Alnylam Pharmaceuticals Inc (ALNY) 2014 Q4 法說會逐字稿

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss fourth quarter and year-end 2014 financial results. (Operator Instructions) Please be advised that this is being taped at the Company's request. I would like to turn the call over the to the Company.

Good afternoon everyone. I am 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 be accessed by going to the Investors page of our website the www. Alnylam.com. During today's call, as outlined on slide two, 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 are developing RNAi therapeutics for rare diseases, Cardi-Metabolic Disease, where we are focusing on the unmet needs in dyslipidemia, hypertension, NASH, and type-2 diabetes. And Hepatic-Infectious Disease, where we are 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 there 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 readouts, which we believe together reinforce a significant potential for RNAi therapeutics as a whole new class of medicines.

Akshay's 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 are 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 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 sharing 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 critical end points. Indeed we believe this is a critically important theme for Alnylam going forward and you will 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 continued to advance other programs across our pipeline, and I'm 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 will 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 efforts in this area. Patisiran is our lead program and 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 over10 countries open. Revusiran is our most advanced subcutaneously administered investigational RNAi therapeutic in the clinic today, and it's focused on the 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 these programs and I will start with the results we presented this past October at the American Neurological Association meeting. There we presented interim six month results from our ongoing Phase 2 OLE study of Patisiran patients with FAP. Results showed a mean 0.95 point decrease in the modified neuropathy impairment score mNIS+7 at six months in19 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 the seven 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 result stems from an open label study in a small number of patients, we are encouraged by the data as they suggest evidence for possible disease stabilization in Patisiran treated subjects. In addition to this, Patisiran treatment sustained a sustained mean serum TTL 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 after one year of therapy with no drug-related serious adverse event to date, and all 27 patients enrolled in the study continue to receive drug treatment. Of course we will be very interested to see how these results including the mNIS+7 look at 12 and 18 months. And as John mentioned, we are excited to announce today we plan to present 12-month data at the American Academy of Neurology meeting in Washington, D.C. on April 21st. As I mentioned our APOLLO Phase 3 trial of Patisiran is on going. 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 end point of the study is the difference in the change in mNIS+7 between Patisiran and placebo at 18 months. It is the same neuropathy impairment score we're employing in our Phase 2 OLE study. We're really pleased with the pace of enrollment in APOLLO and we've guided that we would expect to file our NDA for this program in 2017 if the study is successful.

Let's now turn to recent progress with Revusiran. At a meeting held during the American Heart Association meeting in November we presented a [positive] initial Phase 2 data set with patients with TTR cardiac amyloidosis where we showed 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 a safety profile that supported advancement into Phase three. 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 15th. 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 onto 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 evaluate the safety and tolerability of long-term dosing with Revusiran for up to two years, and will also measure effects of treatment toward a number of clinical end points including mortality, hospitalization, and six-minute walk distance, in addition to cardiac markers. We intend to report clinical data from this study about once a year with initial data in late 2015.

To help put these future early data into context we have also announced today that we plan on sharing the results of a natural history study of several hundred 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 on the study's timeline as enrollment continues during the course of this year.

I will now move on to discuss our latest progress with ALN-AT3 an RNAi therapeutic targeting anti-thrombin for the treatment of hemophilia and rare bleeding disorders. As John noted, we view this as a very exciting and innovative program since anti-thrombin knockdown has the potential to rebalance the coagulation cascade in patients with hemophilia and other rare bleeding disorders, which should lead to a [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 [co] at a very low dose of ALN-AT3 at 45 micrograms per kilogram we have demonstrated an up to 70% knockdown of anti-thrombin with effects lasting for about two months. Importantly there was a statistically significant up to 334% increase in thrombin generation. These changes in thrombin generation in severe hemophilia are as if we have 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. It's a highly sensitive method that shows clear differences in patterns between normal blood and blood from hemophilia subjects. We are able to use this method in the most advanced hemophilia subject in the cohort. Remarkably we've been able to document an 80 knock down dependent improvement in whole blood clotting in hemophilia. On day one with no significant decrease in anti-thrombin, you can see the characteristic ROTEM profile for a subject with [fivia] 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 clot shows that the strength of the clot has improved significantly. These encouraging results area also supported by bleeding data where the subject who normally bleeds 10 to 12 times per year when using on demand prophylaxis, has remained bleed free for 47 days as of the data cutoff date of January 6th. Of course these are early results from our Phase 1 study in only a few patients, and we 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 a recent period we 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. This study is first being conducted in healthy volunteers and will 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 with 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 dehydrogenate, a measure of red blood cell hemolysis. At the ASH meeting in December we presented pre clinical 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 biweekly or monthly subcutaneous dosing for over seven months. This level of inhibition of complement activity exceeds the 80% threshold established by existing therapies to be associated with clinical benefit. So if these results translate to humans we would have a high level of confidence that ALN-CC5 could emerge as a potential new therapy for complement-mediated diseases.

Also from our generic 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 for asymptomatic high excreters or ASH patients. And then in AIP patients who experience recurrent porphyria attacks. We were very much looking forward to the continued advancement of ALN-S1 including the start of our Phase 1 trial in mid 2015 with data expected in early 2016.

I would like to now review progress from our Cardio-metabolic pipeline. Of course our leading program in this STAr is our ALN-PCSsc program targeting PCS-K9 in development for the treatment of hypercholesterolemia. Our pre-clinical data 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 the Phase 1 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 part of the Medicines Company who lead clinical development of the program from Phase 2 onward and commercialization of the program if successful.

We also made great progress in the quarter from our third and final STAr, focused on Hepatic-Infectious Disease, where we are developing RNAi therapeutics to address major global health burdens. We have now selected our 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 an up to 3.9 log reduction of HBV (inaudible) after a subcutaneous dose.

Moreover, I think it is notable that our HBV program employs the same GalNac-Conjugate platform that was employed by Regulus with their 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 will agree that it has been an especially exciting and productive time for us as we continue to lead the translation of the 5 STAr RNAi towards the development of innovative medicines . I will 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 year-end 2014 financial results and 2015 guidance. In 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 collaborations 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 was $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 pre-clinical programs. We expect that R&D expenses will increase significantly 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 is due primarily to an increase in non cash stock based compensation expenses. We expect the 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, the fair market value of our investment in Regulus as of December 31st 2014 was $94.6 million as compared to $45.5 million at the end of 2013. As Akshay commented we are pleased with the recent progress 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 heard from John and Akshay, we had a tremendously productive fourth quarter and recent period as we continue to lead the translation of the science of RNAi and build the industry's leading pipeline of RNAi therapeutics. In addition to pipeline progress we were excited to launch our Alnylam 2020 guidance for the advancement and commercialization of 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 we will turn to our 2015 goals and guidance. First with regard to our Patisiran program we are on plan and continue to enroll patients in our Phase 3 APOLLO study. As Akshay mentioned, we currently have over 30 active sites in over10 countries. As we have previously guided, assuming the study is positive, we expect that this study will enable a possible NDA submission in the 2017 time frame. 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-month mNIS+7 data at the American Academy of Neurology meeting in Washington, D.C. on April 21st.

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 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 an updated data set from the Revusiran Phase 2 study at the upcoming American College of Cardiology meeting in San Diego on March 15th. In addition at this meeting we will also plan to present data from a 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 a potential to explore monthly subcutaneous doses.

We plan to share additional data from this trial in mid 2015 at ISCH 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 are advancing ALN-AAT, an RNAi therapeutic in development for the treatment of alpha-1 antitrypsan 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 expect to identify a development candidate in mid 2015 with an 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 an 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 very data and very event rich year with readouts expected from five clinical programs and eight 8 RNAi therapeutic programs expected to be in the clinic for the end of the year. We look forward to sharing more updates from our pipeline in the coming weeks and the months. I will now turn the call back over to Cynthia. Cynthia?

Thanks, Barry. Operator we will now open 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 will now take your questions.

(Operator Instructions) Our first question comes from Alethia Young from Deutsche Bank.

Hey, great. Thanks for taking my questions, guys. I could have a hundred questions with this much stuff as you have going on, but I could limit myself to two.

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

Fair point. The first question is, we have [been] at this before, six-month point with that, but what are the expectations that you're looking for at 12 months heading into this data set? And then, I guess, I just kind of want to think about like is there an opportunity to present the data set again at the end of the year as well for Patisiran?

Right, those are great questions. We are 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 would like to see if that evidence continues. Obviously it is six additional months beyond what we have 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 of interest to see what we see at 12 months. And we haven't seen the data internationally so we don't know. We would like to see that evidence of stabilization continue. Akshay, do you want to comment any further?

No, I think you covered it.

In terms of other readouts, Alethia, I mean look, we have committed to present data once a year. I -- we want to make sure our clinical organization is focusing on execution and not on database locks and analyses with excessive frequency. I think Akshay would appreciate that. Let's see what we see at 12 months and then we'll, if we feel there is a benefit in looking again we will certainly update you at that time.

Great. And then just on hepatitis-B, it looks like you selected a candidate, so congrats. I guess I'm just curious. It looks like the candidate obviously leverages Regulus' technology, but how do you think about the space right now as far as, like, maybe like if you talk about [Tekmira] and Encore, what they are doing RNA, but they are also kind of looking at pills. Like do you guys think that you need to do that? Like, what is your strategy and how has that evolved?

We are staying committed to RNAi as an approach. We think that is an approach that's a winning approach. As you know we also have a program targeting PDL-1, liver specific knockdown of PDL-1 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 will continue to do. There are other drugs that are being developed by other companies for that are on the market including nucleoside analogs as well as Interferon. Those drugs will be used as part of the therapy for HBV infections. So I think we feel that our focus should remain on RNAi because that's what we are very good at. We think our approach will be very important for the treatment of HBV, but I'm sure that our therapies will be combined with other drugs that are on the market today or that are in development from other companies. We'll see how that emerges over time.

Great, thanks.

Thanks, Alethia.

Our next question comes from Ted Tenthoff from Piper Jaffray. Please go ahead

Hi, Ted. (multiple speakers)

Hey guys, congrats on all of the progress. Really exciting, and a dramatically strengthened balance sheet.

Thank you.

(inaudible- multiple speakers) Sanofi participate and retain their equity position. Two quick questions if I may. First, with respect to the hemophilia data this summer, do you think that is something that might be able to make for Vienna, for EHA in June in order to increase your exposure to the European hematologists? And then secondly, getting really excited for the CC5 readout. Maybe you can put into 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 have been public about this, is we are aiming for ISTH, which is the large hemostasis and thrombosis meeting that happens every two years. EHA is also a very good meeting, but ISTH is international happening in Toronto this year. Of course we have to see if our abstracts are accepted. We don't know that at the present time. Keeping our fingers crossed, and I would be surprised if they weren't, not to jinx it, we should be presenting at that meeting. Akshay do you want to comment on the second question?

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

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 are SAD and MAD in healthy volunteers, and they will provide key data readouts as to the safety and pharmaco-dynamic and pharmaco-kinetic activity of the drug. Specifically from a PD or pharmaco-dynamic view point we'll have C5 knockdown. As you know we can get well in excess of 99% knockdown with this drug in non-human primates. And we also 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 suppression serum hemolytic activity. So those are the key readouts beyond safety. And then later we hope to transition ultimately into Part C of the study which is in PNH patients themselves. And in addition to types of readouts I just mentioned, we'll have the additional LDH readout, lactate dehydrogenase, the enzyme that's released from red cells as they're hemolyzed by complement in that disease. And it's -- the [C] levels go down very rapidly as the disease comes under control. So those are the spectrum of endpoints we'll be looking for from this study.

I just remind you, Ted, that we have guided that we'll plan on that 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 study, Part C of the study by the end of the year. So I think the expectation should be 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 2016.

Excellent, you thank you.

Our next question comes from Alan Carr from Needham & Company. Please go ahead.

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

How are you?

Good, thank you. So you are scaling up the organization here with the new cash that you brought in and I was wondering if you can give us a sense of what the organization is going to look like at the end of 2015 in terms of the scale and the proportion is going to be invested in your existing, the sort of rare disease effort versus metabolic and HBV. And then the second question is around the Patisiran Phase 3 trial and how that is coming along. Have you seen a shift as a result of the OLE data? And has that had any impact on the Revusiran Phase 3 trial? Thanks.

Those are great questions. Well, I mean, let me start on the people side of saying that remarkably Alnylam is only 250 people right now with a pipeline of six programs in the clinic. It is two in Phase 3. We have been pretty lean to say the least. We are 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 sensibly chew. And so it is really quite remarkable.

The growth there is going to be relatively modest. Where we are really adding quite a bit of resources is within our development organization where consistent with the scope and scale, and expansion of our development pipeline we obviously need people on board to prosecute and advance those programs. Of course we are 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 toward the back end of the overall R&D process and the early commercial process, and that is how we plan on adding people into this year. And that will continue into 2016, 2017 and beyond as we get closer to market. So quite a bit of exciting growth. On APOLLO, do you want to comment?

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 internationally, but the investigators and the patients in the patient advocacy groups as they've heard about the data. And this has been a tremendous spurt to the enrollment study which is very exciting; it was already going well. We are very pleased with the boost we got from that, and it continues. Of course we are very well deployed now, we're active in over 30 sites in over 10 countries. So I think it just -- we are really very excited about the progress and looking forward to the (inaudible) of data and what they can further do to help the effort both for patients and investigators. 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 also off to a great start.

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

Yes, I mean, we haven't shared all of the details of the exact operational plans, but I think it is suffice to say at this point 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 we are going to be in. There may be some change to that. The bulk of the effort is achieved 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 may see on clintrial.gov right now. There will be expansion on that study for sure.

Great, thanks very much.

Great, Alan, thank you.

(Operator Instructions) And our next question comes from Terence Flynn from Goldman Sachs. Please go ahead.

Thanks for taking the question. 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. What should we really focus on here? With the Patisiran data it was pretty easy given it was mNIS, but really for Revusiran I know there is a host of data. Where would you have us zero in on? Thanks.

Akshay, do you want to handle that?

For Revusiran of course, the first and foremost is always to continue to demonstrate the safety of the product as these patients get dosed out at significantly longer time frames. In addition we will be very interested to see how the exploratory efficacy endpoints go. Two facets of that part of the story is the natural history data coming out in March where we will start sharing with everybody our understanding of important aspects of the disease like six-minute walk, distance, hospitalization rates, mortality. These are all important facets of the disease, of course, and they factor into our study.

Later in the year when we come out with the first lot of Phase 2 early data from Revusiran, the exploratory efficacy outcomes we'll share will involve things like six-minute walk, distance, and additional bio markers like BMP. Much as we did with Patisiran and the neuropathy endpoint, these are all pioneering and important studies. We have to dose these patients and understand exactly the rate of change over time in their disease. We are excited about the hypothesis and we anticipate that we will have an impact on six-minute walk distance and the other outcomes, but it will take time. We look forward to the first data.

And maybe just one on hemophilia. I was wondering if the chronic tox work is done there and if you started the monthly dosing cohort yet. Thanks.

Yes, so I think at this point the dosing is now complete in the chronic studies, and we are looking at final histopath and so forth, but we are encouraged by everything we have seen to date in those studies. And then in terms of the Q monthly dosing, we are getting ready to start that. We did add a third cohort and with the Q weekly regimen we have had before, but right now we are not yet started on the Q monthly but we will soon.

Great, thanks, guys.

Our next question comes from Adam Walsh from Cannacord. Please go ahead.

Hi, thanks a lot for taking my question, guys.

Thanks, Adam

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 have shown some data with AT3 with more to come in the middle of this year, but we are not going to see Phase 1 data from the AS1 program until early 2016. So how should we think about the timing around a Genzyme opt-in decision for those programs, and what kind of data do they want to see for each product before making a decision?

Barry, do you want to handle that?

Yes. Thanks for the question, Adam. The way the Genzyme agreement works is after the two TTR programs between now and 2019, we have to serve them up eight proof of principles, and proof of principles are very clearly defined in the contract. The way to think about those is in most cases it is our Phase 1 data that is designed. So in the case of AT3 specifically, as we've committed we will plan on starting with Phase 2 the end of the year and contractually that means that around the end of the year we would submit a package to them that they would have some amount of time to decide again based upon the contract.

For AT3 they have got to make a decision whether they are in or not. If they are in and it's first round after Phase 1, they can become a regional partner for us, meaning we keep US and Europe, they're partner for the rest of the world. After they see the porphyria data for AS1, they then make a decision whether they want to be a co-development partner with us on hemophilia, in which case they become a regional partner on porphyria. Or if they want porphyria globally meaning they get it to take globally and they become a regional partner with us on hemophilia. That will all play out in the next year, year and a half.

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 time frame.

That's helpful. Thanks a lot.

Thank you, Adam.

Our next question comes from Stephen Willey of Stifel. Please go ahead.

Hi, thanks for taking my questions.

Hi, Steve.

Hi, how is it going? With respect to the staff update that we will be getting at AIN, will you also be giving us in addition to the mNIS+7, some of the cardiac bio marker data that was previously provided during the six-month update?

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

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

Akshay, you want -- will I think we have been petty open about the trial design elements of ENDEAVOUR. If what you're saying is will we -- will you understand better our statistical plan and our statistical analysis? Probably because you will 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 any effort that there might be in terms of trying to reduce the heterogeneity of the patient population. Specifically with respect to baseline six-minute walk times et cetera, et cetera.

We weren't -- we weren't planning on providing any more color on that. Those are details in the protocol that for right now are proprietary to Alnylam. And given that this is a competitive space, I am not inclined to give all of our details out to the outside world. We will probably keep that quiet for the time being, but we have obviously controlled for all of the factors and have been -- are very well educated on how to design this type of trial.

I appreciate it. Thanks.

Yes.

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

Hey, Mike.

Hey, guys, thanks for taking the question. I wanted to -- I got on the call a little 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 ACC.

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

I thought I heard a number, sorry.

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

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

Several hundred, okay. Because I think -- I mean, a lot of my questions are related to what Steve and Terence have been asking. It sounds to me like by your answer to the previous question, John, that there will be a pretty good read across from discovery to sort of the baseline characteristics of the patients enrolled in ENDEAVOUR. Is that a fair statement?

There certainly will be data from the natural history study. Discovery is a different study. That's an on going screening study. The natural history study that has no name other than natural history unless we give it one, is going to provide information around the rate of progression. It is a cross sectional analysis of existing data, it's retrospective and will provide as much information as we can glean from those type of data how these patients progressed. And just as a reminder it includes both FAC and SSA/

Oh, okay. That's very good to know. Thank you. And then I just -- just a quick question on PCS. You've said a number of times that potentially once per quarter therapy, but given that the study so far is 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 one study we are doing -- SAD which is where we are now, and multi dose. 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? That will be informative if we look at their LDL levels at day 90, we will have a very good sense as to whether or not Q quarterly is something that is an attractive option at that point. I think we will get all of the information out of the Phase 1 that will inform the conduct of the Phase 2, And just as a reminder, that study will be done by the Medicines Company.

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

I think if we reproduce the data we have in non human primates where at day 90 they were over 50% reduction of LDL cholesterol. It was not the nadir reduction at day 30 where it was more like 60% to 70% reduction, but I think the area under that curve is a pretty attractive area to the curve for LDL reduction for sure.

Thanks so much for taking my questions.

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

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