Ionis Pharmaceuticals Inc (IONS) 2020 Q4 法說會逐字稿

Good morning, and welcome to Ionis Pharmaceuticals Fourth Quarter and Full Year 2020 Financial Results Conference Call. As a reminder, this call is being recorded.

At this time, I would like to turn the call over to Wade Walke, Vice President of Investor Relations, to lead off the call. Please begin.

Thank you, Tom. Before we begin, I encourage everyone to go to the Investors section of the Ionis website to find the press release and related financial tables, including a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We also have posted slides on our website that accompany our discussion today.

With me on today's call are Brett Monia, Chief Executive Officer; Beth Hougen, Chief Financial Officer; and Richard Geary, Executive Vice President of Development. And joining us for Q&A are Onaiza Cadoret, Chief Corporate Development and Commercial Officer; and Eric Swayze, Executive Vice President of Research.

I would like to draw your attention to Slide 3, which contains our forward-looking language statement. We will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional details.

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

Thanks, Wade. Good morning, and thank you for joining us on today's call. Last year marked a new beginning for Ionis. With new leadership in place, we laid out of bold new vision for the business and took important steps towards realizing our goal of having 12 or more medicines on the market in 2026. Key to our new vision is our strategy to maximize the value of each medicine in our wholly owned portfolio.

Today, our focus is primarily on commercializing our rare neurological and cardiometabolic disease medicines. For those opportunities outside these core areas, we will set a course forward that maximizes the value of each medicine, which may include Ionis commercialization or partnering. Last year, we accelerated our commercial strategy by acquiring Akcea. This transaction also enabled us to strengthen our organization and to recognize the full value from Akcea's rich product portfolio. Further, our distribution agreement with Sobi made it possible for us to restructure our European operations, which further streamlined our business.

We were able to unlock substantial resources through these transactions, which we are investing in the business in the following 3 key areas: first, we're advancing and expanding our wholly owned pipeline; second, we're building our commercial capabilities in support of our rich pipeline as we prepare to launch prioritized medicines from the Ionis wholly owned pipeline; and third, we're broadening the reach of our technology through investments in medicinal chemistry, human genomics, validation of new routes of delivery and through other means. We believe investing in these 3 key areas provides the greatest potential to drive future growth and to achieve our goal of 12 or more medicines on the market in 2026.

Last year, we made substantial progress towards achieving this goal with numerous significant advances across our rich late- and mid-stage pipeline. We now have 6 Phase III studies underway, including 3 studies with wholly owned medicines. We also have a prolific mid-stage pipeline of medicines advancing towards Phase III development, many of which are expected to reach pivotal trials in the near term. With so many programs in mid to later stages of development, together with our historically high rate of clinical success, today, we are in the enviable position of delivering a steady cadence of Phase III data readouts for many years to come.

And we're especially excited about the upcoming Phase III readout of the VALOR study for tofersen in patients with SOD1-ALS with data expected in the second half of this year. Positive results from this study would put us one step closer to providing the first ever disease-modifying therapy for ALS. And importantly, positive tofersen results would also provide for the first time tangible clinical evidence that treatment is possible for patients with ALS, providing hope for all patients suffering from this devastating disease.

And more broadly, tofersen's success, once again, demonstrate the power of our antisense technology to pioneer new markets and deliver transformational medicines to patients.

In addition to advancing our pipeline, we're also expanding the utility of our technology, having now demonstrated proof-of-concept for aerosol delivery of antisense medicines to the lung. Based on these results, we're well on our way in building a new pulmonary disease franchise with the potential to treat conditions, such as cystic fibrosis, COPD, IPF and asthma. We've only scratched the surface of the unique capabilities of our antisense platform. With the medicines advancing in our pipeline today, we have the potential to continuously pioneer new markets in areas of significant unmet medical need and change the standards of care for diseases needing better treatment options for many years to come.

As we begin the year in 2020, we, of course, could not have imagined the challenges the society would face from the global COVID-19 pandemic. Because of the dedication of our employees and strength of our technology and our business, we were able to successfully manage the evolving pandemic and achieve our key goals for 2020. This includes achieving our 2020 financial guidance while advancing our pipeline and our technology. As Beth will describe in more detail, we plan to put our substantial financial resources to work even more this year by increasing our investments in our medicines and our technology. We believe this has the greatest potential to drive future revenue and earnings growth.

And with that, I'd like to turn the call over to Beth to review our 2020 financial results and our 2021 financial guidance, which is focused on maximizing the value of our wholly owned pipeline. Then Richard will discuss our key recent pipeline achievements and highlight important areas of focus for this year. After Richard, I'll wrap up our prepared remarks before taking your questions. Now over to Beth.

Thank you, Brett. I'm pleased to say that we exceeded our 2020 guidance with revenues in excess of $700 million and net income of $111 million on a non-GAAP basis. We achieved these results while continuing to invest heavily in our rich pipeline, with a focus on our wholly owned medicine. And we're particularly pleased with these results given the challenging global pandemic environment. In the fourth quarter of 2020, we took important steps toward our goal of creating a stronger, more efficient company when we acquired Akcea and moved our European operations to a distribution model. Together, these transactions unlocked substantial cost savings that we plan to reinvest to drive future revenue growth.

I'll talk more about that in a few minutes, but first, I'll walk through our 2020 financial highlights beginning with revenue. Last year, about 50% of our total revenue came from our marketed products, with the majority coming from SPINRAZA. Most of the remaining 50% of our revenue came from 8 different partners, as together, we advanced more than 20 programs. Our ability to generate revenue from numerous diverse sources is a key element of our financial strength.

SPINRAZA continued its blockbuster performance last year, generating over $2 billion in global sales. We earned $286 million in royalty revenue as a result, and virtually all of that revenue falls to our bottom line as profit. Biogen remains committed to enhancing patient outcomes and reinforcing the proven efficacy and safety profile of SPINRAZA in SMA patients of all ages. The RESPOND study and the DEVOTE study are 2 examples of this commitment. The RESPOND study, which is now underway, is evaluating SPINRAZA's potential benefit in SMA patients who have experienced a suboptimal response to gene therapy. And the DEVOTE study, which is evaluating the potential to deliver even greater benefit with higher doses of SPINRAZA compared to the currently approved dose, is now enrolling patients in the pivotal blinded cohort.

Given SPINRAZA's robust efficacy and safety profile established in SMA patients of all ages, SPINRAZA continues to be a foundation of care for the treatment of these patients. And with over 11,000 patients on treatment at the end of last year and over 60,000 SMA patients in markets where Biogen has a commercial presence, we believe SPINRAZA's future remains bright.

TEGSEDI and WAYLIVRA had combined product sales of $70 million, an increase of more than 65% compared to 2019 as these medicines launched into new markets and new patients began treatment in existing markets. TEGSEDI has demonstrated consistent quarterly growth since launch, driven by new patient growth in established markets such as the U.S. and in new markets across Europe. Last year, we achieved pricing and reimbursement in numerous new countries, bringing the market to which TEGSEDI is commercially available to 15. Notably, we began generating revenue in countries across Southern Europe, including Portugal, which is strategically important because of its large endemic hATTR patient population. We began recognizing revenue in Canada, and we continue to expand into Latin America. Patients in Brazil and Argentina are being treated with TEGSEDI under a named patient program administered by our partner, PTC.

In its first full year of commercial sales, WAYLIVRA achieved important successes despite the pandemic. Through the efforts of our European team, we achieved pricing and reimbursement in 6 major European markets. WAYLIVRA is under review for marketing authorization in Brazil through PTC, and we are optimistic about a potential approval this year. PTC is continuing its efforts to expand access in other Latin American markets as well.

During 2020, we earned R&D revenues of approximately $365 million, slightly above our annual average of $350 million. Approximately 80% of our R&D revenues from medicines in our leading cardiometabolic and neurology franchises, with more than $165 million from our cardiometabolic franchise and over $125 million from our neurology franchise. Additionally, we earned nearly $50 million from Alnylam last year. This included $41 million in sublicense fee revenue we earned in the fourth quarter when we obtained a favorable award in our arbitration [proceeding].

As 2020, once again, demonstrated, our ability to consistently earn revenue from multiple sources is a key pillar of our financial strength. As we projected in our 2020 guidance, our non-GAAP operating expenses increased compared to 2019. The increase was driven by growth of just over 10% in non-GAAP R&D expenses related to advancing our Phase III programs for TTR LICA and APOCIII LICA plus our wholly owned medicine.

Our SG&A expenses on a non-GAAP basis were slightly lower year-over-year, primarily from reduced travel and related expenses due to the pandemic. We exceeded our net income guidance of meaningfully profitable with net income of $111 million on a non-GAAP basis. And we ended 2020 with nearly $2 billion in cash, enabling us to increase our investments across our business.

As a result of our Akcea and Sobi transaction, we recognized approximately $400 million of related expenses in Q4 of last year. Importantly, most of these expenses were noncash and nonrecurring. We excluded these expenses from the non-GAAP results I just reviewed with you because they do not reflect our normal ongoing operations. These expenses were comprised of $31 million of severance and retention costs, $59 million of noncash stock-based compensation expense and $312 million in a noncash adjustment of our valuation allowance for our federal deferred tax assets.

I'd like to just take a couple of minutes to provide some additional information about the adjustments to our valuation allowance. Since Akcea's IPO, we have been required to report our federal taxes as 2 separate companies. That meant that Akcea's operating losses and R&D tax credits were not available to reduce Ionis' taxable income during that time. As a result of the acquisition, we were able to reconsolidate the 2 companies for federal tax purposes, and we'll now combine Akcea's expected losses with Ionis' taxable income, resulting in tax losses for the next few years as we make significant investments to drive future revenue growth from our rich pipeline. Additionally, this means Akcea's pre-acquisition federal tax assets of nearly $300 million are now available to us to reduce our consolidated taxable income in the future. However, because we anticipate consolidated tax losses in the near term, we are required to establish a valuation allowance against these deferred tax assets. So while it's a large number, it's important to note that this is a noncash adjustment based on technical accounting guidance and reflects the substantial tax benefits we have available to us to reduce our consolidated taxable income in the future.

Now I'd like to provide some color on the financial benefits from our Akcea acquisition and the restructuring of our European operations. Last year, we put our strong balance sheet to work when we reacquired Akcea. The acquisition provided us with significant financial benefits. First, we retain the full value of Akcea's rich portfolio, which we expect to drive considerable revenue growth in the future; second, we are realizing significant cost savings from the efficiencies we are achieving by operating as a single company; third, we gained full access to Akcea's substantial cash balance of nearly $400 million at the time of the acquisition, enabling us to freely use it to maximize the value of our medicines; and fourth, we gained access to the nearly $300 million of Akcea's deferred tax assets I discussed a few moments ago.

We are also realizing significant financial benefits from our Sobi transaction. Restructuring our European operations improves our bottom line by enabling us to distribute TEGSEDI and WAYLIVRA in a more cost-effective manner by leveraging Sobi's commercial infrastructure and reach across Europe. As a result, we expect to realize substantial savings. In aggregate, we expect to realize more than $50 million of savings in 2021. And we are putting these substantial savings to work by reinvesting them in other value-driving areas of our business.

Now turning to our 2021 financial guidance. We are projecting to earn more than $600 million in revenue, incur operating expenses in the range of $675 million to $725 million. And end 2021 with a net loss of less than $75 million, assuming the low end of expenses, all on a non-GAAP basis. Our 2021 guidance reflects our new strategy to maximize the value of our wholly owned medicine, focused primarily on commercializing our rare neurological and cardiometabolic disease programs. Our guidance also reflects the shift in revenue for TEGSEDI and WAYLIVRA in Europe from product revenue to royalty rev.

As I mentioned a few moments ago, our restructured European operations will provide us with substantial savings, which we are redeploying to achieve our growth objectives. As we've always done, our R&D revenue is probablized, based primarily on the anticipated timing of the many different milestone payments we anticipate achieving as we advance partnered programs. Because of this approach, we have upside opportunity, particularly since we expect our R&D revenues to be higher in the second half of the year compared to the first half. We expect our operating expenses to increase as we invest in driving future growth. That means investing our resources in 3 key areas: advancing and expanding our wholly owned pipeline, building our commercial capabilities and broadening the reach of our technology.

Our investments in our pipeline are focused on advancing our ongoing Phase III studies for TTR LICA and APOCIII LICA, starting a new Phase III study for APOCIII LICA in a larger patient population, advancing ION363 in patients with FUS-ALS into Phase III development and continuing to progress our multiple mid-stage programs. We are also investing in building our commercial capabilities. With Akcea, we acquired a strong commercial foundation and we continue to build on that foundation. Specifically, we have established a new product strategy team, which is focused on go-to-market strategies and indication optimization, ahead of launching our wholly owned benefit. And we are investing to broaden the reach of our technology, ensuring our platform remains innovative and competitive.

We expect our R&D expenses to increase approximately 25% to 35% in 2021 compared to last year. And because most of our synergies are within SG&A, we expect our SG&A expenses to decrease. We can increase our investments, as I just described, while projecting a modest net loss this year because of our multiple sources of revenue and the significant cost savings we realized from acquiring Akcea and restructuring our European operation.

Our capital allocation strategy is focused on investing internally for growth. We strongly believe this is the best use of our capital. We are confident that investing in our medicines can grow future revenues at double-digit rates as we bring more and more new medicines to the market, and achieve our goal of 12 or more marketed products in 2026.

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

Thank you, Beth. We made important progress across our portfolio in 2020, including moving many of our wholly owned programs closer to markets. We're pleased with the performance of our Phase III assets with several key achievements last year. The Phase III studies of tominersen for Huntington's disease and tofersen for SOD1-ALS achieved full enrollment. We initiated Phase III studies with 2 of our rare wholly owned cardiometabolic disease programs, TTR-LRx for patients with TTR cardiomyopathy and APOCIII-LRx for patients with FCS. And importantly, all 6 of our Phase III studies continue to progress well.

We also made substantial progress with our mid-stage programs, including reporting positive data from 6 studies, initiating more than 10 new Phase II studies and expanding the reach of our technology by demonstrating our ability to safely deliver antisense medicines by aerosol to the lung. We are well positioned for a very busy year of catalysts, the first significant of which is the Phase III data for the VALOR study of tofersen in patients with SOD1-ALS. ALS is a disease, particularly of importance for us because antisense technology is ideally suited to address the root causes of ALS, we have leveraged our platform to develop medicines to treat all forms of this disease. Today, with 4 medicines in development, we believe we could truly have ALS surrounded. Tofersen has the potential to become the first disease-modifying treatment for ALS, which we believe will fundamentally change the ALS treatment landscape. Positive tofersen data would also give us greater confidence for our programs for the treatment of other forms of ALS. We believe tofersen may also have the potential to slow progression or even delay the onset of disease in presymptomatic SOD1-ALS patients, similar to the profound effects demonstrated by presymptomatic SMA patient treated with SPINRAZA before symptom onset. Biogen plans to initiate the ATLAS study this year to address this question, and hopefully demonstrate a similarly profound benefit for tofersen in presymptomatic ALS patients.

Our next ALS program to enter development is ION363 for the treatment of FUS-ALS, which we plan to move directly into a pivotal study shortly. FUS-ALS is a devastating, rapidly progressive form of ALS caused by mutations in the FUS gene. So we are pleased to be moving so rapidly to evaluate this medicine in patients with such a clear unmet medical need. And importantly, ION363 is Ionis' first wholly owned ALS medicine to enter the clinic. In addition to these exciting ALS catalysts, we have a busy agenda from programs across our wholly owned portfolio.

Coming up in the first half of this year, we look forward to multiple catalysts, including key data readouts and study initiations. We plan to report top line Phase II data from PKK-LRx and GHR-LRx for the treatments of HAE and acromegaly, respectively. We also plan to present more detailed data from our ENaC-2.5Rx and AGT-LRx programs at upcoming scientific meetings taking place in May.

At the American Thoracic Society meeting, we plan to present Phase II data for ENAC-2.5Rx in patients with cystic fibrosis. And at American College of Cardiology Conference, we plan to present Phase II data for AGT-LRx in patients with resistant hypertension. Each of these medicines has the potential to change the standard of care for these indications. Additionally, these medicines have the potential to address additional indications, representing further opportunities for growth.

Looking at upcoming study initiations, we are very close to starting a Phase II study for ION373 in patients with Alexander disease. Together with ION363 for patients with FUS-ALS, these programs represent significant advancement among our wholly owned neurological disease medicines. We plan to advance AGT-LRx into a larger Phase IIb study in resistant hypertension patients on 3 or more antihypertensive medications, a population representative of real-world patients. This study is expected to get underway soon. We also plan to study AGT-LRx in patients with heart failure in a Phase II study, expected to start midyear. And also in the first half, we look forward to advancing ION224, our wholly owned medicine targeting DGAT2 and our most advanced medicine in development for NASH into a Phase IIb study.

Looking to the second half of this year, we expect even more key value-driving events. We plan to further expand our pulmonary disease franchise based on a growing body of data supporting aerosol delivery and antisense medicines to the lung, in addition to continuing to advance our Phase II study in patients with COPD, we look forward to advancing our cystic fibrosis development program with the initiation of a larger Phase IIb study of ENaC-2.5Rx in cystic fibrosis patients not amenable to CFTR modulators. Biogen recently offered an early preview of our Alzheimer's disease program, noting that MAPTRx demonstrated durable time and dose-dependent reductions in CSF tau protein and was generally well tolerated in the Phase I/II study in Alzheimer's disease patients. With Biogen, we look forward to reporting these results later this year. And as I mentioned, we, of course, look forward to data from Phase III VALOR study of tofersen in patients with SOD1-ALS later in the second half.

In addition, in the first half of this year, we plan to host a series of disease-focused educational webinars, with invited experts who will discuss current treatment options and needs for patients with cystic fibrosis, hereditary angioedema and acromegaly. We look forward to hosting these webinars prior to top line data reports for each of these programs. Around the middle of the year, we plan to wrap up this series with an investor-focused webcast to talk specifically about data from these programs in the context of the unmet market need. Importantly, with our pipeline progress to date and our key anticipated data catalysts this year, we are well positioned for a steady cadence of Phase III data for years to come. These data support our goal of 12 or more medicines on the market in 2026, including potentially 6 or more wholly owned medicines.

And with that, I'll turn the call back over to Brett to close this portion of the call.

Thanks, Richard. This is an exciting time for Ionis as we expect to accelerate our next stage of growth and deliver a growing number of new transformational medicines to patients in need. We have the potential to bring 3 new medicines to market by 2023. And looking further ahead, we are well on our way to achieving our goal of 12 or more medicines on the market in 2026, over half from our wholly owned pipeline.

In support of our new vision to commercialize our wholly owned medicines, we're making significant investments to aggressively advance these programs forward. And also as part of our strategy as the wholly owned pipeline develops, we're setting our plans to determine the best path forward for each asset to maximize value to patients and to shareholders. And from across our entire pipeline, we look forward to a continuous flow of Phase III data readouts for many years to come.

In addition to investing in our wholly owned pipeline, we're investing in building our commercial capabilities and implementing our plans to commercialize our own medicines, advancing our technology and potentially expanding it with new technologies that complement our antisense platform. We believe these investments will provide substantial returns, including double-digit revenue growth. And this growth will be driven as successful Phase III programs enter the market, generating more value from the wholly owned programs we commercialize, and from those programs partnered today and those we retain longer before we partner in the future.

Before we close this portion of the call, I want to take a moment to recognize Rare Disease Day, which is being celebrated around the world this week. For many years, Ionis is dedicated and continues to dedicate substantial resources to serve patients suffering from rare diseases, such as SMA and ALS. We're proud to say that in the case of SMA, we, at Ionis, pioneered a new market and brought the first disease-modifying medicine to these patients, many of whom are with us today because of SPINRAZA. In the case of ALS, in just a few short months, we, again have the potential to deliver the first disease-modifying medicine to treat ALS. We're proud of these achievements, but we're only at the beginning. Of course, Rare Disease Day is about the patients and families living with rare diseases. Through our strong partnerships with these brave people, we're confident that we will continue to provide transformational medicines for more patients for many years to come. With that in mind, please join me in recognizing and celebrating dedication and accomplishments of the brave patients suffering from devastating rare diseases as well as the families who care for them.

And with that, I'll open the call for questions.

(Operator Instructions) And the first question comes from Yaron Werber with Cowen.

Really nice progress. Two questions. Beth, maybe just for your housekeeping and then a question more about the pipeline. Just on -- in terms of top line, your guidance for more than $600 million in revenues. Can you give us a little bit of a sense, how are you looking at SPINRAZA? Are you kind of expecting it to be kind of flattish in a growing segment? Or are you expecting a little growth? And I know collaborative revenues you mentioned are going to ramp more in the second half, but anything you can guide us there.

And then a quick question on the ENaC-2.5 technology, I mean, it sounds like we're going to get data shortly, the study is fully dosed to Phase IIa, and you're noting that you'll start a Phase IIb now, which is in CF this year. Can you just remind us are we mostly going to be looking at expression in the CF patients? Or are we going to be able to also look at some kind of a pulmonary function like FEV1 or is the study just too small, the Phase IIa?

Sure, Yaron. So thinking about our top line guidance for this year, when you think about the commercial revenue stream, really, the only impact to commercial revenue is the transition for TEGSEDI and WAYLIVRA from a product sales top line in Europe to royalty revenue in Europe. We continue to think that SPINRAZA has a very bright future, as I mentioned. We see the opportunity to continue to expand the numbers of patients on treatment, primarily outside of the United States. But I think the strong efficacy of SPINRAZA, that's been well-established in more than 11,000 patients for 7-plus years for many of those patients, really bodes well for SPINRAZA's future. And so we're not anticipating a negative impact at all on the top line with regard to SPINRAZA.

And then on R&D revenues, as we always do, we probablize the many, many milestone opportunities we have over the course of the year. And by doing that, we know that we have lots of opportunity to overachieve on our top line as the year progresses, and we achieve those milestone events and the payments that go with them. So starting here in February, we'd like to make sure that we have guidance that we can achieve. But consistently in the past, we have outperformed that guidance and we certainly have those opportunities this year as well.

Thanks, Beth. And to address your -- I'm sorry, was there a follow-up?

I was just going to ask Beth, just remind us if you don't mind, with Sobi, the royalty and milestone agreements and what you've disclosed? So it will make sure everybody gets it correct in the models.

Yes. Sure. We haven't disclosed the actual royalty percentage. But think about it in the general range of royalties associated with a drug that we share in many of the post-marketing activities. So we're -- continue to supply drug and handle the distribution. We continue to manage safety. We continue to be actively involved with KOLs and with setting the global strategy and working very closely with Sobi. So think about it really as a relationship in which we share in the opportunity for top line growth.

And then to address your question, Yaron, on ENaC. So as a reminder, last year, we demonstrated and presented data on demonstrating robust reductions of ENaC levels in the lung of normal volunteers following aerosol weekly delivery with excellent safety and tolerability. This year, at the ATS meeting in May, we plan to present our first data in patients with cystic fibrosis and in our Phase II study, which is complete now, and we'll share the results from that study.

In that study, indeed -- and because this is our first experience in patients, safety and tolerability will be very important to demonstrating and we're looking forward to sharing those results. In addition, as you said, it's a small study. It's also a short study. I think it's 3 months or so in duration. But we will be presenting data on lung function. And we're very much looking forward to sharing -- presenting that data at ATS this year. So stay tuned for that.

And then in addition, just as a reminder, ENaC is the first of several drugs moving into development for pulmonary diseases with -- delivered by aerosol. We're starting -- planning to start another clinical trial this year to coincide with the ENaC studies. And also the ENaC, we also have a Phase II study for ENaC and COPD that's ongoing. And then more coming behind the new clinical start this year. So we're very much looking forward to building this franchise out for pulmonary diseases.

The next question comes from Paul Matteis with Stifel.

This is Alex on for Paul. I was just curious about this new HFrEF program for the AGT product and what the rationale is for that mechanism of action and whether development there is pending anything in hypertension? Or if you plan to go in that direction regardless of how the hypertension program goes?

Richard, would you like to take that?

Sure. Happy to. So as you know, RAS inhibitors have been used in heart failure. And our preclinical work certainly points to a robust effect by targeting angiotensinogen in heart failure models. In addition to that, the idea here is certainly not a new one. But the design of the study in HFrEF patients allows us in a population where a lot is known about heart failure and the effects of RAS inhibitors as well as safety in that regard, will allow us to do a strong proof-of-concept study. It's powered to get us a bit more information, not only on biomarkers, but also on functional output. So we're excited about getting our first look in heart failure in humans with reduced -- with the reduced effect.

And as a reminder, Alex, again, we're planning to present much more detailed data, full data set from our Phase II study in patients with refractory hypertension at ACC in May.

The next question comes from Jim Birchenough with Wells Fargo.

Congrats on all the progress. Terrific stuff. Maybe on the financials and then a pipeline question. On the financials, just Beth, does the SPINRAZA royalty outlook contemplate some COVID recovery and less spacing out of intrathecal injections, just interesting how you're thinking about that? And then remind us if you're at the point with PTC where you've reached the sales threshold where you're participating in some of the upside from Latin America for TEGSEDI and WAYLIVRA?

Sure. Jim, so with SPINRAZA, I think we and Biogen certainly anticipate that the COVID environment is going to ease over the course of this year. And as Biogen noted in their year-end earnings call a few weeks ago, they're already seeing patients move back to SPINRAZA from competitive products, primarily because they're seeing the need for the efficacy that SPINRAZA affords. And so the fact that, that's already started in the fourth quarter, and we anticipate that to continue throughout this year and to be aided by the fact that the pandemic is starting to ease certainly in the U.S. and around the world as well.

For PTC, we were -- we hit that point where we started the clock on the 12 months. And so we would anticipate that we may be able to see some contribution from PTC sales in Latin America this year, but it will be late this year.

Great. That's helpful. And then maybe on the pipeline and for Richard, just on FUS1-ALS. Could you speak about the strength of supportive data, whether it's just the biologic rationale or any preclinical data and how that compares to the strength of support for SOD1-ALS? Just trying to get a sense of how validating one may be for the other.

And then second part is just on your chart of catalysts or milestones, Huntington's update in terms of natural history study and open-label extension is listed sometime in 2021. And so just maybe if you give us a sense of what you would expect to see in contrasting those 2 groups?

Yes. I'll give a high level, and then I'll pass it over to my colleague, Eric, to flesh it out a little bit. FUS-ALS, of course, is a monogenic form and hereditary form of ALS. And because there is a known causative genetic component here that we can directly target, we believe that the FUS-ALS compound, which we've shown is a very good drug for lowering FUS to FUS genetic component bodes well for us and allows us, in fact, with our conversations with regulatory to move directly into a study that is registrational. And I'll pass it over to Eric for any other comments.

Yes. Thanks, Richard. It's mostly right, FUS is a known genetic cause of ALS, much like SOD1 drive SOD1-ALS. It's known to be pathogenic protein, which accumulates and aggregates themselves. And so it's similar to tofersen and that we're reducing a genetic cause and reducing the pathogenic protein. And we do have preclinical data that supports that reducing FUS can provide a benefit. So I do think it's similar to the tofersen program in that regard.

And then I think you asked about Huntington and what Roche is planning to present. And I can just really refer you to their statements where they are continuing to plan to present some data from the open-label study in the natural history study at some point in 2021. And then beyond that, we're really focused on the Phase III study, which is progressing and scheduled for readout in 2022, which I think is the key definitive experiment for Huntington's disease.

The next question comes from Tyler Van Buren with Piper Sandler.

Just a couple of questions. On the financial side, you guys have been profitable over the last few years. So I guess based on the guidance, this would be the first year you guys would be turning a net loss. And obviously, that's justified by having -- pushing the wholly owned programs moving forward. But should we expect kind of a modest net loss like this for the foreseeable future in the next several years? Or will it continue to grow?

And then the second question on the pipeline is just related to the Phase II programs. We have a decent amount of clarity on the Phase III programs when we'll get those readouts, when they could reach the market. But I guess, as we look across the 2 -- or the 4 Phase II readouts over the course of the first half, which one of those do you think could make it to market first or which 1 or 2? And when might that be?

So thanks for the questions, Tyler. We have -- it's -- we're in an enviable position with a very strong balance sheet at Ionis to invest in all aspects of the pipeline and our commercial strategy and our technology to really maximize the value for Ionis, to grow Ionis, for the benefit of patients shareholders and the like. And that's exactly what we're doing now, as you know. And we're going to continue to do that, to maximize our upside in all possible ways. We're not really projecting right now what next year or the year after will look like, but we will continue to invest over the next few years. Of course, we also have the benefit of multiple sources of revenue as Beth will -- said in her presentation as well as she reminds us of all the time through R&D revenue, partnerships as well as our commercial revenue. And we expect our net commercial product to be tofersen. And TTR LICA polyneuropathy and Huntington. Potentially those 3 medicines reaching market in 2023. So you can see how the commercial revenue as well as the R&D revenue will really offset those investments in the future. Too early to project on profitability for 2022. But certainly, we're going to be continuing to invest. Beth, would you like to add anything to that?

No. I think that was extremely well said, Brett. Maybe the only thing I will add is that we have a long history of financial discipline, and we will continue to exercise that discipline while investing deeply in our wholly owned pipeline and our technology and really ensuring that our medicines are prepared and ready to successfully launch when they get to market.

And as far as your -- Tyler, your question on Phase II readouts, which we have a lot coming, in the first half of this year, we have 3 wholly owned rare disease programs, hereditary angioedema, acromegaly as well as the ENaC cystic fibrosis program. I think based on what we see as the next step for those programs and the size of the next studies that would require them, that would allow them to be registered and improved, I would have to say that the acromegaly program with me and Richard is the furthest along there pending positive data from the study that's going to read out this year -- this first half of this year. It's probably positioned well for -- to a pivotal study. Would you say, Richard?

Sure. And I would say that the -- after the Phase IIb for cystic fibrosis, there would be positioning for Phase III, but there's work to be done there. And then for PKK-L, you're also in a position depending on the results of this Phase II study. But if positive, that too could move relatively quickly.

Right.

The next question comes from Vincent Chen with Bernstein.

Maybe just one quick question. I was wondering now that you had a little more experience dosing RNA into the CNS, how do you think about likely dosing regimens for this? I noticed, for example, that the FUS-ALS program is dosed, I guess, after the initial loading dose every 2 months, which is kind of the -- I guess the midpoint of the doses you tried in Huntington's, and somewhat less frequent dosing than the SOD1 program. How do you think about the dosing required to treat CNS diseases?

Eric, do you want to?

Yes. Sure. I mean, we're always looking at extending our dosing regimen and making them consistent with the duration of action of the drug. And so in our earlier programs, we're working out how to dose the CNS and learning how to get those drugs delivered in a way that they could reduce their targets, understanding those relationships. And as we learn more and more, we're understanding how to extend the dosing regimen. So I would look for continued expansion and extension of our dosing regimens in the clinic. It's a key objective. And we think the profile of the drug supports it, and we're working across all of our clinical programs to try and understand how we can best extend dosing because, obviously, extended dosing is much more convenient for patients. An example of that would be in the Huntington program where we work with Roche to get the every 4-month dosing into the Phase III program, that's ongoing and scheduled to read out in 2022. So we think that's a good benefit, and we can transfer that and hopefully extend it across more programs.

And if I could just add to that -- if I can just add to that really quickly, Vince. Our strategy to enhance durability and reduced dosing frequency is coming in 2 forms, right? We're learning how to select molecules more optimally that allows us to have a longer duration of effect. And also through medicinal chemistry, new chemistries that are coming down the pipe. And then the last thing I would mention is, as we and Biogen have said, we have demonstrated very durable reductions in tau. In our study with MAPT in patients with mild Alzheimer's disease. And that data will be presented this year. And I think it's going to be very telling how durable that is, the effects we're seeing in that molecule.

Have you gained any insight into -- I guess, using the Huntington's data, where you do now have some patients who have been treated on every 4-month dosing. And I guess, the open-label extension of the initial GENERATION HD1 patients. Have you gained incremental sort of PK/PD insights into sort of what -- I guess, feasibility of longer dosing? And is there a reason why FUS is dosed more frequently then I guess what you're doing in Huntington's? Does that matter? For example, are you trying to -- does it matter from knocking down further? Just kind of curious what the thinking is there.

Well, for some of the diseases like ALS, they're very aggressive diseases. And so you want to get enough drug onboard quickly to make a difference and reduce the protein quickly because the patients are progressing fairly rapidly, and so that's been some of the thinking in ALS. Huntington is a much slower progressing disease. And so you can take some time to get the drug to steady state and get the -- and dial in the level of target reduction that we want. And I really think that some of it is a matter of, as you say, understanding the PK/PD of the drug, and it takes time and some good human clinical experimentation to get that and really understand how our drugs are working in the CNS of humans as opposed to preclinical species. And so in addition to what Brett said, in terms of optimizing chemistries and understanding how to design the drugs, there's also just optimizing our dosing regimen and understanding how our existing drugs work. And that's what we did along with Roche in some of the hunting experiments that led us to an extended interval.

The next question comes from Joel Beatty with Citi.

Congrats on the progress. Could you tell us more about the Phase II trial that's ongoing for ENaC and COPD? And I mean the first part of that question is, when could we see data from that trial? And then the second part is, how predictive is your cystic fibrosis clinical data in predicting efficacy for COPD?

Richard, (inaudible).

Yes. So with our Phase I, Phase IIa experience with the ENaC molecule, we were able to look at a broad spectrum of genetic modifications. And that led us to move into COPD because in addition to the ENaC target gene going down, we saw other important genes. I don't think we've disclosed at this point, but there will be more information coming out. In regard to what else we saw in that early work that led us to move fairly rapidly into a COPD trial. COPD trial likely reporting out, I don't know what we've put out publicly, probably early next year as well as the Phase IIb also would be next year, 2022.

And Joel, that's a study in COPD patients, nearly 200 patients for a little over 3 months or so of treatment, which the primary change would be FEV1. So we'll be looking at real clinical function outcomes in that COPD study.

Yes. And just to add that if you think about ENaC inhibition as a way to rehydrate the lung. And so there's a strong rationale for using it in COPD, just like in cystic fibrosis because you can restore the hydration balance by inhibiting ENaC.

Next question comes from Yale Jen with Laidlaw & Company.

Congrats on the progress. My first question is that in terms of R&D revenue sort of anticipation for the 2021. Are you guys not including any possible partnership, and that's why you have the current projection? Or that's part of things already sort of included?

Yale, sorry, could you repeat your question? I didn't quite hear you.

For the R&D revenue of 2021, are you guys not including any revenues from potential new partners? Or just -- and that's what the current estimate to be?

Great question. So I want to reiterate that our top line guidance really reflects the new strategy to hold on to our drugs longer, partner -- if we do partner later in development and to really advance broad pipeline of wholly owned medicines to the market, primarily in neuro and cardio. So really, as we think about our R&D revenue, it's based off of amortization from prior upfronts and milestones as well as a whole host of potential milestones and licensing fees across our current partnered programs in drugs and later stage research programs.

Okay. That's very helpful. Maybe just one question for Brett, which is that you mentioned that you're also contemplating potentially new technology to complement the current technology you have. What's likely to be an ideal technology that may be [sitting] into the build?

So thanks, Yale. Think about the technology investments that we're making in 2 way or in 2 buckets, if you will. The first, our technologies or investments in technology that expand the reach of our current technology, antisense. So new chemistries, new LICA chemistries, that open up new tissues like muscle, cardiac tissue, immune cells, cancer cells. We're working on that with both -- with partners as well as heavy investments internally. New routes of delivery is another example of that to expand the scope of our technology like we do with pulmonary and before that intrathecal, and we're doing more. Genomics is 1/3 where everybody knows, genomically-linked targets are the best targets from a validation standpoint prior to you validating a target with the drug. And we're investing in that. We have lots of hits. We have a lot of genomic targets that we're very excited about that are very novel. And these are through partnerships as well as work we're doing with our functional genomics group internally. That's bucket one.

Bucket two is what I think you were really asking about, which is new platforms, new complementary technologies outside of antisense. And I really can't provide much detail there, except that we are investing in reviewing and conducting proof-of-concept studies and doing work in various areas to do things, to invest in technologies that can do things maybe more more effectively, more efficiently that antisense is -- has less success in doing. So technologies, for example, that can more effectively upregulate the expression of change. Of course, we can do that with our technology. SPINRAZA's the perfect example of that. But it's less robust to be able to do that. And technologies that do that will help us complement the things we can do to expand our reach for antisense. And that's a little further out, but we're working on it. And we're working on it very seriously, so stay tuned.

The next question comes from Luca Issi with RBC.

Congrats on the progress. I have 2, one on HAE and one on AGT. So on HAE, I think there was some interesting back and forth on the editorial of the New England Journal of Medicine a couple of weeks ago, where essentially, the debate was around inhibiting liver PKK versus inhibiting plasma kallikrein, which is what Takhzyro is doing and whether maybe knocking down liver PKK is less preferable than what Takhzyro is doing. So wondering if you have any thoughts on that and maybe bigger picture, if you can offer any color on how should we think about the upcoming Phase II data?

And then on AGT. I know you have 2 molecules in development at this point. Wondering if you can comment on how you're thinking about the relative prioritizations of one versus the other, given, again, one is already in Phase II versus the other just enter Phase I in healthy volunteer. So any color there would be helpful.

Thanks, Luca. Maybe I'll take a stab at the HAE question. Richard can fill in and then take the AGT question, the 2 molecules. So by far, the vast majority of kallikrein is derived from the hepatocyte, the liver, whether it's in the plasma or what's elsewhere or what's in tissues. We are blocking prekallikrein with our mechanism of action that essentially prevents the production of prekallikrein into the plasma as well as the metabolite of prekallikrein, kallikrein, the active molecule that leads to bradykinin production and hereditary angioedema attacks. So we're doing -- we're actually -- we feel that our mechanism, our approach is superior to an approach targeting kallikrein because we prevent the module from ever being made. We don't have to mop it up after it's been made. And we think that this is the -- potentially a superior approach to prophylactic treatment of hereditary angioedema. And we're really looking forward. The New England Journal data you referred to is very encouraging, and we look forward to presenting that Phase II data in this first half of this year.

Richard if you want to add to that, please do or jump into AGT.

No, I think you covered that nicely. So I'll jump into AGT for just a minute. We have 2 molecules, one that is a Phase IIb ready and one that is not yet in the clinic or its just started in the clinic, I should say, our Phase I study for ION904 has started. And so we're moving forward with the 2.5 LICA now. A thing to remember is that the 2.5 LICA is a, based on all of our preclinical data, significantly higher potency molecule. So we think of it in 2 ways. First, in heart failure, it would be highly perhaps beneficial to have a molecule that we can administer very infrequently with a subQ approach. And in addition to that, the 2.5 LICA gives us a potential for oral. So it's really a play on really moving into a best -- first and best-in-class for that indication. And so we're moving that one forward quickly, and we'll have data along the way in the Phase I trial to be able to read out exactly what that potency looks like in that potency and duration of action. So look for that.

The next question comes from Jessica Fye with JPMorgan.

This is Daniel for Jessica Fye. Focusing on near-term readout in acromegaly, given that growth hormone receptors are found in multiple tissues throughout the body, do you see a risk in targeting a liver-specific growth hormone receptor expression alone with your LICA product? And then when it reads out, what should we expect with the top line data?

So...

I can take that.

Okay. Go ahead.

Yes. Thank you, Daniel. So first of all, yes, we are targeting liver, where the majority of the receptor, at least, systemically lies. And so the initial is in addition to somatostatin analogs, which have already gathered up inhibition of majority of the receptors. And now what we're doing is significantly reducing the activity in the liver. Again, I think wait for the data, but the top line data is going to be IGF-1. And we'll be looking at also a -- probably not top line, but later, we'll be able to report out all of the information on quality of life, where we're seeing some exciting kind of results. So I think that's the what you're going to be able to see as we move forward and why we think liver targeting is likely to be not only additive, but potentially even as a single agent. We've started our single agent study now.

Yes. And I'd just add to that, the liver is also the primary source of IGF-1, in addition to the growth hormone receptors in hepatocytes, which, of course, drives this disease. And what we're hoping to show is that patients who are poorly controlled on somatostatin analogs, that we can get a fair number of those patients, a good number of those patients under control. It's a normal of [analogs]. And that's what we're hoping to do. And we think this mechanism has the potential to do that. So we're looking forward to sharing those results.

The next question comes from Mani Foroohar with SVB Leerink.

We'll start with a specific one and then go on to a more general one. There's been a little discussion about the HAE opportunity on this call. Can you give any more detail on where you see the opportunities at commercially and clinically, in terms of frequency of administration, depth of attack reduction, where you see that opportunity and how that would translate into a clinical trial design that can generate a label that could support the success in a pretty competitive market?

And then the second question more broadly, there's a lot of discussion around oligo therapeutics outside of the liver, expanding into other other areas of therapy, mostly by your competing companies who seem to be unaware of SPINRAZA, success in CRS. As you think about producing data of effective knockdown and therapy in lung and other indications, how should we think of other target tissues? How should we think about the tempo with which that could translate into an acceleration on the R&D partnership side as you sort of expand out the aperture of potential target tissues that you could find -- in which you could find partnerships?

So thanks, Mani. Great questions. So I'd like Onaiza, who is on the call, who hasn't had a chance to speak up, to talk about the opportunity that we see in HAE. As you say, it's -- there are drugs out there already that are treating this disease. But we think we like the potential of our current molecule. But I'd like Onaiza to maybe speak to this.

Sure. I'd be happy to. Mani, so as I think it's already been said, but I think it's worth reiterating is that we're really looking at a treatment that's designed to prevent attacks rather than simply kind of treat acute episodes on demand, right? And we expect an improved tolerability profile in existing therapies as well. I think the name of the game over here in this marketplace has really been about 0 attacks. And as you said, Takhzyro has done a nice job as they've entered the market with that. What we see as a continued opportunity from an efficacy perspective is the durability of response. We know that initially, you can get down to 0 attacks, but can you actually maintain the 0 attacks over time. And we really believe that the PKK, again, the mechanism and what's already been described on the call will help us achieve that. And of course, we'll see that as the Phase II data comes out. But that is really where the positioning competitively of the product will be. And then, of course, we know that the current treatments on the marketplace have a more viscous, difficult to inject profile as well, and we'll certainly beat that profile as well. So that's the way we're looking at it.

And so we're excited. We think our PKK LICA molecule has the potential to be the best in the class. We have to prove it, of course, with respect to reduction in attack rates. But we shall see. We're certainly getting great reductions in PKK, which is the cause of this disease. I mean bradykinin is, but PKK is the promoter of bradykinin levels.

Regarding other target tissues, Mani, there are a lot of questions in your question. So let me take a stab at it. And if I don't get it right, I would just follow-up. But yes, our CNS platform, we've just begun to scratch the service of new molecules, new drugs for devastating neurodegenerative diseases that are coming into our pipeline. Our pipelines are already very rich, and it's going to get richer with more and more neuro drugs as we continue to validate the platform showing again and again robust reductions in target in CSF as we're doing again this year with tau program. As we've done in the past with Huntington and SOD1 and SPINRAZA, and more is coming. And as Eric referred to earlier, we're continuing to optimize delivery to the CNS with less frequent dosing, and we continue to move forward with new molecules to do that.

Lung is a potential new franchise. We're very excited about this. Years ago, we've had a long program, and we showed we had evidence of activity, but it wasn't good enough. And we went back to the lab and develop new chemistries. Gen 2.5, which seems to be getting it done. We're getting great target engagement, excellent safety and tolerability, and that's a new franchise that we're very excited about opening up new organs and tissues.

And then with respect to -- outside of new routes of delivery, we're continuing to look at routes of delivery all the time. But outside of that are new chemistries to open up the new organ systems and tissues. And we believe that we will be in development this year for a muscle LICA program. That's our plan, that's our goal. And we can't provide more details on that at this time, but that's just one of several that we think are going to be coming for targeting muscle. And not just skeletal muscle, but also heart failure, cardiac tissue. And we're very encouraged by what -- the work we've done so far, the data we've generated. And more are coming, too. And we've also talked about our pancreatic data cell program. We've done work with AstraZeneca, we're doing our work ourselves. And we have other LICAs coming for new cell types and tissues that we're very encouraged by the data we've generated so far.

And with respect to partnerships, I'm not sure if you meant bringing -- partnering, out-licensing or in licensing, but I'll assume you mean in-licensing, we've already established partnerships in -- with companies and investing our capital to broaden our scope in LICA chemistries. And we're planning -- hoping to do more of that, so that we're going to take advantage of partnerships to expand our LICA platform to complement all the great work we're doing here at Ionis under our roof in our medicinal chemistry program. I hope that answered your question.

Yes, that's helpful. One of the -- I think what I was thinking about is if you look at consensus estimates looking out forward, they don't contemplate acceleration in your R&D revenue from expansion into a broader universe of out-licensing opportunities for you? I was thinking should we think about other opportunities, should you prove out delivery in lung, delivery in muscle, serially other -- in other tissue types. Should we thinking -- should we think about this changing the top line sort of CAGR as it were of growth of R&D? Should we think of this as more of a step function as one of your smaller RNAi competitors who've discussed it? Just how do you think about the size and the speed of which you guys could capitalize on potential expansion in R&D revenue if you're attacking different tissue types?

I think that was more of my question.

Sure. Well, expanding the scope of the platform, certainly, will drive even more interest by other companies wanting to partner with us to take advantage of all the great progress we're making. I mean we -- there's so much interest already in what we're doing today. And then there's also tremendous interest in working with us to develop these technologies. We're working with AstraZeneca on new chemistries and new routes of delivery, and we're working with Biogen on new chemistries to maximize delivery to muscle as well as CNS. And there'll certainly be interest as we expand its scope by other companies that will want to take advantage of this in the future. And sure, we'll be doing more partnerships in the future.

But as we emphasized in the -- earlier in the call today, we will be very selective in the partnerships we do. They -- not just for the R&D revenue that you referred to, although that's nice, it's really to bring strategic value to the company, to really expand the scope of our technology and to really strengthen our leadership position in this space. So I do think that partnerships based on advancements we're making in the technology that you referred to are likely in the future. I also think that partnerships for some of the broader indications that we're working on are possible, too, even without those, within the existing pipeline. So lots of potential for partnerships down the road, lots of interest. And we will be selective and will not just do partnerships for the sake of financial return, but also for strategic value.

The next question comes from Jason Gerberry with Bank of America.

This is Chi on for Jason. I guess the first one on Huntington. Can you outline some of the things you'll be looking at with your natural history cohort and open-label data that you're going to be presenting sometime this year? What can get you comfortable in ability to show improvement on functional endpoints in Phase III ultimately? Curious how important is it to see your [matching natural history cohort] is deteriorating over a 15-month observation period?

I guess the second question on HAE. Just to confirm, to generate competitive data and to compete in the space, is the thought that you will need to generate longer-term follow-up data beyond the typical 6-month trial to prove better maintenance of attack reduction benefit?

Eric, would you like to talk about the Huntington [OLE], and I'll take the HAE.

Yes. So we touched on this a little bit earlier on the call. And again, Roche has stated that sometime this year, they're going to discuss some data from the OLE and natural history studies. And you'll see what they present and beyond that, I really can't comment. But I do think that the key endpoint and the key thing to focus on is the ongoing Phase III that's scheduled to read out in 2022. Huntington is a slowly progressing disease, and the study is powered to give the drug the time to lower mutant Huntington, which we know it does and have a disease benefit and really test the hypothesis that lowering mutant Huntington will make a disease benefit. So that to me is the key experiment.

And regarding the HAE question, the Phase II study, as we've said, we'll read out and we'll present top line data, at least, the first half of this year in patients with hereditary angioedema. We're looking at frequency of attack rates in over about a 3-month period of time. There's a wealth of data published with existing therapies on attack rates that we will compare to. We'll look at it and we'll ask -- we'll answer -- ask ourselves whether or not we're competing, we're competitive or potentially even superior in attacking -- in reducing attack rates. And based on the data, we have to read the data, we'll decide on the next steps. We, obviously, have already various options in place based on the data outcome. But I would not rule out this program, as Richard referred -- mentioned earlier to move to a pivotal study based on the Phase II data that comes out first half of this year. We have to look at the data, and then we have to decide what the best Phase III strategy would be.

One other piece of information to add to that, Brett, is that we have moved all eligible patients into an open-label extension that allows us to continue to monitor attack rates on the long term. So we have an open-label extension for the Phase II program that is ongoing, has already started. Many of these patients have been in the open-label extension for many months. And so that is where we're going to get long-term data very quickly.

Yes. And I will just add to the need, I think you said beyond 6 months. So if you take a look at the real-world data and how patients are doing currently, you start seeing excursions from their therapies as early as 3 months and then more substantial declines between that 3 to 6-month period. So we don't think that we would need data well beyond that period to demonstrate it.

The next question comes from Salveen Richter with Goldman Sachs.

This is Sonya on for Salveen. A few quick questions from us. I was wondering, could you give us the status on your Prion disease asset and when you can expect data there? I think there was going to be a trial initiation sometime mid-year? And then also on the muscle LICA, if you could give us some color on what indications you would potentially go into? That would be really helpful.

Eric, would you like to run with that?

So I'll start with muscle LICA. We're not really prepared to discuss exactly what indications we're going into at this time on the muscle program. But we're very, very excited about what we're doing in terms of being able to target the muscle, and there's lots of opportunities there -- in there across various spaces of neuromuscular disease. And as for the Prion program, I can't provide too much color on timing, but we are -- have identified several candidate molecules and working as hard as we can to rapidly get the best candidate forward and move it to patients.

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

Well, thank you, everybody, for joining us on today's call, and thank you for all the questions in the Q&A session. Obviously, here at Ionis, we're very excited about the future -- the present and the future of the company. And we look forward -- very much looking forward to providing additional updates on the progress -- the great progress we're making in Ionis throughout the remainder of the year. So thank you again for joining, and have a great day.

This concludes our conference. Thank you for attending today's presentation. You may now disconnect.