PhD -- Chief Executive Officer

Barry, do you want to handle that?

Barry Greene -- President

Yeah, David it's a great question and we highlighted this in the call. The issue, as we think about ATTR amyloidosis over the next several years, is not who has which part of the pie. It is identifying patients early, getting them in appropriate diagnosis and getting them on the right therapy. The longer -- the earlier we can diagnose patients the better opportunity we have to have a 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 polyneuropathy, we believe the data are very clear on ONPATTRO being a very good choice for those patients.

John Maraganore, PhD -- Chief Executive Officer

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 and 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 -- 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

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

David Lebowitz -- Morgan Stanley -- Analyst

Thanks for taking the question.

Operator

Our next question comes from Ed Tenthoff of Piper Jaffray. Please go ahead.

Edward Tenthoff -- Piper Jaffray -- Analyst

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

John Maraganore, PhD -- Chief Executive Officer

Yeah, Manmeet do you want to, you want to provide?

Manmeet S. Soni -- Chief Financial Officer

Yeah. As we've discussed right earlier majority of the revenue came from the United States, right. Currently, I think we are not providing any further color based on the competitive reasons.

John Maraganore, PhD -- Chief Executive Officer

Yeah, for competitive reasons, Ed, we're going to -- 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 US, but Europe is strong. We're very pleased with Europe.

Edward Tenthoff -- Piper Jaffray -- Analyst

Excellent. Thank you and again congrats on good launch.

John Maraganore, PhD -- Chief Executive Officer

Sure, thank you.

Operator

Our next question will come from Anupam Rama of JP Morgan. Please go ahead.

Anupam Rama -- JP Morgan Chase & Co -- Analyst

Hey, guys. Thanks so much for taking the questions and 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 US, how do you think about maximizing enrollment here in the US for the cardiomyopathy population? Thanks so much.

John Maraganore, PhD -- Chief Executive Officer

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 expand access sites are full, largely driven by better recognition of the wild-type population. In fact what many of the cardiologists that are amyloidosis experts are saying is that about 15% of patients with heart failure with preserved ejection fraction are driven by ATTR amyloidosis and obviously most of those are wild-type. So the EAPs rapidly accrued and we see that as a very good sign we you think sign as we think about cardiac manifestations enrolling our trials both hereditary and ATTR, the number wild-type patients seems to be increasing dramatically.

John Maraganore, PhD -- Chief Executive Officer

And anything to add on the clinical trial side.

Akshay Vaishnaw, MD, PhD -- President, Research and Development

Yeah, I mean I just following up on Barry's comments, what's 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, the Pfizer seems to be saturated currently. So, you know, we've launched APOLLO-B, the majority of patients in APOLLO-B will be wild-type much housing ATTR-ACT with the Pfizer tafamidis study and we are confident that due to the prevalence and the need for access to therapies for these folks will be enrolling in the US, in Europe and elsewhere. And so, we will supply more details on timelines 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. Please go ahead.

Alan Carr -- Needham & Company -- Analyst

Hi, thanks for taking my questions. (inaudible) 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? Can you go over a bit more about-you have a slide on givosiran and the patient population, I'm wondering if can give us any more resolution on how many patients specifically have been identified there? Thanks.

John Maraganore, PhD -- Chief Executive Officer

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 a very complicated process for some patients. As institutions are getting more comfortable with the access and as we highlight our call, we had outstanding access and we've really partnered with payers in the United States and now across the world, the institutions are not having a rough time getting reimbursed for purchasing of vials and 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 that 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 they 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 are seeing outside the hub.

Alan Carr -- Needham & Company -- Analyst

To what extent is that growing? Is that stable or do you think that'll keep expanding -- that number, the 25%?

Akshay Vaishnaw, MD, PhD -- President, Research and Development

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

John Maraganore, PhD -- Chief Executive Officer

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 is about 1,000 patients that have recurrent attacks and about 5,000 that are risk at attack. These are patients that physicians report under their care and of course as we get closer to launch, we'll get more granular on how many patients we see attractable for givosiran.

Akshay Vaishnaw, MD, PhD -- President, Research and Development

Yeah, I'll just add that we have very active patient --. Go ahead, Alan. Sorry.

Alan Carr -- Needham & Company -- Analyst

I'll let you finish.

Akshay Vaishnaw, MD, PhD -- President, Research and Development

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

Alan Carr -- Needham & Company -- Analyst

All right. Thanks for taking my questions.

Akshay Vaishnaw, MD, PhD -- President, Research and Development

Thank you.

Operator

Our next question comes from Mani Foroohar of SVB Leerink. Please go ahead.

Mani Foroohar -- SVB Leerink -- Analyst

Hey guys, thanks taking my question and congrats on the quarter. A couple of little ones quickly from me. You said gross to net in the US is in the mid 20s, correct?

Manmeet S. Soni -- Chief Financial Officer

The global one was mid 20s, that's what we said on the call, Mani.

Mani Foroohar -- SVB Leerink -- Analyst

Okay. With more VBAs coming on, something like 10 of them on board now, I presume some element of that is an accounting for potential impact of VBAs. To help give us a feel of 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 from these patients -- for these patients?

Manmeet S. Soni -- Chief Financial Officer

So, Mani let me start with how we account to give a little bit color on, 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 have already reserved. When we book revenues, we proportionately book a reserve for them. So every quarter we true up our reserves if needed, if we see a change in our estimate. Currently, I would say we are -- on the US side, we are in low 20s as a GTN which will provide you color, which will include -- which includes even the VBA impact as we had guided, previously right. US was always in low 20s and combined global is in mid 20s. Does that help you provide both answers on the VBA and the overall split off GTN?

Mani Foroohar -- SVB Leerink -- Analyst

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

John Maraganore, PhD -- Chief Executive Officer

Yeah, Akshay?

Akshay Vaishnaw, MD, PhD -- President, Research and Development

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 and I imagine that we're going to attempt to enroll as many patients and as we can in these studies, both in US, Europe and elsewhere before the approval of tafamidis. But given the staggered approvals and reimbursement that will occur for tafamidis in US and around the world, there will still be a large pool of accessible patients for trials and so again we are confident that we can enroll studies like APOLLO-B, HELIOS-B later in the year and access these patients and as far as the timelines are concerned, more details to follow later in the year.

Barry Greene -- President

Yes, actually 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 tafamidis approval. So, we feel very confident actually there is large population here and we'll be able to enroll the studies fairly rapidly.

Mani Foroohar -- SVB Leerink -- Analyst

Great and thanks for taking my questions. Congrats again.

John Maraganore, PhD -- Chief Executive Officer

Thanks, Mani.

Operator

Thank you. Our final question from today's question-and-answer session will come from Terence Flynn of Goldman Sachs. Please go ahead.

Gavin Scott -- Goldman Sachs -- Analyst

This is Gavin on for Terence. Thanks for taking the question. I apologize if you answered this already, but we're just curious on the percentage of patients identified in Alnylam Act. How many of those transition ultimately to the hub and start therapy? And then any color on in home infusion versus the hospital setting would be great? Thank you.

John Maraganore, PhD -- Chief Executive Officer

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 -- we don't use that information to, you know give our -- 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 the physician diagnosis of patient and then observers 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 question?

Barry Greene -- President

Yeah, just a little bit more to make the point. Alnylam Act is one of the genetic testing services out there. There are other genetic testing services as well as physicians using commercial insurance to genetically test. So it really represents a sampling of the increased genetic testing that's going on out there and again as John highlighted, overall improvement 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've highlighted this in the previous quarter. It's been interesting that most patients actually are reporting, this is anecdotal, but reporting back through our patient hub that they are enjoying their local infusion centers and we've actually had patients who went to home infusion and went back to 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, PhD -- Chief Executive Officer

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.

Duration: 61 minutes

Call participants:

Christine Lindenboom -- Vice President of Investor Relations and Corporate Communications

John Maraganore, PhD -- Chief Executive Officer

Akshay Vaishnaw, MD, PhD -- President, Research and Development

Barry Greene -- President

Manmeet S. Soni -- Chief Financial Officer

Yvonne Greenstreet, MBChB, MBA -- Chief Operating Officer

Maury Raycroft -- Jefferies -- Analyst

Ritu Baral -- Cowen -- Analyst

Alethia Young -- Cantor Fitzgerald -- Analyst

Paul Matteis -- Stifel -- Analyst

Vincent Chen -- Bernstein -- Analyst

Gena Wang -- Barclays Bank -- Analyst

Whitney Ijem -- Guggenheim Securities -- Analyst

David Lebowitz -- Morgan Stanley -- Analyst

Edward Tenthoff -- Piper Jaffray -- Analyst

Anupam Rama -- JP Morgan Chase & Co -- Analyst

Alan Carr -- Needham & Company -- Analyst

Mani Foroohar -- SVB Leerink -- Analyst

Gavin Scott -- Goldman Sachs -- Analyst

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