Ladies and gentlemen, thank you for standing by and welcome to the Alnylam Pharmaceuticals conference call to discuss first quarter 2017 financial results. 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.

Good morning. I am Christine Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, Chief Executive Officer, Barry Greene, President, Akshay Vaishnaw, Executive Vice President of R&D and Mike Mason, Vice President of Finance and Treasurer. In addition, Yvonne Greenstreet, Executive Vice President and Chief Operating Officer is in the room and available for Q&A. For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the Investor page of our website, www.alnylam.com. During today's call, as outlined in slide two, John will provide some introductory remarks and provide some general context, Akshay will review recent clinical updates, Mike will review our financials and Barry will provide a brief summary of upcoming milestones before opening the call for your questions. Before I begin, 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 our 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. With that, I would like to turn the call over to John.

Thanks, Christine, and thank you everyone for joining us this morning. During the first quarter of 2017 and recent period, we made important progress in advancing RNAi therapeutics through clinical trials and towards the market. With 2017 promising to be a key year for company, as we read our results of our Phase 3 study of patisiran and if positive, file our first applications for regulatory approvals, advance three additional programs into Phase 3 trials and prepare to make the anticipated transition to a commercial stage company. We believe these key events put us well on track to meeting our Alnylam 2020 goals of becoming a multiproduct commercial stage company with a deep and sustainable development pipeline by the end of 2020. In my introductory remarks, I would like to provide some further context on these key 2017 events. First, starting with patisiran, an investigational RNAi therapeutic for the treatment of patients with polyneuropathy due to hereditary ATTR amyloidosis. We look forward to reporting topline data from the APOLLO Phase 3 trial in mid-2017, likely in the September timeframe. And assuming positive results, expect to submit an NDA and MAA at year-end. We are encouraged about APOLLO based on the continued promising results from our ongoing Phase 2 open label extension or OLE study of patisiran where we are seeing consistent evidence for potential halting or improvement of neuropathy progression in patients with hATTR. Now, as many of you are aware, we expect that Ionis will very soon report their topline results from their Phase 3 NEURO-TTR study of IONIS-TTRRx, an antisense program in hATTR. While we do expect this study to be generally positive confirming the TTR lowering hypothesis, there is certainly a chance for mixed or even false-negative results based on their smaller sample size, shorter study duration,…

Thanks, John, and good morning everyone. As John noted, we are very focused on the advancement of our pipeline of investigational RNAi therapeutics and in particular our late stage programs. Let's begin with our programs in hATTR amyloidosis which include patisiran and ALN- TTRsc02 This is certainly a big year for patisiran with our Phase 3 APOLLO study read out later this year in September timeframe. As John commented, we believe we have good reasons to be encouraged by the prospects of patisiran based on our Phase 2 OLE study results. At the AAN meeting last week, we presented final results from the patisiran Phase 2 OLE study. At 24 months, patisiran showed a mean decrease in the modified neuropathy impairment score or mNIS+7 of seven points, providing continued evidence that patisiran has the potential to halt or improve neuropathy progression in patients with hATTR amyloidosis. This compares favorably to an expected mean 26 to 30 point increase in mNIS+7 at 24 months estimated from analyses of historical datasets in untreated hATTR amyloidosis patients with similar baseline neuropathy impairment. At this meeting, we also presented results from a new post-hoc analysis exploring the relationship between baseline neuropathy severity and changes in mNIS+7. In this analysis, patients were grouped into tertiles according to their baseline NIS scores as shown on slide nine. Patients in all three groups showed a mean improvement in mNIS+7, including patients with the greatest degree of neurologic impairment at baseline. Specifically, patisiran administration was associated with a mean 7.4 point decrease in mNIS+7 in this group with the greatest impairment at baseline. This analysis suggests that the potential clinical effects of patisiran are observed across the full range of disease severity. Moreover, in the first post-hoc exploratory analysis of its kind, patisiran administration was found to be…

Thanks Akshay. I will be referring to slide 19 for a discussion of our first quarter 2017 financial results. We maintained a solid balance sheet ending the first quarter of 2017 with $962.2 million in cash, including restricted investments. Our GAAP revenues were $19 million in the first quarter of 2017 as compared to $7.3 million in the first quarter of 2016. Revenues for the first quarter of 2017 included $12.3 million from our alliance with Sanofi Genzyme, $6.4 million from our alliance with The Medicines Company and $0.3 million from other sources. The increase in revenues in the quarter ended March 31, 2017 as compared to the prior year period was due primarily to higher revenue from our alliance with Sanofi Genzyme. We expect net revenues from collaborators to continue to increase on a quarterly basis during the remainder of 2017 due primarily to an expected growth in revenues from Sanofi Genzyme related to increased expense reimbursement as well as the potential receipt of milestone payments under our agreements with Sanofi Genzyme and The Medicines Company. Moving to expenses. R&D expenses were $87 million in the first quarter of 2017 as compared to $96.3 million in the first quarter of 2016. The decrease in R&D expenses for the quarter ended March 31, 2017 as compared to the prior year period was due in part to a decrease in non-cash stock-based compensation expense as a result of the vesting of certain performance-based stock option awards during the first quarter of 2016 upon completion of enrollment in our APOLLO Phase 3 clinical trial for patisiran. We expect that R&D expenses will remain relatively consistent with the first quarter during the remainder of 2017 as we continue to develop our pipeline and advance our product candidates into later stage development but expect…

Thanks Mike. As you heard from John earlier, we are executing on our late stage pipeline in 2017 to achieve our Alnylam 2020 profile marking our transition from a late stage R&D company to a multiproduct commercial organization and achieving a profile rarely seen in the biopharmaceutical industry. A critical part of this transition is the expansion of our quality, medical affairs, manufacturing and commercial capabilities to support multiple planned consecutive product launches in 2018, 2019 and 2020. These efforts include building our capabilities in the United States, Canada and Western Europe for patisiran and fitusiran and then growing globally with givosiran and future products, assuming positive read outs and regulatory approvals. Let me highlight a few activities as part of this important build. First, we continue to build our quality organization in support of our overall GxP activities in preparation for preapproval inspections and of course future high quality compliance organization. Additionally, we now have an active medical affairs effort in North America and Western Europe, where our team is working on educating physicians and patient organizations on several things, including the RNAi mechanism of action, on hereditary ATTR diagnosis, on the clinical importance of thrombin generation hemophilia and other rare bleeding disorders as well as the enormous burden of disease in the acute hepatic porphyries. In our technical operations and manufacturing team, we have secured our network of contract manufacturing organizations and have completed validation of drug substance and drug product processes and batches in support of potential patisiran NDA and MAA submissions at year-end. We have also been preparing for preapproval inspections. We also continue to build out our Norton, Massachusetts drug substance facility for future drug supply. Finally, we are building out our commercial teams in North America and Western Europe with a key focus initially…

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

[Operator Instructions]. Our first question comes from Ritu Baral from Cowen and Company. Your line is open.

Good morning everyone. Thanks for taking the question. Barry, I wanted to dig in a little more on the CMC, specifically based on your slide and the comment, it looks like Alewife is going to be primarily responsible for patisiran drug supply. Can you take us through who is responsible for fill and finish? Maybe where you are on stability testing? And whether you are planning on redundant supply or just having enough inventory to address any potential issues in market supply?

That's a great question, Ritu. Barry, take it away.

Yes. Thanks Ritu. Several questions there. So let me start with patisiran and just say this, we have secured the supply chain of the raw materials, drug substance and drug product as well as fill and finish. Across that supply chain, there are multiple redundant sites, Specifically for drug substance, we have, as we mentioned, fulfilled our validation batches with a third-party manufacturer and we will be building inventory as a strategy for launch readiness. As you mentioned Alewife here in Cambridge will be our local drug product supply and again our strategy is to build inventory for launch. And then we have multiple fill and finish sites online for both U.S. and Europe. So we feel pretty good about the about patisiran. The initial strategy will mainly be security build and then over the course of launch, we will have redundant systems set up as well.

Got it.

There was also a question on stability, Barry. You want to take that.

Sorry about that. Yes, stability. So in patisiran, we run multiple stability lots and we have stability out over two years that will require a cold chain storage delivery.

Got it. And you mentioned inspections. Can you tell us which of the facilities still need inspections or which of them are GMP certified at this point?

Yes. So the CMOs we are working with have had preapproval inspections for other products. As you are probably aware, as we get closer to a positive APOLLO and filing, that's when the preapproval inspections mainly happen. And really, it's up to the agencies for where along the supply chain they want to inspect, both on CMOs and our sites as well. But we are prepared across the sites and across the supply chain for those inspections.

Great. Thanks for taking all the questions.

Great. Thanks Ritu.

And our next question comes from Alan Carr from Needham & Company. Your line is open.

Hi. Thanks for taking my questions. I wonder if you could talk about the TTR program here. If the patisiran trial reads out positive, where does TTRsc02 stand? And how quick you think you can move that forward with patisiran? And then the other question is, with respect to your commercial build, what's your thoughts on timing for sales force and that sort for thing? Thanks.

Terrific. Well, we will have Akshay answer the first question and Barry, the second. So Akshay.

Yes. Hi Alan. So with respect to the TTRsc02, as you know we have presented very exciting Phase 1 data showing greater than 89% knockdown with durability after six months from a single injection and we are excited to move that forward as soon as APOLLO reads out. I think that leads to rapid engagement with the regulatory agencies and depending on the exact nature of the data from APOLLO, I think we can negotiate variety of approaches to seeking approval for TTRsc02. So provided the data is robust and the primary endpoints met and we can show relationships in TTR knockdown and the clinical outcomes, I think we can have a conversation about further developing TTRsc02 on approval based on TTR knockdown and safety. We could also have conversations about single arm studies and comparative historical controls. It would be difficult to do a comparative study at that point. So there are a number of approaches we are working through and certainly the details of how APOLLO reads out and the content of that data will be very important to discussion.

All right. Barry, on the commercial question?

Yes. So as we talked about on the call, we have been steadily building out all the capability required to go-to-market including medical affairs and commercial. So we have got medical affairs folks deployed in U.S. and in Europe to help the education of hereditary ATTR amyloidosis and really initiate the patient finding activities. As I mentioned on the call, we are targeting general managers in the major markets in Europe and that's a little bit different for patisiran than it might be for other products because of the uniqueness of where patients are found, for example, Spain, Portugal, so the Iberia, Sweden as well as Germany, U.K., France. And those general managers are in place and as I mentioned on the call, will be heading, will be highlighting the head of our European Canadian organization as well. Post-APOLLO, we will be building out other countries throughout Western Europe and Canada and the United States again we are well on our way for patient finding, diagnosis and access as well. We think that the timing works well for post-APOLLO to really then be bringing on the in-field force account management sites and we are preparing to do that post a positive APOLLO.

What's the scale of the sales force that you are thinking of in the U.S.?

Well, you can imagine, for competitive reasons, we are not giving detailed information on all of our field deployed folks, but for U.S. and Western Europe and Canada, less than 100 people required in the field across all the countries I mentioned and the U.S. have an effective launch and subsequent commercialization of patisiran. So it really is a very focused effort, as you often see with orphaned and rare diseases.

Great. Thanks very much.

All right. Thank you Alan.

And our next question comes from Do Kim from BMO. Your line is open.

Hi. Good morning. Thank you for taking my questions.

Good morning.

Hello.

Yes. Good morning.

Hi. For patisiran, I thought the Phase 2 final data continued to look strong, but how should we think about the secondary endpoints that didn't move toward improvement, like mBMI or intra-epidermal nerve-fiber density. And is there a natural history that would compare that to?

Yes. That's a great question. I will just comment and then Akshay can take it over. Keep in mind that the study is not comparative to placebo and so what we appear to see at some of those endpoints is stability over two year period which is itself quite encouraging, based on the natural history. But Akshay, do you want to give some further color on that?

Yes. I think you said the main thing that we don't have a comparator arm and I think there aren't very good historical data sets around mBMI and this spectrum of, the last one or stage one or stage two patients that we have in the face of label extension study. But I think given the totality of the data set where we have seen changes, reductions in over 70% of patients in mNIS +7, improvements in nerve density and now a very, I think, rather interesting and impressive reductions in amyloid burden. If we add a comparator arm, I would be optimistic that patisiran changes in mBMI would be superior to placebo. So we will have to wait for APOLLO. I think the retention of 25 patients in the study for almost three year is really [indiscernible] speaks to, by inference to have this drug as likely performing from a safety and efficacy viewpoint in this single arm study. So that makes us feel optimistic about that endpoint. Vis-à-vis the density work, I think we got to be very cautious. The very fact, number one, that we are seeing increases in nerve density in an inherited neuropathy that's inexorably progressive is absolutely remarkable and this is something that all the KOLs remarked upon. Now with the specifics of where the curves are at different time points, remember the biopsies are taken randomly from different parts of the leg at the sequential time points. And so the amount of nerve, how can I put this, the change in amyloid burden on the nerves and the exact dimension is varied along the length of the nerve in the legs and the alms. So depending on where exactly the biopsy is taken at the sequential time points will profoundly will alter the result. So if at one-time point happened to get a patch of nerve that was very damaged, you will see more damage if at another time point you see an area that's less damaged, you will see less evidence of nerve density loss. You got to have average the whole thing out. You have got to look at the whole population. And that's where the result, I think, looks impressive. So the fact that one or two patients may skew a particular time point is probably not relevant.

It's just worth adding on this point that these biopsy samples are all read in a masked manner by a central lab metal and a lab that is world-renowned for this type of analysis. So it is something which is reassuring that we are seeing these type of effects in a blinded fashion with an objective what really is an objective measure of clinical activity for the drug.

As is the other relationships that we have shown before, the degree of knock down of transthyretinis is related to changes in mNIS +7. That's also very objective. So I think all these factors together suggest that something important happening in this study.

Great. Thank you. That was very helpful.

Yes. Thank you.

And our next question comes from Geoff Meacham from Barclays. Your line is open.

Hi guys. This is Evan, on for Geoff. Thanks for taking the question. One on fitusiran. When we think about where this fits in with all the novel agents in development, where do you see this study with gene therapy long acting factor? How should we be thinking about the competitive landscape with these novel assets coming forth?

Yes. Let me take a start and then maybe Akshay or Yvonne or Barry might want to comment. This is an exciting time for hemophilia. This is an era where patients really suffering with this disease are going to see a level of innovation that they have not seen for decades, really since the advent of recombinant DNA technology nearly 20 or 30 years ago, 30 years ago. Nothing has really come forward that is close to the level of innovation that one sees these days for people living with hemophilia. So it's a very, very exciting time. There is a buzz in the patient communities when we go to meetings and also in the in the scientific conferences and so forth. Very exciting time. Now when we think about the landscape of medicines that are emerging right now, when we think about the subcu drugs, which is emicizumab or ACE-910 and patisiran. And when we think about the gene therapy products for heme A and for heme B, there is no doubt that all of these approaches show promise, that all of these approaches have the potential to together disrupt the age-old use of factor, the way it's been used in the old days and that, from the standpoint of a market disruption and new innovation, is a real opportunity, in our view, for all of these medicines to do very well in, what is today, a $10 billion market. So it's our view that obviously depending on final clinical trial results, that patisiran is going to fit in very nicely into this landscape of emerging changing dynamic market and it's going to be a product that is really differentiated. It's obviously a subcu drug given once a month that is going to be effective, we believe in heme A and heme B. Of course, there is nothing in heme B like patisiran, because emicizumab or ACE-910 is limited to patients with heme A and of course both emicizumab and patisiran are going to very meaningful for patients with inhibitors and of course that's not a realm where gene therapy type products will emerge. I am of the view that gene therapy is going to be important in this space. I don't think it's going to have a very rapid uptake. There is going to be a number of barriers to entry that relate to long-term safety and variability of response. But the data are in fact promising and I think that gene therapy will emerge as one of the treatment options out there. So that's a long-winded answer to your question and let me see if any of my colleagues have anything else to add to it that I haven't quite covered. And they are shaking their heads saying, no. But does that answer your question, Evan?

That does most definitely. And then one, when we get the potential Ionis data, what are some of the things that we need to watch out for so we don't have that misreading of the data and inaccurate extrapolation into the APOLLO trial?

Well, Evan, it's going to depend a little bit on how much clarity is in what Ionis shares and it's sort of hard for me to prejudge what that is or is not going to be. But look, we do expect it to be positive. We do expect them to have sufficient power with all the limitations that we discussed to still eek out a positive study. But there, if it's borderline, like p=0.55 or something, that could reflect the fact that they are underpowered and had a shorter timeline or a time frame for their primary endpoint than we did. And so I think we are all going to have to see what's disclosed by Ionis and then obviously interpret that as we will all interpret it. But we do expect it to be positive. We do know that have had a lot of adverse event issues and that's going to factor into their efficacy results that they a lot of discontinuations. And so how transparent they will be on that in their top line release, we don't know at this point in time. We can only speculate on that. Anything else to add from the team?

Thank you very much. I appreciate it.

Great, Evan.

And our next question comes from Alethia Young from Credit Suisse. Your line is open.

Hi guys. Thanks for taking my question. A couple, sort of tied in together. One, just in your conversations with the FDA like, is a trend enough on the Norfolk score? I know it's one of Ionis' primary endpoints. So I just wanted to reconcile the two points there. And then also when you are thinking about filing these two in the U.S. versus the EU, if this was obviously approved in Europe and not the U.S., but are there different dynamics and in thinking about regulatory filings there? Thanks.

Yes. Akshay, do you want to comment? I will just start by saying we don't want to get into the details of our regulatory discussions for competitive reasons at this point. But Akshay, you want to comment?

Yes. I think overall, Alethia, when it comes to working with the FDA and any regulatory, in general, the key principle is as long as there is internal consistency within the data set, I think we can have important dialogue of how to get a medicine approved for these high unmet need patients. So the specifics of what the Norfolk may or may not be and the trends, there is no point in discussing that. We have to look at hitting the primary and the overall internal consistency of the data set and does it point to drug having done something important with an adequate safety profile in this patient population. And that really is how the agency thinks about it. With respect to the EMA, those principles are equally important there. And so we look forward to working with them within the protocol that was partly discussed with both agency prior to initiation of Phase 3. So we feel we are aligned in our approach. And we will find out in September.

Yes. I would just add, Alethia, that you can imagine that if our study shows a very large treatment effect and is very robust, the quality of life measure is important and obviously, one would like to hit it and we believe that we will hit it. But if the importance of it is different then in a study outcome which is more muted, maybe more or less of a treatment effect, less robust P value, then the agency and ultimately payors looking for what's the clinical impact to that becomes much more important. So that's another way to look at it in part. Barry, do you have a comment?

Yes. You also asked about U.S. and Europe. The only that I would add is that even though tafamidis is in the market in most countries in Europe, but the agencies and the countries themselves that we had been meeting with for scientific recognized the unmet need that remain is very, very high.

Great. Thanks.

Yes. Thanks Alethia.

And our next question comes from Ted Tenthoff from Piper Jaffray. Your line is open.

Great. Happy Friday everyone.

Happy Cinco de Mayo.

Cinco de Mayo, exactly. So a comment, if I may, first and then a question. And just listening to comments and it really took me back all the way to the IPO and your guys appreciation for the sheer scale that was going to be required to take a new class of medicines to patients. I am pleased to see all that progress and the continued commitment to doing this the right way as you build up the commercial organization and seek the first regulatory approval. My question is on givosiran and I was really impressed by the preliminary data. I think this is pretty unique opportunity for Alnylam. What's still really has to be done before we start the Phase 3 here? It's really just finalizing that dose, optimizing that dose? Do you feel pretty comfortable with the endpoints?

Yes. Akshay, do want to comment?

Yes. Thanks Ted. With givosiran, as you said, the preliminary data, indeed very encouraging and the PRIME designation attest to that. The key thing to wrap up now is to share the data from this Phase 1 study with the agencies and finalize the trial design. We feel that we have got through the literature, through working with KOLs around natural history, study and discovery and what we have learned from the Phase 1 study itself, we have got a very good handle on the primary endpoint revolving around the attack frequency. These attacks were clinically devastating and therefore meaningful. So no one would, I think, debate importance of attacks. And know, we are in the process of working with regulators and we feel we are on track to start what will be hopefully a very straightforward, placebo-controlled study comparing patients with givosiran to placebo and determine attack frequency. The current trial, I think, has given us great insights into the dosing frequency that we will need to maintain optimal suppression of attacks and at the ICPP towards the end of June, we will share all of those data with you.

Great. And I guess a quick follow-up to that. How important is patient selection going to be in that Phase 3 study? Is the magnitude greater and it should play out versus placebo. But how are you thinking about patient enrollment criteria?

Yes. It's a great question.

Yes. Enlistment, of course, was very important when you are listing a signal that you want to address with an important drug like this. So we are going to reach for patients with recurrent attack and we are thinking about patients with multiple attacks, approximately something like four or more attacks per annum. We do want to finalize that with the regulators. I don't think there should be a big debate around that. But that's the obvious area to focus on and it's the highest unmet segment.

Does that answer your question?

It sure does. Thanks guys.

Great. Thanks Ted.

And our next question comes from Christopher James from Ladenburg Thalmann. Your line is open.

Hi. Good morning guys and thanks for taking my question. I just have one question regarding the histology data at AAN last week. You might have touched upon this earlier. But can you comment on, how did the skin biopsy data, namely the reduction in amyloid compare with the increases in nerve density data and changes in mNIS+7? Can you comment on at least directionally or magnitude of change? And will you be including any of this in your filing?

Yes. Great question.

Yes. So Chris, the latter part of your question first. We have similar types of data on nerve density and amyloid content. That will be submitted with APOLLO. We obviously don't have those data yet. That's all in process. But I think that will be a very important part of the data set. And so that's one thing. With respect to relationships between nerve density or neuroid density and the amyloid change, again that's something we were discussing earlier. Imagine a nerve traveling the length of the leg from the thigh down into the lower leg, there will be patchy deposition of amyloid all along the length of that nerve and nerve density will vary along the length of that nerve. It will be lowest distally and it will be greater proximally. Now when you do biopsies over time, you are not sampling exactly the same area over and over again. So variations can easily result within a patient. And I think the important thing is to look at the overall result. And the one we are seeing, as we discussed, I think is very important and the types of the setting, I mean it never has really been shown in any other inherited neuropathy, to my knowledge. And so we are very excited by these findings. With a larger data set like APOLLO, where hundreds of patients were involved, I think the kinds of correlations you are talking about will be much easier to analyze at the group level.

And I will just, Chris, that we are really impressed with the number of patients in APOLLO who have agreed to do the biopsy. It's not a mandatory requirement as it typically isn't in a protocol. But we have pretty significant numbers of biopsy samples, actually. So that will be a meaningful part of our APOLLO review and certainly our submission to the FDA and EMA.

Great. Thank you for taking the question.

And our next question comes from Paul Matteis from Leerink. Your line is open.

Great. Thanks so much guys and congrats on all the progress. Two quick questions. One on quality of life. I am wondering, do you think 15 months or 18 months are long enough to show benefit in quality of life for the TTR knockdown therapies? And then second, thanks for sharing some thoughts on the revusiran analysis. Do you think that this kind of analysis is going to be important for FDA as part of the patisiran regulatory review, given that it's the first RNAi therapeutic that would be reviewed for potential approval? Thanks so much.

Great. Those are great questions. Akshay, do you want to handle it?

Yes. So with respect to the patisiran QOL question, what we know is there are very good relationships between change in NIS and change in these QOL parameters. We have shared those data previously. And that's really very, very encouraging. And I think the kinds of changes in NIS that we are seeing in the context of this Phase 2 open label extension study, if we have changes of that type or greater, we can be optimistic that there should be notable changes in the Norfolk score in the APOLLO study. So certainly, with a sample size of 225 followed after 18 months and changes of this magnitude based upon the TTR knockdown that we have, we feel like we are in a good place and we are optimistic. Now if you have a smaller file size, if your TTR knockdown knowledge is great, if there has been great discontinuation rate from the study, we don't know. And so hard to speak to other circumstances. But certainly in our context, I think, we are feeling optimistic. With respect to your question on revusiran, I think first and foremost, the agency literally uses this phrase with all forms when drugs are being discussed. It's a case-by-case basis. So in the first setting, patisiran will be evaluated in and of itself. And that will be first line of practice. Now within that context, certainly cardiac safety will be borne in mind also by them and I think what we see in terms of cardiac safety with respect to the Phase 2 open label extension study looks quite encouraging. If you look at the overall study, the cardiac parameters have been stable. We haven't had any cardiac morbidity and mortality of note. And so we think as the cardiac issue is examined, we hope that APOLLO too will provide favorable outlook as the Phase 2 study is done. Ultimately, it will be a matter of review and if they have questions about revusiran, we are happy to share data our data as we have been doing, as the investigation has been ongoing. And we are going to bring all the data out in the summer anyway, as John commented earlier. So that's how we think about it currently.

And I will just add that we have had good discussions with the FDA already on the revusiran investigation and we will update them yet further. So they are aware and I think pleased with the thoroughness and the type of work that we are doing on that matter. And so that's something which we will certainly engage with them before we go publicly, but we have already had engagement with them on that in a very thorough and definitive manner.

Okay. Great. Thank you so much.

Thank you Paul.

And our last question comes from Madhu Kumar from Chardan. Your line is open.

Hi. Thanks for taking my questions. First one is, thinking about the hemophilia space, particularly ACE-910 from Roche and the data we are going to be getting at ISTH on the HAVEN 1 trial, what do you understand to be an unacceptable safety profile for a hemophilia drug in the inhibitor population? And then thinking about the Phase 3 studies in TTR polyneuropathy of yours and Ionis', what do you guts think is a reasonable discontinuation rate? Is it what's been seen in the Phase 2 open label extension for patisiran or something greater considering the presence of a placebo arm?

Those are two great questions. Let me do the first one of them and then maybe Akshay, you take the second. In terms of the emicizumab data that will be presented at ISTH, we all look forward to seeing it. Roche's top line that it is a positive study and that doesn't surprise any of us. Of course, there have been five thromboembolic events of note to-date, one which was sadly fatal and obviously we will get more color, I am sure, on those events and the overall safety profile as well as the effectiveness profile of emicizumab at ISTH. So I think it will be premature for us to comment on what's a minimal profile. Obviously it needs to have a competitive hemostatic profile of reducing ABR. I think that we can expect that to be the case. And of course the safety profile beyond these five known thromboembolic events, you should continue to look, these look good because certainly in the non-inhibitor population that's going to be an important factor. Obviously, in the inhibitor population, there is a very high unmet need and even the current profile that's emerging for emicizumab is likely to be used at least in some patients. So I think their uptake of that product is going to be partly influenced by what's happened to date and let's see if that holds just with those five events. So we will have to see, it might be a little bit too premature to speculate I think at this point. And then the second question, Akshay, on the fitusiran?

On the fitusiran, sorry, the discontinuation rate, that's right. We have excellent retention, as you commented, in the Phase 2 open label extension study. I can say that retention in the Phase 3 study has also been excellent without getting to the specifics of the numbers. And we were powered to drop our rate well in excess of what has been seen and given that the study is approaching its last patient, last visit, I think we feel very good about maintaining adequate power per the original hypothesis when the study was designed. So I think that's as much as I can say as far as any competitor trial, you will have to speak to them. But I think we are going to be in good shape from that perspective.

I will just add, Madhu, that we have also been pleased with the very high number of patients that have transitioned from APOLLO in to the APOLLO open label study, which is also a good sign of retention and patient interest to stay on top in the therapy. And as you may know, we have recently opened up an expanded access program to make patisiran available and there is very strong interest in that program by patients that were tabled to enter into the clinical studies and that just highlights the unmet need and also the favorable experience we have had to-date with patisiran from a safety perspective and also based on the Phase 2 open label data from an efficacy perspective as well. So that's encouraging.

All right. Thanks very much guys. Have a great weekend.

Yes. You too, Madhu.

And at this time, I am showing no further questions.

Great. Well, thank you everyone for joining us this morning. As I said at the beginning, 2017 is a pivotal year for Alnylam's transition toward a commercial stage company, which is very exciting and we look forward to updating you on our progress in the months to come. Thank you.

Ladies and gentlemen, thank you for your participation in today's conference. This concludes the program. You may now disconnect. Everyone have a great weekend.