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

Terence Flynn - Goldman Sachs & Co. LLC Ted A. Tenthoff - Piper Jaffray & Co. Gena Wang - Barclays Capital, Inc. Madhu Kumar - B. Riley FBR, Inc. Vincent Chen - Sanford C. Bernstein & Co. LLC Maury Raycroft - Jefferies LLC Alan Carr - Needham & Co. LLC Irina Margine - Cowen and Company David N. Lebowitz - Morgan Stanley & Co. LLC.

Ladies and gentlemen, thank you for standing by, and welcome to the Alnylam Pharmaceuticals Conference Call to discuss First Quarter 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 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 on the phone are John Maraganore, Chief Executive Officer; Barry Greene, President; Akshay Vaishnaw, President of R&D; Manmeet Soni, Chief Financial Officer; and Yvonne Greenstreet, Executive Vice President and Chief Operating Officer.

For those of you joining 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 in slide 2, John will provide some introductory remarks and provide some general context; Akshay will review our R&D progress; Manmeet will review our financials; Barry will provide an update of our commercial readiness efforts; and Yvonne will provide a brief summary of upcoming milestones before opening the call for your question.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospect, which constitute forward-looking statements for the purpose of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recently Annual Report on file with the SEC.

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 a useful information to investors regarding our financial condition and results of our operation.

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I will now turn the call over to John..

Thanks, Christine, and thank you, everyone, for joining the call today. The first quarter of 2018 was an exciting time as Alnylam continued its transition toward a commercial-stage company and toward achievement of our Alnylam 2020 goals. We are at the cusp of bringing patisiran to the market, with approvals anticipated in the U.S.

in mid-2018 and in the EU in late 2018. With today's announcement of having enrolled our 30th patient in ENVISION, we are now positioned to have top line Phase 3 interim analysis results with givosiran in the September timeframe, with a potential NDA filing at/or around year-end, assuming positive results.

And now, we believe today's update on our lumasiran program will significantly accelerate our timeline for bringing yet another potential breakthrough medicine to patients with the Phase 3 start moved up to mid-2018 and top line data expected in 2019 which, if positive, could enable an NDA in early 2020.

In addition, we remain on track to start another Phase 3 later this year for ALN-TTRsc02, a once-quarterly subcutaneous treatment option for all forms of ATTR amyloidosis, with the potential to significantly extend our opportunity across all patient groups.

Akshay will go into these important development milestones in just a minute, and Barry will discuss our commercialization efforts shortly thereafter, but let's take a step back to reflect on how Alnylam is now positioned for the future.

As a company, we expect to have launches of four potentially transformative medicines, three of which are designated breakthrough therapies by the FDA, on an annual basis between 2018 and 2021.

We have global rights for all of these programs and intend to commercialize them directly in North America, Europe, Japan and other significant markets around the world, creating a steady flow of Phase 3 data readouts, regulatory submissions, potential product approvals, and the opportunity for significant revenue growth over this period and beyond.

At the same time, our partner, The Medicines Company, has fully enrolled its Phase 3 ORIONs 9, 10 and 11 trials of inclisiran with over 3,500 patients and data expected in 2019.

And our partner, Sanofi, is advancing fitusiran in the ATLAS Phase 3 trials, with the goal of expanding its newly-acquired leadership position in hemophilia, a 10-billion dollar market. In both cases, Alnylam stands to benefit with significant royalties that approximate profit share levels.

And with our product engine capable of yielding two to three new INDs per year and possibly more, we believe we have the pipeline to continue to deliver sustainable growth from 2021 and beyond. In short, we believe the next three to four years are truly going to be remarkable for Alnylam's evolution, growth and value creation.

Of course, what matters the most is the difference we can make in patients' lives, and as we advance patisiran, givosiran and lumasiran and then ALN-TTRsc02 towards the market, we're very excited about the potential impact we can have for patients, their families and their caregivers.

So, with that, let me turn the call over to Akshay to review our recent R&D highlights. Akshay, take it away..

Thanks, John, and good afternoon, everyone. Let's begin with patisiran, which is in development for the treatment of hereditary ATTR amyloidosis.

Patisiran is currently under regulatory review by the FDA and EMA, and we continue to work collaboratively with both agencies through the patisiran review process, with the goal of making this medicine available to patients as quickly as possible upon approval. As you know, last fall, we presented results from the APOLLO Phase 3 study of patisiran.

In APOLLO, patisiran demonstrated the potential to improve these manifestations in a majority of patients with a negative change in 18 months in the mNIS+7 primary endpoint and the Norfolk-QOL key secondary endpoint compared to baseline.

Patisiran is the only investigational or approved therapy to have demonstrated potential improvement in hATTR amyloidosis disease manifestations in the majority of patients in the pivotal study. Furthermore, patisiran was associated with an encouraging safety profile.

APOLLO is the largest clinical study of patients with hATTR amyloidosis conducted to date, and we continue to gather and analyze new data to describe the diverse aspects of patisiran's efficacy and safety.

In this regard, we were pleased to present new data just last week at the AAN Conference from a post-hoc analysis of APOLLO data, looking at the impact of patisiran treatment on hospitalization and mortality. In the figures on slide 8, mortality and hospitalization events depicted over 18 months.

The figure on the left depicts composite rate of all-cause hospitalization and mortality. As you can see, there was an approximately 50% decrease in this rate over 18 months in patisiran-treated patients relative to placebo.

Similarly, in the figure on the right, we observed an approximately 45% reduction in the composite rate of cardiac hospitalization and all-cause hospitalization – and all-cause mortality in patisiran-treated patients relative to placebo.

We believe these post-hoc data strengthen the existing body of evidence demonstrating that patisiran, if approved, has the potential to be a transformative treatment for patients with all forms of hereditary ATTR amyloidosis.

As you may recall, with regard to safety and tolerability in the APOLLO study, there were 13 deaths overall, none of which were considered related to study drug; and the frequency of deaths was lower in the patisiran group as compared to placebo.

Adverse events leading to treatment discontinuation were lower in the patisiran group as compared to placebo. The most commonly reported adverse events that occurred more frequently in patisiran-treated patients were peripheral edema and infusion-related reactions. These were generally mild to moderate in severity.

We also recently presented additional data at the ISA Meeting in March. These included results from the cardiac subpopulation, highlighting that patisiran treatment was associated with improvements in multiple measures of cardiomyopathy.

These improvements, in conjunction with demonstrated benefits and neurologic improvement, appear to be associated with favorable effects on gait speed, an important indicator of functional status.

Furthermore, improvements across a range of echocardiographic parameters, including left ventricular wall thickness and left ventricular strain, as well as a positive effect on levels NT-proBNP, a cardiac stress biomarker, also seeks the potential for significant benefits of patisiran for patients with hATTR amyloidosis with cardiac involvement.

We believe we're on track for mid-2018 approval in the U.S., with an August 11 PDUFA date and a late 2018 approval in the EU where our application is being reviewed under an expedited assessment. We also plan to submit a J-NDA in Japan in mid-2018, as well as other regulatory packages in additional rest of the world countries later in the year.

In addition to patisiran, we're also developing ALN-TTRsc02 as an investigational RNAi therapeutic for ATTR amyloidosis. ALN-TTRsc02 uses our ESC-GalNAc conjugate platform technology and allows us subcutaneous administration.

In a Phase 1 study, single doses of ALN-TTRsc02 demonstrated robust TTR knockdown and was maintained for over 300 days and supported the potential for a low dose of 25 milligrams given as a once-quarterly subcutaneous injection to achieve levels of TTR knockdown comparable to those observed with patisiran in the APOLLO study.

ALN-TTRsc02 is generally well-tolerated, with no SAEs or study discontinuations due to AEs. Consistent with our previous guidance, we expect to advance ALN-TTRsc02 into a comprehensive pivotal Phase 3 program in late 2018.

While our final trial designs are pending FDA and EMA alignment, we believe that a study with TTR knockdown as an endpoint would support an approval of ALN-TTRsc02 in the hATTR amyloidosis population, bringing a very attractive subcutaneously administered treatment option to patients as rapidly as possible.

Regarding the wild-type ATTR opportunity, we'll need to see the complete result from Pfizer's ATTR-ACT study with tafamidis later this year. But we're now considering the potential for a head-to-head study comparing ALN-TTRsc02 with tafamidis in the setting of ATTR cardiomyopathy including wild-type disease.

Let's now turn to our givosiran program, where we've also made significant progress in recent months. As you know, givosiran is in development for the treatment of acute hepatic porphyrias. At EASL last month, we presented complete data from all four-dose cohorts from part 3 of the Phase 1 trial, as well as data from the ongoing OLE study.

In part 3 of the Phase 1 study, givosiran administration resulted in reductions in both minor level in the acid or ALA, the primary neurotoxic intermediate responsible for disease manifestations, and porphobilinogen or PBG, another disease biomarker.

Moreover, given givosiran administration led to mean reductions in the of the annualized attack rate of 83% and in the annualized hemin consumption of 88% relative to placebo.

The vast majority of the Part C patients rolled over into the early study and have now received givosiran treatment for up to 22 month, with the mean treatment duration of about 11 months. With expanded dosing, there was evidence for further improvement of clinical activity as patients transitioned from the Phase 1 into the Phase 1/2 OLE.

Specifically, we observed mean reductions in AAR of 93% and annualized hemin use of 94%, relative to the attack rate and hemin use recorded for the Phase 1 run-in period.

These reductions in AAR and hemin use exceeded those observed in the treatment period during Phase 1, suggesting that continued givosiran dosing can generate even further amelioration to these symptoms. In terms of safety, six patients presented with serious adverse events in the Phase 1 study with none assessed as related to study drug.

In the OLE study, two patients had SAEs, one SAE assessed to be definitely related to givosiran occurred in a patient who had an anaphylactic reaction after receiving the third dose of givosiran. The patient had a past history of asthma, oral allergy syndrome, and allergic reactions to acne cream and possibly latex gloves.

The event resolved with medical management and the patient subsequently did continue from the study. Furthermore, there were no anti-drug antibodies, including IgE, detected in this patient.

Notably, this case represents the only report of an anaphylactic reaction that we have seen in over 2,500 patients dosed with GalNAc conjugate of siRNAs across our entire pipeline, giving us reassurance that this is an isolated event.

We also announced today in our earnings release that we've enrolled the first 30 patients in the ENVISION Phase 3 study of givosiran. These patients comprise the total (13:19) in which we will report results from an interim analysis when they reach three months of dosing.

This interim analysis will evaluate reductions in the levels of urine ALA as a surrogate endpoint that is reasonably likely to predict clinical benefit.

If the interim analysis is positive and pending regulatory support, we'll then be in a position to file an NDA for an accelerated approval based upon the interim study result at/or around year end 2018, representing a significant acceleration in our efforts to bring this promising investigational medicine to patients.

We've also announced in our earnings release that we've had positive discussions with European regulators regarding the path forward with givosiran.

On some of the path forward for conditional marketing authorization under an accelerated pathway, market access considerations lead us to believe that the best path forward in Europe is to wait for the full ENVISION's trial results in 2019 and then submit the MAA with full results assuming they're positive.

Let's turn now to recent progress of lumasiran, which is in development for the treatment of primary hyperoxaluria type 1 or PH1. As a reminder, PH1 is an ultra-rare orphan disease primarily in children in which oxalate crystals build up in the kidney, leading to painful and recurrent kidney stones and damage the kidney and other tissues.

Treatment options are limited, and typically involve chronic dialysis and often a dual liver-kidney transplant. Lumasiran targets the enzyme glycolate oxidase, thereby depleting the substrate necessary for the production of oxalate, which directly contributes to the pathophysiology of PH1.

We were very pleased recently to announce that we've retained global rights of lumasiran following the decision by Sanofi to decline its opt-in for lumasiran's development and commercialization.

We've now completed enrollment in the Phase 1/2 study with 20 PH1 patients, and we expect to report additional clinical results later this year with patients now beginning to roll over into the Phase 1/2 OLE study which will evaluate the long-term safety and efficacy of lumasiran in PH1 patients.

Based on our promising Phase 1/2 data, we were pleased to receive Breakthrough Designation in the U.S. and PRIME designation in the EU. Just this morning, we announced that we've reached our alignment with the FDA on the design of our pivotal trial for lumasiran.

Specifically, the pivotal trial will have a primary endpoint based on reduction of urinary oxalate at six months. The study will have a sample size of approximately 25 patients.

Based on this design, we now expect to start the Phase 3 study in mid-2018, earlier than our previous guidance of late 2018, and to report top line results from this trial in 2019.

Assuming positive results, we expect to be in a position to submit an NDA in early 2020, which represents a significant acceleration in our efforts to bring this investigational medicine to patients.

Let's turn briefly to our (16:08) program, and I'll begin with our fitusiran program, which is in development for the treatment of hemophilia and rare bleeding disorders. Our Phase 2 OLE study is back up and running and in the first quarter, we were pleased, together with our partners at Sanofi, to initiate dosing in the ATLAS Phase 3 program.

Turning to inclisiran for the treatment of hypercholesterolemia, we've been very impressed with the execution by our partner, The Medicines Company, having fully enrolled the ORION-9, 10 and 11 studies with 3,660 patients. Hereto, we look forward to seeing topline results from the Phase 3 program in 2019.

Importantly, these studies comprised a larger safety database for GalNAc-siRNA conjugate and we look forward to further safety updates going forward, which so far have been encouraging. As of now, the inclisiran studies have provided us with over 1,000 patient years of exposure and every day adds another five years of safety data.

The Medicines Company is also planning to conduct a cardiovascular outcomes trial, ORION-4, which is expected to enroll 15,000 patients and begin in mid-2018. Finally, we're also excited about our next wave of clinical programs.

We've guided to have at least one new CTN in 2018, and we are on track to achieve or exceed this goal, which also includes the advancement of our ESC+ platform programs beginning with our ALN-AAT02 program for Alpha-1 antitrypsin deficiency-associated liver disease, and ALN-HBV02 with our partner, Vir.

In summary, we had a very exciting first quarter of 2018 and in the recent period having now advanced a pipeline with four programs in Phase 3 with one under regulatory review and multiple earlier stage programs. With that, I'll now turn it over to Manmeet to review our financial results.

Manmeet?.

our cash position, our first quarter results, and our updated 2018 financial guidance. So turning to slide 19, let me start with our cash balance. We maintained a strong balance sheet, ending the first quarter of 2018 with approximately $1.6 billion in cash, cash equivalents, fixed income marketable securities, and restricted investments.

Moving to our financial results for the first quarter, we recognized $21.9 million of collaboration revenue during the first quarter of 2018 as compared to $19 million during the first quarter of 2017.

The amount recognized during the first quarter of 2018 relates primarily to the achievement of $50 million milestone payment due from Sanofi Genzyme upon dosing of the first patient in the ATLAS Phase 3 program for fitusiran recognized using the proportionate (sic) proportional performance method based on the new revenue recognition standard.

As a result of our adoption on January 1 of the new revenue recognition standard, we recognized significantly lower revenues during the quarter from our allies at Sanofi Genzyme. To compare under the previously applicable revenue recognition guidance, we would have recognized approximately $33 million more in revenue during the first quarter.

Moving to expenses, our GAAP R&D expenses were $96.9 million in the first quarter of 2018 as compared to $87 million in the first quarter of 2017. Non-GAAP R&D expenses were $86.7 million in the first quarter of 2018 as compared to $78.3 million in the first quarter of 2017.

The increase in R&D expense was due primarily to increased compensation and related expenses as a result of an increase in head count during the period as we expand and advance our development pipeline. Non-GAAP R&D expenses exclude stock-based compensation expense.

Our GAAP G&A expenses were $72.4 million in the first quarter of 2018 as compared to $38.5 million in the first quarter of 2017. Non-GAAP G&A expenses were $63 million in the first quarter of 2018 as compared to $31.5 million in the first quarter of 2017.

The increase in G&A expenses was due primarily to an increase in commercial and medical affairs head count and commercial-related services to support corporate growth and prepare for the potential launch of patisiran in 2018 and potential additional product launches in 2019 and thereafter.

Non-GAAP G&A expenses also exclude stock-based compensation expense. With respect to guidance for 2018, we remain on track to end 2018 with approximately $1 billion in cash, cash equivalents, and fixed income marketable securities, restricted cash, and restricted investments.

We believe this will provide Alnylam with a very strong balance sheet at the end of 2018 to support continued development and commercial activities.

As you may have noted in the press release issued today, we updated our 2018 annual non-GAAP R&D expense guidance to be in the range of $420 million to $460 million as compared to our previous guidance range of $400 million to $440 million.

This increase of $20 million in the non-GAAP R&D expense guidance range reflects additional expenses expected due to the inclusion of the lumasiran program and our ongoing program portfolio. We are also reaffirming our 2018 annual non-GAAP SG&A expense guidance to be in the range of $280 million to $320 million.

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

Barry?.

Thanks, Manmeet. As you've heard from John and Akshay, we've made remarkable strides in the first quarter in recent period. Let me first provide some comments on our commercial preparation for patisiran. As of now, we believe we are launch-ready in the United States. Our U.S.

field team is onboard and we're in a position to get patisiran to patients as soon as possible once the drug is approved. We'll also soon be launch-ready in Europe where we've begun to hire and onboard our field and customer-facing team in our earliest launch countries. Outside of the U.S.

and Europe, we also plan to have an Alnylam presence in Japan later this year. As you are aware, a key challenge in hereditary ATTR amyloidosis, as in many orphan diseases, is raising awareness and improving patients' identification. The opportunity to find more patients is dramatic. The field is finding new pathogenic mutations annually.

With the emergence of three companies actively educating on this disease, we feel confident that we can make significant inroads on awareness, and in shortening the diagnostic process. To do so, we must acknowledge the challenges we've seen in the patient journey to diagnose and develop ways to address them.

As we speak with patient groups, they report that many patient journeys take longer than two years, and some have reported over a decade of misdiagnosis and hospitalizations. Alnylam has been working diligently to improve diagnosis through a number of initiatives.

For example, we have a program called Alnylam Act, a free third-party genetic testing service in the U.S. and Canada. At the AAN Meeting last week, we provided an update on the success of Alnylam Act where approximately 4,600 samples have now been tested, which has led to the identification of TTR mutations in about 350 patients.

Among other efforts, we're also pleased to have an active expanded access program in the U.S. and Europe, providing early access to patisiran in response to requests from treating physicians for eligible patients.

As we announced in our press release, we've now fulfilled physician requests for more than 150 patients who have been dosed with patisiran in the U.S. and certain European countries.

We believe this is indicative of the unmet need in hATTR amyloidosis and a measure of the increased disease awareness among health care professionals, and patients and their families. It seems that we're now seeing a new beginning where in certain instances patients are coming forward to seek help with greater knowledge of their potential disease.

Aided by genetic testing and counseling and the hope of treatment, some diagnosed patients are also starting to come forward to help other family members seek diagnosis. While most have not historically pursued testing for their families, we're getting to see the very beginning of a trend in this direction.

And certainly, this is a transformative time for patients with hATTR amyloidosis. We're incredibly excited as we plan to launch the first ever commercial launch of an RNAi therapeutic, and we're on track with launch readiness, as I mentioned before.

Just like the steps we've taken to prepare for patisiran's commercial advancement, we're now taking similar activities for givosiran. For example, we recently expanded Alnylam Act to include testing and counseling for individuals who may carry gene mutation known to be associated with porphyrias.

To date, approximately 50 samples have been submitted by physicians with patients that exhibit symptoms consistent with porphyrias, out of which eight have tested positive for known mutations associated with the disease.

Furthermore, now that we have global rights to lumasiran, we're putting in place the capabilities to support PH1 community in raising disease awareness. Now, I'd also like to spend a moment to touch on the recent top line results regarding the Phase 3 ATTR-ACT study with tafamidis.

We look forward to seeing complete results from the study which we now expect in late August at the ESC Conference in Munich. At a high level, a positive outcome from this study is very good for patients, clearly having more treatment options available serves to benefit patients particularly when it comes to a rare, devastating fatal disease.

As we discussed on this call and previous calls, the biggest challenge for hATTR amyloidosis is disease awareness and patient finding.

Therefore, we believe that having other companies actively working to raise disease awareness, shorten the patient journey and improve patient diagnosis will result in expansion of the overall market in a way that should ultimately increase the number significantly of patients diagnosed.

We see the hATTR amyloidosis disease setting as one that will benefit substantially more for market growth versus just market share. Similar to what's been seen before in other market settings like multiple sclerosis and HAE.

And, of course, given the data from APOLLO in terms of primary and subsequent analysis, we remain confident that the patisiran product profile will be the best in class for patients. As patisiran is the only investigational or approved therapy that has been demonstrated to show improvements in disease manifestations in the majority of patients.

And now, we expect there'll be more patients and they'll be identified sooner, leading to potentially greater benefit. With that, I'll now turn the call over to Yvonne to review our mid-2018 goals.

Yvonne?.

Thanks, Barry. I'll be referring to slide 24 to review our mid-2018 goals. In 2018, most importantly, we expect to transition to a commercial space company with U.S. approval launch of patisiran anticipated in mid-2018, and EMA approval of launch in the EU anticipated in late 2018.

We will also start our global efforts on patisiran with a J-NDA filing expected in mid-2018 and additional rest of world regulatory submissions by year-end. In the September timeframe, we expect to report topline interim analysis from the ENVISION Phase III study of givosiran in acute hepatic porphyrias leading to a potential year-end NDA submission.

And as we announced this morning, we also expect to start our lumasiran Phase III study in mid-2018. Also, we'll be advancing our additional Phase III programs together with our partners. With fitusiran, we and Sanofi expect to enroll patients in the ATLAS Phase III program throughout the course of this year.

And we'll also continue to support The Medicines Company as they execute on the ORION Phase III program. And they have also guided their intention to kick off a cardiovascular outcome study called the ORION-4 in mid-2018. With that, I will now turn the call back to Christine to coordinate our Q&A.

Christine?.

Thanks, Yvonne. Operator, we will now open the call for your questions. For those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions..

And our first question comes from the line of Alethia Young with Credit Suisse. Your line is now open.

Hey. This is Alli (29:25) on for Alethia. Thanks so much for taking the question.

Just with the tafamidis' recent results, can you give a bit more color on how you think this impacts the market opportunity for patisiran in hereditary ATTR patients who don't have neuro symptoms? So just can you give more details on what your strategy to compete in this segment will be? Thanks..

Yeah, great. Thanks, Alli (29:46).

Do you want to handle that, Barry?.

Yeah. So, Alli (29:50), as we talked about in the call, the biggest issue we face with hereditary ATTR amyloidosis, and that's a global (29:57), is getting patients found and appropriately diagnosed. As I mentioned, the patient journey can be extremely long with many patients reporting taking two years and some over a decade to get properly diagnosed.

So we believe that in general with more voice out there educating cardiologists, neurologists, neuromuscular specialists, gastroenterologists to look for the red flag symptoms of the disease and get diagnosis earlier, that the market growth and number of patients can be significant.

So we're looking forward to seeing all the data for all the products out there, including tafamidis, we don't know the data yet. And again, we believe that multiple voices will significantly increase the pool.

Now, as we think about the various products, we're incredibly secure in the product profile we have with patisiran both in terms of efficacy and safety and, as mentioned in the call, believe that it's the most attractive profile and option for patients..

Yeah. I'll just add one thing, Alli (30:57). Obviously, the patients, we'll have to see how the data come out with tafamidis, we look forward to that in August.

But patients will, if we look at the historical tafamidis data where you see a slowing of disease progression, patients will have a choice to either have a drug like patisiran, which is well-tolerated and shows a significant improvement in the disease in the majority of patients versus a drug that slows things down a little bit.

So that's the type of trade-off that will be out there for patients, and we think that'll be relevant for all segments of the hereditary ATTR population.

Of course, we don't have data to support the wild-type setting and that clearly is an area where tafamidis might be useful until we have data with our TTRsc02 program, which we're also advancing into the wild-type setting. So I hope that answers your question..

Great. Thanks..

Thank you..

Thank you. And our next question comes from the line of Terence Flynn with Goldman Sachs. Your line is now open..

Hi. Thanks for taking the question. Maybe just wondering if you guys are still confident you'll be able to secure a broad label for patisiran that would allow you to treat a range of hATTR patients. And then on Slide 8, you show this composite of hospitalization mortality.

So when we see the tafamidis data later this year, do you think we're going to be able to compare across these studies? Or are there any important differences as we think about kind of comparing and contrasting these different data sets? Thanks..

Thanks, Terence. Let me just touch on the first one, and then Akshay should as well, and then we go to the second question.

Look, we believe that the totality of the APOLLO data for patisiran demonstrate an effective patisiran across the entirety of hATTR disease manifestations, and the data are very strong across primary endpoints, secondary endpoints, and exploratory endpoints.

And our submission to the FDA has been around a broad indication, and we believe the science and the data support that. Now, there's always a review process, and so we will always have that discussion with the FDA. But we believe and still feel confident around our data set that supports a broad label.

So Akshay, anything to add to that?.

Yeah. No. I mean I agree with that, and I just think the sheer consistency of endpoints that we – the outcomes of the endpoints that we had both across the neuropathic aspects, cardiomyopathic aspects, as well as quality of life, activities of daily living, body mass, and the autonomic features including diarrhea.

Everything was in favor of the drug, and so that's also very encouraging and bodes for potential improvement in patients with a wide spectrum of disease.

With respect to the recent release of the post-hoc analyses looking at all-cause hospitalization mortality overall, and then also then in the cardiac hospitalization setting, these data, obviously, with the caveat of them being post-hoc are nevertheless rather encouraging, 45% to 50% reductions in event rate across the two analyses relative to placebo and I think quite consistent with the overall picture as I just outlined in terms of all the other newest endpoints that favored the drug.

As to comparing to any tafamidis data released later in the year, these are separate studies, and of course, we have to be cautious when comparing two separate studies. The study populations were different. This is an hATTR amyloidosis population that have had neuropathy and cardiomyopathy.

The tafamidis study is in a population that's been defined as having TTR cardiomyopathy, both mutant and wild-type. And so, I think, we'll have to look at the data in more detail before we attempt to analyze what are the (34:49) in which patients are most appropriate to get either drug..

The only other thing I'd add, Terence, in terms of looking at it, remember that clinical studies are what they are. The clinical study data will see for tafamidis when we see it in August with a longer study, so it's hard to compare endpoints, time points as well..

Thank you. And our next question comes from the line of Ed Tenthoff (sic) [Ted Tenthoff] with Piper Jaffray. Your line is now open..

Great. Thank you very much.

Can you hear me okay?.

Yes, we can hear you..

Yeah.

You didn't change your name to Ed did you, Ted?.

Say again? Say again?.

You didn't change – the operator called you Ed. Never mind..

Yeah, that's all right. That's all right. It happens a lot. So excellent update. I really appreciate the detail you guys are providing and congrats on lumasiran. I wanted to get a sense for that market opportunity. Obviously, we've been focused on sort of some of the other assets and near-term milestones.

So I wanted to get a sense of really how big that market opportunity was. I want to sort of snuck up on me a little bit. Appreciate it. Thanks..

Yeah. Let me start and then Barry and perhaps Yvonne can jump in as well if I left something unturned. I'll start by just really emphasizing the enormous disease burden in this setting, obviously, typically presents within the pediatric setting, so these are children.

In fact, the patients in our Phase 1/2 study we have kids as young as six years of age. They develop these kidney stones, recurrent kidney damage. They can develop broader systemic effects including cardiac manifestations.

It is ultimately a fatal disease for many patients with really only a double liver/kidney transplant as the only available treatment option for them. So just a disease of enormous burden..

Yeah..

The epidemiology data would indicate that there are a few thousand patients in U.S. and Europe that are out there, but there are also likely patients that have more milder forms of the disease that are not currently diagnosed as having mutations in the gene that is responsible for primary hyperoxaluria.

Of interest, there was a recent science paper that highlighted in a (37:30) study the identification of a significant number of patients with the disease mutation who prior to that had not been diagnosed. So, again, a few thousand patients, probably some level of under diagnosis, maybe not as much as we see with hATTR..

Yeah..

But a few thousand patients in the U.S. and Europe. I don't know if Barry and Yvonne....

Yes. I guess I'd add in is, just to emphasize what John said, very, very sick kids find their way to pediatric nephrologists and get diagnosed.

And we see an opportunity, obviously, to intervene earlier in diagnosis and maybe prevent kids from going on dialysis, or those that are already on dialysis, lowering the burden of dialysis, which is, as we talked about, six days a week, probably needs seven, but six days a week to give moms a break.

But as John mentioned, what we're also going to be exploring are those that have PH1 but develop kidney stones a little bit later in life. It could be in their teens or their early 20s that still live with significant risk due to the disease. And understanding that patient population is something we're embarking on.

Now, that could broaden out the number of potential patients as well..

And Yvonne, anything else to add? No. You're set. Good.

Ted, hopefully, that helps?.

It does. And I just have to comment. I think back to the IPO and 14 years of progress, and it's really great to see you guys delivering here on the promise of RNAi. So, keep up the good stuff..

Thank you, Ted..

Looking forward to the patisiran launch. Thanks..

Thank you, Ted..

Thank you. And our next question comes from the line of Gena Wang with Barclays. Your line is now open..

Thank you for taking my question. Maybe just follow Terence's question.

Wondering, have you submitted new data for all-cause hospitalization and mortality to the FDA, and do you expect these data to be included in the label?.

I think I could quickly handle it. These are data that are in the NDA submission, and we would not expect these type of data in a label, it's a post hoc analysis, Gena, so we would not. But certainly, these data are in the NDA, and these are data that we'll certainly aim to publish in the future.

Anything to add to that?.

None. Agree. Agree..

Okay.

And then just quickly, do you have any change on the pricing strategy giving tafamidis data?.

Barry, do you want to handle it?.

No. We use the same strategy we've articulated before. We believe that patisiran is offering extremely high value for this rare, debilitating, often fatal disease with reversal of disease manifestations in a majority of patients, and they're going about it that way.

We're also, as we've articulated, working with payers to make sure that the right kind of agreements are put in place so that access is not an issue, and that's going incredibly well..

Okay.

And last, just quickly on lumasiran, what is the European feedback on registration trial? Is it possible to also have a biomarker as a primary endpoint?.

Yes.

Akshay, do you want to handle that?.

Yes. We have that work ongoing, but we're confident because of the body of work that already exist in the literature that urinary oxalate represents biomarkers that could support approval. So work is ongoing, but we're confident. Yes..

And we will certainly engage the EMA. We have prime designation as you know, Gena. We'll engage the EMA on the study design features that we've discussed with the FDA but feel pretty good about how we'll move forward there..

Thank you very much..

Thank you..

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

Hey, guys. It's Eric (41:33) in for Anupam. Thanks for taking the questions. I just wanted to follow up on your comments about the potential breadth of hereditary ATTR label with patisiran and just wondering whether they similarly apply to CHMP as well as FDA.

Are there sort of any differences in the conversations that you're having around label breadth between the different agencies? And secondly, it sounds like from their recent earnings call that Pfizer is also looking to re-engage or re-pursue tafamidis in the U.S. for polyneuropathy.

I'm just wondering based on what you're hearing from physicians whether you anticipate tafamidis either through (42:22) clinical development being sort of a hurdle to commercial uptake? In predominately polyneuropathy patients, do you kind of see a window with which you kind of have to execute on to establish patisiran as a standard of care in a population? Thanks..

Yeah. Let me tackle the questions, and then Akshay and Barry can jump in, Yvonne as well. The first question on EMA. Well, first of all, we're not, Eric (42:55), going to go into details or discussions which are confidential with regulators, and we're dealing with a competitive landscape as well so we're going to be protective around that.

But we have – we do believe the data from patisiran and APOLLO support the broad label, and we believe that that broad label is supported both in the U.S. and in Europe, so we've kept consistent with that. But these are discussions that are still ongoing with regulators and ultimately, we'll see where the labels end up.

But we do believe the data support the breadth of impact across the entirety of hereditary ATTR. So that's the answer to your question there.

Regarding your second question on tafamidis, we think it's possible that they will – I mean, if I were them, I would look for a broad label as well including the neuropathy segment that it's possible that they get that with the FDA. As you know, they were rejected in the U.S.

because they didn't hit their primary endpoint but they were approved in Europe. So I think it's very possible that they get a polyneuropathy on their label. But I think that we know what tafamidis does in that setting, and it slows down disease a little bit.

And if you go to the 80 milligram dose, you're not going to do better than diflunisal which is a much better stabilizer than tafamidis. And we know what diflunisal does in that setting. It slows things down a little bit but people still progress.

So I don't think there's any doubt in the minds of physicians who treat these patients that the stabilizers have really shown the relatively incremental impact on neuropathy progression of these patients. So they may well get the label. That's great. Terrific.

But I don't think it'll change how physicians look at using an agent like patisiran which really has a very strong impact compared to an agent like tafamidis or for that matter diflunisal which really only slows down progression.

Akshay, anything else?.

Yes. I would just add that in terms of again comparing across trials of caution, but some notable things about that, (45:06) beauty of efficacy relates to V30M.

And for the family's impacting non-V30M-related disease, there's a wealth of literature that's accumulated that patient seems to progress quite quickly at least (45:21) literature I think of experts as well. And it has its modest effect when it does have an effect as John outlined.

We also don't know of it, in fact, in any great detail in the sort of protean manifestations of the disease when we think about the (45:36) features they've got and all these other things. We've demonstrated the gait speed. Many other features. We've shown data on that.

So of course we're glad that patients will have another option and we look forward to seeing the tafamidis data but certainly our package around the APOLLO looks the most superior to all the data that are out there in terms of the comprehensive effect on both neuropathy and cardiomyopathy and the proportion of patients that have the potential to actually improve from the disease..

Got it. That's helpful. Thanks for taking the questions..

Yeah. Thanks, Eric (46:13)..

Thank you. And our next question comes from the line of Madhu Kumar with Riley. Your line is now open..

Hey, guys. Thanks for taking my question. So I was wondering kind of the timeline for the APOLLO open label extension trial ending.

And then secondly, when you're thinking about the ALN-TTRsc02 study and hATTR amyloidosis, how do you think about the positioning of that relative to the launch of patisiran and kind of as patients get found, whether they enroll into the ALN-TTRsc02 Phase III as compared to going onto patisiran commercially?.

Yeah. Those are two great questions.

Akshay, do you want to handle them?.

Yes. The open-label extension study is going well as we've previously reported at ISA earlier this year. We intend to continue with it as our commitment to the further study of the drug to fully elucidate the efficacy and safety profile, and that cohort will be dosed for up to five years.

And with respect to the ALN-TTRsc02 program, again, our commitment to this patient community and this disease is to study all the drugs we have in hand, and so we'll move expeditiously with our ALN-TTRsc02.

And we also have to remember that the approval of patisiran will be sequential across various territories, and I'm sure that will offer opportunities for patients to receive the patisiran drug if it's approved in their territory, or to go onto ALN-TTRsc02 if they wish to participate in the clinical trial..

Yeah. So maybe just adding to that last point a little bit, Madhu, we're going to be very careful to make sure that we think about how we do clinical studies with ALN-TTRsc02 in the context of our patisiran launch.

And, as you know, there are many countries in Europe, for example, where even with the EU approval, which we expect this year, reimbursement will take time, and therefore those patients might be appropriate to be considered in the clinical study, while the reimbursement process for patisiran is being reviewed by governments.

So, there will be a thoughtful process to make sure that we don't, if you will, cannibalize the initial growth of patisiran by the conduct of ALN-TTRsc02 clinical studies..

And then kind of following on the hereditary TTR trials of sc02, how long do you think you have to treat to show kind of durable TTR knockdown in a Phase 3 trial?.

I could sort of proficiently point to the Phase 1 study and say a single dose would be sufficient to show durable knockdown. I think, from the viewpoint of regulators and the entire community, we want to show multiple dose exposure in the context of Phase 3.

And as we've guided, Madhu, once every three months, it is not out of the question with the kind of (49:18) we see. So, I think we'll have a multi-dose approach dosing likely once every three months..

Okay. Thanks..

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

Congratulations on the progress, and thanks for taking the question. One on the ALN-TTRsc02 development approach. You mentioned that the development approach for ALN-TTRsc02 wild-type will depend a bit on what the data looks like for tafamidis, the ATTR-ACT study, in August.

Could you provide a little bit more color on what you'll be looking for in the tafamidis data to determine the right approach? What are the ranges of designs or approaches you consider? Would the endpoints change? Would the arms change? Would the timing duration change? And what sort of tafamidis results would potentially tilt you toward one-for-all design or another?.

Well, I mean just real briefly, I mean obviously we're speculating a little bit here, Vincent, and Akshay should comment as well, but if the tafamidis data are very modest and largely driven by changes in CV hospitalization and the changes are relatively small, we might still consider doing the placebo control study.

I mean, I think that's one option. I don't think we expect that. If, in turn, the results are a little bit more robust and they're saying there's an impact in the 20% to 30% range on CV hospitalization and mortality, we would likely go to a head-to-head comparator study where we want to demonstrate the superiority of ALN-TTRsc02 against tafamidis.

So, we feel very strong and good about that potential, given all the data we have. So, those are sort of the two bookends from my perspective.

I don't know, Akshay, anything to add?.

I agree with you, John. Those are the main issues..

Yes..

And is it fair to say that you would probably need to do a similar endpoint for the all-cause mortality and cardiovascular hospitalizations or (51:19) to go with something (51:21)?.

Oh, yeah. No, no. Our previous plans before the tafamidis top line was that we would need to do a CV hospitalization mortality study endpoint in that setting..

I see. Thank you very much. I'll hop back in the queue..

Great. Thanks, Vincent..

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

Hi. Congrats on the progress, and thanks for taking my questions. Just to follow up on the earlier questions.

For patisiran, do you plan on doing and would it be possible to do a 30-month comparison between the APOLLO data and natural history data, looking specifically at survival or cardiac outcomes? And for the outcomes data that you have, do you plan on publishing these data for reference?.

Yeah. I mean that's certainly something that we will be following up on, just as the natural course of things. Some of the preliminary post-hoc analysis that we presented here, we look forward to validating with outcomes from early study and comparing historic controls, as you say.

Now, as to whether that would lead to potential label changes, the reimbursement environment setting, and how that will be interpreted there, we'll have to see, but I think if tafamidis gets approved with the prospectively-designed study, whether primary endpoint incorporated hospitalization and mortality, I think those kinds of analyses, comparison to historic controls wouldn't be seen necessarily as sufficient from a regulatory perspective, although we will certainly publishing those kinds of findings.

And I'm confident, based on the preliminary post-hoc analyses, that we will have encouraging data then..

Got it. Very helpful.

And when considering some of the positive cardiac data you've reported for patisiran, do you have any perspective on how regulators will weigh data from the different measures and biomarkers that you're looking at?.

Yeah.

Akshay?.

Yeah. I mean, I think we have provided data both on BMP, which is an important biomarker that's been associated with adverse outcomes in cardiac amyloidosis, both TTR and AL amyloidosis. We think the literature supports that, experts support that. So, we think that's an important biomarker to include in any potential label.

Similarly, left ventricular strain. And then, finally, the left ventricular strain, and then finally the left ventricular (53:57) state of the structural changes that we're seeing are quite striking.

And I think if a prescriber is to know what potential benefits the patient may have, we would want that to be incorporated to show that, by inference, that would suggest that TTR has been mobilized from the heart. And finally, all of that added up to an association with an increase in walk speed (54:19) placebo.

And so, that was one of the pre-specified endpoints (54:23) would expect that to be incorporated in the label. So, that's how we're looking at it..

Great. Thank you very much..

Thank you..

Thank you. And our next question comes from the line of Alan Carr with Needham Companies. Your line is now open..

Great. Thanks for taking my questions. A couple of them. One, you spent – you've mentioned a few times about the need to find more of these hATTR patients.

Maybe in light of the progress that you've made with the Alnylam Act program, can you give us a sense of having diagnosed patients you think there are out there in relation to the total prevalence estimate? And then, also with lumasiran, the Phase 3 design that you announced earlier, is that a single-arm trial where you're just tracking change from baseline, or are you going to have a comparator in that? Thanks..

Yeah. Great.

Well, let's – I mean, the first question, Barry, why don't you handle that?.

Yeah. So, Alan, as you know, to help out answering that question since there aren't specific numbers, we would put what we believe are the right kind of diagnosis range based upon what we're hearing versus the epidemiology.

And as a demonstration, even in endemic areas, like Portugal and Japan, we believe the diagnosis rate once a patient hits the system is only about 50%, and we know many areas the diagnosis rate can be as low as 20%. So – and that doesn't even acknowledge the timeframe difference that it takes.

I've already mentioned that most patients report that it's taken over two years to get appropriately diagnosed, and some over a decade. So, as we increase diagnosis rate and shorten the patient journey, the end should greatly grow over a period of time.

And that's the effort to get out and educate, because often patients will report that they've seen two or three gastroenterologists, two cardiologists, two neurologists, and then finally somebody figures out what's going on after all those medical visits.

So, the opportunity to educate, raise disease awareness, shorten the patient journey, and improve diagnosis is enormous here..

Yes.

And Yvonne, do you want to comment a little bit on the lumasiran program design and those elements there?.

Yes, of course. So it will be a placebo-controlled study, and we'll be kicking that study off shortly as we described in our goals, and we're very confident of the outcome there given the endpoint of oxalate (57:15). So, we're pretty excited to get that started and looking forward to the (57:19) in due course..

And just one other thing to add – one other thing to add there is we've only presented the first cohorts worth of data back in November at the ASN meeting, and we'll present – we now have 20 patients in the Phase 1/2 study, which we'll present later in the year.

And we're obviously very enthusiastic, as is the FDA and EMA, about those data, so we look forward to presenting those data later on..

So, 25 total divided across two arms?.

Yes. And obviously it will be an even number..

All right. Thanks for taking my question..

Thank you. And our next question comes from the line of Irina Margine with Cowen. Your line is now open..

Hi, guys. Thanks for taking my question..

Sure..

I just wanted to quickly follow up on the label questions, and then I have another quick one on givosiran.

In your view, what would constitute a broad label? Would it specifically have to mention cardiomyopathy symptoms, or just simply not be restricted to patients with pure neuropathy? And how do you expect payors to act in each of these scenarios?.

Yes. Let me start it, then maybe Akshay can go in. I mean, at one lab, at one book, there's always bookends, right? At one bookend, a broad label would have an indication statement that says patisiran is indicated for the treatment of hereditary ATTR amyloidosis, period, and would have a lot of the cardiac data within the label.

At another bookend, it would say neuropathy and it wouldn't have any of the cardiac data in the label. Those are the two bookends. We don't expect that last bookend. We do believe that the indication statement is supported by the data, and obviously we're talking to regulators in the U.S.

and EU to support that, and we look forward to announcing it when we have that label, but we believe the data are certainly there to support it.

Anything to add?.

I agree..

Great. Thank you.

And then on givosiran, what will be the pricing strategy given that the initial data will only include the AHA biomarker levels and very preliminary attack rate data? And based on your conversations so far with payors, do you expect they will be willing to cover patients who only have one or two attacks per year versus more than three or four? And that's....

Yes. Those are great questions.

Akshay – or Barry, sorry, do you want to handle that?.

Yes. So, we're in preliminary discussions with folks about the disease burden, and keep in mind that the artifact of the clinical trial for two or more attacks in the six months (01:00:15) to show a difference. We have the powerhouse certainly.

But you can imagine that a patient who's hospitalized once a year but that hospitalization is for 12 days or those living in significant chronic pain were debilitated and unable to work are also very sick patients. And at the end of the day, payors understand that. In the United States, we don't think that the limited initial data will be problematic.

And keep in mind, we already have, as Akshay commented on the call, pretty profound attack data already. So, we'll be able to talk to the full set of data.

And as we mentioned, in Europe, we'll wait for the full trial because that is an instance where, in most countries, you go through the health technology assessment process once and have to get it right. So that's one where we want full body of data before negotiating access..

And I would just add to what Barry said, that there have been at least two independent tests with the hypothesis that givosiran suppresses clinical attack. There was the initial placebo-controlled element of the Phase 1 study, and then the placebo patient, and then of course we have this very impressive reduction in attack rate.

Subsequent to that, the placebo patients were rolled over onto active drug, and once again, they showed a reduction in attack rate growth through the placebo phase. And so that's rather compelling.

And all of those data, as well as the long term open-label extension data, some of which we released earlier this year at the EASL meeting, all of that will be in the label, and I think very compelling in addition to the relationship we've shown between ALA and attack rates.

And so that would compel, I think, most people to reimburse the drug and help patients with the drug..

And just one more thing to add. This is a disease with just enormous burden with patients that – sadly, their lives are just completely destroyed by this disease, ravaged by this disease. And so the impact of givosiran is quite clear, and ALA is a biomarker that is very predictive of clinical benefit, so that's very helpful..

Great. Thank you so much..

Thank you..

Thank you. And our next question comes from the line of David Lebowitz with Morgan Stanley. Your line is now open..

Thank you very much for taking my question. Out of curiosity at the interim analysis, I know that sufficient ALA reduction was generally spoken about as being able to lead to an eventual submission.

Are there any other efficacy requirements beyond that that need to be met to enable a submission?.

I mean, the simple answer is no, but obviously the FDA is going to look at the entirety of the package and they're not going to see any attack rate data. We've agreed to them with that. But they'll see safety data, and they'll see attack rate data from the other studies that are ongoing, of course, as well.

But you've already seen quite a bit of those data, and they look very, very encouraging. So, yeah.

I think, of course, as always with something like this, there's a discussion with the FDA after we get the top line results, but I think we're encouraged by the discussions we've had up until this point where they understand the enormous disease burden and the importance of getting a new medicine out as quickly as possible..

Thank you for that. And one more question. With respect to the cardio population, you spoke about the Alnylam Act effort to diagnose patients.

I apologize if I missed this, but how many patients have been identified to this point, with Alnylam Act but also prior to?.

So, are you talking about porphyria or hATTR?.

hATTR..

So, I think the numbers are – top of my head, we had 4,600 samples since inception, and there have been over 350 patients with TTR mutations that have been detected..

That's right..

That's just in that program. And keep in mind, David, that that is still just the tip of the iceberg of numbers of physicians that are using the program, and it's not being used in Europe, for example, so it's really just a small sampling.

And, of course, there are many, many more patients that were already diagnosed outside of that region of the testing program..

Do you have any estimate on patients diagnosed before the program in the U.S.?.

I mean, certainly our belief is that there are at least a few thousand patients in the U.S. that are in the system that are diagnosed..

Thank you for answering my questions..

Thanks, David..

Thank you. And that's all the time we have today for question and answers. So, with that, I would like to turn the call back over to management for any closing remarks..

Good. Well, thanks, everybody. Obviously, it's an exciting time at the Company. We're on the cusp of launching patisiran and we can't wait to get the approval, get the label, and get out and bring this medicine to patients who need it. Thank you very much..

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..