Cynthia Clayton - Vice President, Investor Relations and Corporate Communications John Maraganore - Chief Executive Officer and Director Barry Greene - President and Chief Operating Officer Akshay Vaishnaw - Executive Vice President, Research and Development and Chief Medical Officer Michael Mason - Vice President, Finance and Treasurer.

Alethia Young - Deutsche Bank Ted Tenthoff - Piper Jaffray Alan Carr - Needham & Company Terence Flynn - Goldman Sachs Adam Walsh - Canaccord Steven Willey - Stifel Mike King - JMP Securities.

Welcome to the Alnylam Pharmaceuticals conference call to discuss fourth quarter and yearend 2014 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, everyone. I'm Cynthia Clayton, Vice President of Investor Relations and Corporate Communications at Alnylam.

With me today are John Maraganore, our 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.

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 at www.alnylam.com. During today's call, and as outlined on Slide 2, John will provide some introductory remarks and general context for some of our recent progress and activities.

Akshay will summarize the clinical progress across our three strategic therapeutic areas. Mike will review our financials and guidance. And Barry will provide a brief summary of recent business highlights and goals for 2015 and beyond, before we open the call up to your questions.

Before we 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 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.

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 obligations to update such statements. I will now turn the call over to John..

Thanks, Cynthia. Welcome and thanks everyone for joining us this afternoon. During the fourth quarter of 2014 and recent period, we have made excellent progress, as we continue to advance RNAi therapeutics to patients and to the market.

At our recent R&D Day, we introduced our new pipeline growth strategy, where we intend to expand our pipeline in three strategic therapeutic areas or STArs.

Genetic medicines, where we're developing RNAi therapeutics for rare diseases; cardio-metabolic disease, where we're focusing on the unmet needs in dyslipidemia, hypertension, NASH and type 2 diabetes; and hepatic infectious disease, where we're advancing RNAi therapeutics to address global health burdens.

In addition, we recently launched our Alnylam 2020 guidance, where by the end of 2020 we expect to achieve a company profile with three marketed products as well as 10 clinical programs, including four of those in late stages of development across our three STArs.

Alnylam 2020 marks our expected transition from a late-stage clinical development company to a multi-product commercial-stage company with a sustainable pipeline. A profile that we believe has rarely been achieved in the biotech industry.

The fourth quarter of 2014 and recent period were also notable due to many important clinical data read outs, which we believe together reinforce a significant potential for RNAi therapeutics as a whole new class of medicines. Akshay is going to go through this in more detail in just a minute, but I wanted to highlight a couple of key points.

First, an important milestone for the period was the six-month clinical data that we read out from our Phase 2 open-label extension study or OLE study with patisiran.

With the important caveat that this is an open-label study in a small number of patients, we were certainly encouraged by what we believe to be evidence for possible stabilization of neuropathy progression after the first six months of treatment.

We're also pleased today to announce that we plan to present 12 month Phase 2 OLE data for patisiran at the American Association of Neurology Meeting in April. We really look forward to seeing these important results and sharing them with you at that time.

Secondly, with our ALN-AT3 program for the treatment of hemophilia and rare bleeding disorders, we were very pleased to recently report early data from a study, our Phase 1 study, in subjects with hemophilia, showing what we believe to be initial evidence for potential correction of the hemophilia phenotype with ALN-AT3.

We look forward to showing more data from this program in mid-2015, and then again in late 2015. Now together, we believe these clinical data with patisiran and ALN-AT3 form the beginnings of an important bridge for RNAi therapeutics from target gene knockdown to clinical endpoints.

Indeed, we believe this is a critically important theme for Alnylam going forward, and you'll see much of this materialize in 2015, as we generate data to establish the key links between target gene knockdown and clinical outcomes across a wide range of programs.

Now, during the period we also continued to advance other programs across our pipeline, and I am very proud of our team's execution in this regard.

This includes our ENDEAVOUR Phase 3 study with revusiran, which now becomes the company's second RNAi therapeutic to enter a Phase 3 trial; and we filed three clinical trial applications for ALN-PCSsc, ALN-CC5 and ALN-AS1 and have initiated Phase 1 studies for two of those programs.

As a company, we now have six programs in clinical development, which we believe creates a very compelling profile for continued value creation. In closing, it should be very clear that 2015 is going to shape up to be a very exciting year with multiple clinical readouts from five of our key programs.

So with that, I'll now turn the call over to Akshay to provide you with some more details on recent clinical progress at Alnylam.

Akshay?.

Thanks, John, and hello, everyone. We have indeed continued to make great progress with our pipeline of RNAi therapeutics. Let me begin with our RNAi therapeutic programs for the treatment of TTR-mediated amyloidosis or ATTR. As you know, we have two assets in this area.

Patisiran is our lead program, and is aimed at the treatment of ATTR patients with familial amyloidotic polyneuropathy or FAP. This program is in a Phase 3 trial called APOLLO, and we now have over 30 sites in over 10 countries open.

Revusiran is our most advanced subcutaneously administered investigational RNAi therapeutic in the clinic today, and it's focused on treatment of ATTR patients with familial amyloidotic cardiomyopathy or FAC. This program is also in a Phase 3 trial and that trial is called ENDEAVOUR.

Let's turn to some of the data generated from both of these programs, and I'll start with results we presented this past October at the American Neurological Association Meeting. There we presented interim six-month results from our ongoing Phase 2 early study of patisiran patients with FAP.

Result showed a mean 0.95 point decrease in the modified Neuropathy Impairment Score or mNIS+7 at six months in 19 patients with mNIS+7 data available for the current analysis.

As you can see on Slide 11, this decrease in Neuropathy progression compares favorably with 7 to 10 point increase in mNIS+7 at six months that can be estimated from historical data sets in untreated FAP patients with similar baseline characteristics.

With the very important caveat that our results stem from an open-label study in a small number of patients, we're encouraged by this data. They suggest evidence for possible stabilization in patisiran treated subjects.

In patient patisiran treatment achieved a sustain mean serum TTR knockdown at the 80% target level for over nine months, with an up to 89.6% knockdown achieved between doses.

Patisiran was also found to be generally well-tolerated in this study after one year of therapy with no drug-related serious adverse events to date, and all 27 patients enrolled in the study continued to receive drug treatment. Of course, we'll be very interested to see how these results, including the mNIS+7, look at 12 and 18 months.

And as John mentioned, we're excited to announce today that we plan to present 12-month data at the American Academy of Neurology Meeting in Washington D.C. on April 21. As I mentioned, our APOLLO Phase 3 trial of patisiran is ongoing.

APOLLO is a randomized double-blind placebo-controlled study, designed to evaluate the efficacy and safety of patisiran in ATTR patients with FAP, and if successful, to support marketing authorization for patisiran in countries around the world.

The primary endpoint of the study is the difference and the change in mNIS+7 between patisiran and placebo at 18 months. This is the same Neuropathy Impairment Score we're employing in our Phase 2 early study.

We're really pleased with the pace of enrollment in APOLLO and we've guided that we would expect to file NDA for this program in 2017, if the study is successful. Let's now turn to recent progress with revusiran.

A meeting held during the American Heart Association Meeting in November, we presented a positive initial Phase 2 data set in patients with the TTR cardiac amyloidosis, where we shared robust knockdown of serum TTR of up to 98.2% with weekly subcutaneous injections of revusiran.

Revusiran was also shown to be generally well-tolerated in these patients with advanced disease, demonstrating the safety profile that supports advancement into Phase 3. We're announcing today that we plan to share additional results from the Phase 2 study at the American College of Cardiology Meeting in San Diego on March 15.

These data will simply provide a more complete data set from the Phase 2 study we already reported on. The patients from our Phase 2 revusiran study are now rolling over on to an open-label extension study, where they will be able to receive revusiran for an extended period of time, similar to what we've done for patisiran.

The early study will then took a long-term dosing with revusiran for up to two years, and we'll also measure effects of treatment toward a number clinical endpoints, including mortality, hospitalization and six-minute walk distance, in addition to cardiac biomarkers.

We intend to report clinical data from the study about once a year with initial data in late 2015. To help these in future early days into context, we've also announced today that we plan on sharing the results from the natural history study of several 100 patients at the upcoming ACC Meeting in March.

Another milestone for our revusiran program occurred this past December, when we initiated our ENDEAVOUR Phase 3 trial. This is a randomized, double-blind, placebo-controlled study, where we are looking at two co-primary endpoints measured at 18 months.

One being the change in six-minute walk distance between drug and placebo and the other being reduction in serum TTR between drug and placebo. ENDEAVOUR is enrolling initial subjects and we'll provide more guidance from the study's timeline as enrollment continues during the course of this year.

I'll now move on to discuss our latest progress with ALN-AT3 and RNAi therapeutic targeting antithrombin for the treatment of hemophilia and rare bleeding disorders.

As John mentioned, we view this as a very exciting and innovative program, since antithrombin knockdown has the potential to rebalance the coagulation cascade in patients with hemophilia and other rare bleeding disorders, which should lead to an enhanced thrombin generation, improving hemostasis and a possible disease modifying effect providing what may amount to a functional cure.

At the ASH Meeting in December, and then updated more recently at the Goring Coagulation Conference in January, we are pleased to present interim results from our ongoing Phase 1 trial, including what we believe to be initial evidence that ALN-AT3 can potentially correct the hemophilia phenotype.

Specifically, in the second dose cohort at a very low dose of ALN-AT3 at 45 micrograms per kilogram, we've demonstrated up to 70% knockdown of antithrombin with effects lasting for about two months. Importantly, those are statistically significant up to 334% increase in thrombin generation.

These changes in thrombin generation in severe hemophilia are as if we've transformed the disease to a milder hemophilia phenotype, where patients rarely bleed and do not require replacement therapy. To illustrate this in a different way, Slide 18 shows results from a whole blood clotting test called the ROTEM.

This test measures the changes in viscosity in blood during coagulation. A highly sensitive method, which shows clear differences in patterns between normal blood and blood from hemophilia subjects. We're able to use this method in the most advanced hemophilia subject in the cohort.

Remarkably, we've been able to document an 80% knockdown dependent improvement in whole blood clotting in hemophilia. On day one, with no significant decrease in antithrombin, you can see the characteristic growth in profile for a subject with severe hemophilia.

And then on day eight and even further on day 21, you can see the improvement in whole blood clotting, as if the subject's disease is being transformed from severe to mild. Specifically, you can see a significant shortening in clotting time and clot formation time.

Furthermore, the increased thickness of the ROTEM shows that the strength of the clot has improved significantly. This encouraging result is also supported by bleeding data, where the subject who normally bleeds 10 to 12 times per year, when using on-demand prophylaxis, and remain bleed-free for 47 days as of the data cut-off day of January 6.

Of course, these are earlier results from our Phase 1 study in a few patients, and we'll plan on presenting results twice more this year. But in aggregate, we believe these results highlight the potentially transformative opportunity for ALN-AT3 as a possible functional cure for hemophilia.

Also, during the recent period, we have made progress with ALN-CC5, a subcutaneously administered investigational RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. Most importantly, we recently initiated a Phase 1/2 clinical trial with ALN-CC5.

The study is first being conducted in healthy volunteers and we'll evaluate the safety and tolerability of single and multiple subcutaneous doses of ALN-CC5. Secondary objectives include evaluation of clinical activity for ALN-CC5, as measured toward knockdown of serum C5 and the inhibition of serum hemolytic activity.

The study will then be conducted in patients with paroxysmal nocturnal hemoglobinuria or PNH. Of interest, this part of the study will include an exploratory evaluation of the effects of ALN-CC5 on levels of lactate dehydrogenase, a measure of red blood cell hemolysis.

At the ASH Meeting in December, we presented preclinical data with ALN-CC5, showing an up to 99.2% knockdown of serum C5 and up to 96.2% inhibition of serum hemolytic activity in non-human primates with bi-weekly or monthly subcutaneous dosing for over seven months.

This level of inhibition of complement activity exceed the 80% threshold established by existing therapies to be associated with clinical benefit. So if these results translate to humans, we'd have a high level of confidence that ALN-CC5 could emerge as a potential new therapy for complement-mediated diseases.

Also from our genetic medicine STAr, we were very pleased earlier this year to file a clinical trial application for ALN-AS1, a subcutaneously administered investigational RNAi therapeutic targeting ALAS-1 for the treatment of hepatic porphyrias, including acute intermittent porphyria or AIP.

This trial will be conducted initially in AIP patients who are asymptomatic high excreters or ASHE patients. And then in AIP patients who experience recurrent porphyria attacks, we were very much looking forward to the continued advancement of ALN-AS1, including the start of our Phase 1 trial in mid-2015 with data expected in early 2016.

I'd like to now review progress from our cardio-metabolic pipeline. Of course, our leading program in this STAr is our ALN-PCSsc program targeting PCSK9 in development for the treatment of hypercholesterolemia.

Our preclinical data for this program are supportive of a once-monthly and possibly once-quarterly subcutaneous dosing regimen, which we believe could represent a highly competitive target for our profile.

We recently initiated a Phase I study in normal healthy volunteers, with elevated baseline LDL cholesterol, and expect to present initial clinical results in mid-2015.

Recall, that the ALN-PCSsc program is partnered with The Medicines Company, who will lead clinical development of the program from Phase 2 onwards and commercialization of the program if successful.

We also made great progress during the quarter from our third and final STAr, focus on hepatic infection disease, where we are developing RNAi therapeutics to address major global health burdens. We've now selected our development candidate for ALN-HBV in development for the treatment of HBV infection.

ALN-HBV utilizes our ESC-GalNAc-Conjugate platform, which will enable treatment of HBV infection with a monthly subcutaneous dose regimen. In rodent models of HBV infection, we have demonstrated up to 3.9 log reduction of HBV surface antigen after single subcutaneous dose.

Moreover, I think it's notable that our HBV program employs the same GalNAc-Conjugate platform that was employed by Regulus with RG-101 program in HCV. We certainly view their data in HCV as an encouraging sign for what we might expect with our ALN-HBV program in HBV. Accordingly, we look forward to filing an IND for this program in late-2015.

In summary, I hope you'll agree that it has been especially exciting and productive time for us, as we continue to lead the translation of the size of RNAi towards the development of innovative medicines. I'll now turn the call over to Mike for a review of our financials.

Mike?.

Thanks, Akshay. I will be referring to Slide 25, for a discussion of fourth quarter and yearend 2014 financial results and 2015 guidance. This quarter we maintained a solid balance sheet with $881.9 million in cash, cash equivalents and marketable securities.

We also improved our cash position in Q1 of 2015, as a result of a public offering of common stock that we completed in January. Along with concurrent private placements from Genzyme, generating net proceeds of $567 million and bringing our balance sheet to over $1.4 billion on a pro forma basis.

Our GAAP revenues for the fourth quarter of 2014 were $24 million as compared to $10.8 million in the fourth quarter of 2013.

GAAP revenues this quarter included $8.8 million related to our collaboration with Monsanto, $6.9 million of revenues related to our collaboration with The Medicines Company, $5.5 million of revenues from our alliance with Takeda and $2.8 million of revenues from research reagent licenses and other sources. Moving to expenses.

R&D expenses were $55.5 million in the fourth quarter of 2014 as compared to $32.1 million in the prior-year period. This increase was due primarily to additional expenses associated with the advancement of a number of our clinical and preclinical programs.

We expect that R&D expenses will increase significant in 2015, as we continue to advance and expand our pipeline across our three STArs. However, going forward, we expect a significant share of the expenses on our patisiran and revusiran programs to be shared with Genzyme, pursuant to the terms of our alliance agreement.

G&A expenses were $14.2 million in the fourth quarter of 2014 as compared to $8.3 million in the fourth quarter of 2013. This increase was due primarily to an increase in non-cash stock-based compensation expense. We expect that G&A expenses will increase slightly in 2015.

The GAAP net loss for the fourth quarter of 2014 was $21.4 million as compared to a GAAP net loss of $32.4 million for the same period in the previous year. Regarding our equity investment in Regulus Therapeutics.

A fair market value of our investment in Regulus as of December 31, 2014, was $94.6 million as compared to $45.5 million at the end of 2013. As Akshay commented, we're very pleased with the recent progress at Regulus and with our 12% equity position in that company.

With respect to guidance for 2015, we expect we will finish the year with greater than $1.2 billion in cash, which we believe will provide us with a strong balance sheet to enable us to execute on our Alnylam 2020 guidance. I will now turn the call over to Barry..

Thanks, Mike, and hello, everyone. As you've heard from John and Akshay, we had a tremendously productive fourth quarter and recent period, as we continued to lead the translation of the science of RNAi and build the industry's leading pipeline of RNAi therapeutics.

In addition to our pipeline progress, we were excited to launch our Alnylam 2020 guidance for the advancement and commercialization of our RNAi therapeutics.

Specifically, by the end of 2020, we expect to achieve a company profile with three marketed products as well as 10 RNAi therapeutic clinical programs, including four in late stages of development across our three STArs.

We also recently formed a new agreement with Isis Pharmaceuticals, extending our decade-long alliance to lead the development and commercialization of RNAi therapeutics. Now, I'll turn to our 2015 goals and guidance. First, with regard to our patisiran program, we are on plan and continue to enroll patients on our Phase 3 APOLLO study.

As Akshay mentioned, we currently have over 30 active sites in over 10 countries. As we previously guided, assuming the stud is positive, we expect that this study will enable a possible NDA submission in the 2017 timeframe.

We also continue treating patients on our patisiran Phase 2 OLE study, and as mentioned, we are announcing today that we plan to present additional data from that study, including 12 months mNIS+7 data at the American Academy of Neurology Meeting in Washington D.C. on April 21.

Now, with revusiran, we are currently enrolling FAC patients in our Phase 3 ENDEAVOUR study. We are also in the process of rolling over patients from the Phase 2 revusiran trial on to a Phase 2 open-label extension or OLE study and we plan to present initial data from that study in late 2015.

We also plan to share updated data set from the revusiran Phase 2 study at the upcoming American College of Cardiology meeting in San Diego on March 15. In addition, at this meeting, we'll also plan to present data from our natural history study of patients with TTR, cardiac amyloidosis.

Now, moving on to ALN-AT3, we are continuing to enroll additional dose cohorts in the Phase 1 trial with the potential to explore monthly subcutaneous dosing. We plan to share additional data from this trial in mid-2015 at ISTH, and then again later this year.

With ALN-CC5, we are enrolling subjects in the Phase 1/2 study and plan to present initial data in mid-2015 with additional data expected in late-2015. With ALN-AS1, we expect to initiate the Phase 1 trial in mid-2015 and to report initial data in early-2016.

Also, from our genetic medicine STAr, we're advancing ALN-AAT, an RNAi therapeutic in development for the treatment of alpha-1 antitrypsin deficiency-associated liver disease. We remain on track to file a CTA for this program in mid-2015.

With our ALN-GO1 program for the treatment of primary hyperoxaluria type 1 or PH1, we except to identify development candidate in mid-2015 with IND expected in 2016. With ALN-PCSsc, we plan to present initial data from the ongoing Phase 1 trial in mid-2015.

And finally from our RNAi therapeutic product perspective with ALN-HBV, we plan to file an IND for this program in late-2015. Now, as Mike said, we plan to end the year with greater than $1.2 billion in cash. In summary, 2015 promises to be a varied data and very event-rich year with readouts expected from five clinical programs.

And eight RNAi therapeutic programs expected to be in the clinic by the end of the year. We look forward to sharing more updates from our pipeline in the coming weeks and months. I will now call back over to Cynthia.

Cynthia?.

Thanks, Barry. Operator, we will now open up the call up for questions. As a reminder to those dialed in, we would like to ask you to limit your questions to two each. We'll now take your questions..

[Operator Instructions] And our first question comes from Alethia Young from Deutsche Bank..

I can have a hundred questions with so much stuff that you have going on, but I will limit myself to two..

You can always get back in the queue afterwards, Alethia..

The first question is, we've guided this before, kind of six month timeframe with that, but like what are expectations that you're looking for 12 months heading into this data set? And then, I guess, I just kind of want to think about like is there a opportunity to present this data set again at the end of the year as well for patisiran?.

I mean, we're obviously excited to see what we see for the 12 month data. We were very encouraged at six months to see what looks like evidence for disease stabilization as compared to historical data. I think, Alethia, we'd like to see if that evidence continues obviously at six additional months beyond what we've shared before.

We know that the historical progression rate based on our natural history study and other studies as well should be in the range of approximately 20 point increases in the mNIS+7. So it will be have interest to see what we see at 12 months.

We haven't seen the data internally, so we don't know, but we'd like to see that evidence of stabilization continue.

Akshay, do you want to comment any further?.

No. I think you covered it..

And then in terms of other readouts, Alethia, I mean look we've committed to present data once a year. We want to make sure that our clinical organization is focusing on execution and not on database locks and analyses with a excessive frequency, I think Akshay would appreciate that.

But let's see what see at 12 months and then if we feel that there is benefit in looking again, we'll certainly update you at that time..

And then just on Hepatitis B, I mean it looks like -- this is lot to the candidates, so congrats. And I guess I'm just curious -- and it looks like the candidate obviously leverages Regulus' technology.

But just how do you think about the space right now as far as like, maybe like if you talk about Tekmira and OnCore, whether they're doing RNAi, but they are also are kind of looking at pills, like do you guys think that you need to do that, like what's your strategy and how has that evolved?.

Yes. I mean we're staying committed to RNAi, as an approach, we think that's an approach that's a wining approach. As you know, we also have a program targeting PD-L1, liver-specific knockdown of PD-L1 as well as a program looking at Hepatitis Delta. These are all going to be RNAi therapeutic programs.

That's what we do well and that's what we're going continue to do. There are other drugs that have been developed by other companies or that are on the market including nucleoside analogs as well as interferon those drugs will be used as part of the therapy for HBV infection.

So I think we feel that our focus should remain on RNAi, because that's what we're very good at. We think our approaches will be very important for the treatment of HBV, but I am sure that our therapies will be combined with other drugs that are on the market today or that are in development from other companies.

And we'll see how that emerges over time..

Our next question comes from Ted Tenthoff from Piper Jaffray..

Two quick questions, if I may.

First, just with respect to the hemophilia data this summer, do you think that's something that might be able to make for Vienna, for EHA in June in order to kind of increase your exposure to the Europe hematologist? And then secondly getting really excited for the CC5 readout? Maybe you can just put in perspective, what we should be expecting from that?.

Let me handle the first one, and then Akshay can handle the second one. Our goal and we've been public about this is we're aiming for ISTH, which is the large hemostasis and thrombosis meeting that happens every two years. EHA is also is very good meeting, but ISTH is international. It's happening in Toronto this year.

Of course, we have to see if we our abstracts are accepted, we don't know that at the present time. So keeping our fingers cross and I'd be surprised if they weren't, not to jinx it, we should be presenting at their meeting. Akshay, do you want to comment on the second question..

Sorry, Ted, can you just repeat the second part..

So with respect to the CC5 update, the Phase 1 update, just remind us what we should be expecting from that?.

The study kicks off with Parts A and B which was started in healthy volunteers and they will provide key data results, as to the safety and pharmacodynamic and pharmacokinetic activity of the drug, specifically from a PD or pharmacodynamic view point will have C5 knockdown.

As you know we can get well in excess of 99% knockdown with this drug in non-human primate. And we'll provide evidence for suppression of serum complement hemolytic activity. And again in primates, we've consistently demonstrated that we can get above that 80% threshold of suppressions in serum hemolytic activity.

So those are the key readouts beyond safety. And then later we hope to transition ultimately into Part C of the studies, which is in PNH patients themselves.

And in addition to the types of readout I just mentioned, we'll have the additional LDH readout, lactate dehydrogenase enzymes that's released from red cells as they're hemolyzed by complement disease, and the serum levels go down very rapidly, as the disease comes under control.

So those are the spectrum of added points we'll be looking from the study..

And I'll just remind you, Ted, that we've guided that we'll present data in mid-2015 and late 2015 from the C5 program and that our goal is to have our initial patient with PNH enrolled in the Part C of the study by the end of the year.

So I think the expectation should be mostly on the Parts A and B of the study in terms of data readouts for this year with the Part C data most likely being early in '16..

Our next question comes from Alan Carr from Needham & Company..

So you're scaling up the organization here with the new cash that you brought in.

And I was wondering if you could give us a sense of what the organization is going to look like at the end of '15 in terms of scale? And proportion is going to be invested in your existing sort of rare disease effort versus metabolic and HBV? And then the second question is around the patisiran Phase 3 trial.

How that's coming along? Have you seen a shift as a result of the OLE data? And have that had any impact on the revusiran Phase 3 trial?.

Well, I mean let me start on the people side of saying that remarkably Alnylam is only 250 people right now, with the pipeline of six programs in the clinics, and two in Phase 3. So we've been pretty lean to say least. We're going to probably end the year with about 350 employees in the company.

And of course, a lot of the growth -- I mean our research organization is incredibly productive. They are generating more development candidates with our reproducible modular platform than our development organization can sensible chew. And so it's really quite remarkable. So the growth there is going to be relatively modest.

Where we're really adding quite a bit of resources is within our development organization, where consistent with this scope and scale and expansion of our development pipeline, we obviously need people on board to help us prosecute it and advance those programs.

Of course, we're also adding people within manufacturing, and our quality organization, and even some people within our small, but appropriately sized commercial organization, and of course medical affairs as well.

So it really is, as you would expect Alan, growth that goes towards the backend of the overall R&D process and all the commercial process, and that's how we plan on adding people into this year. And that will continue into '16, '17 and beyond, as we get closer to market. So quite a bit of exciting growth.

On APOLLO do you want to comment?.

Yes. Alan, that's an important question.

Of course, we are delighted with the data from the Phase 2 early study of patisiran where we showed that seemingly stabilization of the neuropathy score, and those data really have excited everybody, not just internally, but the investigators and the patients in the patient efficacy groups, as they've heard about the data.

And this really has been a tremendous spur to the enrollment of study, which is very exciting. It was already going well, but we are very pleased with the boost we got from that and continues. Of course, we are very well deployed now. We are active in over 35 in over 10 countries.

So I think we're really very excited about the progress, and looking forward to the 12 months data and what they could further do to help the effort, both for patients and investigators.

And overall, I think the totality of our efforts in the TTR space are truly registering with the patient communities and the physicians, and so our revusiran efforts in Phase 3 are also off to a great start..

Will you be adding any more sites in any more countries or are you at the level that you think you should be on?.

I mean, we haven't shed all the details of the exact operational plans. But I think it's suffice to say that at this point in a one year into the study, we've made a lot of the progress that we needed to make in terms of the numbers of sites, the numbers of countries that we were going to be.

And so there maybe some change to that, but the bulk of the effort is achieve, and that is a question of driving hard on the enrollment..

Obviously, with ENDEAVOUR, which is the revusiran program, there will be a larger number of sites and countries as compared to what you might see in ClinicalTrials.gov, right now. So there is going to be expansion on that study for sure..

And our next question comes from Terence Flynn of Goldman Sachs..

Just one on revusiran. I was wondering if you can help frame expectations for us for the open-label extension data and also the natural history study. Just what should we really focus on here? I mean, the patisiran data, it was pretty easy, given it was mNIS.

But really for revusiran, I know there is a hosted data, but really where would you have a zero in on?.

Akshay, you want to handle it?.

So for revusiran, of course, first and foremost, always it continues to demonstrate the safety of the product that these patients get dosed up and significantly longer timeframes. In addition, we'll be very interested to see how some of the exploratory efficacy endpoints go.

Two facets to that, part of the story is the natural history data set coming out in March, where we'll start sharing with everybody our understanding of important aspects of a disease like six-minute walk distance, hospitalization rates, mortality, these were all important facets to disease of course and they all factor into our study.

And later in the year, when we come out with the first lot of Phase 2 early data from revusiran, the exploratory efficacy outcomes will show, we'll really involve things like six-minute walk distance and additional biomarkers like BNP.

But much as we did with patisiran and the neuropathy endpoint, these are all pioneering and important studies, and we have to dose these patients and understand exactly the rate of change overtime in their disease. We're excited about the hypothesis.

We anticipate that it will have impact on six-minute walk distance and the other outcomes, but it will take time. And so we look forward to the first lot of data..

And then maybe just one on hemophilia.

I was wondering if the chronic tox were is done there and if you've started the monthly dosing cohort yet?.

So I think at this point the dosing is now complete in the chronic studies, and we're looking at final histopath and so forth, but we're encouraged by everything we've seen to date in those studies. And then in terms of the Q monthly dosing, we're getting ready to start that.

We did add a third cohort and with a Q weekly regimen that we have before, but right now we're not yet started on the Q monthly, but we will soon..

Our next question comes from Adam Walsh of Canaccord..

With respect to ALN-AT3 and the ALN-AS1 under the Genzyme collaboration, Genzyme has the opt-in right to choose between one of those two programs on human proof-of-principal. You've already shown some data with the AT3 with more to come in the middle of this year, but we're not going to see, I guess Phase 1 data from AS1 program until early 2016.

So how should we think about the timing around the Genzyme opt-in decision for those programs? And what kind of data do you think they want to see for each product before making decision?.

Barry, do you want to handle that?.

So the way the Genzyme agreement works is that after the two TTR programs between now and 2019, we have to serve them up eight proof-of-principals. And proof-of-principals are very clearly defined in the contract. But the way to think about those is in most cases it's our Phase 1 data that's designed.

So in the case of AT3 specifically, as we've committed we'll plan on starting the Phase 2 end of the year. And contractually, that means that around the end of the year we would submit a package to them as they have some amount of time to decide, again based upon the contract.

For AT3, they've got a make a decision whether they're in or not, and if they're in, in this first round after Phase 1, though they can become original partner for us, meaning we keep you us in Europe, they partner for us to growth.

After they see the porphyria data for AS1, they then make a decision whether they want to be a co-development partner for us on hemophilia, in which case they become a regional partner on porphyria or whether they want porphyria globally, meaning they get it to take globally and they become a regional partner with us on hemophilia.

And that will all play out in the next year or year-and-a-half..

Yes. I would expect that given timing for AS1 data and for them to review the package that that should be something that will ultimately be decided in the mid-to-late 2016 timeframe..

Our next question comes from Steven Willey of Stifel..

Just with respect to the [ph] SAP update that we're going to be getting at AAN, will you also be giving us in addition to the mNIS+7 some of the cardiac biomarker data that was previously provided during the six months update?.

Yes, you bet. As I hope you guys can appreciate, we provide all the data. You will see it all. So we expect to provide updates on those cardiac subgroup patients as well..

And then with respect to the natural history data that we're going to be getting in March, will you also be giving us, will that be kind of an opportunity for us to maybe get a little bit more of an idea as to some of the more specific trial design, logistics of ENDEAVOUR..

I think we've been pretty open about the trial design elements of ENDEAVOUR.

If what you're saying is, will you understand better our statistical plan and our statistical analysis probably, because you'll see the underlying data that was used for the most part essentially for how we designed ENDEAVOUR, is that what you mean?.

Yes, I guess, just kind of any effort that there might be in terms of trying to reduce some of the heterogeneity of the patient population, specifically with respect to kind of baseline six-minute walk times et cetera, et cetera?.

We weren't planning providing anymore color on that. I mean those are details on the protocol that provide now are proprietary to Alnylam. And given that this is a competitive space, I'm not inclined to give all of our details out to the outside world.

So we're going to probably keep that quite for the time being, but we've obviously controlled for all those factors, and are very well-educated on how to design this type of trial..

And our last question comes from Mike King of JMP Securities..

I got on the call a little bit late, so I did not hear the number that Akshay gave as far as the number of patients in the natural history study for revusiran that will be available at SEC?.

Mike, I actually didn't gave a number, so you didn't miss anything..

I thought I heard a number, sorry..

Yes, but just to the inquiry, it's going to be substantial data set in triple digit numbers of patients. So I think people will find it a pretty comprehensive assessment of the many different aspects of this devastating cardiological disease..

I believe in the prepared remarks, Mike, we said several hundred..

Because I mean a lot of my questions are related to what Steve and Terence have been asking.

I guess, it sounds to me like by your answer to the previous question, John, that it will be a pretty good read-across from DISCOVERY to sort of the baseline characteristics of the patients enrollment in ENDEAVORS, is that a fair statement?.

Yes, there certainly will be data from the natural history study, which is not our -- DISCOVERY is a different study that's a ongoing screening study, but the natural history study that has no name, other than natural history.

It must be given name, is going to provide information around the rate of progressions, it's a cross-sectional analysis of existing data to retrospective and it will provide as much information as we can glean from those type of data around how these patients progress. And just as a reminder it includes both FAC and SSA..

I just had quick question on PCS. You've said a number of times that potentially once-per-quarter therapy, but given the study so far it's going to do monthly consecutive doses times two.

How should we think about the next dosing cohort as far as the intervals, will you do both monthly and quarterly or how should we think about that?.

For the Phase 1 study, we are doing SAD, right, which is where we are now and then multi-dose. And in the multi-dose phase it is Q monthly. Of course, our clarity around quarterly will become incredibly self-evident as we look at the time course for LDL reduction in the subjects that get one single-dose, right.

And so that will be very informative if you we look at their LDL levels at day 90, we'll have a very good sense as to whether or not Q quarterly is something, which is an attractive option at that point in time. So I think we'll get all the information out of the Phase 1 that will inform the conduct Phase 2.

And just as a reminder that study will be done by The Medicines Company..

And I don't know if you can speak to it now as far as what level of persistent reduction in LDL cholesterol you'll meet to see at day 90, in order to feel comfortable that you can go with Q quarterly dosing?.

Well, I think if we reproduce the data we have in non-human primates at day 90, there were still over 50% reduction of LDL cholesterol. It wasn't the Nadir reduction at day 30 or so, where it was more like 60% to 70% reduction, but I think the area under that curve is a pretty attractive curve for LDL reduction for sure. End of Q&A.

So thanks everyone. Thanks for joining us. Listen, as Barry said, I think 2015 is going to be a very data-rich event-rich year for Alnylam. And we look forward to sharing further updates with you in the weeks and months to come. Good night, everybody..

Ladies and gentlemen, this does conclude today's conference. Thank you for attendance. You may now disconnect. Everyone have a great day..