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Edited Transcript of ALNY earnings conference call or presentation 7-Feb-19 9:30pm GMT

Q4 2018 Alnylam Pharmaceuticals Inc Earnings Call

Cambridge Feb 11, 2019 (Thomson StreetEvents) -- Edited Transcript of Alnylam Pharmaceuticals Inc earnings conference call or presentation Thursday, February 7, 2019 at 9:30:00pm GMT

TEXT version of Transcript

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Corporate Participants

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* Akshay K. Vaishnaw

Alnylam Pharmaceuticals, Inc. - President of Research & Development

* Barry E. Greene

Alnylam Pharmaceuticals, Inc. - President

* Christine Regan Lindenboom

Alnylam Pharmaceuticals, Inc. - VP of IR & Communications

* John M. Maraganore

Alnylam Pharmaceuticals, Inc. - CEO & Executive Director

* Manmeet Singh Soni

Alnylam Pharmaceuticals, Inc. - Senior VP ,CFO & Principal Accounting Officer

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Conference Call Participants

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* Alan Carr

Needham & Company, LLC, Research Division - Senior Analyst

* David Neil Lebowitz

Morgan Stanley, Research Division - VP

* Edward Andrew Tenthoff

Piper Jaffray Companies, Research Division - MD & Senior Research Analyst

* Emma Kathleen Nealon

Cantor Fitzgerald & Co., Research Division - Analyst

* Gena Wang

Barclays Bank PLC, Research Division - Research Analyst

* Mani Foroohar

SVB Leerink LLC, Research Division - MD of Genetic Medicines & Senior Research Analyst

* Matthew Alexander Bannon

JP Morgan Chase & Co, Research Division - Analyst

* Paul Andrew Matteis

Stifel, Nicolaus & Company, Incorporated, Research Division - Co-Head of the Biotech Team, MD & Senior Analyst

* Ritu Subhalaksmi Baral

Cowen and Company, LLC, Research Division - MD and Senior Biotechnology Analyst

* Terence C. Flynn

Goldman Sachs Group Inc., Research Division - MD

* Vincent Chen

Sanford C. Bernstein & Co., LLC., Research Division - VP

* Whitney Glad Ijem

Guggenheim Securities, LLC, Research Division - Senior Analyst of Biotechnology

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Presentation

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Operator [1]

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Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call Fourth Quarter and Full Year 2018 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.

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Christine Regan Lindenboom, Alnylam Pharmaceuticals, Inc. - VP of IR & Communications [2]

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Good afternoon. I'm Christine Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are John Maraganore, Chief Executive Officer; Barry Greene, President; Akshay Vaishnaw, President of R&D; and Manmeet Soni, Chief Financial Officer. Yvonne Greenstreet, our Chief Operating Officer, is traveling today and will not be available for today's call. For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the Investor page of our website, www.alnylam.com.

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

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those that are 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 views as of any subsequent date. We specifically disclaim any obligation to update such statements.

Please also note that the press release and related financial tables, including a reconciliation of GAAP to non-GAAP measures that we will discuss today, can also be found on the Investor page of our website. We believe non-GAAP measures provide useful information to management and investors regarding our financial conditions and the results of our operation.

With that, I'll turn the call over to John.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [3]

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Thanks, Christine, and thank you, everyone, for joining the call today. I'm going to keep my remarks relatively brief so we can dive into the meat of the call. We believe 2018 was a better year for Alnylam, in which we saw the approval and subsequent launch in the U.S. and EU of ONPATTRO, heralding the arrival of RNAi therapeutics as a whole new class of innovative medicines. Barry will get into the specifics later, but while still early, we're pleased with how the launch is going. With over 200 patients receiving treatment with commercial ONPATTRO in the U.S. and EU as of the end of 2018, we believe we are seeing strong patient and physician demand as well as excellent commercial execution by our U.S. and EU teams.

While we're focused in the near term on launching ONPATTRO into the market of hATTR amyloidosis patients with polyneuropathy, we're also excited about the significant growth potential of our ATTR franchise in the mid- and longer term. This includes potentially expanding the ONPATTRO label into the hereditary and wild-type cardiomyopathy segments with the APOLLO-B study as well as advancing our investigational RNAi therapeutic, vutrisiran, initially for hATTR polyneuropathy patients through our HELIOS-A study. Then longer term, we're committed to developing vutrisiran for the treatment of hereditary and wild-type cardiomyopathy patients with the HELIOS-B outcome study that we expect to start later this year.

Akshay will summarize how our clinical development efforts can potentially help realize this growth.

The bottom line here is that over the next few years, we anticipate having thousands of ATTR amyloidosis patients on either commercial product or in a development program with an investigational RNAi therapeutic. All in all, we believe that this provides significant opportunity for patient impact and allows Alnylam to achieve sustained and continued growth, with potential value creation for shareholders.

Now beyond ONPATTRO and vutrisiran, we're also advancing a large number of additional programs, building what we believe to be the foundation for yet further patient impact and company growth. In particular, we believe that we're positioned, assuming positive study results, to have essentially annual launches of innovative medicines over the next several years, including givosiran or lumasiran, where we have global rights, and then inclisiran and fitusiran, which are being advanced by our partners.

And beyond these Phase III programs that are nearing potential commercialization, we have a rich pipeline of yet additional programs in clinical and late-preclinical development. Altogether, we believe that this is a compelling profile for potential value creation, very much in line with our Alnylam 2020 goal of becoming a multiproduct commercial biopharma company, with a deep clinical pipeline fueled by a robust discovery engine for sustainable innovation, a profile rarely achieved in the biotech industry.

So with that, I'll turn it over to Akshay now to review our latest pipeline progress in more detail. Akshay?

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Akshay K. Vaishnaw, Alnylam Pharmaceuticals, Inc. - President of Research & Development [4]

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Thanks, John, and good afternoon, everyone. Let me start with patisiran, which is the nonbranded name for ONPATTRO. We announced last month our plan to pursue potential expansion of the ONPATTRO label to include hereditary and wild-type ATTR cardiomyopathy. As you know, last September, we were pleased to have exploratory cardiac endpoint data from the APOLLO Phase III study published in the journal, Circulation. These data highlighted the potential for patisiran to favorably impact some cardiac manifestations of hATTR amyloidosis and support continued evaluations for clinical research. These encouraging exploratory cardiac data have led us to now reach alignment with the FDA on a new study, APOLLO-B, which is in line with the randomized double-blind placebo-controlled study of ONPATTRO, with 6-minute walk distance as the primary endpoint after 12 months.

APOLLO-B is expected to enroll about 300 patients within the wild-type or inherited ATTR amyloidosis with cardiomyopathy, including patients who are either naive to TTR stabilizers or those progressing while receiving TTR stabilizers. We expect this study to start in the middle of this year, and if positive, we believe it will support an expanded label for ONPATTRO in the '21 to '22 time frame.

As you know, we're also advancing vutrisiran as a potentially best-in-class therapeutic for ATTR amyloidosis. Vutrisiran is our investigational subcutaneously delivered TTR-lowering agent. We believe that a once quarterly low-dose, low-volume subcutaneous injection that achieves an approximately 90% knockdown of TTR and is generally well-tolerated, could be a very attractive option for patients.

Late last year, we initiated the HELIOS-A Phase III study of vutrisiran in hATTR patients with polyneuropathy. It is an open-label study, where we're looking at neurological impairment and quality of life in 9 months and comparing the results in vutrisiran-treated patients to the placebo arm of the APOLLO study. This innovative study design is aimed at bringing vutrisiran to the market as rapidly as possible.

Later in 2019, we also plan to initiate an outcome study for vutrisiran, which will be called HELIOS-B. If successful, we believe HELIOS-B will facilitate vutrisiran's entry into the significant and growing wild-type ATTR market opportunity.

Let's move on to givosiran, an investigational RNAi therapeutic in development for the treatment of acute hepatic porphyrias. We're now just about a month away from reporting top line results from the ENVISION Phase III study, and we're very excited to soon see these in full results from the first-ever Phase III study of a GalNAc conjugate siRNA. As a reminder, patients with porphyria have enormous disease burn and can suffer from frequent life-threatening porphyria attacks, often requiring hospitalization. This is a frail population with significant underlying disease manifestations and complications from therapy, including iron overload and chronic hemin administration. Recurrent-attack porphyria patients also exhibit neuropathy with chronic pain, fatigue and also liver dysfunction and renal disease. Clearly, there's a very high unmet need for new therapies to help these patients.

ENVISION study overenrolled with 94 porphyria patients and also enrolled much more rapidly than we had originally expected. Top line results we report in next month will include data on the primary endpoint of annualized attack rate and safety. Full study results are expected to be presented in oral presentation at the European Society of the Study of the Liver, or EASL, on the morning of Saturday, April 13, in Vienna.

If the study results are positive, we plan to complete our rolling NDA submission in the middle of this year, which could support an approval for givosiran in late 2019, early 2020.

We also expect to open a global EAP to make givosiran available to patients prior to regulatory approvals and reimbursement decisions.

In the meanwhile, we're extremely pleased, just yesterday, that the New England Journal of Medicine published results from our Phase I study of givosiran, and we believe this publication is such a highly esteemed peer review journal, reflecting the enormous potential of givosiran to transform the lives of patients with acute hepatic porphyria. We're proud that this is now the sixth New England Journal paper to describe clinical results for an RNAi therapeutic coming from our scientists, clinicians and collaborators.

I'll now turn to recent progress with lumasiran, and RNAi therapeutic we're developing for primary hyperoxaluria type 1 or PH1. Based on very promising Phase I/II study results, we were pleased to initiate the ILLUMINATE-A Phase III study last year. This is a randomized double-blind placebo-controlled study in approximately 30 patients with PH1.

The primary endpoint in this study is the reduction of urinary oxalate at 6 months relative to baseline in the lumasiran group relative to placebo.

We expect to report top line results from ILLUMINATE-A in late 2019 and if positive, to submit regulatory filings beginning in early 2020. In addition to this pivotal trial, we intend to initiate in mid-2019 both the ILLUMINATE-B study in patients less than 6 years of age with preserved renal function and ILLUMINATE-C study in patients with more severe renal impairment. Outside of the full Phase III program that I just highlighted, we have 2 additional programs currently in Phase III trials: fitusiran, in development for the treatment of hemophilia, is being advanced by our partner, Sanofi, in the ATLAS Phase III program; inclisiran, in development for hypercholesterolemia, is being advanced by our partner, The Medicines Company, in the ORION Phase III program.

Finally, one area that we're especially excited about is the progress that we have made at Alnylam in the delivery of our RNAi therapeutics to the central nervous system and the eye. This opens up an exciting new landscape of disease opportunities that we can pursue by leveraging our RNAi therapeutics platform.

And with that, let me now turn it over to Barry to review our commercial and medical affairs progress. Barry?

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [5]

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Thanks, Akshay. As John said, we're extremely pleased with the supply chain, commercial and medical affairs capabilities we've built and our progress on the ONPATTRO launch. In terms of our commercial performance, as you've read, we've achieved $12.1 million in global net revenues from ONPATTRO in Q4 and $12.5 million for the full year 2018. We're very pleased that as of year-end 2018, we have over 200 patients on commercial ONPATTRO worldwide. Now if we include patients receiving patisiran in our clinical studies and our expanded access program, we had about 550 patients receiving the drug as of year-end 2018, representing a future pool of patients that we expect over time to come onto commercial ONPATTRO.

To give some additional color on market dynamics in the United States, we can look at start forms that we've received in our Alnylam-assisted patient hub. As a reminder, our U.S. start forms represent most, but not all of our U.S. patient demand, since many patients also receive ONPATTRO outside of Alnylam-assist via supply through our distribution channel.

From launch through year-end 2018, we received 250 start forms. We're very pleased to see that we're now getting a growing number of start forms from patients who did not participate in the expanded access program. We're also very pleased to see that we have a mix of physician prescribers from ONPATTRO, including neurologists, cardiologists, hematologists and other specialties, which really speak to the multisystemic nature of hATTR amyloidosis.

In terms of the payer mix, approximately 62% of start forms, as we expected, in the United States are from patients covered by Medicare, while approximately 32% were from patients covered by commercial insurers. Importantly, we have not encountered significant headwinds on reimbursement from ONPATTRO in the U.S. In fact, we currently have patients on commercial drug from each one of the top 5 U.S. payers. We also are making solid progress on value-based agreements, or VBAs, and expect to have around 90% of commercial patients covered by VBAs.

Now let me turn to the EU, where we've also made good progress advancing pricing and reimbursement procedures with authorities in 15 countries across Europe, together representing the vast majority of hATTR patients, amyloidosis patients with polyneuropathy in Europe. Recent examples of our progress include positive technology assessment reports of authorities in Germany and Sweden, the special innovation designation of ONPATTRO by Italian authorities and favorable reimbursement alignment with authorities in the Netherlands.

On the medical affairs front, one of the biggest challenges in this rare disease is raising awareness and improving diagnosis of hATTR amyloidosis with polyneuropathy.

As we've highlighted previously, our Alnylam Act program is a third-party genetic screening initiative and is facilitating improved diagnosis of patients suspected of having hATTR amyloidosis. As of February 6, more than 10,900 samples have been submitted, out of which 726 have tested positive for a pathogenic TTR mutation. We've also seen success with our patient advocacy initiatives as well as our digital disease awareness campaigns.

As we've discussed previously, another potential driver of improved diagnosis is the availability of new therapies. Post-launch, we're hearing many anecdotal stories from patients and the physicians about their positive experience with ONPATTRO. We believe these positive patient and positive physician experiences will contribute to raising awareness, improving diagnosis and supporting earlier treatment of hATTR amyloidosis patients with polyneuropathy. With that in mind, we've launched a new promotional campaign that highlights ONPATTRO's ability to avert the polyneuropathy manifestations of ATTR amyloidosis as demonstrated, in addition to other benefits, in the APOLLO Phase III study. We believe this effort will help highlight the clinical benefits and unique characteristics of ONPATTRO.

I'll now turn the call over to Manmeet to review our fourth quarter and full year performance. Manmeet?

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Manmeet Singh Soni, Alnylam Pharmaceuticals, Inc. - Senior VP ,CFO & Principal Accounting Officer [6]

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Thanks, Barry, and good afternoon, everyone. Please refer to our press release issued earlier today for a summary of our financial results for the fourth quarter and full year 2018.

Let me start with our cash balance. We maintained a solid balance sheet, ending 2018 with approximately $1.13 billion in cash, cash equivalents, marketable debt securities and restricted investments, excluding equity securities. Following our Alnylam public offering last month, we currently have a pro forma cash balance of approximately $1.5 billion.

Moving now to our revenues. We recorded $12.1 million of ONPATTRO net product global revenue during the fourth quarter of 2018 and $12.5 million since the middle of August U.S. launch date through the end of the year. As expected, our gross to net discount in the U.S. was approximately 23%, mostly related to mandatory discounts for 340B entities and reserved for Medicaid patients. Also, as expected, our gross to net in the EU was generally higher than in the U.S. We will continue to update on our expected gross to net discounts as we progress with the launch of ONPATTRO and actual payer mix.

Cost of goods sold were $1.8 million for the full year, which equates to approximately 14.5% as a percentage of net product revenues. In the long run, we expect normalized cost of goods sold to be in the mid- to high teens as a percentage of ONPATTRO product revenues, including royalties paid to third parties.

Moving to other operating costs and expenses, I will refer here to our full year 2018 results. GAAP R&D expenses were $505.4 million for the full year 2018 as compared to $390.6 million for the prior year. Non-GAAP R&D expenses were $424.9 million as compared to $338.8 million for the prior year. This lies in the lower-end range of our non-GAAP R&D guidance of $420 million or $460 million. The increase in non-GAAP R&D expenses was due to increased compensation and related expenses as a result of increased manufacturing expenses associated with our late-stage programs and increased headcounts during the period as we continue to expand and advance our development pipeline.

Turning to SG&A. GAAP SG&A expenses were $382.4 million as compared to $199.4 million for the prior year. Non-GAAP SG&A expenses were $305 million as compared to $158 million for 2017. We ended within the midpoint of our non-GAAP SG&A expense guidance in the range of $280 million to $320 million for 2018. The increase in non-GAAP SG&A expenses was due primarily to an increase in commercial and medical affairs headcount and commercial-related services to support corporate growth and the launch of ONPATTRO in 2018 and potential additional country launches of ONPATTRO in 2019.

Non-GAAP SG&A expenses also exclude stock-based compensation expense.

With respect to guidance for 2019, we expect that annual non-GAAP R&D expenses will range between $520 million and $560 million and annual non-GAAP SG&A expenses will range between $390 million and $420 million. We expect that our current cash, cash equivalents and marketable debt securities will support company operations for approximately 2 years based upon our current operating plan.

As of now, we will not be providing any revenue guidance for 2019. We will continue to evaluate the possibility of providing guidance once we have better visibility on the ramp of the launch, market dynamics and key metrics over the next several quarters.

I will now hand it back to John to review our 2019 goals. John?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [7]

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Thanks, Manmeet. As I mentioned earlier, 2018 was a landmark year for Alnylam, and we envisioned 2019 shaping up to be equally transformative. Overall, we're executing on 6 Phase III programs, expect to report 3 Phase III data readouts and if positive, expect to file 2 NDAs. More specifically, starting with ONPATTRO, while we continue our global commercial execution, we'll also be planning to initiate our APOLLO-B Phase III study in mid-2019, which is aimed at supporting a potential expansion of the ONPATTRO label to include both hereditary and wild-type cardiomyopathy. With vutrisiran, we plan to enroll the HELIOS-A Phase III study throughout the course of the year and initiate our HELIOS-B outcome study in late 2019.

Moving to givosiran, as Akshay highlighted, we expect to report top line results from the ENVISION Phase III study very, very soon in March. And of course, if the results are positive, we'll plan on completing our rolling NDA submission as well as filing an MAA in mid-2019.

With lumasiran, we expect to complete enrollment in the ILLUMINATE-A study in the middle of the year and to report top line results from that study in late 2019.

With inclisiran, our partners at The Medicines Company have guided to have top line results from the ORION's 9, 10 and 11 studies in mid- and late 2019 and assuming positive data, to submit an NDA for inclisiran by the end of the year. Of course, we'll also continue to advance in the rest of our pipeline as well as exciting preclinical efforts, and we'll highlight those milestones throughout the course of the year as they occur.

So with that, let me now turn the call back to Christine to coordinate our Q&A session. Christine?

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Christine Regan Lindenboom, Alnylam Pharmaceuticals, Inc. - VP of IR & Communications [8]

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Thank you, John. Operator, we are ready to open the call for questions. (Operator Instructions)

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Questions and Answers

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Operator [1]

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(Operator Instructions) And our first question will come from Paul Matteis with Stifel.

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Paul Andrew Matteis, Stifel, Nicolaus & Company, Incorporated, Research Division - Co-Head of the Biotech Team, MD & Senior Analyst [2]

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And congrats on all the progress. One question for Barry. Barry, I was wondering if you can comment on the times to get drug that you're seeing in the channel for patients starting on ONPATTRO, what the trajectory looks like, and how this has been changing at all with your progress on reimbursement.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [3]

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Yes, Barry, go ahead.

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [4]

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Yes, Paul, great questions. So as we highlighted on previous calls, our intention is to get the time from many, many weeks to only a couple of weeks, and we're seeing progress. We have examples now of a start from coming in -- in patients literally getting on drugs in a couple of weeks. It does depend on where they're being infused, what the insurance looks like, but those times are coming way down and we're really excited about the progress we're making.

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Operator [5]

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Our next question will come from Alan Carr with the Needham & Company.

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Alan Carr, Needham & Company, LLC, Research Division - Senior Analyst [6]

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Maybe we can talk about how things are going for ONPATTRO U.S. versus Europe, what are your expectations for the relative ramps between those 2 over the course of this year into next year.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [7]

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Yes, that's a great question, Alan. Barry, you want to handle that?

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [8]

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Yes. So Alan, we're not really giving a breakdown of guidance as you are aware. We've launched immediately in the United States after the August 10 approval, where we had boots on the ground that Monday and we had drug ready to be shipped within 48 hours as we committed and even highlighted how well the overall launch is going. Europe is quite different because in certain countries, like Germany, we can launch immediately. Other countries require us to work through the health technology assessment process before naming our price and getting paid for it. So we're in the process, as highlighted on the call, of working through that in 15 different countries. And getting the right access by country will really determine the launch order and then how the trajectory in Europe progresses. But we're happy with the progress so far in Europe and what we're seeing.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [9]

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Yes, I'll just add, Alan, that from our perspective, Europe is showing itself strong at this point. And there is strong patient demand. There's a very strong KOL awareness with ONPATTRO and the -- and obviously, the features that they've seen in the clinical studies, and that helps a lot in that effort.

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Operator [10]

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Our next question will come from Maury Raycroft with Jefferies.

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Unidentified Analyst, [11]

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This is [Mitchell] on for Maury. For at-home infusion of ONPATTRO, how many patients have access? Are doctors providing the option to all patients? And can you walk us through how cost and reimbursement can factor in to this service?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [12]

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Yes, thanks, [Mitchell]. Barry, you want to handle it?

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [13]

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Yes, so in the United States, and then in many countries in Europe, home infusion is immediately available. Obviously, in certain European countries, it's all paid for -- are mostly paid for and taken care of by the country with single payers. In the United States, home infusion is available to all the commercial plans right now and it's offered by all the commercial plans. It is something that the physician talks to the patient about and is offered. For a new patient, the physician is telling us they typically like to see the patient once or twice after institution and infusion to check the patient out, and after that, happy to move to home infusion. It's interesting that, and we highlighted this at the JPMorgan Conference, only about 25% of the patients on commercial drug have chosen home infusion. And in fact, what we hear in market research from patients is they're actually enjoying their infusion experiences. They have met people they enjoy, they meet other patients, their nurses and actually, enjoying the infusion experience, which is a pleasant surprise for us.

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Operator [14]

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Our next question will come from Alethia Young with Cantor Fitzgerald.

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Emma Kathleen Nealon, Cantor Fitzgerald & Co., Research Division - Analyst [15]

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This is Emma on for Alethia. Are you seeing any patient switch from tafamidis in some of these markets, and is it really what you expect that dynamic to look like as the launch progresses?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [16]

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Yes, that's a good question, Emma. Barry, do you want to handle that?

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [17]

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Yes. So we have to look at the United States differently than many of the countries in Europe. As you know, the Phase III study in polyneuropathy missed the endpoint. It was not approved in the United States. But given the endemic nature of the disease, it was approved in Europe and other countries around the world. So it's been used for multiple years. As we also know, again, back to polyneuropathy, is many physicians report significant progression in as little as 6 months in published literature onto tafamidis. So the dynamic outside the United States is, in fact, patients looking for a progression in -- physicians looking for progression in patients and when appropriate, assuming an on-label patient, switching them to ONPATTRO. We are seeing that dynamic and do anticipate more of that. Obviously, the whole dynamic in the United States is something we'll see in the future as tafamidis hit the U.S. market with different labeling.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [18]

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I'll just add, Emma, that -- I'll remind you that in our APOLLO Phase III study, about 50% of patients had previously been on a stabilizer, and many of those patients chose to come on to a randomized placebo-controlled study because they get either progressed on the stabilizer, or they want to participate in these availability of a TTR silencer like patisiran. So that's an important and useful data point if you just look at our clinical trial experience alone.

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Emma Kathleen Nealon, Cantor Fitzgerald & Co., Research Division - Analyst [19]

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Great. And then are you able to provide any color on the pricing then from ONPATTRO in Europe as you're going through some of these reimbursement discussions?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [20]

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I missed your question there, Emma. Can you repeat that?

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Emma Kathleen Nealon, Cantor Fitzgerald & Co., Research Division - Analyst [21]

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On the pricing band in Europe.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [22]

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Oh, yes, Barry, you want to comment on that?

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [23]

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Yes, as we've commented on previously, on a global basis, the per vial price, we're going to keep it at a very, very tight level.

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Operator [24]

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Our next question will come from Ritu Baral with Cowen.

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Ritu Subhalaksmi Baral, Cowen and Company, LLC, Research Division - MD and Senior Biotechnology Analyst [25]

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Apologies for the noise. A question actually about APOLLO-B, as you look through some of the design elements and the assumptions, why 12 months, how many wild-type patients you're expecting and potential timing around that, those enrollments and data?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [26]

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Yes, terrific. Akshay?

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Akshay K. Vaishnaw, Alnylam Pharmaceuticals, Inc. - President of Research & Development [27]

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So in terms of the length of the study, as you know, from the APOLLO -- original APOLLO study, that at the 9-month endpoint, all the clinical endpoints hit, and so we're very confident that a 12-month time point is a suitable time point for 6-minute walk distance. We also know from the ATTR-ACT study that 6-minute walk distance [has been started] significant earlier than 12 months with tafamidis. So clearly, this is a significant clinically relevant endpoint that is amenable to change at earlier time points than potentially other endpoints, such as mortality or hospitalization. So that was the rationale behind that. Now with respect to the split between wild type and mutant, obviously, there are many more wild-type patients than the hereditary TTR patients, but I think the majority of the study would be filled with wild-type patients. Hard to say how much right now. Again, historical experience, mostly (inaudible) might be wild type, but that's a speculation on my part at the moment. And then finally, with respect to [basal] the timing, with respect to the initiation of the study in ATTR, it's hard to comment on the exact time line [for it] but as we have suggested, we anticipate approval in the '21 to '22 time frame. And we feel that overall total time that we're consistent with them.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [28]

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And Ritu, if you can -- yes, if you can go on mute because you got a lot of background noise.

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Operator [29]

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And we have a question from Anupam Rama with JPMorgan.

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Matthew Alexander Bannon, JP Morgan Chase & Co, Research Division - Analyst [30]

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This is Matt on for Anupam. One for you Barry. Just wondering about the ONPATTRO value-based agreements. How long do you anticipate it taking to get the remainder of those in place to get that 90% of commercialized covered? And then what does one of those agreements typically look like?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [31]

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Barry?

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [32]

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Yes. Thanks. So as you know, part of our patient access philosophy was to proactively offer value-based agreements. And that strategy has proven incredibly useful in opening a dialogue with payers and as we talked about in the call, even outside of finalizing value-based agreements, we're really not hitting the payer headwinds. The partnership with the payers to try to find and treat their patients has been really spectacular, and they've really stepped up on medical policies to really help educate and ensure that patients have access. So I give the payer community a lot of credit on the partnership we've seen. In terms of the value-based agreements we've highlighted, we've got 3 complete, and we anticipate, by the end of the year, having about 90% of patients covered by VBAs. It's hard to name time frames because of the back and forth between the different back-office folks to finalize the letter of the VBAs, but the conversations are going well. And I'd say, it's a sort of end-of-year goal to have 90% of all the patients covered. It's important to note that even without the VBA in place, as I said, we are having great dialogue with payers and really not running into reimbursement issues with patients at this point.

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Operator [33]

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Our next question will come from Dave Lebowitz with Morgan Stanley.

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David Neil Lebowitz, Morgan Stanley, Research Division - VP [34]

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How are you going to manage with the HELIOS-B and APOLLO-B trials starting later this year? Are they going to be completing the overlapping populations? Are they going to be at the same sites? How are you going to manage those 2 groups?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [35]

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Yes, that's a great question, David. Akshay, do you want to comment a little bit on the APOLLO-B and HELIOS-B?

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Akshay K. Vaishnaw, Alnylam Pharmaceuticals, Inc. - President of Research & Development [36]

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Yes, there's certainly going to be some overlap between the study populations from those 2 protocols that involve patients with wild type and hereditary TTR cardiomyopathy. But the situation is, what should I say, mitigated by several important factors. Firstly, there are a very significant number of wild-type patients that currently have no treatment at all. Many of them despite the potential approval of tafamidis in months to come may be in a territory where tafamidis may not be available or some other therapy may not be available for them. The availability of patients with hereditary TTR, similarly that varies by territory. And so between the need to do a robust study that encompasses a range of mutations and geographies that satisfies the regulators and the availability of the various drugs that are being recently approved or about to be approved, we're confident that we can ensure enrollment without competing between the studies or competing between other goals of the company.

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Operator [37]

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Our next question comes from Gena Wang with Barclays.

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Gena Wang, Barclays Bank PLC, Research Division - Research Analyst [38]

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One quick one regarding the 726 patients that had positive TTR mutation identified through Alnylam Act. Just wondering how many of these patients are addressable for ONPATTRO?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [39]

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That's a great question, Gena. I mean, at a high level, we don't know because we don't have specific details on these patients. This is a service that we're providing for the medical community, and it's to help patients basically be able to get diagnosis. And so we don't have any information about anything more specifically about those patients as a result. Barry, anything else to add?

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [40]

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No, you got it. As John said, this is a service that we offer for the benefit of patients to help improve overall diagnosis. The fact we're seeing so many pathogenic hits demonstrates a major unmet need and the patients benefit. I will add that Alnylam Act doesn't represent all the genetic testing that's being done. There are other free genetic testing offered by other companies, and now that we have commercial drugs, many physicians are choosing to use commercial insurance to pay for genetic tests. So we're delighted that genetic testing is being so well amplified out in the community representing the unmet need and the need to help find these patients with the genetic testing.

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Operator [41]

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Our next question comes from Whitney Ijem with Guggenheim.

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Whitney Glad Ijem, Guggenheim Securities, LLC, Research Division - Senior Analyst of Biotechnology [42]

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One on givosiran headed into the Phase III data. I guess, kind of can you remind us, first of all, for the 1,000 and 5,000 patient numbers you talk about for recurrent and sporadic, are those based on identified or diagnosed patients? Or is that an epidemiologic estimate? And then in terms of use of givo on the 2 different populations, how do you think about that? And what are, I guess, some of the endpoints in the Phase III data that we should look for to help us get a better sense of that?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [43]

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Two great questions. Maybe, Barry, you can start with the epi, and then, Akshay, you can cover the second question on the data that we should look for to cover both sides. Go ahead.

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [44]

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Yes, the numbers that we quoted, the 1,000 and 5,000 is -- are based on bumps in seats if you will. These are patients that the porphyria network believes they had in their coverage universe, and then we triangulate that at the various centers. The epidemiology represents much, much greater numbers, but of course, we don't all fully yet understand the penetrant. So we feel pretty good about that. The other thing to keep in mind is that the attack rates are a way that we've been able to do a clinical study. As we move forward with data commercially, we're going to look more at severity of patients, so patients that mainly have one attack if I can say it, over year can be even more disabled than patients who have more attacks because of the severity of attack. So we're going to look at severity of patients and the overall manifestation of disease. And of course, the detailed readout of our data will help us understand just how many patients we may be able to benefit.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [45]

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So Akshay, on the clinical studies?

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Akshay K. Vaishnaw, Alnylam Pharmaceuticals, Inc. - President of Research & Development [46]

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Yes. So I think the key aspect here is that we know that by targeting ALAS1, we are down-regulating the key mediators of the acute hepatic porphyrias, namely aminolevulinic acid and porphobilinogen or ALA and PBG. And it was the relationship between the levels of ALA and PBG and the predispositions attacks that really convinced the FDA to allow us to proceed with the study and even encouraged us to do the interim analysis that we did, looking at those biomarkers. Now whether you have 10 attacks a year or 20 attacks a year and of course, there are patients who suffer greater with that kind of frequency or whether you have 2 attacks a year, which in and of itself is not trivial, it is -- those attacks are mediated by ALA and PBG. So I think if the Phase III study reads out and convincingly shows consistent and durable reductions in ALA and PBG, which is what we anticipate based on the interim analysis in these endpoints in the study, then that bodes well for very frequent attack patients or even those with more sporadic attacks. And let's recall that these patients suffer, though, in not just from the acute attacks but even if there's symptomatologies between attacks. And I hope -- and we're going to be measuring this with nausea and fatigue and pain scales. I hope that those inter-attack symptoms will also abate or reduce. Let's look at the data when they come out. But if they do, then, again, that bodes well for patients that don't have the horrific -- in terms of attacks a year, but maybe have 2 or 3 because they too need help, and we believe this drug should help them.

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Operator [47]

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Our next question will come from Mani Foroohar with SVB Leerink.

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Mani Foroohar, SVB Leerink LLC, Research Division - MD of Genetic Medicines & Senior Research Analyst [48]

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I've got a quick one for Manmeet. So regarding the 2 years of runway to operating plan, I'm scratching a little bit on what's baked into that plan because you had a number of pivotal readouts, number of launches. What is baked in, in terms of potential expense to build up commercial infrastructure around vutrisiran to address the APOLLO-B population, the HELIOS population? And any additional incremental R&D build-out for assets that come out of the CNS, liver, ophtha portfolio. And then I have a quick follow-up.

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Manmeet Singh Soni, Alnylam Pharmaceuticals, Inc. - Senior VP ,CFO & Principal Accounting Officer [49]

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Sure. So Mani, if you refer to our guidance on R&D, which we gave this optimum for $520 million to $560 million range. That covers all of the plans, all the Phase III trials, which are going and the initial plans for building up inventory even for givosiran. So all of that's included into our guidance for 2019.

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Mani Foroohar, SVB Leerink LLC, Research Division - MD of Genetic Medicines & Senior Research Analyst [50]

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Okay. And as a quick follow-up, should we think about the growth in the stock-based component of comp as approximately in line with the percentage year-over-year growth in non-GAAP R&D expense, non-GAAP SG&A expense, are they approximately in line? And how do we -- how should we think about any potential chunkiness around events this year?

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Manmeet Singh Soni, Alnylam Pharmaceuticals, Inc. - Senior VP ,CFO & Principal Accounting Officer [51]

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Yes. And I think that's the reason we are not able to guide our GAAP expenses, and we have taken a measure to guide our non-GAAP expenses because it's very difficult to estimate stock-based compensation expense, realizing that most of -- or some of our stock based are dependent upon performance milestones and it depends on a couple of those factors. But to highlight or to answer your question simply, you should expect pretty much in the range what we had in 2018 as our stock-based compensation for 2019. You should not expect a huge jump from here.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [52]

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And Barry, do you have anything to add?

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [53]

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Well, just to give some color, you asked about -- Manmeet very well answered kind of the R&D expenses and the fact that the expense were baked in for the Phase IIIs we have planned in the time horizon. In terms of preparation for launch of givosiran, the capabilities that we built across supply chain, medical affairs and commercial are all leverageable for the givosiran launch. So very little has to be added in that respect. We will be adding additional customer-facing roles, but as a percent of our overall population base, that's pretty small add to prepare for givosiran.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [54]

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Yes. And I mean, just to take it one step further Mani, the -- you've mentioned our CNS and ocular investments as well, I mean, those are very small through the 2-year -- approximately 2-year period of our cash balance in light of the fact that there are still just -- well, we'll be just starting clinical studies during that period of time. So that's not really a major part of the expense but is an area that we are advancing with strong focus.

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Operator [55]

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(Operator Instructions) And our next question will come from Vincent Chen with Bernstein.

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Vincent Chen, Sanford C. Bernstein & Co., LLC., Research Division - VP [56]

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Thinking toward the givosiran readouts and trying to better understand the potential likelihood for additional liver function test elevation. Could you help us better understand the typical characteristics of the ALT elevations you've seen today with the siRNAs, both the one in the ENVISION study and also those in other programs, which are thoughts you attributed to a similar mechanism? I guess, for example, when in the course of treatment do ALT elevations typically occur? Are these events that typically occur fairly early on in the course of treatment for a given patient? Or can they occur at various points stochastically throughout the course of treatment? And as you think about this right now, is this likely to be a onetime highly rare event with givosiran? Or would you expect this is likely something where some minority of patients will have some sort of response like this and those patients simply won't be amenable to givosiran treatment, which is fine?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [57]

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Yes, Vincent, thank you. Akshay?

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Akshay K. Vaishnaw, Alnylam Pharmaceuticals, Inc. - President of Research & Development [58]

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Yes, thank you, Vincent, for the tripartite question. I mean, firstly, the LFT, I would say that it's not typical of the platform given that, as we have seen across the platform and we reported about 2% to 4% of patients may get LFT changes and there very well characteristically appear to be bumps in ALT, which are transient and reversible, not associated with a high [raw score]. That's important to note. And when they do come on in that minority of patients, they tend to come on, I would say, within weeks or months of the initiation of the RNAi therapeutic. Now we have plenty of examples of RNAi therapeutics that we've put in the clinic, where we've had no significant LFT changes at all. And I think in that regard the inclisiran experiments being reported by medicines companies, it's very important to note where over 3,000 patients, I believe, have been exposed to inclisiran, now many of them for over a year. And as you've heard from JPMorgan, the last DSMB met and guided that they should take the significant Phase III studies, 3 of them to completion and that, at that time, there appeared to be no significant safety concern, including the [safety of] LFTs. So I guess a very stringent task of one of our drugs in a very large population, many of the patients being elderly and fragile. The last question of why this might happen and what we can do to attenuate it, if I interpreted your question properly, let's also remember that the LFTs that we reported often occur in patients, they may be predisposed for one or more reasons. For example, in the context of porphyria, many of these patients have significant iron overload from human treatment and in what way that may synergize with treatment or may in and of itself be causing LFTs as a topic yet to be understood. So disease predisposition's important and what's causing the experience, we reported many of those patients have hepatitis B or hepatitis C as a background risk factor. So as usual, it's complicated, but it seems to be a low incidence event, transient, reversible. And the couple of INDs we filed recently with AAT02 and HBV02 are investigating the impact of this rather elegant GNA modification of the [C] sequence to see whether we can attenuate off-target effects and thereby aggregate LFT changes. And so those are the interesting studies to follow this year. But overall, we're optimistic about the progression and outcome, and the overall risk/benefit I still think will be very much in favor of the drug that's out there.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [59]

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Yes. And I would just add, Vincent, that as a reminder, at the time of the interim analysis, there was only one discontinuation from study and there -- we'll obviously update you on the full results. That was at 50% of the enrollment. We'll update you with the full results in the coming weeks, and we'll just wait till then. But I concur with Akshay's comments on this as well.

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Operator [60]

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And next question comes from Edward Tenthoff, Piper Jaffray.

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Edward Andrew Tenthoff, Piper Jaffray Companies, Research Division - MD & Senior Research Analyst [61]

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Nice update. Two questions if I may. Firstly, when it comes to kind of tafamidis coming into marketing cardiomyopathy, how would you guys detail ONPATTRO in those mixed patients? Do you get a sense that docs may be leaning more towards treating the cardiomyopathy? Do you think it'll be a situation where whichever manifestation is more prevalent? Do you think some patients may even get both? I mean, how are you guys kind of thinking about tafamidis as certainly not in the polyneuropathy patients but in those mixed, where they do have the cardiac enrollment?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [62]

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Yes, Ted. It's a great question. I'm going to let Barry answer, but just as a reminder, before Barry answers it, we are obviously not going to get into any details around our strategy because that is competitive. So I think, Barry, maybe you can make some high-level comments on this without getting into any details.

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [63]

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Yes. I mean, Ted, I would have said the best defense is offense, but maybe the Super Bowl is different than that. Look, we are out there in The United States promoting on-label, which is to treat the polyneuropathy of hereditary ATTR amyloidosis patients. Now we are educating disease awareness broadly across multiple disciplines, and as you've seen, we have interesting uptake with cardiology -- hematology representing the multisystem nature of the disease. So very simply, if a patient is an on-label patient, we believe -- recognizing that we have not been head-to-head studies that are on-label patients with polyneuropathy, we have the best drug for those patients based upon the APOLLO data and the lack of the polyneuropathy data for others. And that's sort of our approach, to make sure that on-label patients get an opportunity to get ONPATTRO. And what we're hearing, as I highlighted on the call, early commercial launch is -- and this isn't certainly every patient, but good patient stories and good physician experiences. And as you know, positive physician experiences often drive choice.

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Edward Andrew Tenthoff, Piper Jaffray Companies, Research Division - MD & Senior Research Analyst [64]

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Yes. And then are you able to discuss the APOLLO cardiac data with U.S. and/or European physicians?

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Barry E. Greene, Alnylam Pharmaceuticals, Inc. - President [65]

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So discuss. So in a promotional context, our salespeople can only promote on-label. In The United States, those data are not on-label, so the answer is no. In Europe, depends on the country and what the country rules allow. But in general, those are on-label, so when asked, they can be engaged. Now of course, in the context of medical information, the physicians are interested in talking about the data, they're certainly free to ask questions, and we have a variety of techniques for scientific exchange. They can ask for medical information request, which come in a letter. They can ask for some person to physically show up and talk to them. But those are reactive only upon physician requests.

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Edward Andrew Tenthoff, Piper Jaffray Companies, Research Division - MD & Senior Research Analyst [66]

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Yes, I appreciate that, and that's really clear. One last one if I may because I really like the program. How are things going with our friends Vir and the HBV program?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [67]

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It's going great. I saw George Scangos just a couple of weeks ago, and he was excited with the progress they're making. The dose escalation is proceeding in the human volunteer study, and we will look forward to having data from that effort later this year. It's an important program. As a reminder, Ted, we have an opt-in, a free opt-in at the end of Phase II to have 50% of the value of that program. So we have very strong economic incentive in the success of that effort, and we look forward to data readouts later this year from that.

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Operator [68]

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Our next question will come from Paul Matteis with Stifel.

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Paul Andrew Matteis, Stifel, Nicolaus & Company, Incorporated, Research Division - Co-Head of the Biotech Team, MD & Senior Analyst [69]

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Just a couple quick ones on cemdisiran. I saw you announced a program in IgA nephropathy. I was wondering if you'd talk about the clinical rationale there and the planned study design. And then secondarily on that same asset, I was wondering if myasthenia gravis is on your radar given that the data for Soliris in gMG definitely suggests a different biological role for C5 and maybe suggests that cemdisiran could potentially have a comparable profile.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [70]

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Yes, all of those are great -- 2 great questions. I'm going to turn it over to our resident complementologist, Akshay, to comment on both.

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Akshay K. Vaishnaw, Alnylam Pharmaceuticals, Inc. - President of Research & Development [71]

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Thanks, John. Regarding cemdisiran in IgA nephropathy is relatively straightforward in addition, obviously, to the significant unmet need. The IgA nephropathy represents globally the most common inflammatory monocyte [disease] resulting in renal failure, and so there's no question that these folks need help. Even though many of them get better by themselves, there are hundreds and thousands others globally in totality that suffer significantly with renal impairment or renal failure. The evidence for complement activation is clear, and you see local complement deposits in the glomerulus, including C3 deposits and split complement products there. And finally, it's unsurprising that the complement is part of the pathophysiology because the iatrogenic basis of the disease would be more worked out. Now we know that it's due to an autoantibody complex depositing in the renal glomerulus and these complexes activate complement. We know immune complexes activate complements. So we think that in combo with other inflammatory renal disorders, the rationale for complement is strong, and so we've initiated this study, there is a run-in period, do the study to understand what's going on in terms of complement turnover and renal function and then they get dosed with cemdisiran for a period of time. We're doing all of this for -- as a prequel to expanding cemdisiran studies into a broader range of indications and with the proof of concept we hope for IgAN in hand, will be -- will expand to myasthenia gravis, which is body pain and other validated setting for complement inhibition. So I hope that addresses some of your questions.

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Paul Andrew Matteis, Stifel, Nicolaus & Company, Incorporated, Research Division - Co-Head of the Biotech Team, MD & Senior Analyst [72]

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Yes. And on myasthenia gravis, any additional thoughts there?

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [73]

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As to when we will initiate? No, I think, Paul, I think Akshay sort of wrapped it in to the last part of his question, which is simply to say that we're obviously interested in the -- in that indication, the validation of complement's role in that indication, not only in the eculizumab experience, but I also think the recent raw data in that regard holds encouraging results for that regard. And yes, we do believe that if this thesis plays out that it will be of interest to test cemdisiran in that setting. So we certainly have it on our radar, but there's no specific guidance that we're giving at this point in time.

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Operator [74]

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And our last question will come from Terence Flynn with Goldman Sachs.

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Terence C. Flynn, Goldman Sachs Group Inc., Research Division - MD [75]

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Sorry, I jumped on late, so apologies if this was already asked. But any insights you guys can share on the ONPATTRO start forms in January versus December? And if you can't answer that, maybe can you tell us in terms of givosiran just how much data will actually be in the top line press release in March ahead of the EASL conference? I'm not sure how strict they are about data disclosures. I just want to understand how much data will actually get in the press release.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [76]

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Yes, Terence, let me answer -- this is John. Let me answer both of those questions. I mean, we unfortunately can't give you any color on January because we'll need to wait for our first quarter results. But again, we do think we're pleased with how the launch is going as we reported our fourth quarter, and we're pleased with what -- how it's going. So that's point #1. Point #2 on what we expect to report on the top line, look, I think a good example of what we will top line is what we did with patisiran when the APOLLO data were out, which is p-value, commentary on primaries and secondaries that hit without any data per se and then enough safety information -- certainly not tables of safety data, but enough safety information on relevant safety findings so that investors can understand the full balance of the data. So that -- if you looked at the patisiran top line that we did in 2017, that's a good example of sort of a template that we would look to. If there's any other things that emerge that we feel -- without compromising our presentation for the whole day at EASL, we'll consider. But that's what -- I think that's what I would guide you to look at as a good metric. Akshay, anything else to add to that?

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Akshay K. Vaishnaw, Alnylam Pharmaceuticals, Inc. - President of Research & Development [77]

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I think all good. Yes, thank you.

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John M. Maraganore, Alnylam Pharmaceuticals, Inc. - CEO & Executive Director [78]

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All right. Well, thank you. Thank you. So with that, want to thank everybody for joining us this late afternoon. We're excited about 2019 and the progress that we are expecting to make and look forward to updating you very soon, especially on the upcoming givosiran data from ENVISION. So stay tuned. Thank you, everybody.

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Operator [79]

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Thank you, ladies and gentlemen. This concludes today's teleconference, and you may now disconnect.