Christine Regan Lindenboom - Alnylam Pharmaceuticals, Inc. John M. Maraganore, Ph.D. - Alnylam Pharmaceuticals, Inc. Akshay K. Vaishnaw - Alnylam Pharmaceuticals, Inc. Manmeet Singh Soni - Alnylam Pharmaceuticals, Inc. Barry E. Greene - Alnylam Pharmaceuticals, Inc. Yvonne Greenstreet - Alnylam Pharmaceuticals, Inc..

Ritu Baral - Cowen & Co. LLC Maury Raycroft - Jefferies LLC Geoffrey Meacham - Barclays Capital, Inc. Vincent Chen - Sanford C. Bernstein & Co. LLC Paul A. Matteis - Leerink Partners LLC Eliana Merle - Credit Suisse Securities (USA) LLC Anupam Rama - JPMorgan Securities LLC Edward Tenthoff - Piper Jaffray & Co. Christopher S.

James - Ladenburg Thalmann & Co., Inc. Mike G. King - JMP Securities LLC.

Ladies and gentlemen, thank you for standing by, and welcome to the Alnylam Pharmaceuticals Conference Call to discuss Second Quarter 2017 Financial Results. There will be a question-and-answer session to follow. Please be advised that this call is being taped at the company's request. I would now like to turn the call over to the company..

Good afternoon. I'm 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 we have made available via webcast can also be accessed by going to the Investors page of our website, www.alnylam.com.

The press release and related financial tables including a reconciliation of GAAP and non-GAAP net loss that we will discuss today can be found on the Investors 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 provisions 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 recently 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'd 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 3 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 three separate Phase 3 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 3 trial in the coming weeks, and assuming positive results, expect 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 2 open-label extension, or 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 3 results for inotersen, the 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 fitusiran for hemophilia, givosiran for porphyria, and, with our partners at The Medicines Company, inclisiran for hypercholesterolemia.

The ATLAS Phase 3 program for fitusiran 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 3 study by end of the year, and The Medicines Company has announced agreement with the FDA on a Phase 3 program for inclisiran, with the study in patients with atherosclerotic cardiovascular disease expected to commence in late 2017.

Strategically, these three Phase 3 programs, in addition to patisiran, 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 what we believe to be the transformative potential of fitusiran, givosiran and inclisiran.

Finally, as we shared during our RNAi Roundtable Webinar earlier today on revusiran, we have included 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 hypothesis. There was no clinical evidence for 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 the contribution of the drug.

But as we discussed earlier today, there was some evidence that lower than expected mortality on the placebo arm at the 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 have indeed made strong progress in our pipeline of investigational RNAi therapeutics. Let's begin with our programs in hATTR amyloidosis, which includes patisiran and ALN-TTRsc02. This is really a big year for patisiran with our Phase 3 APOLLO study readout 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 2 OLE study results and the mechanism validating Phase 3 top line efficacy results for inotersen. At the same time, we're also advancing ALN-TTRsc02 as a subcutaneous alternative. We expect to advance this program into Phase 3 in 2018.

Now, the (8:00) earlier this year, we presented final results for the patisiran Phase 2 OLE study shown on slide 8.

At 24 months, patisiran showed a mean change in the modified neuropathy impairment score, or mNIS+7, of negative 7.0 points, providing continued evidence that patisiran has the potential to halt or improve neuropathy progression in patients with hATTR amyloidosis.

Note, at the time we present the (8:23) patients in the Phase 2 OLE study showed no change or a decrease or improvement in the 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 effects of patisiran was observed across the full range of disease severity.

In addition and 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 a mean increase in sweat gland nerve fiber density observed in the same skin biopsy samples, we believe these exploratory analyses support the therapeutic hypothesis that the reduction of mutant and wild-type TTR can potentially lead to reduction of TTR amyloid deposition and increased nerve regeneration.

Regarding safety 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 four 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 seven patients, all of which were unrelated to study drug, including two 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 2 OLE study have rolled 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 2 early patients continue on study with approximately 3 years 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 to providing a subcutaneous RNAi treatment alternative for patients with hATTR amyloidosis. We shared our initial Phase 1 data (10:44) showing dose-dependent knockdown of siRNA TTR with very low doses of ALN-TTRsc02 and with the durability (10:53) for months up just a single dose.

At our fitusiran Roundtable this past week, we were very pleased to provide updated results from our ALN-TTRsc02 Phase 1 study, which is shown here on slide 12. In those 18 subjects in ascending dose (11:07) 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 more can possibly (11:21) semi-annual fixed dose of either 25 milligrams or 50 milligrams could provide the same level of TTR knockdown observed with patisiran. Regarding safety results, ALN-TTRsc02 is 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 3 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 (12:07) 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 of 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 are highlighted in the paper on the Phase 1 results, which were recently published in The New England Journal of Medicine.

And at the ISTH meeting in Berlin in July, we presented new results from our ongoing Phase 2 OLE study highlighted here on slide 14. The study was opened to patients who had previously enrolled in the Phase 1 study. A total of 33 patients were enrolled and given dose of either 50 milligrams or 80 milligrams monthly via subcutaneous injection.

Fitusiran achieved a consistent level of AT lowering (13:05), approximately 80%, resulting in increases in thrombin generation to the low end of the range thrombin generation observed in healthy volunteers.

The effects of fitusiran on thrombin generation resulted in a low median ABR of one in all patients and zero 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 (13:45) being mild to moderate. Very importantly, there were no thromboembolic events including treatment of breakthrough bleeds.

Asymptomatic ALT elevations greater than (13:55) positive patients with all (14:02) at the time, the data cutoff. Overall, we believe the benefit risk of patisiran remains very encouraging. Accordingly, we're very pleased to have initiated our ATLAS Phase 3 program for fitusiran.

ATLAS will enroll approximately 250 patients in three 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 three ATLAS studies, we will be enrolling patients with severe hemophilia A or B.

Amongst other standard exclusion criteria, we're going to exclude patients for RNAi positive for HCV meaning they have an active infection. We will of course include patients who have been treated for and cured of HCV. The three ATLAS studies are outlined on slide 15, and are as follows.

ATLAS-INH is a nine-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 nine-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 givosiran, which we're developing for the treatment of acute hepatic porphyrias. Hepatic porphyrias are a group of ultra orphan diseases caused by genetic defect in the heme biosynthetic pathway. They are devastating diseases with enormous disease and economic burden.

In this disease, there's buildup of toxic heme (15:51) intermediates lead to incapacitating and potentially fatal attacks with symptoms that include severe abdominal pain, peripheral and autonomic neuropathy and neuropsychiatric manifestations. Porphyria attack 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, acute preparation of heme that is administered (16:32) via central line. We also noted from our EXPLORER natural study of 112 acute attack porphyria patients that there's an enormous economic burden associated with the disease.

Indeed, as we presented in ICPP in June, an analysis of costs associated with acute hepatic porphyria patients with recurrent attacks reveal 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, givosiran targets the liver-expressed ALAS1 gene which is an enzyme upstream of the genetic defects in acute hepatic porphyria and the enzyme responsible for overproduction of ALA and PBG, the two toxic heme synthetic intermediates that mediate (17:22) porphyria attacks.

Our therapeutic hypothesis is illustrated on slide 17 is advancing ALAS1 with givosiran with lower levels of ALA and PBG, and thereby have the potential to reduce the number, frequency and severity of porphyria attacks in patients.

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

At the ICPP meeting in Bordeaux, we presented new results that included all available data from cohorts 1 through 3 and Part C of the ongoing Phase 1 trial, as well as cohorts 1 and 2 of the ongoing Phase 1 OLE study. These data are highlighted on slide 18.

As a reminder, our (18:10) Phase 1 study is being conducted as a randomized double-blind placebo-controlled trial with patients with recurrent porphyria attack are monitored prospectively during a 90-day running period, randomized to receive drug or placebo in a 3 to 1 allocation, and then monitored prospectively for a 180-day treatment period.

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

In the first three unblinded cohorts, our treatment cohorts of 12 patients from Part C, givosiran treatment – treated patients experienced the mean 63% reduction in the annualized number of porphyria attacks relative to the run-in period. The (18:54) effect was consistent across a wide range of baseline attack rates.

In a separate analysis of attacks treated at a healthcare facility or with hemin administration, treatment with givosiran was associated with a mean 76% reduction in annualized attack rate relative to placebo.

Moreover, when we look at the annualized hemin administration relative to the running period, we observed a mean 73% decrease in hemin use for our patients on givosiran.

From the Phase 1 early results, initial data from the eight 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 six patients randomized and received givosiran in Phase 1, the mean annualized attack rate of nine during the treatment period was reduced further to five in the OLE study with a mean follow up of 111 days.

For the two patients randomized to receive placebo in Phase 1, mean annualized attack rates of 29 and 23 were observed in the combined run-in and treatment periods. As of the early days for ICPP, no attacks had occurred in these two patients following givosiran administration.

Turning to safety results on slide 21, and givosiran administration was generally well-tolerated in Part C of the Phase 1 study and in the ongoing OLE study with a mean of 169 days and 91 days on treatment, respectively, and up to 12 months on givosiran treatment.

There were four non-drug related SAEs in those three patients including a previously reported death due to hemorrhagic pancreatitis which was considered to be unlikely related (20:33). There was no drug-related discontinuation. All patients reported mild to moderate AEs that were possibly drug-related including ISRs of erythema and hypersensitivity.

Myalgia, headache and moderate renal impairment were also reported in a patient with a history of renal impairment. In aggregate, we're very encouraged by the clinical activity and tolerability profile for givosiran, now gratified by the recognition of givosiran's potential from regulatory authority.

This past quarter, we were very pleased when the FDA granted givosiran breakthrough designation. This follows the prime designation received from the EMA in Q1. We've now been engaged with both FDA and EMA in discussions on our Phase 3 study design and our overall efforts to bring givosiran to patients as rapidly as possible.

As a next step, we look forward to the start of our Phase 3 program expected in late 2017. 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 MAA on plans for the Phase 3 clinical program for inclisiran, designed to support submission of an NDA and an MAA.

The Phase 3 program will comprise clinical trial in subjects with atherosclerotic cardiovascular disease and familial hypercholesterolemia and we'll collectively enroll approximately 3,000 subjects randomized treatment with inclisiran or placebo.

Following patisiran and givosiran, we expect inclisiran to be the third RNAi therapeutic to enter Phase 3 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 the substantial safety base that we obtained from the inclisiran program supports 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 the recent stock offering. I'll be referring to slide 24 for a discussion of our second quarter 2017 financial results.

We entered 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 right to purchase in a concurrent private placement shares of common stock at the public offering price resulting in additional proceeds of $21.4 million. The net proceeds from the public offering in private placements 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 capabilities 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.

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 3 program for fitusiran.

G&A expenses were $45.8 million in the second quarter of 2017 as compared to $18 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 head count 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, will push us closer to 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 and fitusiran and growing globally with givosiran and in 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 (28:12) efforts (28:13) 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 3 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 in the 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, (28:49) additional clinical results in late 2017.

Following the initiation of the ATLAS Phase 3 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 3 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 3 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. As a reminder, to those dialed in, we would like you to ask to limit yourself to one question each and then get back in the queue if you'd like to ask additional questions..

Our first question comes from the line of Ritu Baral with Cowen. Your line is open..

Hi, guys. Thanks for taking the question.

Folks, 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 like skin biopsies was one mentioned in your previous webcast..

Yes. Great. I mean, Ritu, those are great questions. Akshay should comment as well, but the brief answer on revusiran is that it's a completely different molecule in a different setting and there's really – we obviously share the data with investigators, we share 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 we look at this data obviously very thoroughly. But as an appetizer, I mean if you look at the Phase – OLE data, significant number of patients there with (31:45) coexistent 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 phase data from APOLLO. So I think people are satisfied with the transparency and the depth which we'll share..

Okay. And then the commercial question, Barry, you want to (32:08) that..

Yes. Ritu, as you're aware, there's a significant amount of disease awareness going on in neurology and cardiovascular settings and there are number of programs to try 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 neurology and cardiovascular setting are aware of the disease. So that it's on the list of potential diagnosis and we're well on our way to doing that..

(32:41 – 32:58) I think it's a way of making sure that the 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, and I would just finally add that 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 diagnosis, helping to find patients and then ultimately when new medicines are approved and available, those medicines will become available to them for (33:33) treatment..

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

I mean, it's – Ritu, (33:45) yes, it's very easy obviously to do genetic testing nowadays, either saliva or blood and one can get the sample analyzed..

Great. Thanks for taking all the questions..

Thanks, Ritu..

Thank you. Our next question comes from the line of Maury Raycroft with Jefferies. Your line is open..

Hi. Thanks for taking my question. So, the RNAi webinars have been really helpful. So thanks....

Good..

...for putting this 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..

Yes..

I'm just wondering if you can comment on the relative exposure differences between patisiran and givosiran and if this could translate to, A, 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 three weeks, so 21 milligrams every three weeks. So the total exposure is under 1 gram of (34:54) thank you very much, is under 1 gram compared to the 28 grams that is administered for what's 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 the 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 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..

Good..

I'll hop back in the queue. Thank you..

Great..

Thank you. Our next question comes from the line of Geoff Meacham with Barclays. Your line is open..

Hey, guys, afternoon. Thanks for the question..

Absolutely. Thank you, Geoff..

Yes. Just wanted to ask a couple, John, on your commercial readiness for patisiran. First, I know, not directly comparable but are there any lessons to be learned from the (36:31) launch? And the second, and again, I'm not sure if you want to talk to 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. I know obviously you're probably going to have the benefit of having Sanofi Genzyme help out in a lot of the stuff too..

Yes. Those are great questions. Let me just say one thing for starters, which is that the beginning of lessons learned from (37:01) versus patisiran is have a really great strong efficacy package and safety package. And I think it begins there and I think that will need to be differentiating and we believe we will be differentiating.

But I think beyond that, maybe Yvonne has a color..

(37:18) as well. I think (37:22) much broader range of patients given our profile. So, of course, as you know, we know from the (37:31) situation just approved ex-U.S. and restrict it to (37:37) stage 1.

And given the population that we're studying in our APOLLO study, we should be able to attack a (37:46) 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 bit on Geoff's questions?.

Yes. Sure. It does start, Geoff, with the strength of the target product profile, what kind of patients we're enrolling, 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 of majority of patients have stabilized or improved in their disease, then the value proposition is considerably better than (38:17) proposition which slowed progression of the disease in some patients.

And as Yvonne said, it 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 (38:37) was able to achieve.

The other two keys are long-term continued relationship with the key opinion leaders and the patient advocacy groups. And we've been doing that, what, for six years, seven years now working (38:49). So those relationships 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 the positive data with 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 what the open-label extension data.

Does that answer your question?.

It does. Yes.

But I just wanted to – does the (39:26), do you have a good sense for how many of those were written by KOLs versus those in 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, probably the best way to think about it is there's certain countries that have well-organized centers of diagnosis, places like France, for example, where significant number of patients are captured.

There's other countries, Germany, United States that are far less organized and one of the things that we're doing is setting up centers of excellence so that patients can be screened rapidly and diagnosed rapidly. (40:009) has been out there for a couple of years, certainly helps our efforts because they have raised awareness.

The biggest challenge, frankly, is that because of the results, pricing hasn't been in line with orphan pricing and countries like the UK are not reimbursing to them. So, their results resulted in kind of lack of enthusiasm in many countries..

Right. Okay. That's helpful. Thanks, guys..

Thanks, Geoff..

Thank you. Our next question comes from the line of Vincent Chen with Bernstein. Your line is open..

Congratulations on the progress and thank you very much for taking my questions..

Thank you..

On the topic of payer discussions, it sounds like you probably had a range of discussion with payers around reimbursement.

Could you provide us with a little bit more color on those? In particular, how are you thinking about what the appropriate pre-authorization and re-authorization criteria might be, and how might have patients' 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. If you could appreciate that we are in a competitive situation here.

So, Barry, why don't you go ahead?.

Yes. So to John's point, I mean, 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.

parallel discussions, there's 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 earlier. At the last RNAi Roundtable about a 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 efforts?.

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 and motor symptoms in the limbs, along with signs of impotence or gut symptoms or heart symptoms, particularly if there's a family history, it should be considered for either the genetic approach to look for 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 this tends to be adopted quickly in a more widespread fashion.

Yvonne, did you have anything to add?.

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

Good.

Does that answer your question?.

Yes. Thank you very much and congratulations again..

Thank you..

Thank you. Our next question comes from the line of Paul Matteis with Leerink Partners. Your line is open..

Great. Thanks so much for taking my questions. I had one for Akshay on APOLLO. And, Akshay, it struck me earlier today when you were speaking about the patisiran early data versus the (43:48) data that you're pointing out for patisiran that you've shown disease symptom reversal.

I was wondering if this is your base case (43:59) expecting to see regarding efficacy in Phase 3. And your opinion regarding whether or not the fact that the patient population is more sick in APOLLO versus the Phase 1/2 could render it more challenging to show disease reversal, and then I have one quick follow-up..

Yes. I mean, (44:17) I'm going to speculate on the fact that (44:19) findings that we're going to get from APOLLO, but one thing we obviously do feel confident about based on our own Phase 2 open-label extension observations as well as (44:29) validated and I think we'll meet our primary endpoint. That's all I can say.

Now, as to the issue of how effective could patisiran be as a function of severity of disease, one of the interesting things we've noticed both, without (44:47) colleagues have reported the same is that in fact (44:51) regardless of the disease severity at baseline.

And so, I think without greater knockdown with patisiran and with the data enhancing the Phase 2 open-label extension both the progression of (45:09) of patients. So those changes in regression amyloid on the biopsies and evidence in their 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 of the Phase 2 open-label study and it's 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 it small which you would 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. Thank you. That's very helpful.

And if I might just ask one quick question on a protocol dynamic for outlets, I'm wondering if you put any specific direction in the protocol for how physicians should be dosing bypassing agents in patients with inhibitors and how the dosing paradigm for bypassing agents and then you (46:36) Phase 3 program for emicizumab? Thank you so much..

Yes. 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 from the context (46:51) administered bypassing agents to patients that may need them during the onset (46:58) in particular and so that has generally meant you start with a lower than usual dose of our patient you monitor and you see (47:06) which I think we demonstrated in the Berlin meeting and other previous meetings that we've had.

The first dose is generally effective at a lower dose than the patient normally in years. And for those learnings have been converted into specific kinds in the protocol for Phase 3. I think in the (47:25) speculating here, but the word I've heard back is, in fact, there wasn't strict guidance given on the use of rescue agents.

And so, again, as you know, people have speculated that they may have converted to some of (47:38)..

Yes. I will just add, Paul, that it is reassuring that in our Phase 1 and Phase 2 experience with fitusiran that we have had more breakthrough bleed treatment events with (47:59) than the entirety of the data presented on a HAVEN 2, HAVEN 1 or HAVEN 2, whichever, for emicizumab. And that's encouraging to be seen (48:12)..

And to quantify that (48:15)..

That's right..

And basically the reason it's been treated with (48:16)..

Yes. That's correct..

(48:19)?.

Yes. That is correct..

Okay. Great. Thank you very much for the detail. Appreciate it..

Thank you. Our next question comes from the line of Alethia Young with Credit Suisse. Your line is open..

Hi, guys. This is Eliana in for Alethia. Thanks so much for taking the question.

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 file-able 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 endpoints they're focused on such as proBNP or (48:57) or if they're just looking for sort of the overall profile showing stabilization? Thanks..

Oh, Akshay, that's your question..

Yes. Just on the outset, I would say all data are file-able. I mean, we are obliged, and in fact, to file all data. So, all cardiac data in addition to neuropathy and every other last data will be filed.

Now, as to 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 being (49:28), how valid and robust the data are.

And so in that regard, I think the biomarker data that we provide were increasingly in those interest in using (49:34) patients and prognosticate on where patients are going to end up will be useful and important. The (49:44) 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 outcome (49:57) versus placebo. And they want to help prescribe and guide them appropriately to the use of the agents. So I think if the data are sufficiently robust and encouraging, they will include them in the label..

Great. Thanks..

Thank you..

Thank you. Our next question comes from the line of Anupam Rama with JPMorgan. Your line is open..

Hey, guys. Thanks so much for taking the question. 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 timeframe for APOLLO.

This coming weeks mean that it could be like right after the holiday or even earlier, and what are the factors that might shift the timeline up or out in either direction? Thanks so much..

Thanks, Anupam. No. 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 timeline..

Okay. Thanks so much for clarifying..

Yes. Thanks, Anupam..

Thank you. Our next question comes from the line of Ted Tenthoff with Piper Jaffray. Your line is open..

Great. Thank you very much for the update, and I apologize if this question has been asked. I've been having telephonic issues, but I wanted to 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 of specialty pharma, sales force, medical liaisons, maybe you can update us on where you are in that process. Thank you..

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 – what we said on the call, Ted, is we encourage everybody to listen to the patisiran Roundtable. 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, in 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 – 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 does the pacing group help here in terms of sort of rallying and educating patients? I have to imagine this is a – it's a pretty motivated pacing group..

Yes. The answer is a lot.

Barry, do you want to comment any further on that?.

Yes. I think the answer is a lot, and it depends on country. 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 strong and stronger patient advocacy. The voice of the patients certainly will matter here in a big way..

Excellent. Thank you so much..

Thank you, Ted..

Thank you. Our next question comes from the line of Christopher James with Ladenburg. Your line is open..

Hey, guys. Thanks for taking the questions. I guess assuming positive data from patisiran, maybe kind of piggyback on (54:19) 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, CJ. 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 a competitive landscape here. So we're going to be a little bit careful. But I think Barry's point is the right one.

If patisiran demonstrates the type of value that we have seen in the Phase 2 open-label study, then this is a medicine that is going to provide enormous benefit for patients, first and foremost. It's in orphan setting, and it's going to be price 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 or 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. Thank you. And then maybe lastly, can you maybe walk us through, assuming positive data, steps through speaking to the FDA filing and do you expect an FDA panel? Thanks..

Yes.

Akshay, do 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..

Got it..

And it's possible, CJ that because there are two agents in the field, that both agents might be discussed at the same advisory panel..

Got it. Got it. Thank you, guys..

All right. Thank you. Thank you..

Bye-bye..

Thank you. Our next question comes from the line of Mike King with JMP Securities. Your line is open..

Hey, guys. Thanks for taking the questions and fitting me in. Just two real brief ones. Just thinking with the theme of market preparation and patient out and physician outreach. I notice 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?.

I guess what I can say Mike is what you have noticed is that unbranded disease awareness aim towards healthcare providers was launched months ago, and very recently, you see this on social media and others, patient indication, again, unbranded has been launched. And I think it's fair to say it's 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 seems very well received and time will tell, but we think that will lead to short invitation journey in finding patients more rapidly..

Okay, great.

Can I just ask you a quick question on sc02?.

Yes..

Yes..

I asked basically similar question last quarter.

I just wondered 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 – have a clinical endpoint for approval?.

Yes. It's a topic of active discussion internally, Mike. I think that – two things, really, one is we're very, very impressed with the data of our TTRsc02. I mean, it's stunning if you look at the updated data that we 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 in frequently a 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 that will soon be a topic of discussion with the regulators as well.

But we're very confident that there is a very attractive path forward for the drug and we remain very bullish around the prospects forward based on the data that we've got right now..

Great. Thanks so much for taking the questions..

Good. Thanks, Mike..

Thank you. And I'd now 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 toward a commercial stage.

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..