Good morning, and welcome to Ionis Pharmaceuticals Second Quarter 2019 Financial Results Conference Call. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Walke, Vice President of Investor Relations, to lead off the call. Please begin.

Thank you, Nicole. Before we begin, I encourage everyone to go to the Investor section of Ionis Web site to find the press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We've also posted slides on our Web site that accompany our discussion today. With me on the call are Stan Crow, Chairman of the Board and Chief Executive Officer; Beth Hougen, Chief Financial Officer; Brett Monia, Chief Operating Officer; and Damien McDevitt, Chief Business Officer, who will join us for Q&A. I would like to draw your attention to slide three, which contains our forward-looking language statement. We'll be making forward-looking statements, which are based on current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. With that, I'll turn the call over Stan.

Thanks, Wade, and good morning everyone. Thank you for joining us on today's call. In the first-half of 2019, we achieved a substantial number of value-driving successes across our business, further strengthening our financial position as we enter the second-half of this year. We finished the first-half of the year with revenues of $460 million. This is an increase of more than 75% compared to last year, putting us on track to deliver our fourth consecutive year of operating income, and our third consecutive year of net income. We achieved these strong financial results while continuing to invest as aggressively as it makes sense broadly across our entire business, including commercializing, to medicines, and advancing our pipeline and technology. SPINRAZA's blockbuster performance continued into the first-half of this year. SPINRAZA remains the worldwide standard of care and the only therapy approved for the treatment of SMA patients of all ages and all SMA types. Having now treated some SMA patients with SPINRAZA for approximately seven years, we now have patients who began treatment as adolescents and are now young adults. I'm particularly gratified to think about these young adults who, before SPINRAZA, would have faced a life of progressive weakness and increasing dependence. Today, they are able to live longer, more independent and more productive lives. And that's just the beginning. Babies with SMA are now being treated before becoming symptomatic. And the vast majority of those babies are maturing like normal healthy children, and can look forward to a life of independence and productivity. Our commercial affiliate, AKCEA, has now completed the first two quarters of the TEGSEDI launch, and reported $10 million in product sales in the second full quarter of launch. That is a 40% increase compared to last quarter. While it is still early in the…

Thank you, Stan. Our financial results for the first half of this year continues to build on our multi-year growth trajectory. We ended the first half with total revenues of more $460 million. A more than 75% increase over the same period last year, driven by growth in both commercial and R&D revenues. Our significant revenues resulted in continued growing profitability with operating income of $190 million and net income of $162 million for the first half of this year, both on a non-GAAP basis. We also maintained our substantial cash position by ending the quarter with $2.3 billion even while investing broadly across our business. In the first half of 2019, SPINRAZA generated over $1 billion in worldwide net sales. A nearly 30% increase compared to 2018. These strong results put SPINRAZA well on track to significantly exceed 2018 revenue. Reflecting SPINRAZA's strong performance our royalty revenue also increased by more than 30% to $130 million. Notably in the second quarter, we reached the highest royalty rate. The number of SPINRAZA patients on treatment worldwide increased by approximately 12% compared to last quarter. And now, approximately 8400 patients are being treated with SPINRAZA. In the U.S., the number of patients on SPINRAZA increased compared to last quarter. Adult patients, which make up the largest patient segment, continued to be significant driver of growth the second quarter. Outside the U.S., the number of patients on SPINRAZA also increased. In this case, by approximately 17% compared to last quarter. This growth was driven by new patients in larger mature markets along with rapid uptake in more recently launched markets including in Asia and Latin America. Biogen continued to increase reimbursement for SPINRAZA around the world in the second quarter. Formal reimbursement is now in place in over 35 countries with the…

Thanks. Beth. Today, we have three recently approved medicines in a pipeline of over 40 medicines advancing through development. In the first-half of 2019, we achieve numerous pipeline successes. And through the remainder of this year and into next year, we look forward to additional programs achieving significant value driving catalysts. SPINRAZA is the worldwide standard of care in the treatment of estimated patients of all ages and all estimate types and emerging data from longer term SPINRAZA treatment continue to demonstrate even better performance. We continue to see the infants treated before symptom onset developed like normal, healthy kids. This is demonstrated again in new data from the ongoing nurture studying patients treated for up to 45 months and supported by new long-term data showing continued improvement in over 300 patients treated for up to five years. SPINRAZA labels recently expanded in Europe. What is difficult to improve -- although it's difficult improve upon SPINRAZA's efficacy and safety profile, we invite pursuing a follow-on -- medicine with potential for reducing those in frequency to once or twice per year and we look forward to advancing the follow-on medicine into development potentially late this year, or early next year. As part of the ongoing launch of TEGSEDI, when AKCEA continue to present data supporting the benefit hATTR patients are experiencing with TEGSEDI treatment. Earlier this month, we present the new data from the NEURO-TTR open-label extension study demonstrating durable and substantial advocacy with long-term TEGSEDI treatment in patients with hATTR polyneuropathy with no new safety issues identified. Moving on to WAYLIVRA in the U.S. when AKCEA continue to recognize the unmet medical need of FCS patients for a safe and effective medicine for this rare and debilitating disease. And we're encouraged by our recent productive interactions with the FDA to…

Thanks, Fred. We've built Ionis on a foundation of our efficient technology culture supporting maximum innovation and a business model that enables us to maximize the value each of our medicines in our pipeline and that are being commercialized. Our business strategy is succeeding. And today, we're sustainably profitable. And Ionis is delivering more value to patients and shareholders every day. With the approval of WAYLIVRA, we now have three medicines approved in the last two years or so. Our medicines continue to advance in late stage development. We're on track to achieve our goal of four Phase 3 studies underway by the end of this year and our mid-stage pipeline continues to advance as demonstrated by the numerous Phase 2 readouts since study initiations already accomplished this year. Our technology continues to advance as well and it's advancing at an even more rapid pace. We look forward to giving you a glimpse of our exciting progress in the technology at a webcast focused on our technology later this year. We have more than, we have more and more Ionis owned programs that we are developing for our own account. And we're continuing to maximize the value of our medicines by identifying the optimal commercialization path and retaining more economic value. The business success and financial strength we've built, gives us confidence that we will continue to develop value for our patients and our shareholders in the short term and for years to come. I look forward to updating you on our continued achievements throughout the rest of this year. And with that, we'll open up the call for questions. So you can set us up for questions. I appreciate it.

Thank you. [Operator Instructions] Our first question comes from Tyler Van Buren of Piper Jaffray. Please go ahead.

Hey guys, good morning, and congrats on the progress and the positive broadened study results, and with respect to WAYLIVRA, can you remind us of the opportunity in FPL and the prevalence in the patient breakdown as we think about adding that on top of the existing FCS syndication?

Yes, thanks. FPL is rare indication of course, and the size of the FPL population, if I recall correctly, is about -- is similar to FCS, maybe around 3,000 patients or thereabout. So, we think of the opportunity as being roughly similar to the FCS opportunity, and we believe that the combination of the two will be an important contributor to our future revenues.

Okay, that's helpful. And then with respect to the Phase I TTR LRx update in September, could you give us maybe a glimpse of what additional information we'll see at that meeting that could be meaningful for the pathway forward? And then as a follow-up to that, what have you seen so far that gives you confidence that you could have a potential follow-on product that's dose once or twice a year?

Sure, Tyler. I'll will take that. This is Brett. So, yes, we're looking forward to sharing the results of our Phase I study on TTR LICA. We're very encouraged by the results so far. Our TTR LICA is performing like all of our LICAs, with excellent potency, pristine safety and durability. And we'll share that data. We'll share the pharmacodynamic, the TTR lowering data and we'll show the safety data. And we'll also give you probably a glimpse of what our Phase III designs are going to look like in polyneuropathy cardiomyopathy, since we're gearing up to start those studies. We can dose the free - we can utilize, we will have two options for dosing frequency for our LICA strategies. We can go monthly, easily, like we are doing for most of our programs, we can go quarterly or even less frequent if we choose to. We're settling on the exact - and that's based on the wealth of data we have with all of our LICAs. It's just the durability of efficacy that we see, they're all same. We're settling on the dose frequency right now. The truth is, Tyler, we don't see a significant advantage to going less frequent in monthly from a patient convenience standpoint. And we think there are advantages to actually going to monthly as well. We can talk in more detail about that maybe in the presentation. But we have the option - we have options monthly, quarterly, whatever we want to do. But I think we're selling on monthly right now.

So, Tyler, the question that you asked about if once or twice a year, may have been related to the follow-on to SMA to SPINRAZA?

Yes.

in that case, obviously and intrathecal administration for most of our intrathecal drugs, we give them a quarterly or a little less frequently. And across the board, we're working on new molecules that we think will allow us - will support much less frequent dosing. There, I think there's real value in maximizing the space between doses. Because it's obviously a procedure that requires meaningful effort. So the way I think of it is that for systemic administration, we're in position to provide the patient dose frequency that makes sense. We've looked through our pipeline and we've talked to patients, we've talked to providers. And our conclusion is that by and large, monthly dosing is the easiest thing for patients and providers to work with. For intrathecal administration, our intention is to have drugs there that can be dosed as infrequently as possible. And we're making great progress there.

Great. Thanks for taking the question.

Yes, but I wouldn't want people to confuse. We're are not seeking to make annual dosing systemically. We don't think that's the best -- or even semi-yearly. We don't think that's the best solution for most patients, very different from intrathecal.

Thanks again.

Our next question comes from Jim Birchenough of Wells Fargo. Please go ahead.

Hi, guys. Congratulations on all the progress. Couple of questions. I guess the first one is just on Huntington's. That's becoming a very high-profile program. There has been some attention on neurofilament light chain increases that appear transient, and ventricular volume increase, and a bit of speculative backfill on it may be being related to wild-type knocked down or to ASOS in general. And so could you perhaps address that directly and more meaningfully address whether - and maybe just address this directly whether Roche's extension to every four month dosing had anything to do with either of those phenomenon? I think it'd be helpful just to have you speak to that.

Jim, I'll take that. This is Brent, again. So the intention, enthusiasm for our Huntington program with Roche is warranted for sure. I mean, this is a very exciting program. Patients are in desperate need for this medicine. And Roche is doing a great job in developing this drug and we're looking forward to continuing presenting data on the open label extension this year or early next year. So regarding the data that was presented at AAN earlier this year and published in New England Journal of Medicine; as you indicated, with continued dosing of our Huntington medicine, we saw a transient increase in NFL and the ventricular volume that was coming back down to baseline and was essentially a baseline with continued dosing, And with that continued dosing, of course, Huntington levels are continuing to be driven down further, which that data by itself indicates that has nothing to do with Huntington reductions, because you would expect the - if it was related to that, there would be continued increases in neurofilament. But we don't see that. So it's clearly not related to Huntington reduction in the sense of toxicity. With respect to the dosing frequency and the changes to that, early on in the Phase III study, we have just begun the Phase III study when data was coming out from the open label extension looking at Huntington reductions by both monthly and bimonthly dosing. And what was clear in the open label data was that the bimonthly dosing and even potentially a tri-annual dosing was getting us well below the threshold that was necessary for Huntington reductions to produce potential benefit based on all the preclinical data we had. Since Roche had just begun that study, they wanted to offer greater convenience to patients with bimonthly and tri-annual dosing. Considering the drug has been administered [indiscernible] so they made that decision and it really had very little impact on the Phase III study; including, when do you expect to readout is expected. But in no way was it related to any adverse events or SAEs that we were seeing and that correlated in any way with the transient NFL changes that we saw or check the volumes that we -- that changes that we saw in the study.

Simplest explanation is the decision was consistent with our goal to maximize the time between intrathecal injections. And once we had data that told us that we could do that, we did it. With regard to the question of whether it's related to ASOS in general, let me say that at Ionis, we have more experience with intrathecal administration of RNA targeted therapies than the rest of world combined and multiplied by 10. And we are very confident that ASOS administered intrathecally are safe and well tolerated. And I'm sure investors are as well, all they have to do is look at seven years of experience with SPINRAZA.

That's helpful, Stan and Brett. Just following up on the Factor XI opportunity and the data update that we'll get. I guess just if you could remind us what the -- if there's an opt-in milestone payable if Bayer moves forward with one or both of those? And maybe comment on your level of confidence that they will move forward with a Factor XI directed antisense approach.

Jim, yes, there is a milestone payment for their decision to move forward in the development. And right now Bayer is reviewing with us the data from both the Phase I LICA drug, as well as the Phase II study in end stage renal disease patients. And in that study, of course, we have safety, tolerability, Factor XI reductions, evidence of prevention of thrombosis, as well as bleeding. Bayer is very excited about Factor XI as a program and our antisense medicine in particular. And they made a strong commitment to this pathway, in the Factor XI specifically, and I'm feeling very good about they're likely moving forward with this program based on all the enthusiasm that they've shown. I mean, the data that we have seen so far is very encouraging, as has been the data that we presented previously from our knee replacement study and published in New England Journal of Medicine. It's a very exciting program and it's, again, it's a program that has a potential to treat millions of patients at risk for thrombosis, who are also at risk for bleeding.

Everything we see from these drugs, teaches that they are really important assets in our pipeline. So speaking, not for buyer, but for us, we are really excited about these products. And we'll be developing them through Bayer or other ways. But I'm entirely in agreement with Brett, that we're optimistic that Bayer will move forward rapidly with these agents.

Great. Thanks for taking the questions.

Thank you.

Our next question comes from Paul Matteis of Stifel. Please go ahead.

Hey, guys, this is Neil [ph] on for Paul. Thanks for taking the question. Congratulations the way you delivered data. And I hear you on the positive interactions with the FDA for FCS, and if you could provide any details there would be great. But I'm assuming you're limited there. And could you touch on the regulatory path specifically for FPL in the U.S. and then just the overall U.S. strategy there? Thanks.

Well, you're right. We can't add any comments further to what we've said about our interactions with the FDA. And I'm hesitant today to get into details on FPL, because we just have the data. And so what we're going to need to do is finish the analysis of the study. It's actually fairly complicated analysis, obviously, different kinds of data. And then take the opportunity to sit down with regulators and see what of sorts of criteria they're going to want us to be to achieve a path to commercial opportunities with the FPL; given this, again, the rare size of this disease population. So I think you're just going to have to give us a little time to get more information from regulators about the process.

Got you. That makes sense. And then maybe just one more on the earlier stage pipeline. Could you touch on the Phase II initiative for the pre-Kallikrein program and HAE?

Sure, happy to. So it's a LICA drug and PKK LICA. And we are -- and it's performing like all of our LICA drugs with excellent potency and tolerability, safety, durability. We are actually pursuing multiple indications for our PKK LICA drug. The first drug, it is in a competitive environment, hereditary angioedema; and we're starting that study in HAE patients now and we're looking forward to providing benefit as measured by reducing frequency of attacks, HAE attacks in these patients. This has a potential to be a very convenient drug for these patients, a very effective drug. We know we can reduce PKK reduction or levels and reduce the activity of Kallikrein pathway substantially, 80%-90% range or so. And we think that that based on everything we've seen, it's going to really have a positive impact HAE. In addition, we haven't disclosed the indication yet, but we're also now exploring multiple other indications that are relevant to the Kallikrein pathway. And one in particular will share some information on maybe later this year, early next year, an indication that we think, is even broader than for HAE, and news on that will be coming soon.

It's a competitive area. And so, we're not willing today to discuss the various indications that we're pursuing or considering to pursue, but we're excited about the product.

Thanks for the info, guys.

You bet.

Our next question comes from Chad Messer of Needham & Company. Please go ahead.

Great. Thanks for taking my question. And congrats on both the clinical and financial results. For Factor XI, you mentioned you even barely deciding to take one, or both of the LICA and the older school antisense forward, can you describe a situation and when a sort of a scenario which bringing both forward would make sense?

Well, in principle, it will generally relate to timing. In the case of the parent, we already have a very significant face to experience, very positive data and the total knee replacement in earlier data and patients with end-stage renal disease. This study is really a confirmatory study in those patients, and so larger study. So I think the equation that needs to be written in all of these cases, where we have the LICA form, as well as the parent that are being developed, really boils down to timing and dollars. And APOCIII is exactly analogous and there, of course, we went ahead and developed products WAYLIVRA because it was close to the market. And we thought it could provide benefit to patients who had rare diseases. And now, we're following up with the APOCIII LICA and of course, we're tremendously excited about that drug because of its -- it being a LICA and it's breath utility . So we'll sit down with there, and we will write that equation and look at the value and make or pay financially and patient centered decision that makes sense.

All right. Yes, now, that makes sense to me. And then just one more I'll just kind of can't help myself here, because I'm really excited about this. I understand we may be getting an oral anti-sensitive to the clinic soon, and probably have to wait to get a lot of details on that. But can you share what you can about that now and maybe talk about what sort of technical advances made that possible?

Well, I'm not sure where you have heard that. But before, I get to a comment about that. I do want to return to this interesting challenge that we face and have faced and I think fairly successfully. And that is that technology is not static. It's constantly evolving. And in our technology webcast, I hope we get a chance to demonstrate to you the breadth of advances that are taking place. And as those advances take place, we see improvements in drug performance. And so, the way we have managed the conversion of generation-to-generation to five, the conversion of both of those to LICA is a pathway that will be pursuing in the coming years as these new advances come forward. And, yes, it is an interesting challenge to manage. But it's a great problem to have, to be constantly making better and better drugs. So we're excited about it. With regard to oral, these are the things I'm prepared to say today. If you go back and look at Canamrow [Ph], we showed in human beings in a Phase I study that we got sufficient oral viability to reduce apoB-100 and reduce LDL. So that demonstrated that it's really more of an engineering issue. And the challenge there is to find a solution where you have open enough drug, that the size of the pills and the cost of therapy and all of those things are reasonable. So, just as we've been making advances, everywhere else, we've been working steadily on taking that basic observation that we can do this and now making it a commercially attractive opportunity. And we discussed advances in our technology when we think they're ready to be incorporated into drugs, and when we have our conviction that we're right. And so, we will follow that course with oral, you will hear from us as soon as we're confident we have achieved what we meant to achieve. We hope that that can be in the near future.

All right, well, certainly stay tuned on that. That's very, very exciting.

Because there's a lot of words will say nothing I know. But okay.

Yes. And anyway, obviously very game changing in terms of the indications that would allow you to consider, so…

Anyway as you know, and it's actually the last frontier for instance, we now have demonstrated that we can give these medicines by every single route of administration that's ever been tried, I believe, including enema for local colon disease. And so, oral really is the last hill to climb. And, we've been climbing it. And we look forward to getting to the top.

Okay. Thanks.

You bet. Thanks Chad.

Our next question comes from Ritu Baral of Cowen. Please go ahead.

Hi, guys, thanks for taking the question. As we look forward to the LICA TTR Phase 1/2 data release? What level of TTR knockdown are you guys targeting? What would make you happy? I understand that the dose ranging study, how should we -- how should we think about that dose ranging data and what you guys feel you need to move the needle on to get a clinical benefit. And then, as you think about that, Phase III program Brett, I understand you wanted to you know give more detail later. But should we be thinking about it significant differently than the patisiran Helios programs? Especially, I think HELIOS-A was allowed to use the control group from the original technology Apollo study, are their sort of creative ways around long extended studies for the potential LICA TTR Phase III?

With regard to the first question, review, I think you just should refer to APO(a)-LRx and all the other LICA bottom-line is that we can dial in pretty much whatever reduction we want. And so, we have the ability to make that choice, just by picking up the dose. And we already know the level of reduction that gives us the kinds of results we've done with TEGSEDI and we have a very clear idea of the level reduction we want out of the LICA, so that it's maximally competitive. And then we're going to leave it there. With regard to the Phase III trials for polyneuropathy. And for the cardiac indication, I'll turn that over to Brett.

Sure, Stan. Hey, we're good.

Okay.

So yes, we have had very productive and recently completed our discussions with regulatory agencies and we are settling on the final design of this study. I mean, let's face it, we all talk to the same regulators, the same divisions and we have the option to do the type of study you refer to for polyneuropathy if we chose to. We're thinking through that. I think, if we can be even more creative and to bring this patient -- this drug to patients as rapidly as possible, but that's certainly an option, the open label study that you referred to you for polyneuropathy. For the cardiomyopathy, our discussions have also gone very well with regulators. Pfizer has done an outstanding job with tafamidis in the study they conducted and the outcome of tafamidis for patients in desperate need, particularly, the wild-type cardiac patients, they set the bar. I mean, to me, an outcome study is not just important for approval, but I think an outcome study is important for payers and for patients who want to get the drug. So that will certainly be an important component to our cardiac study, but we're also thinking of creatively on ways we can bring this medicine even faster to patients. And I think we'll share some of that data in September at the annual meeting.

Got it. That's helpful.

Next question -- go ahead.

Oh, sorry. Thanks. My next question was on the complement program. When could we expect the geographical atrophy program - sorry, trial data? And how are you thinking about the next indication and the different markets, do you guys prefer to go into sort of the more competitive complement space, the less competitive space? And how are you thinking about potential differential pricing or differential profile as you look across the complement disease landscape?

Well, we're reducing complement B. And what we believe is that a really valuable way to alter the complement pathways in general. And we're very confident that as a LICA, that the overall performance of the drug will match up against anything out there that reduces complement system activity. So we look at the opportunity as very broad and we're planning to enter some interesting indications as well as those that have been well-trod and are competitive. We think we've got a winner. The study in the eye is a large, longer-term study. And it's just getting underway. So it's going to be awhile before we'll be able to talk about those data. And I'd like to see how the enrollment goes for a bit more and how the overall study appears to be performing before I start handicapping what you don't want to date when we're going to have some information about that.

Got it. When do you think you might announce the next indication for FP LRx?

Once again, given the breadth of interest in the complement pathway and the number of companies involved and number of drugs; we think the clinical plan that we have is a competitive advantage. And so we're going to be fairly precious about what we're willing to tell people. And we're very precious today. I'm not willing to tell you anything.

Our next question comes from Yale Jen of Laidlaw & Company. Please go ahead.

Thanks for taking the question. Again, add my congrats for the progression so far. Maybe I just have two quick ones. First one is that HBV program you have with the PSA. I know you have some data report earlier of [indiscernible], Could you give us a little bit more detail in terms of what the target is? And also, you also have LICA version of that, and what could we anticipate from these two programs going forward?

Hey, Yale, this is Brett. Yes, as we mentioned in the webcast, we're very excited about this program, as is GSK. And GSK will be presenting data with us later this year at a medical meeting. As you know, one of the things that hinders current medicines nucleoside analogues that target HBV is that they can block polymerase and replication of the virus, but they don't eliminate the virus. And that root cause is -- turns the disease into a chronic disease. That still causes problems for many important problems for patients. Our strategy using an antisense mechanism is to be able to target all the transcripts that are produced from the HBV circular DNA, which -- there's basically four transcripts, right, there is the polymerase, there is the core protein, there's the S antigen. And our mechanism targets all those transcripts. And that gives us a significant advantage, because that potentially allows us to not just block the replication, but to eliminate the virus entirely, essentially causing a functional cure. We have to prove that of course. But so far, the data is very encouraging. More on how we're targeting the transcript, we're going to keep that to ourselves a little while.

And on the LICA and parent, we're just, we're collecting data on both. The parent is more advanced of course. And so it's another one of those situations toward of like in [indiscernible] 3 like Factor XI, in which we'll look at the performance of both and we'll look at the time advantage of one versus the other. And in this case, GSK will make all those decisions. Obviously, we are optimistic that GSK would choose to move forward with the program. But we would be delighted to have it back. And if it were our choice than we'd use the same sort of equation that we've written for these other drugs as well.

Okay, great. Maybe just one follow-up questions here. You mentioned that you have great equity in intrathecal injection and that the next-gen product basically and even more less frequent dosing. Just in general, without revealing your base secret, what are the sort of typical formulation or other aspect to enable these type of -- even less frequent dosing sort of potential?

It's not a change in formulation. I mean, these medicines, like all of our medicines except for oral are just basically formulated in saline. It should change in the chemistry and that supports than longer duration and also higher dosing if we choose to go there. So it's fairly straightforward sort of engineering challenge. And then the art form here is to make sure that we've got a molecule that's going to give us at least every six months dosing, but really hope for much longer than that. I think we're almost there. And so we look forward to moving that forward. And obviously, as that experience teaches how to do it, as we learn how to do it, then that is something that we can apply to all of our intrathecal programs just as the LICA program and Generation 2.5 can be applied to all of our systemic programs. So think of it in an entirely analogous way to what we've done in the rest of the body, Yale.

Ultimately you could have, for instance, most of your antisense product maybe in two years in almost in yearly dosing possibility if that's the best treatment paradigm for specific indication?

Well, I certainly am not ready to say we're going to have all that accomplished in the next couple of years. But we are making very good progress to our far less frequent dosing in the central nervous system. And we are optimistic that we're going to be able to bring that to the clinic here and improve. But what we've seen in animals, we can see in humans. And once we have that, obviously then we'll be converting our intrathecal administrations to those kinds of forms going forward. So stay tuned. I think we're going to be excited about what we're able to share with you.

Great, thanks a lot. Appreciate it.

You bet.

Our next question comes from David Lebowitz of Morgan Stanley. Please go ahead.

Thanks for taking my question. Quick question on TEGSEDI. To this point after several quarters in the market, is there a specific profile of patient that typically chooses TEGSEDI versus the other options out there at this point?

Not that we have yet. And our hope is of course that patients have a wide range of TEGSEDI, because of its convenience of administration and the freedom from freeing up of the limitations of the disease. But I think it's too early to make judgments about that today.

Fair enough. And I'm understanding that it's approved for a different indication. Is there any feedback or commentary or hearing anything on Tafamidis from the doctors?

Yes…

So in terms of impact on TEGSEDI, I mean, we're still - we haven't seen much of an impact. We're still getting increases in prescriptions from cardiologists, neurologists and hematologists. We have a 50% increase overall in prescriptions in the U.S. in the last quarter. As you heard during the call that the earnings was $10 million, which is a 40% increase over the first quarter. So, we haven't- it's early still, but we haven't really seen much of an impact.

Thanks for taking my questions.

Our next question comes from Jessica Fye of JP Morgan. Please go ahead.

Hey guys, good afternoon. Following up on the earlier question on Huntington's, what do you expect physicians will be focused on when that OLE data is presented?

Well, Jess, I think the physicians will be focused on lots of things. I mean, they're going to certainly be focused on the durability of mutant Huntington reductions in the OLE, which will be out. It will be 15 months or longer patients will be on drug. And the -- and how the patients are getting on with their dosing, safety, tolerability. And we don't know for sure yet of what's going to be presented. But I think we would expect that considering there'll be 15 months of data with natural history in parallel and published natural history data, I think we'll expect to see some signs of clinical endpoints, some aspects of clinical results in that update as well. And I think that's what the physicians would be looking for.

We've described the endpoints that are going to be measured for efficacy and the Huntington's endpoint. So I mean, we will be analyzing the data with regard to those endpoints of safety, tolerability and all that. Next question please.

Our next question comes from Jim Birchenough of Wells Fargo. Please go ahead.

Yes, hi guys. Just a couple of follow-ups. I guess, Stan, just maybe at a higher level, you've had tremendous revenue growth and you've had several years of profitability. Just from a financial perspective, are you at the point where we should start focusing on earnings growth or is the goal here to continue to grow the top line, reinvest in the business and stay cash flow positive, but not necessarily get people too focused on earnings growth, are we at that point?

Well, first of all, Jim, thank you, because Beth is sitting next to me and he's about to go to sleep. And I'll give you my answer and then Beth will give you the correct answer, if that's necessary. We're excited about where we are financially. And we see continued growth in revenues and continued growth in earnings and continue increasing investment while we do all that. And for us, that's just a really exciting moment. So, I would say you focus on earnings growth, we are an earnings story today and have been with an extraordinary pipeline and an opportunity to create value that's still stochastically increasing as the pipeline advances. Exciting to us, and we welcome that kind of focus.

Completely agree.

That's the first time. Okay, I -- with that, and Jim, thanks for asking the financial question. I really do mean that. With that, I think we've completed the Q&A. I want to thank everyone for your thoughtful attention and excellent questions. We look forward to keeping you progressed. We expect as the year progresses to continue to report financial successes and high planning commercial successes, and our coaches had an extraordinarily exciting moment in our history that we look forward to sharing with you. Thank you.

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