Alnylam Pharmaceuticals Inc (ALNY) 2016 Q1 法說會逐字稿

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss first-quarter 2016 financial results. (Operator Instructions) Please be advised that this call is being taped at the Company's request. I would now like to turn the call over to the Company.

Good afternoon. I'm Christine Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today here are John Maraganore, Chief Executive Officer; Barry Greene, President and Chief Operating Officer; Akshay Vaishnaw is actually under the weather today, so joining us will be Pushkal Garg, Senior Vice President of Clinical Development; and Mike Mason, Vice President and Treasurer. In addition, DA Gros, Senior VP, Chief Business Officer, is in the room and available for Q&A.

For those of you participating via conference call, the slides we've made available via webcast can also be accessed by going to the investor 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. Pushkal will summarize recent clinical progress, Mike will review our financials, and Barry will provide a brief summary of goals for 2016 and beyond before opening the call for your questions.

I'd like to remind you that this call will contain Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of Safe Harbor provisions 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 annual report on file with the SEC. In addition, any forward-looking statements represent our views only as the date of this recording and should not be relied upon as representing our views on any subsequent date. We specifically disclaim any obligation to update such statements.

And with that, I'll now turn the call over to John.

Thanks, Christine, and thank you, everyone, for joining us this afternoon. During the first quarter of 2016 and recent period, we made excellent progress as we continue to execute on our Alnylam 2020 strategy and advance RNAi therapeutics to patients and to the market.

Before Pushkal goes into our recent pipeline progress in more detail, I'd like to provide some context on recent news, news that we are announcing today, and upcoming milestones. First, we are very encouraged by the progress we're making across our entire portfolio. As of today we have 10 programs in clinical stages and two programs in Phase III across a broad range of disease indications.

By the end of the year, we expect to have 11 clinical stage programs and three programs in Phase III. In this regard we believe we are tracking very well against our 2016 goals. We are especially pleased with recent progress and news on our ATTR amyloidosis program. With patisiran, our program for the treatment of hereditary ATTR amyloidosis with polyneuropathy, or hATTR-PN, we are very pleased to have completed enrollment in our APOLLO Phase III trial.

Based on strong interest in the program from both the physician and patient communities, we substantially over-enrolled the trial, ending with 225 patients enrolled. I'd like to commend the excellent work of our clinical operations and medical affairs teams in ensuring the execution of this trial.

We started a full year beyond -- behind the Ionis/GSK program; and from our perspective, we have more than caught up. We now remain firmly on track to view results in mid-2017 and, if positive, expect to make our first regulatory submissions later that same year. We also continue to be encouraged by the tolerability and initial evidence for clinical activity from our Phase II open-label study, where we recently reported complete 18-month data at AAN.

Pushkal will go into the details in just a minute, but we continue to see evidence for potential halting of neuropathy progression. And we are particularly excited to have presented the first reported evidence of a correlation between the degree of TTR knockdown and subsequent improvements in neuropathy impairment scores.

Turning to revusiran, which is being studied for the treatment of hereditary ATTR amyloidosis with cardiomyopathy, or hATTR-CM, we are also making really strong progress on our ENDEAVOUR Phase III trial. And we are announcing today that we now expect completion of enrollment in late 2016, setting us up for an expected data readout in mid-2018. We also look forward to continuing to share data from our patisiran and revusiran OLE studies, and we plan to have our initial 24- and 12-month data readouts presented in July at the ISA meeting, assuming abstracts are accepted.

We now believe to have a substantial lead over the Ionis/GSK program in terms of the cardiomyopathy studies. And this is particularly the case given the clinical hold that remains on the Ionis program.

Finally, I want to comment on some new CC5 guidance that we're providing today. We'll be presenting our initial PNH data from a handful of patients in our Phase I/II at an oral talk at EHA on June 11. So we are unable to share specific results today due to the data embargo.

However, at a top level, our results today demonstrate evidence for clinical activity in PNH. And based on LDH data, we now believe that the optimal and most competitive development path for ALN-CC5 in PNH is for eculizumab poor responders and for eculizumab sparing. Accordingly, we believe it now makes sense to transition to a Phase II study that explores this path forward, and we expect to start that study by year's end.

We view PNH is a potential rapid development path and as an initial beachhead for potential regulatory approval and commercialization. In parallel, we will also begin to evaluate ALN-CC5 as monotherapy and potentially with anti-C5 monoclonal antibodies in a broader range of indications outside of PNH, where complement activity mediates disease pathophysiology.

Of course, we have lots more to update you on, including great progress in our patisiran studies and other new programs that we have put into the clinic. With those introductory comments, I'd like to now turn the call over to Pushkal to review our pipeline progress. Pushkal?

Thanks, John, and good afternoon, everybody. We indeed continue to make great progress with our pipeline of RNAi therapeutics.

Let me begin with our programs in our genetic medicine STAr and start with our therapeutics for the treatment of TTR-mediated amyloidosis. As you know, we have multiple product candidates in this area.

First, patisiran. As John mentioned, we completed enrollment in the APOLLO study early in the first quarter and affirmed our previous guidance that we expect to report data in 2017. If APOLLO is positive, expect to submit an NDA and MAA for patisiran in late 2017. As a reminder, and as shown on slide 7, the APOLLO Phase III trial is a randomized, double-blind, placebo-controlled global study designed to evaluate the efficacy and safety of patisiran in patients with hereditary ATTR polyneuropathy. The primary endpoint of this the study is the difference in the change in a modified neuropathy impairment score, or mNIS+7, from baseline to 18 months between patisiran and placebo. The study was significantly over-enrolled, with a total of 225 patients with stage one or two disease compared to the originally anticipated enrollment of 200.

Turning to the new results presented from our Phase II open-label extension study at AAN, we were very pleased to show continued evidence for potential halting of neuropathy progression. Specifically, as highlighted on slide 8, there was a mean decrease in the mNIS+7 neuropathy impairment score of 0.8 points, which compares favorably to an estimated mean increase in mNIS+7 of 22 to 26 points over 18 months, based upon analyses of historical data sets in untreated patients with similar baseline characteristics.

Similar results were observed in patients with or without concurrent tetramer stabilizer use.

In addition, patisiran administration was associated with a statistically significant approximately 77% needing improvement in nerve fiber density, based on blinded reads of distal thigh sweat gland biopsy samples. Further, over the 18-month period, patients with associated cardiomyopathy showed stability in their echocardiographic, biomarker, and functional measures, including 10-meter walk speed. Serum TTR levels were also measured throughout the OLE study and showed sustained TTR knockdown for over 24 months, with a mean maximal knockdown of 92% over the entire period and a mean post-dose knockdown of 87% at 18 months.

In addition, we also presented the results of an exploratory analysis examining the relationship between the degree of TTR knockdown with subsequent changes in mNIS+7. In the analysis, intersubject differences in the degree of TTR knockdown were compared to changes in mNIS+7 at six, 12, and 18 months to assess the effects of patisiran administration. There was a linear correlation between the degree of serum TTR knockdown and changes in mNIS+7. Specifically, greater degrees of TTR knockdown resulted in greater levels of mNIS+7 improvement.

These results were statistically significant at six and 12 months and showed a favorable trend at 18 months. Importantly, this is the first reported evidence that correlates the degree of knockdown with improvements in mNIS+7, supporting the therapeutic hypothesis that reduction of mutant and wild-type TTR may be associated with potential halting of neuropathy progressions in patients with hereditary ATTR polyneuropathy.

Patisiran administration was also found to be generally well tolerated in these patients, with up to 25 months of treatment. SAEs were reported in five patients, and all were unrelated to study drug. The majority of reported adverse events were mild to moderate, and the most common drug-related or possibly drug-related AEs were flushing, which occurred in 22.2% of patients; and infusion-related reactions, or IRRs, which occurred in 18.5% of patients.

All IRRs and drug-related flushing AEs were mild in severity and did not result in any discontinuations. We expect to present 24-month data from the patisiran open-label extension trial during the International Symposium of Amyloidosis in Sweden in early July, pending abstract acceptance.

Let's now turn to revusiran, which is our most advanced subcutaneously administered RNAi therapeutic in the clinic today, which utilizes our first-generation STC GalNAc chemistry platform. Here we are focused on the treatment of ATTR amyloidosis patients with cardiomyopathy.

As John mentioned at the top of the call, due to strong patient and physician engagement, we are now guiding that we expect ENDEAVOUR to complete enrollment by the end of this year and read out in mid-2018. As a reminder and as shown on slide 9, the ENDEAVOUR Phase III trial is a randomized, double-blind, placebo-controlled global study designed to evaluate the efficacy and safety of revusiran in patients with hereditary ATTR cardiomyopathy.

The co-primary endpoints of the study are the change compared to baseline in six-minute walk distance and the percent reduction in serum TTR between placebo and revusiran-treated patients at 18 months. The trial is designed to enroll up to 200 patients.

We are also currently conducting a Phase II OLE study in which patients who participate in the Phase II trial were eligible to roll over into the OLE study and receive revusiran on an ongoing basis, similar to what we've done with patisiran. Pending abstract acceptance, we anticipate presenting 12-month Phase II OLE data for revusiran at the ISA meeting in July.

Finally, with our TTR programs, during the first quarter we filed a clinical trial application for ALN-TTRsc02, an ESC GalNAc conjugate targeting TTR. Based on the emerging profile of the prior ESC GalNAc conjugates and the preclinical profile of this candidate, we expect it to support a potential once-quarterly subcutaneous dose regimen. Assuming a positive Phase I study, we will plan to initiate a Phase III in 2017.

We are now entering a very exciting period for fitusiran, or ALN-AT3, which is in development for the treatment of hemophilia and other rare bleeding disorders -- a large orphan market where substantial patient needs exist. We view this as a very exciting and innovative program where lowering of anti-thrombin is aimed at promoting sufficient thrombin generation to restore hemostasis, thereby preventing bleeding in patients -- in people with hemophilia.

During the recent period, we initiated a dosing of hemophilia patients with inhibitors in part D of an ongoing Phase I clinical trial evaluating a once-monthly subcutaneous dose regimen of fitusiran. Both patients with hemophilia A and B with inhibitors have now been dosed. We can now confirm that these data will be presented in just a few months in an oral presentation at the World Federation of Hemophilia in Orlando, Florida, on July 27.

As a reminder, recent interim data from the Phase I study of patisiran were presented at ASH last year and are summarized on slide 12. The interim data showed dose-dependent anti-thrombin lowering of up to 88% with monthly dosing of fitusiran. Fitusiran also demonstrated significant increases in thrombin generation and a reduction in median annualized bleed rates, or ABR, of 85% to 92% when compared to historical on-demand ABR for these patients.

Fitusiran was also shown to be generally well tolerated, with no clinically significant increases in D-dimer, a biomarker of excessive clot formation. There were no SAEs related to study drug and no discontinuations. The three drug-related AEs were all mild.

We now remain on track to initiate two Phase III trials: the first in mid-2016 in hemophilia A and B patients with inhibitors, and the second in late 2016 in hemophilia A and B patients without inhibitors. To that end we've now initiated discussions with global regulatory authorities to confirm specific trial designs.

We also continue dosing patients in an ongoing Phase I open-label extension where once-monthly doses of fitusiran are administered to hemophilia A or B patients with or without inhibitors. And we now have patients that have been dosed up to 10 months in that study.

Turning to ALN-CC5, we continue to advance this investigational RNAi therapeutic for the treatment of complement-mediated diseases. Based on emerging data from part C of the ongoing Phase I/II trial in a small number of patients with PNH, we've now seen preliminary evidence for clinical activity in patients enrolled in the study.

Based on these data, including data on LDH, we believe that the optimal and most competitive development path for ALN-CC5 in PNH is for eculizumab poor responders and for eculizumab sparing. As a result of this, we plan to transition towards a new Phase II study focused on that development path, and we expect to start the study by the end of 2016.

We are pleased to announce today that we plan to present initial data from part C of the ongoing Phase I/II study in about five patients with PNH in an oral presentation at the European Hematology Association meeting on June 11. We're also planning to present updated healthy volunteer data from parts A and B of the Phase I/II study at a meeting later this month. In parallel with the focused Phase II study in PNH patients, we also plan to initiate studies of ALN-CC5 as monotherapy and/or in combination with anti-C5 monoclonal antibody in additional complement-mediated disease indications such as atypical hemolytic uremic syndrome and myasthenia gravis, starting in early 2017.

We've also continued to make progress across our other genetic medicine clinical programs, including ALN-AS1, ALN-AAT, and ALN-GO1. Of these we are now entering an exciting stage in our ALN-AS1 acute hepatic porphyria program. Specifically, over the past quarter we transitioned to part C in the ongoing Phase I study, where ALN-AS1 is being evaluated in porphyria patients with recurrent attacks.

We're planning on presenting initial data from this part of the study later this year. And if the results are positive, we should be in a position to start a Phase III trial in 2017.

Another exciting development for the quarter was the initiation of a Phase I/II clinical trial for ALN-GO1 being developed for the treatment of primary hyperoxaluria type I or PH1. PH1 is an orphan disease where specific genetic defects result in excessive oxalate production, recurrent kidney stones, and eventual renal damage and failure. Many of these patients are children who require chronic dialysis and 24/7 fluid to prevent formation of stones, and the only cure is a double kidney/liver transplant.

The Phase I/II trial will be conducted initially in normal, healthy volunteers and then in patients with PH1. We expect to present initial data, including from patients with PH1, by the end of this year. During the recent period we also received orphan drug designations for ALN-GO1 from EMA and FDA.

I'll turn now to our cardio-metabolic disease and hepatic infectious disease STArs and review the progress there. In the case of our PCSK9 program with The Medicines Company, we are pleased with the enrollment progress in the ORION-1 Phase II study and look forward to initial results that The Medicines Company has guided to report later this year. As highlighted on slide 16, a key goal here will be to confirm the potential for quarterly or biannual dosing in addition to confirming safety in a much larger patient population of 480 patients with atherosclerotic cardiovascular disease compared to the 69 volunteer subjects we studied in our Phase I study.

In the case of our ALN-HBV program, we filed our CTA and have received approval to start the Phase I study. We'll provide more details on the design once the trial is initiated, but you can expect it to be a robust study in both volunteers and HBV-infected patients.

In summary, we believe that we are making excellent progress on our RNAi therapeutics pipeline across all three of our STArs. It's been an especially exciting and productive time for us as we continue to lead the advancement of RNAi therapeutics as a whole new class of innovative medicines. I will now turn the call over to Mike for a review of our financials. Mike?

Thanks, Pushkal. I will be referring to slide 19 for a discussion of the first-quarter 2016 financial results. We continue to maintain a strong balance sheet, ending the first quarter of 2016 with approximately $1.2 billion in cash as compared to $1.28 billion at December 31, 2015. Our financial strength allows us to continue to invest in a broad pipeline of investigational RNAi therapeutics across our three STArs aligned with achieving our Alnylam 2020 goals.

As for financial guidance this year, we are updating cash guidance today to end 2016 with greater than $1 billion in cash, including $150 million of restricted marketable securities that we received from credit agreements that we entered into with Bank of America and Wells Fargo in April 2016 to offset anticipated cash needs related to the building of our new manufacturing facility. The maturity of these facilities is five years, and the interest rate is LIBOR plus 45 basis points.

The GAAP net loss for the first quarter of 2016 was $103 million or $1.21 per share on both a basic and diluted basis, including $23.5 million of non-cash stock-based compensation expense; as compared to a net loss of $50.8 million or $0.62 per share on both a basic and diluted basis, including $8.2 million of non-cash stock-based compensation expense for the same period in the previous year.

Revenues were $7.3 million for the first quarter of 2016 as compared to $18.5 million for the same period last year. Revenues for the first quarter of 2016 included $4.4 million from our alliance with Sanofi/Genzyme, $2.7 million from our alliance with The Medicines Company, and $0.2 million from other sources.

The decrease in revenues in the quarter ended March 31, 2016, compared to the prior-year period was due primarily to the completion of the Company's performance obligation under the Monsanto agreement in February 2015 and the completion of its revenue amortization under the Takeda agreement in May 2015, partially offset by higher revenue from its agreement with Sanofi/Genzyme. We expect net revenues from collaborators to increase during the remainder of 2016 due to expected increases in expense reimbursement and an expected milestone under our agreement with Sanofi/Genzyme.

Turning to R&D expenses, they were $96.3 million in the first quarter of 2016, which included $14.4 million of non-cash stock-based compensation; as compared to $58 million in the first quarter of 2015, which included $5.3 million of non-cash stock-based compensation. The increase in R&D expenses as compared to the prior-year period was due primarily to higher clinical trial and manufacturing and external service expenses resulting from a significant advancement of the Company's pipeline.

In addition, compensation and related expenses and non-cash stock-based compensation expenses increased during the quarter ended March 31, 2016, as compared to the quarter ended March 31, 2015, due primarily to a significant increase in headcount during the period as the Company expands and advances its development pipeline; as well as the one-time non-cash charge of $5 million related to the vesting of certain performance-based stock-option awards during the quarter ended March 31, 2016. The Company expects that on a quarterly basis in 2016, R&D expenses will increase from the first quarter as it continues to develop its pipeline and advance its product candidates into clinical trials but will have variability on a quarterly basis, depending on timing of manufacturing batches, clinical trial enrollment, and stock compensation expense.

Finally, G&A expenses were $21.1 million in the first quarter of 2016, which included $9.1 million of non-cash stock-based compensation; as compared to $12.7 million in the first quarter of 2015, which included $2.9 million of non-cash stock-based compensation. G&A expenses increased due primarily to increase in non-cash stock-based compensation, due to an increase in headcount as well as the one-time non-cash charge of $3 million related to the vesting of the performance-based stock-option awards which I described earlier. The Company expects that on a quarterly basis in 2016, G&A expenses will remain relatively consistent with the first quarter of 2016.

I will now turn the call over to Barry.

Thanks, Mike. As you heard from both John and Pushkal, we had a tremendously productive first quarter of 2016 as we continue to build the industry's leading pipeline of RNAi therapeutics and advance our innovative medicines to patients and get ever closer to being commercial. Looking forward, this will be a very data-rich period, with 10 clinical readouts still anticipated this year.

Now let's turn to an update on our 2016 goals and financial guidance announced in January, as shown on slide 21. With regard to our patisiran program, we achieved our goal of completing Phase III APOLLO enrollment. Assuming positive data from the trial, we expect APOLLO will enable NDA and MAA submissions in late 2017. We also continued treating patients in our patisiran Phase II OLE study and plan to present additional data, including the initial 24-month data from Phase II OLE at ISA in July, pending abstract acceptance.

With revusiran, we are currently enrolling hATTR-CM patients in our Phase III ENDEAVOUR study and now anticipate completing enrollment in the trial later this year and having data from this trial in mid-2018. We're also treating patients of a Phase II OLE study with revusiran; and we plan, pending abstract acceptance, to present 12-month data from that study also at ISA in July. Additionally, with ALN-TTRsc02, having now filed our CTA we are on track to start our Phase I at midyear to present initial Phase I in late 2016.

Now, moving on to fitusiran, we are continuing to enroll additional dose cohorts in the ongoing Phase 1 trial, including hemophilia patients with inhibitors receiving monthly subcutaneous injection. We anticipate further presentation of Phase 1 at the World Federation of Hemophilia in July; and additional data, including one -- Phase I OLE results in late 2016, likely at ASH.

We are also excited for the planned start of our two Phase III trials in mid- and late 2016 in hemophilia patients with and without inhibitors, respectively. Now, with ALN-CC5 we plan to present updated healthy volunteer data from parts A and B of our Phase I/II study at the ERA-EDTA meeting later this month; and then, as you heard, plan to present part C of the Phase I/II trial in PNH patients at the EHA meeting in June. We're also now transitioning towards a Phase II study to evaluate ALN-CC5 in PNH patients for eculizumab poor responders and for eculizumab sparing, which we expect to start by the end of this year.

With ALN-AS1 we anticipate being able to present initial data in late 2016 from patients with recurrent porphyria attacks. With ALN-AAT, we're on track to present initial Phase I data in mid-2016.

Now turning to our ALN-GO1 program for the treatment of PH1: as you've heard, we have started our Phase I/II trial and plan to present initial data by the end of this year.

Turning to our cardio-metabolic disease STAr with ALN-PCSsc with our partner The Medicines Company, we anticipate initial Phase II data to be presented later this year.

With our hepatic infectious disease STAr, we filed our CTA and received approval for ALN-HBV to start our Phase I study, and we anticipate doing so midyear.

Finally, as you heard from Mike, we've updated our financial guidance today to end the year with greater than $1 billion in cash, including $150 million in restricted marketable securities pursuant to the credit agreement we entered into last month in connection with our new manufacturing facility, all described by Mike. Now, in summary, we are poised for quite a data-rich 2016.

For the next few months alone you can see the significant news flow associated with our CC5, patisiran, revusiran, and fitusiran programs. We also will be hosting our RNAi Roundtable series this summer, and we look forward to sharing that schedule with you in the next few weeks. So with that, I will now turn the call back over to Christine to coordinate our Q&A. Christine?

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

(Operator Instructions) Alethia Young, Credit Suisse.

Congrats on the progress this quarter. Two -- since you only said two, I guess, you know, I'm thinking about eculizumab and the sparing versus the poor response. Is that how you are going to pursue going forward in other indications in complement-mediated diseases?

And the second question is: when you think about 1210 and comparing there, how do you think about -- do you think that your strategy would change depending on the different outcomes we could see with 1210? Thanks.

Yes, thanks, Alethia. Let me make some comments; and then, Pushkal, if you want to jump in, as well.

For -- as it relates to the other indications, we believe that monotherapy may very well be the best path forward in these other indications. We haven't yet -- obviously, we'll evaluate monotherapy in the other indications as well, but there may be other settings where using it in combination with eculizumab or anti-C5 antibodies generally speaking would be warranted as well. But certainly our thinking is that monotherapy would be explored in those other settings in general.

And as it relates to 1210, you know, look -- 1210 is still yet to be read out in terms of specific data. So we'll have to see how that looks. Clearly, the approaches that we are proposing here we think will be valuable, whether it's 1210 or eculizumab alone. So it doesn't really influence too much based on what happens with 1210.

Pushkal, you want to add anything to that?

Yes, maybe just two quick points. I think one is that PNH cells -- in PNH patients, there is this vulnerability because of defects in CD59, so they may be particularly vulnerable. And so there may be somewhat different thresholds with other complement-mediated diseases. So I think the opportunity to pursue both monotherapy and/or combination approaches, as John outlined, are viable there. And we are going to evaluate those going forward.

So I think -- and we do know certainly that there is an unmet need for patients who are not fully adequately controlled in a number of these diseases that we can potentially address with ALN-CC5. So that's what we are going to be looking to pursue.

And I'll just add: our investigators are extremely excited about the data that we'll be presenting in June in terms of the potential for both poor responders and also for sparing. So when you see those data, you'll have a better sense of why we think there is a very interesting opportunity here.

Okay, great. Thanks.

Terence Flynn, Goldman Sachs.

This is Cameron filling in for Terence. Thank you for taking our question.

Maybe first off, can you share anymore data on the C5 program that led to your decision, particularly anything on knockdown or LDH changes? And then, second -- oh, go ahead.

Yes, Cameron, we have an oral presentation at EHA which is under data embargo. So we really can't share anything beyond the top-line conclusions that we've shared today. So you'll just have to wait until June 11, when those data are presented.

Okay. And then for the C5 program more broadly, do you have any thought of exploring additional doses or schedules?

Sure. Pushkal, you can comment. I think we feel pretty good about the dose and dose schedules that we've got as it relates to the mechanism of our drug, which is to essentially knock down liver-derived C5 all the way to the floor.

And so when you have that type of a biomarker, and you are getting a very complete effect through our mechanism of action, it's very easy to get to being comfortable around the right dose and the right dose regimen. And we don't think there's anything about dose and dose regimen here that changes our conclusion about how we would go forward. Pushkal, do you want to add anything to that?

Yes. I would just say, we studied -- and you will see -- both from the parts A and B in healthy volunteers and part C, we studied a pretty broad range of doses. So I think that's very informative to us as we pursue the upcoming Phase II study and some of the indications next year that we'll be pursuing. And we'll be able to share more at EHA.

Okay. Thanks for taking the questions.

Ritu Baral, Cowen.

First question is on ENDEAVOUR. Can you comment a little bit about how the conduct of that study is going and dropout and compliance as you are seeing it right now, probably on a blinded basis?

Sure. We can certainly give you very broad comments on that, Ritu. I mean, obviously, as we announced today, the enrollment is going far better than we had expected, I think it's fair to say.

We plan on being fully enrolled by the end of the year. We are well over 50% into the study enrollment at this point. And all sites are enrolling pretty positively. Total number of sites now, Pushkal, are --?

Roughly 60 or so.

Roughly 60 worldwide. And so it's going very well. Obviously we've been benefited here by the continued and protracted clinical hold that Ionis are in, because it's removed any competition for enrollment in the space. And while that's obviously not necessarily the best thing for patients per se, from a competitive standpoint it's obviously very good for us and for the enrollment in the study.

You know, I don't think we can really comment on discontinuation rates right now, but I think we can just say in general that we are pleased with the profile that we are seeing from a blinded study. There's nothing that has us concerned. And that, to some extent, is reflected in the rate of enrollment that we have as well in the study. So so far so good, Ritu.

Got it. Next question is on the C5 program. As you look at the Phase II that you mentioned and also potential pivotal studies for eculizumab sparing, what do you think the pivotal endpoint would be? What do you think the endpoint is going to be for your Phase II, and what do you think is an acceptable pivotal endpoint along those lines -- along those (technical difficulty) for C5 development?

Great. Let me have Pushkal address those questions.

So I think it's a very interesting question. I think the nice thing about PNH is that there are clearly measurable biomarkers, the most prominent of which is LDH, that can be measured in serum and has been associated with -- you know, when it's not controlled, poor prognostic outcomes for patients with this disease.

And we know, based on data in the literature as well as what we are hearing from investigators, that there are a fair number of patients who actually don't have their LDH fully controlled and then are at ongoing risk for thromboembolic events and ongoing hemolysis. So we think that that is something subject to discussion with health authorities that could potentially be a registrable endpoint in PNH.

But there may be also opportunities to show symptom improvement. There are patients who have residual symptoms in the course of being treated with eculizumab, where combination approaches, sparing approaches may be able to -- with ALN-CC5 we may be able to alleviate patient symptomatology as well. So we are going to be exploring those sorts of avenues as we build that package up and generate the Phase II data and then take that to health authorities.

Got it. Thanks for taking the questions.

Alan Carr, Needham and Company.

A couple of them. One of them -- I wanted to -- I wondered if you could elaborate a bit on AS1, what you are looking for from the Phase I data. You mentioned that Phase III might be coming up pretty soon. So if you could talk about that program a little bit more?

And then I also noticed in your press release -- you didn't have it in your prepared remarks, but it looks you're, with another candidate, going after HAE. Wondering if you could comment on that too -- what sort of profile you think you might be able to put together.

Yes, let me make a couple comments. Let me address this last one, and then, Pushkal, you can get porphyria.

So with ALN-F12, which is a program that we just put into development, it's targeting Factor XII. And the goal there is to explore it for hereditary angioedema. Also potentially thromboprophylaxis. There's a very interesting data set around Factor XII and its involvement, obviously, in thrombosis. And there's an approach there that might be worth exploring as well. We are going to look at both as opportunities.

But for HAE specifically, Alan, the profile that we think we can achieve with ALN-F12 as a potential sub-Q quarterly drug for the prevention of attacks in patients with HAE that -- we think that would be a very competitive profile versus the existing drugs that are out there, but also the Dyax/Shire drug that's in development.

So at a very high level that's where we are going with that program. But it's still preclinical. We'll obviously update you more when we get that into the clinical stages. So let me turn to Pushkal, then, on porphyria.

Sure, thanks, John. So Alan, on the AS1 program for porphyria, recall that acute hepatic porphyrias really are due to defects in the heme biosynthesis pathway, in AIP, specifically the defect in this -- in an enzyme PBGD. But what happens in all of these is that you get a buildup of these toxic metabolites, most prominently ALA and PBG.

And it's that buildup of those metabolites that's thought to relate to the various neurovisceral symptoms that these patients get -- pain, attacks, etc., that can be treated sometimes with hemotin, etc., although not terribly effectively in many patients. And so what we are doing with AS1 is we are looking at blocking an upstream enzyme in the pathway to prevent the buildup of these toxic intermediates, ALA and PBG.

So when we think about what we're going to look for in the Phase I study, in addition to safety and tolerability, of course, we are going to be looking to see in these patients who are what we call asymptomatic hyper-excreters in parts A and B of the Phase I/II study. And then in AIP patients with recurrent attacks in part C of the study, that we get good knockdown of ALS1.

But most importantly we would like to see that we can bring those ALA and PBG levels which are elevated back close to normal. I think that's going to be the strongest indicator for us in terms of something that we are actually -- has the potential to be meaningful for these patients in aborting the attacks or preventing the attacks.

In part C we will be enrolling patients who have recurrent attacks. It's a small cohort of patients, but ideally we'll be able to see even some impact in terms of attack frequency or severity in that. But that is a small cohort of patients. So really what we're going to be looking at is being able to bring those levels of those toxic intermediates down closer to normal for these patients.

And what we've guided, Alan, is that we expect to have data in the recurrent-attack patients by the end of the year.

Your thoughts on what an endpoint might be for registration? Or is it too early for that?

Pushkal?

Well, we haven't had those discussions. So everything is subject to that discussion with the health authorities.

But I think we are looking at endpoints and considering endpoints that relate to really what's most troubling to these patients, which is frequent recurrent attacks and trying to prevent those from happening in patients on ALN-AS1. Those attacks often require intensive treatment, visits to urgent care facilities, hospitalizations, etc., and so we'll be looking at some sort of an attack-related endpoint.

Frequency or severity, something along those lines?

Yes, I think probably some combination of those.

Okay. Thanks very much.

Mike King, JMP Securities.

Just want to start with a comment that I think Barry looks awesome with a hardhat. (laughter)

Thanks, Mike.

If you're selling framed copies of that, please, I will take one.

We'll send you a framed, signed one.

Signed! Yes, definitely.

I hate to belabor the C5 program, but I'm just anticipating the inbound questions I'm going to get about it. And I just wonder if you guys feel that you have the appropriate construct. I know that you have all the pharmacodynamic markers that you want; that's typical of all of your assets. I'm just wondering if there is something unique about the biology of complement that has you going the route you are going as opposed to a monotherapy in PNH.

Yes, you know, Mike, I think -- this is a really active drug. When you look at our part A and B data that we presented at ASH, we are getting 99%-plus knockdown of C5. You know, it's really hard to squeeze out much more out of a biological system like a human being than that level. And so -- and, you know, obviously, I won't refer to data in PNH which is under embargo, but there's no reason to believe that a PNH patient would be different than a volunteer in terms of that.

Right.

So there may well be factors that are related to extrahepatic supply of complement factor C5. That's in play. Or it could be other factors.

But I think we'll have to wait till the data comes out at EHA for the clarity on that. What we can say now is that we have clinical activity. We think that the most competitive profile is as a drug to be used for sparing of eculizumab or for eculizumab corresponders. And we have data that convince us that that's a really attractive path forward, as well as our KOLs.

So you'll see those data in a few weeks. Not -- EHA is not that far away. And then that will add some clarity to all that. But we do feel that the path forward, at least in PNH, is in that way. For other complement diseases, for reasons that -- partly that Pushkal mentioned, it's unclear that you need to have another antibody present. It could very well be that monotherapy is fully sufficient.

Okay. Thanks for the detailed answer there, John. Just switching quickly to the TTR programs, we checked the ISA website, and it said that abstract acceptance cut-off date was April 28. So I'm just wondering, is the expectation that if you get accepted for both -- one or the other, patisiran or revusiran, that they would be accepted as late-breakers? Thank you.

You know, that's news to us on the April 28. I'm looking at Pushkal. He was equally surprised by that.

But we haven't received notification yet. But we are -- that's a meeting that we are pretty active in, so I would be surprised if we don't have both of those presentations there. I would be shocked.

But obviously, you know, we'll have to wait for the organizers to notify us formally if that's the case. April 28 was last week. You know, meeting's in Uppsala. Mail goes slowly from Uppsala. (laughter)

Yes, I'm well aware of the timelines of academic organizations. They are not quite the same as ours. All right, thanks, guys.

Michael Schmidt, Leerink Partners.

Just one more on C5. Just to understand next steps -- so the Phase II trial in early 2017, so that is in both poor responders as well as well-controlled PNH patients? Is that correct?

So the goal is in 2016, by this year's end, is to start that trial. And Pushkal, do you want to give some color on the current thinking?

Yes. So, Michael, the current thinking, as John said, is to start a Phase II study at the end of this year that would really be looking at ALN-CC5 in PNH patients who have somewhat elevated -- you know, who are not fully controlled on eculizumab, and looking accommodation approaches both with full dose and in a sparing type of regimen to really explore that combination approach in PNH.

So these will be patients who are not fully controlled with eculizumab. And as far as we understand from both literature and as well as talking to our investigators, and why the investigators are excited about this, is there is a substantial proportion of patients who do have -- aren't fully controlled with eculizumab, where this combination approach may make sense -- and/or sparing approach.

Yes. So that was my next question, I guess. What percentage of patients is considered poor responders? And what gives you confidence that you can add -- you know, that the drug works in those patients?

I think our understanding is that it's approximately 20% to 30% of patients who actually may not have adequate control on eculizumab alone. And in terms of what gives us confidence, I think what I'd have to say is that some of the data that we are looking -- that we've gotten from part C, that we'll be presenting June 11 -- you know, unfortunately, we can't speak more about now, I think is what gives us the appreciation that this may be the best development path and an appropriate development path, based on the data that we've already seen.

All right, thanks. I want to do circle back to the TTR program as well. And so with the ENDEAVOUR trial enrollment going well, I was wondering -- you know, I know you are running this genetic screener study or feeder study?

Yes. DISCOVERY.

Right, exactly. So I was wondering what you're seeing, now that you've probably screened a significant amount of patients, in terms of how the market looks? Does it meet expectations in terms of the mutation frequencies that you are seeing, the patient numbers? Does it all add up to your expectations?

It's a great question. Pushkal, do you want to comment?

The discovery -- I think what I would say is, if you'll recall, the DISCOVERY study was really looking at patients who had sort of some characteristic signs in terms of echocardiographic or EKG changes as well as symptoms that made their -- the suspicion of ATTR amyloidosis a potential for them. And I think what really was highlighted is how quickly that study enrolled over 1,000 patients.

And I think that was really the testament to the number of patients who potentially meet -- you know, have these sort of difficult-to-diagnose congestive heart failure types of profiles that may have cardiomyopathy. So I think that if I would say anything, and others may want to chime in, it highlights actually that there's probably a pent-up demand for new therapeutics for this disease, since the unmet need is actually larger than we may have thought.

Barry?

I agree with that. And, Michael, what I would say is that what we are seeing for revusiran and this cardiomyopathy is not uncharacteristic of what we've seen in other orphan diseases, where diagnoses are suggested and a potential therapeutic opportunity is presented, the patient numbers seem to grow. And as you've heard, there was some skepticism about how many patients were out there.

And even in light of another Phase III running with Pfizer, we are quickly enrolling this study. And that should be proof point about how well we're finding these patients.

Okay, great. Thanks so much.

Ted Tenthoff, Piper Jaffray.

Thanks for the thorough update. So with all the other questions focused on pipeline and all the C5 questions, I kind of want to go a different direction and ask about the manufacturing facility. How long is it going to take to build this out? And how should we be thinking about scale once you get there?

Yes, great question. Barry, you want to handle it?

Yes, Ted, so we'll be operational in 2018. We are talking about a state-of-the-art 200,000 square foot facility on 12 acres just south of here in Norton. And the reference that Mike made earlier is we had our groundbreaking for the facility last week, which was met with tremendous reception in Norton and Massachusetts.

We will continue to work with third-party clinical manufacturers and commercial manufacturers. As you are well aware, our pipeline is growing tremendously; and particularly with some of the cardio-metabolic and hepatic infectious programs, the capacity that we are going to need exceeds the capacity that exists today. So by having our own manufacturing facility that we can also then expand on, we could meet the needs of our growing pipeline for the next five or six years to come. And clearly, if we continue to be successful, there may be other manufacturing moves we make down the road. But this will help us for the next five or six years, for sure.

Cool. And Barry, just to pick up on that point, how does this also sort of affect future potential partnering opportunities? Is this something where you guys would continue to be the manufacturer of product? It seems to me like it could strengthen negotiating positions.

Yes, that's a good point, Ted; particularly as we look at the larger population diseases, our ability to -- with effective cost of goods, supply, significant amount of product to these large populations will be critical to the kind of margins that any partner might be needing, particularly outside the US and Western European markets. So by having our own facility, we'll be able to scale appropriately.

Cool, awesome. Thanks for the update.

Christopher James, FBR and Company.

Congrats on the progress. Just two quick ones. And I hate to belabor the CC5 opportunity, but quickly, how do you define the poor responder? And then, secondly -- I'm sorry -- ?

Yes, that's a great question. But go ahead with your second question first.

And then -- second question is just as good. (laughter) What are you -- how do you think about the potential combinability with eculizumab?

Oh, good. That's a good one, too. So Pushkal, do you want to handle both of them?

Yes, let me start, then. So, thanks, Christopher.

I think in terms of ecu poor responders, I think the way we think about that is probably in a couple of dimensions. Certainly there are patients for who, for example, are having breakthrough hemolysis symptoms within the dosing interval of, you know, an every-14-day dosing interval for eculizumab; or patients who are not adequately controlled -- the need to have dose escalation, and even in some of those instances are not fully controlled from either a symptomatology perspective -- or, as I was speaking earlier, there's epidemiologic data in these patients to suggest that having an LDH lactic dehydrogenase level that's more than normal, more than 1 1/2 times the upper limit of normal, is associated with ongoing risk for thromboembolic events.

So when we think about patients who are poor responders, we think about those patients with either persistently elevated LDH and/or persistent symptomatology on doses of eculizumab. So that's the first part of your question. And I apologize, what was the second part?

The second excellent question was on combinations. How readily -- I mean, Chris, your question is how readily achievable is the decline?

Combinable.

Yes.

Yes.

Yes. And I think -- look, I think we are -- we've already in part C, as you may recall the study design, we actually had a period of time where we were actually giving both drugs in combination. I mean if you're going at it from a clinical perspective -- make sure -- I want to understand your question. Certainly the most important thing is around safety and tolerability, as you are giving -- one is ID, one is subcutaneous. There is no issue there.

And so in terms of the consequences of C5 knockdown or complement inhibition, those are the same. We manage these patients in terms of potential for risk for infection, etc. So we are not concerned in any -- sort of in a general-principle way of combining these two therapies. And we think that there can be an additive pharmacologic effect that could be a real benefit to these patients. And I think that's some of the data that we want to speak to, and it's prompting our thinking around the development path here.

Great. Thanks, guys.

Anupam Rama, JPMorgan.

This is Eric in for Anupam. Thanks for taking the question. Just a couple TTR-related ones from us today.

First, with ENDEAVOUR, can you remind us what the allowance is for concomitant stabilizer use? And whether -- what proportion of patients you might expect to be also on stabilizers with revusiran, and what in the way you are expecting in terms of the incremental impact? And then I also have a follow-up.

Yes, so that's a simple one. In the protocol, patients cannot be on concomitant use of TTR stabilizers, either tafamidis or diflunisal. So it's a pure study, placebo-controlled, no stabilizers in both arms.

Got it, thanks. And just a question related to the post-liver transplant study in FAP patients. Just wondered if you could briefly talk about the rationale and the opportunity with that trial, and whether this might be described as a label broadening opportunity, getting revusiran in into FAP? Thanks.

Sure. Let me provide some context and then give it to Pushkal on the label broadening.

But the reason we are doing that study -- a small study -- is as we begin to advance patisiran and revusiran and, in fact, TTRsc02 going forward, we are interested in the entirety of the TTR disease segments. And it includes cardiomyopathy patients. It includes polyneuropathy patients. It includes the wild-type patients that we'll certainly be exploring with TTR-CO2 in the future.

But there are patients also that have had a liver transplant that are progressing on their liver transplant because of the production of the wild-type TTR protein. And we had quite a bit of interest from investigators for us to do something about those patients. And obviously our desire is to help those patients. And so that's why we are doing the study: to provide evidence that the drug can be safely administered to that population and that, hopefully, we can provide some evidence that we are stabilizing disease progression that occurs in those patients.

Tragically, because these patients have no resort after having received a liver transplant, as they progress they have nothing they can do but succumb to the disease. So that's where we are pursuing it. I mean, Pushkal, do you want to comment a little bit on the regulatory label expansion side of it?

Yes, absolutely. So I think -- you know we are doing this study; it's in approximately 12 patients with revusiran in patients who are post-liver transplant. And certainly our thinking is that as we -- A, those data will be inherently important as they are to sort of understand both safety and tolerability, and the impact of TTR-lowering in these patients, and whether we can have a favorable impact in terms of their disease course. But it would certainly be our intent to take those data when they mature to health authorities in the context of our regulatory negotiations, and pursue labeling if the data are encouraging, and show that there may be benefit to these patients.

So absolutely that would be our intent. As John mentioned, we would really like to develop a series of therapies that will address the full range of disease manifestations of TTR amyloidosis. And we think that this is an important aspect of that.

Okay, great. Thanks.

I would now like to turn the conference to Mr. John Maraganore for any closing remarks.

Thanks, everyone, for joining us this afternoon. You are going to have a lot more data coming out this year. We already have some data in May, and June, and July which I think will be quite exciting. And then stay tuned for more info on our RNAi Roundtable.

Until then, have a great rest of the day, and we'll talk soon. Thanks. Bye-bye.

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