Stan Crooke - Chairman and CEO Lynne Parshall - COO Beth Hougen - CFO Sarah Boyce - Chief Business Officer Wade Walke - VP of Corporate Communications and IR.

Jim Birchenough - Wells Fargo Securities Chad Messer - Needham & Company Jessica Fye - JP Morgan Philomena Kamya - Stifel Eric Schmidt - Cowen and Company Salveen Richter - Goldman Sachs Yale Jen - Laidlaw & Company.

Welcome to the Ionis Pharmaceuticals First Quarter Financial Results Conference Call. Please note, this event is being recorded. Leading the call today from Ionis is Dr. Stan Crooke, Ionis’ Chairman and CEO. Dr. Crooke, please begin. .

Good morning and thanks everyone for joining us on today's call to discuss our first quarter financial results and business highlights.

On the call today, Beth will walk you through our financial results, and Lynne had planned to discuss the progress that we're making across our business, including our three Phase 3 drugs and our recent announcement of our new commercial partner for Kynamro.

But she has got laryngitis, so she is on the phone and Sarah will go over and do this for her. I will then provide some comments on the Merck-Ionis litigation against Gilead and how this relates to advances we’ve made and continue to make in basic research and technology and how these innovations with core of Ionis is generating continued value.

Then I’ll close with a brief summary of our upcoming events. Let me turn with our most recent news, Kynamro. We think Kynamro is a valuable drug. We reacquired Kynamro and found what we believe the ideal partner for Kynamro.

By this Kastle deal, we have been impressed with the quality and the experience of the Kastle team, they plan to have a single focus Kynamro, the commitment is high. We believe Kastle will invest in the marketing, sales and support functions that are necessary to commercialize Kynamro to its fullest potential.

And Kastle, well, leaves us the opportunity, if Kastle goes well beyond the United States, we think the financial terms are attractive, has the potential up to $95 million in in net payments, we also received 10% common equity stake in Kastle and we will receive double-digit royalties beginning next year.

So this is very much a bet on Kynamro and Kastle, our perspective.

Just two weeks ago at the AAN meeting, we reported new data for nusinersen from the ongoing open-label Phase 2 study in infants with Type 1 SMA, and encouraged with all the evidence of the benefit we are seeing in these babies, including event-free survival, increased muscle function, achievement of new developmental milestones and increases in electrophysiological measurements now.

We also understand the challenge for getting an approval based on historical control. The substantial past and recent experience even the rare disease situations, those and any approach other than working co-operatively with regulatory agencies around the world into prolonged delays.

We are working closely with Biogen to execute what we believe is the best strategy to gain the most rapid approval possible for nusinersen. We are pleased with the interactions we are having with regulators, moving on a path designed to achieve the earliest possible approval.

We started this year with excellent progress in our pipeline and as you will see from this report, we remain in a very strong financial position, on track our 2016 financial guidance.

Joining me on today’s call are Lynne Parshall, Chief Operating Officer, who as I said, because of her laryngitis not available [ph] very much, if at all, Beth Hougen, Chief Financial Officer; Sarah Boyce, Chief Business Officer; and Wade Walke, Vice President of Corporate Communications and Investor Relations.

And now Wade, could you read our forward-looking language statement please?.

Yes, thanks, Stan. I remind everyone that this conference call includes forward-looking statements regarding the financial outlook for Ionis, Ionis' business, the business of Akcea Therapeutics and the therapeutic and commercial potential of Ionis' technologies and products and development.

Any statement describing Ionis’ goals, expectations, financial or other projections, intentions or beliefs, including commercial potential of nusinersen, IONIX-TTRRx, volanesorsen and Kynamro is a forward-looking statement and should be considered an at-risk statement.

Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics and any endeavor of building a business around such drugs.

Ionis' forward-looking statements also involve assumptions that if they never materialize or prove correct could cause its results to differ materially from those expressed or implied by such forward-looking statements.

Although Ionis' forward-looking statements reflect a good-faith judgement of its management, these statements are based only on facts and factors currently known by Ionis. As a result, you are cautioned not to rely on these forward-looking statements.

These and other risks concerning Ionis' programs are described in additional detail on Ionis' annual report on Form 10-K for the year ended December 31, 2015, which is on file with the SEC. Copies of these and other documents are available from the company. And now, I would like to turn the call over to Beth..

Thanks, Wade. Good morning, everyone and thank you for joining us. I am pleased to report that we maintained our strong financial performance and in the first quarter with a pro forma net operating loss of $35 million and more than $700 million of cash.

Our expenses for the quarter were right on track and because much of our planned revenue for the year is in the latter part of the year, we are on track to meet our guidance of pro forma net operating loss in the low $60 million range and the year-in cash balance in excess of $600 million.

In our year-end call in February, we projected 2016 revenue of more than $240 million, the majority of which comes from milestone payments as our partner program advance. Our ability to generate substantial revenue from milestone payments is the natural result of our large advancing pipeline and our partnering successes.

Because we are generating such a significant amount of our revenue from milestone payments, our revenue and our pro forma net operating loss fluctuates on a quarterly basis. The variations and the timing of our revenue quarter-to-quarter and year-to-year are expected and consistent with our projections.

In the first quarter of 2016, we earned $37 million in revenue, including more than $16 million from the amortization of up-front payments and more than $15 million from milestone payments.

Our milestone payments in the first quarter included $12.5 million from Biogen for advancing nusinersen and IONIS-BIIB4Rx, and $1.5 million from GSK when they initiated the Phase 1 study for IONIS-HBV-LRx.

Under our agreement with Kastle, we are eligible to earn up to $95 million, including $15 million up-front payment, which we will recognize in the second quarter. An additional $10 million payment on the third anniversary of the deal and up to $70 million in sales related milestone payments. We also received a 10% equity stake in Kastle.

Starting in 2017, we will earn royalties in the mid-to-low teens on global net sales of Kynamro. And under our arrangement with Sanofi Genzyme, we are eligible to receive a 3% royalty on sales of Kynamro and 3% of the cash payments we receive from Kastle, plus a modest one-time payment for transition purposes.

Over the remainder of 2016, we have many opportunities to earn additional payments from our partners. Assuming we successfully complete the Phase 2 study of IONIS-FXIRx, we will earn $55 million milestone payment from Bayer.

We also have the opportunity to earn $25 million for first drug under our cardiometabolic and renal disease collaboration with AstraZeneca and $10 million for advancing the first drug under our J&J collaboration.

We also have numerous opportunities to earn meaningful milestone payments as we advance research programs and drugs under our Biogen collaboration. Our operating expenses for the first quarter were in line with our expectations.

A significant portion of our expenses were associated with five Phase 3 studies and three open-label extension studies for our Phase 3 drugs. In addition, we have been funding Akcea’s pre-commercialization activities and preparation for the launch of volanesorsen, following the successful completion of the Phase 3 study.

In the first quarter, we continued to advance our technology and our product line, while managing our expenses prudently. This was due in part to the substantial leverage we achieved when our partners performed many activities that move our programs forward effectively and efficiently.

Our achievements to-date have positioned us for continued financial strength. And now I would like to turn the call over to Sarah..

Thanks, Beth. We are well along in preparation of NDA packages for all three of our Phase 3 drugs in anticipation of Phase 3 data for each of them in the first half of next year. As Stan mentioned, two weeks ago at the AAN meeting, we provided an update from our ongoing Phase 2 open-label study in infants with Type 1 SMA.

When we began the study, we hoped to delay the progression of SMA to keep these babies from losing more muscle function and succumbing to respiratory failure. What we are observing in this study has greatly exceeded our hopes.

We are observing the infants in this study treated with nusinersen are not only living longer than natural history would project, but also improving. We have yet to reach a median event-free age in this study. All of our infants continuing in the study are now toddlers. They are all over the age of 2 and several over 3 years old.

And these children are doing things that you would never expect from an infant with Type 1 SMA. These infants are living longer without requiring permanent respiratory assistance. We are also observing increases in their muscle function measured by CHOP INTEND scores that correlates with the achievements of new and unexpected development milestones.

When we last updated, we had infants in this study sitting unaided. This is remarkable for babies diagnosed with Type 1 SMA, who are never expected to sit. As of the latest data analysis in January, even more babies are sitting unaided. But remarkably, we now have babies crawling, standing and even walking.

We also provided for the first time at AAN, a look at the electrophysiological measurements we are collecting in the study. We have observed increases from baseline in CMAP after two measurements for motion nerve in both the arm and the leg.

CMAP is electrophysiological measure that is used to monitor the functional state of motion nerve and muscle units and can provide insight into the normal development or degeneration of a neuro resistance.

According to published natural history data on infants with Type 1 SMA, CMAP measurements declined sharply after symptom onset remained low and do not improve overtime.

To see increases in CMAP in these infants in our study is quite promising, and very different from what CMAP history would predict and consistent with what we are observing, and consistent with all other increases in muscle function we are observing.

This data continues to support our confidence that nusinersen can provide significant therapeutic benefit to patients with SMA for whom there are no approved therapies.

We see a large opportunity for nusinersen to potentially provide value to patients with SMA and to create a considerable commercial opportunity for about 30,000 to 35,000 patients with SMA in EU, US and Japan.

And if nusinersen is made available to increase – is able to increase the survival of Type 1 infants, who make up half of the estimated patients born each year, the size of the patient population is likely to grow substantially.

Biogen will be responsible for providing nusinersen and we are confident that the drug price will reflect the value that nusinersen could bring to infants and children with a potentially fatal progressively debilitating rare disease. We believe nusinersen has the potential to create a fundamental change in the course of this terrible disease.

We expect it will be priced accordingly. And we understand the significance of these results to the families of babies and children with SMA. We understand that every month matters and the frustration families must feel waiting for nusinersen to proceed through the required clinical development and regulatory framework.

We and Biogen are doing everything in power to expedite nusinersen through developments and approval. All of our positive regulatory interactions give us confidence that we are on the right track to achieve the approval of nusinersen as soon as possible.

And Biogen continues to move ahead with the preparation to commercialize nusinersen, so that after we file and obtain approval, Biogen can rapidly make nusinersen partly available to patients. While of course we understand that the families for patients and their families the time it takes to develop nusinersen seems quite long.

In fact, it is actually quite remarkable that we are close to commercialization just four years after entering the clinic. We are also making significant progress with IONIS-TTRRx.

In July, at the International Society of Amyloidosis meeting, we plan to report our latest data from the open-label extension study for IONIS-TTRRx and talk about some plans to provide an update on the very encouraging data from its open-label in patients with TTR cardiomyopathy.

We will also – we will review both of those update more broadly at our R&D Day on July 13. We are on track to have data from the Phase 3 NEURO-TTR study in the first half of 2017. We continue to observe robust participation in the open label extension study from patients who are eligible to roll over into that study.

Today with JFK, we are conducting a broad development programs designed to cover all forms of TTR amyloidosis. We believe that IONIS-TTRRx could be a significant value to patients with TTR amyloidosis. This is a fatal, debilitating, multi-organ disease for which patients have very limited therapeutic options.

If our NEURO-TTR study is positive, GFK plans to file first for marketing approval of IONIS-TTRRx in patients with polyneuropathy form of TTR amyloidosis. There are approximately 10,000 patients worldwide with familial amyloid polyneuropathy.

GSK will be responsible for pricing IONIS-TTRRx and we are confident that the drug’s price will reflect the significant potential value of this drug to patients with TTR amyloidosis and is likely to be comparable with other drugs needed to treat severe diseases and orphan patient populations of a similar size with unmet medical need.

GSK also plans to evaluate IONIS-TTRRx in patients with cardiomyopathy form of TTR amyloidosis. GSK is working closely with the FDA to address that question on the study to get the Phase 3 CARDIO-TTR study underway as quickly as possible.

In order, in the CARDIO-TTR study, GSK plans to evaluate IONIS- TTRRx in an orphan study in patients with the familial form of TTR amyloidosis as well as the wild type form. These patients have a buildup of TTR amyloid in the heart muscles and [indiscernible] of the same rate with the similar constellation of symptoms.

We continue to plan NEURO-TTR study and we are still on track to complete the first - we are still progressing on track to complete the study in the first half of 2017. GSK has already begun commercial activity to support NDA and MAA filings needed for the approval or launch of IONIS-TTRRx in patients with polyneuropathy.

These activities are timed such that once the phase 3 NEURO-TTR data is hand, GSK will be ready for the marketing approval without delay. The breadth of GSK’s sales and marketing organization around the world is important to ensure that IONIS-TTRRx is quickly established as a standard of care.

We believe GSK is the right partner to maximize the commercial opportunity. Because TTR amyloidosis is a multi-organ disease, there is significant overlap in symptoms assessed in patients with polyneuropathy and cardiomyopathy forms of the disease.

We believe the one product will streamline the regulatory process, physician education and the sales effort. We hope to be able to show more of these plans at R&D Day and as the program advances. Akcea is continuing to make excellent progress preparing to file for approval and to launch volanesorsen.

We have two Phase 3 studies of volanesorsen ongoing for two life-threatening orphan and genetic diseases, SPS and FPL. Akcea’s Phase 3 study in SPS patients is fully enrolled with data planned for the first half of 2017 and the Phase 3 study in FPL is well underway. Both of these diseases are marked by extremely high levels of triglycerides.

FPL and SPS are estimated to affect 3,000 to 5,000 patients worldwide. Given that SPS and FPL are both genetic diseases, we believe that the patient numbers will actually be higher for two reasons. First, as you find one patient, you often locate the family of patients.

Second, as typically found with orphan diseases, once the treatment is developed and awareness of the disease and the clarity of the diagnosis is defined, many more patients are likely to be more formally diagnosed with the correct disease name.

Akcea is actively engaged in a variety of activities to identify patients, prelaunch as well as to raise awareness of the diseases and streamline their diagnosis. While it is too early to comment on a specific price of volanesorsen, we believe volanesorsen’s price consistent with all of our Phase 3 drugs will affect the potential value of this drug.

Mostly recently we announced that Kastle Therapeutics has acquired Kynamro Pharma. In this transaction not only do we receive upfront dollars and equity, but we also have the potential to milestones payments, including payments associated with various sales levels plus ongoing loyalties on sales beginning in 2017.

We look forward to potentially adding commercial revenue in the form of Kynamro royalties to our financials next year. Placing Kynamro in the hands of a partner would be ability and commitment to maximize its potential was important for us.

Despite the emergence of new cholesterol lowering therapies, there still remains a significant unmet need for homozygous and phage patients. Kastle believes that Kynamro has a lipid lowering profile to fulfill the need.

The Kastle team’s background and expertise and successfully marketing orphan drugs for under-diagnosed rare diseases should be a great fit for Kynamro.

They have committed to investing significant resources to fund the market for Kynamro to increase the potential commercial value of Kynamro, Kastle has already initiated activities to identify new patients to bring on to therapy in the United States and to pursue market approval in other countries.

And now I would like to turn the call back over Stan for closing remarks..

Thanks, Sarah. We have three Phase 3 drugs. They are all first in class, they are all new chemical entities, better in development for three different uses where we are completing Phase 3 clinical trials at the same time, this achievement that we're tremendously proud of, one that very if any biotech companies have achieved.

There are solid reasons, possibly optimistic about each of these Phase 3 programs. First, consider [indiscernible] and we're comparing our Phase 2 results to historical controls, being the physicians treating these patients are excited about what we're seeing, These data give us confidence that the Phase 3 trials will confirm optimism.

Now focus on volanesorsen, drug designed to treat patients with extremely elevated triglycerides. Primary endpoint in our Phase 3 trial for volanesorsen is triglyceride reduction.

In our Phase 3 program with an extensive amount of data that shows that volanesorsen substantially reduced triglycerides in every patient population we studied from patients with moderate to extremely high triglycerides including dramatic reduction in patients with FCS.

Phase 2 data set then supports our optimism that the Phase 3 trials from volanesorsen will be positive as well. And we have a similar position on IONIS-TTRRx. Note the cause of TTR amyloidosis is a TTR protein, protein that causes amyloid acts to form and to grow. As shown in normal volunteers and patients in 80% average reduction of TTR protein.

Moreover in Dr. Benson's study in patients with cardiac form of TTR amyloidosis, these significant reductions in TTR are correlated with patients. Again, multiple data sets support our optimism with the Phase 3 trial of IONIS-TTRRx will be positive.

But as we look ahead, we have the opportunity to show benefit with not just one Phase 3 drug, three Phase 3 drugs and our three new chemical entities in multiple different patient population and the data from each of these drugs should be available in the first half of next year.

Well along in the NDA preparation for all three drugs and plan to file rapidly after positive Phase 3 data. Of course it means that we could have all three drugs on the market over the course of the next couple of years. That’s a really remarkable position to be in, but that’s not all.

We have pipeline rich in value and opportunities and we'll be updating you on a number of the other drugs in the pipeline as the year progresses.

We plan to present additional data from our other programs this year with initial clinical data from [indiscernible] We hope to see results similar to those with our [indiscernible] it was 30-fold more potent than the unconjugated parent drug and weekly ED50 dose 4.5 milligrams, displayed an excellent tolerability profile.

With potency and that our lipid technology provides supports for potential for ultra-low dosing, ultra-low volumes as well as less frequent dosing which can substantially improve patient convenience and compliance and it allows us to expand antisense drugs into additional diseases and even larger patient populations that are getting underway.

In addition to [indiscernible] data at our R&D day in July, we plan to present additional lipid measurements from a Phase 2 study looking at [indiscernible] Phase 2 data from study evaluating IONIS-AR2.5Rx in patients with advanced solid tumors and Phase 2 interim data from the study evaluating IONIS-GCGRx in patients with type 2 diabetes.

So we're looking forward to sharing all that information with you at that meeting. Now, before I conclude and open the call for Q&A, I want to just take a minute to comment on the recent news on the Merck-IONIS patent infringement. This is what's important to me about that.

First, we found that all 10 claims of the two patents involved in the dispute were valid. This once again emphasizes the quality and broad scope of our innovation. Second, it emphasizes the breadth, depth, value of our intellectual property. We continue to expand as we advance our technology.

Having led innovation for good many years, we continue to be impressed with the fact that innovation almost always but it is sometimes very difficult to predict exactly what specific element of an invention will generate value at a particular time.

For example, as a relationship that we have with Merck, in the late 90s of course we've always been interested in the initial chemistry of ASOs, hence with the building blocks nucleosides that we worked with Merck to develop nucleoside analogs which they might use to treat ACV and we might use with advanced ASO additional chemistry and ASO performance.

Our research led directly to the patents that are being litigated by Merck with Gilead, but the fact that the jury confirmed that all claims in both patents were valid, great news for us.

Even though there are additional legal steps that are underway, the confirmation of the validity of these patents is another important demonstration of the value of our innovation over the outcome, all upside for us and no cost associated with this litigation and we get 20% of whatever is awarded to Merck, actually they pay their litigation expenses.

While looking at the work that we were doing in the 90s with Merck might not have been able to predict exactly the value, these person would have known that value was built [indiscernible] work with Merck was also consistent with our interest in the treatment of ACV at the time.

Coincided with our early interest in using ASOs to alter micro RNAs, that working with Merck showed that we understood ACV and that was essential in the discovery of anti-HCV properties of miR-122 inhibitors.

That led directly to the identification of the first miR-122 inhibitor, the potent HCV agent which in turn helped us found Regulus to focus broadly on micro RNA therapeutics.

Now, Regulus has continued to move the miR-122 program along showing excellent results and all this research is connected and the key point I am making is basic research and technology advancement which are at the core of IONIS need to generate ever-increasing value.

Now that value may not be as obvious as a Phase 3 drug, there is tremendously important short and long-term value. And today in the company, innovation is an all-time high.

Progress is even faster than in the past and the breadth of activities we have is remarkable such as the enormously exciting neurological disease pipeline that we've added to our portfolio that we discussed a couple of weeks ago.

We continue to make transformative advances on a technology which broaden and expand the application of antisense technology to new mechanisms, targets and new diseases.

I am really hoping that you can join me at our upcoming R&D day during which I will spend some time mapping out the future potential of antisense technology based on the innovations that we're making today.

Having in hand today a pipeline of rich and opportunity focused on bringing new drugs to patients with the highest unmet medical needs have an almost unlimited potential for the future. And with that I'd like to turn the call over – open to Q&A. Gary, if you can set us up for Q&A please. .

[Operator Instructions] The first question comes from Jim Birchenough with Wells Fargo Securities. Please go ahead..

Just on the S&A program, Stan perhaps in terms of nursing and getting it to patients as quickly as possible, can you maybe discuss some of the regulatory options and whether an accelerated call filing is possible or whether there is some way to shorten the review cycle once you have phase 3 data, just interested in what measures are open to shorten that time to get this to the patient?.

I’m just a bit uncomfortable getting into any detail about this given the fact that we’re engaged in a variety of conversations with regulatory agencies around the world and of course I don’t want to get into kind of argument.

I think what I can say is that we’ve continued to have these productive interactions and we have asked that we believe assures earliest filing and as much as we possibly can, the most rapid and productive interactions that would lead to the earliest approval that's really all I feel comfortable touching just now and Lynne with her laryngitis may have less to say, you want to add or subtract anything Lynne?.

No, I was just going to say exactly what you did, and thank you..

I tried, I can’t pull out detail Jim..

That's understandable, so maybe just a second question on TTR program and the update we’re going to get shortly from either those updates would we get some visibility on what the issue might be holding back the cardio TTR program and is there any additional detail you can just provide on that?.

We will be providing an update in July on the open label cardiac study done by Dr. Benson and we’re encouraged by what we’re seeing. And I should also add of course that familial polyneuropathy study continues nicely.

The concern therefore focuses and derives from monitoring and questions that the cardiovascular division or cardio renal division of the FDA asked. We’re making sure that this very long outcome study going to be possible.

Little concerns do focus on platelet reductions we have seen some platelet reductions in patients treated with TTR, included essentially all of the negative earning possible, hard to understand the mechanism.

What I can tell you right now is we believe those events are quite manageable and monitorable as we are doing in the FAP study and that we think there is potential for some interaction between amyloid protein TTR, although proteins are known to associate with platelets that cause issues and the fact that we are affecting those protein levels and that work is still in progress and so that's about as much as I can say today..

And then Stan maybe just to follow-up quickly on that, I think what I'm hearing is that this is unique situation involving the interaction of the antisense with the amyloid and amyloid with the platelet but something I'm presuming you haven’t seen in any of the program as you’ve been developing your antisense over the last several decades?.

With the [indiscernible] chemistry which is what chemistry is that’s in the TTR drug. They are now, I would guess more than 10,000 patients that have been treated and we have many thousands of patients that we have treated that our safety database. They also have patients who have been treated now for longer than five years on amro.

And so on in a database of that size of course you're going to see some platelet reductions in this, there are all kinds of platelet reduction go on in clinical trials but the observations in the TTR study appear to be limited to the TTR disease situation, I think one of the things that everyone should recall is that as we advance our technology into a wide range of diseases very sick patients that cover drug disease interactions that you have to deal with, this is manageable in a TTR patients and we are just that..

The next question comes from Chad Messer with Needham & Company. Please go ahead..

A couple more on TTR, with the cardio program you’re enrolling patients with both familial and wild-type. I presume there is an analogous situation in neuro, wanted to know if you're going to do anything to address those patients.

And then if I can just add another one on TTR, you now with your partner GSK, you kind of broadly going after all the TTR patients but sometimes back you made a decision to focus in neuro, just wondering if there is a rationale at the time for going after that sub-population..

I think let me make sure I understand your question but in the outcome study, GSK plans to initiate in the cardiac form of the disease, you’re right, it will be both the familial as well as wild-type and the decision to do that was based on a great bit of work that GSK did to others that demonstrated that once the diagnosis will fade, there might be some difference in the agents.

Once the diagnosis was made the clinical course was very similar. In the FAP study, we have a significant fraction of patients who do have cardiac form of the disease and they will be evaluated definitely as a subgroup, a specified subgroup phase 3 study and know.

If I understand the question that you asked final question that you asked about the history, it goes like this, we initiated the FAP study immediately after Phase 1. And we want to get some early evidence in that study of results as particularly GSK wanted that before beginning cardiac study.

And there was also a good bit of work going on to evaluate what was the best course with the cardiac patient. So that time was very well spent because GSK decided that initiate a large outcome study just to first hard endpoint cardio vascular outcome study needed to be conducted in this patient population.

But it was staggered, it was done I think as you expect issue information and help with the design of what would be an optimal cardiac study.

But did I get your questions right Chad?.

Yeah mostly, I guess I was just wondering if there was something about the end points in neuro that you thought might be easier or easier to hit or more well understood and I think maybe to summarize what I'm hearing you saying, correct me if I'm wrong there was more to learn about the planning of a cardio study and so waiting there may be made more sense?.

Well, some, yeah, remember we have a partner and these investments are very substantial, we move from Phase 1 to Phase 3, FAP and so the decision was to gain some experience before investing in this very large cardiac outcome study. And to use that time to design the most wholesome approach to any broad approval in the cardiac indication.

So it was a bit of a decision having to do with costs and risks and the amount of information that you like to have before you go all in..

The next question comes from Jessica Fye with JP Morgan. Please go ahead..

Maybe going back to the regulatory side with SMA, Stan you talked about the risk of filing too soon without completely understanding what the regulators want to see as it could ultimately result in a longer time interventional approval compared to getting it right the first time.

Within that framework, can you give us any color on whether the FDA agrees on the natural history information that you’ve gathered about whether that’s reflective of the current standard of care.

And then second on LP(a) program in aortic stenosis, it looks like there is evidence that patient progress faster in their stenosis when they have elevated LP(a). But can you talk about any evidence that the elevated levels are truly colossal, so that we can have greater confidence than bringing them down would help slow that progression? Thanks..

We have had a series of conversations with regulatory agencies and while there are always questions about historical controls, I think there is general agreement that the standard of care in our study is as close to equivalent standard of care that was in the natural history study that we used as a comparison that could possibly be.

And the study was done in the same centers by the same physicians and almost contemporaneously. And the other thing to remember is that the clinical course has not changed several years.

So I think I would not want to apply that imply that regulatory agencies are ever thrilled about having the historical controls as an approach but as - in that context I think the historical controls are considered high quality and appropriate historical controls.

And then, your question about - did I answer that question, Jessica?.

Yes, thank you..

And with regard to aortic stenosis, you're absolutely right I think the data support the notion that patients who have elevated LP(a) and aortic stenosis have a more rapidly progressing clinical course leading eventually to either valve replacement or congestive heart failure.

And the evidence that [indiscernible] is also both genetic that is they are genetic studies have suggested and mechanistic. Bulk of the lipid community at least I talk to feel that the principal problem is oxidized phospholipids, which stimulate the anti-inflammatory response wherever they accumulate including vessels and valves.

And APO(a) is the principal oxidized phospholipid lipoprotein. And so there is evidence certainly that suggests that APO(a) is causing, when you blaze your ground with new targets and new opportunities, in the end you ultimately prove the truth of that the drug that works and so that's what we're doing.

And obviously if you have additional questions, we can set you up with [indiscernible] two of the world leaders in scanning APO(a) and it’s physiologic effects..

The next question comes from Steve Willey with Stifel. Please go ahead..

Hi this is Philomena Kamya in for Steven Willey, thanks for taking the questions, we were just wondering when we can expect an update from the STAT3 program?.

We've updated it some and it’s progressing. As I said, one of those stages in which you’re making progress, but there is not a cut point or an end point that is appropriate one to bring all the data together. What I would say is, we and AZ are encouraged by what we’re seeing and the trials are progressing.

Lynne, do you want to add anything to that if you can?.

No. The study is ongoing and I think we plan to have data next year on that..

We have seen very interesting results with complete responses and we’ve discussed the issues on looking at both the [indiscernible] activities as well as the direct anti-tumor effects and the decision to move in combination with that..

Understood.

And just as a second question, there is actually a collaboration with Biogen, can we expect the disclosure of the target for BIIB, 4, 5 and 6 soon?.

Well, they will be disclosed, but the decision about exactly when we will be able to talk about what those targets are is Biogen’s..

May I add one thing Stan? The one thing that you might do is look at the various presentations that we made at AAN and that may give you some strong clues as to what those targets could be..

We mentioned at the AAN that we had systematically evaluated where those go after in [indiscernible] and as we learn, they were very broadly distributed.

We moved more aggressively into a wide range of diseases and we emphasized that we were moving just some of the very large categories of diseases, just Parkinson’s and Alzheimer’s and other types of neurodegenerative disorders. So it would be a perfectly reasonable thing to assume that those Biogen drugs are targeting diseases like those..

Okay, great. Thank you very much and congratulations on the progress made thus far..

The next question comes from Eric Schmidt with Cowen and Company. Please go ahead..

Good morning. Thanks for taking my question. Stan, on the TTRRx program now, you’ve indicated that the monitoring issue related to thrombocytopenia, can you give us a sense of the scope of the thrombocytopenia that you observed in that population.

Was it a substantial percentage, was there any grade 3 or grade 4 events?.

I don’t want to get into more detail in a study that is ongoing and blind, give you numbers that I know will change as we progress. These TTR patients are very sick, have multiple organ failures. They have problems in renal function, platelets and many other things that are ongoing as a result of the disease process.

And we have had a handful of -- less than that of, meaningful declines in platelets that of course we’ve been monitoring carefully. That is really all I’m comfortable saying.

Lynne, do you want to lend on that at all?.

No..

Okay.

Maybe in terms of the question that he was asking about this being a potential platform issue or the concern out that this could be a platform issue, I know you have a very large safety database of generation 2.0 patients that have been treated, can you give us a sense of the incidence of ITP in that database, have you looked at that?.

Well, we haven’t. ITP really just boils down to finding platelet antibodies and no other cause of platelet reduction. And we have not had sufficient, there have been declines in platelets across a big database, but there hasn’t been sufficient platelet issues that we’ve focused significantly on until we begun encountering these issues.

So they’re very limited. And we’re, there will be variations depending on the disease and the sequence and so on and that effect. We think the problems that we’re experiencing are related to the drug disease interaction..

Is there a preclinical model that could inform that hypothesis that you see it, again, I don’t know if there is even a lot of TTR where you can still clear?.

And there have been studies that have shown that amyloid protein interacts with platelets and activates them and that sort of thing and of course we do most of our -- we do our large scale testing in monkeys and in monkeys, you have all kinds of complicated issues that complement so on.

So it’s in nature that we have to primarily get into clinic and that’s what we’re doing..

Okay. Thanks.

Maybe just a quick one for Beth, obviously, it looks like the 2016 revenue is second half weighted, but are there particular lumpy or large milestone payments that you are expecting that we could get a read on just to provide a little bit more visibility on the incoming revenues?.

Sure, Eric. The three in particular that we’ve been guiding folks to are of course the $55 million milestone from Bayer that we would earn on the completion of the Phase 2 study in the dialysis patients. And that will be late this year we would anticipate.

There is a $25 million milestone payment that we could earn from AstraZeneca for advancing the first drug into development under the cardiorenal collaboration with them and that would be second half. And then the third large milestone payment is $10 million from Johnson & Johnson for moving a first drug under that collaboration into development.

And then of course there is a number of other important and fairly significant milestone payments under Biogen and both research and drug development that could come in throughout the course of the year..

Perfect. That’s helpful..

Eric, we’ve been doing this for a long time. It was this model and we’re highly confident that we’re going to meet or exceed our financial guidance..

The next question comes from Salveen Richter with Goldman Sachs. Please go ahead..

Thanks for taking my question. Just with regard to TTR again, so in terms of the platelet issue, would that be particularly problematic in patients with cardiomyopathy whether either in conjunction with polyneuropathy or is that primary manifestation..

We don’t think so. We think the difference is a different division of the FDA, but there is no reason to believe that the situation will be different patient populations. And so we don’t think so..

Great.

And then could you help us frame expectations for the Factor XI data coming in the second half, where should we look for it and what exactly, how many patients exactly we’re looking for here??.

Remember, this is a study to set the stage for the large studies that Bayer will be conducting in patients with [Technical Difficulty] function.

And so the main goal of the study is to understand the pharmacokinetics, so we could define dose and dose frequency because there are difference in clearance rate, patients who have failure and are undergoing dialysis and those sorts of things. So, our primary goal is safety and to help us pick dose or doses charged studies.

We’ll be looking at patients who need anti-thrombosis and that renal function. So that’s what we’re doing. I can’t remember the exact numbers, it’s I think 40 or 50 patients.

Lynne, do you remember?.

It’s between 40 and 50 patients. Yeah..

And it’s going along nicely. And I think we are very confident today that we will have all the information we need from the study based on what we’re seeing to help us pick a good dose and a good dose schedule, both for the upcoming studies. So we think we’re very optimistic, it’s going to give us exactly what we need..

The next question comes from Yale Jen with Laidlaw & Company. Please go ahead..

Good morning and thanks for taking the questions. Many of those have been answered. So I have two big ones.

The first one is that in terms of the patient recruitment for the Nusinersen Phase 3 study in infants, we know that you guys guided that patient recruitment should be completed this quarter, is there any update on that or anything in terms of status?.

It’s progressing as we described..

Again, you anticipated to complete this quarter as your previous guidance..

Yes, yes. It will get done..

Okay. And the next question is for the Dr.

Benson’s presentation for the TTR, and what venue this presentation will be presented?.

I can’t remember, but I imagine, Sarah or Lynne, it does..

Yeah. It’s at the ISA meeting, which is the International Society of Amyloidosis that’s held over the 4th of July weekend..

Okay. Great.

And the last question here is one of the programs have not been mentioned too much which is for the [indiscernible] I guess that the Phase 1/2 study was started in the third quarter, would you have any other comment or maybe any color on this program?.

Not today. It’s progressing..

The next question is a follow-up from Jim Birchenough with Wells Fargo Securities. Please go ahead..

Hi, guys.

One of the program you haven’t spent a lot of time on discussing and maybe Stan with GSK is a partner, Hepatitis B is an emerging area of focus and just wondering if you can talk about the targets you’re pursuing in that collaboration and how you think about that program fitting in with other developments in Hep B drug developments?.

No. We’re excited about it and GSK is very excited about it. There are a couple of drugs in that program and unfortunately Jim, it’s a very competitive area and so GSK is anxious that we not discuss it in any more detail..

Got it.

And I hate to do this, but just going back to the platelet issue in the TTR program, I think it’s important to understand what this isn’t and so just wondering is there an issue of antibody generation to the antisense that’s interacting with the platelet, is there any direct antisense effect on platelets that you’ve seen in the past, just trying to rule out things that might be concerning more broadly?.

We have not ever identified, not ever, I don’t, I direct to anti platelet anti ASO antibody..

This concludes our question-and-answer session. I would like to turn the conference back over to Dr. Crooke for any closing remarks..

Well, thank you very much everyone and appreciate all the thoughtful questions. We continue to make broad progress and we’re looking forward to the completion of these Phase 3 programs successfully again, updating you in more detail on the Phase 2 pipeline and the progress and the technology in coming months. Thanks very much..

The conference is now concluded. Thank you for attending today’s presentation. You may now disconnect..