Good morning and welcome to Ionis Pharmaceuticals Third 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, Investor Relations, to lead off the call. Please begin..

Thanks John. Before we begin, I encourage everyone to go to the Investor section of Ionis website 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 have also posted slides on our website that accompany our discussion today.

With me on today’s call are Stan Crow, our Chairman of the Board and Chief Executive Officer; Beth Hougen, Chief Financial Officer; and Brett Monia, Chief Operating Officer. I like to draw your attention to Slide 3, which contains our forward-looking language statement.

We'll be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties to our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional details.

And with that, I'll turn the call over to Stan..

Thanks, Wade, and good morning, everyone. Thank you for joining us. Our commitment to innovation has led to the increase in value of our commercial medicines, our pipeline and technology, which today is reflected in our robust financial performance.

Because of our strong performance in the first nine months of this year, we are significantly increasing our 2019 guide to – of significant improvement. We’re on track to deliver approximately $1 billion in revenue, more than $375 million in operating income, and more than $300 million in net income.

This means that we expect to deliver our fourth year of operating income, our third year of net income. We’re achieving these strong results while continuing to invest as aggressively as justified across every element of our business.

We’re achieving success and making progress broadly throughout the business and we’re extremely pleased with SPINRAZA’s continued blockbuster performance.

SPINRAZA is the worldwide foundation of care for the treatment of all SMA patients of all ages supported by growing body of data, continuing to show [they have getting] getting stronger the longer they are treated with the product. We’re already seeing positive momentum at AKCEA as Damien assumed his leadership role.

Damien is adding key new member to the AKCEA leadership team, with skills necessary to help the organization reach its commercial and development goals. The first of several additions to the senior management team is Kyle Jenne, who was recently promoted to Chief Commercial Officer after leading the AKCEA’s U.S.

commercial organization TEGSEDI and WAYLIVRA. Importantly, we’re beginning to see momentum build at TEGSEDI and WAYLIVRA. AKCEA is expanding the market opportunity for TEGSEDI across the world. With approval in Brazil, TEGSEDI is now the first RNA-targeted therapy approved with a treatment of patients with TTR polyneuropathy in Latin America.

Given the substantial number of patients with the hereditary form of this disease in Brazil, Latin America is the key strategic region for TEGSEDI therapeutic that add market development and medical support in place in Brazil and we plan to start launch activities for TEGSEDI AKCEA. AKCEA is also beginning to make significant progress in EU.

TEGSEDI is now on the market in the UK following acceptance by NICE and the Scottish Medicines Consortium.

Akcea successfully completed pricing negotiations in Germany and successfully completed a pricing negotiation in Germany and successfully completed reimbursement negotiations in Austria and Sweden where TEGSEDI is now on the market and preparations for additional EU country launches are underway.

WAYLIVRA is now on the market in Germany with FCS patients benefiting from the only medicine approved for the treatment of this devastating disease. Additionally, AKCEA is preparing for more EU country launches next year. PTC is preparing to expand WAYLIVRA into Latin America, and in the U.S.

and Canada, we believe new long-term data and our experience in the EU will support our ongoing efforts with regulators to find a path to the market for WAYLIVRA. Damien and his team have also gained momentum in strengthening and advancing the AKCEA pipeline.

Most recently, we and AKCEA entered a collaboration with Pfizer to develop and commercialized AKCEA-ANGPTL3-LRx for the treatment of certain metabolic and cardiovascular diseases.

This collaboration was substantial up front and backend economics and targeted for diseases that are very large patient populations is further evidence that our partners have confidence in our technology and its ability to provide benefits to patients with diseases both rare and much more common.

Additionally, AKCEA will soon have two medicines in Phase 3 development, AKCEA-TTR-LRx and AKCEA-APO(a)-LRx, and early next year, AKCEA plans to report data from Phase 2 studies of AKCEA-APOCIII-LRx and AKCEA-ANGPTL3-LRx.

In addition to our recent achievements with medicines in the AKCEA pipeline, we also achieved multiple value driving successes across the broad Ionis pipeline this quarter. We’re on track to achieve our goal of ending 2019 with four Phase 3 programs underway.

Pivotal studies are progressing for patients with Huntington's disease and SOD1-ALS and Phase 3 programs for TTR Amyloidosis and LPA driven cardiovascular disease are beginning very shortly. We made substantial progress with our medicines other than these to better addressing diseases with large patient population.

In addition to the new collaboration with Pfizer for ANGPTL3-LRx, buyer financed to advance LICA Factor XI medicine for the treatment of patients with thromboembolic disease and GSK licensed our HBV program for the treatment of chronic hepatitis B virus infection. Our neurological disease pipeline advanced as well.

Biogen dosed the first patient in its Phase 1/2 study for the treatment of patients with Parkinson's disease, another large disease. We also added three new medicines for our neurological pipeline, two partner with Biogen and one that’s wholly-owned.

Importantly, we continue to strengthen our position as the leader in RNA-targeted drug discovery and development and our technology continues to advance at an increasing pace.

Today, we can achieve these substantial financial and businesses successes, while continuing to broadly and aggressively invest across our businesses, including investing in growing our commercial medicine and advancing our pipeline in technology.

These are, of course, our highest priorities because we believe these investments have the greatest potential to create patient and shareholder value, and because of our strong balance sheet and cash flow, we can achieve all of this and achieve all these goals while also returning value to our shareholders in the near-term.

So, today, I'm pleased to announce that our Board of Directors has authorized an initial share repurchase program of up to $125 million with the potential of for us to consider additional repurchases in the future as part of our overall capital allocation strategy.

This action reflects the confidence that we have in our business and our commitment to creating near-term and long-term value. We also believe that at today’s stock-price, buying back our shares is a really good investment.

And now, I’ll turn it over – turn the call over to Beth to provide a financial update followed by Brett, who will update you on our pipeline progress..

Thank you, Stan. Our strong financial results continued in the third quarter. In the first nine months of this year, we delivered operating income of $217 million and net income of $189 million both on a non-GAAP basis. We also achieved substantial operating income and net income on a GAAP basis.

These strong results were driven by nearly $630 million in revenue, a more than 50% increase compared to last year. Growth in both commercial revenues, including SPINRAZA’s continued blockbuster performance and R&D revenues as our partnered programs advance, contributed to the substantial increase.

In the third quarter, we maintained our strong balance sheet with $2.2 billion of cash, and we expect our cash balance to increase when we receive payments from Pfizer and Bayer this quarter. SPINRAZA generated over $1.5 billion in worldwide net sales through the end of the third quarter, an increase of nearly 25% compared to last year.

Reflecting SPINRAZA’s joint performance, our royalty revenue of $212 million increased by more than 25%, compared to last year. The total number of patients on SPINRAZA treatment increased by approximately 11% from last quarter to more than 9,300 patients worldwide. New patient starts in both the U.S. and around the world contributed to this growth.

In the U.S., adult patients were a significant driver of growth in the third quarter increasing by 8% over last quarter and as the largest SMA patient segment, we and Biogen believe that adult SMA patients represent a continued opportunity for growth.

Now approved in over 50 countries and with reimbursement in place in 40 countries, the number of patients on SPINRAZA outside the U.S. increased by approximately 18%, compared to last quarter.

Strong performance in established markets such as the EU and Japan, plus rapid up take in key markets in Latin America and Asia Pacific were primary drivers of this growth. Additionally, the first SMA patients in China recently began SPINRAZA treatment.

Biogen expects growth to continue in these key markets and believe that the global opportunity for SPINRAZA is much larger than initial estimates with more than 45,000 patients in markets where Biogen has a direct presence.

Importantly, as the body of evidence supporting the robust profile of SPINRAZA continues to grow, we believe SPINRAZA will remain a global foundation of care for the treatment of SMA patients of all ages and type.

Turning now to TEGSEDI and WAYLIVRA, we earned $29 million from product sales of TEGSEDI and WAYLIVRA during the first nine months of this year. The AKCEA team continues to make progress with the launch of TEGSEDI.

In the U.S., AKCEA’s focus is on disease education, particularly in community centers while maintaining strong relationships with physicians and the academic centers. Additionally, use of AKCEA’s genetic-testing program is growing with more than 1,000 physicians now using the program.

Both of these initiatives are translating into more physicians prescribing TEGSEDI. Outside of the U.S., we are extremely pleased that following approval in Brazil TEGSEDI is now the first RNA targeted therapy approved for the treatment of people with TTR polyneuropathy in Latin America.

PTC Therapeutics plans to start their launch activities in Brazil immediately. We also look forward to potentially expanding more broadly in other Latin American countries. Additionally, patients are now on treatment in Austria, Sweden, and in all four countries in the UK, and AKCEA’s preparation for additional EU country launches are underway.

AKCEA’s patient support program is now up and running across all commercial markets and feedback from physicians has been quite positive. So, we're pleased to see this program expand with the TEGSEDI launch.

Patients are now being treated with WAYLIVRA in Germany following approval in the EU and AKCEA is preparing to launch in additional EU countries next year, we look forward to potentially expand into Latin America also through PTC.

Reflecting the substantial and increasing value of our technology, R&D revenue increased by more than 55% to $377 million.

R&D revenue included $198 million in license fees revenue from Novartis, GSK, and [indiscernible], $100 million from amortization of upfront payments for advancing numerous programs in research and development and $64 million in milestone payments, including nearly $25 million from Biogen, which included most recently a milestone payment for initiation of the Phase 1/2 study targeting [indiscernible] for the treatment of people with Parkinson's disease.

We expect to recognize substantially all of the $250 million upfront payment we generated for Pfizer's license of AKCEA-ANGPTL3-LRx in our fourth quarter results. Our recent license of AKCEA-ANGPTL3-LRx demonstrates the increase in economics we can command for our medicines and technology.

In addition to the $250 million upfront payment, we are eligible to receive up to $1.3 billion in milestone payments and tiered double-digit royalties on net sales. Moreover, Pfizer is adding substantial value by conducting future development and regulatory activities and paying for these activities.

Additionally, we will recognize the $10 million milestone payment from Bayer in full in our fourth-quarter results. Bayer will assume the development of Ionis Factor XI-LRx, which represent substantial value to us. Our non-GAAP operating expenses increased to $412 million in the first nine months of this year, compared to last year.

We are investing broadly across our business, including investing in commercializing TEGSEDI and launching WAYLIVRA in the EU advancing and expanding our pipeline and advancing our technology. Our strong financial performance this year has led us to improve our 2019 guidance. We are now presenting to earn $1 billion in revenue.

We are maintaining our original guidance for operating expenses, while continuing to aggressively invest across the business. However, we do anticipate being at the lower end of the range for both R&D and SG&A expenses.

We are increasing our operating income guidance to more than $375 million, which represents more than five-fold increase over last year. And importantly, represents an operating margin of nearly 40%. We’re also increasing our net income guidance to more than $300 million and we are increasing our cash guidance to $2.2 billion.

Our highest priority investments are our commercial medicines, broad pipeline, and our technology. Our strong balance sheet and cash flow combined with our commitment to continued profitability means we are also able to begin returning value to shareholders through an initial share repurchase program about $225 million.

We plan to make stock repurchases under this program, in open market transaction. And we anticipate that if the conclusion of this nation program we will consider additional share repurchase programs to provide even more value to shareholders.

The increasing value of our technology, financial strength, and ability to return value to our shareholders further distinguishes us from our peers. And with that, I’ll turn the call over to Brett to provide an update on our pipeline..

Thanks, Beth. Today, we have three medicines on the market of pipeline of over 40 medicines advancing through development and many more progressing through research towards clinical trials. SPINRAZA is the global foundation of care for the treatment of SMA patients of all ages in all SMA types.

And Biogen continues to report new, even longer-term data demonstrating improved patient performance with prolonged SPINRAZA treatment. A new data from nurture study of pre-symptomatic infants now on treatment for approximately 45 months, we continue to see kids developing like their normal healthy counterparts.

Remember, without SPINRAZA these babies would have rapidly [indiscernible] with their disease. And patients with later on SMA in the shine study, some of whom began the study as kids and have now reached adulthood, continues to show stabilization nor improvement in measures of their disease.

Today, some patients treated with SPINRAZA in the shine study have gained the ability to walk on [indiscernible]. Biogen is also preparing to explore the potential of achieving even greater benefit with a higher dose of SPINRAZA with over 9,000 patients on SPINRAZA today including some patients who have been on treatment for nearly 6 years.

SPINRAZA is well established safety profile is supportive of expanded dosing. Biogen's Phase 2/3 devote study which we expect to begin soon will evaluate the safety and potential to achieve increased efficacy with a higher dose with SPINRAZA with fewer loading doses in SMA patients of all ages, including the adults.

Additionally, we and Biogen are developing a follow-on medicine for the treatment of SMA focused on less frequent dosing, which could enter development next year. Ionis HTTRx, also known as RG6042 is progressing in a comprehensive Phase 3 program in patients with Huntington's disease.

Roche recently announced expanded enrolment in the Phase 3 generation HD1 study. This expansion will enable a more thorough evaluation of each treatment group, including the every four-month dosing regimen. It also allows Roche to add patients from China to this study.

This pivotal study along with the Phase 1/2 open label expansion in natural history studies are all important elements of Roche’s comprehensive clinical program to thoroughly evaluate the potential of Ionis HTTRx to be the first disease modifying medicine for the treatment of Huntington’s disease.

The Phase 3 [valor] study of tofersen is also progressing well. Biogen is evaluating this medicine for the treatment of patients with SOD1-ALS, and hopes to bring 2% of patients with this devastating disease rapidly responsible.

Biogen also we recently initiated a Phase 1/2 study of our medicine targeting [mark-2] the most common genetic cause of Parkinson's. This study will enroll patients with work to mutations as well as patients with sporadic form of Parkinson’s disease, which together represents over 3 million patients worldwide.

Under our collaboration with Biogen, we now have eight medicine in development on top of a substantial research stage pipeline that together addresses a broad range in neurologic diseases, including Alzheimer's disease. [Indiscernible] generation in various forms of both ALS and Parkinson's disease and many more.

In parallel, we also continued to advance and expand our pipeline wholly on medicine.

In addition to the advances we’re making across our pipeline, advances in our technology continue to enhance the performance of our medicines, expand their commercial potential and enable a broad and robust pipeline of potentially transformative medicines for many years to come.

Today our partners are recognizing the substantial commercial potential, which is reflected in the increasing value we received from our collaborations. This value, of course, is based on the confident our partners recognize in our technology to treat a broad range of diseases from rare and the most common effecting millions of patients.

For example, GSK recently licensed our HBV program and has repeatedly expressed strong enthusiasm about its potential to treat the more than 200 million patients around the world with chronic hepatitis B virus infection that are not adequately treated with currently available therapy.

Furthermore, this year, several of our partners have also made substantial investments in medicines developed with our LICA platform technology. We address large patient populations. Our partners are attracted to the robust efficacy profile with LICA medicines based on LICA’s increased potency enabling low-volume monthly or even less frequent dose.

More importantly, our partners are confident in the favorable safety profile of our LICA platform as demonstrated by a total of over 1,100 people treated to take the LICA medicine, including nearly 300 patients treated for up to one year in the Phase 2 study of AKCEA-APO(a)-LRx.

High partner confidence in our LICA technology is being demonstrated in many. For example, Pfizer licensed AKCEA-ANGPTL3-LRx to treat millions of patients with certain metabolic and cardiovascular. Bayer chose to advance Ionis' Factor XI LRx to treat millions of thromboembolic diseases.

And Novartis is advancing AKCEA-APO(a)-LRx for the millions patients with Lp(a)-driven cardiovascular disease. This study, together with the outcome study for AKCEA-TTR-LRx for patients with TTR cardiomyopathy will be the first cardiovascular outcome studies for an antigenic medicine.

Furthermore, we continue to innovate and advance our antisense technology. This investment has paid and continues to pay substantial dividends.

Today, our antisense drugs incorporate many of these advantages to benefit patients across a broad range of diseases through advancements in medicinal chemistry, and optimization and validation of nearly all routes of delivery, we can target most organs and cell types with our antisense medicines.

For example, we have already shown the feasibility of aerosol delivery to the lung, but with enhanced performance of our antisense medicines along with more potent chemistries, we have substantially potential for commercial success for a broad range of diseases further expanding the reach of our technology.

Our first gen 2.5 pulmonary delivering medicine targets the epithelial sodium channel or ENaC in the long.

We are advancing this medicine for the treatment of people with cystic fibrosis and other pulmonary disease and we look forward to sharing results from our ENaC Phase 1/2 study next year along with updates in other pulmonary programs emerging within our pipeline. We’ll also make substantial progress in advancing oral dosing of our antisense medicine.

We believe we’re on the verge of developing a commercially viable oral antisense by combining our Gen 2.5 chemistry with our LICA chemistry.

The ability to deliver an antisense medicine as a daily tablet will represent yet another significant advance with the potential to provide substantial value to patients enabled, once again, by our pioneering research. We look forward to sharing results from these early clinical studies next year.

The first nine months of this year has been quite exciting, highly productive and eventful. We look forward to numerous additional value driving events through the end of the year and around next year. I look forward to providing further pipeline and technology highlights in the months to come.

And now, I’ll turn the call back over to Stan to close this portion of the call..

Thanks, Brett. We build Ionis on a foundation of our efficient technology and today the value of our technology is reflected in our financial strength and it's a product directly of our business model. Our financial strength then gives us the flexibility to maximize the value of each of our medicines and our technology.

Our partners are recognizing the value of our technology as demonstrated by the substantial economics of our recent transactions. Our business strategy is succeeding, and today, we are sustainably profitable, and Ionis is delivering more value to patients and shareholders every day.

Importantly, we’re delivering value while investing in the future potential of our business, including advancing our pipeline of over 40 medicines, growing our pipeline of wholly-owned medicines, advancing our technology in an ever faster pace, and potentially delivering commercially attractive aerosol and oral medicines, and enabling new routes of administration, while advancing new medicines for broad new therapeutic areas.

On December 13, we plan to host a webcast to discuss many of the recent advances in our technology. This will be a deep dive in the exciting science that we’re working on right now and we believe positions the technology to be ever more powerful in the years to come.

I look forward to the opportunity to discuss our work with you in this form and just as an aside, this is for real techno geeks, it's probably not for the faint of heart, but we hope you’ll join us anyway. So, watch for more information about the webcast, which will be announced very shortly.

The business successes and financial strength we built give us confidence that we will continue to deliver value to our patients and shareholders today and in the years to come. And with that, I'll turn the call over for Q&A. Sean, if you can set us up for Q&A please..

We will now begin the question-and-answer session. [Operator Instructions] Our first question today will come from Chad Messer with Needham & Company. Please go ahead..

Great. thanks for taking my question and congrats on the very strong financial results. I believe these – share buybacks are really good sort of indicator of how you're feeling about the business. .

Hi, Chad. Appreciate it..

Just wondering if you could share your thoughts about some recent comments from Pfizer about since the tafamidis launch, I believe they said they identified over 4,000 patients with TTR cardiomyopathy, especially given that you guys are about to start a trial in that indication?.

Well, I think they know this disease and the space extremely well, and we believe that there is a sizable market opportunity there and we’re very confident that the LICA form of TEGSEDI is going to deliver a great performance for us like the other LICA performances of other medicines have done..

Alright, great.

And then, as you know, very excited about the concept of an oral antisense and I’m sure we’ll, you know, be hearing a lot more about that in the future, but any thoughts on what makes sense to move first either new indications that, you know, might not have been as amenable to, you know, using a subcu injection or, you know, basically newer forms of existing sort of tried-and-true drugs that you have?.

You will be hearing a lot more about it and you’ll first hear it, as Brett describes it on December 13, at our upcoming technology webcast. And the answer to your question is, I'd say all of the above..

Alright, kind of what I was expecting. Looking forward to that webcast and congrats again..

Okay, thanks so much Chad..

Our next question will come from Jim Birchenough with Wells Fargo. Please go ahead..

Yes, hi, guys. Let me add my congratulations and great to see the share buyback and the confidence underlying that.

So, a couple of questions, I guess, number one, just thinking about the financial side of things, could you maybe give us some sense of how we should think about the outlook both in terms of revenues and earnings? Do we expect revenues to be a little lumpy given the contribution of R&D revenues and then to smooth out over time and just want to make sure we’re still guiding or expecting a sustainable profitability? And then, I’ve got a follow-up..

Well, yes, we now are reporting our first year of operating income and our third year of net income. And we’re very confident and optimistic that next year will be another successful year financially and across the business.

We are really excited about the things that are going on in the company and AKCEA and look forward to another better year next year..

And then just in terms of capital allocation, I think, one of the things you've highlighted historically or maybe even more recently is just investment in technologies that could maintain your leadership in the genetic medicine space.

And so, could you maybe talk to your efforts to go beyond antisense or extend your dominance in this area of medicine? And how you're allocating capital to that?.

Yes. We are excited about that, Jim, and it is progressing, and it is progressing on two or three broad fronts. Number one, is any access to anything that might enhance the performance of the technology we've invented today. Number two, is to expand our use of genomic information to an even greater extent than what we're doing today.

And then number three, we're looking for the next antisense technology. Yes, and if you think about those three components of the investment strategy, you would expect investments in the first couple of components long before the third, because enabling technologies like antisense don't come along every day.

So, I do expect that you'll begin to see some investments in those areas in the coming months based on the progress that we've made so far..

And then maybe just final question.

I know there's not much you can say on partner programs, beyond what partners have said and what you said in your prepared remarks, but maybe for your wholly-owned pipeline, what are the key products that you're most excited about? Maybe a question for Brett, and maybe speak to the visibility will get on those wholly-owned products over the next year or so?.

Brett?.

Yes. Sure, Jim, The – thanks for the question. Our wholly-owned pipeline is growing rapidly across all therapeutic areas, or many therapeutic areas.

I suppose the answer depends on how advanced the program is, plus, coupled with how potential – what the potential is for the – for that medicine to have a big impact to be a transformative medicine on the market.

I'd have to highlight a couple of three growth hormone receptor for acromegaly is a very exciting program that is in Phase 2 and it's due to readout next year and potentially move on to Phase 3. So, that could be a wholly-owned program that's in patients with acromegaly in Phase 3 next year. Our TMPRSS6 program is very exciting.

It's a program that has the potential to treat multiple disease populations, including beta thalassemia intermedia, alpha thalassemias, as well as myelodysplastic syndromes, MDS. So, lots of opportunity for that drug. It's performed very well in Phase 1, and is in Phase 2, and it's moving very rapidly.

And then our neuro pipeline, it’s also worth commenting on Alexander's disease, prion disease, Lafora disease are all moving forward very nicely. And obviously, we have validated nerve degenerative diseases with our platform. So, that has a very high potential upside on that.

And then the last thing I would say is, watch out for our lung platform or run a pulmonary disease pipeline. As I mentioned in the webcast, our ENaC program is in Phase I, is showing great promise and more to come behind that..

And Jim, I would add TTR-LRx is our number one asset that's wholly-owned. It's going to be commercialized through AKCEA. We're really excited about the potential of the lack of form of tech savvy to deliver incredible value.

And if you look at the economics of the large medicines that we have, APO(a), APOCIII, ANGPTL3, of the Parkinson's and Alzheimer's medicines and Factor XI, I think people tend to have forgotten how extraordinary the data with Factor XI were in that 300 patients of knee replacement study.

I think it's, to some extent, a mistake to focus solely on our wholly-owned pipeline because of the dollars that will come from those large products that are licensed under the economic terms we have, are going to matter a great deal. And it's – and again, it's manifestation of the business model work.

So, I fully subscribed to what Brett said, but I would add the comments that I made, obviously since I just did it..

Correct. Well, thanks for taking the questions..

Okay, thanks..

Our next question will come from Tyler Van Buren with Piper Jaffray. Please go ahead..

Hi, guys, congrats on the results. I know in the press release under key upcoming events, you didn't give a timeline, of course. But I just want to get your updated thoughts on timing of Huntington's data, of course.

And then once we get the data with the open label, what would you expect these patients to show on the composite endpoint and what would be a successful outcome with the active therapy?.

It sounds like a question that Brett should answer and I should avoid..

Thanks, Stan, and thanks, Tyler. Well, I mean, the data that we're all focused on, of course, is the randomized Phase 3 study, which stood, as Roche said, filing 2022 range, or if not sooner, and that's what we're laser focused on is that randomized pivotal study.

Regarding the open label data, Roche has said that they will share the results of that study next year, which will include open label data from both the Phase 2 study that we conducted as well as the Phase 3 study – the initial start of the Phase 3 study, which evolved about 100 patients, which then the dosing regimen was changed versus a lot of data there plus the natural history data.

As far as what to look for, obviously, in the randomized study, you're looking for a significant improvement in clinical endpoints compared to the placebo group. That's obvious in the rating scale for Huntington's as well documented and has been published on. Sort of the open label data, it's going to be looking for strong trends, I would say.

It's a small, relatively small sample size relative to the Phase 3 randomized study.

And it's going to be compared to natural history data, but it's – they are going be looking for, I assume, Roche is going to be looking for many of the same benefits in clinical endpoints that are going to be part of the Phase 2 – that are part of the Phase 3 study, maybe just some subcomponents to that, such as cognition or motor function or those sorts of things.

But they're going to be looking for strong trends and clinical endpoints that differentiate from the ongoing natural history work that they're doing..

Just to add a comment or two. We remain based on what we're observing, encouraged, as does Roche about the ongoing open label study. And I think we were very pleased that Roche made the decision to focus on the every four-month dosing. We've always felt that that was the best dose schedule for this medicine.

And so, all-in-all, we like the decisions that Roche just made and we're encouraged by the performance that we're seeing in the open label study..

Okay, thanks for that. And then on TEGSEDI, we're seeing a slower trajectory in the launch relative to Onpattro.

So just broadly, could you maybe help us understand what’s going on other than obviously, you guys launched a quarter later is – are you guys maybe in different territories and receiving different uptake in different territories? For example, in Europe, should Portugal come online soon and then also in the U.S.

I noticed the slide actually did not list U.S. as a territory.

So, maybe you guys are seeing slower uptick in U.S., which is a larger percentage of Onpattro sales?.

Yes. So, the – we certainly are happy – we're certainly considered the U.S. very important market. And if it's not on the slide, it was an oversight sorry. What we're looking at right now is not so much what happened last quarter, but what's happening in the coming quarters.

And we are optimistic with the new leadership at AKCEA, we're seeing very significant shifts in momentum. I do think that we will see growth accelerate a bit in the U.S., obviously Brazil is a really important opportunity for us. We are very pleased with what’s happened in Sweden, the UK and Austria.

So, these new markets are important and of course Portugal is an important opportunity for us too.

So, TEGSEDI is a little behind of what we hoped, but based on the new team and the progress that we are seeing out of them, I think we are optimistic that next year we will see an even better performance, and hopefully in this next quarter we will see an improvement..

Okay. Thank you so much..

Our next question will come from David Lebowitz with Morgan Stanley. Please go ahead..

Thank you very much for taking my question.

Would you be able to give us a run through of the recent HPV data and I guess talk about the reason that the non-LICA form of the drug is being pushed forward as opposed to LICA form?.

Yes. We don't have a full answer to that question. What we do believe is that HPV infection has an effect on the asialoglycoprotein receptors. So, we didn't see the level of increased potency that we expected, but we saw also great performance out of the parent.

And so, we agree with the decision that PSK has made, and we’re excited about what we’re seeing with the drug. It is also a little further along. So, overall, I think the performance of the parent was very exciting, haven’t seen those kinds of viral reductions in quite a while. And it looks like [the drug]..

Thanks for taking my question..

Brett, do you want to add anything to that?.

No, I don't. Stan, I think you got it. You covered it nicely..

Our next question will come from Vincent Chen with Bernstein. Please go ahead..

Congratulations on the progress. Speaking about the less frequently dosed SMA drug that you alluded to and how that might work. I have a bit of a geeky question about this one.

Broadly, what's your approach to this? You probably won’t say, what technology is, but is it more a matter of increasing the half-life of the active fraction of drug? Is it increasing dose, is it increasing our drug to enter the cell or that escapes the endosome? Is that increasing potency or something else to the extent to provide some color, and could you readily apply this to other programs in the portfolio such as the Huntington's program and what implications you might just have for the therapeutic windows in these drugs?.

These are really solid questions and we will get into more detail on December 13, and I think you will enjoy what we can tell you then much more than what I'm going to tell you now. We continue to invest obviously in all of those areas, of medicinal chemistry and remember that neurological program is relatively newer compared to other programs.

And so, you were still exploring novel medicinal chemistry approaches that we think can add some value there. We know that these drugs distribute very broadly in the central nervous system. And we understand the fact there is that define how long they last.

So, it’s just taking all of the knowledge that we have, plus all that we’ve learned over 30 years and applying it. We will be talking about endosomal release.

That gets very technical and complex and I don't think I want to get into it, try to explain it on this call, but that’s another area of very, very active progress for us, and approving delivery within the cell, as this as well as improving delivery to the cell or focal points for the – of what we're doing in core antisense reserve.

Did that help you? I hope..

Yes. Thank you very much. I look forward to the third..

Yes. We will be talking at some length about all that..

Our next question will come Ritu Baral with Cowen. Please go ahead..

Hi guys, thanks for taking the question and thanks for sequencing my questions perfectly. I did want to follow-up Stan on the new CNS programs that you mentioned.

I believe you mentioned that there were two new programs with Biogen and then one wholly-owned, can you elaborate a little more of where they some of the ones that Bret mentioned, the prion disease etcetera? Would love to know what’s in the pipeline and what sort of timelines we could be seeing for four clinical data from – of the additional CNS programs?.

So, we will take that. But before we get into that, I wanted to remind people of how exciting 12% is. And we are based on all of the observations with that medicine. We and Biogen are really excited about that drug. And that is, you know, is an importantly relatively near-term opportunity.

And so, with that addition, I will turn the question over to Brett..

Sure. Thanks. Thanks, Ritu. So, we’re continuing and we will continue to add new exciting programs to the neuro pipeline with Biogen.

The two recent programs that were entered into our development pipeline, our targets that are undisclosed at this point [indiscernible] but the wholly- owned program is our Lafora drug, and we’ve talked about Lafora disease before which is a glycogen storage disease of the CNS. So, we're very excited about that program.

The prion drug you mentioned before is not a Biogen drug, it is a wholly- owned program by – from Ionis, and we are expecting that to reach development shortly. And that really has a, you know a rather, that’s not an ultra-rare disease. That’s a disease with very significant populations to be treated. So, more and more drugs are coming.

We don’t disclose them with Biogen right up front, but our wholly-owned pipeline for neuro continues to expand as well..

And it is a little early Ritu to just give you, even a general sense of when there is going to be clinical data. I think we will hold off on that until next year when it will become much clear..

Got it.

And then pulmonary programs that you are going to talk a little bit more about on December 13, are those programs based on I guess, new formulations like encapsulation or something involving enhancement agents like your oral program or these sort of pure, is it a pure potency play for delivery?.

It’s a pure potency play. You will recall that we showed quite a many years ago, that these agents are really very nice to delivery by aerosol. We took the IL-4 drug into clinical trials and we demonstrated broad distribution, a meaningful pharmacology.

We didn’t feel it was in the end quite good enough to continue developing for asthma and that given all the other medicines are available, but that blazed the trial, and so these are formulated very simply just in sailing and they could be administered then by any of the devices that you – that you know about and so the key chain is increase in potency and we are seeing really remarkably exciting performance now in the lung.

And, you know like every organ that we work on, before we really move drugs forward, we invest in understanding the organ and how these drugs distribute not just to the organ but in the various cells of the organ and so we know all that. And Brett will share some of that with you at the December 13 call..

Great. Thanks for taking the questions. Congratulations on that oral poster at DIA. Everybody was at that poster, to the exclusion of the open bar..

We are excited. Do you remember, we will remind you on the 13 that we already showed it was feasible with KYNAMRO. What we needed was just a big step up in potency and we think we go it. And you will be hearing a lot more about that in the coming months, not just from us..

Thanks..

Okay. Next question..

Our next question will come from Jessica Fye with J.P. Morgan. Please go ahead..

Hi. This is Daniel for Jessica Fye. Thanks for taking our questions.

In light of the platelet decline observed with the HBV LICA product, can you make the case for widening the product expect issue versus a reason to worry about the other LICA products as well?.

No, I won’t do that. I will tell you it is not an issue at all. There is a lot of confusion about that. What actually happened was very minor declines in platelets that are not even, not remotely clinically significant and it was just the way the data represented.

There really is no significant platelet issue, even at doses of 418 mg a month with the LICA drugs. That’s what those data actually show.

Brett, do you want to add anything to that?.

Just to add to that those were as you said Stan, those were at very high doses and the drops in platelets were not clinically meaningful in anyway. So, really it has no bearing at all on our LICA platform.

And again, the confidence has been demonstrated by the licensing of drugs like Factor XI LRx and ANGPTL#-LRx and Lp(a)-LRx (sic) [APO(a)-LRx] by Novartis and Bayer and Pfizer just illustrates the confidence in our LICA platform from not just on efficacy, but also safety and tolerability..

Even at 480 mg a month we did not have a single patient who have gotten below normal level if I recall correctly in that study..

That’s correct, Stan..

It was simply the way that it was presented that caused a confusion. We regret that, but those are the facts..

Thank you..

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

Hi, thanks for taking my question and congratulations on the results. First of all, on behalf of your investors thank you for returning capital to shareholders rather than the reverse, which seems to be the normal in my coverage..

By the way we are not normal..

I have a couple of quick questions. First, regarding the ENaC opportunity, how do you guys think about the role of that in cystic fibrosis patients, given the number of failure effective oral therapies, would that be developed as an add-on, would that be developed in failures an and then I have one more question after..

One of the most interesting things about that is this directly at the cause of the disease. It’s not a modulator, it is not a modifier, it improves the performance of that sodium channel and in fact it reduces.

And so at least based on animal data and early returns from the clinic, I think we have a significant winner there not just for cystic fibrosis, but other lung disorders.

And what I like about it is it is a primary mechanistic approach to managing the disease that is accessible to antisense and really very difficult to do with other technologies because of their lack of specificity.

Brett do you want to add anything?.

Yes. Just add this, Mani, the ENaC should do all of what you said. It should be useful for patients that progress on small-molecule CFTR inhibitors or activators. It should be effective for – as add-on therapy and as well as those that have mutations that are not treatable.

So, the 10%, 15% of patients that are not treatable with the combo small molecules for CFTR are going to be treatable with ENaC because of its mechanism of action.

And as Stan mentioned, cystic fibrosis is we think is just one indication we think that this drug has the potential to treat a much broader population as well on patients with different types of pulmonary diseases..

Yes. I would add one more comment. We, as a general rule, want to lead, as we have, we have spent [indiscernible] Factor Xi and so on. So, for us to pursue an opportunity in cystic fibrosis, we really had to be very convinced that we had something that could do something that is very substantial these patients can use and we believe that.

And we believe that the mechanism can provide benefit in a number of other important pulmonary diseases and so this is for us a much more important investment than simply cystic fibrosis, which is important, but it is a broader investment..

Okay. And for my follow-up, when I look at the TTR-LRX study, correct me if I am wrong, but it sounds like you guys are allowing essentially unlimited tafamidis use in both arms? Tafamidis obviously is an active drug in cardiomyopathy with an overall survival benefit.

How do you think about maintaining balance, drop ins so presumably you will have efficacy in the placebo patients who will do worse? So, you may have more tafamidis drop-in in the placebo arm, how do you expect to maintain balance and think about the impact on powering assumptions for the scale of the study as a whole?.

Brett?.

Yes, sure. Mani. As you are referring to the cardiomyopathy study obviously and we are allowing patients to have standard of care in the control group or on top of TTR LICA. And we'll stratify appropriately so that we’re not imbalanced for patients on tafamidis, patients on any other forms of standard of care that they wish to take.

So, we can control for that and overpowering assumptions are about based on the wealth of data that’s out there from Pfizer tafamidis phase 3 study, as well as our own study with TEGSEDI in same – in similar patient population.

The other thing I wanted to, maybe I could just add to that Mani is, just to drive your attention, remind you that we have an investigator study, Phase 2 study in progress in which we are looking at TEGSEDI in patients with cardiomyopathy both wild-type and hereditary. That's with Dr.

Merrill Benson in Indiana University, and we just -- he just presented an update on patients that have been treated would take three years or longer with TEGSEDI and which he has shown strong evidence for patient benefit on all kinds of clinical endpoints compared to natural history.

So, we also have that data to fall back on as a natural history and the performance of TEGSEDI in patients with cardiomyopathy. So, we feel very confident in the powering assumptions of our phase 3 cardiomyopathy study and we are confident that we will be well balanced in our treatment arm versus our control group..

And things are getting ready to get underway in a big way here, so we will be, you should be hearing about from us about all of that in the very near future..

Great. Thanks for taking my questions guys..

Our next question will come from Paul Matteis with Stifel. Please, go ahead..

Hi, guys. Thanks for taking the question. This is Nate on for Paul.

Maybe just to put a finer point on the prior question about the ENaC, on the clinical studies, would you think you are enrolling all CS patients or would you narrow it down to patients who are aren’t currently eligible for CFTR modulator?.

I don't think we want to get into details of the clinical development program beyond what Bret said. We think it’s an agent that can be used as a single agent and we think it can be used in combination and we believe that can be used in patients who have mutations that are unresponsive to current therapy. I think we will leave it there..

Got it. That makes sense.

Could you just discuss the inhaled dosing route given the pulmonary mucus burden? I mean, I know it translates on it, but is that a crazy concern? Or is that something you guys have looked at so far?.

No, it’s not a crazy concern at all. It’s something we looked at very carefully. We had the benefit of having clinical experience with IL-4 in meaningful asthmatic patients. And then we looked very, very carefully in animals and asked, does a significant mucus barrier affect distribution to the bronchioles and to the layer – the smaller airways.

The answer was no. And based on the early returns in the clinic, we believe the humans are telling us now as well.

So, absolutely something that we were concerned about, but we think we’ve resolved it and I think that Brett will be sharing some of that with you on December 13, is that right Brett?.

Yes, that’s correct Stan..

Got you. And then maybe one more.

On HPV, message understood loud and clear on the platelet declines, but can you help us understand why GSK was dosing at 120 mgs per week in the first place?.

Yes, because that is the only time, you know we’ve gotten 13, 14 LICA, liver LICA drugs in development. That is the only example where we didn’t see the expected level of increase in potency. And we know it is tied in some fashion to the HPV infection, but beyond that still very much a research project throughout what happened.

But that’s the reason, we just didn't get the level of potency that we have seen with the other 12 or 13 liver LICAs..

Got you. Interesting, thanks for the color..

Our next question will come from Eli Merle with Cantor Fitzgerald. Please go ahead..

HI, guys. Thanks so much for squeezing me in.

Just in terms of the Factor B program, could you explain a little bit more of your scientific rational, I guess your decision to target Factor B versus D, and I guess, your perspective on the clinical advantage or key differences between the targets, and I guess given that your partner Roche has already studied programs looking at factor D and geographic atrophy with some what sort of mixed results, maybe you can comment on the thoughts on Factor B versus D specifically in geographic atrophy? Thanks..

Well, I will comment that we typically, when we were in one of these pathways like crowding factors and complement and so on, look at everything. It’s easy for us to do.

And so, we look at all of the various factors and based on all the data we had, we believe that that will be – offers a significant advantage as both potentially and benefit and safety, compared to some of the other complement factors. So, it’s based on data.

Brett, do you want anything to that?.

Yes. Just a little bit, it’s certainly based on the data we’ve generated directly, looking at different complement factors in our annual models, but also, where Factor B lies in the alternative complement pathway it is – I don't want to get into the fine details, but it is a more relevant target to that pathway in Factor D.

And of course, what is really interesting and important to remember is that Roche developed a Factor D antibody and they came to the conclusion that Factor B was a better target, which is why they partnered with us on this program for age-related macular degeneration. So, it's based on our data, as Stan said.

It is based on what we would expect in the pathway. In the confident pathway, and we're not the only ones that believe in Factor B, Roche does too..

And the study is progressing well. So, we're going to have some answers here, it’s going to be awhile, but the study certainly is progressing. Wade, how many more questions? I think, we should probably bring this to a close..

That is the last one, Stan..

That’s great. Well thanks everyone. We appreciate your attention on this busy day. And we look forward to continuing to deliver great results this year and the rest of this year and next year.

And look forward to sharing some of the nuts and bolts, the pixels behind the big picture with you on December 13 as we focus on the technology and the advances that we’re making..

The conference has now concluded. Thank you for attending today's presentation. And you may now disconnect..