Alnylam Pharmaceuticals Inc (ALNY) 2017 Q1 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Alnylam Pharmaceuticals Conference Call to discuss First Quarter 2017 Financial Results. (Operator Instructions) Please be advised that this call is being taped at the company's request.

I would now like turn the call over to the company.

Good morning. I'm Christine Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, Chief Financial Officer; Barry Greene, President; Akshay Vaishnaw, Executive Vice President of R&D; and Mike Mason, Vice President of Finance and Treasurer. In addition, Yvonne Greenstreet, Executive Vice President, Chief Operating Officer is in the room and available for Q&A.

For those of you participating in the conference call, the slides made available via webcast can also be accessed by going to the Investor page of our website, www.alnylam.com.

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

Before I 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 our 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 annual report on file with the SEC.

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any 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 morning.

During the first quarter of 2017 in recent period, we made important progress in advancing RNAi therapeutics through clinical trials and toward the market. With 2017 promising to be a key year for our company as we read out results of our Phase III study of patisiran and, if positive, file our first applications for regulatory approvals, advance 3 additional programs at the Phase III trials and prepare to make the anticipated transition to a commercial stage company.

We believe these key events put us well on track to meeting our Alnylam 2020 goals of becoming a multiproduct commercial stage company with a deep and sustainable development pipeline by the end of 2020.

In my introductory remarks, I'd like to provide some further context on these key 2017 events. First, starting with patisiran, an investigational RNAi therapeutic for the treatment of patients with polyneuropathy due to hereditary ATTR amyloidosis, we look forward to reporting top line data from the APOLLO Phase III trial in mid-2017, likely in the September time frame and, assuming positive results, expect to submit an NDA and MAA at year-end.

We are encouraged about APOLLO based on the continued promising results from our ongoing Phase II open-label extension, or OLE, study of patisiran where we've seen consistent evidence for potential halting or improvement of neuropathy progression in patients with hATTR.

Now, as many of you are aware, we expect that IONIS will very soon report their top line results from their Phase III neuro TTR study of IONIS-TTRRx, an antisense program in hATTR. While we do expect the study to be generally positive, confirming the TTR-lowering hypothesis, there is certainly a chance for mixed or even false-negative results based on their smallest sample size, shorter study duration, use of a co-primary endpoint structure that includes quality of life, potentially higher discontinuation rates due to adverse events or other factors and slower, less robust TTR-lowering effect, amongst other possibilities. Accordingly, a potentially mixed or negative IONIS study outcome needs to be viewed in the context of their drug and their study, not ours.

The second area of major focus for Alnylam in 2017 is the expected advancement of 3 additional programs into Phase III, including fitusiran for hemophilia, givosiran for porphyria and with our partners at The Medicines Company, inclisiran for hypercholesterolemia.

Strategically, this positions Alnylam to have a steady flow of Phase III readouts and, if positive, commercial launches on potentially an annual basis going forward starting in 2018. With fitusiran, we're completing our alignment with regulators on the ATLAS Phase III program, and we fully expect to initiate the Phase III program by the end of Q2 in line with our guidance.

With givosiran, our recent prime designation with EMA has opened the door for discussions on the potential for a more accelerated path for this program in porphyria, while our guidance remains with the start of Phase III in late 2017.

Finally, with inclisiran, our partners at The Medicines Company have completed their discussions with the FDA confirming an LDL lowering Phase III trial as a foundation to support an NDA filing. And MedCo has updated their guidance to now report Phase III data in 2019.

In the coming quarter, we'll also be sharing new data for both fitusiran and givosiran. And we are very excited for what we believe to be the transformative potential of these investigational medicines.

It should go without saying that putting 3 highly-innovative medicines at the Phase III trials in any given year is a level of productivity rarely achieved in even established major global pharma companies, let alone in an emerging biopharma company like Alnylam.

The third area of major focus for Alnylam in 2017 is the buildup of our quality medical affairs, manufacturing and commercial teams and capabilities in North America and Western Europe in anticipation of our potential 2018 launch of patisiran and future product launches. I want to have Barry update you on those activities at the end of this call, but rest assured that we're building an amazing team with world-class capabilities.

Now before I turn the call over to Akshay to review our pipeline progress, I do want to briefly update you on the conduct of our revusiran investigation. As a reminder, revusiran was an investigational RNAi therapeutic that was in development for the treatment of patients with cardiomyopathy due to hATTR amyloidosis, a program that we discontinued in the fourth quarter of 2016 due to an imbalance in mortality events in the -- observed in the endeavor Phase III trial. We are on track to conclude and report the findings of this investigation this coming summer. And we expect to include this report as part of our RNAi Roundtable Webinar series. We will share the date for this event as well as the rest of our roundtable events in the coming weeks.

When we report our results, I think you'll be reassured by the thoroughness of our investigation and our transparency. We also intend to publish these findings in a peer-reviewed journal article.

In the meanwhile and based on current status of this investigation, we continue to remain confident that the revusiran findings have no read-through to the rest of our platform.

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

Thanks, John, and good morning, everyone. As John noted, we are very focused on the advancement of our pipeline of investigational RNAi therapeutics and, in particular, our late-stage programs.

Let's begin with our programs in hATTR amyloidosis, which includes patisiran and ALN-TTRsc02. This is certainly a big year for patisiran with our Phase III APOLLO study read-out later this year in the September time frame. As John commented, we believe we have good reasons to be encouraged by the prospects of patisiran based on our Phase II early results.

At the AAN meeting last week, we presented final results from the patisiran Phase II early study. At 24 months, patisiran showed a mean decrease in the modified Neuropathy Impairment Score, or mNIS+7, of 7 points, providing continued evidence that patisiran has the potential to halt or improve neuropathy progression in patients with hATTR amyloidosis.

This compares favorably to an expected mean 26 to 30-point increase in mNIS+7 at 24 months estimated from analyses of historical data sets in untreated hATTR amyloidosis patients with similar baseline neuropathy impairment.

At this meeting, we also present a results of a new post-hoc analysis, exploring the relationship between baseline neuropathy severity and change in mNIS+7. In this analysis, patients were grouped into tertiles, according to their baseline NIS scores, as shown on Slide 9. Patients in all 3 groups showed a mean improvement in mNIS+7, including patients with the greatest degree of neurologic impairment at baseline; specifically, patisiran administration was associated with a mean 7.4 point decrease in mNIS+7 in this group with the greatest impairment at baseline.

This analysis suggests that the potential clinical effects of patisiran observed across the full range of disease severity.

Moreover, 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 analyses of skin biopsy samples from the distal thigh and distal leg. This decrease in mean dermal amyloid content is consistent with the statistically significant mean increase in sweat gland nerve fiber density observed in exploratory analyses of the same skin biopsy samples over 24 months.

Taken together, these exploratory analyses support the therapeutic hypothesis that reduction of mutant and wild-type TTR can potentially lead to a reduction of TTR amyloid deposition and increased nerve generation.

Turning to safety. Patisiran administration was found to be generally well-tolerated in patients with hATTR amyloidosis after 25 months with no decrease -- and with no drug-related serious adverse events reported. Drug related or possibly drug-related adverse events occurring 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 are 10 reports of assays 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 tests, hematologic parameters including platelets. Patients who completed dosing in the Phase II early study have rolled into the global APOLLO-OLE study. We plan to report initial first 6 months base from those patients in late 2017.

As of today, we are pleased that more than 20 patients have now completed 3 years of dosing. Of course, in the meanwhile, we continue dosing patients in the APOLLO Phase III trial. It continues to be pleased with the ongoing conduct of the study and the low discontinuation rate as we now approach our last patient, last visit milestone this summer.

The study remains blinded, but we're certainly encouraged, from an overall safety perspective, by the periodic oversight of unblinded safety data by the study's Data Monitoring Committee. We're also encouraged by the very high percentage of patients who've elected to enter the APOLLO early study after completing 18 months of dosing in APOLLO.

By all accounts, we certainly look forward to seeing the APOLLO's study results later this year.

Let's now turn to our fitusiran program for the treatment of hemophilia and rare bleeding disorders, where we've continued to make great progress. Fitusiran is an investigational RNAi therapeutic targeting antithrombin, or AT, and is designed to increase thrombin generation and, thus, provide hemostasis in people with hemophilia. We believe that fitusiran could address the unmet needs in both hemophilia A and B with the potential to provide consistent and durable hemostatic protection for all patients and potentially 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. At the recent EHA meeting in Paris, we presented new results from an exploratory analysis of fitusiran Phase I study. In this analysis, we looked at 21 total bleed events in 41 hemophilia A and B patients treated with fitusiran after great -- greater than 75% antithrombin lowering was achieved. Treatment of all breakthrough bleed events with replacement -- in fact, that all bypassing agent resulted in successful hemostasis without any thromboembolic events.

In addition, we presented results from stability studies of fitusiran, which supported greater than 2 years' shelf life at room temperature storage conditions. This stability profile could potentially facilitate treatment in regions where cold chain storage requirements represent a challenge to patient access. We believe these later stage sets are promising for fitusiran's potential as a treatment option for hemophilia patients with and without inhibitors. Moreover, these fitusiran results continue to highlight what we believe to be a very competitive profile for this innovative investigational medicine.

We're excited to announce today that we'll report additional data from the fitusiran Phase II early study in an oral presentation on July 10 at the ISTH Meeting in Berlin. About 30 hemophilia A and B patients with or without inhibitors continue to receive fitusiran in the Phase II early study with the most advanced patient out to 2 years of treatment and with more than 15 patients at over 1 year of dosing.

We're now transitioning fitusiran into a comprehensive Phase III program called ATLAS. As shown on Slide 30, the ATLAS program is expected to include 3 separate Phase III trials running essentially in parallel towards the goal of obtaining broad-based approval for fitusiran in hemophilia A or B patients with or without inhibitors. We're now finalizing alignment with regulatory authorities on the pivotal study designs and expect to start ATLAS by the end of Q2, consistent with our earlier guidance.

Let me now turn to recent progress with givosiran, which we are developing for the treatment of acute hepatic porphyrias. The porphyrias are a group of ultra-rare orphan disease caused by genetic defects in the heme biosynthetic pathway in the liver. These are rare, devastating diseases with enormous burden. In porphyria, buildup of toxic heme intermedius leads to incapacitate and potentially fatal attacks with symptoms that include severe abdominal pains, peripheral and autonomic neuropathy and neuropsychiatric manifestations.

Porphyria attacks typically last for days and require hospitalization. At the beginning of March, the FDA hosted a patient-focused drug development meeting on acute porphyria, where we were able to hear from patients living with this devastating disease. Patients described the pain during an attack as incompatible with life. And the majority of patients reported chronic pain even in between their attacks. Currently, the only available treatment for acute attacks is hemin, a preparation of heme derived from human blood administered by a central intravenous line. Hemin is associated with a number of complications, including chronic phlebitis or coagulation abnormalities. There are no approved therapeutics for prophylactic use, although Hemin is sometimes used in this manner in patients who experience recurrent attacks.

Chronic administration of Hemin may result in renal insufficiency, iron overload, which can, in turn, lead to liver cancer, systemic infections secondary to central venous access and in some instances tachyphylaxis, underscoring the high unmet need in this disease.

Givosiran targets the liver expressed ALAS1 gene, which is an enzyme upstream for genetic defects in the acute hepatic porphyrias and the enzyme responsible for the overproduction of ALA and PPG, the toxic heme synthetic intermedius that mediate porphyria attacks.

Our therapeutic hypothesis is that silencing ALAS1 with givosiran will lower levels of ALA and PPG, thereby reducing the number, frequency and severity of porphyria attacks in patients.

As a once monthly or potentially once quarterly subcutaneous investigation RNAi therapeutic treatment to prevent debilitating porphyria attacks, givosiran could be a transformative therapy for patients with this high unmet need disease. Recently we were pleased that the European Medicines Agency, or EMA, granted givosiran a prime designation. The purpose of the prime program is to bring treatments to patients faster by enhancing the EMA support for the development of medicines for diseases where there is an unmet medical need and where early clinical data show potential to benefit patients. Through the prime program, Alnylam will have enhanced scientific and regulatory support from EMA, including its advice on optimization for the development pathway, the potential for accelerated assessment of the MAA. Our plan is to now complete dosing of several additional cohorts for acute porphyria patients. As we announced in our press release this morning, we expect to present the next tranche of data on June 26 at the International Congress on Porphyrins and Porphyrias, or ICPP, meeting in Bordeaux, France.

Let's now turn to inclisiran, an investigational RNAi therapeutic targeting PCSK9 that's being developed in collaboration with our partners at The Medicines Company. At the American College of Cardiology Meeting in mid-March, positive final results represented from the ORION-1 Phase II trial of inclisiran, specifically as illustrated on Slide 16, reported significant and sustained reductions in LDL of over 50% that was sustained for 6 months, supportive of a once quarterly or biannual dosing regimen for further development.

Importantly, the material safety issues were observed and the overall incidence of adverse events for inclisiran were similar to placebo. Specifically, there were no investigational drug-related elevations of liver enzymes in a neuropathy, changes in renal function from cytopenia or anti-drug antibodies. The overall incidence of treatment emergent adverse events was 76% in both patients randomized placebo and patients randomized to inclisiran with no significant difference between inclisiran-dosed groups.

Injection site reactions associated with inclisiran were infrequent mild to moderate and transient. As a testament to the importance of the overall findings of these results, we're concurrently published in the New England Journal of Medicine.

Recently, The Medicines Company announced the conclusion of its meeting with the FDA regarding the go-forward clinical path for inclisiran. The FDA has confirmed that an initial approval for inclisiran could be supported by 3,000-patient randomized, double-blind, placebo-controlled study with LDL lowering as the primary endpoint followed by confirmatory cardiovascular outcome study. This initial Phase III study in atherosclerotic cardiovascular disease, or ASCVD, patients is expected to start in mid-2017 with a readout in 2019.

Finally, we'll also continue to advance a number of earlier-stage programs, including ALN-CC5 for complement-mediated diseases, ALN-GO1 for primary hyperoxaluria and ALN-HBV for hep type B infection. An important milestone in this basket of programs was the initiation of patient dosing for our GO1 program where we are now looking to see this investigational RNAi therapeutic can reduce levels of urine oxalate that's responsible for the underlying renal pathology. Notably, this is our first and the industry's first RNAi program where we're enrolling pediatric patients. And we certainly aim to make a difference in the lives of young children living with this very serious condition.

And with that, I'll now turn the call over to Mike for a review of financials. Mike?

Thanks, Akshay. I will be referring to Slide 19 for a discussion of our first quarter 2017 financial results. We maintained a solid balance sheet and in the first quarter of 2017 with $962.2 million in cash, including restricted, in essence.

Our GAAP revenues were $19 million in the first quarter of 2017 as compared to $7.3 million in the first quarter of 2016. Revenues for the first quarter of 2017 included $12.3 million from our alliance with Sanofi Genzyme, $6.4 million from our alliance with The Medicines Company and $0.3 million from other sources. The increase in revenues in the quarter ended March 31, 2017, as compared to the prior-year period was due primarily to a higher revenue from our alliance with Sanofi Genzyme.

We expect net revenues from collaborators to continue to increase on a quarterly basis during the remainder of 2017, due primarily to an expected growth in revenues from Sanofi-Genzyme related to increased expense reimbursement as well as the potential receipt of milestone payments under our agreements with Sanofi Genzyme and The Medicines Company.

Moving to expenses. R&D expenses were $87 million in the first quarter of 2017 as compared to $96.3 million in the first quarter of 2016. The decrease in R&D expenses for the quarter ended March 31, 2017, as compared to the prior-year period was due, in part, to a decrease in noncash, stock-based compensation expense as a result of divesting of certain performance-based stock option awards during the first quarter of 2016 upon completion of enrollment in our APOLLO Phase III clinical trial for patisiran.

We expect that R&D expenses will remain relatively consistent with the first quarter during the remainder of 2017 as we continue to develop our pipeline and advance our product candidates into later-stage development but expect that certain expenses will be variable, depending on the timing of manufacturing batches, clinical trial enrollment and results, regulatory review of our product candidates and programs and noncash, stock-based compensation expenses due to the potential vesting of performance-based awards.

G&A expenses were $38.5 million in the first quarter of 2017 as compared to $21.1 million in the first quarter of 2016. The increase in G&A expenses for the quarter ended March 31, 2017, as compared to the prior-year period was due primarily to an increase in headcount to support corporate growth and to prepare for the potential launch of our first commercial product. We expect that G&A expenses will increase on a quarterly basis during the remainder of 2017 as we continue to grow our operations, including the anticipated build-out of our commercial infrastructure, but expect that noncash, stock-based compensation expenses will be variable due to the potential vesting of performance-based awards. The GAAP net loss was $107.3 million as compared to a net loss of $103 million for the same period in the previous year.

With respect to guidance for 2017, we remain on track to end 2017 with greater than $700 million in cash, including $150 million in restricted investments. We believe this provides Alnylam with a very strong balance sheet at the end of 2017 to support development in commercial activities in 2018 and beyond.

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

Thanks, Mike. As you heard from John earlier, we are executing on our late-stage pipeline in 2017 to achieve our Alnylam 2020 profile, marking our transition from a late-stage R&D company to a multiproduct commercial organization and achieving a profile rarely seen in the biopharmaceutical industry.

A critical part of this transition is the expansion of our quality, medical affairs, manufacturing and commercial capabilities to support multiple planned consecutive product launches in 2018, 2019 and 2020. These efforts include building our capabilities in the United States, Canada and Western Europe for patisiran and fitusiran and then growing globally with givosiran and future products, assuming positive readouts and regulatory approvals.

Let me highlight a few activities as part of this important build. First, we to continue to build our quality organization in support of our overall GXP activities in preparation for preapproval inspection and, of course, to ensure a high-quality, compliant organization.

Additionally, we now have an active medical affairs effort in North America and Western Europe where our team is working on educating physicians and patient organizations on several things, including the RNAi mechanism of action, on hereditary ATTR diagnosis, on the critical importance of thrombin generation in hemophilia and other rare bleeding disorders as well as the enormous burden of disease in the acute hepatic porphyrias.

In our technical operations and manufacturing team, we've secured our network of contract manufacturing organizations and have completed validation of drug substance and drug product processes in batches in support of potential patisiran NDA and MAA submissions at year-end. We've also been preparing for preapproval inspections.

We also continue to build-out our Norton, Massachusetts drug substance manufacturing facility for future drug supply. Finally, we're building out our commercial teams in North America and Western Europe with a key focus initially on patient access and our product value dossiers to secure rapid and strong reimbursement for patisiran and future products. In Western Europe, we're completing recruitment of the country general managers for all the major markets and will soon announce ahead of our European and Canadian business.

Across our quality, medical affairs, technical operations, manufacturing and commercial activities, we are building the Alnylam for tomorrow, which will fulfill our mission of bringing innovative medicines to patients in need.

Importantly, you can expect Alnylam to be as innovative as a commercial stage company as we've been as an R&D company. And as someone who's been involved with many successful commercial launches and products, I couldn't be more excited by what we can and will do in coming years.

With that, let's now turn to Slide 22 for a review of our 2017 goals and guidance on upcoming data presentations. With our patisiran program, we continued dosing patients in our APOLLO Phase III study and look forward to reporting top line data from the study in mid-2017 with more complete data in late 2017. Assuming positive results, we expect APOLLO will enable possible NDA and MAA filings at year-end, putting us in a position, assuming regulatory approval, to launch our first commercial product next year in 2017 -- 2018.

With fitusiran, we expect to initiate the ATLAS Phase III program by the end of Q2 in line with our guidance. We also plan to present additional data from the Phase II OLE study of fitusiran at the ISTH Meeting on July 10 and then again in late 2017.

Now turning to givosiran. We look forward to presenting additional data from Part C of the Phase I trial in recurrent porphyria attack patients in mid-2017 at the ICPP Meeting in late June. We plan to rapidly advance this program into a Phase III trial, which we expect to start later this year.

Regarding inclisiran, our partners of The Medicines Company are planning to initiate a Phase III study in patients with ASCVD in mid-2017. We also expect to advance additional programs from our early and mid-stage program and to report additional clinical data from these programs throughout the year.

Finally, as Mike said, we expect to end 2017 with greater than $700 million in cash, including $150 million in restricted investments, a balance sheet that will sustain us in the future.

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) And our first question comes from Ritu Baral from Cowen & Company.

Barry, I wanted to dig in a little more on the CMC, specifically based on your slide and the comment. It looks like Alewife is going to be primarily responsible for patisiran drug supply. Can you take us through who's responsible for fill-in finish? Maybe where you are on stability testing and where -- whether you're planning on redundant supply or just having enough inventory to address any potential issues in market supply?

That's a great question. Barry, take it away.

Several questions there. So let me start with patisiran and just say this: We've secured the supply chain throughout raw materials, drug substance and drug product as well as fill finish. Across that supply chain, there are multiple redundant sites. Specifically for drug substance, we have, as we mentioned, fulfilled our validation batches with a third-party manufacturer and we're building inventory as the strategy for launch readiness. As you mentioned, Alewife here in Cambridge will be our bulk drug product supply. And again, our strategy is to build inventory for launch. And then we have multiple fill finish sites on line for both U.S. and Europe. So we feel pretty good about patisiran. The initial strategy will mainly be security build. And then over the course of launch, we will have redundant system set up as well.

And there's also a question on stability, Barry. You want to highlight that?

Yes, stability. So we have -- in patisiran, we run multiple stability lots. And we have stability out over 2 years that will require a cold chain storage delivery.

Got it. And you mentioned inspections. Can you tell us which of the facilities still need inspections or which of them are JMP certified at this point?

Yes. So the CMOs we're working with have had preapproval inspections for other products. As you're probably aware, as we get closer to a positive APOLLO and filing, that's when the preapproval inspections mainly happen. And really, it's up to the agencies for where along the supply chain they want to inspect, both on CMOs and our sites as well. But we are prepared across the sites and across the supply chain for those inspections.

And our next question comes from Alan Carr from Needham & Company.

Whenever you talk about the TTR program here, with -- if the patisiran trial retail positive, where does TTRscO2 stand? And how quickly do you think you can move that forward with patisiran?

And then the other question is with respect to your commercial build. What's your thoughts on timing for sales force and that sort of thing?

Terrific. Why don't we have Akshay answer the first question and Barry the second. So Akshay?

Yes. So with respect to TTRscO2, as you know, we've presented very exciting Phase I data showing greater than 80%, 90% knockdown with durability up 6 months from a single injection. And we were excited to move that forward as soon as APOLLO reads out. I think that leads to rapid engagement with the regulatory agencies. And depending on the exact nature of the data from APOLLO, I think we can negotiate a variety of approaches to seeking approval for TTRsc02. So provided the data robust and the primary endpoints met and we can show relationships between TTR knockdown and the clinical outcomes, I think we can have a conversation about further developing TTRsc02 and approval based on TTR knockdown and safety. We could also have conversations about single-arm studies and compare the historical controls. That will be difficult to do a comparative study at that point. So there are a number of approaches we're working through. And, certainly, the details of how APOLLO reads out and the content of that data set will be very important in the discussions.

All right. Barry, on the commercial question?

Yes. So as you -- we talked about on the call, we have been steadily building out all the capability required to go-to-market, including medical affairs and commercial. So we've got medical affairs folks deployed in U.S. and in Europe to help the education of hereditary ATTR amyloidosis and really initiate the patient-finding activities. As I mentioned on the call, we are targeting general managers in the major markets in Europe. And that's a little bit different for patisiran than it might be for other products because of the uniqueness of where patients are found. For example, Spain, Portugal, Siberia, Sweden as well as in Germany, U.K. France. And those general managers are in place. And as I mentioned in the call, we'll be heading -- we'll be highlighting the head of our European-Canadian organization as well. Post APOLLO, we'll be building out other countries throughout Western Europe and Canada. In the United States, again, we're well on our way for patient-finding diagnosis and access as well. We think that the timing works well for post APOLLO to really then be bringing on the in-the-field force account management types and we're preparing to do that post a positive APOLLO.

What's the scale of the sales force that you're thinking of in the U.S?

Well, we're not -- you can imagine -- so for competitive reasons, we're not giving detailed information on all of our field-deployed folks. But for U.S. and Western Europe, Canada, less than 100 people are required in the field across all the countries that I mentioned. And the U.S. have an effective launch and subsequent commercialization of patisiran. So it really is a very focused effort, as you often see with orphan and rare diseases.

And our next question comes from Bill (sic) Kim from BMO.

For patisiran, I thought the Phase II final data continued to look strong. But how should we think about the secondary endpoints that didn't move toward improvement, like VMI or intraepidermal nerve fiber density? And is there a natural history that would compare it -- that to?

Yes. That's a great question. I'll just comment and then Akshay can take it over. I mean, keep in mind that the study is not comparative to placebo. And so what we see -- appear to see on some of those endpoints is stability over a 2-year period, which is itself quite encouraging based on the natural history.

But, Akshay, do you want to give some further color on that?

Yes. So I think you said the main thing, that we don't have a comparator arm. And I think there aren't very good historical data sets around mBMI. And this spectrum of last ones or Stage 1, Stage 2 patients that we have in the Phase II open-label extension study. But I think given the totality of the data set where we're seeing changes -- reductions in over 70% of patients in mNIS+7, improvements in the density and now very -- I think rather interestingly and impressively reductions in amyloid burden. If we had a comparator arm, I'd be optimistic, but patisiran changes in mBMI would be superior to placebo. So we'll have to wait for APOLLO. I think the retention of 25 patients in the study in that for almost 3 years is really another sign that speaks to -- by inference, to how this drug is likely performing from a safety and efficacy viewpoint in this single-arm study. So that makes us feel optimistic about that endpoint. Vis-à-vis the nerve density work, I think we're going to be very cautious. The very fact, number one, that we're seeing increases in nerve density in an inherited neuropathy that's inexorably progressive is absolutely remarkable. And this is something that all the KOLs remark upon.

Now with the specifics of where the curves are at different time points, remember, the biopsies are taken randomly from different parts of the leg at the sequential time points. And so the amounts of nerve -- how can I put this, the exact -- the change in amyloid burden on the nerves and the exact damaged nerves varies along the length of the nerve, in the legs and the arms. So depending on where exactly the biopsy is taken at the sequential time point will profoundly alter the results. So if you, at one time point have to get a patch of nerve that was very damaged, you will see more damage if you -- another time point, you see an area that's less damaged, you'll see less evidence of nerve density loss. You've got to average the whole thing out. You've got to look at the whole population. And that's where the result, I think, looks impressive. So the fact that 1 or 2 patients may skew a particular time point is probably not relevant.

It's just worth adding on this point that these biopsy samples are all read in a masked manner by a central lab, in a lab that is world-renowned for this type of analysis. So it is something which is reassuring that we're seeing these type of effects in a blinded fashion with an objective -- what really is an objective measure of clinical activity for the drug.

As is the other relationships that we've shown before that the degree of knockdown of transthyretin is related to the changes in mNIS+7. That's also very objective. So I think all these factors together suggest there's something important happening in this study.

And our next question comes from Geoff Meacham from Barclays.

This is Evan on for Geoff. One on patisiran. When we think about where this fits in with all the novel agents in development, where do you see this sitting with gene therapy, long-acting factor? How should we be thinking about, I guess, the competitive landscape with these novel assets coming forth?

Yes. Let me take a start and then maybe Akshay or Yvonne or Barry might want to comment. This is an exciting time for hemophilia. This is an era where patients really suffering with this disease are going to see a level of innovation that they have not seen for decades. I mean, really, since the advent of recombinant DNA technology nearly 20, 30 years ago -- 30 years ago, nothing has really come forward that is close to the level of innovation that one sees these days for people living with hemophilia. So it's a very, very exciting time. There's a buzz in the patient communities when we go to meetings and also in the scientific conferences and so forth. Very exciting time.

Now when we think about the landscape of medicines that are emerging right now, when we think about the subcu drugs, which is emicizumab or ACE910 and fitusiran and then we think about the gene therapy products for heme A and for heme B, there's no doubt that all of these approaches show promise, that all of these approaches have the potential to together disrupt the age-old use of factor the way it's been used in the old days. And that, from the standpoint of a market disruption and new innovation, is a real opportunity, in our review, for these -- for all of these medicines to do very well in what is today a $10 billion market. So it's our view that obviously depending on final clinical trial results, that fitusiran is going to fit in very nicely into this landscape of emerging, changing dynamic market. And it's going to be a product that is really differentiated. It's obviously a subcu drug given once a month that is going to be effective. We believe in heme A and heme B. Of course, there's nothing in heme B like fitusiran because emicizumab or ACE910 is limited to patients with heme A. And, of course, both emicizumab and fitusiran are going to be very meaningful for patients with inhibitors and, of course, that's not around where gene therapy-type products will emerge.

I'm of the view that gene therapy is going to be important in this space. I don't think it's going to have a very rapid uptake. There's going to be a number of barriers to entry that relate to long-term safety and variability of response. But the data are, in fact, promising. And I think that gene therapy will emerge as one of the treatment options out there. So that's a long-winded answer to your question.

And let me see if any of my colleagues have anything else to add to it that I haven't quite covered. And they're shaking their heads saying no.

But does that answer your question, Evan?

No -- that does most definitely. And then one, when we get the potential IONIS data, what are some of the things that we need to watch out for so we don't have that misreading of the data and inaccurate extrapolation into the APOLLO trial?

Well, Evan, it's going to depend a little bit on how much clarity is in what IONIS says. It's sort of hard for me to prejudge what that is or is not going to be. But, look, we do expect it to be positive. We do expect them to have sufficient power with all the limitations that we discussed to still eke out a positive study. But there are -- if it's borderline like P is equal to 0.055 or something, that could reflect the fact that they're underpowered and had a shorter time line or timeframe for their primary endpoint than we did.

So I think we're all going to have to see what's disclosed by IONIS and then obviously interpret that as we will all interpret it. But we do expect it to be positive. We do know that they have had a lot of adverse event issues. And that's going to factor into their efficacy results if they have a lot of discontinuations. And so how transparent they will be on that in their top line release? We don't know at this point in time. We can only speculate on that.

Anything else to add from the team?

No, that's good.

And our next question comes from Alethia Young from Credit Suisse.

A couple sort of tied in together. One, just in your conversations with the FDA, like, is a trend enough on the Norfolk score? I know it's one of IONIS's primary endpoints. so I just want to reconcile the 2 points there. And then also when you're thinking about filing these 2 in the U.S. versus the EU, tafamidis was obviously approved in Europe and not the U.S. But are there different dynamics in thinking about regulatory filings there?

Yes. I mean, Akshay, do you want to comment? I'll just start by saying that we don't want to get into the details of our regulatory discussions for competitive reasons at this point.

But Akshay, do you want to comment further?

Yes. I think overall, Alethia, when it comes to working with the FDA and any regulator, in general, the key principle is as long as there's internal consistency within the data set, I think we can have an important dialogue of how to get a medicine approved for these high unmet need patients. So the specifics of what the Norfolk may or may not be and the trends that there is no point in discussing that, we have to look at hitting the primary and the overall internal consistency of the data set. And does it point to the drug having done something important with an adequate safety profile in this patient population? And that really is how the agency thinks about it.

With respect to the EMA, those principles are equally important there, and so we look forward to working with them with the protocol. We've thoroughly discussed with both agencies prior to initiation of Phase III. So we feel we are aligned in our approach. And we'll find out in September.

I would just add, Alethia, that you can imagine that if our study shows a very large treatment effect and is very robust, the quality of life measure is important. And, obviously, one would like to hit it, and we believe that we will hit it. But as the importance of it is different than in a study outcome, which is more muted. Maybe it's more or less of a treatment effect, less robust of a p-value, then the agency and ultimately payers looking for what's the clinical impact of that, because much more important. So that's another way to look at it, in part.

Barry, did you have --

Yes. You also asked about U.S. and Europe. The only thing I'd add is that even though tafamidis is in the market in most countries in Europe, both the agencies and the countries themselves that we've been meeting with for scientific advice recognize the unmet need that remains is very, very high.

And our next question comes from Ted Tenthoff from Piper Jaffray.

So a comment, if I may, first and then a question. And just listening to the comments today really took me back all the way to the IPO and your guys' appreciation for the sheer scale that was going to be required to take a new class of medicines to patients. So I'm pleased to see all that progress and the continued commitment to doing this the right way as you build on the commercial organization and seek the first regulatory approval.

My question is on givosiran. And I was really impressed by the preliminary data. I think this is a pretty unique opportunity for Alnylam. What still really has to be done before we start the Phase III here? Is it really just finalizing that dose, optimizing that dose? Do you feel pretty comfortable with the endpoints?

Yes. Akshay, do you want to?

Yes. Thanks, Ted. With givosiran, as you said,

the preliminary data, indeed, very encouraging and the prime designation attest to that. Key things to wrap up now is to share the data from this Phase I study with the agencies and finalize the trial design. We feel that we've got through the literature, through working with KOL and the natural history study and DISCOVERY and what we've learned from the Phase I study itself, we've got a very good handle on the primary endpoint revolving around the attack frequency. These attacks are clinically devastating and, therefore, meaningful. So no one would, I think, debate the importance of attacks. And so we are in the process of working with regulators, and we feel we're on track to start what will be hopefully a fairly straightforward placebo-controlled study comparing patients, givosiran to placebo, and determine the entire frequency. The current trial, I think, has given us great insights into the dose of frequency that we'll need to maintain our optimal suppression of attacks. And that the ICPP, towards the end of June, will share all the data with you.

Yes. Great. And then, I guess, a quick follow up there. How important is patient selection going to be in that Phase III study? I mean, the magnitude is great enough. It should play out versus placebo. But how are you thinking about patient enrollment criteria?

It's a great question. Akshay?

Enrichment, of course, it was very important when you're eliciting a signal that you want to address with an important drug like this. So we're going to enrich for patients with recurrent attacks. And we're thinking about patients with multiple attacks, probably something like 4 or more attacks per annum. We do want to finalize that with the regulators. I don't think there should be a big debate around that. But that's the obvious area to focus on and it's the highest unmet need segment.

And our next question comes from Christopher James from Ladenburg Thalmann.

I just have one question regarding the histology data at AAN last week. You might have touched upon this earlier. But, I guess, can you comment on how did the skin biopsy data, namely, the reduction in amyloid compare with the increases in nerve density data and changes in mNIS+7? Can you comment on, at least directionally or magnitude of change? And will you be including any of this in your filing?

Great question.

Yes. So Chris, the last part of your question first. We have similar types of data on nerve density and amyloid content. That will be submitted with APOLLO. We obviously don't have those data yet. That's all in process. But I think that'll be a very important part of the data set. And so that's one thing.

With respect to relationships between nerve density or neurite density and the amyloid change, again, back to something we were discussing earlier, imagine a nerve traveling the length of the leg from the thigh down into the lower leg. There'll be patchy deposition of amyloid all along the length of that nerve. And nerve density will vary along the length of that nerve. It'll be lowest distally and it will be greater proximally. Now when you do biopsies over time, you're not sampling exactly the same area over and over again. So variations can easily result within a patient. And I think the important thing is to look at the overall result. And what we're seeing, as we discussed, I think is very important. And the precedent set, I mean, it's never been shown in any of the inherited neuropathies, to my knowledge. And so we're very excited about these findings.

With the larger data set like APOLLO where hundreds of patients were involved, I think the kinds of correlations you're talking about will be much easier to analyze at the group level.

And I'll just add, Chris, that we're really impressed with the number of patients in APOLLO who have agreed to do the biopsy. It's not a mandatory requirement, as it typically isn't in the protocol. But we had pretty significant numbers of biopsy samples, actually. So that will be a meaningful part of our APOLLO review and certainly our submission to the FDA and EMA.

And our next question comes from Paul Matisse from Leerink.

Two quick questions. One on quality of life. I'm wondering, do you think 15 months or 18 months are long enough to show a benefit in quality of life for these TTR knockdown therapies?

And then second, thanks for sharing some thoughts on the revusiran analysis. Do you think that this kind of analysis is going to be important for FDA as part of the patisiran regulatory review, given that it's the first RNAi therapeutic ever to be reviewed for potential approval?

Right. Those are great questions. Akshay, do you want to handle it?

Yes. So with respect to the patisiran QOL question, what we know is there are very good relationships between changing this and changing these QOL parameters. We've shared those data previously. And that's really very, very encouraging. And I think the kinds of changes in this that we're seeing in the context of this Phase II open-label extension study, if we have changes of that type or greater, we can be optimistic that there should be notable changes in the Norfolk score in the APOLLO study. So certainly, with the sample size of 225 followed out to 18 months and changes of this magnitude based upon the kind of TTR knockdown that we have, we feel like we're in a good place and we're optimistic. Now if you have a smaller sample size, if your TTR knockdown is not as great, if there's been greater discontinuation rate from the study, we don't know. And so it's hard to speak to other circumstances. But certainly, in our context, I think we're feeling optimistic.

With respect to your question on revusiran, I think, first and foremost, the agency literally uses this phrase with all sponsors when drugs are being discussed. It's a case-by-case basis. So in the first setting, patisiran will be evaluated in and of itself and that will be first line of practice. Now within that context, certainly, cardiac safety will be brought in mind by (inaudible) by then. And I think what we see, in terms of cardiac safety with respect to the Phase II open-label extension study looks quite encouraging. If you look at the overall study, the cardiac parameters have been stable. We haven't had any cardiac morbidity and mortality of note. And so we think as the cardiac issue is examined, we're hoping APOLLO II will provide a favorable outlook as the Phase II study is done. Ultimately, it will be a matter of review. And if they have questions about revusiran, we'd be happy to share our data as we have been doing, as the investigation's been ongoing. And we're going to bring all the data out in the summer anyway, as John commented earlier. So that's how we think about it currently.

And I'll just add that we've had good discussions with the FDA already on the revusiran investigation, and we'll update them yet further. So they're aware and, I think, pleased with the thoroughness and the type of work that we're doing on that matter. And so that's something, which we'll certainly engage with them before we go publicly. But we've already had engagement with them on that in a very thorough and definitive manner.

And our last question comes from Madhu Kumar from Chardan.

First one is, thinking about the hemophilia stage, particularly ACE910 from Roche and the data we're going to be getting at ISTH from the HAVEN 1 trial, what do you understand to be an unacceptable safety profile for a hemophilia drug in the inhibitor population? And then thinking about the Phase III studies in TTR polyneuropathy, your's and IONIS', what do you guys think is a reasonable discontinuation rate? Is it what's been seen in the Phase II open-label extension for patisiran? Or something greater, considering the presence of a placebo arm?

Those are two great questions. Let me do the first one and then maybe, Akshay, you take the second. The -- in terms of the emicizumab data that will be presented at ISTH -- we all look forward to seeing it -- Roche has top line, that it is a positive study and that doesn't surprise any of us. Of course, there have been 5 thromboembolic events of note to date, one which was sadly fatal. And, obviously, we'll get more color, I'm sure, on those events and the overall safety profile as well as the effectiveness profile of emicizumab at ISTH. So I think it would be premature for us to comment on what's a minimal profile. Obviously, it needs to have a competitive hemostatic profile of reducing ABR. I think that we can expect that to be the case. And, of course, the safety profile beyond these 5 known thromboembolic events needs to continue to look -- needs to look good, because certainly in the noninhibitor population, that's going to be an important factor. Obviously, in the inhibitor population, there's a very high unmet need. And even the current profile that's emerging from emicizumab is likely to be used, at least in some patients. Now I think their uptake of that product is going to be partly influenced by what's happened to date, and let's see if that holds just with those 5 events. So we'll have to see, might be a little bit too premature to speculate, I think, at this point.

And then the second question, Akshay, on the patisiran?

On the patisiran -- sorry, i just -- the discontinuation rate, that's right. We've had excellent retention, as you commented in the Phase II open-label extension study. I can say that retention in the Phase III study has also been excellent, without getting into the specifics of the numbers. And we were powered to drop our rate well in excess of what has been seen. And given that the study is approaching its last patient, last visit, something I think we'd very good about maintaining adequate power per the original hypothesis when the study was designed. So I think that's as much as I can say. As far as any competitor trial, you'd have to speak to them. But I think we're going to be in good shape from that perspective.

I'll just add, Madhu, that we have also been pleased with the very high number of patients that have transitioned from APOLLO into the APOLLO open-label study, which is also a good sign of retention and patient interest to stay on top of -- in the therapy. And, as you may know, we've recently opened up an expanded access program to make patisiran available. And there's very strong interest in that program by patients that weren't able to enter into the clinical studies. And that just highlights the unmet need and also the experience -- the favorable experience we've had to date with patisiran from a safety perspective and also based on the Phase II open-label data from an efficacy perspective as well. So that's encouraging.

And at this time, I'm showing no further questions.

Great. Well, thank you, everyone, for joining us this morning. As I said at the beginning, 2017 is a pivotal year for Alnylam transition toward a commercial stage company, which is very exciting. And we look forward to updating you on our progress in the months to come. Thank you.

Ladies and gentlemen, thank you for your participation in today's conference. This concludes the program. You may now disconnect. Everyone, have a great weekend.