Alnylam Pharmaceuticals Inc (ALNY) 2014 Q3 法說會逐字稿

Ladies and gentleman thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss third quarter 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 conference over to the Company.

Good afternoon. I'm Josh Brodsky, the Manager 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 and Chief Medical Officer and Mike Mason, Vice President of Finance and Treasurer. Laurence Reid, our Chief Business Officer is also here 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 2 John, will provide some introductory remarks and provide general context for some of our recent progress and activities. Akshay will summarize the clinical and preclinical progress with our pipeline. Mike will review our financials and guidance and Barry will provide a brief summary of certain business highlights and goals for 2014 and beyond, before opening the call for your questions.

Before we begin, I would like to remind you that this call will contain remarks concerning Alnylam 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 Josh and it's great to have you fill in today for Cynthia since she's not feeling well. Welcome and thanks everyone for joining us this afternoon.

During the third quarter of 2014 in recent period, we continued to execute on our efforts to advance RNAi therapeutics to patients and the market. We reported on several meaningful clinical and preclinical data sets, which together continue to reinforce what we believe to be the significant potential of RNAi therapeutics as a whole new class of genetic medicines.

Akshay will go through our pipeline progress in more detail momentarily, but I wanted to highlight some key points. First, an important milestone for the period was the six-month clinical data that we reported from our phase 2 open-label extension, or OLE, study with patisiran.

With the important caveat that this is an open-label study, in a small number of patients, we are very encouraged by what we believe to be evidence for possible stabilization on neuropathy progression after the first six months of treatment. We believe these new data form the beginnings of an important bridge for RNAi therapeutics from target gene knockdown to clinical endpoints.

Indeed this is an important theme for Alnylam going forward, as we generate data to establish the key links between target gene knockdown and clinical outcomes across a wide range of programs. For example in our hemophilia program, we'll look forward to seeing the potential relationship of antithrombin knockdown with increased thrombin generation and reduced annualized bleeding rates in people with hemophilia.

In our PCSK9, we'll look forward to seeing the potential relationship of PCSK9 knockdown with decreased LDL-cholesterol levels in people with hypercholesterolemia. In our complement program we'll look forward to seeing the potential relationship of C5 knockdown with hemolysis inhibition and/or lactate dehydrogenase levels in patients with PNH.

In short these are a growing number of important bridges, correlating target gene knockdown and clinically meaningful end points to what we expect to read out over the next 12 months to18 months. To me that's very exciting. I'd also like to highlight our operational execution of programs across our pipeline.

This includes our TTRsc, or revusiran program where we have completed our phase 2 study, started our phase 2 OLE, and based on favorable discussions with FDA and EMA, are now well prepared for the expected start of our phase 3 cardiac amyloidosis study by this years end.

Also we're now making strong progress on enrollment in our AT3 hemophilia program and expect to share important data at ASH regarding this program. We expect to share, of course, a more complete data set next year, likely at the ISTH meeting in June.

Finally, we recently filed our PCSK9 CTA and in fact just a few hours ago we received approval of that CTA filing. I think it's fair to say that receiving our CTA approval for this new filing within about a week after submission, should tell you that we are preparing excellent data packages. With molecules that have a wide therapeutic index and compelling critical value propositions.

Were also on track to file our CC5 CTA by years end and then our AS-1 porphyria IND is expected to de filed by the end of this year or early next. Now, as we enter the final couple of months of 2014 we very much look forward to sharing additional clinical and preclinical updates from our pipeline during AHA in November and at the ASH meeting in December.

Importantly, we plan to recap these and other efforts as well a share with you some of our future plans for the development of RNAi therapeutics at an R&D day that we plan to host on Friday, December 12, 2014 in New York City. We invite you to join us and hope that you can attend. Because we'll be providing some exciting details about the Company going forward and we'll be providing more details on the R&D day in the weeks to come.

Finally, I'd like to touch briefly on a recent news that the leadership change at Sanofi. The bottom line here is that we don't anticipate any impact to our partnership with Genzyme, as a result of these developments. Chris Viehbacker is a great leader and we have enjoyed working with him. We certainly wish him well. However our partnership is with Genzyme and Sanofi, not with one person.

Accordingly, we expect our relationship to remain very strong as we are working together to deliver important innovations for patients. With that I'll now turn the call over to Akshay to provide you with some more details a recent clinical and preclinical progress. Akshay?

Thanks John and hello everyone. We have indeed continue to make great progress with our pipeline of RNAi therapeutics. Let me with our patisiran program.

Patisiran is our lead 5x15 genetic medicine program and is aimed at the treatment of TTR mediated amyloidosis or ATTR patients with Familial Amyloidotic Polyneuropathy, or FAP. This program is enrolling patients in our phase 3 APOLLO trial, a randomized double-blind placebo controlled study, designed to evaluate the efficacy and safety of patisiran in ATTR patients with FAP.

The primary endpoint of the study is the difference in the change in the modified neuropathy impairment score, or mNIS+7, between patisiran and placebo at 18 months. APOLLO is designed to demonstrate the efficacy and safety of patisiran in support of [marketing utilization] in countries around the world. We're pleased with the pace of enrollment in APOLLO and we now have over 26 site active in nine countries.

In the meantime at the American Neurological Association meeting in October, we presented interim six-month results from our ongoing Phase 2 OLE study of patisiran in patients with FAP. The result showed a mean 0.9 point decrease in mNIS+7 at six months in 19 patients with mNIS+7 data available for the current analysis.

This decrease in neuropathy progression compares favorably with the 7-point 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 a very important caveat that our results stem from an open-label study, in a small number of patients, we're encouraged by these data as they suggest evidence of disease stabilization in patisiran treated patients.

Of course, we'll be very interested to see how these outcomes look at 12 and 18 months, which the data we should be in a position to see over the next year. In addition, patisiran treatment achieved the same mean serum TTR knockdown at the 80% target level for over nine months with an actual 89.6% knockdown achieved between doses. Overall, we view this as an important result for many reasons.

First, this consistent level of knockdown gives us confidence in our potential to maintain knockdown throughout this study and also in APOLLO, since we're using the same dose and dose regimen. Further these results show that we're achieving between 80% to 90% TTR knockdown with minimal inter-subject variability over the nine-month period.

So we can imagine that the area under the curve for TTR knockdown is exceeding the 80% level and actually may be approaching the 90% level. Finally, it should be noted that this is now what we believe to be the industry's best evidence to date that RNAi can be achieved in humans over a long duration of treatment.

Patisiran has also found to be generally well tolerated in this study after one neuropathy, with no drug-related serious adverse effects to date. And all 27 patients enrolled in the study continue to receive drug treatment. Also for our ATTR program we're advancing revusiran, also known as ATTRsc for the treatment of ATTR patients with cardiac amyloidosis.

This program is in a pilot Phase 2 study aimed at evaluating the tolerability and preliminary clinical activity of ALN-TTRsc in patients with familial amyloidotic cardiomyopathy, which is caused by autosomal dominant mutations in the TTR gene or senile systemic amyloidosis, which is caused by idiopathic accumulation of wild type TTR in the heart.

In the study, as shown on slide 12, revusiran was administered over a five-week period and we collected data on tolerability, TTR knockdown and certain exploratory clinical endpoints. Just this morning we announced that we have completed enrollment in this study with 26 TTR Cardiac Amyloidosis patients. We look forward to presenting initial results from the study at the meetings to be held during American Heart Association meeting, later this month.

Regarding this data presentation we believe that tolerability and TTR knockdown results will be of particular interest, especially in light of the disease population, which is both frailty to the disease burden and comprised of elderly subjects. Initial clinical endpoint results should really be considered exploratory in light of nature -- exploratory in nature in light of the short duration of treatment, 35 weeks. And the relatively smaller sample size for the pilot Phase 2 study.

We also announced this morning that our revusiran OLE, or OLE study is open for enrollment. The OLE study will evaluate the safety and tolerability of long-term dosing with revusiran for up to two years, and will also measure effects of treatments toward of a number of clinical endpoints, including mortality, hospitalization, 6-minute walk distance, in addition to cardiac biomarkers.

We believe this longer duration of treatment should be particularly informative regarding the tolerability and potential clinical activity associated with chronic dosing. In addition to clinical endpoints, such as mortality, hospitalization, 6-minute walk, cardiac echo and MRI, we will also collect data on amyloidosis in the heart by technician imaging and amyloid deposition from fat pad aspirates.

Of course we'll also collect data on cardiac biomarkers. We intend to report clinical data from the study about once a year with initial data in 2015. In addition, as John mentioned, we have completed discussions with regulatory authorities in both the US and EU regarding the design of a Phase 3 study with TTR cardiac amyloidosis patients. And we remain on track to initiate the study by the end of this year.

We will share the specific designs of this Phase 3 trial, upon study initiation. I also want to point out that at the OTS meeting in October we presented results from nonclinical chronic GLP tox studies with revusiran, in rats and non-human primates showing that chronic dosing with revusiran was generally well tolerated.

The completion of these toxicology studies confirms the wide therapeutic index for revusiran and provides encouraging results for our overall GalNAc-si RNA conjugate platform. It also enables the advancement of revusiran into a Phase 3 clinical trial. And supports the potential filing in the future of a new drug application, or NDA.

Beyond that effort we also continue to enroll patients -- we continue to enroll people with hemophilia in our Phase 1 trial with ALN-AT3, a RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia and Rare Bleeding Disorders.

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. Resulting in the potential for in-home thrombin generation and improved hemostasis.

Recall that this past May, we reported initial topline positive data from that single-dose healthy volunteer, Part A of the study, which was comprised of four subjects, randomized 3-1, drug to placebo. We then transitioned to the multiple ascending dose, Part B, of the Phase 1 study, which is designed as an open-label multi-dose escalation study enrolling up to 18 people with moderate to severe hemophilia A or B.

The primary objective of this part of the study is to evaluate safety and tolerability of multiple doses, specifically three doses, of subcutaneously administered and ALN-AT3 hemophilia subjects. Secondary objective, include [assessment] of clinical activity as determined by knockdown of circulating AT levels, an increase of thrombin generation at pharmacologic doses of ALN-AT3.

After a slow initial start into the hemophilia phase of the study, we're now encouraged by enrollment progress and prospects with completing the study in the first half of next year. We intend to present clinical results from the Phase 1 of the year at the ASH meeting in December.

We now expect this presentation to include initial tolerability and clinical activity data from the first lowest dose, dose escalation cohort of subjects with hemophilia. In addition to data from one cohort enrolled in the single ascending dose phase, performed in healthy volunteer subjects. In addition, we expect to share the initial tolerability data from the second hemophilia dose cohort.

We expect to provide a more complete presentation of the ALN-AT3 Phase 1 data in mid-2015, likely at the ISTH meeting. Also during the recent period, we made progress with ALN-PSCsc, a subcutaneously administered RNAi therapeutic targeting PTSK9 for the treatment of hypercholesterolemia.

We recently filed a CTA ALN-PSCsc and expect to initiate a Phase 1 study either later this year or early next, with initial clinical results expected in mid-2015. ALN-PSCsc is now our third-down GalNAc-si RNA conjugate to enter clinical development stage.

And the second program using our enhanced stabilization chemistry or (ESC)-GalNAc technology that provides enhanced potency and durability with a wide therapeutic window. Recall that the ALN-PSCsc program is part of The Medicines Company who will lead the development of the program from Phase 2 onward and ultimately the commercialization of the program.

I'd like to now turn to our preclinical pipeline beginning with ALN-CC5, a subcutaneously administered RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated disorders.

At the International Complement Workshop in September, shown here on slide 18, we presented new data in non-human primates demonstrating potent and clamped C5 knockdown, as well as robust inhibition of complement activity in non-human primates, for up to 100 days, with a subcutaneous monthly dosing regimen.

We're also encouraged by our new data in rodent disease models, including members neuropathy and anti-collagen induced arthritis. We remain on track to filing a CTA for ALN-CC5 by the end of this year and expect to present initial clinical results in mid-2015. In addition we plan to present additional preclinical results from this program at the upcoming ASH meeting in December.

Amongst other activities detailed in our press release, we've also made continued progress on additional development stage programs. In particular, with ALN-AS1 an RNAi therapeutic in development for the treatment of hepatic porphyrias, where we remain on track to track to file an IND later this year or early next.

In this program we have also initiated the EXPLORER trial, a prospective observational study of patients with hepatic porphyrias, which aims to characterize the clinical cause, management and disease burden of patients that suffer from recurrent attacks.

Finally and in closing, I want to highlight the positive interim clinical data from Regulus Therapeutics with their compound, RG-101. A GalNAc-Conjugated anti-miR targeting microRNA-122 for the treatment of hepatitis C virus infection. As reported by Regulus, interim results from the ongoing clinical study demonstrated that the treatment with a single subcutaneous dose of 2 mg/kg of RG-101 as monotherapy resulted in significant and sustained reduction in HCV RNA, as well as to mean viral load reduction of 4.1 log at day 29.

Importantly RG-101 employs Alnylam's proprietary GalNAc-Conjugate delivery technology and these data provide yet another clinical proof of concept for GalNAc. We're pleased to be an approximately 12% of Regulus and we believe that their continued progress has the potential to deliver many meaningful values to Alnylam shareholders.

In summary and I hope you'll agree, there has been an especially exciting productive time for us, as we continue to lead the translational of the science of RNAi toward the development of innovative methods. I'll now turn the call over to Mike for a review of our financials. Mike?

Thanks Akshay. I will be referring to slide 21 for a discussion of third quarter 2014 financial results.

This quarter we maintained a strong balance sheet with $915 million in cash, cash equivalents, and marketable securities. Our GAAP revenues for the third quarter of 2014 were $11 million as compared to $9 million in the third quarter 2013. GAAP revenues this quarter included $5.5 million related to our collaboration with Takeda, $3.4 million related to our collaboration with Mansanto, and $2.1 million related to our collaboration with The Medicines Company, research reagent licenses and other sources.

This includes a $1 million payment from Arrowhead for the advancement of their AAT program to the start of GLP tox studies. Arrowhead is licensed for their AAT program with our Alnylam intellectual property under the Roche agreement that they acquired in 2011.

Moving to expenses R&D expenses were $46.3 million this quarter as compared to $34.5 million in the prior year period. This increase was due to additional expenses related to the significant advancement of our clinical and preclinical programs. We expect that research and development expenses will increase slightly for the fourth quarter of 2014 as we advance certain programs into later stages of clinical development.

G&A expenses were $9.9 million in the third quarter of 2014 as compared to $6.8 million in the third quarter of 2013. The increase in G&A expenses in the third quarter of 2014 as compared to the third quarter of the prior year, was due primarily to an increase in general business activities and certain professional services during the third quarter of 2014 as compared to the same period last year.

For the fourth quarter of 2014 we expect the G&A expenses will remain consistent with third quarter of 2013. The GAAP net loss for the third quarter 2014 was $44 million as compared to a GAAP net loss of $29.7 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 September 30, 2014 was $41.3 million as compared to $45.5 million at the end of 2013. As of October 31, 2014 the value of this investment has increased to $117.7 million.

With respect to guidance for 2014 we are now increasing our year and cash guidance and expect we will finish the year with greater than $860 million in cash. Which provides us with a strong balance sheet to invest in a broad pipeline of genetic medicines and to maintain financial independence through multiple product launches.

Of course starting in 2015, 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. Accordingly, we see our non-GAAP net loss to be beneficially impacted by this alliance starting in Q1 2015. I will now turn the call over to Barry

Thanks, Mike. As you've heard from John and Akshay we've had a tremendously productive third quarter in recent period as we continued to lead the translation of the science of RNAi into the industries leading pipeline of RNAi therapeutics.

In addition to the steady presentation of clinical and preclinical data we've had a very productive quarter with regard to our intellectual properties state. Specifically, we received a Notice of Allowance from the US Patent Office for a new patent covering conjugate based delivery of RNAi therapeutics. Known as the Manoharan 478 patent, which has now issued.

As we believed before, this patent issuance further strengthens our view that anyone developing GalNAc-Conjugates for RNAi therapeutics will require a license from Alnylam's IP portfolio. We're certainly open to provide such licenses on a target by target basis for disease areas outside our core strategic interests.

We also received two Notice of Allowance's from the US Patent Office for patent applications from that Tuschl II family the 262 patent and now issued 829 patent. These new patents have very broad claims that exemplify our Alnylam leading IP position in the entire field of RNAi therapeutics. Now I will turn to our 2014 goals and guidance.

As we have announced the start of the year we now expect to significantly exceed our original 5x15 guidance. When we launched our Alnylam 5x15 strategy in January of 2011 we stated that we expected to have five programs in clinical development by the end of 2015.

We now expect to exceed that guidance with six to seven programs in clinical development by the end of 2015, including at least two programs in phase 3 and five to six programs that will have achieved human proof of concept results. We're on track to achieve this expanded guidance.

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 26 sites in nine countries. As we've previously guided, we believe this study will read out in about two to three years from now. And if 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 in our patisiran Phase 2 OLE study and we look forward to sharing additional data from that trial in 2015. With revusiran, ALN-TTRsc, we plan to share initial Phase 2 data in the coming weeks and we remain on track to initiate our Phase 3 trial by the end of the year.

With the ALN-AT3 Phase 1 study, we plan to present initial our tolerability and clinical activity data from the one human volunteer cohort and the first low dose cohort in addition to tolerability data from the second hemophiliac cohort at the ASH meeting in December. And expect to share a more complete data readout from this trial in mid-2015.

We remain on track to start our PSCsc Phase 1 study this year or early next. And we plan to file a CTA for ALN-CC5 later this year and file an IND or IND equivalent for ALN-AS1 either later this year or early next. With ALN-AAT, we remain on track to file an IND for this program in mid-2015.

With our hepatitis B program ALN-HBV, we continue to expect to designate our development candidate by the end of the year with an IND following around the end of 2015. And as Mike said, we've increased our year end cash guidance and plan to end the year with greater than $860 million.

In summary, the remainder of 2014 and into 2015 has promised to be a very data and event rich period. And we look forward to sharing more updates from our pipeline in the coming weeks and months. Josh, I'll now turn the call back to you.

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

(Operator instructions)

First question comes from the line of Alethia Young, Deutsche Bank.

Hey, guys. Congrats on the progress this quarter and I'm glad it got a name change. That's pretty cool.

Well it's the nonproprietary name for ALN-TTRsc and we wanted to introduce it today.

I guess I'll ask two questions I get commonly and one of them is around the strategy forward in hemophilia. Are you think about maybe going more after the inhibitors in rare bleeds? And how do you think maybe vying for that potential study?

And then the second question is just when you look at the data coming at AHA, I know we're only looking at five weeks, but and we saw kind of what some biomarkers adjust at six weeks at ANA, but I guess I'm just wondering how you think about contextualizing these two data sets based on difference and time duration or if there's anything to read at all?

Yes that's great. Let me handle both and then Akshay can chime in if I miss something. So on the hemophilia program Alethia we have a very broad perspective on where this program can go.

We think it really could be very disruptive in the entire hemophilia space. And our plans are to advance it not only in the inhibitor patient population, where there's very high on that need, but also in the patient population who are receiving on demand Factor VIII or Factor IX therapy, right now. Where they treat themselves when they bleed and the therapy like ALN-AT3 that can reduce the frequency of bleeding can be transformative.

And then on top of it we also see opportunities in the rare bleeding disorders space. Factor VII deficiency, Factor X deficiency, von Willebrand disease. So our vision is very broad-based with that program. And you're going to see us doing multiple Phase 2's and then ultimately Phase 3's for that program to ultimately get a very broad opportunity or capture the broadest opportunity with that product. So we're very excited about it.

We'll have initial clinical data at ASH, which I think will be of interest to people. But then obviously he more complete data set from the Phase 1 will likely be at the ISTH the meeting in June of next year. And then regarding the TTRsc or revusiran Phase 2 data, I really encourage people to really focus on tolerability data. This is a population that's elderly, frail, that have con meds, including diuretics. They have renal impairment.

And I'd encourage people to focus on the TTR knockdown that we see and to confirm that in fact we're seeing translation of that knockdown between volunteers and patients. With five weeks of treatment, I think people should not expect to see much of anything on the clinical endpoint data, because frankly it's too short of a treatment. I think with that gets more interesting with revusiran is now with the start of our open-label study where we're going to be treating patients out for two years.

And of course we'll be reading out data at least once a year and updating people on that as we continue or as at that time we'll be accruing patients into our Phase 3 study with revusiran in TTR cardiac amyloidosis. So that's my perspective. I mean Akshay, I don't know if there's anything to add to that. But please chime in.

No I think you covered all the main points, John.

Great. Alethia does that answer your question?

Yes, thanks.

Next Ted Tenthoff, Piper Jaffray.

Hi, Ted. Ted? Maybe he can call back.

Next Alan Carr, Needham & Company.

Hi, thanks for taking my questions. Couple of them. One of them, you mentioned there was some enrollment challenges earlier with AT3, wonder if you could comment briefly on that?

And then you mentioned that previous question that you'd be expanding that program correctively I'm wondering if that something that -- I mean do you plan on running a lot of Phase 2's in 2015 assuming good data here?

And then also can you comment on a couple of your newer programs, your GO-1and AGT? And how many of these do think you'll be running in parallel in 2016? Thanks.

Yes great questions. Do you want to handle the first one on AT3 and then I'll handle of the preclinical?

Yes I think overall the AT3 program is obviously terribly exciting. It's going well, the preliminary data in May I think had set the scene for part B of the study in hemophilia subjects. With the knockdown that we showed there in healthy volunteers. Alan, when you're in a new indication sometimes learn factors that influence your study design. And we've learned things as we've gone on and we've made some sensible needed changes to the protocol of the enrollment.

Going very well now and I think we're back on track. And as we guided we'll be presenting data both at ASH for the early cohorts in the hemophilia portion of the study. Then a complete study in first half of next year. So I don't think there's any really big meaningful delay here and I think still feeling great about this program and the quality of the data.

And Alan you had a second question on AT3 and I want to make sure we capture related to just what we might --

Do you think you'll be able to expand aggressively with these other Phase 2 trials in hemophilia next year even?

Akshay you can answer too, I mean absolutely. We're not giving guidance yet for 2015. But it's going to be a big year for that program in terms of what type of trials we expect to run.

And we're going to be very aggressive on a because we think it's an important opportunity. And it's just an enormous amount of disease burden in people affected with hemophilia that we want to solve with this approach. Anything to add to that Akshay?

And then Alan your question on the preclinical programs. We're very excited about both of the ones you mention. I mean GO-1 in Primary Hyperoxaluria, ultra rare orphan disease very high on that need. Animal data with our GalNAc-Conjugate siRNA shows very impressive efficacy in these preclinical models. The genetic data support the target very nicely. It's really just in the sweet spot of where we can have an a high impact drug.

And obviously with GalNAc technology there's just not a single liver target and that we can't go after with this approach. And we're going to do this one and it's going to be a great program for us. And the goal is to have that in the clinic in 2016. And then in the Angiotensinogen program, which is I think really an amazingly exciting program in the setting of hypertensive disorders of pregnancy, including preeclampsia.

I mean this is a very innovative program. We haven't given guidance on this one yet in terms of when we'll be in the clinic. As you can appreciate, Alan, it's got a much more complex development plan that one has to think through. We're talking about potential use in pregnant mothers. So we're not going to give guidance on that yet until we have our arms around the development path going forward. But it's a program that we're very committed to.

The unmet need in preeclampsia is unbelievably high. And the morbidity associated with that disorder for mothers and their infants and their families, is just something which this approach has the potential to be meaningful for. And therefore we're just not going to let it go unanswered. So we'll advance it, but we need to get our arms around the development path further for reasons that I think that you can appreciate.

Okay great. Thanks very much.

Good. Thanks, Alan.

(Operator instructions)

Next Mike King, JMP Securities.

Thanks good afternoon guys. Thanks for taking the question and let me add my congratulations as well. If I could maybe follow-up it sounds like Alethia and I are talking to the same investors, who and probably talking to the same KOLs both on AT3, and I'm still going to call it TTRsc for now.

Just on AT3, I'm just curious about one question that came up to me was I guess some investors have talked to KOLs that feel that a development path in inhibitor patients would have to go on top of NovoSeven. Could you comment about that?

Well NovoSeven is used to treat bleeding not to prevent bleeding. And so any development path of the drug on top -- in inhibitor patients would of course require or have to include the need to use Factor VII or for that matter FEIBA if there's a bleed. Okay and so that's certainly part of the process of understanding our development plans for the product in that setting.

But it is not that NovoSeven is used for prevention. These are patients that don't have anything for prevention and go throughout the course of their year bleeding 20 plus times a year. And then of course treat themselves with drugs like NovoSeven or FEIBA.

Of course our goal here would be to reduce that instance of bleeding from 20 plus times a year to much smaller number. And that's where the real value proposition would exist for patients with inhibitors.

Right, but you did say that -- but you do want to develop AT3 as well for on-demand use as well correct or not?

Yes, absolutely. No we don't think this is just for inhibitors, we think it has a broader potential. Because we're talking about a drug that's a once monthly subcutaneous injection.

Yes.

It's a transformative therapy for people with hemophilia.

Just to be clear Mike, when we want to mention the on-demand patient it will be prophylaxis in that patient group too, rather than treatment when they bleed. We'd be preventing bleeds there too. The key here is resetting the coagulation cascade that dramatically brings down annual bleeding rates across all of these patients.

Okay great. And then just to turn it up again to the TTRsc patient population. John you pointed out they're elderly and frail. But in a more of a real world I mean this is a FAP population with FAC involvement. Is it fair to say that this is not a representative population of sort of the what you would conceived as the average FAC patient that's out there in the United States at this time?

Well maybe Akshay you can answer that.

Yes Mike I think what we're trying to emphasis is that the Phase 2 study is very important, you're trying to establish the safety of revusiran in TTR cardiac amyloidosis. And so there's a spectrum of patients and there. But the most important underlying feature in common with Phase 2 and Phase 3 would be these patients have heart failure. Heart failure is a significant medical [event] with a significant five-year mortality, in general forget this very nasty amyloidosis disorder.

And they have renal impairment associated with that. And so we're just emphasizing that those factors are very important to study and establish our safety in that context. And I'm sure in Phase 3 patients will have heart failure and renal impairment and we'll be glad that we've study them in Phase 2 to establish the baseline profile.

Mike, keep in mind that the FAC patient group, many of these patients have a two to four-year life expectancy. So as John and Akshay mentioned they are frail. Now certainly with a potential treatment in revusiran and our discovery effort, our aim is to start identifying these patients earlier and earlier and earlier. But in today's world they have heart failure.

Right. I was going to ask you about DISCOVERY. I didn't want to run a foul of your two question rule, but I'm just curious with regard to that and maybe this will just count as a follow-up. Do we know what sort of average age of diagnosis is a FAC patient without any FAC involvement versus someone who is purely a FAC patient, are they really that much different?

Yes the technical FAP patient with a polyneuropathy will be in their 40s early 50s. They can be older but they're definitely going to be younger than a typical TTR cardiac amyloidosis patient, they'll be in their 60s onward. And I think the mean FACs will end up being somewhere around 65 or so.

And the mean [FAC] age in the Phase 2 study will probably be in the 70s

Yes it will be higher.

But they won't have the wasting and other aspects of FAP impact, will they?

Heart failure in and of itself is a wasting disorder. The body doesn't -- so they may well have lost some weight due to that issue. But it's a different disease, I think we have to establish the safety profile. And I think we're feeling confident that the Phase 2 data set is a significant step forward for us. Both in terms of understanding the safety and knockdown and setting us up for Phase 3 in a corresponding population.

Okay, great. Thanks for the added color and I'll get back in the queue.

Good. Thanks, Mike.

Next Ted Tenthoff, Piper Jaffray.

Great. Thank you very much.

You're here now, love it.

Sorry about that. I've been jumping around between calls, I apologize. So that means I have no idea which questions have been asked. Sorry about that. Maybe you can tell us I'll take a shot in the dark, obviously we'll be up in Boston next week.

Maybe you can tell us a little bit about hepatitis B program and sort of a competitive environment around that exciting marketplace. And sort of what you plan to show us and kind of what is the plans are for 2015 there?

Yes no thanks Ted and we hopefully we'll see you at the Liver meeting next week as well. The HBV program we're always very excited about. It came out of our acquisition of Sirna, the deal that we did earlier this year. And of course you know Merck Sirna had generated some very compelling data in chimps, in chronically infected chimps showing an over 2 log reduction of surface antigen levels in chronically infected animals.

And of course they developed this initially with a lipid nanoparticle approach that we don't think is the right approach in hep B because lipid nanoparticles really need pre-medication from a tolerability standpoint and that just wouldn't work in hep B. In fact that's one of the reasons that Merck didn't pursue that approach because of the premed challenges with LMPs. But of course we've got this beautiful GalNAc technology that allows us to overcome that.

And so over the course of the year we've been working to convert the sRNA that was previously encapsulated in the LMP into a GalNAc-Conjugate. And we're making tremendously great progress you'll see some updates on that next week. We expect to have our development candidate by the end of the year in that program. And then we're going to turn the Alnylam crank on that program and do what we've now done and shown everybody that we can do reproducibly, time and time again of filing our CTA in that program.

And we expect that to happen around years end of next year. And then advance into Phase 1. I think what you can expect for our program is that we're going to have a robust sRNA, very potent. One that has a very wide therapeutic index and one that allows us to move very quickly into clinical development to demonstrate the ability of this drug to knockdown surface antigen levels.

And then ultimately in larger studies to show improved seroconverstion rates. So we're very excited about the program. I think there's quite a bit of interest in what we're doing for good reasons. I think the clinical validation of our GalNAc platform is incontrovertible. Look at our -- look at all the data you've seen to date, look at even the Regulus data in some regard.

And you can quickly, I think extend the belief set, that says that our program will probably be the best in class approach. It's certainly going to be the only one that'll be sub-Q in the RNAi field in HBV and we think it's going to be the winning strategy. It is a big, big market huge unmet need. Lots of opportunity and again lots of interest in the program.

Excellent. Well again, keep up the great work guys it's really exciting to see.

Thanks Ted.

(Operator instructions)

Next Stephen Willey with Stifel.

Hi good afternoon and thanks for taking my question. Just to follow-up on Mike's question regarding I guess the FAC versus FAP.

So I guess it is safe to assume that you would expect the FAC patients entering the open-label extension study to have meaningfully different baseline cardiac biomarker data relative to the subset of FAP patients with cardiac involvement that we saw at ANA?

Akshay you want to?

That is indeed true. The patients in the Phase 2 study with revusiran have established TTR cardiac amyloidosis and so there are various cardiac biomarkers, BNP, troponin, et cetera. So is radiologic data baseline will be different. And show a well-established [mark] disease.

Okay just a follow-up to I think a comment that you made, John regarding or Barry, the additional IP that's been solidified around the GalNAc-Conjugate. And I think, Ted made a comment around being willing to ascribe licenses on the target by target basis that are outside of the core therapeutic focus.

Is it safe to say or safe to assume that essentially every program within your pipeline right now is kind of considered to be within the quote, unquote, core therapeutic focus?

Yes I would think that's a good assumption, Steve. I mean honestly we're not interested -- we're interested in advancing our medicines to patients and obviously in fiduciary manner maximizing the value of that effort to our shareholders.

And that means when you've got a program that you're investing in and making it a proprietary program, you don't typically want to invite competitors in it, even if they're not you necessarily a strong of a competitor based on the technical data. That is just the nature of pharmaceutical R&D. It's been that way in the industry forever. And so yes anything that we're working on we're not interested in licensing because we have a competitive program that we are maximizing the value of that for Alnylam shareholders.

But a good example in the case of our Regulus relationship, we license them our GalNAc technology and we don't have a competing program in HCV. And they have access to our technology toward miR-122 and we're delighted with the opportunity to build value for shareholders based on that license that we've given them.

And I think that's a good example of that. And we'll do that for other companies that have got targets of interest to them that aren't of interest to us. And that's part of the way that we think about building value.

Understood.

Barry anything to add to that?

No I think you got it.

Thanks and congrats on a productive quarter.

Thank you Steve.

I'm showing no further questions at this time. And I would like to turn the call back to management for any closing remarks.

Great. Well thanks everyone for joining us this afternoon. Obviously the year has been transformational for the Company. And there's still a lot more to come. So we look forward to sharing with you further updates and we'll be obviously in touch in the weeks and months to come. Thank you very much.

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