Joshua Brodsky - Senior Manager, Investor Relations and Corporate Communications John M. Maraganore - Chief Executive Officer & Director Akshay K. Vaishnaw - Chief Medical Officer & Executive Vice President Michael P. Mason - Treasurer & Vice President-Finance Barry E. Greene - President & Chief Operating Officer.

Anupam Rama - JPMorgan Securities LLC Ritu Baral - Cowen & Co. LLC Alethia R. Young - Deutsche Bank Securities, Inc. Cameron A. Bradshaw - Goldman Sachs & Co. Alan Carr - Needham & Co. LLC Michael G. King, Jr. - JMP Securities LLC Ted A. Tenthoff - Piper Jaffray & Co (Broker) Michael W. Schmidt - Leerink Partners LLC.

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to discuss the Second Quarter 2015 Financial Results. There will be a question-and-answer session to follow. Please be advised this call is being taped at the company's request. I would like to turn the call over to the company..

Good afternoon, everyone. I'm Josh Brodsky, Senior Manager of Investor Relations and Corporate Communications at Alnylam.

With me today are John Maraganore, Chief Executive Officer; Barry Greene, President and Chief Operating Officer; Akshay Vaishnaw, Executive Vice President of R&D and Chief Medical Officer; and Mike Mason, Vice President of Finance and Treasurer. In addition, D.A. Gros, our new Senior VP and Chief Business Officer, is in the room and available for Q&A.

For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the Investors page of our website, www.alnylam.com. During today's call, as outlined on slide two, John will provide some introductory remarks and provide general context for some of our recent progress and achievements.

Akshay will summarize recent clinical progress. Mike will review our financials and guidance, and then Barry will provide a brief summary of recent business highlights and goals for 2015 and beyond, before we open the call for your questions.

I would like to remind you that this call will contain certain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these forward-looking statements and as a result of various important factors, including those discussed in our most recent released quarterly report on file with the SEC.

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update such statements. With that, I will now turn the call over to John..

Thanks, Josh, and thanks everyone for joining us this afternoon. During the second quarter of 2015 and recent period, we made excellent progress as we continued to execute on our Alnylam 2020 strategy and advance RNAi therapeutics to patients and to the market.

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

First, we now have seven RNAi therapeutic programs in active clinical development, including two in Phase 3 and by the end of 2015, we plan to have eight programs in clinical development across our three Strategic Therapeutic Areas or STArs.

A major recent highlight was the emergence of new clinical data that continue to highlight what we believe to be the promising potential for RNAi therapeutics. In this regard, we reported in April on very encouraging 12 month clinical data from our Phase 2 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.

With our hemophilia program, we were very pleased in June to report interim data from our ongoing Phase 1 trial showing what we believe to be continued evidence that ALN-AT3 can rebalance hemostasis through normalization of thrombin generation in people with severe hemophilia.

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 critically important theme for Alnylam going forward, as we continue to advance in late-stage development and toward commercialization.

We also reported positive initial data from our Phase 1/2 study with ALN-CC5 in June where we showed robust knockdown on serum C5 and we saw initial evidence for reductions in complement activity, including inhibition of serum hemolytic activity.

ALN-CC5 clearly works in man and with this study now well into its multi-dose phase, we fully expect to achieve our target level of hemolytic activity inhibition with this agent. Of course, we're now also engaged in a rather large and broad based drug development effort across our seven clinical programs.

We are noting today some adverse events, specifically Injection Site Reactions or ISRs that have led to study discontinuation in three patients in our revusiran Phase 2 OLE study.

Nevertheless, and very importantly, our overall experience continues to support what we believe to be a very encouraging tolerability profile for RNAi therapeutics across hundreds of human volunteers and patients that are currently enrolled and currently being dosed in ongoing studies.

A second important point I'd like to make is that we are now entering a very data-rich back half of the year where we expect to present important clinical data from six distinct clinical programs. For starters, later this month, we'll be sharing data from the ALN-PCSsc Phase 1 trial.

If we can achieve once-monthly subcutaneous efficacy, we believe we'll have a very competitive profile versus anti-PCSK9 monoclonal antibodies. And then, for every additional month of durability we achieve thereafter, this will provide us with even a stronger competitive profile.

Indeed, it's important to remember that the anti-PCSK9 monoclonals act by mopping up the PCSK9 in plasma and that their optimal effects require twice monthly dosing. And then we announced today that we're going to share initial Phase 1 data for our ALN-AS1 porphyria program in mid-September.

This is way ahead of our previous guidance for data in early 2016. There is enormous unmet need for new medicines in porphyria, and our investigational RNAi therapeutic has the potential to block the production of the toxic heme synthesis intermediates that mediate life-threating attacks in these patients.

Now, beyond these two important data readouts in August and mid-September, we'll have more clinical data in October, in November and in December from our two TTR programs, ALN-AT3 and ALN-CC5, amongst other program updates. We very much look forward to sharing all of these results during this very dynamic and data-rich back half of the year.

Now, finally, I'd like to emphasize the very unique opportunity Alnylam is creating for patients and shareholders.

With our GalNAc conjugate platform, especially our second-generation ESC approach and our focus on genetically validated liver-expressed disease genes, we've built 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 three or more new programs into the clinic every year with multiple new Phase 3 trial starts expected over the next 12 to 24 months.

In conclusion, we believe that we're 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 build what we believe will emerge as a top tier biotech company.

With those introductory comments, I'd like to now turn the call over to Akshay to review our pipeline progress.

Akshay?.

A Natural History Study, where we are learning about the severity of porphyria attacks and the enormous burden of disease for patients. And we also plan to show these initial data from the prospective Natural History Study at the ICPP meeting in September.

Finally, from our Genetic Medicines STAr, we have been advancing ALN-AAT, an RNAi therapeutic in development for the treatment of alpha-1 antitrypsin deficiency associated liver disease.

Patients with this disease present with liver cirrhosis of varying degrees due to a mutation in alpha-1 antitrypsin gene and the misfolding of the mutant Z-AAT protein. Alpha-1 liver disease can lead to hepatocellular carcinoma and the only treatment option currently available is a liver transplant.

We've recently initiated our Phase 1/2 study and plan to present initial data from this study in early 2016. I'll now turn to a review of progress from our cardio-metabolic disease pipeline. Of course, our leading program in this STAr is ALN-PCSsc, which targets PCSK9 and is in development for the treatment of Hyperglycerolemia.

Our Phase 1 study is being performed in normal healthy volunteers with elevated baseline LDL cholesterol and we announced today that we have completed enrollment in this study. Subjects are randomized 3:1 drug to placebo and received either single or multiple doses of drug.

We will present initial clinical results from this Phase 1 trial at the ESC Conference on August 30 that will include data on safety and tolerability of single and multiple subcutaneous doses of ALN-PCSsc in about 70 subjects and data on the drug's effects on PCSK9 levels and on LDL cholesterol.

We plan to present all data that are available as of the data cut-off date, including initial multi-dose results. It's also worth noting that we can evaluate the potential for quarterly dosing based on a single offending dose data since we followed these subjects for well over 90 days.

Recall that ALN-PCSsc is part of The Medicines Company, who will lead clinical development of the program from Phase 2 onwards and commercialization, if successful. Also in the Cardio-metabolic STAr, we continue to advance a number of additional programs, including our efforts on ALN-AC3, an investigational RNAi therapeutic targeting ApoC3.

We're very excited about this program, which, like PCSK9, targets an exquisitely well validated human disease target in cardiovascular disease. Finally, we're also making strong progress in our Hepatic Infectious Disease STAr and are on track to file our CTA for ALN-HBV in late 2015.

We continue to be excited by ALN-HBV as we believe that it has the potential to emerge as the best-in-class RNAi therapeutic in the field, with potential for a subcutaneous once monthly dosing profile and a wide therapeutic window. In summary, we're making excellent progress on the RNAi therapeutics pipeline across all three STArs.

It's certainly been an especially exciting and productive time for all of us as we continue to lead the translation of the science of RNAi towards the development of innovative medicines. I'll now turn the call over to Mike for a review of financials.

Mike?.

Thanks, Akshay. I will be referring to slide 24 for a discussion of second quarter 2015 financial results. This quarter we maintained a solid balance sheet with $1.4 billion in cash, cash equivalents and marketable securities. Our GAAP revenues for the second quarter of 2015 were $8.7 million as compared to $7.3 million in the second quarter of 2014.

GAAP revenues this quarter included $3.4 million from our alliance with Takeda, $2.6 million related to our alliance with The Medicines Company, $2.6 million from our alliance with Genzyme, and $0.1 million from research, reagent licenses and other sources.

Moving to expenses, R&D expenses were $67 million in the second quarter of 2015, as compared to $44.7 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.

In addition, compensation, non-cash stock-based compensation and related expenses increased during the second quarter of 2015, as compared to the second quarter of 2014, due primarily to a significant increase in head count during the period, as we continue to advance our growing development pipeline.

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

G&A expenses were $14.6 million in the second quarter of 2015, as compared to $11.5 million in the second quarter of 2014. This increase was due primarily to an increase in consulting and professional services related to an increase in general business activities.

For the remainder of 2015, we expect that G&A expenses will increase slightly in comparison to the first half of 2015. The non-GAAP net loss for the second quarter of 2015 was $71.8 million, as compared to a non-GAAP net loss of $48 million for the same period in the previous year.

The non-GAAP net loss for the second quarter of 2014 excludes the $3.9 million reduction to in-process R&D expense for the purchase of the Sirna RNAi assets from Merck. The GAAP net loss for the second quarter of 2015 was $71.8 million as compared to a GAAP net loss of $44.1 million for the same period in the previous year.

Regarding our equity investment in Regulus, the fair market value of our investment in Regulus as of June 30, 2015, was $64.6 million, as compared to $94.6 million as of December 31, 2014.

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 continue to provide us with a strong balance sheet to execute on our Alnylam 2020 strategy. I will now turn the call over to Barry..

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

As John mentioned, this will be – continue to be a very data-rich period in the coming months. With regard to our patisiran program, we're on plan and continue to enroll patients in our Phase 3 APOLLO study. As mentioned, we currently have over 40 active sites in over 15 countries.

As we previously guided, assuming a positive study, we expect that APOLLO will enable a possible NDA submission in the 2017 timeframe.

We also continue dosing patients in our patisiran Phase 2 OLE study and plan to present additional data, including full 12-month data at ANA in September and initial 18-month mNIS+7 data in the European ATTR amyloidosis meeting in early November in Paris. Now, with revusiran, we're currently enrolling FAC patients in our Phase 3 ENDEAVOUR study.

We're also dosing patients in a Phase 2 open-label extension study, and we plan to present additional revusiran data from that study in November, either at the European ATTR amyloidosis meeting or at AHA, pending abstract acceptances.

Now, moving to ALN-AT3, we are continuing to enroll additional dose cohorts in the ongoing Phase 1 trial, including people with hemophilia receiving a monthly subcutaneous dose regimen. As Akshay mentioned, we plan to share additional data from this trial in late 2015, likely at ASH in early December, again, pending abstract acceptance.

Also in late 2015, we plan to initiate dosing in our Phase 1 OLE study with ALN-AT3, in which people with hemophilia enrolled in the Phase 1 study can enroll in the OLE study and receive ALN-AT3 on an ongoing basis for an extended period.

Turning to ALN-CC5, we continue dosing healthy volunteers in the multi-dose phase of our Phase 1/2 study and plan to present initial data from these cohorts as well as longer follow-up from the single-dose cohorts in late 2015, also likely at ASH pending abstract acceptance.

In addition, our plan is to still to continue to enroll PNH patients in Part C of the study by the end of the year. With ALN-AS1, we announced today, we expect to present initial data from the Phase 1 trial at ICPP meeting September 15, ahead of schedule.

ALN-AS1 has the potential to give promising therapy for patients with hepatic porphyrias and this upcoming presentation should be of great interest to the patient community and the clinicians and caregivers who manage this devastating disease. With ALN-AAT, the Phase 1/2 trial is now ongoing.

We expect to present initial clinical data from this trial in early 2016. With our ALN-GO1 program for the treatment of Primary Hyperoxaluria Type 1, we expect to develop – select a development candidate in mid-2015 with an IND expected in 2016.

We plan to present preclinical data from this program in an oral presentation at the European Society of Pediatric Nephrology, or ESPN Conference on September 5. Turning to our Cardio-metabolic STAr with ALN-PCS, we have completed enrollment in our Phase 1 study and plan to present initial data from the trial at the ESC meeting on August 30.

As John noted, we believe that achievement of an efficacious monthly, subcutaneous profile will be highly competitive as compared to anti-PCSK9 monoclonal antibodies. And every month of additional durability is expected to provide yet further differentiation in this field.

Now, within our hepatic infectious disease STAr, we're continuing pre-clinical studies with ALN-HBV in support of a CTA filing, which we expect to happen later this year. ALN-HBV will mark our eighth pipeline program to enter clinical development. And wrapping up, as Mike said, we remain on track to end the year with greater than $1.2 billion in cash.

Now we want to remind everyone about our online RNAi round table series that we've been hosting. As we announced in our press release today, we've now filled out the rest of schedule with five remaining RNAi round tables to be held later in August and September, the details of which are shown here on slide 27. I invite you to attend.

In summary, we're now poised for a very data-rich back half of 2015. We very much look forward to sharing more updates from our pipeline in the coming weeks and months. At this point, I'd like to turn the call back to Josh.

Josh?.

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

. Our first question comes from Anupam Rama with JPMorgan..

Hey, guys. Thanks so much for taking the question. I know you announced a development candidate today for targeting TTR that could support once monthly or even quarterly dosing. I'm wondering if you could help put into context the improvement in potential dosing frequency into the context of the medical unmet need in FAP and FAC that you see. Thanks..

Yeah. It's a – Anupam, it's a great question and before I turn it over to Akshay to answer the question fully, I'll just say that we're very excited about this development candidate.

It's been in the works for quite some time, and we're going to share a lot of specific data on this at the OTS Meeting in October, which is being held in – where is it being held – in Europe someplace. Sure. Netherlands. So, let me now turn it over to Akshay to address the second part of your question..

Yeah. Hi, Anupam. I mean, we are very committed, and have been for some time, to the TTR space and the range of diseases, FAP, FAC, SSA, and we're developing a range of options. We have intravenous patisiran. Of course, we also have subcutaneous approaches.

And TTRsc02, our announcement today looks to us, based on everything we understand about these (ESC)-siRNA conjugates that we are building now, to be by far and away the most potent and best conjugate we've built in association with the program.

And it looks, at least based on animal work, like it could readily be a once-monthly to once-quarterly injection at low doses. And I think ultimately, a product like that is going to be very important in the management of these patients, as we look across the spectrum of TTR diseases.

And we will feather that in, and create that as an option for patients, as the entire sort of programs develop. But we are pretty excited and confident, based on understanding of the ESC platform, that this is going to be a very important low dose, infrequent option for patients..

Awesome. Thanks for taking our question..

Thanks, Anupam..

Our next question comes from Ritu Baral with Cowen..

Hi, guys. Thanks for taking the question. Could we -.

Thanks, Ritu..

Could we get a little more detail on the FAC injection site reactions that you mentioned? Could you characterize the diffuse rash a little better, and where along the treatment duration did the really problematic reactions emerge, since it was in the open-label?.

Sure.

Akshay, you want to speak to that?.

Sure. Yes, I mean, Ritu, we described three patients today that had discontinuations, and of the three, two had diffuse rash. And by diffuse rash, what I mean is a rash extending somewhere beyond the injection site.

And with respect to where they were in terms of the duration of the exposure, you know, I think all the patients are out into many months of exposure. They are all at slightly varying stages, and these patients weren't necessarily the most advanced in terms of the extent of exposure.

In fact, there are other patients who have been dosed longer and are doing just fine. So I don't think there is any evidence that this is some exposure-based event..

So, there was no associated anaphylactoid reactions, or was there – did they have reactions that got worse and worse, or was it sort of...?.

No, none that were reported. And in fact, there were no sort of anaphylactoid reactions or reactions that got worse and worse..

Got it. And then, my second question is on the porphyria data.

Given it's so early, was that just a function of enrollment, or were you seeing a biological effect essentially – or biochemical effect, earlier than you had expected?.

Well, Ritu, let me answer that. I mean obviously, we'll have to wait just a few weeks here before we talk about the specific effects and any data regarding that. You know, we, of course, are able to look at these patients. We've had good enrollment in this study. The study is being performed in Sweden. The site there is extremely poised.

They've done studies in these ASH patients before, and so we've been very pleased with the enrollment. So that's helped considerably. But let's wait till this mid-September meeting, you know, in Germany, and we'll have an opportunity of sharing those specific data with you..

Got it. Fair enough. I had to try. Thanks, guys..

Of course..

Thanks, Ritu..

Our next question comes from Robyn Karnauskas with Deutsche Bank..

Hey, guys. This is Ale on for Robyn. Thanks for taking the questions..

How are you?.

Good, how are you?.

Great..

So my first question is on PCSK9.

At this upcoming readout, will we get a good feel if quarterly dosing is possible? And secondly, how do you think the recent approvals and labels affect your market opportunity?.

Yes. So I will answer the first part, and then maybe Barry can answer the second part. You know, obviously, in the study, we're going to report all the data we've got. It's about 70 subjects worth of data. These are subjects that had elevated LDL cholesterol at baseline. In the multi-dose phase of the study, we also explored on statins and off statins.

And we've been able to follow subjects beyond 90 days from the single dose phase of the study so to the extent that the pharmacology supports quarterly dosing, we'll be able to infer that very clearly from the quarterly dose – from the subjects that get single doses that are followed for considerable long periods of time.

So I think we'll certainly be able to address the profile of the drug at this upcoming presentation. And let's just wait for the presentation before we get into any further detail. But Barry, you want to talk with about the recent approval and label -.

Yes. Absolutely..

And our thoughts on that?.

Absolutely. And just to emphasize the point we made earlier, first in class synthesis inhibitor with the once monthly or less frequent subcutaneous opportunity, we think is incredibly competitive.

So from the regulatory path perspective setting up the commercial opportunity, we find a tremendous synergy between our belief set and what's now been proved out in Europe and the U.S. which is that, on LDL lowering, as long as the cardiovascular outcome study is up and running, a drug with can be approved.

So we find that rewarding as well as the label that was granted so far. And then the pricing is consistent with our belief set, on that $10,000 to $15,000 per patient per year price set.

So they are defying the market that a first in class RNAi synthesis inhibitor can come behind and I think have a big impact on the market that's being defined by the PCSK9 antibodies..

Great. Thanks.

And then just a quick follow up on hemophilia, can you characterize the PK or give context as to what doses we might start to move into the threshold of over or greater than 66% knockdown?.

Yes.

I think what you're asking is, what doses do you think will get us to the consistent over 66% knockdown?.

Yeah, yeah..

The first dose cohort monthly is using the equivalent of 75 micrograms per kilogram times three monthly; in other words, 225 micrograms per kilogram monthly. And we are going to be very likely exploring dose escalation as well beyond that dose.

And again, we'll have a considerable number of additional subjects, 9 to potentially 12 additional subjects worth of data at ASH, again, pending abstract acceptance. So there will be a lot of information there, and we're very encouraged by the program.

We thought the data at ISCH were very exciting, and we believe that we'll continue to show the important approach that this can present for hemophilia patients..

Great. Thanks, guys..

Great. Thank you..

Our next question comes from Geoff Meacham with Barclays..

Hey, guys. It's actually Mike (41:05) in for Geoff. Thanks for taking the question..

Hey, Mike (41:08).

How are you?.

Good. Thanks. Just with respect to the ALN-CC5 program, you mentioned beginning dosing in PNH by year-end 2015. Could you maybe just remind us what endpoints you'd be looking at there, and then sort of how you're thinking about the bar to sort of moving that program forward? Thanks..

Yeah. Absolutely. Let me have Akshay answer that..

Yeah. Sure. Of course, first and foremost, we'll want to understand safety in that population. Beyond that, PNH patients with the validation of C5 as a target offer a range of other very important biochemical and other endpoints. So LDH, lactate dehydrogenase, is a very important marker for clinical efficacy.

And just as eculizumab has shown, we hope to show reductions in LDH. And underlying that, the basis for that reduction in LDH would be reductions in hemolysis, which would be associated with reductions in C5.

So we'll also aim to show substantial reductions in C5 levels, just as we've begun to show in the Phase 1 study in healthy volunteers associated with significant suppression of serum hemolysis. So, those are some of the key datasets and I think that they set us up hopefully to show clear validation of ALN-CC5 for PNH, accelerating us into Phase 3..

Yeah.

And I'll just add to Akshay's comments, Mike, that at ASH – at the upcoming ASH Meeting, we would expect to have results of our single dose – complete single dose results combined with a multi-dose result and our expectation is very much that we will see a very complete inhibition of serum hemolytic activity, just as we've seen in non-human primates.

So, that is something that we'll present in December. And then by starting our first PNH patients by the end of the year, we'd expect to see these type of LDH data that are very de-risking and important, probably sometime in 2016, right. So – but that's how the news flow – you can expect the news flow to go on that program at this point..

Okay, great. Thanks, guys..

Thank you..

Our next question comes from Terence Flynn with Goldman Sachs..

This is Cameron filling in for Terence. Thanks for taking our question..

Hi, how are you?.

Doing great. Thanks.

So, just a follow-up on the rash in press release, can you give us any more details on the severity of the rash? And how these patients were treated? Were they biopsied? And if so, can you tell us what the findings were? And then finally, were these the three patients that were part of the initial cohort of six patients that had a rash or are they different patients? Thanks..

Yeah, Akshay, do you want to handle that?.

Yeah, so in terms of severity, the patient – the two patients with the diffuse rash. One was a mild rash and one was deemed to be severe. Neither were serious adverse events, so not of the magnitude requiring hospitalization or anything. They – it all resolved spontaneously and so really required no specific treatment that I need to describe.

And in terms of the investigation of biopsy or such, of course, we're bringing you all of the clinical data as we have it today. We're doing everything to understand these events and at the later disclosure in the year when we'll announce the six months data on this study, we'll have many more details and we'll share at that time..

Yes, go ahead..

Our next question comes from Alan Carr with Needham & Company..

Thanks for taking my questions..

Hi, Alan..

Hi. Coming back to the rash, anything – you're running a Phase 3 also.

Can you comment on what you're seeing from the safety perspective there around the rash and discontinuation rate? And then also with the AS1 program moving along here, do you have any estimates of when that might move into registration trials? Would that be a little sooner than you expected? Thanks..

Yes. Sure, Alan.

Well, Akshay, do you want to handle both those questions?.

Sure, yeah. So with respect to the revusiran and rashes in the Phase 3 ENDEAVOUR study, of course we started the study towards the end of last year. It's proceeding nicely. More details to follow.

But with respect to the safety itself, it is a randomized double-blind, placebo-controlled study so I'm sure, Alan, you are not supposed to hear me say that I can't really speak to the safety. But suffice it to say that the overall conduct of the study is fine and it's ongoing and we're excited to continue with it.

So with respect to the AS1, as we announced today, we're excited to present the initial data from the study and we will be looking at very important biochemical markers, such as ALA and PBG, which is the mediator that's believed to off acute intermittent porphyria.

And as that dataset develops through this year and the early part of next year, I think we'll want to give guidance with the additional understanding of the impacts of those effects in actual recurrent attack patients, which we intent to enroll in that study.

We'll be able to give guidance later this year, early part of next year on to the plans for the pivotal. But suffice it to say that we are obviously excited that we are slightly ahead of schedule with presenting the data that we intend to present..

I'll just add to that, Alan, that obviously the Phase 1 study, the porphyria study is doing – is going to go into recurrent attack patients as sort of the Part C of that study and then once we demonstrate in an open label fashion, encouraging data there in addition to potential effects on these biochemical markers, there's really – the plan would be to go right to a Phase 2/3 or pivotal study, of course pending discussions with regulators.

So I think it will move quickly as a program and of course, the other aspect of this program is the enormous unmet need for new therapies here.

I think it'll be of great interest for people to see how we've been able to quantify the disease burden in porphyria in this EXPLORE prospective natural history study because these are subjects that have a very, very poor quality of life for sure. So, you'll see more of that in mid-September..

Great. Thanks for taking my questions..

Thanks, Alan..

Our next question comes from Mike King with JMP Securities..

Good afternoon, guys. Thanks for taking my questions.

I just wanted to – I don't want to harp on this incidence of rash, but I did want to come back to Akshay, because I'm not sure he answered the previous question regarding the denominator of patients, so this was three out of how many at the time that were in the revusiran OLE?.

Yeah. I mean, Akshay can comment as well. But the answer there is of the patients that went into OLE, 25 patients went into the OLE..

Sorry. Yes, I think the question asked about six patients..

Yeah. That's right. There's not six patients..

Yeah..

25 patients went into the OLE..

Right..

Okay. So it's not three out of six. It's three out of 25..

Oh, yeah..

Yes..

Okay, great. That's a lot different. And then I'm just curious, remind us again about, you characterized the new TTR inhibitor as second gen chemistry, but I thought technically revusiran was second gen chemistry. So, perhaps you can just illuminate for us, what the difference between revusiran would be relative to the new TTR inhibitor..

Akshay, you want to handle that?.

Sure. Revusiran is the first conjugate we built, Mike, and that was the first in the clinic, it was the first to show that GalNAc conjugated sRNAs could be very effectively delivered to (49:20).

It being the first generation, naturally the potency and dose that's required is higher than what we've seen with subsequent use of chemistries with the second generation that we call ESC GalNAcs.

And in fact, the entire pipeline beyond patisiran and revusiran, all these other amazing programs that we're now exploring, hemophilia, C5, porphyria, et cetera, these are all based on the second generation chemistry, PCS et cetera, and one of the learnings from that.

And I think we've reported data both for AT3 and C5 is the substantially greater potency associated with the second generation and durability, which leads us to make these statements.

So Q monthly Q quarterly dosing at lower doses, with all those programs and the second generation ESC GalNAc and of course, with that, as you reduce exposure, all exposure-related adverse events would also go down. So overall, it's a very exciting package, I think, with the ESC folks. (50:23).

Right.

So if I can sort of paraphrase from your comments, Akshay, the revusiran is different than everything, every construct that comes from – comes behind it, correct?.

Correct..

That's exactly right. That's correct, Mike..

Great. Okay, super. Now I just want to shift quickly to patisiran to ask you – I know, John, we had spoken recently a couple weeks ago about your taking a look after 100 patients had been on patisiran for 18 months.

But I'm also – I'm asking, is there a possibility of a either shorter interval or lesser number of patients, now that you would be comfortable talking about, as far as when the next analysis occurs, or is that number still fixed?.

Yeah, no, Mike, I think what we discussed was what the potential is for an interim analysis for efficacy with the APOLLO study. And where we are on that is, we are going to have discussions with FDA and EMA to explore that.

What I think I commented to you is that it would be reasonable to consider something like half the study population at the 18-month endpoint as a type of way of doing that type of analysis, which would take you into sometime next year, for when that would take place.

But if and when we reach agreement with the regulatory authorities on this, we'll come back and provide guidance. There are other reasons to not do it, right. There are other reasons to say, let's not take a hit on our power and just complete up the study.

So, we'll have to – we'll get back to you on that when we have clarity with regulators on the path forward. But what I was referring to is really a logical way to think about doing an IA, would be at sort of the mid-mark from an accrual standpoint, at the 18-month endpoint..

Great. Thanks for the clarification..

Great. Thanks, Mike..

Our next question comes from Ted Tenthoff with Piper Jaffray..

Great. Thanks.

Can you hear me okay?.

Yeah. Hi, Ted..

Hey.

How are you guys?.

Good..

Thanks so much for a thorough update. A lot of questions answered. I guess a quick one, if I may, on hepatitis B. Obviously, a very dynamic market. So really, where do you sort of see the role of RNAis fitting into hepatitis B therapy? And remind me, if you would, sort of what the construct, or what the – what ALN-HBV actually is..

Yeah..

Are there multiple sequences within that?.

Yeah. So, let's go – let's address the first question and then the second question. So, in terms of where this fits in, we believe, and the community believes and agrees with us, that an agent that can substantially knock down surface antigen has the potential of changing the dynamic of....

Yeah..

...how HBV is managed. Surface antigen is known to be tolerogenic. It's one of the mechanisms whereby HBV can elude immune detection. And so, clearly, having an agent like an RNAi therapeutic that can substantially knock down and significantly multi-log knockdown of surface antigen, is something that we think we can achieve with ALN-HBV.

And I often refer to the Regulus data with RG-101 as an interesting data point. We're using – I mean, they're using our GalNAc technology and so, look at how impressive they've seen antiviral effects toward HCV, and we think that's a type of knockdown of surface antigen that we can achieve with our drug.

So that's really the key part of where it fits in. We always see it as being used on top of NUCs. It would be illogical not to add it on top of NUCs and, as a result of that, using a single sRNA is something which will be fully able to be done without any emergence of resistance, because there is no active replication of the virus.

So, we'll be able to shut down surface antigen levels very effectively on top of nucleoside analogs, and therefore not have active replication of the virus, and it is a single sRNA.

You want to comment something, Barry?.

I'm just going to also add, John, that we've talked about the fact that ALN-HBV hits all four transcripts..

That's right..

Okay, guys. And then, I guess if I may just sneak in a real quick follow-up there. It seems to me like HBV is sort of outside of this orphan concept. I mean certainly a large – or a liver-focused disease, but outside of the orphan concept.

So where would you guys – I mean is this something you would take further yourselves? Is this something you would ultimately partner? I mean, maybe a little bit early to kind of figure that out.

But what are kind of your long-term strategy here with ALN-HBV?.

You know, Ted, it's great question. As you know, we're developing and broadening our efforts beyond just genetic medicines with our cardio-metabolic STAr, as well as our Hepatic Infectious Disease STAr.

These are all areas where we think our GalNAc platform and our ability to target any liver-expressed disease gene makes sense for us as a company to go toward. And, specifically with HBV and partnering, we'll certainly have a global partner there for ex-U.S. and ex-Europe. But we plan on maintaining our U.S.

and European rights for that program, because that's a commercial footprint that we plan on building as an organization. We are not a company that is going to license away substantial product rights. We want to retain that value for our shareholders, and we think it's ultimately the best way to build value as a company.

So HBV will stay in our hands, at least in our territories. But we will probably, for Asia and other parts of the world, find partners to help us advance that program..

Great. That's super helpful. Thanks so much, guys..

Great. Thank you..

Our next question comes from Michael Schmidt with Leerink..

Hey. Good afternoon, and thanks for taking my questions..

Hi, Michael..

Hey. I'm sorry to harp on this, but one more on the rash. My question there is – were these one-off events, or did they occur repeatedly in the same patients, and what might a biologic explanation be? And then the other question was on PCSK9. I know The Medicines Company is taking over Phase 2 development.

But I was wondering what Phase 2 plans might look like in terms of magnitude, extent and timing?.

Great. Well, I think, on the second one, first, if I may – and then I'll hand it over to Akshay – we'll give more guidance on that in the coming weeks. Right. So, as we present data, there will be additional guidance in terms of plans going forward. So please stay tuned on that one, Michael.

But then Akshay, do you want to handle the first question?.

Yes, sorry.

Just to recap the question, Michael, were they recurrent was the question?.

Yes, recurrent or one-off events and what might the sort of mechanistic explanation be?.

Yes. In terms of mechanism, I think we will accept that subcutaneous therapeutics, regardless of class, are associated at some discrete level with injection site reactions. And even with revusiran in the Phase 2 study, we reported some injection site reactions, which in some subjects were recurrent. So you know, no surprise there for us.

And, indeed, in these three individuals, some of them were recurrent. The diffuse rash that I described wasn't a recurrent diffuse rash as such. And that's how we've got the clinical understanding at the moment. You know, with respect to the pathophysiology, I think someone else asked about if we got biopsies.

You know, we're trying to understand all of this right now and later in the year when we present the 6-month data, we'll present all the laboratory analyses that we are doing to try and characterize this further. But, the clinical understanding is as I described it today and in the press release..

And I'd just add, Michael, that, you know, this is related to other oligonucleotide therapies as well. Drisapersen has an over 70% incidence of injection site reactions. Mipomersen has equally great level of injection site reactions. You know, we're not seeing that high of incidence in our study. And so this is really oligonucleotide type things.

But it also happens with other classes of drugs. It happens with protein therapeutics, Embrell, others. So it is part of drug development and obviously it's something which we want to be transparent about and that's why we're reporting it. But the full data will come out when we present our data it in November with the 6-month update from revusiran.

The good news is that patients – the vast majority of the patients are tolerating the drug well and continue on study..

Yeah, understood. Great. Thank you. (59:49).

Yeah, good. All right. Thank you..

And I'm not showing any further questions at this time. I'd like to turn the conference back over to our host..

Okay. Well, thank you, everybody. Appreciate the time today. As I said earlier, this is going to be a very data-rich period in the back half of the year and we can't wait to share all the data with you, all right. Thank you. Bye, bye..

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful day..