Ionis Pharmaceuticals, Inc.
Q2 2015 Earnings Call Transcript

Published: 9 Nov 2015

[Operator:]

Good day everyone, and welcome to Isis Pharmaceuticals Third Quarter Fiscal Results Conference Call. Please note that today’s event is being recorded. Leading today’ call from Isis is Dr. Stan Crooke, Isis Chairman and CEO. Dr. Crooke, please begin.

[Stan Crooke:]

Good morning, and thanks everyone for joining us on our call today to discuss the third quarter financial results and recent business highlights. On the call today, Beth will walk you through our financial results, Lynn will discuss the business highlight for the quarter, Olive [ph] will give you an update on our [Indiscernible] and I’ll close by focussing on how the advances from raking our technology translate into real value on our pipelines today. Our solid progress in all areas of our business is reflected in our strong financial results. In the first nine months of the year, we reported a proforma net profit of $25 million and we ended the quarter with more than $800 million in cash. These were both significant increases compared to last year. We have 38 drugs in development with the potential of the fundamentally changed the way a wide range of diseases are treated. We have a pipeline of first-in-class or best-in-class drugs on many of which we have reported positive clinical data already this year. We have potential near term commercial opportunities in our three drugs that are completing Phase 3 in a large pipeline of drugs in Phase 2. We expect complete enrolment in both the Phase 3 studies were conducted for ISIS-SMNRx in the next several months. And now that the generic name for SMNRx has been approved, going forward we’ll refer to the drug as [Indiscernible]. Last week, we presented positive data from two clinical trials on our Phase 3 drug ISIS-HTTRx, these data provide additional support for the broad development plan that we and our partners at GSK are conducting for ISIS-HTTRx [ph] as the drug can treat all forms of TTR amyloidosis. We also provided more details on GSKs plans for the Phase 3 TTR cardiomyopathy study and on GSKs progress on its pre-commercialization activities. We plan to complete enrolment in our ongoing Phase 3 study in FAP patients this year. We also expect to complete enrolment in our Phase 3 study of volanesorsen in patients with FCS this year and we are making solid progress in FPL. Yesterday, we reported that in the Phase 2 study, I should say LRx demonstrated significant reductions in Lp(a) which is a key driver for cardiovascular disease the results were equivalent whether the patients had significant re-elevated Lp(a) or extremely elevated Lp(a). In addition, we observed more than 30 fold increase in potency with ISIS-APO(a) LRx our lighter version of our APO(a) drug, or particular importrance is that we observed no ISIS or -- syndrome in patients treated with this new drug. These data support the potential to dose this and our other LICA drugs, weekly, monthly quarterly or even less frequently with the small and conveniently administered dose. This profile should open up much broader patient population for all of our LICA drugs. We’ll discuss each of these developments in more detail during the rest of the call this morning. Joining me on today’s call are Lynne Parshall, Chief Operating Officer; Beth Hougen, Chief Financial Officer; Sarah Boyce, Chief Business Officer; Paula Soteropoulos Ex-Chief Executive Officer and Wade Walke, Vice President of Corporate Communications and Investor Relations. And now, Wade, will you read our forward-looking language statement.

[Wade Walke:]

Thanks, Stan. A reminder to everyone that this conference call includes forward-looking statements regarding the financial outlook for Isis, Isis' business, and the business of Akcea Therapeutics, and the therapeutic and commercial potential of Isis in technologies and products in development. Any statement describing Isis' goals, expectations, financial or other projections, intentions or beliefs, including the commercial potential of volanesorsen, ISIS-SMN Rx, [Indiscernible] and ISIS-TTRRx is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing, and commercializing drugs that are safe and effective for use as human therapeutics and in the endeavor of building a business around such drugs. Isis' forward-looking statements also involve assumptions that if they never materialize or prove correct could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Isis' forward-looking statements reflect a good-faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis' programs are described in the additional detail in Isis' annual report on Form 10-K for the year ended December 31, 2014, and in its most recent quarterly report on Form 10-Q which are on file with the SEC. Copies of these and other documents are available from the Company. Now I would now like to turn the call back over to Beth.

[Beth Hougen:]

Thank you, Wade. We ended the third quarter on a strong financial position with the pro forma operating income of $29 million and pro forma net income of $25 million. Our operating in the first nine months were significantly improved over the same period last year in which we recorded a pro forma net operating loss of $35 million and a pro forma net loss of $47 million. We also ended September with more than $800 million in cash. Our financial results reflect the success of our drugs and development which have generated nearly $300 million from our partners so far this year. During the first nine months of this year we earned $232 million of revenue which was an 80% increase compared to the same period in 2014. Our revenue in 2015 was largely comprised of the $91 million we earned from our license of ISIS-FXIRx to Bayer amd $90 million of revenue from milestone payments. In addition to bolstering our financial results, the milestone payments we have reflected significant progress our partnered to programs have achieved this year. In the third quarter we added a $22 million milestone payments for Roche for initiating the Phase 1/2 study of ISIS-HTTRx; and $11 million of milestone payments for Biogen for advancing the Phase 3 studies of nusinersen. Furthermore, we earned $50 million of revenue through September 30 this year primarily from the amortization of upfront payments from our partnerships. Consistent with our guidance, our year-to-proforma operating expenses increased by about $40 million over the same period last year, primarily because four of the Phase 3 studies we are conducting are nearly fully enrolled and have entered their expensive stage. In addition, our expenses this year have increased Akcea has begun to prepare to launch and commercialise volanesorsen. As we look at the fourth quarter, we’ve already earned $16 million in milestone payments and we have the opportunity to earn additional milestone payments as their partnered programs continue to advance. We are projecting a continuing increase in our operating expenses as their Phase 3 programs progress and we also expect and see this expenses continue to increase as they made progress on the Phase 3 study of volanesorsen in patients with familiar partial lipodystrophy and build a commercial team and infrastructure to prepare to commercialise volanesorsen globally. As the results of our strong financial results so far this year, we expect to improve upon our revised guidance of a pro forma net operating loss in the low $30 million range in cash of more than $750 million. We plan to provide estimates of our 2015 year-end results in early January. And now, I’ll turn the call over to Lynne

[Lynne Parshall:]

Thank you, Beth. We’ve reported encouraging data on all of our Phase 3 drugs this year, substantially derisking these programs. This data demonstrates that our drugs have the potential to fundamentally change the way diseases are treated. Any one of these events would have made 2015 a successful year for Isis. The combination of all of these events further illustrates our growth trajectory. Our SMA program is progressing well. We expect to complete enrolment of both of our nusinersen Phase 3 studies by early next year. Data from open label Phase 2 studies suggest the drug may bring significant benefit to patients with spinal muscular atrophy. Importantly, since our last data cut off in April of this year, there have been no new events of death of permanent ventilation reported in the Phase 2 open-label study and infants with SMA. This means that we have had only one of them in over a year in this study. Over 70% of the infants who enrolled in the 12-milligram cohort remain on study an these children are all over 21 months old with an average age of well over two years, in fact in this study we now have a child with type 1 SMA who is older than 3 years of age. SMA is a heart breaking and fatal disease in its most severe form, with no approved therapies. As we’ve recently said with the SMA community we are doing everything we can to advance nusinersen through development and approval as rapidly as possible. And early and important step that’s helped us move more rapidly with receiving fast track designation from the FDA. This has facilitated our positive interactions with the FDA. Our communications with regulators in both the U.S. EU are going well and we are continuing to engage in regular and productive discussions with health authorities. Our goal in these conversations is to achieve the most expeditious path through the market for nusinersen. These conversations take time, but they have our absolute focus and commitment. We and Biogen are actively working on preparations for regulatory filings that we’ll be ready to file at the earliest possible date and we are particularly pleased that Biogen is already working on pre commercial activities with nusinersen. We are very excited about the rapid progress in our TTR program. As Dan said, enrolment should complete by the end of the year in our Phase 3 study in patients with FAP. Our program focussed on cardiomyopathy is also advancing well. Just last week, Dr. Merrill Benson presented data from his Phase 2 study and we achieved our stabilization of disease in patients with TTR cardiomyopathy treated with ISIS-TTRRx. Based on Dr. Benson’s natural history study one would expect significant disease progression over a 12 month period if these patients were not treated. While our Phase 2 data are early, they increase our confidence in the outcome of the Phase 3 study GSK is initiating. Of particular importance we and GSK have decided Phase 3 program for ISIS-TTRRx, expanding all forms of TTR amyloidosis. In addition to our study in FAP in which enrolment is completing, GSK has been initiating a Phase 3 study in patients with TTR amyloid cardiomyopathy, including patients with FAP and patients with wild type TTR amyloidosis. Obviously this broad Phase 3 program significantly expands potential market opportunity for ISIS-TTRRx. The new GSK Phase 3 study is very robust measuring clinical outcomes intended to provide a wealth of definite data that supports the value of the drug. We believe that these data if positive should be compelling to payers, treating physicians and patients. The profile of ISIS-TTRRx continues to look for an attractive and ongoing studies. Today, a 100% of the patients who have completed the Phase 3 set study have elected to continue in our open label extension study and our retention rate in the parent study is also very high. We are seeing a low incidence of injection side reactions, no flu-like symptoms and patients on ISIS-TTRRx do not need to be pre-treated with steroids or antihistamines. In addition, the drug is quite convenient, with one subcutaneous injection once a week. Patients appreciate the convenience at home dosing of our drug, having one drug and one product presentation provide significant benefit to the development and commercialization plans for ISIS-TTRRx. Because the TTR amyloidosis is a multi organ disease there is significant overlap and symptoms have each manifestation of the disease having one product will streamline the regulatory process physician education and the sales effort. GSK has began NDA planning in preparations and is well along in plenty activities to support the global launch of ISIS-TTRRx. The breadth and depth of the GSK sales and marketing organization around the world is important as it shows that ISIS-TTRRx is quickly established in standard of care. We believed all along that GSK is the right partner to maximize this commercial opportunity. This is even truer now that the opportunity for ISIS-TTRRx is expanding to include all forms of TTR amyhloidosis. Before I turn the call over to Paula, I’d like to provide an update on our Factor XI. Earlier this month, we initiated a Phase 2 study of ISIS-FXIRx which if positive should set the set for Bayer’s first Phase 3 study. We showed in our initial Phase 2 study in patients undergoing total knee replacement surgery that ISIS-FXIRx may be an effective and safe anti-thrombotic. This is a drug that may for the first time decrease thrombotic events without increasing bleeding risk. Patients of our Phase 2 study with fully anti coagulant with ISIS-FXIRx before, during and after their surgery with no increase in bleeding, something that cannot be safely done with any other anti-coagulant today. The unique profile of ISIS-FXIRx may allow it be used for currently available anti-thrombotic cannot, such as in patients who cannot tolerate any bleeding risk. This opens significant opportunities. For example, it’s well known that end stage renal disease patients receiving chronic dialysis have significantly increased risk of thrombotic events, despite their need for drugs to prevent blood clot, traditional therapies have limited efficacy in these patients. The newer anti-thrombotic Factor XA inhibitors are also not good therapeutic options because they expose these patients to unsafe bleeding risk. Based on its initial profile I suspect ISIS-FXIRx could be a novel, safe and effective drug for these patients. In fact, patients with end stage renal disease with an initial population that they are just planning to pursue, both these efforts in this population we’ve initiated a 50 patients double blind placebo controlled Phase 2 study in patients on dialysis. In this new patient population we are evaluating the safety and efficacy of ISIS-FXIRx in preventing blood clots using 200 milligrams or 300 milligrams dose weekly for 12 weeks. We are also evaluating the effect of dialysis drug for distribution and half life. We expect to complete this study in the second half of 2016. When we complete the study successfully we’ll be able to build or earn $55 million milestone payment from Bayer. We are looking to Bayer’s initiation of additional clinical studies of ISIS-FXIRx in 2016 they could further broaden the drugs potential. Now I’d like to turn the call over to Paula.

[Paula Soteropoulos:]

Thank you, Lynne. At Akcea, we are building a high-caliber development and commercialization company. Our focus is to bring transformative medicines to patients through our robust lipid portfolio of targeted antisense drugs. Akcea’s first priority is to realize the significant near term commercial opportunity that volanesorsen presents. We are conducting two Phase 3 studies in two distinct ultra rare genetic diseases. Both Familial Chylomicronemia Syndrome, or FCS, and Familial Partial Lipodystrophy, or FPL, are life threatening chronic rare diseases that are associated with significant morbidity and premature death. The Phase 3 study in patients with FCS is progressing according to plan and we expect to complete enrolment by the end of the year. The FPL Phase 3 study has also begun and is progressing well. Our pre-commercialisation activities are underway and the momentum is building. Among those physicians who understand and have treated FCS and FPL patients, there is an acute sense of unmet need. Our focus is to further identify [Indiscernible] care throughout the patient journey. We plan to work with centers of excellence and leading care -- to increase the medical understanding of both of these rare diseases. In this way, we will significantly raise disease awareness that should lead to earlier diagnosis and earlier and aggressive treatments. Our growing commercial organization is also working closely with the developing group which has shown optimal, regulatory and reimbursement assets for volanesorsen. We are building a dedicated team that can deliver this transformative drug to our patients. Their scientific and clinical proven expertise in selling ware to these drugs. We are also bringing in the right talent to support our patients and showing long term compliance. At Akcea in addition to the near term rare disease occasion that present opportunity for volanesorsen we have a deep pipeline of medicines targeting additional lipid and cardiovascular diseases. And then weekend at AHA we heard a lot of excitement among physicians about our pipeline in particular volanesorsen and we also heard a lot about lot of buzz about Lp(a). Elevated Lp(a) is a major driver of cardiovascular disease. Today there is no specific medicine to specifically or substantially lower Lp(a). We believe adjusting Lp(a) is the next important horizon in lipid focused cardiovascular disease treatment. So just yesterday we reported data from two different drugs in our Apo(a) program, both showing unprecedented specific reductions in Lp(a). Our LICA conjugated drug ISIS-APO(a) LRx demonstrated more than a 30 fold increase in potency over the uncongugated form of the drug. And this means that we could dose ISIS-APO(a) LRx weekly, monthly, quarterly or less frequently. And we also observed no ISRs or flu-like symptoms which significantly enhances the tolerability profile of the drug. Given a remarkable profile for ISIS-APO(a) LRx and our clear understanding of the next studies which we would need to conduct with either drug we are moving forward with the LICA drug ISIS-APO(a) LRx for all disease opportunities without losing any time in the overall development program. This means that we can initiate a Phase 2 studies in two distinct populations of patients with elevated Lp(a). The first in patients who alter recurring cardiovascular disease and the second in those with calcific aortic valve stenosis. So we remain on track with our original development timeline which means we plan to start two Phase 3 studies in 2017, early 2018. We are aggressively moving ISIS-APO(a) LRx forward for all disease indications including a broader market opportunity. And we plan to commercialise ISIS-APO(a) LRx using the expertise we are building for volanesorsen. And now I’d like to turn the call over to Stan.

[Stan Crooke:]

Thanks Paula. It is certainly very exciting to see the progress that’s being made at Akcea and couple that excitement to the advances in the pipeline of first-in-class drug to reduce under treated lipid clauses of cardiovascular disease. But perhaps the highlight of the quarter is clinical performance of ISIS-APO(a) LRx. This is important implications for our LICA platform and for the seven other LICA drugs that we have in our pipeline today. Given our prudent, our current generation two plus drugs are, we hope that we might see as much as a tenfold increase in potency by adding LICA. The fact that we achieved more than a 30 fold increase in potency engagements [ph] with superb tolerability is potentially another game changer. That once again suggests broadband enhanced opportunities for our platform. Just to put this in perspective, a greater than 30 fold increase in potency supports our ability potentially dose with ultra low volumes making this cutaneous injection almost unnoticeable. This also supports the potential dose weekly, monthly, quarterly or even less frequently. So with our LICA technology we created the platform, a technology platform that brings value, enhances tolerability and improves the convenience and ease of administration and provides the flexibility to optimize treatments schedule to support uptake and adherence in different patient population. Since we have eight LICA drugs in development with more on the way next year, this advances much more important than just improving the performance of the single drug. In the coming months we will have additional clinical data from a number of LICA drugs that we have in development. And as Paula said, we'll be getting the Phase 2b program underway on ISIS-APO(a)Rx. We have a great pipeline of first-in-class drugs that are performing very well. We are reaping the rewards of years of efforts with the enhance potency and potential for variant frequent dosing with LICA and/or Generation 2.5 drug dramatically increasing the value that we can create going forward. Remember that LICA and Generation 2.5 chemistry has increased potency through mechanisms. So when combined, we now believe that we can create a drug that is orders of magnitude more important than our already potent generation 2.0+ drug. And we expect to put our first Generation 2.5 LICA drug in development next year. Clearly, our first priority is to focus on our Phase 3 drug. As Lynne mentioned, we and Biogen are focused on advancing nusinersen through development and approval as rapidly as possible. Together with Biogen we've engaged in important discussions with regulatory agencies in both the U.S. and Europe to work toward that goal these conversations take time, but they have our absolute focus and commitment. In the meantime we continue to be very encouraged with forms of nusinersen in our open-label studies and the pace at which our Phase 3 studies are progressing. Over the next 18 months or so, we will have data from all of our ongoing Phase 3 studies, these studies are positive, support market application for nusinersen and patients who had both infant and child would forms of SMA, volanesorsen and patients with FCS and ISIS-TTRRx and patients with FAP. These are indications represent life threatening rare diseasess to which there are no therapeutic options today. I think that's a remarkable line up of first-in-class and best-in-class drug moving quickly towards the market. And then when you add that to that the exciting lineup for Phase 2 drugs that are in development as well as the advances that we're making in the technology, I think you understand why we at ISIS so excited about what the future holds for us. Now with that I'd like to turn the call over for Q&A and forget to mentioned, Richard, forgive me, that Richard Geary is here as well to answer any questions that you may have. So, please set us up for question, [Indiscernible].

[Operator:]

At this time we'll begin question and answer session. [Operator Instructions] Our first question today comes from Jessica Fye from JPMorgan. Please go ahead with your question.

[Jessica Fye:]

Hi, guys. Good morning. Thanks for taking my questions. First, I'm not sure if this for Paula, but on APO(a)Rx, for APO(a), you have a few different size of the potential target at patient populations you're going after over time, but I think you're taking a LICA version forward for all of those groups and clearly looks better than the original version. But can you talk about how you think about pricing for a product like this with those varying population sizes?

[Lynne Parshall:]

Sure, Jessica. So what we need to remember is that value creation is the most important thing, and so the product will be priced in accordance with the value that it brings. So starting with the rare disease and then being priced according to the value as we expand the indication.

[Jessica Fye:]

Okay. Got it. And just couple of more if I can. For TTR, a question about the FAC study endpoints, I guess, is there some scenario where you miss on the CV primary endpoint but, for example, show a clear benefit on six minute walk, TTR knockdown, is that still a fileable study. Is that still – does that works for registration in your eye?

[Stan Crooke:]

We think so. We think that is entirely feasible. In fact, I think those are endpoints that are being used by others in an effort to get approval for FAC, so, yes.

[Jessica Fye:]

Okay. Got it. And just last one on SMA, can you talk about when we might see the next say, conference presentation or next open-label update for that Phase 2 infant study?

[Stan Crooke:]

I don't want to be precise about that, because we have a good many conversations in progress at this point. And so what I'd like to do is to say that we remain highly encourage by what we're seeing and encourage by the conversations that we're having with regulatory agencies. And that's our primary focus. And then, we will of course share the information that we have is as soon as consistent with getting the drug approved in the most rapid way.

[Jessica Fye:]

Okay. Got it. Thank you.

[Operator:]

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

[Eric Schmidt:]

Maybe a follow-on question to Jessica's on nusinersen. Lynne and I'm not sure you have much of an answer for this one either Stan or Lynne, but I think Lynne mentioned that the conversations with regulators are preceding well, but it takes time. I guess my question is when do you think we'll have clarity on a filing time line or strategy here?

[Stan Crooke:]

That sounds like a question that I should let Lynne answer.

[Lynne Parshall:]

I was hoping you were going to answer, Stan. The discussions are proceeding well until they're finished. We can't give you any more clarity, but I will say that we're working closely together with regulators to be able as rapidly as possible to make the drug available. And one point I would make and its probably obvious to everybody on the phone is that when you file is much less important than when you actually get approved. And so, we're working on a path that we and the regulators have confidence, will be positive path to approval.

[Stan Crooke:]

I'll add to that Eric, but there is not – there is never a minute when the team at Isis is not aware of how urgent to need of these infants and their families to have therapy and we're pushing as absolutely hard as we can consistent with the outcome that's needed, which is approval of the [Indiscernible] at the earliest time with the least amount of delay.

[Eric Schmidt:]

Okay. I mean, there is – I guess being speculation and investment circle that as you get closer and closer to the end of the Phase 3 study, it maybe on a more awkward to file for approval or receive approval just months or weeks before you might be unblinding a pivotal trial. Do you sense that concern at the agencies?

[Stan Crooke:]

No, we don't.

[Eric Schmidt:]

Okay.

[Stan Crooke:]

And I think its peculation. It has the time lines, a little different from what are in our minds. So we haven't experienced any significant negativity or concerns about any of that in our conversations either in the U.S. or the several countries in Europe with whom we've spoken.

[Eric Schmidt:]

And just last one from me maybe for Beth, you're going to hit a couple of milestones in terms of completing enrollment in nusinersen, the type 1 study and TTR FAP study or those – or either those associated with milestones you can disclose?

[Beth Hougen:]

We do have a number of milestones coming out in the fourth quarter and also early next year as we progress those studies, but the major next financial payments that come with both of those studies are going to be the licensing events and we haven't disclosed timing of those other than to say that they will happen after the conclusion of the Phase 3 studies.

[Eric Schmidt:]

Thank you.

[Stan Crooke:]

And the short answer to your question is Eric is yes.

[Eric Schmidt:]

Yes. They'll each be associated with some milestones, undisclosed

[Stan Crooke:]

Yes.

[Eric Schmidt:]

Thank you.

[Operator:]

Our next question comes from Stephen Willey from Stifel. Please go ahead with your question.

[Stephen Willey:]

Yes. Hi, thanks for taking the questions. I know, yesterday at the triple meeting there was a presentation I think a KRAS targeting [Indiscernible] yourselves and AstraZeneca are working. Has that been formally announced I guess as one of the candidates to be moved forward as part of the collaboration? And then can you just remind us how many targets are remaining under AstraZeneca collaboration?

[Stan Crooke:]

There are two collaborations with AstraZeneca, Steve, the first is cancer collaboration. Then the second is the broader collaboration in cardiometabolic disease. Right now, AZ is developing androgen receptor and STAT3. And KRAS is not yet formally a collaboration of developing candidate. We're excited about the data and I think our friends at AZ are excited about the data and we're interested in the target, but it's not a development candidate yet. On the cardiometabolic side, that program is all is brand new. I think we just had to kick off meeting few weeks ago, right Richard.

[Richard Geary:]

Yes.

[Stan Crooke:]

And so, it’s a little early to talk about specific drugs and specific targets there, but that's a fairly broad collaboration in cardiometabolic disease and we hope we'll generate several development candidates for us in AZ.

[Stephen Willey:]

And then, lastly I know there was obviously a bit of reorganization of R&D priorities at Biogen and there are still obviously highlighting SMA and I believe DMPK as well in terms of being priorities for them, but just wondering if reorganization there has any impact on the pace at which some of these new targets that are available under the broader collaboration get identified and moved forward? Thanks?

[Stan Crooke:]

We expect the pace to be quickening if anything. I think the effort with Isis was strengthen in the organization and I think part of the reorganization was to assure that there was flexibility and managing all the opportunities of Isis bringing forward in the Biogen relationship. But Lynne, do you want to add or subtract anything from that?

[Lynne Parshall:]

I would just second what you said, Stan, which is our programs are all in the key strategic areas that Biogen is focusing on and as a result there is an even greater emphasis on the areas in which we're working together.

[Stephen Willey:]

Okay. That's helpful. Thank you.

[Operator:]

Our next question comes from the Yale Jen from Laidlaw & Company. Please go ahead with your question.

[Yale Jen:]

Thanks for taking the questions. The first one for the LICA programs that you've indicated yesterday that about 34 or greater than 34 increased impotencies. Do you see this range is all of that LICA programs you have right now in terms of compared to earlier version or does that range of this impotencies sort of enhancement?

[Stan Crooke:]

Well, what we've seen to-date is very consistent behavior across the board, but will there be some modest range in the potency gain? I imagine there will be. I think the number to keep in mind is 4.5 milligrams per week. 4.5 milligrams a week is the ID50 dose and my sense right now is it we should potencies ID50 doses in that range for all of our LICA drugs. That based on all the information that we have, I think that's a legitimate expectation. And then of course as the next series of LICA results from the clinic are acquired and there'll be quite a number over the next few months we'll have a much better sense of what the actual range would be, but there's every reason I believe that the ID50 doses will be in the same range. And the other thing is important is that, I think we are quite confident that the tolerability profile will be consistent and this both the increased impotency reduction in the volume and the better tolerability makes it such a powerful addition, so no ISRs, no flu-like syndrome. Are we going to have absolute zero forever? Well, no, I mean, you must know that if you're going to inject a drug subcutaneously occasionally you might get a bruise you hit a vessel or something like that. But we do expect the tolerability to be very consistent and very attractive.

[Yale Jen:]

Great. Thank. And just one more follow-up on that, for the TDR programs you are heading for the two FAC and the wild-type TTR next year for the Phase 3 study. My question is just for some reason you have study – endpoint was met for one indication, one patient cohort versus the other patient, would that affect your filing for approval or you can do that separately? Thanks.

[Stan Crooke:]

Richard, do you want to deal with that.

[Richard Geary:]

Yes. Of course, our plans along with GSK are to file as quickly as possible with the first indication which is polyneuropathy indication. So, it is absolutely the case that success on one would support that particular very different manifestation or phenotype and the plan is therefore to more forward with that in mind.

[Yale Jen:]

Thanks. Appreciate it.

[Operator:]

Our next question comes from Josh Schimmer from Piper Jaffray. Please go ahead with your question.

[Josh Schimmer:]

Thanks for taking the question. There been now a few iterations of the antisense platform and we're now on to the LICA conjugated version which is looking pretty exciting. Wondering if you think there is still room for improvement beyond LICA or there still efforts to further optimize the platform and do you feel like LICA is now a stable point to move all the programs going forward to and even kind of rework some of the prior ones? Thanks.

[Stan Crooke:]

Thanks for the question. I think the think that makes at this moment in history for us, so exciting. Is that we have drugs in Generation 2.0 that are excellent drug in Merck [ph] and now we LICA and 2.5 in the pipeline. I suppose its now 11 drugs in the pipeline or 12 drugs in the pipeline. We have 2.5 and LICA. And so, there benefits of those endeavors are tangible and being felt in the pipeline immediately today. But the progress in the basic research is accelerating. The things that we're learning and what we call core antisense research today are just amazing to me. And they already beginning to translate into new mechanisms not just better potency doing the same thing we are doing, but new things that we can do and we'll be talking about several new mechanisms in the coming months that we've invented that open horizons that no one ever dreamt including me that antisense would have. This is the most exciting time in the basic antisense's platform expansion that we've experience, nothing compares to it. You haven't even begun to see the tip of the iceberg of the things that are coming.

[Josh Schimmer:]

As to this specific question is to whether LICA represent kind of the stable platform to now fully advance or do you think you'll have additional improvements on?

[Stan Crooke:]

We're working on different LICAs, if that, that was your question. Is the current LICA construct for improving liver activity likely to be fairly consistent? Yes. But are there new LICAs that were working on that improve other characteristics and entry into other organs? Yes, there are. So, its little earl to predict when and exactly what those are going to look like, but, well, the liver LICA form that we have, that chemistry is pretty well stable. Other approach is our emerging in research that look very exciting to us.

[Josh Schimmer:]

Got it. Thank you.

[Operator:]

Our next question comes from Jon Eckard from Barclays. Please go ahead with your question.

[Jon Eckard:]

Thanks for taking the question. Most of mine have been asked. But with regards to LICA, if you could just remind us of the -- you say you have seven or eight that are in the pipeline are coming out now. Of the other existing collaboration that may not have a LICA to-date, do these collaborations provide automatic access to the LICA technology if the partner chooses or that be an extra add-on payment to those collaborations?

[Stan Crooke:]

Lynne, do you want to answer that.

[Lynne Parshall:]

All of our collaborations provide our partners with the opportunity to access follow-on drug for their program. So, for programs that are liver targeted, the current version of LICA would produce attractive LICA-based follow-on. Of course, in order to come up with that we have do work and our partners will pay us to do work and to the extent that those follow-on drugs represent franchise extensions and continuation to build on the marketing and commercialization work our partners have done, they are really valuable not only to our partners but also to us.

[Jon Eckard:]

Great. And then yesterday, I remember the question came up about how to best strategically work with some of the new agents such as the APO(a) and question about partnering came up. And I think the answer was, we'll assess that maybe do at the right time, I guess with the lot of these agents you have specially in the lipid space, is that reasonable to think that going after the orphan spaces or something that would be a standalone setting and then if you ultimately get opportunities to broaden into larger places that those will be settings? I guess how do you keeping some of these strategic inside most effectively?

[Stan Crooke:]

Well, we took this – for us long plan, hope for important step in forming Akcea for exactly that reason. And so we see Akcea as a commercial ARM for the lipid drug. And certainly Akcea will commercialize the rare disease forms but I wouldn't want to limit Akcea to just the rare diseases. We think Akcea will be able to over time expand to larger indications. For the very, very large indications, there I think they are much more willing to consider partnerships, because partners bring value, they bring the muscle to do outcome studies and large outcome studies and they bring a sales force that is much larger and different from these kinds of sale force that Akcea wants to create. So, I do understand its – that is complex and that we can give you a definitive. Here's our way of partnering on all of our pipeline or this part of our pipeline. But please understand that deciding to form Akcea was a big decision for us and it is a commercial ARM of Isis that we expect to see commercialize of the initial indications for these exciting lipid drugs. Paula, do you want to add anything to that.

[Paula Soteropoulos:]

That just consistent to what you've said is that of course our initial focus to build that commercialization is in the rare disease but we also look to participate in the development and commercialization as we broaden, but then also consider partnerships to really augment our ability to develop a very large disease and increase the reach of this very large rare disease.

[Stan Crooke:]

I guess we're really are feeling very good about the latest strategy has evolved and the flexibility that gives us to sort of maximally take advantage of the commercial opportunities on our plate today.

[Jon Eckard:]

Great and thank you very much.

[Operator:]

Our next question comes from Michael Schmidt from Leerink. Please go ahead with your question.

[Michael Schmidt:]

Hi, good morning and thanks for taking my question. I just had a follow-up regarding the regulatory discussions that you and Biogen are having on the SMA program. And then I wondering do those discussions on the type 1 infantile form of the disease or potentially both types?

[Stan Crooke:]

Lynne, do you want to handle that.

[Lynne Parshall:]

Michael, of course our regulatory strategy and dialogue includes all of the opportunities for registration of the drug, but being able to make the drug available to the infants with type 1 SMA who have rapidly degenerative and fatal disease is our highest priority.

[Michael Schmidt:]

Yes. And should there be the opportunity to obtain early access for patient. How would that effect your relationship with Biogen if at all?

[Stan Crooke:]

Lynne.

[Lynne Parshall:]

I'm not sure I understand the question. Do you mean, if the drug gets approved early how – what happens to our contract with Biogen?

[Michael Schmidt:]

Exactly, My understanding is they are often right after the full Phase 3 data.

[Lynne Parshall:]

So we amended our contract with Biogen about a year ago to anticipate exactly that situation. So, now in addition to having opt-in rights of the completion of the first positive Phase 3 study which is what the original contract said, they also has the rights in the obligation to make it opt-in decision upon acceptance of our first regulatory filing.

[Beth Hougen:]

It's not accepted upon filing.

[Lynne Parshall:]

Upon acceptance file regulatory agency of the filing, yes.

[Stan Crooke:]

Not approval of the drug but acceptance of the filing, yes.

[Lynne Parshall:]

Yes. Thank you for clarifying, Stan.

[Michael Schmidt:]

Okay. Great. Thank you so much and congrats on a progress.

[Stan Crooke:]

Thank you.

[Operator:]

Our next question comes from Doug Adams from Tocqueville Asset Management. Please go ahead with your question.

[Doug Adams:]

I have two questions, the first is last week I noticed that Shire is acquiring Dyax [ph] for $5.9 billion plus which was close to your market cap basically for hereditary angioedema, which I understand you have a drug in Phase 1 and I was wondering how your prospect for that drug will change based on this acquisition?

[Stan Crooke:]

You're right. We do have a drug for hereditary angioedema and we think the profile that drug is very attractive and competitive with the Dyax drug, so we don't – we're not changing our strategy based on the acquisition by Shire or Dyax.

[Doug Adams:]

Maybe the question should be, how are you trying to accelerate the development of that asset in light of how large they consider that in market?

[Stan Crooke:]

We're moving alone. Our focus is primarily to make sure that our drug is significantly more attractive. I think that's that the key rather than. We're not going to catch up but are we going to have an agent that offers significant advantages to the Dyax drug that's where our focus is to.

[Doug Adams:]

Okay. I have another question on Lp(a) and it seems like the FDA breakthrough designation has accelerated the regulatory timelines for the those drug with that designation and Lp(a) certainly looks like the kind of drug that should qualify for it. Are you expecting to apply for that designation?

[Stan Crooke:]

Lynne, do you wan to handle that one.

[Lynne Parshall:]

Actually, when you look at the studies that have been done, breakthrough doesn't particularly accelerate. What you hope the breakthrough gives you is an opportunity for real time discussions with the FDA and more access. So far, we don't think we have a problem with access. This particular division had not been forthcoming, most of those early breakthroughs you see in the of course are in the oncology division. So it is something that's along answer to the fact that yes, its something that we're looking into. But the most important thing is we do have a regulatory strategy to begin to have access to the FDA to educate them about this target and the patient populations and we believe we're going to be able to do that with our without breakthrough.

[Doug Adams:]

Okay. Thank you.

[Operator:]

Ladies and gentlemen at this time we've reach the end of today's question and answer session. I'd like to turn the conference call back over to Crooke for any closing remarks.

[Stan Crooke:]

Well, thanks everyone, for your interest. We think we've had an exciting year so far. And just before we close maybe a quick addition from Wade that just will remind you of a few upcoming events.

[Wade Walke:]

Thanks, Stan. As you can imagine with the pipeline as large as ours, we have a constant flow of important data release and study initiations. Of course, we'll continue to provide updates on our TTR program from the open label cardiometabolic study that Dr. Benson is conducting. You'll see that coming up next year. And we anticipate giving you updates on our DMPK program which is currently in Phase 1/2 in patients with [Indiscernible]. In addition to that, of course we'll have data from about four Phase 1 programs with three of those have been LICA drugs and of course with study initiations we’ll have a number of Phase 1 initiations with three of those being LICA programs as well. So we’ve got a lot going on in with our LICA platform. Additional study initiations next year includes Phase 2 for HPV [ph] of course the Phase 3 study in cardiomyopathy patients that GSK will be conducting and kind of and some others that will give us some more details and as the year goes on.

[Stan Crooke:]

And we’ll also be hearing about technology advances that I think are really quite important to us. And obviously you’ll be hearing about study completions a lot of study completions that are important. So, we think we have a line up of news that will continue to be flowing over next year that we hope will continue to be exciting to people. With that, why don’t we bring the call to a close. I very much appreciate everyone’s interest and thank you once again for participating.

[Operator:]

Ladies and gentlemen, t hat does conclude today’s conference call. We do thank you for attending. You may now disconnect your telephones lines.