Christine Regan Lindenboom – Vice President-Investor Relations John Maraganore – Chief Executive Officer Akshay Vaishnaw – Executive Vice President-R&D Michael Mason – Vice President-Finance and Treasurer Barry Greene – President and Chief Operating Officer DA Gros – Senior Vice President and Chief Business Officer.

Alethia Young – Credit Suisse Alan Carr – Needham & Company Ted Tenthoff – Piper Jaffray Ritu Baral – Cowen Carter Copeland – Barclays Gena Wang – Jefferies Anupam Rama – J.P. Morgan.

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to discuss Fourth Quarter and Year End 2015 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 afternoon. I’m Christine Regan Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam.

With me today are John Maraganore, Chief Executive Officer; Barry Greene, President and Chief Operating Officer; Akshay Vaishnaw, Executive Vice President of R&D and Chief Medical Officer; and Mike Mason, Vice President of Finance and Treasurer.

In addition, DA Gros, Senior Vice President, Chief Business 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 Investors page of our website, www.alnylam.com.

During today’s call, as outlined on slide two, John will provide some introductory remarks and provide general context for some of our recent progress and achievements. Akshay will summarize recent clinical progress and pipeline progress.

Mike will review our financials and guidance, and Barry will provide a brief summary of goals for 2016 and beyond, before opening the call for questions.

I would like to remind you that this call contains remarks concerning Alnylam’s future expectations, plans and prospects, which constitute forward-looking statements for the purpose of 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 filings 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 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, Kristine and thanks everyone for joining us this afternoon. During the fourth quarter of 2015 and the recent period we made excellent progress as we continue to execute on our Alnylam 2020 strategy, and advance investigational RNAi therapeutics to patients and upon the approval to the market.

Before Akshay goes into our recent pipeline progress in more detail, I’d like to provide some context. First, I’d like to make a few comments on the broader equities market and the biotech sector in particular. Despite recent market performance, we believe the fundamentals of our industry are as strong as ever.

These fundamentals are build on several components, a deeper understanding of human biology which is delivering highly innovative drugs that are significantly improving patients’ lives.

The receptive and productive regulatory environment including a record setting year for anomies approved by the FDA in 2015 more than in any other past 15 years as well as the emergence of new expedited approval pathways like breakthrough therapy designations and then an industry that is focused on novel and highly transformative not incremental therapies.

The recent sell-off in the sector has little to do with our innovation ecosystem and we firmly believe that biotech remains one of the most attractive sectors in the overall stock market based on its strong potential for many years to come. As for Alnylam, we believe our fundamentals have never been stronger.

We remain focused on developing medicines that have the potential to be transformational for patients and believe we are well on track to achieve our Alnylam 2020 goals having just ended 2015 with eight programs in the clinic, two in Phase 3 and six programs that had advanced to the point where we have established human proof-of-concept.

The recently complete – the recent completion of APOLLO enrollment for Patisiran puts us Firmly on track for first Phase 3 data readout and assuming that the data are positive, our first regulatory filings in 2017.

As we end 2016, we anticipate having a profile of 11 programs in the clinic, three in Phase 3 and nine programs with established human proof-of-concept.

We believe the goals outlined earlier this year for 2016 of 10 or more anticipated major clinical data readouts that started patisiran Phase 3 trials and three new IND filings that are planned an important steppingstone on the Path to Alnylam 2020 where we intend to be a multiproduct commercial stage company with a robust and sustainable pipeline across our three strategy therapeutic areas or STArs, namely genetic medicine, Cardio-Metabolic disease and hepatic infectious disease, diseases that stand rare to the common and to the global.

Not surprisingly then, we could not be more excited about our prospects going forward. So, with those introductory comments, I’d like to now turn it over to Akshay to review our pipeline progress.

Akshay?.

Thanks John, and good afternoon, everyone. We continue to make great process with our pipeline of investigational RNAi therapeutic. Let me begin with our programs in our genetic medicines STAr and start with investigational RNAi therapeutic for the treatment of TTR-mediated amyloidosis or ATTR amyloidosis.

As you know we have three product candidates in this area. Patisiran is our lead program and is aimed at the treatment of ATTR patients with Familial Amyloidotic Cardiomyopathy, or FAC. As John mentioned, we just completed enrollment in the APOLLO study and reiterated our previous guidance that we expect to report data from APOLLO in 2017.

Due to the competitiveness of this timing versus the IONS GSK program, we are not planning to perform an interim analysis for efficacy. If APOLLO is positive, the company expects to submit an NDA and MAA for patisiran based on an analysis of full APOLLO data set in late 2017.

As a reminder the APOLLO Phase 3 trial is a randomize double blind placebo controlled global study, designed to evaluate the efficacy and safety of patisiran in patients with FAP.

The primary endpoint of the study is the difference and the change in a modified Neuropathy Impairment Score or mNIS+7 from baseline to 18 months between patisiran and placebo. The study was significantly overenrolled with a total of 225 FAP patients with stage 1 or stage 2 disease compared to the originally enrollment target of 200.

All patients completing the APOLLO Phase 3 study are eligible to enroll in the ongoing APOLLO Phase 3 open label extension study, APOLLO only.

Also during the recent period, positive initial 18 month clinical data reported from 20 patients in the Phase 2 open-label extensional, OLE study, which showed continued evidence for potential halting of personal neuropathy progression. Patisiran was also found to well tolerated after nearly two years of drug administration.

As we announced today, we plan to present complete 18 month data from all 27 patients in the patisiran OLE trial in all presentation on April 20th at the American Academy of Neurology Meeting in Vancouver, Canada. As you are aware, ATTR Amyloidosis, including FAP is a generally fatal orphan disease with limited treatment option.

We believe data reported today in our clinical studies provide encouraging preliminary evidence for patisiran’s clinical activity and tolerability while definitive evidence to support registration away for results from our randomized placebo-controlled study of APOLLO.

Let me now turn to revusiran, our most advanced subcutaneously administered investigation RNAi therapeutic in the clinic today and which is being evaluated for the treatment of ATTR amyloidosis patients with Familial Amyloidotic Cardiomyopathy or FAC.

As a reminder, we are currently conducting a Phase 2 early study in which TTR cardiomyopathy patients who participated in our Phase 2 trial were eligible to roll over into the early study and receive revusiran on an ongoing basis.

In this early study revaluating the safety and tolerability of long term dosing with revusiran for up to two years and also measuring effects of treatment on a number clinical endpoints including mortality, hospitalization and six minute walk distance in addition to cardiac biomarkers.

Initial six month data reported in the recent period from the Phase 2 early study showed sustained TTR knockdown representing the longest dosing experience to-date for target gene knockdown with a GalNAc-siRNA conjugate.

In the majority of patients in the early study revusiran was generally well tolerated out 10 months of administration through the data of cutoff date.

Based on the six months data it’s premature to make any conclusions related to effects on clinical endpoints and we will need to see the results at four months and ultimately results from our placebo-controlled study. We expect to present initial 12 months data in mid 2016.

Revusiran is also in a Phase 3 trial ENDEAVOUR now this is the randomized, double-blind, placebo-controlled study where we’re looking at two co-primary endpoints for drug and placebo measured at 18 months, one being the change in six minute walk distance and the other being reduction in serum TTR.

Based on encouraging enrollment in 2015, we recently announced that we anticipate presenting data from ENDEAVOUR in 2018. Finally with our TTR programs we soon expect to file a Clinical Trial Application for ALN-TTRsc02, an ESC-GalNAc-siRNA conjugate targeting TTR.

Based upon the emerging profile of this candidate we expect it support a once-quarterly subcutaneous dose regimen. We’re moving fast on our development of TTRsc02 and plan to report initial clinical data later this year and to start Phase 3 studies in 2017.

Our advancement of TTRsc02 represents our commitment to bring the best innovations to patients who would believe that TTRsc02 has the potential to emerge as the best-in-class approach for all ATTR related syndromes.

I’d now like to move on to discuss the latest progress with patisiran, the one we call ALN-AT3 which is an RNAi therapeutic targeting anti-thrombin in development for the treatment of hemophilia and rare bleeding disorders.

We view this as a very exciting and innovative program, designed to lower levels of AT with the goal of converging sufficient thrombin generation to restore hemostasis thereby preventing bleeding in patients with hemophilia.

At the ASH conference in December, we reported positive interim results from our ongoing Phase 1 trial, specifically in a study performed in 24 patients with moderate or severe hemophilia A or B. Our new interim clinical data demonstrated the subcutaneous administration patisiran achieved potent and dose dependent lowering of AT of up to 88%.

Furthermore AT lowering was associated with statistical significant and clinically meaningful increases in thrombin generation and decreases in bleeding frequency in patients with hemophilia. In particular patisiran administration resulted in up to 85% to 92% reduction in median estimated annualized bleeding rates or ADR.

While exploratory and only in a limited number of patients, the reduction in the median estimate today our results in bleeding rates that are comparable to those reported in the literature for prophylactic intravenous infusions of replacement factors or bypass agents in patients with hemophilia.

We also ported that patisiran was generally well tolerated, including no clinically significant increase within D-dimer, a biomarker of excessive clot formation. We are also encouraged by the overall safety results we reported that include patients with an aggregate of over 300 days of exposure at levels of AT lowering greater than 75%.

Patients are continuing dosing in our Phase I open-label extension study of patisiran and we expect to present date from that study on an ongoing basis at least once per year beginning in 2016.

In addition, we expect to start our patisiran phasing program in Hemophilia A and B including patients with inhibitors and without inhibitors in mid and late 2016. We’ve also enrolled additional hemophilia patients into the Phase I study where we are administering fixed, non-weight adjusted doses of patisiran.

Furthermore we expect soon to start enrolling inhibitor patients into the ongoing Phase I study. Finally, we are pleased to announce our partner Sanofi Genzyme elected to opt-in to the patisiran program for the development and commercialization of this drug outside of North America and Western Europe.

Let me now turn to recent progress with ALN-CC5, subcutaneously-administered investigational RNAi therapeutic, targeting complement component C-5 for the treatment of complement-mediated diseases. Also at ASH Meeting in December we presented positive initial data from our ongoing Phase I/2 clinical trial.

Specifically, news I will show that ALN-CC5 achieved up to 99% Knockdown of serum C5 and a mean max immune inhibition of serum C left for hemolytic activity, a liver assay for complement activity of 84%.

In addition, ALN-CC5 administration resulted in low levels of residual C5, which based comparisons from separate studies were at or below the estimated levels of CC5 observed at therapeutic target of eculizumab and approved anti-C5 monoclonal antibody.

The effects of ALN-CC5 were also found to be highly durable with C5 Knockdown in complement inhibition results supporting a once monthly and possibly a once quarterly subcutaneous dose regimen. Importantly, ALN-CC5 was shown to be generally well tolerated with no clinically significant blood related adverse events through the date of cutoff date.

We believe that these new ALN-CC5 results meet our goal of achieving both inhibition of serum hemolytic activity and highly robust Knockdown serum C5 to very low residual levels.

We are also very pleased with the consistency and durability of ALN-CC5 clinical activity, which we believe supports at least a once monthly and possibly a once quarterly subcutaneous dose regimen. With these data in hand we have now initiated those patients and have a number of patients enrolled in this part of the study.

Particular, we have successfully enrolled both treatment naive and eculizumab treated patients into the study. We look forward to presenting initial results from this new phase of our Phase 1, Phase 2 study including the effects of ALN-CC5 on levels of on levels of lactate dehydrogenase, a marker of endogenous red blood cell hemolysis in mid-2016.

We also continue to refine our development strategy for ALN-CC5, since our goal is to maximize the number of patients who can benefit from C5 Knockdown we plan to develop ALN-CC5 by both as an alternative to eculizumab and also as a foundational therapy with provisional eculizumab and less frequent and lower doses.

In a later setting, we believe that patients could benefit from more consistent efficacy without breaks for hemolysis and that reduce eculizumab dosing as a potential to reduce a significant burden for patients and the broader healthcare system.

Indeed our goal is to improve the management of PNH, another complement mediated diseases with an innovative new approach and we’re excited about the potential to do so with the ALN-CC5. Also during this quarter, we continue to advance our ALN-AS1 program in development for the treatment of acute hepatic porphyrias.

We announced today that we have initiated Part C of the ongoing Phase 1 trial. As parts of the studies being conducted in patients with Acute Intermittent Porphyria, they experienced recurrent attacks.

It’s designed to evaluate the safety and tolerability of multiple does of ALN-AS1 as well as measures of clinical activity, including reduction and frequency and severity of attack symptoms, hospitalizations, quality of life, and reduction in the use of heme and pain medications.

We expect to report initial data from this part of the study in late 2016 and if these data are positive to initiate Phase 3 study in 2017. We’ve also continued dosing healthy volunteers in our ongoing Phase 1 trial of ALN-ATT in development treatment of alpha-1 antitrypsin deficiency-associated liver disease.

In addition, we filed a CTA to initiate a Phase 1 study with ALN-GO1 in primary hyperoxaluria type 1, which should now have been approved by the U.K. authorities and we are pleased to announce today that we have received orphan drug designation for ALN-GO1 from the FDA.

We expect to have clinical data updates from these two programs in mid and late 2016. I’ll now turn to review of progress from our Cardio-Metabolic disease pipeline. Of course, our leading program in this STAr is ALN-PCSsc, which targets PCSK9.

As a reminder, ALN-PCSsc is an investigational RNAi therapeutic, targeting PCSK9 genetically validated protein regulator of LDL-receptor metabolism being developed for the treatment of hypercholesterolemia.

In contrast, anti-PCSK9 monoclonals antibodies, they’re bind to PCSK9 in blood; ALN-PCS is a first-in-class investigational medicine that acts by turning off PCSK9 synthesis in the liver.

Interim results from our Phase 1 study in normal healthy volunteers was elevated baseline LDL cholesterol were announced at the American Heart Association Meeting in November. Subjects in this study were randomized receiving three to one drug to placebo and received either single or multiple doses of the drug in this study.

Where we showed that subcutaneous administration of ALN-PCSsc resulted in an up to 83% lowering of LDLC with an up to 64% mean-max from reduction, comparable to those data published from the results from anti-PCSK9 monoclonals.

The effects of ALN-PCSsc were found to be highly durable with clinically significant and clamp reductions in LDLC, supportive of a potential biannual subcutaneous dose regiment. Specifically, and up to 53% maximum and 47% least squared mean reduction in LDLC was achieved at day 180 after just a single low volume injection.

In addition, ALN-PCSsc was shown to reduce a number of estrogenic lipids including [Indiscernible] and total cholesterol which are both associated with increased risk of cardiovascular disease. ALN-PCSsc was generally well tolerated with no clinically significant drug related adverse events through the data cutoff date.

Recall that our ALN-PCSsc program is part of The Medicines Company, who will lead clinical development of the program from Phase 2 onwards and commercialization of the program if successful. At the beginning of this year The Medicines Company announced the initial of the ORION-1 trial for ALN-PCSsc.

The trial is expected to recruit 480 patients with atherosclerotic cardiovascular disease and elevated LDL-C. In turn, ORION-1 will quickly become the largest ever study of GalNAc-siRNA conjugate providing important safe data for our overall platform. Finally, we’re also making strong progress in our hepatic infectious disease STAr.

We’ve now completed the preclinical IND enabling studies with ALN-HBV that will enable a CTA filing expected in early 2016. Continue to be very excited about ALN-HBV as we believe that it will emerge as a best-in-class RNAi therapeutic in the field with potential for a subcutaneous once-monthly dosing profile, and a wide therapeutic window.

We’re now on track to file our CTA for this program in early 2016 with the start of our Phase 1 study expected at mid year. If ALN-HBV is successful at increasing the rate of [Indiscernible] conversion in HBV patients this program could become an important value driver for Alnylam in the future.

In summary, we believe we’re making excellent progress on our investigational RNAi therapeutics pipelines across our three STArs. It’s certainly been an especially exciting and productive time for us, as we continue to lead the translation of the science of RNAi towards the development of innovative medicine.

In this regard I do want to thank all the physicians and patients engaged in our clinical studies. With your commitment we aim to advance important innovations for patients around the world. I will now turn the call over to Mike for a review of our financials.

Michael?.

Thanks, Akshay. I will be referring to slide 21 for a discussion of fourth quarter and yearend 2015 financial results. We maintained a solid balance sheet ending 2015 with approximately $1.28 billion in cash, cash equivalents and marketable securities.

Our GAAP revenues for the fourth quarter of 2015 were $7.6 million, as compared to $24.0 million in the fourth quarter of 2014. GAAP revenues this quarter included $3.6 million from our alliance with Sanofi and Genzyme, $2.9 million related to our alliance with Medicines Company and $1.1 million from other sources.

The company expects net GAAP revenue from collaborators to remain consistent for 2016 as compared to 2015. Moving to the expenses, R&D expenses were $82.8 million in the fourth quarter of 2015 as compared to $55.5 million in the fourth quarter of 2014.

The increase in R&D expenses for the quarter ended December 31, 2015 as compared to the prior year period is due primarily to higher clinical trial and manufacturing an external services expenses resulting primarily from the significant advancement of the company’s pipeline.

In addition compensation and related expenses increased for the quarter ended December 31, 2015 as compared to the prior year period due primarily to a significant increase in headcount during a period that the company continues to expand and advance its development pipeline.

The company expects that R&D expenses will increase in 2016 as it continues to develop its pipeline and advance its product candidates into clinical trial. G&A expenses were 17.2 million in the fourth quarter of 2015 as compared to 14.2 million in the fourth quarter of 2014.

G&A expenses for the quarter ended December 31, 2015 as compared to the prior year period increased due primarily to an increase in consulting and professional service expenses related to an increase in general business activities. The Company expects that G&A expenses will increase in 2016 as it continues to grow its operations.

The GAAP net loss according to accounting principles generally accepted in Europe for the fourth quarter of 2015 was 90.7 million as compared to a net loss of 21.4 million for the same period in the previous year.

With respect to guidance for 2016, Alnylam expects that its cash, cash equivalents, total marketable securities balance will be greater than 850 million at December 31, 2016. This reflects approximately $100 million in expenditures primarily related to Alnylam’s planned capital investment in the manufacturing facility.

I will now turn the call over to Barry.

Barry?.

Thanks, Mike. You heard from John and Akshay we had a tremendously productive 2015 in recent period as we continue to build the industry’s leading pipeline of RNAi therapeutics and advance for innovative medicines to patients and following approval to the market. Now let’s turn to our 2016 goals and guidance announced in the early January.

As John mentioned, this will be a very data rich period with ten major clinical readouts anticipated this year. With regard to the patisiran program we have achieved our goal of completing Phase III APOLLO enrollment. APOLLO will enable a possible NDA submission in the 2017 timeframe.

We also continue treating patients in our patisiran Phase 2 OLE study and plan to present additional data including complete 18-month data in an oral presentation at AAN in April. We also will present initial 24-month data in mid-2016.

With revusiran, we’re currently enrolling FAS patients in our Phase 3 ENDEAVOUR study and anticipate having data from this trial in 2018. We’re also treating patients with revusiran in a Phase 2 OLE study and we plan to present 12-month from that study in mid-2016.

Additionally, we anticipate it will be a very important year for ALN-TTR02 with a CTA filing planning in the early part of the year, a Phase 1 start mid-year and initial Phase 1 data in late 2016. Now, moving to hemophilia patisiran.

We’re continuing to enroll additional dose cohorts in the ongoing trial Phase 1 trial, including patients with hemophilia receiving a monthly subcutaneous fixed dose regiment. We anticipate presenting additional Phase 1 data in mid-2016 and Phase 1 OLE data in late 2016.

We also plan to start the two Phase 3 trials in 2016 in patients with and without inhibitors respectively. With ALN-CC5, we continue dosing PNH patients in Part C of the Phase 1/2 study and anticipate presenting data in mid-2016 and again in late 2016.

Now, moving on to our Porphyria program with ALN-AS1, we anticipate presenting Phase 1 data and recurrent attach porphyria patients in late 2016. With ALN-ATT, we plan to present initial Phase 1 data in mid-2016.

Now with our PH1program, that’s ALN-GO1 for the treatment of PH1, we expect to treat to start our Phase 1 study in early 2016 and expect to present data in the late part of this year. Now, turning to our three STArs. First, Cardio-Metabolic STAr with ALN-PCSsc, our partners at this company expect to present initial Phase 2 data in late 2016.

With our hepatic infectious disease STAr, we’re planning to file our CTA for ALN-HBV in early 2016 and start a Phase 1 trial with mid-year timing. Now finally as Mike said, we plan to end the year with greater than 850 million in cash. In summary, we are now poised for incredibly data rich 2016.

We very much look forward to sharing more updates from our pipeline in the coming weeks and months. And I’ll now turn the call back over to Christine to coordinate our Q&A.

Christine?.

Thanks, Barry. Operator, if you could open the line now for your questions. As a reminder to those out, we would ask you to limit your questions to two each..

[Operator Instructions] Our first question from the line of Alethia Young from Credit Suisse. Your question please..

Hey, guys. Thanks for taking my question, and congrats on another progress over the past 12 months..

Thank you..

A couple.

I guess, as we’re trying to get closer to the potential approval or hopeful approval of patisiran, I just wanted to think about how doctors, patients alike will, kind of, differentiate in FAP sometimes there is cardiac involvement and Mike they could get access to the drug a little fast faster, they somehow have patisiran, is there an opportunity set of that? And then I have another question as well..

Yes. I mean, I think that’s a great question Alethia. And maybe Akshay, you can begin to answer and then maybe Barry you might want to comment as well..

Within the APOLLO study, we know and we see this already in the Phase 2 early study for patisiran and similarly in the APOLLO study patients have coexisting cardiac disease in addition to the FAP and of course, we are monitoring many of the end points there carefully as well and those would be read out at the time of the Phase 3.

And based on the Phase 2 early we know where we see substantial evidence for stabilization of the disease both in terms of neuropathy and some of those cardiac endpoints, we are optimistic that we have clinical benefit associated with the drug on the cardiac aspects of the disease.

Now, how all of that would be taken and wrapped up into a label and what that means for promotional protease related time but what we do know is that certainly there will be important readouts coming out of APOLLO speaking to both not just the neurological but also the cardiac aspects of the disease..

I agree with that completely. And just to put a fine point on Alethia, assuming the data points in a positive direction we understand that with those with the TTR mutation many patients have a mixed pathology. So obviously we will look at the data and take greatest advantage of the data to treat as many patients as possible..

Following discussions and agreement with the FDA on the right label, of course..

Yep.

And, also I get this question a lot, so I just wanted you to kind of talk about it upfront just thinking about how to enroll like a C5 study if you were to have some success in the middle of the year like kind of a lot of people kind of asking how it would be difficult to enroll and I say that you are thinking about the Monotherapy and the sparing as well, so just maybe if you could give us some more color on that, that would be great..

Yes, Akshay, you do want to do that I think maybe it is useful to highlight the two different types of studies we can imagine, one for monotherapy and the other for foundational therapy on top of provisional eculizumab. .

Yes.

So I think the first thing to say at least here is that, as we reported today, we have begun to enroll PNH patients into Part C and D ongoing Phase 1/2 study and they come in both the flavors that John just spoke of, patients naive to any drugs for PNH including eculizumab and – so they are coming on to ALN-CC5 for the evaluation of ALN-CC5 from a safety and efficacy viewpoint for the monotherapy.

And then in addition we are dosing patients already on eculizumab, but for one or more reasons have active disease potency with elevated LDH and other abnormalities. And so turning to what lies for us beyond that in Phase 3 depending on the data and the outcome from those studies.

As monotherapy we feel confident that we can enroll patients into our PNH monotherapy study with ALN-CC5, because first of all the pharmacodynamics data that we’ve shared and more that will come will, I think, demonstrate the potential for ALN-CC5 monotherapy.

More importantly if we are going to do a monotherapy study, some of these patients we are dosing at the moment we will provide evidence for the justification of ALN-CC5 on its own.

From eculizumab sparing viewpoint, I think, again, we believe that the current data show that ALN-CC5 has rather important pharmacodynamics activity in terms of C5 knockdown with up to 1% residual C5, that’s highly comparable to some of the data of CC5 with eculizumab.

And one can imagine a once monthly or once quarterly, giving that kind of a pharmacodynamics profile, allowing for significant degree of spanning of demand of eculizumab needed and so, for example, one can imagine a once-a-month eculizumab infusion which may be at a substantially lower dose and I think that would be justifiable based on PKMCD [ph] along with our once monthly or once quarterly ALN-CC5.

So, that’s how we’re beginning to think about it, but I think the data coming out middle and later this year from the ongoing exposure with PNH patients will influence and help us design those studies..

I think a very important point to add Alethia is that the human liver over a 90-day period, produces about 4.5 grams of C5 and based on label doses of eculizumab, it requires sic grams of eculizumab basically sop-up all that C5 produced by the human liver.

We’ve shown in our Phase 1 study already that a single injection of ALN-CC5 over the course of a whole quarter substantially reduces the levels of C5 produced in the liver. So, you can imagine the positive impact that would have on generating very low levels of C5 reducing the burden of eculizumab infusions.

But very importantly also improving overall benefit for patients as this plays out by reducing the frequency of breakthrough hemolysis. So, it’s a very compelling approach that of course, really is consistent with our overall goal of maximizing the potential opportunity for ALN-CC5 in patients with complement mediated diseases including PNH..

And just a follow-up on that. I mean as far as like, literally finding the patients, I mean is it the assumption that we should be thinking there are patients in other parts of the world that maybe are not on therapy or – kind of I guess help us understand like kind of the particular populations or what you’re hearing from the community..

Yes, I think there should be patients accessible both in parts of the world where eculizumab is approved, as well as other parts of the world where eculizumab is currently not available. And I can share that some of the patients who were dosing now are certainly in territories where eculizumab is available..

And – absolutely. And then on top of it, don’t forget Alethia that at our R&D Day, Anita Hill said 21% of her patients in leads are unable to get to effective control of their disease with label dose of eculizumab and require either more frequent dosing or higher doses and that is a significant burden on the patients..

Great, thanks..

Thank you. Our next question comes from the line of Alan Carr from Needham & Company. Your question, please..

Hi. Thanks for taking my questions. I was wondering if you could comment on a couple of things.

One of them on spend; what’s your thoughts are here in terms of long-term here in terms of whether or not this will continue to escalate? And then also with respect to the porphyria trial, you just got that started in symptomatic patients and I was wondering if you can comment on what your expectations are for the results when those come later this year? And then also around TTR-SCO2 what the Phase I trial is going to look like.

Is it going to just healthy volunteers, just looking for knockdown, and – or when it comes to the Phase 3 start assuming a good outcome in Phase I, is the results of patisiran trial the gating event for the Phase 3 trial of TTR-SCO2? Thanks..

Well, Alan, if I didn’t like you so much, I would have stopped you after your two questions, because I think we counted four in there. So, let me start and ask Mike and maybe DA to comment on patisiran first. So, Mike..

Yes. So, Alan, looking at 2016, what we’ve guided is cash greater than 850 million.

In that little color on that for 2015 we expect R&D expenses as well as G&A expenses more so R&D expenses to increase in 2016 and along with that as part of the burn for 2016 is around $100 million in expenditures related to a planned capital investment in a manufacturing facility..

Maybe Barry you want to comment little bit on the ongoing horizon?.

Sure. Thanks. Looking forward, obviously as the company continues to advance programs in the Phase 3, Phase 3 is a more expensive than earlier stages of development, and so thinking about spend, spend will increase proportionally. The key thing to remember though is to recall that for our collaboration in rare diseases we are partnered with Sanofi.

And so in terms of what that means regarding burns that can vary based on the reimbursement level that we are getting..

Yes. So I think a long and short of it Alan is that the Sanofi partnership provides us with reimbursement from an R&D expense standpoint and our cash position gives us cash to invest in this pipeline for many years to come. So we are in a very strong position from a balance sheet perspective. It is wonderful to be in this position in this climate..

Do you expect the reimbursement to – is that something that we will start to see more of in 2017 going forward?.

Well, it will be a significant component of this year. You know, we don’t give specific guidance on that but it will be significant from this year and depending on how Genzyme opts into the C5 program, how they opt into the patisiran program.

In other words they go from their regional rights to their 50, 50 rights, it depends upon how they opt to the porphyria program et cetera. Increasingly significant amount of spend will be reimbursed by Sanofi consistent with their rights. .

Thank you. .

Yes. So then you had three other questions. And the other three go right to Akshay, and maybe he will start with the porphyria program and just comment a little bit on the design and study and what we expect to see by year’s end. .

Yes.

So, Alan, the Part 3 of the study follows on from the first two parts which were single and multi-ascending dose studies in asymptomatic high excreter patients, so now I think we unequivocally demonstrated that the activity of the drug clearly reduces the level of the two toxic mediators that bring the disease about and caused the recurrent attacks and they are ALA and PBG.

Now knowing that and doing the measurement where we can bring about the robust reduction in ALA and PBG we’ve moved forward into Part B which is dosing patients with recurrent attack. There is a running Phase where we are documenting number of attacks they get.

Some of them is as many as once a month, for others it’s once every few months, so we are documenting the preexisting attack rate. And then they go on with dosing at the dosing regiment that gives you this potential level of, Alan, PBG knockdown and then we shall count that in that context.

So it’s a placebo control arm as well, so that will give you insight into reduction in attack frequency and as we tend to report the data by year end. So we are looking forward to doing that. We are excited about it certainly. The early PD data from Part A and B are very promising. And then on TTR-CO2. .

Right. Yes. Phase I will be in healthy volunteers, pretty straight forward. We need to demonstrate safety, of course, first and foremost some knockdowns and I think we look forward to exciting results there later in the year.

And in terms of Phase 3 Obviously, I think outcome with patisiran program is a factor in how we think about the overall development of SvO2, but there are other factors to consider.

The revusiran program is going well, those data will be important as well, but a central part of the SvO2 came forward would be on the back drop demonstrating that TTR knockdown was also an clinical benefit in TTR-mediated syndromes and I think that will be an important aspect to market..

Good..

And we’ll obviously look forward to having discussions with regulatory authorities on that path forward. So, thank you, Alan..

Thanks very much..

Yes..

Thank you. Our next question comes from the line of Ted Tenthoff from Piper Jaffray. Your question, please..

Great. Thank you very much for take my question..

Thanks. Thanks..

And I just want to dig a little bit more into patisiran for hemophilia and sort of what the Phase 3s could look like. I think you mentioned that it would be both in inhibitor patients and also non-inhibitor patients.

So, can you give us a sense of sort of how those studies may differ?.

Absolutely.

Akshay, do you want to comment?.

In inhibitor patients, of course, we look forward to enrolling patients in the highest unmet need areas, the hemophilia ALB with preexisting inhibitor and design we will discuss at a later date, but feel confident based on the premiere evidence that we have detail also in non-inhibitor patients that we will get as good ABL signal there.

The APOLLO study will be non-inhibitor patients with hemophilia A or B and again there, the primary endpoints like the first study will be the annualized feeding rate and much more to come on that..

Yes, I think R&D date, I’d just add a little bit, Akshay is right, but just to add little bit more color. One should expect the inhibitor study to be less than 50 patients, the non-inhibitor patient to be – study to be about 150 patients in size.

We can look at an ABR endpoint, for example, over a nine-month period, which is what we share or similar type of period at time. So, those are the types of endpoints, of course, we want to go to the regulators and talk to them about these designs and get them nailed down.

We’ll be having this discussion shortly and we’ll update people as we launch the studies..

Sounds great. Thanks, guys..

Sure. Thank you, Ted..

Thank you. Our next question comes from the line of Ritu Baral from Cowen. Your question, please..

Hi, guys. Thanks for taking the questions today. First question on patisiran and how you start thinking about the commercial positioning versus your Ionis competitor, and what you might be able to do to assist the timeline.

Would you be up for potential rolling NDA, et cetera, how do you see those two drugs specifically for FAP right now? And then I actually have another follow-up..

Good. Well, I’m going to transition it over to Barry.

I’ll just start by saying we were very interested this past November to see the initial Ionis data in terms of TTR knockdown in patients and as we look at those data compared to patisiran over that matter, revusiran, we see our profile being far better than what they are showing in terms of knockdown.

Very specifically, we’re getting a very deep and rapid knockdown of TTR at the 90% level compared to a multi-month slow knockdown required for the Ionis GSK program that gets to no more than a 70%. In fact, with a very wide error bars, so you probably have many patients that are in the 30%, 40% Knockdown in their studies what my guess.

And so that gives us a really strong foundation to have a best-in-class drug. So I’ll start here and then I’ll commercially I will hand it over to Barry..

It starts with – it’s the best product profile and as John mentioned, we believe that from an efficacy, safety and patient experience perspective we are going to have the best product profile and we are going to do everything we can as a commercialized company to ensure the right interface with our patients.

Over and above that, in the orphan disease world the relationships with the key opinion leaders, the investigators is paramount. I would say ours are outstanding. They have known us for seven years and working with this drug.

They not only study [indiscernible] but they are incredibly excited by our commitment continued to invest in innovative medicines of TTRsc02 and that goes a long way. And we have also to the same regard have been building relations with the patient advocacy community. So those matter, relationships and patients best product profile.

In terms of timing, we caught up the exceptional work that our clinical medicine team has done has brought APOLLO to full enrollment by the end of January, over enrolling the study and we assuming a positive readout extensively at the same timing in the United States and maybe even a little bit ahead in terms of approval and in price negotiation in Europe.

So we are in really good shape..

Yes. I would just add to it of course, Ritu we are going to have Alnylam like urgency in the filing of this NDA, which I think will aid us significantly compared to a large pharma company type urgency. I think we will be in a good position there as well.

You have one more question?.

Yes.

How do you see the prioritization of your early clinical programs and preclinical programs particularly the ones that Genzyme doesn’t have partnership with if we are in a pro-attacked bear biotech market what are Alnylam’s priorities and when might you start prioritizing that?.

A great question, Ritu. We brave all our investment Dietz sixes in our pipeline and we are driving based on data and also commercial opportunity.

I think our really top priorities are to drive toward the Alnylam 2020 objective and we are positioned to that with well across the clinical assets today and includes the TTR programs in general but when you look beyond the TTR programs the patisiran, C 5 programs and some of the other programs I would like to go one.

Those are progrooms [ph] that are going to make a big impact and have relatively spritely development house going forward and we have a lot of confidence based on the relationship of biomarkers with clinical relevance that gives us confidence and we understand – those are the drivers and those are the priorities at a high level.

Of course, there are other programs 80s well with the work in metabolic and heap Titans is incredibly important. .

But they are not exactly spritely so to speak..

That’s right. And so we know how to invest to maximize value and we will continue do that as a company. But from where we sit right now we believe that the continued investment with our balance sheet is the right thing that do and that’s what we’re doing as it stands..

Got this. Thanks for taking the questions..

Thank you, Ritu..

Thank you. Our next question comes from the line of Geoff Meacham from Barclays. Your question please..

Hi guys. This is Carter on for Geoff. Thanks for taking our question..

How are you?.

Hey, nice to hear from you, John. Just a follow-up on Ritu’s question in terms of timelines.

Can you maybe just walk through the strategy of not pulling the trigger on the interim analysis? Is it as simple as you feel you’ve caught up or were there other sort of strategic considerations that went into that choice? And then just on TTRSv02, is there any scenario in which you could, I guess, get away with not having to run sort of a longer APOLLO-like or ENDEAVOUR-like study, maybe something driven more on a biomarker non-inferior basis or something like that? Thank you..

Yes. Great questions Carter. Let me start with the first – answer the first one and then Akshay can jump in and he can answer the second one.

As it relates to the interim analysis decision, when we looked at our excellence in terms of finishing approval of APOLLO and the fact that where – as we look at GSK IONS at this point where we’re versus them from a timeline perspective, we have complete caught-up.

It’s in fact; really somewhat unclear actually as to whether or not IONS did even stop their enrollment. They are currently listed as being active on ClinicalTrials.gov. So, we’ve really caught-up. When you look at of what a potential interim might look like.

Let say, you did a 100 patients at 18 months from an interim perspective, it would only buy you about six months of time at most, because of the nature of enrollment into our Phase 3 clinical trial and, of course, you’d have to hit a p-value that is a much, much, much higher standard than what you have to hit at the end of the day, and while we feel very bullish on APOLLO’s powering and in light of our Phase 2 open-label study, you don’t have certainty on that.

You have a smaller sample size, a higher p-value that you have to hit or lower p-value that you have to hit. So, you start introducing some risk in that.

So, in light of the fact that we really caught up, we don’t get that much additional time, it didn’t seem to make sense to take the business risk with of doing an interim analysis with a smaller patients subset with a much higher standard as required.

And on top of that you would only submit often that type of interim analysis results off the primary endpoint of the [indiscernible] not the additional clinical data that comes from the rest of the study, including some of these cardiac endpoint date that might be important for getting a broad label.

So, those are all the factors that weighed into it. I don’t know Akshay, if you have anything to add on that side of it, or you can just go to the TTR-SCO2..

No, I think you covered on patisiran. For SCO2, I think, there are number of ways to think about the further development of that drug beyond the Phase 1. It’s knockdown in FAP, knockdown of TTR in FAP patients. So it still need to get approval on the backdrop of cost effective base from other studies.

It’s that we need to do a small study in FAP patients just to demonstrate knockdown safety and some preliminary stabilization of mNIS much as we’ve done in the Phase 2 early, or something required, I think a lot of this, of course, is pending regulatory discussions and we will share with everybody as soon as we have more news on that.

But I think we are building a very strong foundational base [indiscernible] to really accelerate the development of CR2..

Great. Appreciate the color. Thank you..

Thank you. Our next question comes from the line of Gena Wang from Jefferies. Your question, please..

Hey, guys. Thank you very much for taking my question. So I thought of….

Hi, Gena..

Hi. So I have one question for patisiran and one for Revusiran. For patisiran, the Annualized Bleeding Rate was reported as 2.2 for Part C cohort 23.

So now with three more months treatment – three more months follow-up what will be your expectation for ABR or update at least one data in mid-year? And also do you expect any difference in ABR for the six patients with inhibitor?.

Those were the great questions Gena. Let me give some color on the first part. We were very happy with the ABR rate that we reported at ASH.

That’s very much in line with the ABR rates reported with routine prophylaxis so our once a month drug was showing subcue was showing ABR rates that are similar to what’s been reported with two to three IV infusions a week from drugs like abate and the lactate et cetera, that are use for routine prophylaxis. So those data are very encouraging.

We obviously will be updating data from all of the patients as Akshay said in his comments, in addition to 24 patients we presented at ASH, we have enrolled a couple more cohorts each having three more patients with a fixed dose of drug.

Those data will be presented in the middle part of the year and we will also present whatever data we have in inhibitor patients in the mid part of the year and present whatever data we have in visitor patients and we certainly don’t expect and should not expect any difference in the ABR rate in inhibitor patients because of patisiran.

In terms of the timing for the release there a world hemophilia meeting in July and likely to be a good forum to present the updated data. .

Okay, great. My next question is for revisiran 12 months Phase II OLE data which we should expect in 2016. Since was much higher how should we think about the data interpretation for six months.

Full distance or the percentage of change? And how do you see these through to the Phase III outcome?.

It is a very good question.

Akshay, do you want to handle it?.

I think we are always very transparent in the [indiscernible] change and percent of change and as we go to them previously the anticipation we would see changes at 12 months. I think we yet to wait and see. The tempo of the cardiac disease and how quickly we can see a change in the endpoint within a period of months we are still investigating.

I think in confidence in 18 month sometime frame as we start the Phase III study report duration of the [indiscernible]..

I would just add to that, Gina that the patients in the Phase 2 OLE are actually more advanced in their disease than the patients that we expect to enroll and are enrolling in ENDEAVOUR. And I think ultimately we’ll have to look at their randomized study results to really understand the impact. I think it is a different disease than FAP.

There’s less natural history data that we could really point to, don’t understand it. And so these are all factors that weigh in. But ENDEAVOUR is doing a very clean experiment. We’re looking at the impact of TTR knockdown which is robust and we’ll be able to see how the effect of the drug is versus placebo in that Phase 3 trial..

Great. Thank you..

Thank you..

Thank you. Our final question comes from the line of Anupam Rama from J.P. Morgan. Your question please..

Hey, guys. Thanks very much for taking the question. Just looking through the PNH-CC5 data, help us understand what you’re looking for on LDH here? And are these LDH data sort of gating factors to understanding the longer term development for this program and not only in PNH, but indications beyond even potential layers indications? Thanks. .

Yes. That’s a great question Anupam.

Do you want to handle it?.

Yes, I think, Anupam. The LDH data are important in our evaluation of ALN-CC5, just as they have been important valuation of other agents in PNH including eculizumab, LDH is an important biomarker for red cell hemolysis ENDEAVOUR if anticipated that it should go down substantially if there’s an effective agent on board.

And the agent wouldn’t normalize the level of LDH, that’s not seem to occur at PNH, but the level should approach within 10% or so of the – within normal. So, I think a result like that would signify a significant and early impact in PNH or ALN-CC5 as monotherapy.

If we consider patients and John alluded to this about 21% of patients with PNH have continued ongoing refractory despite PNH, and I think we can state that the reasons for that, I think in addition of ALN-CC5 on the background of eculizumab and we take on those kinds of have patients as well.

Again, we’d anticipate seeing a substantial reduction in LDH in those patients as well..

Does that answer your question, Anupam?.

Yes, yes.

And just sort of gaiting factors trying to understanding the longer term of out lift program rightly and beyond porphyria indications or within the porphyria indications?.

Yes. I think it certainly – in terms of taking on the full extent and the scope of our PNH program this LDH data will be important.

With respect to non-PNH indications, I think that area is something we continue to study and there are a number of factors involved like LDH is more relevant from these other diseases like [indiscernible] where anti-C5 agents have shown promise.

So, that’s – those are topics for another day, but certainly for the PNH phase, the LDH phase is going to be quite impactful..

I think, Anupam, just to add a little bit of color to that. We’re going to be doing more studies outside of PNH probably starting in 2017 and what the PNH studies, of course, will show us is some clarity around dose-dose regimen and so that’s going to be very important for us. So we’ll put it all together.

But 2017 will be a year where we do more outside of just PNH alone because we think the opportunity here goes well beyond PNH, of course..

Thank you. This does conclude the question-and-answer session of today’s program. I’d like to hand the program back to the company for any further remarks..

Great. Well, thanks for joining us this afternoon. We fully expect 2016 to be an exciting year for the company with many clinical data readouts, of course, very important but our focus really remains on the patients that we serve and we are committed with our approach to make an important difference in their lives.

So thank you very much and we will talk to you soon..

Thank you, ladies and gentlemen, for your participation in today’s conference. This does conclude the program. You may now disconnect. Good day..