Alnylam Pharmaceuticals Inc (ALNY) 2017 Q2 法說會逐字稿

Welcome to the Alnylam Pharmaceuticals Conference Call to discuss second quarter 2017 financial results. (Operator Instructions) Please be advised that this call is being taped at the company's request. I would now like to turn over to the company.

Good afternoon. I'm Christine Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, our Chief Executive Officer; Barry Greene, President; Akshay Vaishnaw, Executive Vice President of R&D; and Manmeet Soni, Chief Financial Officer; in addition Yvonne Greenstreet, Executive Vice President, Chief Operating Officer, is in the room and available for Q&A. For those of you participating via conference call, the slides made available via webcast can also be accessed by going to the Investor page of our website, www.alnylam.com.

The press release and related financial tables, including a reconciliation of GAAP to non-GAAP net loss, that we will discuss today can be found on the investor page of our website. We believe non-GAAP net loss provides useful information to management and investors regarding our financial conditions and results of operations.

During today's call, as outlined on Slide 2, John will provide some introductory remarks and provide general context, Akshay will review recent clinical updates, Manmeet will review our financials and Barry will provide a brief summary of upcoming milestones before opening the call for your questions.

Before we begin, I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our view of any subsequent date. We specifically disclaim any obligation to update such statements.

With that, I would like to turn the call over to John.

Thanks, Christine, and thank you, everyone, for joining us this afternoon. During the second quarter of 2017 and recent period, we made continued and meaningful progress in advancing our investigational RNAi therapeutics through clinical trials and toward the market. 2017 promises to be a pivotal year for our company as we open the envelope on our first Phase III results and prepare to make the anticipated regulatory filings for marketing approval and assuming approval, make the transition to a commercial organization.

In addition, we aim to start 3 separate Phase III programs in 2017, positioning us to fulfill our Alnylam 2020 plan of becoming a multiproduct commercial stage company with a deep and sustainable clinical development pipeline by the end of 2020. This is a profile that has been rarely achieved in biotech.

Of course, right now, all eyes are on patisiran, our investigational RNAi therapeutic, which we're developing for the treatment of patients with polyneuropathy due to hereditary ATTR amyloidosis. Specifically, we look forward to reporting top line data from the APOLLO Phase III trial in the coming weeks, and assuming positive results, expect us to submit an NDA by year-end with an MAA following shortly thereafter.

We believe we have strong reasons to be encouraged about APOLLO based on the continuing promising results that we've seen from our ongoing Phase II open label extension, our OLE study of patisiran where we've seen evidence for potential halting or, in fact, improvement of neuropathy progression in patients.

Moreover, we believe the potential clinical efficacy for a TTR-lowering mechanism of action was also validated by the recent positive top line Phase III results for inotersen, an investigational antisense oligonucleotide targeting TTR. Accordingly, we very much look forward to seeing the important results from APOLLO.

In the meanwhile, we're very much in a build phase preparing for our potential transition to a commercial stage company in 2018. Barry will review some of these activities later, but I also encourage you to listen to the webcast of our patisiran RNAi roundtable from last week, where we discussed our commercial readiness efforts in much more detail.

Without a doubt, we're excited about the medical affairs, manufacturing and commercial organizations and capabilities we're building to support our initial commercialization efforts in the U.S., Canada and Western Europe, and we look forward to extending these efforts globally to support givosiran and future programs where we've retained global rights.

We've also recently made great progress with our mid- to late-stage clinical programs, including patisiran for hemophilia, givosiran for porphyria and with our partners at The Medicines Company, inclisiran for hypercholesterolemia. The ATLAS Phase II program for patisiran in hemophilia A and B patients, with or without inhibitors, was initiated earlier this summer, and we're pleased to get this program up and going.

We're also aiming to start the givosiran Phase III study by end of the year, and The Medicines Company has announced agreement with the FDA on a Phase III program for inclisiran with a study in patients with atherosclerotic cardiovascular disease, expected to commence in late 2017.

Strategically, these 3 Phase III programs, in addition to patisiran, petition -- position Alnylam to potentially have a steady flow of commercial launches on essentially an annual basis from 2018 going forward. Of course, we're also very excited about the recent data presentations for which -- for what we believe to be the transformative potential of patisiran, givosiran, and inclisiran.

Finally, as we shared during our RNAi roundtable webinar earlier today on revusiran, we have concluded our investigation into the imbalanced mortality that led to the discontinuation of that product's development in the fourth quarter of 2016. As part of this investigation and as we reviewed earlier today, we explored a broad range of potential hypotheses. There was no clinical evidence for a revusiran-related cardio toxic effect, and there was no evidence for PK- or PD-based toxicity from either TTR knockdown or mobilization. Of course, it's impossible to prove a negative so we cannot fully exclude a contribution of the drug. But as we discussed earlier today, there is some evidence that lower-than-expected mortality on the placebo arm at that time of discontinuation contributed to the observed mortality imbalance and thus, it is possible the imbalance may have been a chance finding. Importantly, we continue to remain confident that the findings with revusiran, a first-generation GalNAc conjugate, do not read through to the rest of our GalNAc platform, and we believe recently reported data from across our pipeline continue to strengthen this confidence.

Now with those introductory comments, I'd like to now turn the call over to Akshay to review our pipeline progress in more detail. Akshay?

Thanks, John, and good afternoon, everyone.

As John noted, we've indeed made strong progress in our pipeline of investigational RNAi therapeutics. Let's begin with our programs in hATTR amyloidosis, which include patisiran and ALN-TTRsc02. This is only a big year for patisiran with our Phase III APOLLO study read-out in the coming weeks. As John commented, we believe we have good reasons to be encouraged by the prospects of patisiran based on our Phase II OLE study results and the mechanism validating Phase III top line efficacy results for inotersen. At the same time, we're also advancing ALN-TTRsc02 as a subcutaneous alternative and we expect to advance this program into Phase III in 2018.

Now at the AAN meeting earlier this year, we presented final results for the patisiran Phase II OLE study shown on Slide 8. At 24 months, patisiran showed a mean change in the modified Neuropathy Impairment Score, mNIS+7, of negative 7.0 points, providing continued evidence of patisiran has the potential to halt or improve neuropathy progression in patients with hATTR amyloidosis. Of note, over 70% of the patients in the Phase II OLE study showed no change or a decrease or improvement in their Neuropathy Impairment Scores.

At the AAN meeting, we also presented a new post-hoc analysis exploring the relationship between baseline neuropathy severity and change in mNIS+7 where the potential effect of patisiran was observed across the full range of disease severity. In addition, as shown on Slide 9, in the first post-hoc exploratory analysis of its kind, patisiran administration was found to be associated with statistically significant decreases in TTR amyloid deposition as measured from blinded analysis of skin biopsy samples. Together with data showing the mean increase in sweat gland nerve fiber density observed in the same skin biopsy samples, we believe these exploratory analyses support the therapeutic hypotheses that the reduction of mutant and wild-type TTR can potentially lead to reduction of patisiran amyloid deposition and increased nerve regeneration.

Regarding Phase II results, patisiran administration was found to be generally well-tolerated in patients with hATTR amyloidosis out to 25 months, with no drug-related serious adverse events reported. Drug-related or possibly drug-related adverse events in 4 or more patients were flushing and infusion-related reactions, all of which were mild in severity and did not result in any discontinuations. There were 10 reports of SAEs in 7 patients, all of which were unrelated to study drug, including 2 previously reported deaths. There were no clinically significant changes in liver function tests, renal function or hematologic parameters, including platelets. Patients who completed dosing in the Phase II OLE study have enrolled into the global APOLLO OLE study, and we plan to report initial 36-month data from those patients in late 2017.

Of note, all 25 Phase II OLE patients continue on study with approximately 3 to 3.5 years of dosing.

In addition to patisiran, and as I commented earlier, we're also developing ALN-TTRsc02 as an investigational RNAi therapeutic for hATTR amyloidosis. ALN-TTRsc02 uses our ESC-GalNAc-conjugate platform and is able at providing a subcutaneous RNAi treatment alternative to patients with hATTR amyloidosis.

We shared our initial Phase I data and our R&D data this past December showing dose-dependent knockdown of serum hATTR with very low doses of ALN-TTRsc02 and with the durability of effect extending for months after just a single dose. At our patisiran roundtable this past week, we were very pleased to provide updated results from our ALN-TTRsc02 Phase I study, which is shown here on Slide 12. In this 80 subject, single ascending-dose study, ALN-TTRsc02 showed what we believe to be a highly encouraging potency towards TTR knockdown and durability of effect. Indeed, our results suggest that a once-quarterly and possible semi-annual fixed dose of either 25 or 50 milligrams could provide the same level of TTR knockdown observed with patisiran.

Regarding safety results. ALN-TTRsc02 was generally well-tolerated supporting further advancement of this investigational RNAi therapeutic. We believe that these positive results position ALN-TTRsc02 to be a promising potential option for hATTR amyloidosis patients, and we very much look forward to advancing this program into planned Phase III studies in 2018.

Now let's turn to our fitusiran program for the treatment of hemophilia and rare bleeding disorders, where we've continued to make great progress. As you know, fitusiran is an investigational RNAi therapeutic targeting antithrombin, or AT, that is designed to increase thrombin generation and thus, provide hemostasis in people with hemophilia. We believe that fitusiran has the potential to address the unmet needs in hemophilia by providing consistent and durable hemostatic protection for all patients and a whole new treatment option for patients living with inhibitors. Moreover, as a once-monthly subcutaneous injection, fitusiran has the potential to address the significant treatment burdens of current management.

Fitusiran data highlighted in the paper on the Phase I results which were recently published in the New England Journal of Medicine.

Now at the ISTH meeting in Berlin in July, we presented new results from our ongoing Phase II OLE studies highlighted here on Slide 14. This study was open to patients who were previously enrolled in the Phase I study. A total of 33 patients were enrolled and given doses of either 50 or 80 milligrams monthly via subcutaneous injection. Fitusiran achieved a consistent level of AT lowering of approximately 80%, resulting in the increases in thrombin generation to the lower end of the range of thrombin generation observed in healthy volunteers. The effects of fitusiran on thrombin generation resulted in a low median AVR of 1 in all patients and 0 in inhibitor patients with a median duration of treatment of 14 months.

Whilst we've not conducted any head-to-head studies, we believe these early results suggest and highlight the promising potential of fitusiran as compared with replacement factor therapy and other agents in development.

Regarding safety results, fitusiran was generally well-tolerated with up to 20 months of dosing with most days being mild to moderate. Very importantly, there were no thromboembolic events, including treatment of breakthrough bleeds. Asymptomatic ALT elevations grew from 3x to the upper limit of normal were observed in some HCV antibody positive patients with all resolved or resolving at the time of the data cut off. Overall, we believe the benefit risk of patisiran remains very encouraging.

Accordingly, we're very pleased to have initiated our ATLAS Phase III program for fitusiran. ATLAS will enroll approximately 250 patients in 3 separate trials at over 100 clinical centers around the world, and we expect to be fully enrolled in these studies over the next year with top line results in mid- to late 2019.

Across all 3 ATLAS studies, we will be enrolling patients with severe hemophilia A or B. Amongst other standard exclusion criteria, we're going to exclude patients who are RNAi positive for HCV, meaning they have an active infection. We will, of course, include patients who have been treated for and cured of ATV. The 3 ATLAS studies are outlined on Slide 15 and are as follows. ATLAS-INH is a 9-month open label randomized and controlled study designed to enroll approximately 50 patients with hemophilia A or B with inhibitors receiving prior on-demand therapy. ATLAS A/B is a 9-month open label randomized and controlled study designed to enroll approximately 100 patients with hemophilia A or B without inhibitors receiving prior on-demand therapy. And finally, ATLAS-PPX is an open label one-way crossover study designed to enroll approximately 100 patients with hemophilia A or B, with or without inhibitors receiving prophylaxis therapy as prior standard of care.

Now with that, let me now turn to recent progress with revusiran, which we're developing for the treatment of acute hepatic porphyrias. Hepatic porphyrias are a group of ultra-orphan diseases caused by genetic defects in the heme biosynthetic pathway. They are devastating diseases with enormous disease and economic burden. In this disease, buildup of toxic heme intermediate leads to incapacitating and potentially fatal attacks with symptoms that include severe abdominal pain, peripheral and autonomic neuropathy and neuropsychiatric manifestations.

Porphyria attacks typically last for days and require hospitalization. At the beginning of March, FDA hosted a patient-focused drug development meeting on acute porphyria where we were able to hear from patients living with this devastating condition. Patients described the pain during an attack as incompatible with life, and the majority of patients reported chronic pain in between their attacks.

Currently, the only available treatment is hemin, a crude preparation of heme administered via central line. We also know from our EXPLORE Natural Study of 112 acute hepatic porphyria patients that there's an enormous economic burden associated with the disease. Indeed, as we presented at ISPP (sic) [ICPP] in June, an analysis of cost associated with acute hepatic porphyrias patients with recurring attacks revealed the average estimated annual expenditure per patient ranges from $400,000 to $650,000, excluding indirect costs such as those associated with lost productivity or workdays for both patients and caregivers.

Turning now to our clinical program. Revusiran targets the liver expressed ALAS1 gene, which is an enzyme upstream with the genetic defects in acute hepatic porphyrias and the enzyme responsible for overproduction of ALA and PBG, the 2 toxic heme synthetic intermediate that mediate porphyria attacks. Our therapeutic hypothesis, illustrated on Slide 17, is that silencing ALAS1 with givosiran will lower levels of ALA and PBG and thereby have the potential to reduce the number of frequency and severity of porphyria attacks in patients.

As a once-monthly subcutaneous investigational RNAi therapeutic to prevent debilitating porphyria attacks, givosiran could be a transformative therapy for patients with disease.

At the ISPP (sic) ICPP meeting in Bordeaux, we presented new results that included all available data from Cohorts 1 through 3 and part D of the ongoing Phase I trial as well as cohorts 1 and 2 of the ongoing Phase I OLE study. These data are highlighted on Slide 18.

As a reminder, our (inaudible) Phase I study is being conducted as a randomized double-blind placebo-controlled trial where patients with recurrent porphyria attacks are monitored prospectively during a 90-day run-in period, randomized to receive drug or placebo in a 3:1 allocation and then monitored prospectively for a 180-day treatment period.

And during the treatment period, givosiran-treated patients showed dose dependent decrease in ALAS1 levels, which was associated with the robust and durable lowering of ALA and PBG.

In the first 3 unblinded cohorts, our treatment cohorts of 12 patients from Part C, givosiran-treated patients experienced the mean 63% reduction in the annualized number of porphyria attacks relative to the run-in period. This treatment effect was consistent across a wide range of baseline attack rates.

In a separate analysis of attacks treated at a health care facility or with hemin administration, treatment with givosiran was associated with a mean 73% reduction in annualized attack rate relative to placebo. Moreover, when we looked at the annualized hemin administration relative to the run-in period, we observed a mean 73% decrease in the hemin use for patients on givosiran.

From the Phase I OLE results, initial data from the 8 patients in cohorts 1 and 2 provide initial evidence that longer-term treatment with givosiran may be associated with continued reductions in the annualized porphyria attack rate. Specifically, for the 6 patients randomized received givosiran in Phase I, the mean annualized attack rate of 9 during the treatment period was reduced further to 5 in the OLE study with a mean follow-up of 111 days.

For the 2 patients randomized to receive placebo in Phase I, mean annualized attack rates of 29 and 23 were observed during the combined run-in and treatment period. As of the early days and for ICPP, no attacks have occurred in these 2 patients following givosiran administration.

Turning to safety results on Slide 21. Givosiran administration was generally well-tolerated in Part C of the Phase I study and in the ongoing OLE study with a mean of 169 and 91 days on treatment, respectively, and up to 12 months on givosiran treatment. There were 4 nondrug-related SAEs in the 3 patients including a previously reported death due to hemorrhagic pancreatitis, which was considered to be unlikely related to the study drug. There was no drug-related -- there were no drug-related discontinuations. All patients reported mild to moderate AEs that were possibly drug-related, including ISRs, erythema and hypersensitivity. Myalgia, headache and moderate renal impairment were also reported in a patient of with a history of renal impairment. In aggregate, we're very encouraged by the clinical activity and tolerability profile for givosiran and are gratified by the recognition of givosiran's potential from regulatory authorities. This past quarter, we were very pleased when the FDA granted givosiran breakthrough designation. This follows the prior designation received from the EMA in Q1. We've now been engaged with both the FDA and EMA in discussions on our Phase III study design and our overall efforts to bring givosiran to patients as rapidly as possible. As the next step, we look forward to the start of our Phase III program expected in late '17.

Let's now turn briefly to inclisiran, our investigational RNAi therapeutic targeting PCSK9 that's being developed in collaboration with our partners at The Medicines Company. As announced in April, agreement has been reached with the FDA and EMA on plans for the Phase III clinical program for inclisiran designed to support the submission of an NDA and an MAA. The Phase III program will comprise clinical trials in subjects with atherosclerotic cardiovascular disease and familial hypercholesterolemia and we'll collectively enroll approximately 3,000 subjects randomized to treatment with inclisiran or placebo.

Following fitusiran and givosiran, we expect inclisiran to be the third RNAi therapeutic to enter Phase III in 2017. Inclisiran remains a very important product opportunity for Alnylam in light of our significant economic participation in the value program. The addition of substantial safety data we obtain from the inclisiran program support the overall safety profile of our ESC-GalNAc-conjugate platform.

Finally, we continue to advance our earlier clinical development programs, which include ALN-CC5 for complement-mediated diseases, ALN-GO1 for primary hyperoxaluria, and ALN-HBV for hepatitis B viral infection. And we look forward to updating you on those efforts in the future.

And with that, I will now turn the call over to Manmeet for a review of our financials. Manmeet?

Thanks, Akshay. Good afternoon, everyone, and thanks for joining us today.

In addition to the significant progress with our pipeline, as Akshay mentioned, we further strengthened our cash position during the second quarter with a recent stock offering. I will be referring to Slide 24 for a discussion of our second quarter 2017 financial results.

We ended the second quarter of 2017 with a strong position with approximately $1.25 billion in cash, cash equivalents and marketable investments, including restricted investments. As previously announced, during the second quarter of 2017, we sold 5 million shares of common stock in an underwritten public offering for net proceeds of $355.2 million. In addition, Sanofi Genzyme exercised its rights to purchase in a (inaudible) and prior replacement shares of common stock at a public offering price, resulting in additional proceeds of $21.4 million. The net proceeds from the public offering and prior replacements were received during the quarter. These proceeds will provide support for our general corporate operations, including the continued growth of manufacturing, quality, commercial and medical affairs categories to support our transition to a commercial stage biopharma company.

The GAAP net loss was $118.4 million or $1.34 loss per share in the second quarter of 2017 as compared to net loss of $90.1 million or $1.05 loss per share for the same period in the previous year. We also disclosed non-GAAP net loss in our earnings release. Non-GAAP net loss is calculated by excluding stock-based compensation expense from GAAP net loss. Please see the appendix included in the slides made available for download with today's call for details regarding GAAP to non-GAAP reconciliation.

The non-GAAP net loss for the second quarter of 2017 was $94.4 million or $1.07 loss per share as compared to a net loss of $74.3 million or $0.87 loss per share for the same period in the previous year.

Our GAAP revenues were $15.9 million in the second quarter of 2017 as compared to $8.7 million in the second quarter of 2016. Revenue for the second quarter of 2017 included $14.4 million from the company's alliance with Sanofi Genzyme and $1.5 million from the company's alliance with The Medicines Company. The increase in revenues in the quarter ended June 30, 2017 as compared to the prior year period was due primarily to higher cost reimbursement revenue from the company's alliance with Sanofi Genzyme.

Moving to expenses. R&D expenses were $90.6 million in the second quarter of 2017 as compared to $83.2 million in the second quarter of 2016. The increase in R&D expenses for the quarter ended June 30, 2017 as compared to the prior year period was due primarily to additional manufacturing expenses related to company's late-stage clinical trials.

In addition, stock-based compensation expense increased as a result of the company's accounting for the achievement of certain performance-based stock option awards during the second quarter 2017 in connection with the initiation of the ATLAS Phase III program for fitusiran.

G&A expenses were $45.8 million in the second quarter of 2017 as compared to $80 million in the second quarter of 2016. The increase in G&A expenses for the quarter ended June 30, 2017 as compared to the prior year period was due primarily to an increase in commercial and medical affairs headcount to support corporate growth and to prepare for the potential launch of the company's post-commercial product.

With respect to guidance for 2017, we remain on track to end the year with greater than $1 billion in cash, cash equivalents and marketable investments, including $150 million in restricted investments. We believe this provides Alnylam a very strong balance sheet at the end of 2017 to support development and commercial activities in 2018 and beyond.

With that, I will now turn the call over to Barry. Barry?

Thanks, Manmeet. As you heard from John and Akshay, we're looking forward to some critical data points this year, which, if positive, puts us closer to our Alnylam 2020 profile, marking our transition from a late-stage R&D company to a multiproduct commercial organization with a sustainable development pipeline, achieving a profile, as John said, rarely achieved in the biopharmaceutical industry.

As part of this transition, we're very focused on expanding our medical [affairs], quality, manufacturing and commercial capabilities to support the potential for multiple consecutive product launches in 2018, 2019, 2020 and beyond. These efforts include building our capabilities in the United States, Canada and Western Europe for patisiran, fitusiran, and then growing globally with givosiran and future products.

As John commented earlier, I encourage you to listen to the webcast of our recent patisiran RNAi roundtable to understand the comprehensive medical affairs and commercial ratings efforts we're putting behind this very important program.

Now let's turn to our 2017 goals and guidance on upcoming data presentations. With our patisiran program, we look forward to reporting top line data from the APOLLO Phase III study in the coming weeks with full results planned for the European ATTR Meeting in November. Assuming positive results, we expect APOLLO will enable an NDA filing at year-end followed shortly by an MAA filing putting us in a position, assuming regulatory approval, to launch our first commercial product in 2018.

With fitusiran, we plan to present additional clinical results in late 2017. Following the initiation of the ATLAS Phase III program in July, we expect to present top line results in mid- to late 2019.

Now turning to givosiran. We look forward to initiating the Phase III study in late 2017 as we finalize our discussions with global regulatory authorities.

Regarding inclisiran, our partners at The Medicines Company are planning to initiate the Phase III study in patients with atherosclerotic cardiovascular disease in late 2017.

We also plan to advance additional programs from our early and mid-stage pipeline and to report additional clinical data from these programs throughout the year.

Finally, as Manmeet said, we expect to end 2017 with greater than $1 billion in cash.

With that, I'll now turn the call back to Christine to coordinate our Q&A. Christine?

Thank you, Barry. Operator, we will now open the call for questions. (Operator Instructions)

(Operator Instructions) Our first question comes from the line of Ritu Baral with Cowen.

So as you look towards the registration path and potential approval of patisiran, do you plan on presenting some of the revusiran safety analysis that you presented earlier in the webcast earlier today, just to -- in an effort to address KOL concerns, any lingering KOL concerns about the side effects, just given the mixed phenotype of some of these patients? And a quick follow-up to that is, can you address some of the commercial strategies that you might have around the patisiran launch to increase diagnosis, I think, at, like, skin biopsies was one mentioned in your previous webcast.

Great. I mean, Ritu, those are great questions. Akshay should comment as well, but the short -- the brief answer on revusiran is that it's a completely different molecule in a different setting. And there's really -- we've obviously shared the data with investigators. We've shared the data with FDA and EMA as well. And so they're generally aware of those data, but they certainly regard those data as being distinct and related to a completely different molecule. Akshay, anything more to...

Yes. And to the point that patisiran, stands in and of itself and when we look at this data, obviously, very thoroughly, but as an appetizer, I mean, if you looked at the Phase [II] OLE data, a significant number of patients there with neuropathy association, one, and two, heart failure because of the cardiomyopathy coexisted with the neuropathy. The safety has held up well and I think bodes well for the APOLLO program overall. And of course, we're going to share all the safety data from APOLLO. So I think people will be satisfied with the transparency and the depth with which we'll share.

Okay. And then the commercial question, Barry, you want to handle that?

Yes. And Ritu, as you're aware, there's a significant amount of disease awareness going on in neurology and cardiovascular settings. And there are a number of programs that tried -- decrease the patient journey and get diagnosis done earlier, including genetic testing, biopsies and other mechanisms to try to help. But the real key is to make sure that people in the neurology and cardiovascular setting are aware of the disease so that it's on the list of potential diagnoses. And we're well on our way to doing that.

(inaudible) in case people are not aware of it, which is the sort of third party genetic testing accounting service, which has been very successful actually in conducting a number of genetic tests and identified patients. So this along with other educational approaches, I think, is a way of making sure that treating physicians are aware of the disease, and as Barry said, we can truncate the patient journey.

I think that's a great point, Yvonne. I would just finally add, we're taking a very significant leadership position in this field as from a company perspective. And I think that the KOLs and the patient communities realize that we're all about helping diagnose this, helping find patients. And then ultimately, when new medicines are approved and available, those medicines will become available to them for their treatment.

So am I hearing you correctly, genetic testing is more practical than biopsies for something like this?

It's -- I mean, it's -- Ritu, it's Akshay. Yes, it's very easy obviously to do genetic testing nowadays either saliva or blood and one can get the sample analyzed.

Our next question comes from the line of Maury Raycroft with Jefferies.

So the RNAi webinars have been really helpful. Thanks for putting those together. So for the presentation earlier today, I was drawn to Slide 44 where you compared the annualized exposure levels of revusiran to the other programs that you have. I'm just wondering if you can comment on the relative exposure differences between patisiran and givosiran, and if this could translate to AE differences in any way?

Yes. So well, I mean, I don't have the numbers in front of me, Maury, but patisiran is given as a 0.3 mg per kg infusion once every 3 weeks, so 21 milligrams every 3 weeks. So the total exposure is under 1 gram of -- my team here is bringing up in the slide, thank you very much -- is under 1 gram compared to the 28 grams that is administered for -- was needed for revusiran. So the exposure is different. It's also a different delivery technology as well. And then if you go to molecules like givosiran where we can imagine a 2.5 mg per kg monthly regimen potentially for that product. There, we're talking about an exposure level that is a little bit higher but is under 2 grams, 2.5 grams per year. So these exposures, of course, are very, very different than what was required with revusiran, which is a first-generation GalNAc conjugate. And while we don't believe there's any evidence for a revusiran-related effect out of the ENDEAVOUR study, and we believe that we can't exclude that, of course, but we don't have any evidence for that. We do also take comfort in the fact that these other molecules in our pipeline are administered at much lower levels. And so that's always a good thing in safety to have drugs that are given at much lower exposures. Does that answer your question?

I think so, yes. I'll hop back in the queue.

Our next question comes from the line of Geoff Meacham with Barclays.

I just want to ask a couple, John, on your commercial readiness for patisiran. First, I know they're not directly comparable, but are there any lessons to be learned from the tafamidis launch? And the second, and again, I'm not sure if you want to talk through the commercial organization details just for competitive reasons, but maybe just help us with the size and scope of MSL's reps, maybe what pricing reimbursement work has been done? And obviously, you're probably going to have the benefit of having Sanofi Genzyme help out in a lot of this stuff, too.

Yes, those are great questions. Let me just say one thing for starters, which is that the beginning of lessons learned from tafamidis versus patisiran is -- have a really great, strong efficacy package and safety package. And I think it begins there. And I think that can -- that will -- and will need to be differentiating and we believe it will be differentiating. But I think beyond that, maybe Yvonne had a comment.

Maybe just to build on that as well. I think (inaudible) who's accessed a much broader range of patients, given our profile. So of course, as we know from the (inaudible) situation just approved ex U.S. and restricted to V30M Stage 1, and given the population that we're studying in our APOLLO study, we should be able to access a much broader range of patients, which I think is a very important differentiation for us.

Absolutely. And then commercially, Barry, do you want to comment a little on Geoff's questions?

Yes, sure. So it does start, Geoff, with the strength of the target product profile, the kind of patients we're enrolling and the impact we have. And we think that if APOLLO has the kind of data that we're seeing in the open label extension study, where a significant number or majority of patients have stabilized or improved in their disease, then the value proposition is considerably better than the tafamidis' value proposition, which slowed progression of the disease in some patients. And as Yvonne said was really restricted to Stage 1 patients. So the value proposition is much stronger, and therefore, the kind of pricing we should be able to achieve is more commensurate with real orphan pricing than tafamidis was able to achieve. The other 2 keys are long-term continued relationship with the key opinion leaders and the patient advocacy groups. And we've been doing that, what, for 6, 7 years now working with the disease. So those relations will pay off over time. We've done a number of pricing panels that help us understand where we're going to be able to position patisiran from a value perspective. And it's in line from a payer view, assuming positive data, with the, again, orphan pricing. So I think we're pretty well set up there to kind of to achieve the kind of results that are commensurate with what we're seeing with the open-label extension data. Did that answer your question?

It does, yes. But I just wanted to -- does the (inaudible) scripts, do you have a good sense for how much -- how many of those were written by KOLs versus those and maybe the broader community? I'm just trying to get a better sense for what you can do to help accelerate identification and things like that.

Yes, we did. So the -- probably, the best way to think about it is there are certain countries that have well-organized centers of diagnoses, a place like France, for example, where a significant number of patients are captured. There's other countries, Germany, United States, that are far less organized. One of the things that we're doing is setting up centers of excellence so that patients can be screened rapidly and diagnosed rapidly. The fact that Pfizer has been out there for a couple of years certainly helps our efforts because they have raised awareness. The biggest challenge they've had, frankly, is that because of the results, pricing hasn't been in line with orphan pricing and countries like the U.K. are not reimbursing to them. So their results resulted in kind of lack of enthusiasm in many countries.

Our next question comes from the line of Vincent Chen with Bernstein.

On the topic of payer discussions, it sounds like you probably had a range of discussions with payers around reimbursement. Could you provide us with a little bit more color on those? And in particular, how are they thinking about what the appropriate pre-authorization and re-authorization criteria might be and how might a patient's mix of neurological and cardiac symptoms figure into this or their stage of progression?

So that's a great question. Barry will answer the elements that he thinks he should from a competitive perspective. But if you can appreciate that we are in a competitive situation here. So Barry, why don't you go ahead?

Yes. So I -- I mean, to John's point, Vincent, there's not a lot that we can say in detail at this point. And again, the results of APOLLO and the impact that patisiran has in the broad range of symptoms will help guide that. But the initial conversation we're having with payers are, first of all, raising awareness that it's a devastating disease. The cost, the burden of the disease is extreme. People can't work or are out of work, can't contribute to society. In certain countries, obviously, can't pay taxes. So in the country level discussions and the U.S. payer-level discussions, there's an appreciation for the disease and really an agreement that if we're able to halt or even, in some patients, reverse the disease, then again, orphan-like pricing is in line with what they expect.

I see. Very helpful. And then a quick question on the topic of patient identification, which you alluded to a little earlier. In the last RNAi roundtable about 1 week ago, the physician expert discussed sets of criteria. I believe they were termed red flag symptom clusters, which a physician might use to assess where to suspect TTR amyloidosis and to decide whether to pursue additional testing. I remember those criteria looking fairly complicated. Is there some sense that you might be able to simplify these into a more easily remembered diagnostic scheme to help drive patient identification effort?

Well, let me turn it to Akshay Vaishnaw to comment on that from a medical perspective.

Yes. I think, from a medical perspective, the core of it is any patient with sensory or motor symptoms in the limbs, along with signs of impotence or gout symptoms or heart symptoms, particularly if there's a family history should be considered for either the genetic approach to look from mutation and/or a biopsy. And in Centers of Excellence, this is already being done. But I think as the drug becomes available and the safety and efficacy data become known and there's a viable treatment option for patients with TTR amyloidosis with a drug like patisiran, I think these standards will be adopted quickly in a more widespread fashion.

Yvonne, did you have anything to add?

No, I think actually, that was very well answered.

Good. Does that answer your question?

Yes.

Our next question comes from the line of Paul Matteis with Leerink Partners.

I had one for Akshay on APOLLO. And Akshay, I -- it struck me earlier today when you were speaking about the patisiran early data versus inotersen data, that you were pointing out for patisiran that you've shown disease symptom reversal. I was wondering if this is your base case for what you're expecting to see regarding efficacy in Phase III? And in your opinion regarding whether or not the fact that the patient population is more sick in APOLLO versus the Phase I/II could render it more challenging to show disease reversal. And then I have one quick follow-up.

Yes. I mean, I don't think I'm going to speculate on the exact efficacy findings that we're going to get from APOLLO. The one thing we obviously do feel confident about, based on our own Phase 2 open-label extension observations as well as the inotersen data is (inaudible) is validated and I think we will meet our primary endpoint. That's as much as I can say. Now as for the issue of how effective could patisiran be as a function of severity of disease, one of the interesting things we've noticed, both with our data and I think inotersen colleagues have reported the same, is that, in fact, TTR seems to be efficacious regardless of disease severity at baseline. And so I think with our greater knockdown with patisiran and with the data in hand from the Phase II open-label extension, both the regression of (inaudible) in about [30%] of patients as well as changes in regression amyloid on the biopsies and evidence of nerve regeneration. We feel optimistic, but I can't speculate as to the exact quantification of that.

I mean, we certainly -- this is John, Paul. we certainly have done the analysis out of the Phase II open-label study and have shown that regardless of baseline disease severity, that we're seeing very striking improvements in neuropathy impairment, certainly compared to the natural history. But in some cases, actual negative changes, i.e., improvement. And then I think Akshay's point on inotersen and their comments, we haven't seen a lot of data from them, of course, but their comments that the more severe patients also appreciated the benefit. And then finally, the diflunisal study results showed that even in the more advanced patients with diflunisal, that there was a treatment benefit, albeit small, which you'd expect for a stabilizer compared to a lower -- TTR-lowering agent, but it was there, and I think that gives us strong comfort around APOLLO in that dimension.

Okay. That's very helpful. And if I might just ask one quick question on a protocol dynamic for ATLAS. I'm wondering if you put any specific direction in the protocol for how physicians should be dosing bypassing agents in cases with inhibitors, and how the dosing paradigm for bypassing agents in any pair that's taken, compares to what Roche employed to their Phase III program for emicizumab.

Great, Paul. Akshay, you want to handle that?

Yes. I mean, Paul, in the context of our earlier development with patisiran, I think we learned a lot about how to, at least in the context of that experience, safely and effectively administered bypassing agents to patients that may need them during the onset period in particular. And so that generally meant you start with a lower-than-usual dose for that patient, you monitor and you see if those hemostasis is achieved, which I think we demonstrated in the Berlin meeting and other previous meetings. That in fact, the first dose is generally effective at a lower dose than the patient normally gets. And so those learnings have been converted into specific guidance in the protocol for Phase III. I think in the Roche instance, I'm only speculating here, but the word I've heard back is that in fact, there wasn't a strict guidance given on the use of rescuer agents. And so, again, as you know, people have speculated that, that may have contributed to some of the serious adverse -- some of the more serious adverse events that they saw.

I would just add. Paul, that it is reassuring that in our Phase I and Phase II experience with patisiran, that we have had more breakthrough bleed treatment events with FEIBA than the entirety of the data presented out of, HAVEN 2 -- HAVEN 1 or HAVEN 2, whichever, for emicizumab. And that's encouraging because we've seen no thromboembolic events.

And to quantify, that's about [56]. (inaudible) that have been treated with FEIBA and any untoward effects.

Yes, that's correct. Yes, that is correct.

Our next question comes from the line of Alethia Young with Crédit Suisse.

This is Ellie on for Alethia. So in terms of APOLLO, what data are you looking for in the cardiac subset population, specifically, what do you think would be good or fillable data in the subset in your view? And is there any color you can give us on what the regulators might be looking for in the subset? Like if they have mentioned any specific endpoint they are focused on such as proBNP or wall thickness or if they're just looking for sort of the overall profile showing stabilization?

Akshay, that's your question.

Yes. Just from the outset, I would say all data are fillable. I mean we are obliged, in fact, to file all data. So all cardiac data in addition to neuropathy and every other last data point will be filed. Now, as for the question of what regulators are looking for and what makes into the label, I think from their perspective, the important things are they look at the nature of the patient population, what's been studied, how valid and robust the data are. And so in that regard, I think the biomarker data that we provide were increasing those interest in using BNP and troponin just to stratify patients and prognosticate on where patients are going to end up will be useful and important. The echo data, particularly LV strain will be very important. And so those are just some of the elements of what I'd point to that they'll look at. Ultimately, it will depend on their judgment of how robust the outcomes post data are versus placebo. And they want to help prescribers and guide them appropriately to the use of the agent. And so I think if the data are sufficiently robust and encouraging, they would include them in the label.

Our next question comes from the line of Anupam Rama with JPMorgan.

Maybe I could just clarify the timing of APOLLO here. I think as of recent conferences as well as last week on the roundtable, you guys were talking about a mid- to late-September time frame for APOLLO. Does coming weeks mean that it could be like right after the holiday or even earlier? And what are the factors that might shift the time lines up or out in either direction?

Thanks, Anupam. No, we -- it is mid- to late-September, which is what we expect. The last few patients are now entering their last dose. And then once we lock the database and analyze the results, we will share the data with you as rapidly as we can. But it's going to be mid- to late-September, that's the expected time line.

Our next question comes from the line of Ted Tenthoff with Piper Jaffray.

And I apologize if this question has been asked, I've been having telephonic issues. But I wanted to ask sort of at a higher level what preparation you're starting to make for success around APOLLO on the commercial side? I know that you were talking about some of the payer discussions and things like that, but in terms specialty pharma, a sales force, medical liaisons, maybe you can update us on where you are in that process.

Yes. Absolutely, Ted. And we touched on some of this, but you're asking a slightly different question here, so it's a useful question for us to answer. Barry, do you want to take it?

Yes, I'll touch -- I mean, what we said on the call, Ted, is we encourage everybody to listen to the patisiran roundtable, where we went through this in a lot more detail, but I'll touch upon it quickly. We're built out now in the United States and the major markets in Europe with leadership. We've got medical mostly in place. We have our supply chain in place, and we're really positioned post-APOLLO, really, to file the NDA and MAA and then we'll be positioned next year to launch the drug with a built out commercial force, medical force and supply chain in place, including the payer and reimbursement. So we're in pretty good shape after APOLLO.

And a lot of the -- a lot of I'll just add to that, Ted, we built out our European organization. We have our headquarters. We've got country managers in the key markets. We have access leadership in those markets locally. We've obviously done the same in the U.S. as well. And we're out there in force and getting ready to be there with this very, very important product.

And how much do the patient groups help here in terms of sort of rallying and educating patients? I have to imagine this is a pretty motivated patient group.

Yes. The answer is a lot. Barry, you want to comment any further on that?

Yes, the answer is a lot and it depends on countries. There are certain countries like the United States and France where there's sophisticated patient groups, and other countries where the patient groups are just starting to form. And keep in mind, Ted, that like many orphan diseases, the course of the disease, the patient population is just getting known and just getting educated. So many countries are frankly forming stronger and stronger patient advocacy. The voice of the patient certainly will matter here in a big way.

Our next question comes from the line of Christopher James with Ladenburg.

I guess assuming positive data from patisiran, maybe can I piggyback on Meacham's question. How should we think about pricing? And this is pricing sort of relative to perhaps Alexion's Soliris in your pricing surveys?

All right. So thanks, C.J. I mean, it's a great question. Obviously, we're -- it's too soon to give you the answer you'd like to have on that and it's also something which is in the competitive landscape here, so we're going to be a little bit careful. But I think Barry's point is the right one. We -- if patisiran demonstrates the type of value that we have seen in the Phase II open-label study, then this is a medicine that is going to provide enormous benefit for patients, first and foremost. It's in an orphan setting and it's going to be priced consistent with orphan medicines that have high impact in an orphan setting. And I think that's where we should leave it at this point in time. Obviously, it's very, very data-driven, no doubt about it, and it's going to be something we spend a lot of time on in the back half of this year, early next year, to get it right. But I think very importantly, we're having conversations with payers. We're having conversations, both government and private payers. We're learning quite a bit about the landscape, and we certainly have put together an overall value dossier that we think supports the value proposition for the medicine if it hits its key efficacy and safety criteria. So we're optimistic that we can support an appropriately valued product.

Got it. And then maybe lastly, can you maybe walk us through, the -- assuming positive data, steps through speaking to the FDA, filing? And do you expect an FDA panel?

Yes. Akshay, you want to comment on that?

Yes, I think it would be conservative to assume that for a first-in-class agent in a disease like this, there would be an Advisory Committee, yes.

And it's possible, C.J., that because there are 2 agents in the field, that both agents might be discussed at the same Advisory Panel.

Our next question comes from the line of Mike King with JMP Securities.

Just 2 real brief ones. Just sticking with the theme of market preparation and patient -- physician outreach. I noticed you guys opened a couple of websites recently to facilitate communication with both audiences. I'm just wondering if you would be willing to give us any kind of qualitative information about how many hits or how popular those websites have become? Have you gotten any feedback or new contacts from the sites at all?

It's a great question. These have been recently put together, so I'm not sure we have a lot of real data. Anything to add, Barry?

Yes, Mike. What I can say, Mike, is what you've noticed is that unbranded disease awareness aimed towards health care providers was launched months ago. And very recently, you've seen this on social media and others, patient education, again unbranded, has been launched. And I think it's fair to say it's been very well-received. And as John said earlier, we are absolutely seen as the leaders in trying to educate the market to look for this disease in patients that they might not have figured it out. So it's being very well-received. And we'll -- time will tell, but we think that will lead to shortening the patient journey and finding patients more rapidly.

Okay, great. Can I just ask you a quick question on SC02?

Yes.

I asked basically a similar question last quarter. I just wonder if sort of the revusiran analysis and your progress with patisiran has changed your view of what your course -- future course for SC02 might be. Is it still your thought that you may get approved on TTR reduction? Or do you think you may have to do -- you have a clinical endpoint for approval?

Yes, it's a topic of active discussion internally, Mike. I think that 2 things, really. One is we're very, very impressed with the data around TTRsc02. I mean, it's stunning if you look at the updated data that we've presented for the first time last week to look at that level of knockdown with the very, very small doses that are administered. I mean, it is clearly supportive of quarterly, if not semiannual dose regimens. And it's very, very encouraging. Safety looks very good. And so we're very impressed with that. And we're very committed to developing it as a best-in-class med across the whole spectrum of ATTR amyloidosis, ranging from patients that have polyneuropathy, patients that have cardiomyopathy and even the wild-type setting over time. And the initial studies will be focused on really introducing this agent relatively quickly -- as quickly as we can to the market so that patients can have an option of patisiran or a subcu option that can be given as infrequently as once a quarter or twice a year. And so that is going to be a focus of ours. Exactly what endpoints we use in the studies and how we do the studies is still an active topic of internal discussion and will soon be a topic of discussion with the regulators as well. But we -- we're very confident there is a very attractive path forward for the drug and we remain very bullish around the prospects for it based on the data that we've got right now.

And I now would like to turn the call back to the company for closing comments.

All right. Well, look, thanks everyone for joining us this afternoon. For those of you that joined us earlier and today, thanks for your commitment to Alnylam during the course of the afternoon.

As I said earlier, 2017 is really a pivotal year for our company transitioning towards commercial space. We could not be more excited about all that, and we look forward to speaking to you in the coming weeks to come. Thanks very much. Bye-bye.

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