Alnylam Pharmaceuticals Inc (ALNY) 2015 Q3 法說會逐字稿

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss the third-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 morning. I'm Christine Regan Lindenboom, 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. For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the investor page our website, www.Alnylam.com.

During today's call, as outlined applied on slide 2, John will provide some introductory remarks and provide general context for some of our recent progress and achievements. Akshay will summarize recent clinical progress, and Mike will review financials and guidance, and Barry will provide a brief summary of recent business highlights and goals for 2015 and beyond, before opening your call for questions.

I would like to remind you that this call contains remarks concerning Alnylam's future expectations, plans, and prospects, which constitutes forward-looking statements for the purpose of Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report filings 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 of any subsequent date. We specifically disclaim any obligation to report such statements. With that, I will now turn the call over to John.

Thanks, Christine, and let me start by welcoming you to the Alnylam team. It's great to have you on board. And for everyone else, thank you for joining us this morning.

During the third quarter of 2015 and recent period, we made excellent progress, as we continue to execute on our Alnylam 2020 strategy, and advance RNAi therapeutics to patients and to the market. Before Akshay goes into our recent pipeline progress in more detail, I would like to provide some context on [a couple of] recent achievements, in addition to some thoughts on the current environment. As I think many of you are aware, we have had a very data-rich year, and the third quarter was certainly no exception.

When we look over our clinical scorecard, we are now advancing a very robust pipeline of potential high impact investigational medicines, addressing major unmet medical needs for patients. This includes seven RNAi therapeutic programs in active clinical development, including two in Phase 3. And by the end of 2015, we plan to have nine programs of clinical development across our three strategic therapeutic areas, or STArs. This means that we expect to exceed our original five by 15 strategy by nearly 100%. Why? Well, we believe this progress is driven by the reproducible and modular characteristics of our RNAi therapeutics platform, where we've demonstrated clinical proof of concept with a very robust, very promising success rate to date. In fact, we now have reported positive human data in all six of the clinical programs for which we have presented results to date.

Our recent clinical data continued to highlight what we believe to be the promising potential for RNAi therapeutics. In the third quarter and recent period, these positive clinical data readouts included 18-month data from our Patisiran Phase 2 open label extension, or OLE study in ATTR polyneuropathy, just last week. Initial six-month data from our Revusiran Phase 2 OLE study in ATTR cardiomyopathy, also just last week. Initial clinical data from our ALN-PCSsc program in hypercholesterolemia in late August, and initial clinical data from our ALN-AS1 program for acute hepatic porphyrias in mid-September.

We also remained focused on pipeline execution this quarter, including strong accrual in our APOLLO and ENDEAVOUR Phase 3 studies. For APOLLO, we have now guided that we expect to complete enrollment in the next three to four months, keeping us on track to file an NDA for Patisiran in 2017, if the study is successful. We will provide guidance on the ENDEAVOUR study timeline sometime next year.

The pace of data generation, of course, will only continue through the end of the year, with anticipated presentations on ALN-PCSsc at the American Heart Meeting later this week, ALN-HBV at the liver meeting, and we'll end the year with what we believe will be very important new data from our ALN-AT3 hemophilia and ALN-CC5 complement disease programs at ASH. Also, as you may have seen in our press release this morning, we plan to dive deeper into some of these clinical programs at our upcoming R&D day in New York City on the morning of December 10. A save the date card and message will be sent out following the call today.

Now, before I turn the call over to Akshay, I want to make a few comments on recent industry event regarding drug pricing. First, the actions of a small number of bad actors and the resultant political demagoguery to paint those actions with a broad brush on our entire industry are both unfortunate and misplaced. This is not what we do in biotech. We are about innovation, patients, and 21st century medicines.

The focus needs to be on the value of innovative medicines and patient access to those therapies. High-impact medicines that significantly reduce the burden of disease for patients, will almost always lower health-care costs in the long-term. First, innovative medicines can reduce the costs associated with disease management in the near-term. Then under the balance struck with Hatch-Waxman the innovative medicines we pay for today become essentially free for our children and our children's children, as generics come to market following a period of exclusivity for the innovator.

We need to have policies that fairly reward the hard-earned discovery and risks taken in development of 21st century medicines to ensure that future generations will reap the benefits of those innovations for healthier, more fulfilling and productive lives. Put another way, if we're not willing to pay for innovation today, our children will be denied access to these life-saving medicines. I'm confident that beyond the election-year rhetoric, policymakers understand the importance and value of biotech innovation.

While Alnylam is still a pre-commercial Company, thinking through the value that our medicines may bring to patients is something that is at the forefront of our discussions and decision-making here at the Company today. As we contemplate the face of Alnylam as a commercial Company, we are actively considering our patient access principles. Our overarching objective is to make the therapies we develop available to all patients who will benefit from them. You can expect us to be as innovative as a commercial stage company, as we been as an R&D company.

You can also expect us to deliver on growth through our R&D product engine and not arbitrary price increases. We look forward to sharing our further thoughts on this in the future. With that, I will turn the call over to Akshay to discuss recent progress across our pipeline program. Akshay?

Thanks, John, and good morning, everybody. As John said, we continue to make great progress with our pipeline of investigational RNAi therapeutics. Let me begin with our programs in genetic medicines STAr, and start with TTR-mediated amyloidosis, or ATTR amyloidosis, for which we have two advanced clinical stage product candidates. Patisiran is our lead program, and is aimed at the treatment of ATTR amyloidosis patients with familial amyloidotic polyneuropathy, or FAP. Patisiran is in a Phase 3 trial called APOLLO.

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 3 trial, and that trial is called ENDEAVOUR.

As John mentioned in the third quarter, we presented 18 month end results at the EC ATTR meeting from our ongoing Phase 2 OLE study of Patisiran in patients with FAP. We're pleased to see continued evidence of potential halting of neuropathy progression after 18 months of treatment in this ongoing OLE study. Indeed, we believe that the small 1.7 point increase from baseline in mNIS+7 is encouraging, as mNIS+7 measured at 18 months is the primary endpoint in our ongoing APOLLO Phase 3 trial with Patisiran. Indeed, our results compare favorably to the 22 to 26 point increase at 18 months for untreated patients, as estimated from a number of historical data sets.

We're also pleased to see a meaningful improvement in nerve fiber density following treatment with Patisiran, providing the first-ever evidence that TTR knockdown can potentially have a positive impact on aspects of nerve regeneration. Furthermore, serum TTR levels were also measured throughout the OLE study, and showed sustained TTR knockdown of up to 96%, and a mean maximal knockdown of 93% for over 21 months. Based on recent competitor data, where it was reported that a 76% mean maximal TTR knockdown was achieved after 10 months of dosing, we're pleased with 93% mean maximal effect achieved with Patisiran within just a few days of dosing.

Importantly, Patisiran administration was also found to be generally well-tolerated in FAP patients out to nearly two years, with minimal drug-related adverse events reported. Finally, as John noted, our APOLLO Phase 3 trial is proceeding well, and we're nearing completion of enrollment. If this study is positive, we believe that it will support regulatory filings in 2017 for marketing authorization in the US, EU and many other territories around the world.

Let's now turn to Revusiran. As a reminder, we're currently conducting a Phase 2 OLE study in which TTR cardiomyopathy patients who participate in the Phase 2 trial were eligible to roll over into the OLE study and receive Revusiran on an ongoing basis. The OLE study is evaluating the safety and tolerability of long-term dosing with Revusiran, for up to two years, and also measuring the effects of treatment toward a number of clinical endpoints, including mortality, hospitalization and six-minute walk distance, in addition to cardiac biomarkers.

Initial data from our Phase 2 OLE trial with Revusiran reported at the EC ATTR meeting last week showed robust and sustained knockdown of serum TTR and a favorable tolerability profile in the majority of patients with TTR cardiomyopathy after ten months of treatment. The sustained and [clamped] TTR knockdown observed represents the longest dosing experience for an GalNAc-siRNA conjugate in humans reported to date.

While it's early in the study and in a relatively small patient population, we are encouraged that the majority of the evaluable patients at six months showed stable six-minute walk distance and no clinically meaningful changes in additional cardiac measures. We believe these data to be encouraging, especially considering the [Phase 3 OLE] population represents a more advanced population than that we are enrolling in the ENDEAVOUR study. We look forward to additional data from the ongoing Revusiran Phase 2 OLE study, and plan to report data from the trial at least once a year thereafter.

ENDEAVOUR, our Phase 3 trial with Revusiran is being conducted in patients with familial amyloidotic cardiomyopathy or FAC, and enrollment is ongoing. This is a randomized double-blind placebo-controlled study where we are looking at two co-primary endpoints measured at 18 months, one being the change in six-minute distance between drug and placebo, and the other being reduction in serum TTR between drug and placebo. We will provide more specific guidance on the study timeline next year.

And finally, in our TTR program, we remain committed to bringing forward continued innovation for patients with ATTR amyloidosis. The this end, we've presented encouraging pre-clinical data on ALN-TTRsc02 during the recent period. We believe this ESC-GalNAc conjugate version of Revusiran will support a potential once-quarterly low-volume subcutaneous dose regimen, providing patients with an important option for the management of their disease. We're currently conducting our IND-enabling studies with ALN-TTRsc02, and plan to file an IND or IND equivalent in 2016 with the initial data in late 2016. Assuming positive clinical results, we expect to initiate a Phase 3 study for ALN-TTRsc02 in 2017.

Turning to our hemophilia and rare bleeding disorder program, we continue once-monthly subcutaneous dosing with ALN-AT3 in our ongoing Phase 1 study, and also initiated our Phase 1 OLE, where patients will receive ALN-AT3 monthly dosing hereafter. Importantly, our partner, Genzyme, elected to opt into the ALN-AT3 program for development and future commercialization in territories outside of North America and Western Europe during the quarter. We look forward to presenting results from about a dozen patients in our Phase 1 multi-dosing cohorts in an [oral] presentation at ASH in December.

In our ALN-CC5 program, we continue to dose healthy volunteers in our Phase 1 study. Specifically, we're currently dosing subjects in the Part B multi-dose phase of the study. We look forward to sharing the results of this study at ASH in early December.

Of note, this will include the first-ever report on results with weekly dose administration of ALN-CC5. On previously-reported ALN-CC5 data, including those in the now-published ASH abstract, pertain to just single doses of study drug. Finally, with ALN-CC5, we're on track to initiate Part C with dosing in PNH patients by the end of this year.

Also from our genetic medicine staff, we advanced ALN-AS1, a subcutaneously-administered investigational RNAi therapeutic, targeting ALAS1 for the treatment of hepatic porphyrias, including acute intermittent porphyria, or AIP. As you'll recall, we recently began dosing in our Phase 1 trial with ALN-AS1. This trial is being conducted initially in AIP patients or asymptomatic high excretors, or ASHE patients, and we plan to transition to symptomatic AIP patients who experience recurrent porphyria attacks as the study progresses.

[While asymptomatic], ASHE patients have elevated levels of ALA and PBG, two heme-synthesis intermediates that cause the life-threatening attacks that occur in AIP patients. Data presented at the International Conference on Porphyrins and Porphyrias showed up to 82% lowering of ALA and up to 93% lowering of PBG in ASHE patients with AIP. These effects were highly durable following a single subcutaneous injection, and we believe these results are supportive of a monthly or potentially once-quarterly dosing regimen. We will now transition to the multi-dose cohorts in the Phase 1 study to explore this (technical difficulty) further.

Importantly, ALN-AS1 has been generally well-tolerated with no clinically-significant drug-related adverse events reported to date. We very much look forward to the continued advancement of ALN-AS1, which we believe has the potential to be a transformative therapy for patients with acute hepatic porphyrias, a group of ultra-orphan diseases with enormous unmet medical need.

In the third quarter, we will finish out in our Phase 1 study of ALN-AAT, an RNAi therapeutic targeting alpha-1antitrypsin, or AAT, for the treatment of AAT deficiency-related liver disease, an orphan disease with very high unmet need. Also, we announced accelerated plans for the development of ALN-GO1, an RNAi therapeutic targeting glycolate oxidase, or GO1, for the treatment of primary hyperoxaluria type 1, an ultra-rare orphan disease with very high unmet need.

Then with GO1, we're on track to file our CTA by year's end, with Phase 1 starting in early 2016. Both ALN-AAT and ALN-GO1 represent the next wave of pipeline programs in our genetic medicines stock, and we have additional as-yet undisclosed programs behind these that will fuel our pipeline for many years to come.

Transitioning to our cardio metabolic STAr, our leading program is ALN-PCSsc, which is a first-in-class investigational PCSK9 synthesis inhibitor in development for the treatment of hypercholesterolemia. Our Phase 1 study enrolled normal healthy volunteers with elevated baseline LDL cholesterol. Initial clinical results from that Phase 1 trial were presented at the ESC conference in late August, and demonstrated robust, dose-dependent and durable reductions in LDL-C of up to 83% with a mean maximal reduction of up to 64%. These results are highly comparable to the levels of LDL lowering reported for anti-PCSK9 monoclonals.

Notably, significant and [clamp] lowering of LDL-C was achieved for over 140 days after a single dose. We believe that these results will support a quarterly and possibly biannual low-volume subcutaneous dose regimen for further study. Moreover, ALN-PCSsc was generally well tolerated with no clinically-significant drug-related adverse events to date. Additional data from this study will be presented in two days at AHA, and we very much look forward to updating you at that time.

In the third quarter, we and The Medicines Company, our partner on ALN-PCSsc, announced plans for further development in the ORION program. ORION will include an initial Phase 2 study of ALN-PCSsc, with plans to begin by end 2015 and a Phase 3 study expected to be in by end 2017. ORION is expected to include a comparative study of ALN-PCSsc with anti-PCSK9 monoclonals. The Medicines Company will lead the program from Phase 2 onwards, and commercialization of the same if successful.

We're also making strong progress in our hepatic infectious disease STAr, where we're focusing on the enormous global disease burden associated with viral pathogens such as HBV. We continue to be excited about ALN-HBV, as we believe 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. We're on track to file our CTA for ALN-HBV in late 2015, and expect our Phase 1 study to begin in early 2016.

In summary, we're making excellent progress on our investigational RNAi therapeutics pipeline across our three 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 medicine. With that, I will now turn the call over to Mike for a review of financials. Mike?

Thanks, Akshay. I will be referring to slide 26 for discussion of third-quarter 2015 financial results. This quarter, we maintained a solid balance sheet with $1.34 billion in cash, cash equivalents and marketable securities.

Our GAAP revenues for the third quarter of 2015 were $6.3 million, as compared to $11 million in the third quarter of 2014. GAAP revenues this quarter included $3 million from our alliance with Genzyme, $2.8 million related to our alliance with The Medicines Company and $0.5 million from other sources. The decrease in revenue in the third quarter of 2015, compared to the third quarter of the previous year was primarily due to the completion of our performance management obligations under the Monsanto agreement in February 2015, and the completion of our revenue amortization under the Takeda to agreement in May 2015, partially offset by an increase in revenues recognized under agreements with The Medicines Company and Genzyme. The Company expects net revenues from collaborators to remain consistent for the fourth quarter as compared to the third quarter of 2015.

Moving to expenses, R&D expenses were $68.6 million in the third quarter of 2015, as compared to $46.3 million in the prior-year period. This increase was due primarily to additional expenses associated with the significant advancement of certain of our clinical and pre-clinical programs. In addition, compensation, non-cash stock-based compensation and related expenses increased during the third quarter of 2015, as compared to the third quarter of 2014, due primarily to an increase in headcount during the period, as we continue to advance our growing development pipeline. We expect that R&D expenses will increase in the fourth quarter of 2015 as compared to the third quarter of 2015, as we continue to advance our pipeline across our three STArs.

G&A expenses were $16 million in the third quarter of 2015 as compared to $9.9 million in the third quarter of 2014. This increase was due to increased non-cash stock-based compensation, and an increase in consulting and professional services, related to an increase in general business activities. For the fourth quarter of 2015, we expect that G&A expenses will remain consistent with the third quarter of 2015.

The GAAP net loss for the third quarter of 2015 was $76.8 million, as compared to a GAAP net loss of $44 million for the same period in the previous year. Regarding our equity investment in Regulus Therapeutics and the fair market value of our investment in Regulus as of September 30, 2015 was $38.6 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 have heard from both John and Akshay, we have had a tremendously productive third quarter and recent period, as we continue to build the industry's leading pipeline of RNAi therapeutics, and advance our innovative investigational RNAi therapeutics to patients and to the market.

Now, let's turn to our goals for 2015 and our 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're on track and continue to enroll patients in our Phase 3 APOLLO study. As announced just last week, we expect the trial to complete enrollment in the next three to four months, and assuming the study is positive, we expect that APOLLO will enable regulatory submissions in the US and EU in the 2017 time frame. We also continue dosing patients in our Patisiran Phase 2 OLE study.

With Revusiran, we're currently enrolling FAC patients in our Phase 3 ENDEAVOUR study. As Akshay mentioned, we will provide further guidance on the timeline for this study in 2016. Now, we are also dosing patients in the Phase 2 OLE study with Revusiran and plan to announce data at least once a year, including complete 12-month data in 2016.

Now moving to our hemophilia program, ALN-AT3, we are continuing to enroll additional dose cohorts in the ongoing Phase 1 trial, including hemophilia patients receiving a monthly subcutaneous dose regimen. As Akshay mentioned, we plan to share additional data from this trial at ASH. Additionally, we've initiated dosing in our Phase 1 open label extension study with ALN-AT3, in which hemophilia patients enrolled in the Phase 1 study can enroll in the OLE and receive ALN-AT3 on an ongoing basis.

With our complement program, ALN-CC5, we continue dosing healthy volunteers in the multi-dose phase of our Phase 1-2 study, and are scheduled to present our first-ever data for these multi-dose cohorts, as well as longer follow-up from the single dose cohorts, at ASH. As guided, we're on track to begin enrollment of PNH patients in Part C of the study by the end of the year.

With ALN-AS1, we continue to enroll patients in our ongoing Phase 1 study. With ALN-AAT, the Phase 1-2 trial is ongoing. And with our ALN GO program for the treatment of PH1, we are on track to file our CTA by the end of this year.

Turning to our cardio metabolic STAr, with ALN-PCSsc, we plan to present additional Phase 1 data at AHA in a couple of days, and The Medicines Company has guided that they expect to start a Phase 2 trial by the end of this year. With our hepatic infectious disease STAr, we're on track to file a CTA with ALN-HBV by the end of this year. As Mike said, we remain on track to end the year with greater than $1.2 billion in cash.

Just summing it up, we look forward to sharing more updates from our pipeline in the coming weeks and months. It will be an incredibly data-rich time. I'll now turn the call back over to Christine for Q&A. Christine?

Thank you, Barry. Operator, we are ready to open the call for questions. As a reminder to those dialed in, we would ask you to limit your question to two each.

(Operator Instructions)

Ritu Baral, Cowen.

For the PH1 program, you mentioned starting in asymptomatic excretors and then translating into patients who are having attacks. Can you clarify when this translation would take place, and how you would evaluate that? Thank you.

Yes, Ritu, thanks for the question. Good to talk to you this morning. I think that is really the porphyria program, AS1.

Yes.

Not the GO1 program. So the porphyria program is indeed currently in these asymptomatic high excretor patients, these so-called ASHE patients, where we have done single-dosing. We're now in the multi-dose arm of that study. And we expect to transition into Part C of the study, which is in recurrent PAC patients early next year. Akshay, anything you want to add to that?

No, I think that's it.

Good.

Great. Thank you.

Anupam Rama, JPMorgan.

Just a quick one for me on the upcoming ASHE data related to AT3. I'm wondering if we'll be seeing any type of annualized bleed rate data by dose, and then can you give us a sense of whether or not there might be any inhibitor patient data at the conference? Thanks so much.

Great, Anupam, great question. So I think, the quick answer is yes, we are going to show annualized bleed data from in the study, based on both dose and also by analysis of anti-trauma knockdown. We think both assessments are important, and as we look at dose, one of the things I think you'll see, Anupam, is that we'll look at prospective bleeding rate data during the initial period of time when the knockout is occurring, where patients effectively don't have robust knockdown. And then, during the subsequent period where they are essentially at their peak level of knockdown.

I think that type of data would be very informative, because it's not going to be based on historical assessments, but rather prospective assessments, and that will obviously give us greater, should give us and others greater confidence around the effects that we are seeing. Regarding inhibitors, we do have an abstract that's ASH, you might have seen it, regarding serum sample assessments in inhibitor patients, but we won't have inhibitor patient data at the meeting. Akshay, anything else to add?

I think you covered it, John.

Good.

Great, thanks so much for taking our question.

Terence Flynn, Goldman Sachs.

Maybe just two from me. First on the C5 program, just wondering if your target level of inhibition of hemolytic activity in the med portion is still 80%? And then any updated thoughts on the design of Part C with respect to the patient population? And then the second question I had is just on financials. Obviously, you have guided to a step-up in 4Q versus 3Q for R&D expense, but just as we think about 2016, should we expect another step-up over 4Q, or is 4Q the right run rate to think about? Thank you.

Thanks, Terence. Let me and Akshay maybe address the first question first. Yes, nothing has changed in terms of our perspective on serum hemolytic activity as a target, and that will certainly be something we share at CC5, at the ASH meeting, regarding the CC5 program. So nothing has changed there.

I do think it is important to also look at residual C5 that we achieve versus free C5, as reported for eculizumab, because that's another way to look at the data, as well. All of the data will be shared, including the serum hemolytic activity, and our view on the 80% target hasn't changed. Akshay, anything to add to that?

No. I think you covered it.

Good. Okay. And then, Mike, you had some questions, Terence had some questions on the forecast.

Terence, we will give our formal guidance during our Q4 call in February for cash for next year, so you can get an idea on burn rate for 2016. And the other thing that obviously, in biotech each quarter there's ups and downs, based on different C&C batches and things like that, enrollment in trials. But we will definitely see an increase in 2016, as we grow our development pipeline compared to the fourth quarter of 2015, and we'll give more clarity on that in our Q4 call.

Geoff Meacham, Barclays.

A question, John, on Revusiran. So the ENDEAVOUR study may take some time to complete enrollment, but I want to get a sense from you as to, aside from the open label extension, what we'll learn along the way? For the DISCOVERY study, is there going to be maybe any, I wouldn't call it an interim look but a description of the patient population? I'm just trying to get a better sense for how you can correlate how the science is advancing with respect to correlating TTR mutations to cardiovascular disease severity, to things like six-minute walk?

Those are great questions. I'm just going to hand it right over to Akshay.

We have, Geoff, you may have seen previously, we brought out some natural history data that we have on the FAC and SSA, and this as an area. That clearly shows, this is a devastating disease, where FAC and SSA both are associated with significant morbidity and mortality in terms of hospitalizations. And death, respectively, median survival is well under five years.

With respect to FAC and genotype, there is some data within that natural history work that we can share again with [folk]. The predominant genotype that's associated with FAC, of course, is V122I, and so the majority of patients both in the ENDEAVOUR study and our patients ultimately when the drug gets approved and the drug is prescribed, the majority of patients will have V122I, and so the data from the natural history work are fairly representative of what we can expect to see within the ENDEAVOUR Phase 3 study.

Apart from that, of course, this Phase 2 for Revusiran, which we just brought out the first lot of data on, and it matures in next year and the year after. We'll very impressing insights, I believe, from the relationships between the mutations and outcomes and also FAC versus outcome and SSA versus outcome after revision of treatment. A number of areas that will provide data and insights, and the other thing is, as evidenced by the recent Paris EC ATTR meeting, the academic field, of course, continues to study this space as well. So that will also buttress the knowledge.

DISCOVERY, you cited as a source of important information. You are right. That is a very important study for us, where we are identifying new patients from the community by working with cardiologists around the country here and in Europe. And the main thing we're learning there is the commonest mutation, of course, is V122I in the new patients we're identifying, so again confirming what we are doing.

I would just add two things quickly from Geoff, from a meeting last week. And Akshay mentioned that it is clear from the data we and others presented that while FAC and SSA are both caused TTR, they are different diseases. FAC caused by the mutation. The diagnosis rates are different. The time course of the disease is different, really enforcing our design for ENDEAVOUR being the right design.

And the second thing I'd add from DISCOVERY is, it is clear from looking at that body of work that this disease is significantly under diagnosed, and in fact, new pathogenic mutations are being found, in fact, we reported two new mutations in the DISCOVERY work from last week. So I think it's an expanding area, an area that we are more confident than ever that removing the pathogenic protein of this mutated TTR has the potential of having an impact on the disease.

Got you. Very helpful. Thanks.

(Operator Instructions)

Alan Carr, Needham & Company.

Can you talk a bit more about the HBV program, what will be your expectations at ASHE? And also over the course of 2016, timelines for getting this into patients? And then maybe also an update, I believe you were looking at other infectious disease indications in the liver, and an update on that too? Thanks.

Great. I think you meant the liver meeting, not at ASH.

You are right. I am sorry.

No problem. And that's just in a couple of weeks. We're going to provide some updated pre-clinical results there. The development candidate is just finishing up its pre-IND studies. We are very much fully on track to file a CTA for that program by the end of this year in December.

We are going to likely be able to initiate our Phase 1 study in the first quarter, maybe toward the end of the first quarter or early second quarter. So early 2016 is our guidance there. And as we get closer to that filing, we will update you on the design of our Phase 1 study. We wouldn't do this just yet, Alan. But I expect that we'll see data sometime next year.

Now regarding other hepatic infectious disease targets, we're quite interested in hepatitis delta as a co-infectious pathogen with HBV where the disease burden is enormous. And we think that our mechanism of action by knocking down surface antigen will really have a high impact, potentially on that disease, and the disease course in those patients. So that's probably of the other areas, where we have the highest level of interest at this time. Akshay, anything else to add to that?

No.

And then a last one follow-up, if you could give us an update, I guess in a broad sense on relationship with Sanofi and when they need to -- when their next decision comes up, in terms of which programs they're going to option or outright in license. When do those decisions come up?

Absolute. Let me start by just saying that we have continued to have an amazing relationship with Sanofi. We spent time, we were in Paris last week, we spent time with Olivier the CEO, and also with their entire R&D with Elias and Jorge. So we had a quite robust set of interaction with them.

As evidenced by their R&D day on Friday, you could see that Alnylam was pretty prominently featured across their pipeline and their R&D activity. The relationship is very strong, just like they did with Regeneron. I think they made a very wise choice to form a partnership with Alnylam with the right type of features to it, where both Alnylam and Regeneron continue to drive and build our companies, and get the benefits of what they can bring globally. But Barry, do you want to comment anymore about other opt-ins and timings and so forth?

Alan, as you know, they've opted into the hemophilia program on a regional basis, so we've retained US and Western Europe, they have the rest of the world. After the Phase 1 readout for the porphyria program next year, they'll have several different options. They can keep the regional relationship with hemophilia and take porphyria globally, so they take the whole thing globally.

Or they can take the AT3 program as a co-co and opt in to porphyria as a regional basis, where we retain US and Western Europe. That is their optionality sometime next year. As you also know that there's a number of other programs coming down the pipe, which I won't go into now, we listed those, where Phase 1 readouts will be late in the year, next year as well. So we will have a number of programs to look at and make decisions about opt-ins for.

Okay. Thanks very much.

Gena Wang, Jefferies.

This is [Shao Ping] for Gena. I just had a quick question about Patisiran, so how do you see the improvement in the nerve fiber density could help Patisiran regulatory approval?

That is a really great question. Akshay, do you want to handle that?

Yes. The nerve fiber density data, just to repeat, we saw a 4.9 millimeter per cube increase from baseline in sweat gland nerve fiber density in the leg, and that's a really, to our minds, a really remarkable result, to show an improved in innovation in a key organ in the limbs, and something that's never been shown before in this disease. And what that serves to do from our perspective we hope regulators will agree, is it provides additional data sets on top of the clinical data we'll be reporting with the new space sorting systems, and the TTR knockdown. It provides an additional data point to say something important is happening with TTR knockdown in terms of outcome. And of course, it begins to explain some of the improvements we are seeing in this.

I can't say any of that conclusively, this is a small Phase 2 open label study, but we will be looking at similar data from the Phase 3 APOLLO study where there too, we have incorporated nerve biopsies. And if these data reproduce in that control study, I think it will be another powerful nugget within the entire data set, that should compel people that Patisiran is an important new agent for familial amyloidotic polyneuropathy. So really very excited about that, and something that's unique to our program, and we also the Paris meeting, showed reductions in non-native TTRs in circulation relative to prior to treatment reductions in the mis-folded protein packet, in half by up to 90%. So these additional data points, I think, will prove very important and interesting at the ultimate filing.

The other thing I would just add to that, I completely agree with what Akshay just said, I would just add and make sure people understand that it's an objective measure. This change in nerve fiber density. It is measured histologically. It's done, the measurements are done in a blind, essentially a mass fashion by our investigator based at Johns Hopkins, who is a world leader in these types of assessments. The, world leader.

So it is a very important element. Just as these type of data have been useful in other rare disease approvals in the past, [fab rees] potentially upcoming data with DMD. We think these type of data are notable and will likely be buttressing of the overall data package that regulators will look at for sure. So we think it is very important, and you are very correct to ask that question.

All right. Thank you so much.

Ted Tenthoff, Piper Jaffray.

We're really excited to see all the progress continuing the back half of this year and what is going to be really busy 2016. My question has to deal with ASH. Just going back through and getting a sense of what to expect, obviously, updates on AT3 and I think also CC5, if I'm not mistaken. So maybe you tell us what we should be expecting at the conference, and what next steps for those two programs will be into 2016?

That is great, Ted. We're really looking forward to the conference coming up. It's going to be a big meeting for us, for sure. With AT3, we're going to be showing data from about a dozen additional patients that have now received monthly dosing of ALN-AT3, and obviously, we'll be sharing knockdown, trauma generation changes, safety very important with this drug, as well as also looking at annualized bleed rates.

Again, as I mentioned earlier in the call, we're going to looking at annualize bleed rates by dose group, as well as by relative change in thrombin generation, and the bleed rate data that we're going to be sharing are prospectively generated, so they are not based on comparisons with historical controls. So I think those type of data will be very helpful. Clearly, where we want to be with ALN-AT3, and we think that we'll be -- come to that point in time, is exiting the year of clarity around the dose [base] regimen that we can then proceed into Phase 3 in the middle of next year, which is our plan. So that's going to be a big data readout.

And then with C5, absolutely, we're going to have C5 data at the meeting. This will include data from our multi-dose cohorts that extend what we did and showed at EHA. Here, I think all eyes should be on the level of knockdown that is achieved, the changes in hemolytic activity, as well as the type of residual levels of C5 we obtained, and how they compare with the 3C5 that's been reported historically with eculizumab, because that is a direct apples to apples comparison. Those types of data sets, I think, will be very -- of great interest to people, and we look forward to sharing them. Can't wait until early December.

Good. Excellent. Thanks so much for the update.

Great, Ted.

Thank you, and at this time, I'll turn the call back over for closing remarks.

Great. Listen, thanks everyone for joining us this morning. Again, look out for our R&D day in December. We would love to see you there, it will be a great meeting.

But I do want to end by just thanking a few groups. First, the Alnylam who have been working tirelessly to deliver these innovative medicines to patients, and then also the physicians and study teams and coordinators who have worked with us on our clinical studies. We now have a significant number of clinical studies that are ongoing. But most of all, I'd like to thank the patients and their families who are participating in our clinical trials. Obviously, our commitment is to you, and to make a difference in your lives. And so with that, I think we can now close. Thank you very much.

Thank you. Ladies and gentlemen, this concludes today's conference. You may now disconnect. Good day.