Alnylam Pharmaceuticals Inc (ALNY) 2014 Q2 法說會逐字稿

Good day, ladies and gentlemen. And welcome to the Alnylam Pharmaceuticals' Q2 2014 earnings conference call. (Operator Instructions). As a reminder this conference call is being recorded. I would now like to turn the conference over to the hosted organization. Please proceed with your opening remarks.

Good afternoon. I'm Cynthia Clayton Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, Chief Executive Officer, Barry Greene, President and Chief Operating Officer, Akshay Vaishnaw, Executive Vice President 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 gentleman webcast by going to the Investors page of our website at www.alnylam.com.

During today's call and as outlined on slide two, John will provide some introductory remarks and provide general context for some of our recent products and activities. Akshay will summarize the clinical progress with our expanded Alnylam 5X15 and broader genetic medicine pipeline. Mike will review our financials and guidance, and Barry will provide a brief summary of certain business highlights and goals for 2014 before we open the call for your questions.

And before we begin I would like to remind you that this call will contain certain 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. The first half of 2014 and recent period have been truly transformative for Alnylam and our continued efforts to advance RNAi therapeutics as a whole new class of medicines. During this time we continued to execute on our expanded Alnylam 5X15 product development strategy and reported on multiple significant clinical and pre-clinical datasets. Some key highlight during the period are initial data from our phase 2 OLE study of patisiran.

Positive type top line data from our ALN-AT3 program which we believe could become a functional cure in the treatment and management of hemophilia. and promising data from our pre-clinical pipeline including ALN-CC5 for complement-mediated diseases, ALN-PCSsc for hypercholesterolemia, ALN-AAT for Alpha1 anti-trypsin deficiency, and ALN-AS1 in porphyria. We also share key technical data on our ESC GalNAc Conjugate platform that allows us to achieve subcutaneous delivery of RNAi therapeutics with highly potent and durable effects. In addition to a wide therapeutic index, a profile that we believe is currently unmatched in the entire RNA therapeutics field. Finally, we added a new program to our pipeline ALN-HPV for the treatment of HPV infection that we believe has a potential to one day become a significant product in an area of very high unmet need.

Many of you have been hearing about the progress we have been making through our RNAi roundtable summer series which is still ongoing through the end of August. I encourage all of you to spend some time to hear our clinical and scientific progress. Of course Akshay will describe some of these results in more detail in just a minute. We now enter a very data rich back half the year. As Barry will highlight, pending certain abstract acceptances, we expect to have presentations in September, October, November, and December across essentially all programs in our pipeline. This includes patisiran clinical endpoint data from our phase 2 OLE study at the ANA meeting, ALN-TTRsc pilot phase 2 data at the American Heart meeting, and initial Phase 1 ALN-AT3 hemophilia data at ASH. You will also hear updates from our pre-clinical programs including our C5, HBV, and PCSK9 efforts, and you will hear about new genetic medicine programs that we've been working on extending the breadth of our pipeline beyond the current 11 disclosed programs.

Regarding pipeline advancement, we're aiming to start our Phase III trial for ALN-TTRsc and TTR cardiomyopathy by year's end, and we're having active discussions with regulators on our proposed Phase 3 design. In the meanwhile, we'll shortly open up our phase 2 OLE study for TTRsc providing patients rolled into phase 2 trial an opportunity for extended dosing. In addition, we're on track to filed INDs or IND equivalents this year for and ALN-CC5 and ALN-PCSsc, and in the case of our ALN-AS1 porphyria program, we're on track for an IND filing either late this year or early next. So we fully expect to end this year with five programs in the clinic, but maybe six genetic medicine programs in the clinic. So clearly a lot going on at Alnylam. Finally, I would like to end my opening remarks by thanking the patients and their physicians who are participating in our numerous clinical trials. We remain committed to making a difference in your lives. I will now turn the call over to Akshay. Akshay?

Thanks, John. We have indeed had a steady stream of data from our RNAi therapeutics pipeline. Certainly got a lot going on. I'll start with our patisiran program. Patisiran is our lead 5x15 program and is aimed at the treatment of TTR-mediated amyloidosis, or ATTR, patients with familial amyloidotic polyneuropathy or FAP. This program is in a phase 3 trial. We now have over 20 sites open in nine countries. As you can see on slide eight, the Apollo phase 3 trial is a randomized double-blind placebo-controlled study designed to evaluate the efficacy and safety pf patisiran in ATTR patients with FAP. The primary endpoint of the study is the difference in the change in the neuropathy impairment score called mNIS+7, between patisiran and placebo at 18 months. Our Apollo trial is intend to demonstrate the efficacy and safety of patisiran in support of multi-authorization in-countries around the world. Regarding ongoing enrollment and duration of study we continue to believe, from this point in time, that the study will take two to three years to read out results, supporting an NDA filing in 2017 assuming the study is positive.

At the International Symposium on Amyloidosis in May, we presented initial results from our phase 2 open-label extension or OLE study, with patisiran. In the OLE study we're measuring a number of clinical endpoints every six months including mNIS+7, which is a primary end point in the Apollo phase 3 study. Enrollment in this trial is now complete with 27 patients, and as of today, with up to nine months of therapy were very pleased to report there have been no study drug discontinuations. At ISA [one sort of] data we present initial positive results from 23 patients showing sustained TTR knock-down over approximately 80% through to day 168. This time period covers up to eight doses of drugs and these data provide the first clinical evidence of sustained RNAi-mediated TTR knock-down in FAP patients beyond two doses of patisiran. Repeat dosing of patisiran was found to be well tolerated with minimal adverse events and the use of our proprietary micro-dosing infusion regimen was found to significantly reduce the incidence of infusion related reactions. In fact we have been very encouraged with the overall safety profile of patisiran in our clinical trial experience to-date.

Across our phase 1, phase 2 and OLE study, patisiran has been found to be generally well tolerated. We plan to report initial clinical end point data from the OLE study at the upcoming American Neurological Association annual meeting being held in October. Initial data set is expected to include six month mNIS+7 results from approximately 20 patients. We'll also present additional endpoint, and of course safety data at that time. We very much look forward to sharing these results although we would like to remind you that the study is open label and that the initial results will be sharing are limited to only six months of dosing. Of course, we will be showing additional data from the early study at least once annually from this point onwards. Also from our ATTR program we're advancing ALN-TTRsc for the treatment of ATTR patients with cardiac amyloidosis.

This program is in a phase -- pilot phase 2 study aimed at evaluating the tolerability and preliminary clinical activity of ALN-TTRsc in patients with familial amyloidotic cardiomyopathy, or FAC, which is caused by autosomal dominant mutations in the TTR gene, or senile systemic amyloidosis or SSA which is caused by the idiopathic accumulation of wild-type TTR in the heart. Based on encouraging enrollment in the study to-date we recently monitored the protocol to enroll up to 25 FAC or SSA patients. The previous enrollment target had been 15 patients. The expanded enrollment more FAC patients into the study where to-date we have had about a two-to-one split of SSA to FAC patients enrolled. Pending abstract acceptance we expect our present data from this phase 2 trial at the AHA meeting being held in November. At that time we will present all available safety, TTR knock-down and clinical end point data from the study.

Any clinical endpoint result needs to be considered exploratory given the small sample side and the very limited duration of treatment of only six weeks in the phase 2 study. Patients completing the phase 2 trial will be eligible to participate in a TTRsc early study for further assessment of general tolerability and clinical activity with long-term dosing, and this study is on track to be initiated in the coming weeks. We expect this TTRsc early study to provide more informative clinical end point data given the extended duration of treatment, and we plan on presenting data from this study at least once annually starting in 2015. In addition we're aiming to be in a phase 3 trial in TTR cardiac amyloidosis patients by the end of 2014. We're actively engaged in discussions with US and European regulators on the optimal phase 3 design, and look forwards to updating you on this later in the year. Of course there are many conversations that have gone into our thinking here, and we recently highlighted these in our TTR roundtable webinar in July.

Importantly, we have used the natural history data set from approximately 400 FAC and SSA. patients to guide many of the design -- many of the design -- considerations in the quarter, and we also made significant progress with our ALN-AT3 program for the treatment of hemophilia and rare bleeding disorders. Just this morning we held an RNAi roundtable webinar for this program and we are very pleased to see the strong level of interest in our efforts here. We too view this as a very exciting and innovative program since we believe anti-thrombin knock-down has potential to rebalance the coagulation cascade in patients with hemophilia and other rare bleeding disorders, resulting in the potential for enhanced thrombin generation and improved hemostasis.

At a World Federation of Hemophilia May we reported initial positive top line data from our ongoing Phase 1 trial. In part A of the study human -- healthy volunteer subjects received a single subcutaneous dose of ALN-AT3 and, per protocol, the maximum allowable level of AT knock-down was set at 40%. Initial results from the full dose cohort of four subjects showed that a single low subcutaneous AT3 dose of 0.03 milligram per kilogram resulted in up to 28% to 32% knock-down of AT at nadir, that was statistically significant relative to placebo with a p value of less than 0.01. This resulted in a statistically significant increase in peak thrombin generation which was temporarily associated and consistent with the degree of AT knock-down. ALN-AT3 was found to be well tolerated with no significant adverse events reported. We're in the beginning stages of part B of the study which is designed as open-label multi-dose, 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 the safety and tolerability of multiple doses, specifically three doses, all subcutaneously administered ALN-AT3 in hemophilia subjects.

Secondary objectives include assessment of clinical activity as determined by knock-down so -- knock-down of circulating AT levels, and increase in thrombin generation at pharmacologic doses of ALN-AT3. Amongst other results we will be quite interested to see the effects of ALN-AT3 treatment on thrombin generation in hemophilia subjects, since thrombin generation has been shown to correlate with bleeding frequency in hemophilia. Assuming abstract acceptance, we intends to presents initial clinical results from the phase I study including all available results in hemophilia subjects, at the ASH annual meeting in December. It's worth noting that ALN-AT3 is our first program to enter the clinical development arena utilizing our enhanced stabilization chemistry GalNAc conjugate technology which enabled subcutaneous dosing with increased potency, durability, and a wide therapeutic index.

As clinical data with ALN-AT3 demonstrates, a ten fold improvement in potency and translation from the non-human primate to human. And as compared with our earlier GalNAc conjugate such as ALN-TTRsc, these results are just an over 50-fold improvement in potency. Clearly this has the pension to have profound implications for our entire pipeline which largely employs our ESC GalNAc technology. Based on these data we presented back in May at TIDES, we have demonstrated that this improved potency and durability stems from a more stabilized [siRNA] molecule as well as an attenuated nucleate environment in the human liver [cytosol.] Finally, as we announced earlier today, we received the orphan drug designation in the EU for ALN-AT3 for the treatment of both hemophilia A and B.

I would like to now turn briefly to our pre-clinical pipeline. As outlined in more detail in our press release we have made very significant progress in these assets, specifically, with ALN-CC5 of subcutaneously administered RNAi therapeutic targeting complement component C5, for the treatment complement-mediated diseases. We selected our development candidate and showed an up to 98.7% knock-down of serum C5, and up to 96.8% inhibition of serum complement activity in non-human primates with weekly subcutaneous dose administration. Assuming abstract acceptance, we intend to present additional pre-clinical results from this program at the ASH meeting in December. Also we are on track to file a CTA for this program late this year and to present initial clinical results in mid-2015. We're very excited about this program since we believe it could be highly competitive with monoclonal antibodies targeting C5 such as eculizumab. In the case of our PCSK9 program we presented single dose data with ALN-PCSsc in primates showing robust knock-down of PCSK9 of up to 96% and a reduction in LDLC of up to 77%.

These results were observed in the absence of statin co-administration. Notably a single dose of ALN-PCSsc maintained a greater than 50% reduction in LDLC for over three months, a level of durability that we believe supports a once monthly and possibly once quarterly subcutaneous dosing regimen. This represents what we believe could be a highly competitive profile with an anti PCSK9 monoclonal anti -- with anti-PCSK9 monoclonal antibodies in what we believe is a significant emerging market. We previously guided that we planned to file an IND or IND equivalent for this program by late 2014 or early 2015. We can now be more precise in our guiding that we expect to file a CTA in late 2014 with initial data expected in mid 2015. As a reminder this program is partnered with The Medicines Company who will advance the program after we complete phase 1. We were pleased to publish data from our ALN-AS1 program in porphyria in PNAS. This is an innovative approach in an ultra rare orphan disease where new medicines are sorely needed. We expect to file an IND or IND equivalent for ALN-AS1 in late 2014 or early 2015. We presented some new data at DDW for our program in Alpha-1 antitrypsin deficiency where we aim to treat the deliver pathology associated with this orphan disease.

Specifically, we selected our ALN-AAT development candidate and presented non-human primate data supporting further program advancement. We aim to file an IND or IND equivalent for this program in mid-2015 and we expect this program to be the seventh clinical program in our expanded Alnylam 5x15 pipeline strategy effort. Finally we are pleased to announce the addiction of a new program to our pipeline, ALN-HBV, a subcutaneously delivered RNAi therapeutic for the treatment of HBV infection. This new program comes from our acquisition of Merck's RNAi assets including the Sirna Therapeutics subsidiary. In the most comprehensive pre-clinical study results presented to-date with an RNAi therapeutic for the treatment for HBV, we reported significant multi-log reductions in HBV surface antigen and HBV viral titres, and showed evidence for an immune-mediated therapeutic effect in chronically infected chimpanzees. Specifically, the new data which were presented at the TIDES meeting in May, demonstrates an up to 2.3 log reduction in HBs antigen. We expect to select a development candidate in late 2014 and plan to file an IND around year-end 2015. As always each of these data sets and publication materials can be found on Capella section of our Company website. And so in summary I hope you will agree it's been an especially exciting and productive time for us as we continue to lead the translation of the science of RNAi towards the development of innovative 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 19 for a discussion of second quarter 2014 financial results. This quarter we maintained a very strong balance sheet with $956 million in cash, cash equivalents, and marketable securities. Our GAAP revenues for the second quarter of 2014 were $7.3 million as compared to $8.7 million in the second quarter of 2013. GAAP revenue this quarter included $5.5 million related to our collaboration with Takeda, and $1.8 million related to our collaborations with Monsanto, The Medicines Company, research reagents licenses and other sources.

Moving to expenses, R&D expenses were $44.7 million this quarter as compared to $24.2 million in the prior-year period. This increase was due primarily to additional expenses relating to the planned significant advancement of certain of our clinical and pre-clinical programs. We expect that R&D expenses will increase slightly for the second half of 2014 as certain of our programs move into late clinical stages. In the second quarter of 2014 we recorded a reduction of $3.9 million to in-process research and development expense in connection with the purchase of a Sirna RNAi assets from Merck. Upon the completion of certain technology transfer activities in the second quarter of 2014 we issued approximately 378,000 shares of common stock to Merck.

In the second quarter of 2014 we re-measured the expense recorded in the first quarter of the 2014 in connection with these shares using the price of the Company's common stock on the issuance date. In future periods there will be no additional charges recorded to in-process research and development related to the purchase of the Sirna RNAi assets from Merck. G&A expenses were $11.5 million in the second quarter of 2014 as compared to $5.8 million in the second quarter of 2013. The increase in G&A expenses in the second quarter of 2014 as compared to the second quarter of 2013, was due primarily to higher non-cash stock-based compensation expense. Excluding non-cash stock-based compensation expense we expect a G&A expenses will remain consistent for the second half of 2014. The non-GAAP net loss for the second quarter of 2014 was $48 million as compared to a non-GAAP net loss of $18.2 million for the same period in the previous year. The non-GAAP net loss for the second quarter of 2014 excludes the $3.9 million reduction to in-process research and development expense for the purchase of the Sirna RNAi assets from Merck.

With respect to guidance for 2014 we expect we will finish the year with greater than $825 million in cash which we believe provides us with a strong balance sheet to invest in a broad pipeline of genetic medicines, and to maintain financial independence through to multiple product launches. And starting in 2015 we expect a significant share of our expenses on our patisiran and TTRsc 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 heard from John and Akshay we had a tremendously productive first half of the year. In addition to the steady presentation of clinical and pre-clinical data we have continued to advance our business objectives. In particular we had a rather active quarter regarding our intellectual property estate. For example, as part of our acquisition of Sirna from Merck earlier this year we obtained over 125 issued patents and a much larger number of pending applications in prosecution. One of these is the in the McSwiggen 406 patent which was recently upheld in oral opposition proceedings in Europe.

This patent includes claims that broadly cover chemically modified siRNAs which we believe are critical to achieve drug like properties with potent and durable effects such as those seen in our ESC GalNAc conjugate platform. Another patent ins the McSwiggen 277 patent which was recently issued by the US Patent Office. This patent includes sequence independent claims that we believe are critical for the development of RNAi therapeutics for the treatment of HBV infection. This patent is not licensed to any other third parties and we aim to build value from this patent through advancement of our proprietary ALN-HBV program. In addition, we received a noticeable allowance for a patent broadly covering conjugate based delivery of RNAi therapeutics. The Manoharan 478 patent includes newly-allowed claims directed to compositions including those comprising a modified RNAi agent linked to a biantennary or triantennary ligand. Specifically, the allowed application includes claims that broadly cover single-stranded or double-stranded chemically modified RNAi therapeutic conjugated GalNAc ligands, independent of length, sequence, or disease target.

We believe that anyone developing GalNAc conjugates for RNAi therapeutics will require a license from Alnylam's IP portfolio. Of course, we're open to providing such licenses on a target-by-target basis for disease areas outside our core strategic interests. I will now turn to our 2014 goals and guidance. As we announced at the start of the year, we now expect to exceed our 5x15 guidance where 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 we will have achieved human proof-of-concept results.

With regard to our patisiran program we're on plan and continue to enroll patients in our Phase 3 APOLLO study. As we have guided before, we believe the study will read out in about two to three years from now and if positive we expect that this study will enable a possible NDA submission in the 2017 time frame. We also continue to enroll and treat patients in our phase 2 open-label extension study and we remain on track to share more findings from the study at the ANA meeting in October. We also continue to enroll patients in our phase 2 study with ALN-TTRsc and are on track to present data from that study late this year.

Finally, we plan to start a phase 3 study of ALN-TTRsc in a TTR cardiac amyloidosis indication by the end of this year. Now regarding our ALN-AT3 hemophilia program, we expect to present initial data from hemophilia subjects later this year. We now plan to file an IND or IND equivalent for ALN-CC5 and ALN-PCS programs also late 2014 and for an ALN-AS1 program either later this year or early next year. Over the course of the year you can also expect us to continue advancing our pipeline as we have done recently ALN-AT which we now plan to file and IND in mid-2015 and ALN-HBV where we plan to select a development candidate by the end of this year and file and IND around the end of 2015

As Mike said, we plan to end the year with greater than $825 million. In summary the second half of 2014 promises to also be very data rich period with multiple presentations and data read outs in September, October, November, and December. With that I'll now call the -- turn the call back to Cynthia.

Thanks, Barry. We will now open the call to your questions. As a reminder to those dialed in we would like to ask you to limit your questions it to two each. Marcus you may now begin the Q&A.

(Operator Instructions). And our first -- our first question comes from the line of Alicia Young from Deutsche Bank. Please proceed with your question.

Hey. Great. Thanks for taking my question and congrats on all the progress, guys

Thanks Alicia.

Yes. It's awesome. So I know, I just want you guys to talk a little bit about what you found most exciting from the Sirna acquisition, and then also just talk a little bit about what things could come in the future because I feel like we've been surprised over the first half the year with some of the many interesting things that have come out of it.

Yes, let me take a stab at that and then Laurence Reid, who obviously played a major role in that acquisition, can also comment. As we said when we did the acquisition there are really three elements of value that we saw within -- within Sirna. The first was the presence of some -- some pretty compelling pre-clinical programs, later stage pre-clinical programs and one of those was ALN-HBV. And I think everyone has seen the data set from that, it's really amazing data in chronically infected chimps.

And there's another program of a similar stage that we haven't disclosed yet. In addition, we commented -- we commented that we acquired quite a bit of IP and Barry mentioned 125 issued patents, a much larger number of pending applications, and you have you've already begun to see the fruits of that in the context of the McSwiggen patent that was upheld in Europe and the McSwiggen 277 patent that was issued in the US and you're going to see a lot more coming out of that estate okay? No question about it. There's a lot of pending applications. It's a very early and broad patent with significant inventive elements within it that you're going to hear a lot more about that, you know, frankly is going to continue to make the RNAi therapeutics field a field that Alnylam is clearly in a position from a dominant position standpoint to build maximal value from.

The third element Alicia, really relates to technology, and some of the technology I think you're going to start hearing a little bit more about later this year. There's an important meeting at OTS, the OTS meeting where there's quite a bit around new technology that's often discussed there, around delivery. And I think you will start seeing some of the fruits of the Sirna acquisition as it relates to technology advancement at the OTS meeting in October. And so a lot more to come for sure. We -- we do like to -- we do like to surprise on the upside in these type of circumstances and obviously there's quite a bit that we acquired from Sirna and we're excited about that acquisition. It was a very smart move. Lawrence, anything else to add to that?

I think you have covered all the main pieces, John. As (inaudible) I mean I think we knew it was going to be a good move at the time we were excited about the -- the breadth of opportunities there and the HBV one has been the most noticeable so far, generated a lot of interest, and really sort of catapulted that program forward and generated a lot of interest in the outside world as well which we're pretty excited about.

Yes, great. Does that an your question, Alicia?

Yes. Can I ask another one?

Sure. You get two.

Awesome. I just wanted to know a little bit more about -- I know I ask all the time -- but just how you're thinking about the secondary end points in the FAP study, and like what we might be able to see there?

Let's -- Let me -- now do you mean the phase 3 study or the phase 2 study?

Ah, the phase 2. It's upcoming (inaudible -- multiple speakers.)

Okay, so do you want to comment Akshay?

Yes. Hi, Alicia. There are a number of exploratory endpoints that we'll be looking at. Obviously TTR knock-down. Primary objective is safety, secondarily TTR knock-down. And then other exploratory endpoints will be biomarkers such as BMT and troponin, and also the very interesting data we want to gather on echo or MRI. Both of these show changes in TTR cardiomyopathy, so we would be interested to see what happens. And also clinical data relating to six-minute walk. So all of these will be presented. Of course these are exploratory. And as I emphasized in the overview, this is a short duration treatment of six weeks. We need to bear that in mind as well.

Yes I'll just add, Alicia, one of the two key reasons we did this study from my perspective. One is first and foremost, you know, patients with FAC or SSA. and heart failure are on many, many concomitant meds, they have impaired renal function, they're obviously in a very tender stage. and from my perspective it was very important and Akshay's as well very, very important to absolutely evaluate the safety of our therapies in the context of diseased patients before running into a Phase 3. Its just a no brainer to do that. So we're very pleased we have done that and obviously the fact that you haven't heard, you know, something bad means so far so good from the safety standpoint. So I think that's -- that's great.

The other thing I think that was very, very important is that, you know, we needed to finish, and are now finishing our chronic tox study -- tox program with ALN-TTRsc. Again, so far so good there, because we wouldn't be having these discussions around Phase 3 without being confident around the safety profile coming out of our chronic tox programs and we needed to do that before we could do extended dosing. So the phase 2 study is limited to six weeks of dosing. And so all of the clinical endpoint data I think needs to be kept in mind with regard to both the exploratory and small sample size intrinsic in the study, but also the fact that it really relates to only six weeks of dosing in the patients. So that's the only other context I would provide Akshay, you agree?

Yes, indeed.

Good. Thanks.

Thanks

Thanks, Alicia.

(Operator Instructions). Our next question comes from the line of Mike King from JMP Securities. Please proceed with your question.

Hey, guys. Thanks for taking the question and congrats on the progress. Can you hear me okay?

Yes. Loud and clear.

Great. So apologies if you have addressed this question. I've been kind of hopping back and forth between a couple different calls. I was wondering at some point were you -- I thought you were undertaking a natural history study for -- for FAC. Is that still part of the plan for the development?

It is. In fact, we have collected a very sizable data set. Akshay, you want to describe it a little bit?

Yes, sure. We've collected data on up to 400 individuals with TTR cardiac amyloidosis, both flavors, the FAC variety that's mutation based, and the wild type SSA. And it's actually a very rich data set comprising of centers from both US and UK, and we have a variety of endpoints gathered all the way from clinical parameters such as six-minute walk, hospitalization, mortality, kind of things. We're featuring heart failure of course as well as biomarkers BMP troponin and some radiologic data as well including echo. So it's a very rich data set. And just as we did with the FAP effort this year at ISA where we showed the FAP natural history data set and then shared with people how it's been very informative in guiding the phase 3 design, we will be sharing these FAC, SSA natural history data in due course.

Yes probably some time next year, Mike. (inaudible -- multiple speakers)

Next year?

Yes. We don't have any immediate plans to share it. I mean obviously we want to use it to our, at least for the time being, to our competitive advantage, but we will certainly share it, you know, in due course likely next year.

Okay. And then a question on PCS. As far as the durability of the potential for once per quarter dosing, is that unique to the target, unique to the construct, unique to that particular chemistry for ALN-PCS? Because I am just wondering if it can be done for PCSsc., why can it not be done for some of the other clinical candidates?

You know, that's a great question, Mike and the answer is it can be done and is going to be done for other clinical candidates. So we're now clearly going with our ESC GalNAc conjugates, we're clearly in a very robust manner moving to once monthly dosing for essentially all the programs. I think that's going to be true with AT3 in hemophilia, which would be very disruptive, in that space, to have a subcutaneous dose administration given once a month. In the case of PCSK9, clearly once monthly is supported. I think there, once quarterly is also going to be quite possible. And so this is turning out to be a key feature for the entirety of our ESC GalNAc conjugate programs.

In some cases with -- with targets where we really want to ratchet it down, all the way down to the floor like C5, we may choose to sick with weekly sub-Q dosing there given that that would be extremely competitive. But there is a potential even there to go to monthly sub-Q dosing. So we're feeling excited about this profile. It's clearly best-in-class across RNAi therapeutics in terms of durability and dose frequency, and it's being achieved with low doses, based -- extrapolated from our AT3 data that is going to be done with less than one ml sub-Q injections. So it's really a very promising development and in the case of PCSK9, I mean quarterly dose administration in that emerging market could be pretty disruptive. Even though we're further behind obviously than the antibodies, it could be pretty disruptive in that whole emerging market and that's going to be fun to watch.

Okay. Great. And then finally just on AT3, I know that you get a fair bit of questions regarding, you know, over shoot on coagulation. I'm sorry -- on -- on -- yes. On AT3. The -- Can you remind us of the intra/inter patient variability -- I know you're, you know, maximizing at 40% inhibition, but I just wonder if you could just remind us what kind of intra and inter patient, or if you don't have the patient maybe from NHPs, how -- what the variability around -- around the mean is there. Thank you.

Sure. Thanks, thanks Mike. A couple things. One is obviously if you -- and you probably did. We had our RNA webinar today -- roundtable today on AT3, and this question came up and -- and actually I think you were on the call. Discussion came up and David Lillicrap, who is the expert in the field, you know, emphasized what we believe for quite some time, is that the risk of thrombosis in the background of hemophilia is incredibly low. So we feel that we have quite a bit of latitude for knock-down without, you know, undue risk at all for thrombotic events, and we're also clearly aiming for a level of knock-down which is between 50% and 80% with that program based on a lot of data including data in animal models but also from human hemophilia plasma. So the data sets are very robust. Now, inter patient variability from our AT3 phase 1, we haven't presents the those data yet.

Our data to data had been top line. So I will encourage you to wait in the ASH meeting in December to see those data along with hemophilia patient data. But you can look at our animal model data from our -- in our corporate deck and standard deviations even when we're at the 50% range, are essentially if I'm recalling the numbers right plus or minus 5%, 6% around each data point. So incredibly consistent effects with tight -- tight results across animals and, you know, I think we're going to see the same type of thing in humans. If you look at our TCRC human data you would see again also data sets that are in our corporate deck pretty remarkable -- remarkably small standard deviations around each data point. So we think that we're going to see some very tight data. But let's wait until December to see it for AT3. Akshay anything else to add?

No, no, I was just going to pick up on your point about what we have seen from previous studies in both pati -- well for patisiran and TTRsc, as you dose ascend, we clearly demonstrated that in fact the (inaudible) get tighter and the inter individual consistency increases. So that's history we will see the data obviously later in the year for ALN83. But the science predicts that should be tight.

Okay. Thank you.

Thanks, Mike.

Our next question comes from the line of Ted Tenthoff from Piper Jaffrey Your line is now open.

Great. Thank you. And I apologize if this question was already asked. I actually just got off a plane so I'm excited that I even have the chance to catch the tail end of the call. When it comes to the hepatitis B program can you give is a sense of when that can go into the clinic and what that competitive profile may look like for ALN-HBV?

Sure. Love to, Ted. So that -- our guidance on that program is that we will select our development candidate by the end of this year, and that we will be filing our IND or IND equivalent for that program around the end of 2015. So we're about a year and a few months away from filing an IND in that program. The program we inherited from Merck that was used in the chimpanzees was evaluated using Merck's lipid nanoparticle technology. We obviously want a -- an approach that supports subcutaneous dosing with our ESC GalNAc conjugate. So compared to the other RNAi approaches out there, this would be the only approach that is sub-Q, and obviously an approach that we know has a very wide therapeutic index, which we expect to be broader than the other competitive programs out there in the RNAi space. And also in our opinion likely to be the case across other RNA authentic strategies.

So it's going to be -- and on top of it Ted as you know it's a very large market. Very substantial market and multiple players if they're successful will be able to reach the market in this case. And if we have a profile that makes us best-in-class, we're going to stand out ahead of the rest. So we're excited about it. We've got the clinical proof obviously compared to some of the other programs that are out there with untested platforms. We have clinically validated approaches for knocking down genes in the liver. I think that's important as well, but clearly we're in a position of strength on the program across technical features also intellectual property. And so we're going to get a vote local of value from that program for sure.

Great. Well I look forward to all the data coming out in the second half on the other programs as well, s thanks for the update.

Terrific. Thank you, Ted.

(Operator Instructions). And our next question comes from the line of Alan Carr from Needham. Please proceed.

Hi. Thanks for taking my questions.

Hey Alan how are you?

Good. How are you?

Good, good.

So big picture question here. So you made a lot of progress in targeting hepatocyte obviously.

Yes.

How much work do you have underway in terms of other cell types or other tissues and obviously lots of opportunities as it is with the cells that you're targeting, but I am curious if these other tissues fit into your long-term plans.

Yes. Well, you know, at one level, Alan, you know, I -- I -- and this sounds crass but I could care less if we ever knock down a gene in another tissue in the body because the liver is such a -- an unbelievable treasure trove of disease targets. If you take today's marketed products that are commercialized that target liver express genes it's over a $50 billion market and so, you know, you we're going to be pretty busy for quite some time knocking down liver express target genes, building a lot of value, making a big difference in people's lives and patients' lives, and building a lot of value for our shareholders. So at some level, you know, if liver is all we ever get with robust and clear effects, we're going to be very, very happy, very busy and a very successful company.

That said, you know, Alicia asked a question earlier about what might be in the back room from the Merck-Sirna acquisition and certainly one of the things that Sirna spent a lot of time doing is looking at extra-hepatic delivery, so I am hopeful that you will hear more about that in the future, and that there's some interesting opportunities there that we will explore in the future. But for the foreseeable future, you know, define it as the next five years, I don't think you're going to see us doing anything but continue to execute on our liver-based strategy. Because of the fact that it's such a modular and reproducible platform for developing innovative medicines, and from a resource allocation standpoint there's so many great opportunities in the liver that we're going to be busy for quite some time. But I'm hopeful that in the future you will see other target cell types and organs accessed with our technology and that will happen.

Great. Thanks very much.

Great. Thank you, Alan.

I have no further questions in the queue at this time. I would now like to turn the call back over to the Company for closing remarks.

Great. Thank you. And listen, thanks everybody for joining us this afternoon. I think you can tell that we have a lot going on over here at the Company. We're excited about the progress we're making, and we really look forward to updating you with our progress in the weeks and months to come. Thank you very much. Bye.

Ladies and gentlemen, thank you for attending today's conference. This does conclude today's program. Have a wonderful day. You may disconnect.