Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals' Conference Call to discuss Second Quarter 2019 Financial Earnings. There will be a question-and-answer session to follow. Please be advised that this call is being taped at the company's request.I would now like to turn the call over to the company. Please go ahead.

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; Yvonne Greenstreet, Chief Operating Officer; and Jeff Poulton, who will assume the role of Chief Financial Officer, effective July 13. For those of you participating via conference call, the slides that are available via webcast can also be accessed by going to the Investor page of our Web site, www.alnylam.com.During today's call, as outlined in slide two, John will provide some introductory remarks and provide general context; Barry will provide an update on our commercial and medical affairs progress; Akshay will review recent clinical updates; Manmeet will review our financials; Jeff will comment on some of his perspectives and priorities as our new incoming CFO; and Yvonne will provide a brief summary of upcoming milestones before we open the call to your questions.I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by those forward-looking statements as a result of various important factors included those discussed in our most recent quarterly 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.And with that, I'll turn the call over to John.

Thanks, Christine, and thank you everyone for joining the call this morning. In the second quarter of 2019, we continued strong execution across both our commercial and R&D objectives. Barry will get into the details on our commercial and medical affairs in progress, but in a high level, as we approach the one-year anniversary of that ONPATTRO launch and approval, we continue to be very pleased with the ONPATTRO uptake, with over 500 patients on commercial drug at the end of the second quarter. Importantly, we continue to see opportunity for steady and continued revenue growth in the quarters and years to come driven by new patient finding, global expansion, and near to mid-term evidenced generation activities.Moreover, advancement of Phase III development activities for our patisiran and Vutrisiran into the entirety of hereditary and wild-type ATTR amyloidosis is expected to expand our opportunity significantly. And of course, our revenue growth is not just about our ATTR program alone since we have a broader portfolio of late-stage assets, including a program in registration. We also made excellent progress against our R&D goals. Akshay will cover this in more detail, but with the positive Givosiran Phase III results and completed regulatory submissions, we believe we're poised for approvals in the U.S. and Europe, and launches of our second product early next year, assuming positive regulatory reviews.Just yesterday, we announced that the FDA has granted Givosiran a priority review with the February 4 PDUFA date, and no need for an ad com [ph]. In addition, we're now positioned for two additional Phase III program readouts by the end of the year, starting with Inclisiran, our [indiscernible] licensed to The Medicines Company will read out in the next few weeks, and then Lumasiran, our wholly-owned primary hyperoxaluria RNAi therapeutic program. And to enable longer-term…

Thanks, John, and good morning everyone. I'll begin by reviewing ONPATTRO's commercial performance in the second quarter. We've achieved $38.2 million in global ONPATTRO net product revenues in the second quarter. As in the first two-and-a-half quarters of launch, the majority of revenues come from U.S. sales and we're now pleased for the first time to provide more color on the geographic split with $10 million from the EU and $28.2 million coming from the United States. As of June 30, over 500 patients worldwide were receiving commercial ONPATTRO treatment.We're quite pleased with the overall growth and continued global demand this quarter even with increasing product options from recent market entrants and the availability of investigational drugs through expanded access programs, investigational clinical trials. As a reminder, there've been three sources of patients that are in our launch today, patients from our Expanded Access Program or EAP, patients who are known to sites and new de novo patients. In the first couple of quarters of launch, we effectively capture the first two sources and we're now very much into the de novo patient pool particularly in the United States.Now, we put patients in clinical trials in our global EAP that number increase to greater than 750 patients worldwide who are now being treated with that. We believe that we're on track to have approximately 1000 patients ONPATTRO across commercial clinical studies and our expanded access program by the year-end 2019, a very exciting milestone in our overall efforts.Let me now turn to the U.S. market dynamics. On the physician front, we're seeing continued growth in both the number of new prescribers as well as repeat prescribers. In fact, over 50% of the prescriptions received in second quarter came from new prescribers. We believe new prescribers will continue to increase the…

Thanks Barry, and good morning everyone. In the interest of time, I'm going to read my prepared remarks, our multiple Phase III clinical programs. We will have a richer opportunity to touch on our broader pipeline later in the year and an R&D day as John mentioned earlier. Let me start with Fitusiran, which is the unbranded name from ONPATTRO. As a peripheral nerve society meeting in June, we presented a new 12 month interim results from the ongoing global open label extension study of Fitusiran showed sustained improvement in neuropathy impairment and quality of life for patients after 13 months of treatment.These policy new results also showed the importance of treating patients early as possible to minimize advancement of disease. The newly presented data also in our view, showed what we believe to be a continued and favorable differentiation profile for Fitusiran including results in patients who experience progression on to families prior to initiating treatment with Fitusiran with the caveat Of course, that there has been no head-to-head studies comparing Fitusiran with abrasions.We now look forward to advancing the evaluation of Fitusiran in the APOLLO-B Phase III aimed at expanding the ONPATTRO label to include Cardiomyopathy include hereditary and wild-type ATTR amyloidosis market. We're on track to start this study later this year and [indiscernible] we will seek regulatory support for expanded label for Fitusiran in the 21 to 22 timeframe. As you know, we're also advancing Vutrisiran, which is delivered by quarterly subcutaneous injection and is also a development for ATTR Amyloidosis. While we've been enrolling hATTR patients with polyneuropathy in the ongoing HELIOS-A Phase III study with Vutrisiran.We're pleased to announce today that we have obtained regulatory alignment on the design of HELIOS-B. HELIOS-B will be a Phase III study of Vutrisiran and inherited wild-type ATTR…

Thanks, Akshay, and good morning everyone. Please refer to our press release issued earlier today for a summary of our financial results for the second quarter of 2019. I would like to take this opportunity to provide a brief overview of three key areas. Our cash position, our second quarter 2019 results and our updated 2019 financial guidance.Let me start with our cash balance. We ended the second quarter with a strong balance sheet of approximately $1.97 billion in cash, cash equivalents, marketable debt securities and restricted investments. Our cash balance includes proceeds of $800 million received in the second quarter attributed to our Regeneron collaboration.Moving now to our revenues, total second quarter revenues were $44.7 million. We recorded $38.2 million of ONPATTRO net product global revenue during the second quarter of 2019, which represents 45% growth from first quarter net product global revenues of $26.3 million. Our global gross to net RGTN percentage during the second quarter of 2019 was in mid 20s.Cost of Goods Sold was $4.3 million for the second quarter, which is approximately 11% as a percentage of net product revenues. We recognize $6.5 million of collaboration revenue during the second quarter of 2019 as compared to $29.9 million during the second quarter of 2018. As expected, the decrease in collaboration revenues is primarily due to a decrease in reimbursement collectivities in connection with our collaboration agreements with Sanofi Genzyme and [indiscernible].Moving to other operating costs and expenses, GAAP R&D expenses $163.9 million for the second quarter of 2019 as compared $137.6 million for the second quarter of 2018. Non-GAAP R&D expenses were $148.6 million, as compared to $126 million for the second quarter of 2018. The increase in non-GAAP R&D expenses was due to increase license fees related to our collaboration agreement with Regeneron and…

Thanks, Manmeet, and thanks for your help in the transition. I'd like to make just a few brief remarks as I to formally assume the CFO role next week. I'm very excited to be joining Alnylam at this stage in its growth as it establishes its global commercial operations. I'm really impressed compressed with Alnylam's technology and team and the company's potential to make a difference in patients' lives with this new frontier of medicine.Strong believe that with its first commercial product today. Prospects for many more commercial products in the coming years beginning 2020 a deep clinical pipeline and robust organic product engine for the future Alnylam is positioned to emerge as a top tier biopharmaceutical company.Consistent with John's earlier comments the key focus for me will be working with my new colleagues to create a roadmap the financial self sustainability is Alnylam becomes a successful global commercial organization with significant top line growth fueled by a deep R&D pipeline. I look forward to this challenge and communicating our plans in the future.With that, I'll now turn the call over to Yvonne to review our goals for the remainder of the year.

Thanks, Jeff, and welcome to the team. We couldn't be happier to have you on board. I'm really thrilled with the progress we've made in 2019 so far, but we still have a number of exciting milestones to look forward to the remainder of the year. The starters we plan to continue our global commercialization of ONPATTRO including launching in Japan and other countries. We also look forward to initiating the APOLLO-b Phase III study in mid 2019 aimed at securing an expanded commercial label for Patisiran to include wild-type and hereditary cardiac amyloidosis.With Vutrisiran, we plan to continue enrolling the HELIOS-A Phase III trial throughout the year and expect to initiate HELIOS-B an outcome study in wild-type and hereditary ATTR cardiac amyloidosis patients in late 2019. With Givosiran we plan on having additional data from ENVISION presented at the ICPP meeting in early September.Turning to the [indiscernible] with enrollment in the ILLUMINATE A Phase III study now complete we plan to report top line results from that study in late 2019. We will also continue enrolling pediatric patients in ILLUMINATE-B and plan to start the ILLUMINATE-C study in PH1 patients with severe renal impairments later in 2019.With Inclisiran, we expect our partners at the [indiscernible] Company to report top line results from the ORION is 9, 10 and 11 studies beginning later this quarter and assuming positive data to submit an NDA for inclisiran by the end of the year. And 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 rest of the year as they occur. In particular, you should expect data readouts from a number of our early and mid-stage clinical programs.Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Yvonne. Operator, we will now open the call for questions 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 question.

Thank you. [Operator Instructions] Our first question is from Alethia Young from Cantor Fitzgerald.

Hey, guys. Thanks for taking my question. And congrats on the progress as you continue this launch. Just one for me maybe, and I have a little bit of a follow-on too, but can you just talk a little bit about Tafamidis [ph] and what you're seeing and hearing from how doctors make decisions, like 50% of your doc talk cardios? And then just kind of tagging on to that, can you talk a little bit more about how the presence of both the Alnylam's drug and the Pfizer drug have driven diagnosis? Can you give any quantitative metrics or is there any other color you can give us around that? Thanks.

Right. Thanks, Alethia. Barry, you want to handle this?

Yes, so Alethia, on the emerging landscape it's too early to give specifics around increased diagnosis and increased speed of diagnosis, other than the color that we are gaining more and more new prescribers every quarter, which is a sign that new people are learning about the disease, seeing the disease, and then are comfortable diagnosing and holding on to their patient. So anecdotally we're definitely seeing increase of awareness. And having multiple players at every cardiology congress educate that this is the disease of ATTR amyloidosis has certainly been helpful for patients in raising awareness.Now, on Tafamidis [ph] specifically again, it's too early in their launch to understand the particular dynamics. What our market research is telling us is that physicians who understand hereditary ATTR amyloidosis even in those mixed phenotype with polyneuropathy; ONPATTRO is the drug of choice, particularly in the United States. And then for those that are wild-type, clearly Tafamidis is a choice. In Europe, where Tafamidis has been present for a number of years, physicians understand the progression of Tafamidis, and we're seeing a number of patients that are switched, hereditary patients from Tafamidis on to ONPATTRO in the major markets where Tafamidis has been used.So does that answer your question, Alethia?

Yes, thanks.

Great, thank you.

We'll go next to Gena Wang from Barclays.

Thank you for taking my questions. First one also regarding the ONPATTRO commercial question, for all the 500 patients on commercial drugs, how many were from ex-U.S.? And also following Alethia's question, 49% demand from cardiologists. How is the payer coverage for these patients?

Great. Let me quickly address the first one and then I'll hand it over to Barry for the second one. We're not breaking out patient numbers by region. We are, for the first time, breaking out revenues, and we're reporting $28.2 million in the U.S. and $10 million in Rest of World, so EMEA in this case. So that's unfortunately we're going to limit it for really competitive reasons.Barry, do you want to answer the second question?

Yes, in terms of U.S. payer coverage, which we reported, I mean we remarkably have external reports saying that 98% of our patients who prescribed ONPATTRO will be reimbursed ONPATTRO is actually quite remarkable. We have not to date had a patient rejected by a payer.

And just to add to that, Gena, we're of the very strong belief that the proactive and high quality approach that we took in engaging with payers as we introduced ONPATTRO to the market, and continue to have discussions with payers, even to this day we're on value-based agreements. These are all elements of what has, I think, been a very successful market asset story for this important medicine in the U.S. market.

Thank you.

And moving on, our next question will come from Whitney Ijem from Guggenheim.

Hey, guys, thanks for taking the questions. The first one I guess I'm going to ask them on Givosiran. So the first one, in terms of the greater than $500 million for Givosiran opportunity, any color you can give us on what that assumes in terms of use in sporadic versus recurrent patients, either kind of in terms of how the drug will be used or relative breakdown in patients in either bucket?

Sure, great question. And maybe just for the benefit of others on the call, obviously the recurring patient population that we have estimated to be approximately a thousand patients in the U.S. and Europe, and there are estimated to be 5,000 patients with sporadic disease defined as three attached or less. Keep in mind that any patient that experiences an attack can experience an attack that can be life threatening. So it doesn't lessen the importance of their disease if they are sporadic patients. But with that, Barry, you want to comment a little bit how we get to the beliefs that around [indiscernible] this $500 million opportunity?

Yes. And, John, you outlined it very, very well. As we have made ultra rare orphan diseases where patient journeys can last 13 to 15 years, and patient show up with three to four unnecessary surgery or missed diagnosed by about a dozen physicians in their journey, we believe that there are probably many more patients than the number that John highlighted out there. As interesting fact, as little as three years, the [indiscernible] consortium which has been studying this disease for 20 years, did not have the benefit of an industry partner do natural history, and by working with them, we have all now understood that two-thirds of patients experienced debilitating chronic pain between [indiscernible]. So as John said, it's not just about attack rate, number of attack, it's about the overall devastating nature of the disease. So when you take the 1000 and 5000 likely growing and multiply that by an orphan price point, we think there is a very significant opportunity.Now, of course, we are going to take the same proactive nature driven by our patient access philosophy with [indiscernible] taking with ONPATTRO will be very proactive with payers to ensuring we put the right value-based agreements in place so that patients in the United States and frankly around the world have access to an important medicine for the devastating disease.

Great. And one quick follow-up on ONPATTRO, any color you can give on the relative ex-U.S. price versus U.S. at this point?

Yes, Barry, you want to comment?

Thanks Whitney. As we have highlighted on previous calls, we've held the price span very, very tight on a per vial basis. And then of course, price varies because it is weigh-based dosing. So in countries with bigger people, it's more dollars per patient per year and smaller people it's less. But the vial price is very, very tight.

Thanks.

Thank you, Whitney.

We will go to next Anupam Rama from JPMorgan.

Hey, guys, thank you so much for taking the question, and congratulations on the all the progress here.

Thank you.

In the U.S. like you have outlined here you are getting about 50% of the ONPATTRO demand coming from cardiologists. Wondering if you could provide any color on some of the OUS prescribing trends, and then maybe any color on the gating factors to starting HELIOS-B for Vutrisiran? Thanks so much.

Right. So let's have Barry talk a little bit about the ex-U.S. trends on prescribers. And then, Akshay, you can handle the next -- the second question. So, Barry?

Yes, thanks Anupam. As you have highlighted the -- and we said about 50% in U.S. our prescribers are cardiologist. Interestingly enough the number of additional specialties including primary care physicians, nurse practitioners is growing. A real sign that as healthcare providers become familiar with the disease, see a patient, they understand how to diagnose and clearly what to prescribe at least in our case with ONPATTRO. Ex-U.S., it really depends on the country. There are some countries like France that are highly coordinated with centers. And they are named centers were neurologist or cardiologist takes care of those patients. And then in places like Germany, it's primarily neurology driven. So, it really depends ex-U.S. on the country and how the centers are established.Turning to Japan, which we mentioned earlier, we believe that the primary prescribers at least in initial launch in Japan will be neurologists because those are the folks that manage the overall disease symptomatology. Now, of course, dynamic -- back to United Sates really the V122I patient population, so in parts of the world where patients of Western African descent, we probably will see bigger uptake in cardiology at least in the hereditary space. So it's following up.

Anupam, following up on the HELIOS-B question, essentially the main gating factor is getting aligned with -- excuse me, getting aligned with regulation agencies globally. And I think we are in great shape now as we reported this morning that we are looking forward to vigorous thought from that program in the second half of this year now. And as you know, we know all details [indiscernible] globally, and we are excited to start enrolling [indiscernible] type patients as well of course in that study.

Does that answer your question?

Yes, great. Thank you for taking my question.

Thank you.

Ritu Baral from Cowen has our next question.

Good morning, everyone. Thanks for taking my question. I have already gotten a few emails this morning on some concerns around U.S. specific growth. I think the assumption is that the Q1 number of Q1 revenue number of 26.3 was largely 95% driven by U.S. understanding you don't want to comment on patient numbers. Can you give us a little more comfort around the U.S. growth rate. Can you comment on how things like HELIOS-A enrollment. How much of an impact that's having on the launch and things like persistence a little more color on persistence of treatment especially given the steroid-free treatment?

Yes, Ritu. First of all I mean the concern about U.S. growth is completely wrong. Actually we've had steady growth in the U.S. and in Europe. Manmeet if you want to comment more specifically to provide some more for that.

Sure John. So Ritu as John mentioned we had consistent growth that is global revenues grew over approximately 45% from Q1 to Q2, but if I split out U.S. and Europe, U.S. was growing even higher. U.S. was growing at a 50% rate from Q1 to Q2. So to give you numbers which were not there and you would see them in the 10-Q filing when you file later today this evening or tomorrow for U.S. last quarter, Q1 was approximately $18.8 million and this quarter is $28 million. So that shows a pretty strong growth of 50% in Europe. We were last quarter at $7.5 million and now this quarter is $10 million, so that also shows a 33% growth but as you know, there are in Europe the growth comes primarily as we launched new countries and we get the final pricing and investment finalized. So as Barry and John mentioned, we are showing the steady and continued growth in our revenue and there is no concern on the both U.S., Europe and global revenue book. I just want to give on, sorry.

Yes, go ahead.

No, Barry if there were some more questions on persistence on adherence.

Yes, Manmeet I think you covered the growth incredible and just to emphasize we are seeing continuous and steady growth in the United States and believe it will continue maybe even a particular uptick in the out quarters because of awareness. In Europe as Manmeet highlighted, we're in countries where launched we continue to see growth and a number of new countries will come on late this year into 2020 and then Japan is coming on late this year and into 2020. So we do see new market entrants and then within each country, steady growth within countries. So that dynamic will continue. You asked about continuation, we see tremendous continuation of patients on ONPATTRO anecdotally we hear tremendous reports about physician experience and patient experience and the adherence rate remains very, very high. It's well way early into our launch to give specific numbers but it remains very high.

And just to follow-up on that Ritu, the Apollo study itself the very low dropout rate that the high conversion rate to the only persistence in the early, there is all evidence that the risk benefit is being well tolerated and patients are staying on drugs. We know from early patients who've been on drugs from 2013, 2014 onwards actually from the original Phase II and then the Phase III was five years into it. So this Barry comment I don't think applies and we have very good evidence accumulating now but patients are tolerating the steroid progression as well which by the way over the years as the dose has been considerably reduced as well.

Got it.

Did that answered your question, Ritu?

The impact of HELIOS-A on that as well on the launch enrollment of HELIOS-A on the launch.

Yes, I mean look I mean as we said from the beginning obviously HELIOS-A patients are potential ONPATTRO patients. We know that and there for every patient that goes to the HELIOS-A, they could be a commercial patient of course. We understand that but we're investing in that program for the benefit of having a new product offering for patients in the future in the not too distant future. That we think will continue to drive growth of the franchise. So it is obviously a very eyes wide open type of decision to do that. Now we are importantly expanding just this past quarter significantly to sites outside the U.S. And we're going to see the benefit of that in countries and markets where there is no reimbursement at the present time. So that will obviously balloon out any affect that might occur on the commercial ONPATTRO growth from clinical studies.

Got it. Super helpful. And that was already three questions. So I'll get back in the queue before Josh comes for me.

Great, Ritu. Thank you. It's your lucky day.

We will take our next question from Paul Matteis from Stifel.

Hi, this is Ned on for Paul, thanks for taking the question, maybe just a quick one on the 1,000 patients by year-end guidance. How are you getting confident in that number in terms of the de novo patient growth rate that you're seeing sequentially and then quick to clarify does that 1000 is that commercial drug or is that include patients and expanded access programs?

Yes, it includes patients in our expanded access program and also in our ongoing open label study. So we do believe that we're on track to achieve that. We're roughly at this point over 750 patients within that universe. And we're very much on track to hit that over 1000 approximately 1000 patient number by the end of the year. So that's encouraging.

Great. And then the de novo patient growth rate just I don't know if you can provide much detail on that subsegment?

Well I mean Barry can comment as well but that's when we talk about growth. Let's be clear we understand the buckets of growth. One is new patient finding, de novo patients being identified and you could look Alnylam Act, we are getting about a couple thousand samples per quarter and we're finding roughly 150 or so patients per quarter.And that's been very, very steady now for over a year of that program. Now those aren't necessarily ONPATTRO patients this is just a number that you can look at as a surrogate marker if you will or patients finding, the patient finding is ongoing and as Barry said earlier, it's not just Alnylam Act, it's other testing programs that are out there some funded by companies, some that are not.So there really is a significant amount of new patient finding happening. And by the way that's just in the U.S. right in Canada as well. So it doesn't reflect new patient finding around the world which is also getting better. So that's one source of growth. The second important source of growth is our global expansion and also in Europe is the expansion of market access on a country-by-country basis and that's a very important source of growth. Barry commented earlier around Japan which we believe by the end of 2020 will be our second largest market. And that's going to be an important source of growth in addition to what's going on in the U.S. and what's going on in Europe and the rest of the world.And the final source of growth which I think it points to the -- what we believe to be a remarkable profile of ONPATTRO is the evidence generation activities that our medical affairs team and for longer term, our clinical development team are engaged in to really strengthen the differentiation of ONPATTRO to help patients understand or physicians understand the best time to use ONPATTRO for their patients to help highlight some of the issues that may exist with other therapies that are out there like disease progression where ONPATTRO can be very helpful. Those types of activities will have both near-term and mid-term implications for growth. So let me pause there Barry anything else to add.

No, you covered it completely.

Great, thank you.

Bravo, thank you guys.

Next we'll go to Vincent Chen from Bernstein.

Congratulations on progress and thanks for taking a question. I was wondering if you could provide a little more color on the folks identified in Alnylam Act with TTR amyloidosis and doses on ONPATTRO, what are the reasons for this recognizing it's a third-party program but you're certainly very plugged in with the TTR community. Could you give us a sense for how these patients breakout. What portion of mutations associate with neuropathy or mix disease versus a more pure cardiomyopathy phenotype or some ending up in trials et cetera or would you expect that many of them do eventually work their way onto ONPATTRO over time and as a quick corollary. How does the pace of new start forms look in the second quarter?

Yes, so maybe just a couple of quick comments and then I'll hand it over to Barry. We don't have a lot of visibility on specific patients in Alnylam Act and that's by design. This is a program that's aimed to help physicians diagnose their patients. It's not anything other than that. And obviously we believe that by improving medical education, improving patient diagnosis that if ONPATTRO is identified as the right choice for treatment for these patients by their physicians, then that will follow. So that has been the philosophy, we just don't have a lot of color, other than that in terms of Alnylam Act. So that's the answer to that one. And then on Start Forms, as we said, last quarter, we moved away from reporting Start Forms as is common in drug launches, because of the fact that it's an emphasize measure of patients, we have patients in the U.S. that come into contact with therapy outside of Start Forms. And of course, our forms are a U.S. specific measure to begin with. So it's not even reflecting true patient growth. The patient number is what you should focus on and obviously revenues. Barry, anything else to add what I just said?

No, I think you covered it well, just back to Alnylam Act. Again, just to reiterate, Alnylam Act is a free third-party generic test that we and other companies, other companies offer other tests for the benefit of patients. And just to give you some color about Vincent, what we often see is a patient will come in after a multiyear journey finally, but be diagnosed with hATTR Amyloidosis. And through genetic counseling identifies that they have this disease to their siblings, children, and others, and those people often then will visit a physician for a genetic test. So Alnylam Act really eases the burden for the benefit of patients to get these genetic tests. As John said, it's an arm's length relationship, because we're in there for the benefit of patients. Now, some patients do not yet have penetrations of disease. But we believe that by raising awareness, remember, this is not about a portion of the pie. It's growing your overall pie that will continue to benefit patients by raising awareness and speed to diagnosis.

Exactly. Thank you very much.

Next question today is from Ted Tenthoff from Piper Jaffray.

Great, thank you very much and congrats on the progress.

Thanks Ted.

Yes, really, really impressive global launch and just a comment, I love that you guys are breaking it out globally, it really gives us a sense of where the patients are coming from and the growth is coming from. So thank you for that. I'm kind of looking at the truce there. I'm really considering sort of how this market could evolve. Tell us a little bit more about where you think sort of IV versus sub-Q might be used. And maybe even if, there would be induction versus maintenance, or just give us a little bit more of a sense of sort of how you see all that playing out. Thank you.

Yes, thanks, Ted, and thanks for your comments earlier. I mean, we're extremely excited about Vutrisiran, it's a once quarterly, low dose, low volume, subcutaneous injection, that, we think is an exciting, expansion of the overall ATTR opportunity. I mean, taking a step back, when you think about this market, you think about hereditary ATTR, polyneuropathy where we are today, and then in the future expanding into cardiomyopathy of our studies are successful. And then, you think about the wild type setting. Again, with studies like APOLLO-B and HELIOS-B assuming those studies are successful; we've got a remarkable opportunity for the overall franchise for many, many years to come.And I think without getting heady, or hidy, in terms of numbers. I mean, this really is a multi-billion type of market opportunity, where Alnylam is poised to be a significant leader. So Vutrisiran really positions us with an -- with a product offering that really provides a great option for patients and HELIOS-A will bring there and the patients, you know, currently rapidly, that study is up and going and rolling, we expect that to read out in the 2122 time period, that'll be important for patients to get access to a sub-Q alternative, like Vutrisiran and then HELIOS-B, which will start after very shortly by the end of the year that really addresses the larger commercial opportunity in the wild-type and hereditary cardiology setting a very, very significant opportunity with a once quarterly subcutaneous option that we think is extremely competitive. And we've done studies to show that it's even preferred over an oral agent given once a day or you know, even less, less excitingly twice a day. So these are really opportunities for market growth and expansion for an Alnylam that is not that far away at all, and very, very exciting to look forward to. So, Barry, anything else to add to that?

No, I think you covered it well. I guess the only two things; One an interesting analog to look at is how the MS. Market developed over last 30 years. And if you think 30 years ago to today and project out the ATTR Amyloidosis mark over the next 10 to 15 years, we can see a dynamic where more prescribers are getting interested diagnosis gets much earlier the disease and patients benefit greater by an earlier diagnosis. So just in addition to what John mentioned, I see those same dynamics playing out with ATTR Amyloidosis.

Great, I appreciate all the color and to building a quick foundation on [indiscernible] so thanks so much.

Thank you. Ed.

And we'll go next to David Lebowitz from Morgan Stanley.

Thank you very much for taking my question. Could you characterize the effort it takes to transition patients that are diagnosed in the Alnylam Act program to actually being patients on drugs? And noticing that there's certainly more patients that are from the cardio and I guess, given that the drugs approved for polyneuropathy coming online for the drug? What would be driving the fact that so many cardio patients are coming on?

Sure, let's -- Barry, do you want to handle that?

Yes, I mean, I guess more broadly and just again to say that there's a number of things we're doing to increase awareness and diagnosis. Hereditary ATTR Amyloidosis is unfortunately a disease, where patients can bump into cardiologists, neurologist, other specialties who miss or miss diagnose the disease and that that dynamic continues until awareness is raised.Now specifically, cardiology front of a patient presents with cardiovascular symptoms, there are tools the cardiologists have and are using now more and more echo technetium scanning that helps point to amyloidosis and specifically ATTR Amyloidosis, which is why we see the cardiology community so interested. And then of course, there are many, many wild-type patients the segment that we're not yet penetrating commercially, we will in the future, assuming positive data, and because there's so many wild-type patients cardiology becoming more and more aware. Now importantly, we're also seeing in the neurology side more awareness of ATTR Amyloidosis hereditary human -- they are looking for the disease using the tools they have. So we see that all the positive signs of improved diagnosis and speeder diagnosis.

Right, I mean…

Yes, I mean just to build on what Barry was saying, if we look at the U.S. landscape, in many senses B12 trial is the commonest mutation. But the other important thing to bear in mind is that there's increasing awareness that a very significant proportion of those patients have neuropathy. And certainly what Barry's seen I've seen when I've spoken to doctors, is cardiologists are looking for neuropathy. They're collaborating with any colleges in multi-functional teams to fully characterize the multisystemic nation of the disease and as appropriate if they have neuropathy than to prescribe a drug like ONPATTRO. So, either buyers are absolutely right, it is a journey, the education awareness is increasing, and it's great that patients who have [indiscernible] and other mutations are getting more fully characterized. So physicians and patients understand the full burden of disease. And whereas I said were appropriate than you are offseason, certainly ONPATTRO is an important choice for them. So does that answer your question?

Thank you very much. I appreciate it.

Right, thank you. Okay, so go ahead Operator, Kim.

That's all the time we have for questions. I'll turn it back to the company for closing remarks.

Great, well, thanks everyone for joining us on the call. We're obviously very pleased with the R&D and commercial progress that we've been making. We are really excited about the company that we're building, the impact we are making on patient's lives. So with that, I look forward to updating you on our continued progress in the coming weeks and months. Have a great rest of day everybody. Bye-bye.

And that does conclude our conference today. Thank you for your participation. You may now disconnect.