Ionis Pharmaceuticals Inc (IONS) 2015 Q4 法說會逐字稿

Good morning and welcome to the Ionis Pharmaceuticals year-end 2015 earnings conference call.

(Operator Instructions)

Please note, this event is being recorded.

I would now like to turn the conference over to Dr. Stan Crooke.

Please go ahead.

Thank you.

Good morning and thank you to everyone for joining us on today's conference call to discuss our 2015 year-end financial results and business highlights.

By the way, I am still trying to recover from this horrible flu that's going around.

So if I suddenly have to step off to cough or something, forgive me for that.

On the call today, Beth will walk you through our financial results and 2016 guidance, then we will discuss the progress that we're making across our business, including with nusinersen and IONIS-TTRRx.

Paula will provide update on Akcea's activities to prepare to commercialize volanesorsen.

I will then close by focusing on some of the advances we're making in our technology and upcoming events.

Over the past several years we've advanced our pipeline so that we now have six drugs in Phase 3 development.

We have also expanded our pipeline to nearly 40 drugs, and we have continued to advance our technology.

We've done all this while exercising sound fiscal discipline.

As a result of our successes in business development over the last four years, our cash and revenues have grown steadily and our pro forma net operating loss has significantly improved.

In addition, last year was the fourth year in a row in which we improved upon our guidance by exceeding business development and pipeline objectives.

We finished 2015 with a pro forma operating loss of only $16 million and with $775 million in cash.

In 2015, we completed a target enrollment in three different Phase 3 studies from three different drugs for three different diseases.

We're moving closer to completing two Phase 3 trials for nusinersen, our drug to treat infants and children with spinal muscular atrophy.

At the same time, we're completing a Phase 3 study of IONIS-TTRRx in patients with peripheral neuropathy, a form of TTR amyloidosis, and we are completing a Phase 3 trial of volanesorsen in patients with FCS.

We plan to have data from all four of these Phase 3 studies in the first half of 2017.

And so the regulatory preparations and launch planning are well underway for all three of these potentially transformational drugs.

And 2015 was an important year for our Phase 3 assets; 2016 and early 2017 will be a pivotal time for these drugs and for Ionis as we and our partners prepare to submit marketing applications and launch these important new medicines.

Our Akcea team is making excellent progress advancing our current suite of lipid drugs.

Akcea is focused on completing the development commercialization of these drugs, which include volanesorsen, IONIS-APOCIII-LRx to treat patients with high triglycerides, IONIS-APOA-LRx to treat patients with diseases caused by elevated LP(a), and IONIS-angiopoietin-like 3 LRx to treat patients with a variety of lipid disorders, including [-- nash].

Akcea is now preparing to launch volanesorsen.

We will be telling you more about their activities today and throughout the year.

We will also provide an update on the continued progress we and Akcea are making with the other drugs in Akcea's pipeline.

Beyond our Phase 3 drugs, we have a large, exciting Phase 2 pipeline that includes IONIS-FXIRx and IONIS-APO(a)-LRx and other several important programs with key clinical data this year.

We also expect clinical data from multiple drugs incorporating our LICA technology and our Generation 2.5 chemistry.

In April, we will be presenting an update on many of our drugs to treat severe neurological diseases at the AAN meeting in Vancouver.

This will give us an opportunity to showcase the progress in our strategic collaboration with Biogen and the progress of our neurology franchise.

We look forward to sharing that with you.

Joining me on today's call are Lynne Parshall, Chief Operating Officer; Elizabeth Hougen, Chief Financial Officer; Sarah Boyce, Chief Business Officer; Paula Soteropoulos, Akcea CEO; and Wade Walke, Vice President of Corporate Communications and Public Relations.

Wade, will you read our forward-looking language?

Thanks, Stan.

A reminder to everyone that this conference call includes forward-looking statements regarding the financial for Ionis, Ionis' business, the business of Akcea Therapeutics, and the therapeutic and commercial potential of Ionis' technologies and products and development.

Any statement describing IONIS's goals, expectation, financial, or other projections, intentions or beliefs, including commercial potential of nusinersen, IONIX-TTRRx, and volanesorsen 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 the endeavor of building a business around such drugs.

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

Although Ionis' forward-looking statements reflect a good-faith judgement of its management, these statements are based only on facts and factors currently known by Ionis.

As a result, you are cautioned not to rely on these forward-looking statements.

These and other risks concerning Ionis' programs are described in additional detail on Ionis' annual report in Form 10-K for the year ended December 31, 2014, and its most recent quarterly report on Form 10-Q, which is on file with the SEC.

Copies of these and other documents are available from the Company.

Now I would like to turn the call over to Beth.

Thank you, Wade.

Over the past several years we have ended each year in a better financial position than we began, and have successfully advance our technology and pipeline.

During this time, we've created a sustainable revenue base from our partnerships, while maintaining a moderate expense level.

In addition, we have consistently increased our revenues in cash balance, while decreasing our pro forma net operating process.

And as we've done the last several years, we significantly improved upon our pro forma NOL guidance and substantially exceeded our cash guidance as a result of the successes we achieved across all areas of our Business.

We ended the year with a pro forma net operating loss of only $16 million, and more than $775 million of cash.

Two large contributors to our strong financial results were the cash and revenue we earned from our partners.

In 2050, we receive more than $320 million of cash from our partners.

We also earned revenues of $284 million, a 33% increase over 2014.

Our revenue in 2015 included $150 million from milestone payments, $91 million from our license of IONIS-FXIRx to Bayer, and $78 million primarily from the amortization of up-front fees and manufacturing services we performed for our partners.

Our milestone payments come from numerous partnerships and drugs in various stages of development across multiple therapeutic areas.

In addition to bolstering our financial results, the milestone payments we earn reflect a significant progress our partnered program has achieved in 2015.

Consistent with our guidance, our 2015 pro forma operating expenses increased over 2014, primarily due to the progress of our Phase 3 drugs, which are in their most expensive stage of development.

In addition, 2015 expenses increased as Akcea began preparing to launch and commercialize volanesorsen.

As we look at this year, we are projecting to earn more than $240 million in revenue, which reflects continued advances in our pipeline this year.

A meaningful portion of our revenue comes from the amortization of up-front fees and, as such, is predictable.

We expect revenue from this source in 2016 to be approximately $70 million.

The majority of our revenue, however, comes from milestone payments as our partner programs advance.

Assuming we successfully complete the Phase 2 study of IONIS-FXIRx, we will earn a $55 million milestone payment.

We also have the opportunity to earn a $25 million milestone payment, assuming we move the drug into development under our cardiometabolic collaboration with AstraZeneca.

We are also planning to advance this drug into development under our J&J collaboration, for which we are eligible to earn a $10 million milestone payment, and we also numerous opportunities to earn significant milestone payments as we advance research programs and drugs under our Viacin collaboration.

At the beginning of each year we list the milestone payments we could are based on the progress we expect to achieve in each of our partnered programs.

We then assign a probability to each of these payments based on our projected likelihood to achieve the payment in the current year.

Milestone payments we project for late in the year will have a lower probability assigned to them than those anticipated earlier in the year.

Our projected revenue for milestone payments is the aggregate of these probablized payments.

As we advance our partner programs and meet milestones, we have the opportunity to improve upon our revenue and pro forma net operating loss guidance as we've done the last several years.

Already this year we have heard $7 million in milestone payments from Biogen for advancing the Phase 3 program for nusinersen and advancing IONIS-BIIB4Rx, and from GSK when they initiated the Phase 1 study for IONIS-HBV-L4Rx.

This year we will conduct a multiple Phase 3 studies, advancing a broad pipeline of drugs, including over a dozen Phase 2 programs, and continuing to build the organization and infrastructure necessary to commercialize volanesorsen.

We are projecting to do all of this while keeping our expenses essentially flat compared to last year.

So, all of this rolls up into our financial guidance of a pro forma NOL in the low $60 million range.

This NOL guidance is only slightly higher than our NOL guidance at the beginning of each of the last several years, even though we are supporting a much larger and later stage development pipeline.

We are also projecting a year-end cash balance in excess of $600 million.

As in the past, we've based our guidance on a conservative projection of our financial results, which gives us the opportunity to meet or improve upon our guidance as we have done the last several years, and as we move forward we intend to continue to achieve successes across all areas of our business while exercising sound fiscal discipline.

Our ability to progress such a large and advanced pipeline with relatively modest resources is due in part to the efficiency of our additive technology and in part to the significant contributions of our partners.

Our partners provide more than just revenue and cash.

They provide resources and expertise that augments and builds upon our internal capabilities.

The work that our partners conduct is work that we don't have to do or pay for.

A good example of this is the CARDIO-TTR Phase 3 study that GSK has planned for IONIS-TTRRx.

This is a 500-patient study spanning multiple years that GSK will conduct and pay for.

Our partners at Biogen, AstraZeneca, and GSK are all conducting clinical studies for our programs.

Our partners also had the global preference and capabilities to support large commercial opportunities for our drugs.

For example, we licensed IONIS-FXIRx to Bayer last May.

Bayer was the ideal choice for a partner to exploit the potential of this novel anti-thrombotic drug as they are an expert in and fully committed to the anti-thrombotic space.

After we complete the current Phase 2 study of IONIS-FXLRx, Bayer will assume all future development and commercialization responsibilities.

As Lynne will discuss next, efforts are under way to prepare for the commercial launch of our Phase 3 drugs, any one of which has the potential to make us profitable.

We're looking forward to adding product revenues and royalties to our base of R&D revenue in the next few years.

And now I would like this call over to Lynne.

Thank you, Beth.

As Beth highlighted, we ended the year in a very strong financial position.

Year-over-year we've consistently maintained solid financial growth while continuing to make equally strong progress in advancing our maturing pipeline and expanding the reach of our technology.

We believe the value we're creating for patients and for Ionis' shareholders with our diverse pipeline of first-in-class and best-in-class drugs is tangible, and the successes of 2015 set us up for an event-filled 2016.

This coming Monday, February 29, is Rare Disease day.

At Ionis, we're committed to bringing new drugs to patients with rare diseases and we have one of the largest severe and rare disease pipelines in the industry.

Last year, our most exciting achievements brought us one step closer to the market for three of our severe and rare disease drugs.

In 2015, we completed target enrollment in three Phase 3 studies for our three most advanced drugs in development, nusinersen, IONIS-TTRRx, and volanesorsen.

As we work to complete these studies, we and our partners are gearing up for multiple regulatory filings and product launches.

We believe the robust development plans we are implementing for these drugs support the significant commercial potential of our late-stage pipeline.

Last month, we provided an update on our ongoing Phase 2 open label study in infants with SMA treated with nusinersen.

We showed for the first time a Kaplan-Meier plot comparing events of death or permanent ventilation in our study from last August with those captured in similar patients in the PNC or natural history database.

The Kaplan-Meier curve provided nice visual representation of the very different event profile in the nusinersen treated infants in our study compared to that which would be predicted by the natural history of this devastating disease.

The babies, now toddlers, who are continuing in our study are all over two years old and we have yet to hit a median event-free age.

This compares to the median event free age of between 6-1/2 and 10-1/2 months predicted by natural history studies.

While the data we reported was from an August data analysis, we also reported that there were no new events of death or permanent ventilation in the Phase 2 open label study during the entire year of 2015.

Importantly, the infants in our study are not only living longer, but they continue to improve in their motor function as evidenced by their improved CHOP INTEND scores and their achievement of motor milestones.

We have babies who can now sit unaided, a development milestone infants with Type I SMA are never expected to reach.

We even have a toddler who is walking unassisted.

We plan to provide another update from this Phase 2 study at the AAN meeting in April.

Our Phase 2 data gives us confidence in the design and potential results from our ongoing Phase 3 studies.

We've completed enrollment in Phase 3 study in children with SMA and we're close to completing enrollment in the Phase 3 study in infants with SMA.

This does affect our Phase 3 data from both of these studies in the first half of 2017 and to file for marketing authorization shortly thereafter, assuming the data are positive.

Biogen continues to make significant investments in supporting the nusinersen program.

In addition to the studies we are conducting, Biogen is currently enrolling infants in the Nurture study.

Nurture is a Phase 2 study in presymptomatic newborns who are genetically diagnosed with SMA.

The Nurture study is designed to enhance our understanding of the value of early diagnosis and therapeutic intervention to potentially change the course of the disease.

Biogen is also conducting the Phase 2 study Embrace in both infants and children with SMA and that study is now fully enrolled.

We feel keenly the urgency to bring nusinersen to patients.

Our communications with regulatory agencies in both the United States and Europe are going well, and we continue to engage in regular and productive discussions.

All of our positive regulatory interactions give us the confidence that we are on the right track to achieve approval of nusinersen as early as possible.

We and Biogen are actively preparing for registration in the United States and Europe, as well as globally so that we will be ready to file for marketing authorization at the earliest possible date.

Biogen is also actively preparing for the global launch of nusinersen.

Biogen is building out its commercial team and is ramping up multiple pre-launch activities, including medical education and disease awareness to support their commercialization of nusinersen.

Our TTR program is on pace with our SNA program.

IONIS-TTRRx has the potential to be the first-in-class and best-in-class drug to treat patients with all forms of TTR amyloidosis.

In 2015, we reported further data supporting the consistent, robust TTR reductions we've observed in multiple clinical studies and in multiple patient populations.

Based on the monogenic nature of this family of diseases, we believe the TTR reductions we are observing should translate into significant therapeutic benefit.

IONIS-TTRRx is convenient and easy-to-use by the patients in our trial.

Patients give themselves one simple injection once a week.

Moreover, having one direct for all forms of TTR amyloidosis provides significant benefit for the development commercialization of IONIS-TTRRx and should streamline the regulatory process, physician education, and sales efforts to reach patients with all forms of the disease.

We completed enrollment in the 15-month Phase 3 study called NEURO-TTR in patients with the familial polyneuropathy form of TTR amyloidosis.

The NEURO-TTR study includes robust primary and secondary end points, such as measures of motor function, which we believe will support the value of IONIS-TTRRx to position patients of payers, and the cardiac sub study should provide early and important evidence on the treatment of FAP.

In addition, we've had less than half of the dropouts we had originally projected.

This low dropout rate allowed us to complete target enrollment in the Phase 3 study late last year with 172 patients.

We are on track to report data from this 15-month study in the first half of 2017.

We and GSK have already started preparing to file for marketing authorizations as quickly as possible after reporting data, assuming the data are positive.

GSK plans to initiate a Phase 3 study of IONIS-TTRRx in patients with both forms of TTR cardiomyopathy, wild type and FAP.

This new study, called CARDIO-TTR, is a robust clinical outcome study intended to provide a wealth of definitive data to support the value of IONIS-TTRRx with physicians, patients, and payers.

We know from the work GSK conducted that although patients with FAP and wild type TTR cardiomyopathy have different genetic causes of their disease, their disease progression is essentially the same.

This means that with a single study GSK believes it can support marketing approval for IONIS-TTRRx in all patients with the cardiomyopathy form of TTR amyloidosis.

So with NEURO-TTR and CARDIO-TTR we have two studies for a single drug that we believe has the potential to help patients with all forms of TTR amyloidosis.

Competitive target product profile and robust development plans should support the broadest label for IONIS-TTRRx, which will be important to establish optimal reimbursement and rapid penetration into the market.

GSK is also initiating a Phase 3 study in Japan evaluating IONIS-TTRRx in patients with FAP to support their plans for global commercialization of the drug.

GSK is well along in preparing for the global launce of IONIS-TTRRx.

They are committed to maximizing the value of the drug and were impressed with how they are systematically implementing their launch preparations.

And finally, let's discuss volanesorsen, our Phase 3 drug that our wholly-owned subsidiary, Akcea Therapeutics, will commercialize.

We have two Phase 3 studies under way and two distinct ultra-rare genetic diseases.

Familial chylomicronemia syndrome, or FCS, and familial partial lipodystrophy, or FPL, are both life-threatening, chronic, rare diseases associated with significant morbidity and premature death.

Our Phase 3 study in patients with FCS, the APPROACH study, is fully enrolled and we are on track to report data in early 2017.

Our Phase 3 study in patients with FPL, the BROADEN study, is well under way and we expect it will be fully enrolled late this year or early next year.

As the Phase 3 program progresses, we and Akcea are preparing regulatory filings that will be in a position to file for marketing authorization very soon after we receive the Phase 3 data, assuming the data is positive.

The Akcea team is also actively preparing for the global commercial launch of volanesorsen.

So, with that, Ill turn the call over to Paula to tell you more about what Akcea is doing.

Thank you, Lynne.

We made significant progress in 2015 in establishing Akcea as the leading development in commercialization company focused on cardiometabolic diseases caused by lipid disorders.

We have also made significant progress in our pre commercial activities for volanesorsen in two rare disease indications, FCS and FPL.

We have hired seasoned professionals whose collective experience includes multiple rare disease launches over two decades plus deep clinical and commercial experience with a focus in lipids, cardiology, and endocrinology.

This extensive knowledge and expertise is exactly what we need to develop and commercialize our pipeline of drugs.

Most recently, we have pointed to Dr. Louis O'Dea as our chief medical officer.

Louis is a board certified physician specializing in endocrinology and metabolism, and a 22-year industry professional.

He has a impressive track record of success in global drug development and regulatory approvals.

Louis has led 13 clinical NDAs, including four orphan drug approvals, which makes him the perfect person to lead the medical, clinical, and regulatory activities for volanesorsen, as well as guide the development of all of the drugs in our pipeline.

With that Phase 3 FCS study for volanesorsen nearing completion, our pre commercial activities for volanesorsen are accelerating.

To build a successful marketing campaign for volanesorsen we detailed the patient journey to understand how physicians make treatment decisions for their patients with FCS and FPL.

We spoke to patients, KOLs, traditional advisory boards, and practicing physicians.

We also visited hospitals and conducted market research projects engaging all of the key healthcare providers from acute care to ongoing care.

Our work confirmed what we already knew, that the clinical profile of volanesorsen holds tremendous promise for patients with FCS and FPL.

Physicians told they were most impressed by the substantial 70% average reduction in triglycerides across multiple patient populations we observed in our Phase 2 studies, and which have been published twice in the New England Journal of Medicine.

They said they've not seen this magnitude of triglyceride lowering in any drug to date, including those currently available or in development.

Through our research we confirm that patients with FCS and FPL are initially seen by a variety of physicians and that it can take some time for these patients to be accurately diagnosed and referred to lipid specialists, who are the right physicians to treat these patients.

Our goal is to get these patients diagnosed earlier and referred to a lipid specialist as quickly as possible.

Based on what we've learned, we have developed a clear plan to do this.

First, we will improve earlier identification of these patients by sure patients and physicians know and consistently use the correct names for these diseases.

Today, it's often the case that FCS and FPL patients are not told the correct name of their disease.

Our efforts to streamline patient identification will also include helping to organize the patients intercommunity where they can share their experiences and provide support and education for each other.

In fact, we have already made good progress on this front.

Last year, we held the first ever patient advisory board for FCS patients and their caregivers in the US.

This event was so successful we are planning another multi-country patient advisory board in Europe this quarter.

Second, we will accelerate referrals of these patients to lipid specialists by working with experts to simplify the diagnosis using the straightforward and recognizable clinical profile associated with these patients.

For example, FCS patients are patient's who have extreme, persistent treatment refractory triglyceride levels, most commonly with a history of pancreatitis or abdominal pain, for which other causes, like gallstones and alcoholism, have been ruled out.

And since both FCS and FPL are genetic diseases, if we find one patient with the disease, we can often identify relatives with the disease.

Finally, we will have streamlined the patient journey by developing much-needed disease education material and hosting forums to educate and raise awareness about the diseases among lipid specialists.

We are beginning to identify and document where these patients are to support a seamless transition to therapy as we prepare for the launch of volanesorsen.

Now turning for a minute to the other drugs in our pipeline.

Coming along behind volanesorsen is the IONIS-APO(a)LRx, the first and only drug to selectively and robustly reduce LP(a) in patients by inhibiting APO(a).

Managing LP(a) is considered the next frontier in managing cardiovascular disease risk.

LP(a) is a recognized independent genetic driver of premature cardiovascular disease, including coronary heart disease, atherosclerosis plaque formation, and calcific aortic valve stenosis, or CAVS.

IONIS-APO(a)LRx is our first LICA drug in development.

We've shown in a recent clinical study that it has the potential to be given as an easy to take low-dose self-injection with flexibility to be dosed weekly, monthly, or quarterly.

These attributes should afford good patient compliance, which are critical components for cardiovascular prevention treatment that must be taken for life.

IONIS-APO(a)LRx has the potential to treat not only the tens of thousands to hundreds of thousands of patients who have cardiovascular disease driven by severely LP(a), but also the millions of patients who are at risk for unaddressed cardiovascular disease due to elevated LP(a).

Given this commercial potential, our development plan for this drug is aggressive.

It first addresses the most acute, highest risk patients, those with premature recurrent CVD.

These patients have early cardiovascular disease, suffer from multiple events, and are already maxed out on available therapies.

This represents the highest unmet need in a smaller orphan size patient population of approximately 50,000 to 90,000 patients globally.

We plan to initiate Phase 2-3 critical study later this year in this definable patient population.

We believe the severity of unmet need in these patients will allow us to reach the market without an outcome study.

In addition, we plan to initiate a second Phase 2-3 clinical study this year in patients with calcific aortic valve stenosis whose disease progression is accelerated by LP(a).

This is a patient population estimated at 175,000 to 300,000 patients globally.

Our studies in this patient population would be modest-sized studies with echo imaging as the primary endpoint.

And, finally, our long-term development plan will be for the potentially millions of patients with cardiovascular disease and high LP(a).

For this much larger patient population we plan to conduct a secondary prevention outcome study.

In addition to volanesorsen for high triglycerides, we are developing the LICA drug, IONIS-APO(c)III-LRx for a broader group of patients with elevated triglyceride levels.

We plan to initiate a clinical study on this program this year.

And, finally, we have begun a Phase 1-2 to study with IONIS-angiopoietin-like 3 LRx in healthy volunteers with elevated triglycerides and in a small set of patients with familial hypercholesterolemia.

This drug targets angiopoietin like-3, a protein associated with a variety of cardiometabolic disorders, including mixed dyslipidemia.

We are developing IONIS-angiopoietin-like 3-LRx for these patients, and potentially for patients with fatty liver disorders, such as treating NAFLD to delay and prevent NASH.

And now I'd like turn the call over to Stan.

Thanks, Paula.

I hope that you agree that these are important and exciting times at Ionis.

I am and confident that there will be consistent stream of news.

In 2016, beginning with the focus on our growing and advancing group of drugs for severe neurological diseases led by nusinersen.

We plan to present an update on the ongoing Phase 2 open label study in infants with FMA in April at the American Academy of Neurology meeting.

As Lynne mentioned, we continue to be encouraged with what we are seeing in this study, in which the infants who are now toddlers are achieving developmental milestones they would not be expected to achieve.

At the AAN meeting there will be a dozen presentations and posters highlighting the potential of our technology to address previously untreatable diseases like SMA, Huntington Disease, myotonic dystrophy type 1, and a host of other neurological diseases.

Pre clinical data from our DM1 program as well as the study design and the ongoing study will be topics at the AAN meeting.

DM1 is a devastating disease for which no treatment exists.

The information we gain from our ongoing Phase 1-2 to study together with the natural history data we advise are collecting will help inform the next clinical studies for this drug.

We look forward to sharing the data from this program with you later this year.

IONIS-HTTRx will be the topic of a presentation at the AAN meeting as well.

IONIS-HTTRx is the first drug to enter clinical development designed to directly target the cause of Huntington's disease.

Phase 1-2 study is well under way, and we plan to report data from this study in 2017.

We and our partner, Roche, are looking forward to evaluating its potential benefit.

In addition to these clinical programs, we have a host of earlier stage programs that will be highlighted at the conference.

The breadth and scope of her neurological disease franchises showcases the progress in our strategic collaboration with Biogen and the potential of our technology to address neurological diseases that are currently untreatable.

We look forward to advancing many of these neurological disease programs into the clinic over the next several years.

A truly remarkable feature of where we stand today is the fact that the technology, despite being fully validated, continues to advance rapidly and these advances are having tangible, immediate benefits on the pipeline.

Today, we have eight LICA drugs in develop.

LICA is a gamer changer because it lowers the dose needed for a 50% target reduction to approximately 5 mg per week.

This means that our drugs should be even better tolerated and can be given weekly, monthly, quarterly or even less frequently.

We also have four-generation 2.5 drugs that are about 10 times as potent as generation 2+ drugs and enable us to engage in targets and tissues like muscle and tumor cells.

We expect to have a LICA generation 2.5 drug enter development this year and that could reduce dosages to a milligram a week or so.

In addition to our LICA and 2.5 advances, we and our collaborators at UCSD recently published a paper, the proceedings in National Academy of Sciences on the application of our new plaque acid expertise to enhance the gene-editing CRISPR technology.

We were able to create CRISPR RNase that could increase the potency and specificity of the CRISPR system.

These synthetic CRISPR RNase are significantly shorter, and up to 75-fold more potent than a modified CRISPR RNase.

Importantly, the specificity of these shorter synthetic CRISPR RNase resulted in far fewer off-target effects, which has been a major concern about the potential application of CRISPR technology as a human therapeutic.

Additionally, these new CRISPR RNase should in vivo delivery without the need for viral vectors.

We believe that these advances could provide a new strategy to unleash the power of the CRISPR Cas9 gene-editing system to create new drugs to treat diseases.

Of course what I've discussed about the advances when breaking in the technology is simply the tip of the iceberg.

As the year progresses, we plan to share many more important advances in our technology with you, so stay tuned.

In that vein, let me conclude with a very quick summary of some of our goals and upcoming events.

We plan to complete the Phase 3 studies for nusinersen, IONIS-TTRx, and volanesorsen and report data from these studies in the first half of 2017.

We plan to report clinical data on a number of our drugs in the pipeline, including open label data from nusinersen and IONIS-TTRx, clinical data from our cancer drugs, IONIS-STAT3-2.5Rx and IONIS-AR-2.5Rx.

We plan to initiate multiple clinical trials, including the Phase 3 CARDIO-TTR study that GSK plans to conduct on IONIS-TTRx.

This large outcome study is designed to broaden the market opportunity beyond FAP into patients with cardiomyopathy form of TTR amyloidosis.

GSK plans to initiate a small Phase 3 study that will support marketing approval of IONIS-TTRx in Japan with patients with FAP.

We will continue to advance technology.

This year we plan to report data from a number of our LICA drugs (inaudible).

And with three Phase 3 drugs poised to read out data in the first half of 2017, we're looking forward to adding product revenues and royalties to our already strong financials.

We look forward to sharing more with you throughout the year, as well as at our upcoming R&D day in New York on July 13.

So mark your calendars for that morning, and we will be sending out more details on this event shortly.

With that, we will bring the call to conclusion and open it up for questions.

Kate, if you could set us up, please.

(Operator Instructions)

Jim Birchenough of Wells Fargo.

Congrats on all the progress.

A couple of questions.

First, just want to make sure I understand the financial guidance and you've got roughly a $60 million NOL but looks like a cash burn closer to $175 million.

Is that just related to timing of milestones and to some non-cash revenues around amortized revenues of prior milestones?

Could you maybe just help us understand that and then I wanted to follow up with some questions on the pipeline.

Hi, Jim.

It's Beth.

Yes.

You're right.

The real disconnect there, the $70 million of our revenue is related to the amortization of upfront payments and the other point is that we have a number of very large milestone payments that are anticipated later in the year and when those are achieved the cash will actually be received in early 2017.

And so there's sort of an artificial disconnect there just because of the December 31 cut off.

Got it.

Okay.

Thanks.

On the pipeline, when we think about TTR, can you remind us of the primary endpoint of Phase 3 and some of the key secondary endpoints.

And I'm interested in the clinical relevance when you think of the morbidity of this disease, what are the key metrics we should be looking for in the Phase 3?

Sure, Jim.

The primary endpoint for the study is a modified neurological impairment scoring system that was designed by us and our consultants to be specifically relevant to patients with TTR.

And so it's a customized but very similar to the NIS plus 7 scoring system, and it does directly look at changes in motor function in these patients over time.

Is there a fairly good correlation between TTR accumulation and that endpoint?

When we think about the substantial TTR reduction you show, what would be the evidence connecting that to improvement in that endpoint?

We think so.

Obviously one of the things that we looked at in designing the endpoint is the changes in neurological impairment in the tafamidis trial where we had voluminous data and so we do believe that if you slow or stop the growth of plaques in patients, you should see significant benefit in terms of reducing the progression of disease in these patients.

Remember, what happens in these patients is the plaque begins to form and then the TTR continues to populate the plaque and the plaque spreads, and that is what causes the progressive neurological impairment and eventually organ involvement in these patients.

So if you reduce the progress or stop the progress of the plaque growth, you should see a benefit in terms of patients not succumbing to the neurological and motor function progression of disease.

In addition, one of the things we're doing in the study that is very interesting is we do have cardiac sub-study where we are looking at a subset of the patients who have cardiac involvement and looking at the progression of their cardiac involvement over the course of the study, and it's interesting because these patients aren't patients who necessarily have cardiac symptoms.

They are patients who in incoming echo imaging in the study we identify plaques in their heart and so we are able to study these patients.

We think that's going to give us very interesting data to help inform our cardio TTR results in the Phase 3 study looking at the cardiomyopathy form of the disease.

Got it, and maybe one final question.

Just on SMA as we think about what appears to be a pretty substantial difference in the Kaplan-Meier curve with the historical control, can you maybe speak to the identification of these patients as Type I SMA both in the historical cohort and in the study just so we know that it's an apples-to-apples comparison that these are true Type I SMA patients that were not somehow misidentifying Type II patients?

Could you maybe speak to how these patients are identified as Type I and how we should feel comfort with historical control?

Absolutely.

Two very important things about that.

While it is the case that a certain percentage, between 10% and 20% of patients with two copies of the SMN2 gene may eventually turn out to be Type II patients, what really distinguishes patients who are going to be Type I and Type II is there age of symptom onset and their age of diagnosis.

So, in both our open label Phase 2 study and in our Phase 3 study the bulk of the patients that we have are patients who show symptom onset before three months of age and are diagnosed close to four months of age.

Patients who have two copies of the SMN2 gene and go on to be Type II generally, and of course there are exceptions to all of this, but generally don't show symptoms until seven, eight, nine months of age and frequently are diagnosed closer to their first birthday.

And so physicians treating these patients feel very much like they are able to tell the difference between a [2 copy] baby who is going to be Type I and a [2 copy] baby who is going to be Type II.

Importantly, we've done sensitivity analyses on the PNCR database and looked at all of these sorts of things like what difference does it make if you look at time of symptom onset, what difference does it make if you look at time of diagnosis, and we have chosen the best matched set from PNCR to match those same characteristics in the patients in our open label study.

Remember that the PNCR was performed by basically the same physicians as in our study and we do have access to all those data and over time we have presented different ways of looking at the PNCR data so that you can see that any way you look at it, whether you look at only the most perfectly matched or the generally matched or whatever.

The differences remained quite large.

So I think that we have a lot of confidence that we are comparing apples to apples.

Great.

Thanks for answering the questions.

Chad Messer of Needham & Company

Great.

Thanks for taking the question and congratulations.

A lot of good stuff going on and a lot more to come.

Can you just repeat back for me the list of programs that got rattled off that we should be looking for data at AAN?

Obviously nusinersen in I heard Huntington's, but I think there was at least one or two others that you mentioned.

And then if I'm not mistaken there's still a couple of unnamed programs in the Biogen collaboration.

I don't know if we're getting any new data on those or if there is anything you can say there.

We are debating whether I am going to get through my answer without coughing or somebody else will to take.

In the meantime, I am coughing.

Nusinersen, there will be a lot of information about nusinersen in a variety of ways.

HTT, DM1, those are all clinical programs and there will be information about all of those, and then there will be data presented on a wide range of other programs, many of which are progressing pretty rapidly toward the clinic, that should give you a pretty good idea of the breadth and scope of the collaboration and how tremendously successful it's been in such a short time.

I think of the next several weeks or so once they put out the timelines for posters and presentations, we do plan on putting that on our website so you can see when the various things are that we are going to be presenting.

Looking forward to that.

One thing that wasn't mentioned or I'm sure there's lots of things you guys haven't mentioned because you only have so much time for the call, but in January you got Kynamro back.

Given how important cardiovascular and lipid diseases are to Isis, can you just talk about your plans are there and what we should expect?

Yes, as of January we got the rights to Kynamro back.

Genzyme at the moment is continuing to supply drug to patients who are currently receiving it, and right now we are in the process of identifying a new partner for Kynamro.

We are early in the process, so it probably will be premature for me to go into a lot of detail.

Suffice it to say, though, we have found that there has been quite a great deal of interest with regards to new partners in taking on and commercializing Kynamro.

We do think that Kynamro is a drug that brings value.

That there are patients who on Kynamro who should continue on Kynamro and patients of a variety of sorts that should consider Kynamro as a treatment option, and so we are committed to finding a solution for these patients.

Our primary focus here is to be sure that patients who really need the drug can get the drug in a way that ensures that they will be able to do that on a consistent basis.

Thank you.

We will have updates for you in the next few months, for sure.

Might we learn how many patients are on Kynamro?

Right now that is not information that Genzyme and Sanofi have made public.

I know, but it's your drug now.

But we are not currently commercializing it.

It's a little complicated.

It is the case that we and Genzyme have agreed to end the partnership and it is the case we have the rights to the drug back, but it is still the case that Genzyme has the NDA and is continuing to sell and do all the things that relate to that, and they have all that information.

We do not.

I understand.

Thank you.

Eric Schmidt of Cowan and Company.

Maybe for Paula first on volanesorsen.

It sounds like you're really getting moving on the pre commercial efforts both in FCS and FPL.

Are you going to target a number of patients you'd like to have identified by launch and are you going to provide Wall Street with updates on your patient identification progress?

Thanks, Eric, for the question.

We are already actively starting to identify patients and it's an important part of our activity to not only reach out to the community but to actually have them identify so that we can improve getting them on to drug or make that an easy process.

That isn't something that we will be reporting over time from now to launch as to how many patients we've identified from this period or anything.

That would not be something that we would do.

One more.

Moving to LP(a).

I think you said you don't expect to be required to perform an outcome study in the severest of populations.

Have you had a chance to [vet] that view already with regulatory authorities?

So, for the severest patient populations, these are patients, just reminding you, is the premature recurrent CVD.

These are the patients that have had an event at a fairly young age and have continuing events, maxed out on therapy and their only risk factor is LP(a), and so we see these patients as a very significant high unmet need.

We are planning to have those discussions with regulators, but that is as we pull together a full package as to our full development plan so that we can work with the regulators so that first of all understanding this very severe unmet need but then also what our plans are for developing the program all the way through those other indications that I mentioned, the calcific aortic valve stenosis and then the broader patient population.

So, the whole development plan is an important part of the conversation.

Got it.

A quick one for Beth on the 2016 financial guidance, revenues of greater than $240 million.

It wasn't clear to me whether that figure contemplated any new business development activity or could be achieved on the existing arrangements?

That $240 million contemplates the amortization upfront from existing relationships as well as milestones from our existing collaborations.

It doesn't contemplate any significant new [BD] activity.

As a general rule, Eric, we have never done that just because we feel it's more conservative and more sensible to see that as an upside and of course I guess that's one reason why we keep meeting our guidance so handily, but I don't think it's ever sensible to count on a deal you don't have.

Great.

Appreciate the clarification.

Stephen Willey of Stifel.

Maybe an additional question for Paula.

I guess in addition to the patient identification work that you are doing, I mean it obviously sounds like you're working on trying to streamline the diagnosis and just kind of wondering if you could maybe provide a little bit of clarity around what you think some of the challenges will be with respect to laying out a diagnostic algorithm for physicians.

It seems like FCS would be a slightly harder diagnosis perhaps than FPL because it is maybe a bit more differential in nature.

And then I guess you also mentioned the notion that a lot of these patients have genetic mutations and just wondering how the mutational screening, if at all, becomes incorporated into that diagnostic pathway?

Yes, sure.

First of all, actually even what I mentioned both FCS and FPL have the ability to have very streamlined, simple diagnostic from a clinical perspective and so with FCS, as I mentioned, you may not look at them and see that they have a disease whereas the FPL they actually can be clinically diagnosed by their appearance in some cases.

With FCS it really is the clinical manifestation.

When these patients present with pancreatitis normally in the emergency room they are in the ICU.

Triglycerides are automatically measured.

It's not even a question, they are automatically measured.

So these patients have very high triglycerides.

They have pancreatitis.

Again, if they rule out the other causes like alcohol, gallbladder, that is something that like today a lot of times these patients are just told you have a genetic cause of your high triglycerides, you need to not eat any fat.

And so what we're trying to do is educate on giving that true diagnosis, that disease a name, but that is something that we're working on through doing for example an electronic medical record studies where we can go in with that criteria and look at triglyceride level, history of pancreatitis and narrow down those patients and find those patients.

So those are a lot of the types of activities that we'll be doing this year to begin to find more patients, educate, and make sure those are streamlined.

On the partial lipodystrophy side, again there's the clinical diagnosis, there's a visual side, but also you have patients who have, for example, a low BMI but extreme insulin use.

And so there are criteria again like that that we would use in an algorithm through electronic medical records and education, so actually both of them have that opportunity where you could get a very good clinical diagnosis without the genetic testing.

Now, in our clinical studies we are doing the genetic testing and confirmation, but we do believe that moving forward that is likely not to be needed commercially.

Steve, this is a triglyceride diagnosis.

So a patient with a triglyceride that is extremely elevated should be considered an FCS or FPL patient and other things excluded.

So I think the steps that Paula's team are taking is first make sure the danger of the diseases are well used and well understood.

They've been changing in the last few years.

To work with the patient advocacies and learning societies to heighten awareness in the general physician and specialist community, and to then get these patients into the treatment care places that they need to get.

It's not so much the diagnosis that's the problem, it's the recognition of the diagnosis by the practitioners that encounter these patients first that's the challenge.

Understood.

I guess with the NextGen like a conjugate APO(c)3, should we be thinking about clinical development essentially as it is trying to recapitulate some of the prior Phase 2 data that's been generated with the first generation product maybe just in an effort to try to characterize what the dosing efficiency is with the glycoconjugate?

We expect the dose to be at the same range as the APO(a), but of course until we get the experiment done we don't know.

So the Phase 2 program will be abbreviated and simplified because we already know what we need to know.

Now we just need to get enough experience with the LICA in Phase 2 so we can move aggressively into more advanced clinical trials.

We don't really feel we have a lot of questions that need to be answered in Phase 2 other than to define the dose and schedule that we want to use.

You'll remember that one of the important things that we learned from the Phase 2 study with volanesorsen is that we got the same triglyceride lowering regardless of incoming triglyceride levels and so we treated patients with extremely high triglycerides all the way down to patients with sort of modestly elevated triglycerides and saw very consistent reductions.

And so we don't feel like -- that's mechanistic and we don't feel like we need to go back through and do all of that work over again for the LICA.

Okay.

And then maybe just one last question.

Stan, you mentioned the PNS paper, which I thought was pretty interesting.

Just wondering if you can maybe characterize that there's been any strategic interest at least in terms of inbound BD opportunities and I guess if so is that something that you would try to keep as an exclusive relationship or do you feel that that is something that you could license out on a non-exclusive basis to multiple parties, I guess specifically in the context of kind of where some of the CRISPR IP is?

Thanks.

We're mulling that over right now.

I think the CRISPR technology has meaningful potential.

There are many, many challenges that have to be overcome before it is fully realized, and we certainly believe that we made an advance and that gives us some control in this space that we want to take advantage of.

So the best strategy to exploit all that is something that we're going to make a decision about over the next few months and I think I will just leave it there, Steve.

Thanks a lot and congratulations.

Jessica Fye of JPMorgan.

Thanks for taking my question.

Two questions for you.

First on TTR.

Can you talk about any differences, if there are any, in the natural history or event rates that you expect in the CARDIO-TTR study for the FAC patients relative to the wild type cardiomyopathy patients?

Have you determined what the mix -- ?

There's been -- a good bit of background work was done in thinking about CARDIO study and a lot of work looking at the rate of progress after diagnosis.

So the main difference between the wild type and the mutant is in the agent which the symptoms present, but since we are only going to be treating patients with symptoms, the important question to ask was after diagnosis what is the rate of progression and the message that we got back that this was the work that GSK did and it also came from all kinds of conversations with experts in the field, is it the rates of progression of those two types of TTR cardiomyopathy are roughly the same and so that was the basis for doing the study as we did it.

We think the data that support that are quite sound.

Jessica, one thing I would add is that as you would imagine we have stratification between the two different types built into the study as well as into the ultimate analyses in the study.

Sure.

So I imagine it will be kind of balanced between the arms, but is there sort of an ideal mix that you want to see between those types of patients?

Is it sort of consistent with the breakdown in the overall populations?

It is consistent with the overall breakdown, roughly with the overall breakdowns in the populations.

Okay.

Got it.

And then just one other question.

Can you just clarify the SMA comments you made earlier in the call?

I know as of JPMorgan you said you had no events in the continuing infant study.

I'm not sure if you can comment, but is that still the case through today?

We don't update that study every call, but what we said in January it was true in January and remains true.

Salveen Richter of Goldman Sachs.

This is Tom on for Salveen.

Thanks to taking our questions.

First, I was wondering if you could give us a little bit more clarity on the filing strategy for nusinersen in SMA Type I?

So you mention you are having productive discussions with the regulators.

Just wondering if you could maybe give us a high level sense of what they want to see in the data?

Is it more safety or any commentary on that would be helpful.

I'm sorry, these are conversations that are taking place with the regulators constantly and so we've said all that we can say at this stage.

Okay.

And then how should we be thinking about timelines for when you might be able to communicate the outcome of these interactions with us?

Lynne, why don't you take the question.

When we have something definitive to communicate, we will communicate it.

At this point, we're having -- our goal is to get the drug approved as rapidly as possible, not to file as rapidly as possible.

As we've been able to see, sometimes filing as rapidly as possible is not the most rapid route to approval.

We will -- if anything changes definitively, we of course will communicate that.

The focus is getting this drug to these babies as quickly as we possibly can and that includes having a positive collaborative relationship with the regulatory agencies around the world.

That is what we're working toward.

We feel the time pressure very keenly on this as does Biogen, and we're doing our best there.

Beyond that, it simply would not be in the interest of the infants to give more information about any of that.

One follow-up question.

So you mentioned pre commercial activities for new centers ongoing with Biogen.

Just wondering if you could give us a sense of whether you are looking to increase awareness for prenatal genetic testing for SMN1?

NURTURE is a study that's really on point there.

The idea of NURTURE is if we get to infants started sooner will they do better?

And the general belief is they will and they are.

And so there will be a strong effort.

NURTURE itself represents the very first step in getting infants diagnosed as early as possible and into care facilities as quickly as possible, and it's really urgent because we know that by the time an infant with Type I SMA is three, four, five months old it could already be too late and so absolutely.

That's a long way of saying absolutely.

Biogen is actively involved in both work to get SMA screening in different states of course because screening at birth is regulated on a state-by-state basis as well as raising awareness prenatal screening.

They have similar activities going on in Europe.

It is more than just diagnosis.

It's managing to get that infant and the family into a tertiary center that can take care of the baby and obviously as it appears that there may be a treatment on the horizon, the whole attitude shifts and awareness grows because of that.

We also benefit greatly from patient advocacy groups, Cure SMA and others, that are playing a great role here.

So this is one of those situations where there is an urgent need.

The time is short, and everyone involved I think recognizes the need to reduce the time to diagnosis and treatment.

Jon Eckard of Barclays

Most of the key topics have been asked about, so maybe FXIRx, you're going to have updated Phase 2 data for end-stage renal disease.

What additional information or insights do you think we could learn about this program based on this disease versus existing data?

Well, this is a very straightforward program that answers one question really, is there any difference in the behavior of the drug in patients who have almost entirely dysfunctional kidneys?

And the reason to answer that question is the buyer is getting ready to do a very large program in patients with renal dysfunction who have atrial fibrillation and other reasons for anti-thrombosis.

So it answers one simple question.

Does the drug behave the same way in patients with no or very little renal function as it does in normal humans?

Great.

And then quickly on the 2.5 -- generation 2.5 technology in some of the cancer programs, what aspects of the results beyond just clinical efficacy would be important to watch with regards to the utility of this drug as you mentioned say in muscle or tumor cells.

For example, is delivery of the drug [knocked down] on the target of the tumor?

What other things should we be looking for from that data set?

I can tell you how I look at it.

When we take a brand new chemistry into the clinic, we typically go first into diseases where safety, where the clinical circumstances are severe enough that safety is not the primary issue and so that is why we took the first two generation 2 product drugs into patients with cancer.

And what we've been watching as that has gone on is does the chemistry appear to be safe?

Is there any new side effect that we might observe?

And are we seeing evidence of activity that we would not have been expected with generation 2. And I think we've reported that pretty much already with STAT3 and in the androgen receptor data gave us even more comfort because STAT3 as a target has some target-related side effects.

So you'll see more androgen receptor data this year and we find them encouraging.

And then of course the next step once we finish with that foray into the clinic was to move into real muscle targets.

And so the most important thing for me in the coming year is what happens in the DM1 study with our DMPKRx-2.5 drug?

That's going to tell us whether we've increased the ability to get in and be active in skeletal muscle.

And what you should look for is any activity because in [RAMs] systemic dosing generation 2 plus you don't see an activity in skeletal muscle, so we want to see activity at some reasonable dose in skeletal muscle and that's the key test for us.

Yale Jen of Laidlaw.

Thanks for taking the questions.

I have two, one in the pipeline side and one in the housekeeping.

In the housekeeping side you mentioned that the 2016 expenses are roughly flat as the 2015 and also noted in the fourth quarter the R&D expenses has increased quite more compared to prior quarters.

So would the fourth quarter be a sort of baseline moving forward or what happened with the reduction over the last -- 2016 in different quarters?

Hi, Yale.

It's Beth.

I would not use Q4 as a baseline for 2016 expenses.

I'd look at total expenses in 2015 roughly around $300 million pro forma without stock comp and use that as a general baseline for 2016.

Q4 obviously things were looking really good for us in 2015 and so we had an opportunity to start some work that we had anticipated starting in 2016 a bit earlier.

So I would not use Q4 as a run rate.

Okay.

Great.

Just a little follow-up in terms of the milestone that you mentioned earlier about the AstraZeneca one.

Could you repeat that and also would that be an additional milestone you anticipate for Factor XI once you finish the Phase 2 study I guess the second half of this year?

There's a $55 million milestone from FXIRx when we finish the renal study, and I don't remember --

There are additional milestones for Factor XI as it progresses in development through the regulatory process.

And then the AstraZeneca cardiometabolic milestone was a $25 million milestone that we are projecting in our guidance for this year.

It's a $25 million milestone late in the year, so probabilized at a very low level right now, so it doesn't show up.

That's one of the swings that happens in our guidance is that it goes from either a probability we put on it to 100% once you get it and it changes things.

That's helpful.

The pipeline question is for the hepatitis B HBV program you have both the conventional and the LICA version.

I guess both are in clinical studies.

Just curious whether you guys are going to eventually advance all to the LICA or you may keep two programs and make the transition much later on?

Of course that's a GSK collaboration and so I don't want to speak for GSK but they are pursuing the development of both drugs right now and they believe there is significant logic for considering developing both.

Michael Schmidt of Leerink Partners.

This is Varun Kumar on behalf of Michael Schmidt.

Thanks for taking questions.

My first question would be on IONIS-FXI.

What kind of efficacy data should we expect this year from IONIS-FXI, and in terms of commercial opportunity can you please talk about how you foresee positioning your product in anticoagulant product space?

Well, the study that we are doing in patients with renal dysfunction is purely to answer the question does the drug behave the same in those patients as it does in patients with normal kidney function and we're just looking at FXI levels.

So we would say it really -- you have to think of it as a pharmacokinetic study principally and a safety study to get us ready to do the rest of the work.

And our positioning of FXIRx is pretty much as we have said.

The initial forays with FXIRx will go into areas where current anti-thrombotics are really not used because of bleeding risk, such as patients in renal dysfunction, but eventually we think it has the properties that would allow us to displace a good many of the other indications in other anti-thrombotics that are out there.

Okay.

Great.

My second and last question is on IONIS-DMPK.

Can you please remind us the timeline for the Phase 1- 2 data readout?

Is it still end of this year?

And what kind of exploratory endpoints are you planning to report, specifically, will it include muscle biopsy data as well.

Thank you.

The endpoints that we are looking at do include muscle biopsies.

There are muscle biopsies prior to dosing and then at the conclusion of dosing, and it's -- we're looking at several different dose groups, so we will have the opportunity to look at a set of transcriptional analyses that should give us a pretty good sense of whether the drug appears to be altering splicing in the way and already processing in the way that it should.

So it is muscle biopsy-driven.

There are also other questions we might ask such as what happens to the diabetes these patients have, if they do, but the primary is the muscle biopsy.

Just to add.

You'll remember that obviously this disease hasn't been studied before with a therapeutic intervention and so the purpose of this study is to broadly explore a whole variety of exploratory endpoints so that we can choose among them the ones that are most sensitive to go into our next Phase 2b and Phase 3 studies.

So we are looking at measures of myotonia, measures of muscle strength, the whole variety of different things as well as transcriptional analyses and muscle biopsies, and so the purpose of this is to inform our next stages of development.

It's on schedule.

We do expect to have data this year from that program.

We are in the final cohort now.

Great.

Congratulations on going multiple Phase 3 studies.

Thank you.

I want to thank everyone for their interest and questions.

With that, I want to bring the call to a close.

We do have an important and exciting year lying ahead of us and look forward to beginning the process and telling you about a little more detail about some of our progress into neurological diseases at AAN in the next few months.

Thanks.

The conference has now concluded.

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