Cynthia Clayton - Vice President of Investor Relations & Corporate Communications John M. Maraganore - Chief Executive Officer and Executive Director Akshay K. Vaishnaw - Chief Medical Officer and Executive Vice President of Research and Development Michael P. Mason - Vice President of Finance and Treasurer Barry E.

Greene - President and Chief Operating Officer Joshua Brodsky -.

Ritu Baral - Cowen and Company, LLC, Research Division Adam A.

Walsh - Canaccord Genuity, Research Division Alethia Young - Deutsche Bank AG, Research Division Michael Werner Schmidt - Leerink Swann LLC, Research Division Alan Carr - Needham & Company, LLC, Research Division Geoffrey Meacham Cameron Bradshaw - Goldman Sachs Group Inc., Research Division Eric W.

Joseph - JP Morgan Chase & Co, Research Division Edward A. Tenthoff - Piper Jaffray Companies, Research Division.

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to discuss First Quarter 2015 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 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 of R&D and Chief Medical Officer; and Mike Mason, Vice President of Finance and Treasurer.

Josh Brodsky, Senior Manager of Investor Relations and Corporate Communications, is in the room with us as well. For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the Investors page of up website at www.alnylam.com.

During today's call, as outlined in Slide 2, John will provide some introductory remarks and provide general context; Akshay will summarize recent clinical progress; Mike will review our financials and guidance; and Barry will provide a brief summary of 2015 goals before we open up the call for your questions.

I would like to remind you that this call will contain certain remarks concerning future expectation, 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 a 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 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.

Now before I turn the call over to John, I would like to take this opportunity to thank everyone at Alnylam for 10 amazing years as the company's Head of Corporate Communications and Investor Relations. As we announced in our press release today, I am going to be leaving Alnylam to pursue personal interests.

Mike Mason will pick up my role for now on an interim basis, and we are planning on recruiting a replacement. To say the least, I'm tremendously grateful for the opportunity to have been a part of Alnylam, to have contributed to its success, and to have been able to work with some of smartest and most dedicated people in this industry.

I have every confidence that the company will see continued success as a top-tier biopharmaceutical company focused on RNAi therapeutics, and I look forward to watching the progress. With that, I'll turn the call over to John..

Thanks, Cynthia. It should go without saying, Cynthia, that we will miss you greatly and can't thank you enough for all of your contributions and dedication to Alnylam. But we're also very happy that you'll have an opportunity to pursue your personal interests, just don't be a stranger.

Turning to our quarterly results, let me start by thanking everyone for joining us this afternoon. During the first quarter of 2015 and recent period, we made excellent progress as we continue to advance RNAi therapeutics to patients and to the market.

Earlier this year, we launched our Alnylam 2020 guidance, where by the end of 2020, we expect to achieve a company profile with 3 marketed products and a deep pipeline of 10 or more clinical programs, including 4 in late stages of development across our 3 strategic therapeutic areas or STArs.

Alnylam 2020 marks our expected transition from a late-stage clinical development company to a multiproduct commercial stage company with a sustainable development pipeline, a profile that we believe has rarely been achieved in the history of biotech. We believe that Alnylam is strongly positioned to achieve these objectives.

Before Akshay goes into our recent pipeline progress in more detail, I'd like to provide some context on recent events and upcoming milestones.

First, a major highlight for the first quarter in recent period was the emergence of new clinical data that we believe has strengthened the important bridge we are building from gene knockdown to potential clinical benefit for patients.

In this regard, we recently reported on very encouraging 12-month clinical data from our Phase II open-label extension, or OLE, study with patisiran.

Specifically, we believe that the results we reported are consistent with our therapeutic hypothesis that TTR knockdown has the potential to halt neuropathy progression in patients with TTR polyneuropathy.

Then turning to our ALN-AT3 program, we were very pleased in January to report OLE data from our Phase I study in subjects with hemophilia, where we showed what we believe to be initial evidence for potential correction of the hemophilia phenotype with ALN-AT3 administration.

We believe these clinical data with both patisiran and ALN-AT3 continue to strengthen the bridge that connects RNAi-mediated target gene knockdown with clinical outcomes, a critical important theme for Alnylam going forward as we go continue to advance in late-stage development and toward commercialization.

A second important point is that we are now in a very data-rich period across multiple programs in our pipeline. As I mentioned, we already had 2 important clinical readouts this year and the upcoming month of June is going to be a big month.

Since we are announcing today that we plan to present data from our ALN-CC5 complement program in mid-June in an oral talk at EHA, and data from our ALN-AT3 hemophilia program in late June in an oral talk at ISTH.

In addition, we plan on presenting a robust data set from our ALN-PCS subcu hypercholesterolemia program in mid-2015, probably at ESC, which will be held in late August.

And as Barry will comment at the end of our prepared remarks, we have even more data to come in late 2015 and many important execution milestones that we aim to achieve during the course of the year. And finally, I'd like to emphasize the very unique opportunity that we believe Alnylam is creating for patients and for shareholders.

With our GalNAc-conjugate platform and our focus on genetically validated liver-expressed disease genes, we now have advanced 6 programs into clinical stages, including 2 programs in Phase III trials, and we expect to end 2015 with 8 programs in the clinic.

Our company has a reproducible and modular platform that has been matched with what we believe to be a compelling and differentiated product strategy for continued value creation.

Indeed, we're positioned to continue to deliver 3 or more new clinical programs into the clinic every year, with multiple new Phase III trial starts expected over the next 12 to 24 months.

In short, we believe that we are now at a very exciting stage of bringing our innovative medicines closer to patients and to the market as we execute on our Alnylam 2020 strategy and strive to emerge as a top-tier biotech company. With those introductory comments, I'd like now turn the call over to Akshay to review our pipeline progress.

Akshay?.

Thanks, John, and hello everyone. We've indeed continued to made great progress with our pipeline of investigational RNAi therapeutics. Let me begin with our RNAi therapeutic programs for the treatment of TTR-mediated amyloidosis, or ATTR amyloidosis. As you know, we have 2 product candidates in this area.

Patisiran, our lead program is aimed at the treatment of ATTR amyloidosis patients with familial amyloidotic polyneuropathy, or FAP. Patisiran is in a Phase III trial called APOLLO, and we now have over 40 sites in over 15 countries open.

Revusiran is our most advanced subcutaneously administered RNAi therapeutic in the clinic today and is focused on the treatment of ATTR amyloidosis patients with familial amyloidotic cardiomyopathy, or FAC. This product candidate is also in a Phase III trial and that trial is called ENDEAVOUR.

Let's turn to some of the data generated from both these programs, and I'll start with results we presented in April at the AAN meeting, where we presented interim 12-month results from our ongoing Phase II OLE study of patisiran in patients with FAP.

At 12 months, we showed a mean 2.5-point decrease in the modified neuropathy impairment score, or mNIS+7, in 20 patients with data available for the current analysis.

As shown on Slide 11, this decrease in neuropathy progression compares favorably with the 13- to 18-point increase in mNIS+7 at 12 months that can be estimated from historical data sets in untreated FAP patients with similar baseline characteristics.

Importantly, there was a consistent effect across all the mNIS+7 subcomponents including more objective measurements.

With the very important caveat that our results stem from an open-label study in a small number of patients, we're encouraged to see what we believe to be evidence for a possible halting of neuropathy progression after the first 12 months of treatment.

Moreover, these data are very encouraging with regard to our APOLLO Phase III study, since the primary endpoint of this study is also the mNIS+7 neuropathy score.

In addition, repeat dosing of patisiran achieved sustained mean TTR knockdown at the 80% target level, with the mean nadir of up to 88% TTR knockdown between doses and up to 96% TTR knockdown on an individual basis.

This consistent level of knockdown gives us confidence in our potential to maintain knockdown throughout this Phase II OLE study and also in our APOLLO Phase III study since we're using the same dosing regimen.

Finally, it is of mention that this is now what we believe to be the industry's best evidence to date, that RNAi can be sustained in humans over a long duration of treatment. And we've seen no evidence to date of tachyphylaxis or an immune-mediated clearance affect.

Importantly, patisiran was also found be generally well tolerated in the study after 17 months of therapy, with no drug-related serious adverse events to date, and all 27% patients enrolled in the study continue to receive drug treatment. Of course, we'll be very interested to see how these results, including the mNIS+7 data, mature going forwards.

And with these encouraging results in hand, we now look forward to sharing 18-month clinical results in late 2015. We also plan on discussing these results with regulatory authorities in the U.S. and EU, as they relate to potential consideration of our APOLLO Phase III study, and we'll update you if and when appropriate.

Turning to APOLLO, I'm very pleased to say that this trial is proceeding well. As a reminder, APOLLO is a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of patisiran in ATTR patients with FAP. And if successful, the study would support marketing authorization for patisiran in countries around the world.

Primary endpoint of APOLLO is the difference in the change in mNIS+7 between patisiran and placebo at 18 months. As I mentioned earlier, this is the same neuropathy impairment score we're employing in our Phase II OLE study. We're also using the same dosing regimen APOLLO as we are in our OLE study.

Furthermore, patients enrolling into the APOLLO study present with a broad range of neuropathy impairment, similar to the patient population in the OLE study. Accordingly, we view our OLE study, especially over time as an important indicator of what we might anticipate seeing for patisiran-treated patients in APOLLO.

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

Of note, the pace of our APOLLO study enrollment has been increasing since our 6-month OLE data was presented this past October, and we expect it to increase still further with the recent presentation of our 12-month OLE results. Let's now turn to recent progress with revusiran.

At the American Oncology of Cardiology Meeting in March, we presented complete results from our Phase II clinical trial with revusiran in patients with TTR cardiac amyloidosis, where we showed robust knockdown of serum TTR of up to 98.2%, with weekly subcutaneous injections of revusiran.

Revusiran was also shown to be generally well tolerated in these patients with advanced disease, demonstrating a safety profile that supports advancement into Phase III.

These patients from the Phase II study are now rolling over into an open-label extension study, where they'll be able to receive revusiran for an extended period of time, similar to what we've done for patisiran.

Of the original 26 patients in the Phase II study, we're expecting most to enroll into the Phase II OLE, and we expect to complete enrollment in the next couple of months.

The OLE study will evaluate the safety and tolerability of long-term dosing with revusiran for up to 2 years, and we'll also measure effects of treatment towards a number of clinical endpoints including mortality, hospitalization, 6-minute walk distance in addition to cardiac biomarkers.

We intend to report clinical data from this study about once a year with initial data in late 2015. We also reported recently on our FAC natural history study results. Its retrospective analysis evaluated disease progression in FAC patients and demonstrated a clear and robust decline in 6-minute walk distance over an 18-month period.

Specifically, at 18 months, the mean decline in 6-minute walk distance was 140 meters. These findings give us confidence that our ENDEAVOUR Phase III trial of revusiran in FAC patients is appropriately designed to show the potential impact of TTR lowering on the co-primary endpoint decline from baseline in 6-minute walk distance of 18 months.

In addition, these data provide context on our ongoing Phase II OLE study of revusiran. We continued enrollment efforts in our ENDEAVOUR Phase III trial with revusiran. This is a randomized, double-blind, placebo-controlled study, which we -- where we're looking at 2 co-primary endpoints measured at 18 months.

One, being the change in 6-minute walk distance between drug and placebo, and the other being reduction serum TTR between drug and placebo. It's still relatively early in the study's initiation, and we'll provide more guidance on the study time line as enrollment continues during the course of this year.

Finally, we're also pleased with the ongoing progress in our DISCOVERY screening study. DISCOVERY is being conducted at large number of centers with the goal of identifying TTR mutations in patients with heart failure and other risk factors consistent with FAC. We look forward to sharing some results from DISCOVERY later this year.

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

We view this is as a very exciting and innovative programs since antithrombin knockdown has the potential to rebalance the coagulation cascade in patients with hemophilia and other rare bleeding disorders, which should lead to enhanced thrombin generation, improved hemostasis, a possible disease-modifying effect, which we believe could result in possible functional correction of disease.

At the Goring Coagulation Conference in January, we were pleased to present interim results from our ongoing Phase I trial, including what we believe to be initial evidence, that ALN-AT3 has the potential to correct the hemophilia phenotype.

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

These changes in thrombin generation in severe hemophilia was as if we've transformed the disease to a mild hemophilia phenotype, where patients rarely bleed and do not require replacement therapy.

We're also able to demonstrate encouraging effects on the whole blood clotting in one subject, showing results consistent with an improvement in the hemophilia phenotype. This subject also remained bleed free for a period of at least 47 days, while his self-reported annualized bleeding rate was 10 to 12 bleeds per annum.

Of course, these are early results from our Phase I study, but in aggregate, we believe these results highlight the significant opportunity for ALN-AT3 as a possible functional correction of hemophilia.

Indeed, we believe that a once monthly subcutaneously administered RNAi therapeutic that provides disease-modifying effects for people with hemophilia and other rare bleeding disorders could be transformative for patients. And we're pleased to report today that we're now transitioning our Phase I study to once-monthly dose cohorts.

We've also announced today that we plan to present additional data from this ongoing Phase I trial in an oral talk at the ISTH meeting in June.

Based on our ongoing enrollment, we expect this report will include results from about a dozen hemophilia subjects and expect to include data on tolerability, antithrombin knockdown, thrombin generation, in addition to preliminary assessment on bleeding frequency.

Finally, we also are reporting today that we've completed our chronic GLP Toxicology Studies for ALN-AT3. These studies included a 9-month study in nonhuman primates, a 6-month study in the rat and a 6-month study in hemophilia mice.

We'll report some of those details of these studies at ISTH, but we are very pleased with the results that they fully support advancement of the program into Phase III. Moreover, these are our company's first results regarding chronic tox studies for our ESC-GalNAc-conjugate platform.

And with the caveats related to antithrombin as a target in this program, this results are certainly encouraging more broadly.

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

This study has been conducted in healthy volunteers and is evaluating the safety and tolerability of single and multiple subcutaneous doses of ALN-CC5. Secondary objectives include evaluation of clinical activity for ALN-CC5, as measured toward knockdown on serum C5 and inhibition of serum hemolytic activity.

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

We're very pleased to announce today that we plan to present initial ALN-CC5 data in mid-June in an oral talk at EHA. Data at EHA will be presented for the initial SAD part of the cohort -- SAD part of the study, where we'll get an early look at C5 knockdown and potential effects on complement inhibition.

Of course, the most robust effect from complement inhibition will likely be fully realized with multi-dose administration of ALN-CC5, and we aim to have those data in late 2015.

Finally from our Genetic Medicine STAr, we recently filed and received approval for our clinical trial application, or CTA, for ALN-AS1, a subcutaneously administered RNAi therapeutic targeting ALN-AS1 in the development -- for the treatment of hepatic porphyrias including acute intermittent porphyria, or AIP.

This trial will be conducted initially in AIP patients for asymptomatic high excreter or ASHE patients and then in AIP patients who experience recurrent porphyria attacks. We very much look forward to the continued advancement of ALN-AS1 including the start of our Phase I trial in the coming weeks with data expected in early 2016.

We've also been actively enrolling AIP patients with recurrent porphyria into our EXPLORE Natural History study, where we're learning about the severity of porphyria effects and the enormous burden of disease for these patients. I'll now turn to review our progress from our cardiometabolic disease pipeline.

Of course, our leading program in this study is ALN-PCSsc, which targets PCSK9 in development for the treatment of hypercholesterolemia.

Our Phase I study continues in normal healthy volunteers with elevated baseline LDL, and we announced today that we've completed the single ascending dose portion of the study and have advanced to the multi-dose phase with or without statin co-administration. We expect to present initial clinical results from this Phase I trial in mid-2015.

And pending abstract acceptance, we believe that we might present these data at the European Society of Cardiology Meeting being held August 29 through to September 2. Of course, we'll provide more specific details when they become available.

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

Also in our Cardio-metabolic Disease STAr, we continue to advance a number of additional programs including our efforts on ALN-AC3, an investigational RNAi therapeutic targeting apoCIII. We're very excited about this program, which like PCSK9 targets an exquisitely well validated human disease target in cardiovascular disease.

And finally, where there no clinical update at this time, we also make -- whilst there are no clinical updates at this time, we're also making strong progress in our Hepatic Infectious Disease STAr and on track to file our IND for ALN-HBV in late 2015.

We continue to be very excited about ALN-HBV as we believe that it has the potential to emerge as the best-in-class RNAi therapeutic in the field, with subcutaneous dosing and a wide therapeutic window. Also, we are making progress on ALN-PDL, an investigational RNAi therapeutic targeting PD-L1.

Here, a liver-specific inhibition of this immune checkpoint inhibitor could become a powerful approach to overcoming T-cell exhaustion associated with HBV infection without broad activation of immunity and untoward side effects thereof. In summary, we're making excellent progress on our RNAi therapeutics pipeline across all 3 STArs.

It's certainly 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?.

$5.6 million related to our collaboration with Monsanto; $5.5 million of revenues from our alliance with Takeda; $2 million of revenues related to our collaboration with The Medicines Company; $1.8 million of revenues from our alliance with Genzyme; and $3.6 million of revenues from research reagent licenses and other sources. Moving to expenses.

R&D expenses were $58 million in the first quarter of 2015, as compared to $43.8 million in the prior year period. This increase was due primarily to additional expenses associated with the significant advancement of a number of our clinical and preclinical programs.

We expect that R&D expenses will increase in 2015 as we continue to advance and expand our pipeline across our 3 STArs. However, beginning in the first quarter of 2015, a significant share of the expenses on our patisiran and revusiran programs are shared with Genzyme, pursuant to the terms of our alliance agreement.

G&A expenses were $12.7 million in the first quarter of 2015, as compared to $8.9 million in the first quarter of 2014. This increase was due primarily to an increase in consulting and professional services expenses related to an increase in general business activities.

In addition, compensation-related expenses increased during the first quarter of 2015, as compared to the first quarter of 2014, due primarily to an increase in headcount during the period. For the remainder of 2015, we expect that G&A expenses will remain consistent with the first quarter.

The non-GAAP net loss for the first quarter of 2015 was $50.8 million as compared to a non-GAAP net loss of $26.3 million for the same period in the previous year.

The non-GAAP net loss for the first quarter of 2014 excludes the $224.7 million charge to in-process research and development expense for the purchase of the Sirna RNAi assets from Merck, for which there was no corresponding expense for the first quarter of 2015.

The GAAP net loss for the first quarter of 2015 was $50.8 million as compared to a GAAP net loss of $250.9 million for the same period in the previous year.

Regarding our equity investment in Regulus Therapeutics, the fair market value of our investment in Regulus, as of March 31, 2015, was $99.9 million as compared to $94.6 million, as of December 31, 2015. We're very pleased with the recent progress at Regulus and with our approximately -- approximate 12% equity position in that company.

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

Thanks, Mike. As you've heard from both John and Akshay, we had a tremendously productive first quarter in recent period, as we continue to build the industry's leading pipeline of RNAi therapeutics and advance our innovative medicines to patients and to the market. I'd like to now turn to our 2015 goals and guidance.

As John mentioned, this will continue to be a very data-rich period in the coming months. With regard to our patisiran program, we are on plan and continue to enroll patients in our Phase III APOLLO study. As Akshay mentioned, we currently have over 40 active sites in over 15 countries.

As we've previously guided, assuming the study is positive, we expect that APOLLO will enable a positive NDA submission in a 2017 time frame. We also continue treating patients on our patisiran Phase II open-label extension study, or OLE study, and now plan to present additional data including 18-month mNIS+7 data in late 2015.

With revusiran, we are currently enrolling FAC patients in our Phase III ENDEAVOUR study, and we're also rolling over patients from the Phase II revusiran trial into a Phase II OLE study, and we plan to present initial data from that study later this year.

Now moving to ALN-AT3, we're continuing to enroll additional dose cohorts in the Phase I trial, including hemophilia subjects receiving monthly subcutaneous doses. As Akshay mentioned, we announced today that we plan to share additional data from this trial in oral presentation at the ISTH conference on June 23, and then again in late 2015.

It is more probable than not that we will be presenting at ASH. Also at ISTH, we plan to present additional ALN-AT3 preclinical data. With ALN-CC5, we're enrolling subjects in a Phase I/II study, and we plan to present initial data at EHA and the oral presentation on June 14, with additional data expected in late 2015.

With ALN-AS1 to treat acute hepatic porphyrias, we are on track to initiate the Phase I trial in mid-2015 and expect to report initial data in early 2016.

Also in our Genetic Medicine Strategic Therapeutic Area, or STAr, we're advancing ALN-AAT and RNAi therapeutic in development for the treatment of alpha-1 antitrypsin deficiency-associated liver disease. We remain on track to file a CTA for this program in mid-2015.

With our new ALN-GO1 program for the treatment of PH1, we expect to identify a development candidate in mid-2015 with IND expected in 2016. With ALN-PCSsc, we're conducting our Phase I study and plan to present initial data from the ongoing trial at ESC starting August 29.

With our Hepatic Infectious Disease STAr, we're developing ALN-HBV, as Akshay mentioned, for chronic HBV infection. We plan to file an IND for this program in late 2015. And as Mike said, we remain on track to end the year with greater than $1.2 billion in cash.

In summary, we continued to be poised for a very data-rich midyear period in second half of 2015, with 8 RNAi therapeutic programs expected to be in the clinic by the end of the year. Certainly, we look forward to sharing more updates from our pipeline in the coming weeks and months to come. Thank you for your attention.

I'd now like to turn the call over to Josh to coordinate our Q&A.

Josh?.

Thanks, Barry. Operator, we'll now open the call up for questions. [Operator Instructions].

[Operator Instructions] And our first questioner is Ritu Baral of Cowen..

My first question is on the APOLLO study.

Given the other -- given what else we've seen at AAN and the competitive landscape for FAP, how do you think of the sort of bar, as far as efficacy and safety, for managing the disease and optimal tolerability for FAP?.

Great question, Ritu. And thanks for coming on the call. Let me make some comments, and then I think Akshay should. I mean, we continue to believe strongly that patisiran represents the best-in-class RNAi or RNA therapeutic in ATTR, without a doubt.

We've got a beautiful data set that we presented today, and which convincingly show safety, which is very important in that indication. It convincingly shows robust knockdown with mean levels of 88%, up to 96%, and then obviously the very encouraging data from our OLE study at 12 months with mNIS+7.

So I don't think there is any question in our mind, and I don't think in the mind of investigators either for that matter, that this is a profile that is very exciting, very compelling and we believe best-in-class. So I think, it stands -- the data stand on their own 2 feet, Ritu.

I mean, obviously our competitors presented some median knockdown data, which is curious to us. But we continue to feel quite convinced with our data. And again, they stand on their own 2 feet.

Akshay, anything to add to that?.

No.

I mean, I do think that we're developing the best-in-class and simply put the efficacy data coming out of the OLE study with the 2.5-point decrease in the mNIS+7, relative to the controls that we look at, the 13- to 18-point increase, I think, say, something important preliminary open-label study data, but nevertheless just hoping of the neuropathy.

So that cannot be more important for these patients that have an inexorable life-threatening disease. And there is no therapeutic available to them that can do that, or on the horizon, other than patisiran from our perspective. And from a safety perspective, it continues to be well tolerated, no drug-related assays.

And overall, the sites are working well with drug. So patients are being retained and it looks very good. So the risk benefit looks excellent..

Yes, I'll just add one thing. We did an extensive roadshow after AAN with our MSL team and our clinical operations team and our clinical team across -- a large number of sites across the world, after those data. And the feedback that we had from investigators was off-the-charts promising. So we're feeling very good about where we are, Ritu..

Great.

And question number two, your thoughts on the path forward for the C5 program in PNH, assuming successful single dose, multiple dose and signals of activity in European H patients, what might a pivotal trial look like?.

Yes. That's a great question, I think.

Akshay, you want to take that on?.

Yes. I mean, Ritu, we're very busy thinking about the pivotal approach for the C5 opportunity in PNH. I think there are a number of considerations, one could do a single-arm study and look at historical control data. Suppression of LDH is the key, fine marker endpoint there.

There are a lot of other additional endpoints one can measure, including need for transfusions, et cetera. One could also do a switch study taking patients off the current medications, eculizumab, and switch them over onto our drug and show maintenance of the effect. And we're confident we'd be able to do that.

And under certain circumstances even a placebo-controlled study may be feasible. So we're looking at various possibilities. And in a due course, once these Phase I data come out, which we are anticipating eagerly, we'll be sharing detail..

One thing I'll add to that, Ritu, is obviously we saw with great interest this paper in Blood by de Latour et al, which really examined the nature of eculizumab dosing in patients with PNH. And well over 50% of patients in the cohort that he was studying had incomplete complement suppression with label-dose eculizumab.

And this group of eculizumab refractory nonresponder, poor responder, whatever you want to call them, patients, represents a very interesting development opportunity for ALN-CC5, in addition to other ways and approaches that we will explore. So I think the data there are quite interesting.

And we look forward to obviously sharing data from that program in the coming weeks and then later in the year. And our goal of course this year is to have our first PNH patient treated in our ALN-CC5 program, which is Part C on the ongoing Phase I/II trial..

Our next question comes from Adam Walsh with Canaccord Genuity..

For the CC5 Phase I/II study, can you give us a sense of when we'll see the first data on LDH reduction in PNH patients?.

Yes. I mean, look, we've guided that we're going to have our first -- our goal is to have our first PNH patient enrolled in the study this year. We think that, that should be achievable. And I think, that will be toward later part of the year. So I think realistically, Adam, it will be in 2016.

We haven't given any specific guidance at this point in time, but I don't think you should expect it this year. I think it's really a 2016 type data point..

Excellent.

And then for the ALN-AAT for alpha-1 antitrypsin liver disease, can you please just remind us, I guess, Akshay, about the Phase I/II trial design and the timing of the first data readout?.

Yes. Great question.

Akshay?.

Yes. So again, the study will be similar to some of our other previous efforts in terms of a Phase I/II design, more details to follow, but incorporating both healthy volunteers and individuals with alpha-1 antitrypsin-mediated liver disease. And in terms of timing of data for the alpha-1....

We haven't given guidance on that. But obviously, we expect that it will go quickly. Our goal is to file our CTA for AAT midyear, this year. We will give more details, Adam, on the nature of our clinical protocol at that time.

But you can expect it to be very well enabled to support advancement of the program, just like all of our other GalNAc-conjugates are enabled these days..

Well, I guess, what I'm asking is it safe to assume that the trial design that you proposed during your roundtable, I think it was last summer, that -- is that likely to hold when you actually design the trial?.

Yes, I think the general construct that we shared back then is still how we're looking at that trial design. And again, when we start the CTA filing, we'll give you the details on our -- when we announce that filing, we'll give you the details on the specifics of that trial design..

And the next questioner is Alethia Young with Deutsche Bank..

One thing, I guess, I just wanted to talk about a little bit is AT3.

And like, I kind of realized you have interesting crossroads depending on how the data develops over the next maybe 6 to 9 months, but what would be the factors that would potentially allow you to move more into like a pivotal study? Like what kind of profile would need to emerge? Or what kind of safety might need to emerge to kind of allow you to move more aggressively with that further?.

Great question, Alethia. And let me start and then I let Akshay jump in as well. Look, we -- our guidance is that we'll start a Phase II for ALN-AT3.

But as we generate data in our Phase I and to the extent that we feel that by the end of this Phase I experience that we can be confident on the dose and dose regimen that would enable advancing into a Phase III trial. We may in fact aim to go just for that Phase III, Alethia, and not do a Phase II.

We'll have a dozen patients worth of data at ISTH, that we'll share with people. We probably will have 20 or more additional -- or not additional, but 20 or more total patients that we would aim to present late 2015 and, more probable than not, at the ASH meeting.

And obviously, those data sets, to the extent that they give us confidence around the overall safety profile of the drug. Certainly that sample size should be sufficient that would support going into a Phase III, but then obviously on dose and dose regimen, then we would likely go that direction faster as opposed to doing a Phase II.

I mean, Akshay, anything add to that?.

Yes. I mean, in some sense, there's nothing magical to Phase II other than fact that Phase IIs are done to define dosing regimen and preliminary of evidence of efficacy and continue the safety experience.

Then as John is guiding, if we can -- can't continue the way we're going, the intention would be to be able to do define that dosing regimen by means of recruiting these 20-or-so patients in totality and define the safety experience.

And provided we have preliminary evidence of efficacy, that should be very encouraging to have a discussion about proceeding to pivotal study..

I would just only add that now that -- as we announced today that we've completed our chronic tox studies, our program is enabled to support the ability to open up open-label extension studies for patients that are in the Phase I.

And that will provide us with longer-term dosing experience from -- for that to support, again, going into the Phase III more rapidly.

So we're in a very good place, Alethia, to move as quickly as we can, because we're very excited about this program, because it really could offer a functional correction of hemophilia in patients with severe disease..

Awesome. And another question, on hepatitis B, I know that guys have had some guidance -- just trying to identify a candidate over the year.

Just wanted to get an update on what's going on there? And any progress maybe preclinical data or evidence that may emerge over the year?.

Which program was that, Alethia?.

Hepatitis B?.

Yes. No, we've identified our development candidate. We announced that -- was it last year? Last year at R&D day. Yes, so we have our development candidate. We're doing our standard GLP Tox Studies and we're very much on track to file the CTA or IND equivalent, whichever way we go, by the end of the year, late this year, which is our guidance.

And so depending on when that filing takes place, that means Phase I for that program which start late this year, early next.

But we're positioned to be able to move ahead, and we have a lot of very nice development candidate data in rodent models, where we've shown and reported up to 4 log reductions of surface antigen with a single dose, subcutaneous dose. So we think this is a program that's going to be a winning program in the field..

And then on -- just a quick -- another question on ALN-PDL.

Can you just describe that program a little bit more verve [ph]?.

Right. So happy to. Let me make some comments, and Akshay, you can chime in. I mean, PD-L1, which is the ligand for PD-1, is of course expressed in hepatocytes and it is up-regulated significantly upon infection of hepatocytes by both hep C, hep B has also been reported.

And it's believed that the up-regulation of PD-L1 in hepatocytes could be a reason why HPV is effectively able to escape immune detection, that T-cell is based on the PD-L1, PD-1 access are essentially exhausted and aren't able to mount an immune response against infected hepatocytes.

There is data with antibodies toward PD-1 in HCV showing that those antibodies are able to generate an antiviral response. However, those antibodies, and that will be true with an anti-PD-L1 antibody, also have a systemic exposure and the downside risk of activating autoimmune disease.

Now in cancer, that's a fair and reasonable trade-off of the benefit that's been seen. But in HBV infection, that wouldn't be an acceptable trade-off. And so here, we take advantage of our GalNAc-conjugate platform to get liver-specific blockade of PD-L1 in a way that would not activate a broader immune response.

And it’s our belief that the approaches for HBV will need to occlude antiviral approaches like our ALN-HBV program, but also elements of activation of immunity like our PD-L1 program. Akshay, I went on pretty long there. Anything to add to that? You're an immunologist..

You did a good job there. For a [indiscernible] of course...

Next, we will hear from Michael Schmidt of Leerink..

Could you remind me of the patient population, or the individuals that are being treated, in the PCSK9 single ascending dose trial? And also could you please comment on next steps in the program and potential next trials there?.

Yes. Let me turn it over for the first part to Akshay and then the second part to Barry. So Akshay do you....

Yes. So for the PCS study, essentially, they're healthy volunteers with modest elevations in their LDL in the sort of 120 to 140 mg per deciliter range..

Barry?.

one, the antibody data in PCSK9 is very encouraging both for knockdown in PCSK9, resulting in LDL reduction and potentially improvement in outcome. So we find those data encouraging.

However, we're also seeing that there is significant number of patients, 10% to 15%, that at the doses they are using are not getting to their target LDL reduction levels.

Highly driven by the fact that many of these patients have high levels of PCSK9 expression, and the data are emerging that higher PCSK9 expression levels are associated with poor outcomes. So we see a couple pass forward for PCSK9 following this study and probably conducting a robust Phase II study to make sure the dose and frequency is well known.

And then a pivotal study for that population that's underserved on other approaches including antibodies, a phase -- a pivotal study on LDL lowering alone. And then we think, to get the broadest activity for PCSK9 being a synthesis inhibitor, that an outcome study will be required.

And the goal here is to have a higher probability of improving patient outcomes by more reliably getting patients to their LDL levels..

And I would just add to that -- that's all right, Barry. But I would just add to that, obviously, one feature of our program that we think is quite interesting and I think will be revealed -- we'll see how it goes in August, if it gets accepted at the ESC conference -- is the potential for monthly, and possibly even quarterly, dose administration.

Based on our primate data, we see a very durable effect in primates of PCSK9 knockdown. And I think if we can reproduced that in humans, it could be very compelling to have a once-quarterly subcutaneous injection in the PCSK9 landscape.

It could be disruptive of the whole market, which of course looks like, we'll see in June here, might begin to materialize as an emerging market for the management of hypercholesterolemia. So let's stay tuned and see how both the Adcon [ph] goes for our friends at Sanofi, and also at Amgen, and then obviously our data in late August, early September.

And then, if we can support that profile, we'll be running pretty hard to have an approach that we think can be best-in-class in the field..

Great.

And then on your apoCIII program, could you talk about how you view that fitting into the sort of high-cholesterol marketplace?.

Yes, that's a great question as well. I mean, we're very impressed with the genetic data on apoCIII that clearly point to the importance of that target in cardiovascular risk, and the genetic data are essentially as good as PCSK9. And gain a function, loss a function mutations -- no known mutations, but that's the only shortcoming compared to PCSK9.

So the data there are impressive. And in our eyes, it seems to be clear that it's obviously about improving trigs, but also improving and lowering non-HDL cholesterol. So elements of the lipid profile that we think are atherogenic and we think are therefore responsible for the beneficial effects of loss of function mutations of apoCIII in humans.

And so it's our belief that an apoCIII siRNA, RNAi therapeutic could be, again, a very compelling opportunity in CBM of disease..

And I would just add for clarity, Michael, that we see this as a broad opportunity in a large population base with the conditions that John described..

Correct..

And the next questioner is Alan Carr with Needham..

I'm wondering if you could talk a bit about, you'd mentioned that you'd finished some tox studies with AT3, I wondered if you could talk about that. I know you are going to present it soon, too, but wondered if you could give us some context around that including the hemophilia mice.

And then also you mentioned that you have, earlier, the kind of data that you'd have at the conference.

But also, can you talk about what Sanofi's options are here? At what point they need to make a decision?.

Yes. Yes, great questions. I'll have Barry deal with the second one. Let me just deal with the first one. Akshay can chime in as well. Yes, it's very gratifying to have now completed our 9-month monkey and 6-month rat and 6-month hemophilia mouse studies. And I think -- and we'll share the data at ISTH, so I don't want to give away all the thunder.

But I think it's fair to say that having now dosed nonhuman primates 9 months at significant levels of antithrombin knockdown, our -- I think that's a very interesting data point.

And then further at very, very high doses giving hemophilia mice 6 months of treatment, where we've essentially ablated any antithrombin in the background of hemophilia is something which also is very encouraging.

We've shown some of those data before as it relates to the survival benefit that accrues to animals that get ALN-AT3 versus those that receive placebo, or saline. So you've seen glimpses of that before. But I think the full data set deserve appropriate presentation at a scientific meeting, and we'll just wait till ISTH for some of that update.

Barry, do you want to highlight the second question on Genzyme's option and timing and....

Yes, sure. So just to set the context. As you're aware, Alan, we're currently partnered on patisiran, revusiran with Genzyme. And they have options across the rest of our genetic medicine pipeline.

The way that the deal works extensively is that following a proof of principle, which in most cases is the end of Phase I, we submit a data package to Genzyme and they decide to opt in or not. In the case of AT3 specifically, there is a little bit of an extra option there, which is that at the end of proof of principle, they can opt in or not.

If they opt in, they can first opt in for a regional collaboration. So we retain U.S. and Western Europe, they're focused on rest-of-world. And then after they see the AS1 proof of principle, so after the AS1 Phase I, they have a decision to make.

And that decision is that they take AS1 globally and the hemophilia program remains a regional program, or they have an option to co-co the hemophilia program and do a regional deal with the porphyria program. So the co-co is that we're co-develop, co-promote U.S.

and Western Europe, they take rest-of-world, and then it's a regional deal for porphyria..

Next we will hear from Geoff Meacham with Barclays..

So I joined the call a little late, so sorry if you've addressed this.

But when you think about patisiran and the 12-month open-label data, how do you balanced the potential to move up the analysis versus waiting for the trial to mature and ran its course? I guess, it's presumably will be tougher to do a study going forward, when you have more agents available from a commercial perspective.

And I have a couple of follow-ups..

Good. That's great question. Let me provide some color and then Akshay can jump in. We view these data very interestingly, obviously, Jeff.

And they certainly suggest that there might be a very strong effect here with patisiran, certainly based on comparative data to natural history datasets that are out there, not just one natural history dataset, but several. And obviously, we do have the opportunity to consider changes in APOLLO, related to potential interim analyses.

We are going to be discussing that with the regulatory authorities and make a decision as to what we might do.

Nothing we would probably do would have any -- would become effected this year because we would want to do in IA at an appropriate time in the APOLLO study, from a number of patient standpoint, that would probably make that IA happen if we do it sometime next year. We're going to talk to authorities.

We don't want to get into the details of regulatory dialogue. And when we have some clarity on that -- if and when we have some clarity on that -- we'll certainly update people, because that change would be material and we want to share that with all of you as well. And -- but that's where we are.

And when we find -- we do find it interesting, we do think there is a possibility there, but we just have to get our arms around implications and also discuss that with regulatory authorities.

I mean, Akshay, anything to add to that?.

No, nothing to add..

Okay. And then just on ALN-AT3, just to dig into the development path a little bit more. Are there -- I saw the data today -- or the studies that you completed today.

Anything else needed to start Phase III? And when you think about kind of the range of options and the speed to market, does it make sense to go after inhibitor population in a Phase III in a tougher population, for example? Or do you feel like you'll have to do kind of a middle-of-the-road step if you want to target out a larger population, perhaps with doing kind of an interim Phase II that has more switching data, let's call it?.

Yes. Great question.

Akshay, you want to handle it?.

Yes. So Jeff, just to recap from the current data. We're excited with the enrollment, and we reported today we'll have a nice data set for ISTH, and that will then be developed further towards the end of the year, going to once-monthly dosing.

And the aim of the current study, this Phase I study, is to really define the dosing regimen and accumulate preliminary evidence of efficacy in the context of obviously good safety, and that would then hopefully power us through to a pivotal study.

And you're absolutely right, we've got a lot of active dialogue right now about the shape of a Phase III study.

And there's no doubt that the inhibitor population represents a very attractive population in terms of unmet need, and the possibility of our drug providing really in a very interesting once-monthly subcutaneous efficacy for that higher unmet need setting. Equally, prophylaxis and severe hemophilia A and B is something we talk a lot about.

And ultimately, we see this is as an agent that has the possibility in the on-demand population and in the rare bleeding disorders. But those first 2 populations I spoke about, the inhibitors and severe hemophilia A and B, are something we talk a lot about..

Yes. And I think just a little more color, Geoff, is we likely do 2 separate studies. And we don't think we have to sequence them, one being in the on-demand patient population and the other being in inhibitors, at the end of the day..

Yes. And just -- I mean, just add to that, Geoff, so the strategy here is after we understand our dosing frequency very well, which we highlighted earlier on the call, we've launched into the biggest unmet need areas, which is inhibitors and these high bleeding on-demand patients that John and Akshay have described.

But you got to imagine that as we get more confident in those studies with safety and efficacy here, there is virtually nowhere in hemophilia we won't be able to go, assuming the drug performs well as desired. This really could be a game changer in all of hemophilia..

Next, we'll hear from Terence Flynn with Goldman Sachs..

This is Cameron filling in for Terence.

Could you please share maybe your latest thoughts on the relevance of extrahepatic C5 with respect to disease activity in PNH?.

Yes. I mean, I'll start and then Akshay can jump in. I mean, there is simply no data on a role of extrahepatic C5, clinically. There's some pre-clinical in vitro-type stuff, but nothing in humans or in disease.

Moreover, we've now, in animal models of disease of local complement disease in the joint, in the kidney and one other tissue bed, which we haven't disclosed yet, we will shortly. We've demonstrated that C5 knockdown in the liver is fully protective of complement disease in the joint, in the kidney and in that other tissue bed.

So simply no data for a local role of C5 in those models. So we'll, of course, have to see the clinical data ultimately to really prove that.

But I think we're feeling pretty good that there is no significant role of any locally produce C5 in the body, and that certainly for diseases like PNH, which are intravascular diseases that knock down a C5 we've proven in animals gives us over 99.2% knockdown of C5 in the central compartment, which is where hemolysis occurs.

Akshay, anything to add to that?.

No. I think you've covered that..

And the next questioner is Anupam Rama. [Operator Instructions].

This is Eric in for Anupam. Just looking for a little more color on the Phase I trial design with AS1.

I imagine, initially, you'll be looking at target knockdown, but are there other biomarkers that or functional endpoints you can kind of speak to that you'll be looking at? And what constitutes proof of principal from the Genzyme collaboration's perspective?.

Yes. Great question. Why don't we have Akshay do the first and then Barry do the second..

Yes.

The Phase I design essentially begins with an exploration of ALN-AS1 in a dose-ascending fashion in ASH individual so vis-à-vis asymptomatic high excreter who may have an attack in the past, or may never haven't had an attack but have high levels of ALA and PBG, the 2 serum biomarkers that are dis-regulated and mediate the pathogenic aspects of disease.

And so, they're quiescent, but they've got these baseline abnormalities in ALA and PBG. So we'll demonstrate knockdown of AS1 associated with the reductions in the circulating levels of ALA and PBG, and that will be an important proof of principle for this drug actually. And then, we transition into authentic AIP patients, who have recurrent attacks.

And there, we'll demonstrate again safety, of course, which is first and foremost, but in addition we'll be looking at impact on ALA and PBG, and we have the opportunity there also to have a look at attack rate, depending on the exact measure of the patients we get in the study, but at a high level that design of the study..

Yes. I would just add to Akshay's point that we're -- a very interesting feature of this study is we're able to measure the levels of AS1, which is our target enzyme, based on urinary levels of the messenger RNA that is captured by a protocol that we've developed and presented pre-clinically.

So that is going to be very interesting feature, but obviously the levels of ALA and PBG, which are these toxic metabolites, are going to be the key thing that we'll be looking to generate.

Barry, on the...?.

And that's the key to the Genzyme package. So what we'll present is our full pre-clinical program, all the safety and tolerability, obviously, from the Phase I, and then the single- and multi-dose data in these ASH patients measuring ALA and PBG, these toxic metabolites. It's that data packet that constitute the POP in the collaboration..

And our last question is from Ted Tenthoff with Piper Jaffray..

Last, but not least, Ted Tenthoff. I didn't get to hear all of the questions, so I'm going to kind of guess at maybe something that wasn't asked. On the hepatitis B program, kind of interesting, there's been a couple of setbacks in the space.

Maybe you can just kind of update us sort of what the progress is there? And sort of any updated view on what you see a sort of competitive landscape in HBV?.

Yes. That's a great question. And it wasn't asked, Ted, so that's good. We're very much on track. We have our development candidate, it's a GalNAc-conjugate subcu. We've shown up to 4 log reductions in surface antigen in a rodent model of HBV infection. So we're feeling very good about that.

We've got a package that we're developing to enable the IND filing, which is on track for being filed later this year. And then obviously, we'll go into our Phase I studies, either late this year or the next year. Haven't given any details around the -- over the exact protocol yet, and we will later on in the year when we file that IND.

But I do think our approach is going to be best-in-class for an RNAi therapeutic targeting HBV. We know of efforts that Isis and Arrowhead and Tekmira.

We believe that ours, across all those efforts, really has the best potency, the best delivery approach and absolutely the best tolerability, which is going to be important in that indication, given the fact that you've got a diseased liver.

And I think that, that's going to be something which will be very important for our approach compared to the other approaches that are out there. And thanks to everyone for joining us this afternoon. Obviously, it's going to be a very exciting period coming up.

And in the meantime, we continue to focus on bringing these medicines to patients and to the market. And with that, one more final thank you to Cynthia and goodbye everybody. Bye-bye..

Bye..

And thank you to all of our participants for joining us today. This does conclude the program. And you may all disconnect. Everyone, have a wonderful day..