Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to discuss the Fourth Quarter and Year End 2017 Financial Results. [Operator Instructions] 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 afternoon. 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, Executive Vice President of R&D; and Manmeet Soni, Chief Financial Officer; and Yvonne Greenstreet, Executive Vice President and Chief Operating Officer. For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the Investor page of our website, www.alnylam.com. During today's call, as outlined in Slide 2, John will provide some introductory remarks and provide some general context. Akshay will review the recent clinical pipeline update, Manmeet will review our financials, Barry will provide an update on our commercial readiness efforts and Yvonne will provide a brief summary of upcoming milestones before opening the call for your questions. I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of 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 quarterly report on file with the SEC. 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 provides useful information to management and investors regarding our financial conditions and results of operations. 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 will now turn the call over to John.

Thanks, Christine, and thank you, everyone, for joining us this morning. The fourth quarter of 2017, a recent period, were marked by a number of notable milestones for RNAi, for Alnylam and for the patients we serve. In this period, we have come closer than ever to delivering on the promise of RNAi and have taken a big step towards fulfilling our Alnylam 2020 strategy of building a multi-product global commercial stage company with a deep and sustainable clinical pipeline and a robust product engine by the end of 2020 A company profile rarely achieved in biotech history. Indeed, we are now at a critical turning point in the Company's 15-year journey of bringing RNAi therapeutics to patients with a whole potential new class of innovative medicines. To begin, I'd like to set the stage with some overall context. First, the big news for the quarter was our report of the positive results from our APOLLO Phase 3 trial of patisiran. Based on these results, we have now completed our regulatory filings with the U.S. and European Health Authorities, notably, in less than 90 days after the announcement of our top line results. I am really proud of our team's execution on these filings, and this highlights Alnylam's sense of urgency and commitment to excellence that we believe will soon be manifest in our commercialization efforts. We also received a number of important regulatory designations for patisiran, including break-through therapy, priority review status as well as an expanded orphan drug designation for ATTR amyloidosis, all by the FDA, and then, accelerated assessment by the EMA and promising innovative medicine designation by the UK's MHRA. We believe that all of these regulatory accolades reflect a very promising profile of patisiran seen in APOLLO and a very high unmet need in hATTR…

Thanks, John, and good morning, everyone. As John highlighted, we've had a productive quarter with many firsts for the company. Let's begin with our programs in hATTR amyloidosis, which include patisiran and ALN-TTRsc02. This undoubtedly was a transformative period for patisiran, with our positive results from the APOLLO Phase 3 study. To recap, patisiran met its primary efficacy endpoint, the change from baseline in the modified neuropathy impairment score, mNIS+7, with a remarkably significant p value of 9.26 x 10-24 and hit all secondary endpoints as well, including the Norfolk Quality of Life score with equally notable statistical significance with a p value of 1.10 x 10-10 at 18 months. The combination of secondary endpoints, which included not only the Norfolk-QOL, but additional readouts in muscle strength, activities of daily living, walking speed, BMI and autonomic function, show the potential for patisiran to uniquely impact patients' lives in a clinically meaningful fashion. In the prespecified cardiac subpopulation, patisiran treatment was also associated with improvement in cardiac structure and function, including a marked improvement in gait speed. These data make patisiran the only therapy, whether investigational or approved, for the treatment of hereditary TTR amyloidosis with evidence of disease reversal in a majority of patients. Based on these data, we recently completed our rolling submission of an NDA to the FDA, where we have breakthrough therapy designation and have also submitted our MAA to the EMA, where we have accelerated assessment status. As John mentioned, we completed both of these regulatory filings in record time and both agencies have accepted our filing. Our PDUFA date from the FDA is August 11. On that note, I too would like to congratulate and thank our teams for these remarkable achievements. Based on these submissions, we expect potential regulatory approvals in the U.S. in…

Thanks, Akshay, and good morning, everyone. I will be referring to Slide 21 for a discussion of our fourth quarter and year-end 2017 financial results and 2018 financial guidance. We maintained a strong balance sheet, ending the fourth quarter and the year of 2017 with approximately $1.73 billion in cash, cash equivalents, marketable securities and restricted investments. Our revenues were $37.9 million in the fourth quarter of 2017, as compared to $17.5 million in the fourth quarter of 2016. Revenues for the fourth quarter of 2017 included $20.1 million from the Company’s alliance with The Medicines Company, $13.4 million from the Company’s alliance with Sanofi Genzyme, and $4.4 million from other sources. Revenues were $89.9 million in the year ended December 31, 2017, as compared to $47.2 million in the year ended December 31, 2016. Revenues for the year ended December 31, 2017 included $54.6 million from the Company’s alliance with Sanofi Genzyme, $30.2 million from the Company’s alliance with The Medicines Company, and $5.1 million from other sources. The increase in revenues during the year was due to increased services performed by us in connection with our clinical development programs for which Sanofi Genzyme had opted in and the achievement of $20 million milestone under our agreement with The Medicines Company upon initiation of its Phase 3 study for inclisiran in early November 2017. Moving to expenses, our GAAP R&D expenses were $117.8 million in the fourth quarter of 2017, as compared to $105 million in the fourth quarter of 2016. GAAP R&D expenses were $390.6 million in the year ended December 31, 2017 as compared to $382.4 million for the prior year. Non-GAAP R&D expenses were $102.9 million in the fourth quarter of 2017, as compared to $95 million in the fourth quarter of 2016. Non-GAAP R&D expenses…

Thanks, Manmeet. As you heard from John and Akshay, the company has picked up remarkable momentum in the fourth quarter and recent period. We're now very focused on preparing for the commercialization of patisiran on a global scale, with an initial focus on United States and Western European territories. For patisiran, the pathway to reach global markets is very clear. As you've already heard from John and Akshay, in the U.S. and EU, we filed our NDA and MAA, and expect decisions in mid-2018 and late 2018 respectively. We plan to begin a global expansion with a Japanese NDA submission to the PMDA in mid-2018 and expect to also file in one or more countries throughout the course of 2018 and beyond. Now we can refer to our APOLLO study population as the basis for an initial blueprint to map out our global reach beyond U.S. and Western Europe. In APOLLO, we enrolled 225 patients in 19 countries across the globe. The diversity of the APOLLO patient demographic highlights significant potential for commercial opportunities in Central and Eastern Europe and in markets like Asia Pacific and Latin America. Now while not in APOLLO, we also see significant opportunities in the Middle East in countries like Turkey, Israel and United Arab Emirates. Our build of the Alnylam commercial and medical customer facing organization is well underway, with planned onboarding of over 250 employees, including medical affairs, patient services, access, marketing and sales professionals in a staged approach tied to regulatory approvals and reimbursement. In the U.S., as things stand, we have our entire field and customer facing team onboard and in training. We plan to be launch ready in Western Europe later in the year, starting in Germany, we have hired and will soon begin to onboard our field and customer…

Thanks, Barry. To echo the sentiments you've heard from my colleagues, the fourth quarter of 2017 and the beginning of this year have been exciting periods of the company. And we're now looking forward to a very eventful 2018. In 2018, most importantly, we expect to transition to a commercial-faced company, with an expected U.S. approval and launch for patisiran in mid-2018, and in the EU in late 2018. We will also start our global effort from patisiran, with a JNDA filing expected in mid-2018 and one or more rest of world regulatory submissions by year-end. In addition, we intend to continue to cement our leadership in the ATTR amyloidosis field with the initiation of a comprehensive Phase 3 development program for ALN-TTRsc02 starting in late 2018. Beyond our ATTR amyloidosis programs, important highlights for the year include our top line interim analysis Phase 3 results for givosiran in acute hepatic porphyrias, leading to a potential year-end NDA submission. Also, we'll be advancing our additional Phase 3 programs together with our partners with fitusiran in the ATLAS program and inclisiran in the ORION program. We expect Phase 3 readouts for fitusiran and inclisiran in 2019, leading to potential approvals in 2020. And as Manmeet said, we're now providing our year-end 2018 financial guidance, which we expect to end with approximately $1 billion in cash. Turning more specifically to expected milestones in new drug for the beginning of 2018. We expect to present additional data from the APOLLO Phase 3 study of fitusiran at the ISA meeting in March. We also expect to present additional Phase 1 and Phase 2 early study results for givosiran at EASL in April. Alnylam and Sanofi expect to enroll patients for the ATLAS Phase 3 program for fitusiran in patients with hemophilia A or B with and without inhibitors throughout the year with a resumption of dosing expected in early 2018. And The Medicines Company has guided its intention to complete enrollment in the ORION-9 and -10 pivotal studies of inclisiran in early 2018, with ORION-11 already now fully enrolled. With that, I will now turn the call back to Christine to coordinate our Q&A. Christine?

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

Thank you. [Operator Instructions] And our first question comes from the line of Ted Tenthoff of Piper Jaffray. Your line is open.

Great, thank you very much. Two quick ones, if I may. Firstly, with respect to commercial preparation, I appreciate the guidance that you're starting to give there. What – where will you be manufacturing drug? And what still has to be done to sort of get through manufacturing, ahead of manufacturing visit and clearance, ahead of review? And secondly, any thoughts on how long it may take to enroll the ATLAS studies? Thanks.

Right. Those are two great questions. Let's have Barry do the first one and Akshay the second.

Yes. So Ted, specifically for patisiran manufacturing, we're in very good shape. The global supply chain is established, as I remarked, for U.S. and Europe, and we're now expanding that to rest of the world. We are a number of drug substance manufacturers. We haven't talked about exactly who we use, but they're well-established manufacturers. As we've disclosed previously, our drug product is made by Alnylam here in our Alewife facility, and it's inspection-ready. We won't comment on specifically, but we're engaged with the agencies on pre-approval inspections and see all that going very well for U.S. and Europe. So I'd say, overall, in terms of manufacturing, we filed everything with the NDA, we're inspection-ready in all of our sites and it's a matter of moving through inspections and timing with the agencies.

Yes. And Akshay?

Yes. And on Atlas, Ted, we were delighted at the end of last year to get things fired up again after the lift of the temporary clinical hold. The filings globally at almost a 100 sites have gone well, the regulatory progress Atlas progress is good. We're expecting enrollment to begin eminently, and of course, the ultimate timing for the data, our Sanofi colleagues will be guiding on that carefully as enrollment progresses, but our plans, originally, were always to get data in the 2019 timeframe.

Great. Excellent. I appreciate it.

All right. Thanks, Ted.

Thank you. Our next question is from the line of Terence Flynn of Goldman Sachs. Your line is open.

Hi. Thanks for taking the question. Maybe one on givosiran. Just wondering if the announcement today regarding the sample size adjustment, if that was based on the current event rate that you guys are seeing or is this just, again, you want to have an overpowered study? And then the second question I had is, Pfizer has an upcoming Phase 3 readout for tafamidis in the cardiomyopathy patients, just wondering if you can could remind us how you're thinking about potential implications of that data set there for your TTR portfolio. Thank you.

Great. Let’s start with givosiran interim analysis and sample size reestimation. Let me just start by saying that this was always actually in the plan, but we realized coming into the year that we haven't provided specific guidance on it, so we wanted to make sure people were aware of the fact that we had this interim analysis in place for resizing. It's a typical approach. And there is certainly no aspect of data that's driving that. That was done actually before enrollment was started in the study. Anything to add to that?

I don’t know. You covered it, John.

Yes, good. And then on the ATTR-ACT study results, maybe Barry, you want to cover that?

Yes. So just as context, and Terence, thanks for asking, Pfizer has a very large cardiovascular outcome all-cause mortality study running in mainly cardiomyopathy patients, both mutant and wild type for TTR amyloidosis. We don't know the outcome we anticipate hearing the results sometime early to mid-this year. And I think, either way, I think we're in good shape for patisiran, given the data we have. If ATTR-ACT is, in fact, a positive, it's further confirmation that modulation of TTR is beneficial for these patients, and as you know, including cardiomyopathy subpopulation, we've shown reversal of disease in the majority of patients. And if ATTR-ACT is negative, then it demonstrates sort of the lack of efficacy we've already seen with tafamidis. So I think, either way, we're in good shape for patisiran.

Yes, I don’t think it changes. Just one another thing to add. I think, Barry, that's all correct, but one thing to add, Terence, is it doesn't change the fact that TTR stabilization with tafamidis is a pretty weak approach. And I think we'll see what the results are, but we wouldn't expect the results to be any more impactful than what we've already seen from tafamidis. And of course, we know that TTR lowering is substantially a better as an approach, overall, and we would expect that to play out in the future.

Thank you. And our next question comes from the line of Vincent Chen of Bernstein. Your line is open.

Thank you for taking the question. I was wondering if you could provide some color on how you're thinking about the likelihood of a broad label for patisiran. I guess both you and I know it's submitted for a broad label since – do we know of advisory committee's plan? So regulators clearly think they have a view on the likely label, whether it ends indeed broader and roughly only. I guess, two parts to the question, one, is it fair to say that the breadth of the label really hinges on how robustly regulators view cardiac substudy, for example, prespecified, robust mutual endpoint? And two, if so, what is your sense from your discussions with the regulators themselves and also with your regulatory consultants with respect to how the FDA is likely to view the robustness/efficiency of the cardiac substudy and the implications for the label?

Okay. Those are great questions. Akshay, do you want to tackle?

Yes. Hi, Vincent, I mean, we’re obviously very hopeful that we can achieve a broad label based on just how comprehensive the data in APOLLO were speaking to all dimensions of the disease, and by that I mean the peripheral neuropathy, the autonomic neuropathy, the cardiac outcomes and all of that then supported by changes in very important secondary measures like Quality of Life, body mass, activities of daily living, et cetera. So I think that is all going to be looked at very carefully by regulators. Equally, they'll want to – I imagine, if you're convinced that the input population that was studied in APOLLO is truly representative of the breadth of what is hATTR amyloidosis. We certainly believe it is. As you know, over 50% of patients had significant cardiomyopathy as well as the neuropathy, and we believe that we have very nicely tested the hypothesis of TTR reduction and its impact on the full breadth of the disease. The cardiac data themselves will, of course, be very important, and I think the internal consistency of all the data will be important. So we've got to allow the regulators to work through all that stuff, of course. And I think that we're optimistic, but let's see where they end up.

Yes, I would agree with that. And obviously, I think it goes without saying that APOLLO – the APOLLO data being as robust as they were and as amazingly consistent across all aspects of the disease is the key point here.

Would it matter at all that there wasn't a primary endpoint focused on sort of cardiac and that the primary was much more focused on the neuropathy? And is there a world where it would be potentially a shorter study just saying, let's redo a cardiac population with the primary really focused specifically on around the cardiac endpoints?

I think there are aspects to your questions which, obviously, we should allow regulators ultimately to answer. But from our perspective, what I would say is that the issue with the label is that you want to inform prescribers and those that will receive the drug, what is the capacity of this drug in terms of the efficacy can confer and what is the – what are the potential issues with safety. That's what we want to do with the label. We feel, and I think most people will agree with, that the fact that the cardiac outcomes weren't the primary endpoint is not the issue here. We prespecified the cardiac outcomes, we've studied them rigorously, we find up to be entirely internally consistent with the other outcomes that we've measured. And so I think in a rare disease population, in a complex disease where, in fact, the cardiac features are part of the predisposing factors to mortality, the regulators would want to look at that very carefully and make sure that they inform prescribers of what is this drug all about and what can it do for patients.

Great. Thank you very much.

Thanks, Vincent.

Thank you. Our next question is from the line of Madhu Kumar of B. Riley. Your line is open.

Thank you guys for taking my question. So thinking about patisiran and ATTR patient finding, what have you learned from the ex-U.S. launch of Vyndaqel that could aid in the genetic testing and expansion of patisiran beyond the initial patients set?

Okay. Good question. Do you want to touch on that first, Akshay, maybe Barry?

Yes, I think some of the key lessons from the Vyndaqel experience sort of follows that, one, the disease is a complex multisystem disease. When most patients have neuropathy and cardiomyopathy and that the current batch of TTR stabilizers, tafamidis, diflunisal, really can't get to the full spectrum of manifestations of this disease. Secondly, the patients breakthrough. And thirdly, the awareness that tafamidis is a therapy available for this disease has just allows more patients to emerge and come out and seek therapy. And we ourselves, on the back of that, are trying to take advantage of heightened awareness of the disease and launched a program, Barry commented on it, for genetic testing in Europe. And we're equally optimistic that some of our early experiences over the last 18-plus months in U.S. will be reflected in the EU, actually even more so, because one of the interesting things in the EU is there are large pockets of patients, whether there's endemic disease by mutations or mutation is concentrated. Of course, Portugal is an example of that, Sweden is an example of that, parts of France are an example of that. The Celtic population across the U.K. and Ireland is an example of that with T60a. And so we think that we will be identifying many patients because of the heightened awareness because of the emergence of new therapies and the availability of our genetic testing.

Yes. I agree with everything Akshay said. I'd add a couple of things to that, which is that particularly now post the patisiran results, where a majority of patients have actually shown disease reversal, it's enhance the call to action. And what we want to happen in the marketplace is when a patient is identified and becomes, if you will, an index patient, they have a call to action that alerts the rest of their family about the disease. When there is nothing to do for a patient, they tend not to want to do that. When there is a probability that the disease can reverse, they can get better, there is a bigger call to action. So I think we're going to see a lot more of that call to action, which should lead to patients self-identifying and coming in for genetic testing. The second thing, we've seen a phenomenon, and we're actually helping to make this happen, our Centers of Excellence. So if a patient comes in and sees a cardiologist who might miss the disease but doesn't see the neurologist who might see the disease or vice versa, that patient is hitting the healthcare system but then leaves the system. So with Centers of Excellence being established and multidisciplinary approaches, the chances of seeing that patient identifying this as hereditary ATTR improves. So in addition to what Akshay said, a couple of behavioral changes should prompt greater momentum in patient finding.

Okay. Great. And then stepping back, so how much has the transition towards ESC+ RNAi technology versus the kind of change in the mix between R&D spend and SG&A spend affected the kinetics of new program IND or CTA filings?

Madhu, I think that we took the purposeful decision last year to really focus on late stage execution of our pipeline versus filing new CTA or IND filings last year. We're going to have one or more filings this year. I'm pretty confident it's going to be more than one. And you're going to see that play out, because we have a lot of very important programs coming forward, and those programs will all be utilizing our ESC+ platform. So it really was more of a explicit decision last year to really focus on late stage development more than any sort of need to pause and do something different.

Thank you.

Thank you. Our next question is from the line of Alethia Young of Credit Suisse. Your line is open.

Hey, guys. Thanks for taking my questions. Maybe a couple. Just can you talk a little bit about what maybe presented for givosiran at EASL and maybe specifically as it relates to pain? And then on TTRsc02, with the start late in 2018, can you just talk about kind of size details of that study and how you kind of prevent that from strategically impacting your upcoming launch? Thanks.

Yes, okay. Great questions. Let me touch on both, and then Akshay can go a little bit deeper on the latter. So with givosiran at EASL, we'll be showing the full Part C dataset in around 15 patients as before. This is the cohorts of patients that were randomized into the double-blind placebo-controlled study. So you'll see the full Part C results, then you will see some I think will be pretty exciting set of data from the open-label extension study. So patients that have now been on therapy for over a year with givosiran, looking at how their disease control has played out and of course, safety as well. So it will be a pretty comprehensive review of that data. And then on TTRsc02, it's – obviously, we haven't yet locked protocols with regulators, so we don't want to get ahead of our skis, I'm talking about patient numbers, but we can confidently expect to be enrolling patients around the world. And obviously, we'll be focusing on patients in territories where reimbursement hasn't happened, as part of the strategy to make sure that we're not limiting full access of patients into the commercial program with patisiran. So that will be one of the approaches that we take there. I don't know, Barry or Akshay, anything else to add to what I just said?

No, you’ve covered it.

Covered it?

Yes.

Thanks, Alethia.

Thanks.

Thank you. Our next question comes from the line of Maurice Raycroft of Jefferies. Your line is open.

Hi, good morning and thanks for taking my questions. To start, I was wondering if you can provide more specifics around practitioners' access to genetic testing through Alnylam Act and if you gaps where certain types of physicians or patients may not be using the free test. And if you can maybe provide a few more specifics around what you're doing to influence the call to action outside of Centers of Excellence.

Okay. Those are two great questions. Akshay, you want to handle?

Yes, let me start off. So in terms of the access, we've made it open access to any specialty that wants to test the patient with suspicious symptoms of hATTR amyloidosis, and to date, we've been very successful. There are hundreds of doctors around the country in the U.S. who have accessed the system. As Barry said, we've had a pretty significant strike rate. And so it's great that patients are having quicker diagnosis, maybe a little more accurate diagnosis made for such a complex, high unmet need disease. One of the – some of the initiatives around that where we're looking to expand things are calling on sites that are not just the expert sites for hATTR amyloidosis, but others with large collections of peripheral neuropathy patients, academic sites, other practitioners who have an interest in peripheral neuropathy, and also spreading to a much larger group of cardiologists. And so that work is underway and I think, can only increase the yield rate and allow more patients to be diagnosed. Of course, we're doing a similar thing in the EU as well now with that initiative there. In terms of call to action, not only are we and our partners in the genetic testing vendors visiting sites and encouraging doctors to participate if they feel they want to act, as it's the first that rules. So highlighting hATTR amyloidosis at both cardiology and neurology conferences and via that, helping educate and inform a new generation of cardiologists, neurologist who really haven't been exposed to this disease of what the disease is all about and the potential emergence of new therapies and what they can do for patients. And that is also helping. So there is a lot of work going on now, and we anticipate a significant uptick in the number of tests.

Yes. The only – I agree with that. The only thing I'd add to that is that as disease education becomes more prevalent with neurologists, neuromuscular specialists, heart failure centers, physicians are moving from a view of I've never seen one of those patients my entire life to maybe I have, let me understand the disease better and get somebody's tests ordered. And then, Maurice, the big, big, big inflection point will come after labeling and after approval when we can actually promote. Keep in mind that right now, it's disease awareness, and our data are available via APOLLO results, but it's the label and really implementing our field force that allows to get out and reach people in a promotional capacity. And that should be a major inflection point for the field.

Great. Very helpful. Thank you.

Thank you. And that does conclude today's Q&A session. I would like to turn the call over to the company for their closing remarks.

All right. Well, thanks, everyone, for joining us this morning. 2017 was obviously an amazing year for Alnylam, and we are just excited beyond belief around what's going to go on in 2018, as we turn commercial. So with that, thanks, everyone, and have a great day. Bye-bye.

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