Q4 2019 Earnings Call
We achieved our primary goal is advancing for medicines at the pastry studies. We achieve positive clinical proof-of-concept results for five minutes. We Advanced five new medicines in the phase one month and we Advanced ten new medicines into development six of which are I own is owned.
Also last year we can.
Can you to advance and broaden the scope of our technology in addition to moving two of our life programs and two-faced research studies? We demonstrated a clinical proof-of-concept for for new like medicines for applications that represent vote fraud and rare patient populations further supporting the potential to expand our technology to be on rare diseases and we advance to new life has changed to developing growing are like a pipeline to sixteen medicines overall.
Additionally, we initiated clinical proof-of-concept studies to evaluate our progress and optimizing oral and aerosol delivery with the initial results expected later this year.
And of course we positive results from these studies are technology could benefit greatly by expanding the scope of our drug Discovery platform substantially.
Today I am this is stronger than ever. Our pipeline of over forty Madison's is Broad deep maturing and growing with multiple programs nearing key value inflection points in this year. We are priority areas of the business that we believe have the greatest potential to create value short-term and long-term for patients and shareholders. For example, we're advancing our technology by asking if I knew like this and further optimizing the additional routes of drug administration's enhance the overall profile of our innocence platform, and we're identifying novel drug targets to continue publishing our Pipeline with Innovative medicines as later stage programs reach commercialisation.
By the end of this year. We also plan to have six phase three studies underway.
Report clinical proof-of-concept results for six or more medicines with two already achieved this year initiate 10 or more new phase two studies in advance at least five new medicines into developing a including several new and exciting ionies owns patents.
Together and he's achieved its position as well to reach our goal of 10 or more new drug applications through 2025.
Additionally this year we're prioritizing the growth and advancement of our ionis own pipeline further developing our commercial strategies and capabilities to ensure we maximize the value of each of our messages as part of this initiative. We recently appointed on a z category and the guy on his leadership team as our chief corporate development and commercialization officer were thrilled to have an age team with extensive experience in building and executing on corporate business and Commercial strategy or leadership will be invaluable as our pipeline advances forward.
a moment Bethel review
Nineteen Financial results in 2020 guidance and ritual recap our latest pipeline achievements and plan 2020 catalysts and I'll close out the call and moderate some questions.
So now I'll turn the call over to a nasal who provide some additional insight into her new role at ionis. Thank you Brett and good morning everyone. I'm quite excited to join ionies at this Transformer time for the company as friends said we are in a unique position of strength. We have an expansive deep and advancing Pipeline with a growing number of late-stage medicines. Our technology is brought applicable enabling us to bring novel medicines to patients and most importantly we have a strong experience team who operate with scientific rigor and Innovative mindset, and I'm very committed to delivering transformational medicines to patients with severe unmet needs. I am excited to assume leadership of the companies corporate development in commercial efforts. Our goal is to maximize the value of each medicine a pipeline remains unchanged.
Looking ahead. We plan to pursue this goal by identifying the optimal commercial strategy pathway and organization.
For each of our medicines while preserving our established culture of scientific innovation.
We plan to develop our commercial capabilities allowing us to bring medicines from our growing his own pipeline to patients in parallels. We will continue to establish strategic Partnerships to develop and commercialize those medicine with the potential to address diseases with the largest patient populations such as our most recent collaboration with visor for Andrew. And like three like, we also look forward to continue to support Axia as they pursue their strategic goals and through the potential addition of a new medicine to the Axia pipeline later this year. I look forward to updating you on a commercial strategy as I am. And with that I'll turn the call over to them. Thank you and Nissa 2019 was an exceptional year including financially we significantly exceeded our 2019 Financial guidance driven by revenue of more than one point 1 billion dollars nearly double compared to 2018.
We learned over 350.
Two million dollars in commercial revenue and over $770 million dollars in R&D Revenue, including nearly four hundred million dollars for licensing lrx off and and you please like three wrecks. Our revenues resulted in substantial non-gaap operating income and net income of over $510 off over four hundred million dollars respectively. We also achieved substantial operating income and net income on a gaap basis.
We achieved these exceptional results will further strengthening our balance sheet. We increased our cash balance to two point five billion dollars and we refinanced a significant portion of our convertible debt, which enabled us to extend the maturity for most of our debt to 2024 a cheese a 1% interest rate, which reduced our annual cash interest expense by approximately 40% and significantly increase our effective conversion price, which may reduce future dilution.
over the last
Several months. We also return value to shareholders by repurchasing two million shares of our common stock through a stock repurchase program. We implemented late last year.
The refinancing of our dad and our share repurchase program underscore the confidence we have in the future of the company and our commitment to creating near and longer-term value for shareholders because of our significant financial resources. We were able to execute these transactions while continuing to invest aggressively across our business.
Now turning to our commercial revenue spinraza generated over $2 billion dollars in worldwide net sales in 2019 resulting in nearly $300,000 in royalty Revenue Toyotas an increase of more than 20% compared to 2018 at the end of last year. There were more than 10,000 patients on spinraza treatment world wide variety and achieve this important Milestone through growth from adult as many patients in the US and growth from both existing and newly-launched markets outside the US.
with the approximate
At least 45,000 addressable patients in Market Square by Jen has a direct presence. We invite and see significant opportunity for growth.
We achieved steady quarter-over-quarter growth throughout 2019 resulting in product sales from Texas City. And we live rep of forty-two million dollars for the year today takes Thursday is commercially available in more than ten countries in the we achieved growth in new prescribing Physicians and patients starts and of particular note in the fourth quarter. We saw fifty-two percent increase in new prescribing Physicians. We continue to see a mix of cardiologists neurologist and hematologists in both the academic and Community settings.
Additionally actually is Market access effort to continue to translate into broad TechCity coverage for patients in the US for not only today but also longer term life outside the US has focused on reimbursement as they prepared to expand into additional countries this year in Latin America and Therapeutics is launching takes anything Raziel and is working to provide access to text Eddie in additional Latin American countries.
We live ra is now on the market in Germany with patients benefiting from the only medicine approved for the treatment of this devastating disease in France. Axia is interesting patients in an 80 you a reimbursed Early Access program additional exe of plans to launch in new EU countries this year with these PTC Therapeutics is working to provide access to we live right across Latin America beginning in Brazil this year assuming approval.
In the We are continuing to work with the FDA with the goal of refiling this year.
Through his efforts. We have a strong foundation for both commercial products that we believe can support expansion into into new markets this year.
Our 2019 Revenue more than doubled to $770 with significant increases in license fees Milestone payments and amortization from home.
Is it?
This growth demonstrates the substantial value of our Pipeline and Technology our R&D Revenue consisted primarily of four hundred ninety million dollars in licensing Revenue, including nearly four hundred million dollars from licensing and you like three r x + x + 115 million + Milestone not including nearly $85 billion dollars for advancing numerous medicines within our neurological disease franchise, including ionis-httrx ionies map and several new programs under our bias in collaboration.
We also recognize nearly twenty-five million dollars for advancing several programs from our cardio metabolic franchise, including our Factor eleven program with their and our medicine for patients with faith with the AstraZeneca our 2019 non-gaap operating expenses increased to six hundred ten million dollars compared to 2018 driven by investments in our paper and Technology consistent with our stated objectives. We also made strategic investments in Technologies. We Believe can expand the reach of our anti since technology and money in developing our commercial capabilities. We continue to be in an enviable position of financial strength this year. We expect to be meaningfully profitable while continuing to invest aggressively in our strategic priorities. The ability to earn revenue from multiple sources is a key element of our financial strength.
We expect growth.
And Commercial revenues driven by continued strong spinraza performance and growing revenue from take City. And we live as we expand into new countries. We also expect to achieve important Milestones is the advanced our medicines in development with these multiple sources of revenue. We project earning more than seven hundred million dollars in revenues this year.
We are projecting 2029 gaap operating expenses of $650 to $690 the increase in our projected operating expenses compared with last year is attributable to Investments. We are making in our ionies owned pipeline these Investments include conducting the ongoing phase 3 program for x e n t t are like o r s and initiating a phase 3 study of x3. And SES patients this year. We also expect to advance our mid-stage pipeline together these Investments support our goal of 10 or more nda's through 2025.
Build the commercial infrastructure necessary to to support takes Eddie's expansion into new countries ahead of those launches because of that. We have the necessary team in place to expand pick said the US and outside the US this means we do not need to increase our sg&a expenses to Support Tech said, he's commercial growth. Additionally. We anticipate them being valuable synergies between takes Eddie and we live rep as we launched both medicine in additional countries throughout the year for these reasons. We are projecting to keep sg&a expenses comprable to our 2019 level will growing take City and we live our revenues.
With two point five billion dollars in cash at the end of 2019. We have the financial strength to fully execute on our strategic priorities.
And with that, I'll turn the call over to Richard to provide an update on our pipeline. Thank you Beth as Brett mentioned 2019 was a year full of important achievements. We made significant progress with our rapidly-growing neurological disease franchise, for example, ionis-httrx for people with Huntington's disease and topher's in for people with side one month entered phase three studies last year and are progressing on schedule. We recently completed enrollment in our Phase 2 proof-of-concept study of iona's map TRX patience with early Alzheimer's disease several months ahead of schedule.
my engine is
Press their enthusiasm for this program as an important part of their already. Robust Alzheimer's disease Pipeline. And in fact late last year Biogen licensed ionies map TRX wage significantly earlier than anticipated supported by encouraging blinded interim data from the ongoing study. Additionally Biogen recently initiated a study of Art and targeting Lark two most common genetic cause of Parkinson's disease. This is an exciting study with which includes patients with both familial Parkinson's associated with locked in a patient's as well as patients with the sporadic form of the disease together these populations represent over 3 million patients worldwide. Also met her this year. We and Biogen Advanced our program for the treatment of the Angelman syndrome into development.
We're particularly excited with the progress. We're making with our pipeline of iona's own medicines.
Dressing neurological diseases patient enrollment is now underway and our phase 3 nirodh TTR transform study of x c o t t o r l or acts in patients with Terry t e r amyloid polyneuropathy.
All right on a cellphone medicine for the treatment of Alexander disease was recently granted orphan drugs. The status by the recognizing the significant need for therapeutic options for patients with this devastating and fatal genetic disease. We also added several additional ionies own neurological disease medicines into development last year's including treatments for lavora and prion disease turning to the recent advancements in our cardio metabolic franchise enrollment is now underway and the Horizon Faith cardiovascular outcomes study for Napleton lrx in patients with established cardiovascular disease and elevated LT with les
We're pleased with how rapidly Novartis advanced.
Axia April a r l r x into phase three development and importantly this medicine is one of our for medicines to advance into phase three last year helping us achieve one of our key corporate objectives at the beginning of this year. We initiated our phase 3 cardio to transform outcome study of x c o t t r l r x in patients with wild-type and hereditary forms of TTR cardiomyopathy. We also reported positive top-line results from Phase 2 proof-of-concept studies for 3 l r x x and your point like 3 l r s
Both medicines achieved their primary endpoint demonstrating robust, triglyceride-lowering and substantial reductions in additional key cardiovascular risk factors with favorable safety and operability profiles think it's worth noting that are cardio metabolic pipeline includes eleven like us to date and we now have data from over 1,100 people treated with like a medicines today including a substantial number of patients treated with like us for one year.
with
16 like us now in development in multiple therapeutic areas, including two and phase three outcome studies. We have substantial evidence that are like a technology characterized by greatly increasing public see and improved dosing regimens represents a real game-changer for our technology.
Finally we Advanced several ionies Island rare disease medicines into phase two development last year including ionies. Ghr lrx for the treatment of acromegaly wage. I only speak klrx for the treatment of hereditary angioedema, and I honestly 2.5 RX are aerosol delivered medicine for Cystic Fibrosis fibrosis and potentially additional pulmonary diseases. All of these programs are on track to report results later this year.
So as you can see, we expect numerous catalysts throughout this year. We expect to have six phase three studies in progress including a plan phase 3 6 x in patients with FCS. We expect to report clinical proof-of-concept studies for oral delivery of one of our anti cents medicines in cardiovascular disease, and we expect results from multiple phase two studies. We also plan to Advanced numerous new programs into mid in early-stage clinical development and to add many new ionies island and partner programs into our pipeline these catalysts together with are broadening and advancing technology position as well. As of his have said to achieve our goal of 10 or more and marketing applications through 2025.
we
Continue to keep you updated on the mini pipeline Catalyst. We expect this year as our medicine continued to advance and development. And with that. I'll turn the call back over to Brad to close off portion of the call. Thanks Richard before we end today. I'd like to remind everyone that this Saturday February twenty nine is rare disease day and in recognition of this important day, please join me in thanking the patients families and Advocates who have been our partners in developing that is seems to transform the lives of patients indeed. I'd like to invite everyone to follow on us on Twitter and Linkedin to learn more about how I onus is Raising awareness for the millions of people worldwide living with a broad range of diseases including thousands of identified rare diseases most often without adequate treatment options.
Today, we're at a unique place in the history of ionis. Our pipeline has broader and more mature than ever before but numerous programs nearly key value inflection points this year. We plan to use our financial strength to invest aggressively in all areas that have the greatest potential to create value for patients and shareholders including growing and advancing our ionies own pipeline further developing our commercial strategies and capabilities to ensure we maximize the value of each of our medicines expanding the reach of our technology by for example, optimizing different routes of Drug Administration and discovering New Life Strategies.
And identifying an increasing.
Investments in complementary technologies that will also expand the reach of our anti sense platform and with that like now to to now open the call for Q&A.
We will now begin the question-and-answer session to ask a question. You may press * then one on your telephone keypad. If you're using a speaker phone, please pick up your handset before pressing the keys off to withdraw your question, please press * then two at this time. We will pause momentarily to assemble our roster.
Our first question comes from Jason gerberry with Bank of America, please go ahead. Oh, hey, thanks for taking my questions. I guess just on edge like three. I was hoping have you guys had a chance to discuss the recent data with Pfizer any commentary that you can provide on that program and and and how your life you're thinking about the profile relative to some recent interim data from from Arrowhead. Second question is just on Huntington's ahead of Tomorrow some days extension data from the the earlier study if you can set the table for for for what we could expect and the importance of those updates just in terms of understanding the broader safety profile of HTT am so
No, thanks for the question. So starting with Andrew like three years, you know, we've partnered that program prior to the unblinding of the face of data last year and Thursday. We and Pfizer we're thrilled with the outcome The Phase 2 results in that study. We achieved our primary endpoints very very high statistical significance a number of secondary endpoints competing this drug very well for later-stage development. And certainly I own is and Axia and Pfizer have gone through the data are continuing to go through the the data in quite quite extensive detail and and forging a path forward next steps for this for this medicine at a later stage development and we place and and uh sharing this data in detail and the second half of this year at a medical meeting to be determined but short short to say we're very exciting job.
Unknown Executive: BF-WATCH TV 2021 Good day, and welcome to the Ionis Pharmaceuticals Q4 and full year 2019 financial results conference call. All participants will be in listen-only mode.
Unknown Executive: Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then 1 on your telephone keypad.
Unknown Executive: To withdraw your question, please press star then 2. Please note this event is being recorded. I would now like to turn the conference over to Wade Walke, Vice President, Investor Relations. Please go ahead.
Wade Walke: Thank you, Sarah. Before we begin, I encourage everyone to go to the investor section of the Ionis website to find the press release and related financial tables, including the reconciliation of the GAAP to non-GAAP financial measures that we will discuss today on the call. We believe non-GAAP financial results better represent the economics of our business and how we manage our business. We have also posted slides on our website that accompany our discussion today. With me on today's call are Brett Monia, Chief Executive Officer; Onaiza Cadoret, Chief Corporate Development and Commercial Officer; Beth Haugen, our Chief Financial Officer; and Richard Geary, Senior Vice President of Development.
Is Pfizer an ex-cia about about these two results? We we view them as being quite very very positive. I don't.
Really like to comment on other people's programs. I'm not very close to those programs like the focus more on exclusively. Really young owners programs, but wage like our medicine and we believe we have the first and invest in class medicine for Target and reboot and like three as far as Huntington's the Huntington's program remains on track. It is is of course targeting the root cause of Huntington's disease. The pastry program is on track to deliver results in a 20 22 on schedule and that's the basic message from the chdi presentation that you'll hear about tomorrow. Cuz a lot of other presentations at the meeting too, but quite simply a message is that um, we have uh, the premier program for targeting potential Target Huntington for Target Huntington's disease that will potentially bring his medicine to patients.
Wade Walke: Additionally, Eric Swayze, our Senior Vice President of Research, will join us for Q&A. I would now like to draw your attention to slide three of the slides that we have for today's call, which contain our forward-looking language statements. We'll be making forward-looking statements that are based on current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional details. With that, I'll turn the call over to Brett.
Brett P. Monia: Thanks, Wade, and good morning, everybody, and thanks for joining us on today's call. I'm very excited to be speaking to you today in my new role as Ionis' CEO. In 30 years, Ionis has achieved enormous success by delivering on our commitment to help patients with the greatest unmet medical needs. Today, we're building upon that success. In fact, I believe that today we have the resources and people to make Ionis among the most innovative, productive, and highest-achieving companies in our industry. So now, to recap last year's achievements. 2019 was an exceptional year.
In the near future. Oh, she's very excited about the program and and the messages that the pastry study remains on track.
Thank you.
Our next question comes from Jim birchenough with Wells Fargo, please go ahead.
Hi guys, congrats on all the progress and the broadening pipeline a couple of questions. I guess just on Capital allocation with 2 and 1/2 billion in cash. Could you talk about your priorities for Capital allocation? And whether we should expect additional share repurchases also wanted to just touch on if you could the revenue guidance for greater than 700 million which is below the 1.1 GB from last year, but I guess if we back up the four hundred million dollar One Time payments, it's suggesting grow beyond that. So if you could comment on that and I guess the final bit is with the coronavirus. Just wondering if you could comment on your exposure for your supply chain to Asia. What kind of question you have is there if there is any exposure. Thanks. Hi Jim. It's it's bad for your questions. So I'll start I'll start off with capital allocation. And as as you know, Brett has has laid out our priorities are to continue to invest aggressively.
Brett P. Monia: From a financial perspective, as Beth will discuss shortly, 2019 was especially good. Spinraza's blockbuster performance continued, and Biogen expects growth again this year, and the commercial launches of Peccetti and Whiteliver have progressed, with plans in place to expand to new markets soon. Together with exceptionally strong R&D revenue, we delivered over $1 billion in revenue, over $400 million in net income, and ended the year with $2.5 billion in cash, outperforming even our improved 2019 financial guidance. Importantly, we achieved these exceptional financial results while investing in all areas of the business that we believe have the greatest potential for value creation, and already this year, we're building upon this momentum to achieve even more success. As Richard will discuss, in 2019, we achieved strategic successes broadly across our pipeline, including in our neurological and cardiometabolic disease franchise.
across the business of
To focus on or Iona sound pipeline to advance our technology to invest in complementary Technologies to broaden the reach of our technology package and with the addition of Anisa on our leadership team. We are now defining further or commercialization strategy and building came and so that will also be an area of investment for the company. So I see first and foremost our investments and our Capital being allocated to those areas of faith in value creation for the company in terms of share repurchase certainly with our stock where it is today. We believe it's a, you know, a very attractive investment opportunity and so that's something we'll be, you know will be considering into the future and we have a portion of our 1% notes that are coming due in about a year and half or something.
Brett P. Monia: We achieved our primary goal of advancing four medicines into Phase III studies. Additionally, we achieved positive clinical proof-of-concept results for five medicines. Last year, we advanced five new medicines into Phase I, and we advanced ten new medicines into development, six of which are Ionis-owned. Also, last year, we continued to improve and broaden the scope of our technology. In addition to moving two of our Leica programs into phase 3 studies, we demonstrated clinical proof of concept for four new Leica medicines for indications that represent both broad and rare patient populations, further supporting the potential to expand our technology beyond rare diseases, and we advanced two new lipids into development, growing our lipo pipeline to 16 medicines overall.
I mean we'll be looking.
What the appropriate actions are for addressing those notes as we go forward?
Brett P. Monia: Additionally, we initiated clinical proof-of-concept studies to evaluate our progress in optimizing oral and aerosol delivery, with initial results expected later this year. And, of course, with positive results from these studies, our technology could benefit greatly by expanding the scope of our drug discovery platform. Today, Ionis is stronger than ever.
Thanks Beth and with respect to coronavirus gym, you know at ionis we take great pride in preparing for a potential crisis before they ever happened and we've been focused on a on this potential pain epidemic and talking about how we're going to protect our employees are clinical trials as well as our supply chain and we don't see any hiccups along the way all that's Richard commented on how we manage our supply chain, which is the question. Yeah specifically on supply-chain course, all of our API. We're not dependent on China or Supply which may be one of the questions certainly all of our clinical supplies are manufactured right here and and then off the drug Supply chains that Supply or drugs are are all also not only multiple pack up opportunities, but also not dead.
Brett P. Monia: Our pipeline of over 40 medicines is broad, deep, mature, and growing, with multiple programs nearing key value in collection. And this year, we are prioritizing areas of the business that we believe have the greatest potential to create value, short-term and long-term, for patients and shareholders, for example. We're advancing our technology by identifying new lipids and further optimizing additional routes of drug administration to enhance the overall profile of our antisense platform, and we're identifying novel drug targets to continue replenishing our pipeline with innovative medicines as later stage programs reach commercialization. By the end of this year, we also plan to have six Phase III studies underway to report clinical proof-of-concept results for six or more medicines, with two already achieved this year.
pendant on China Gorge
Our next question comes from Esther Hulu with oppenheim are please go ahead.
Brett P. Monia: Initiate 10 or more new Phase II studies in advance of at least 5 new medicines into development, including several new and exciting Ionis-owned chemicals. Together, these achievements position us well to reach our goal of 10 or more new drug applications through 2025. Additionally, this year, we're prioritizing the growth and advancement of our Ionis-owned pipeline while further developing our commercial strategies and capabilities to ensure we maximize the value of each of our matters. As part of this initiative, we recently appointed Onaiza Cadoret to the Ionis leadership team as our chief corporate development and commercialization officer. We're thrilled to have Onaiza on the team.
Thank you for taking my question. Just a couple of quick ones for me. How much if your 2020 guidance is driven by spinraza versus other sources then I have a quick follow-up.
Hi, I'm serious Beth good morning. So, you know, as you can imagine spinraza was a significant portion of our commercial revenues in 2019, and we advise and continue to see growth first been rasa frankly in the US and outside the United States. So I would expect to talk to continue to see spinraza being a significant portion of our commercial revenues as as the year unfolds and and then adding to that of course we have take City and we live as they expand into new countries in Europe in particular and then we have a very substantial base of our revenues Anchorage by significant amortization of upfront and Milestone payments and then built on by with licensing fees and Milestone payments.
Onaiza Cadoret: With extensive experience in building and executing on corporate, business, and commercial strategy, her leadership will be invaluable as our pipeline advances. In a moment, Beth will review our 2019 financial results and 2020 guidance, and Richard will recap our latest pipeline achievements and planned 2020 catalysts, and I'll close out the call and moderate some questions. So now I'll turn the call over to Onaiza, who will provide some additional insight into her new role at Ionis. Thank you, Brett, and good morning everyone.
Onaiza Cadoret: I'm quite excited to join Ionis at this transformative time for the company. As Brett said, we are in a unique position of strength. We have an expansive, deep, and advancing pipeline with a growing number of late-stage medicines. Our technology is broadly applicable, enabling us to bring novel medicines to patients. And most importantly, we have a strong, experienced team who operate with scientific rigor, an innovative mindset, and are very committed to delivering transformational medicines to patients with severe. I am excited to assume leadership of the company's corporate development and commercial efforts. Our goal, to maximize the value of each medicine in our pipeline, remains unchanged.
Are partnered programmed in?
development continue to advance
Gotcha. Thank you and in for four wheel of the resubmission of the marketing authorization in the what do you have? What do you need to complete to be able to refile this year?
Yeah, great question. This is Richard. Nothing to complete except writing up the results. So all of the all of the expanded studies in open-label as well as expanded access or being added to the filing and bring us to about a three-fold increase in exposure in patients. And as well as additional safety data, which is very supportive. So that's we should expect that to happen sooner than later in the year then based on what you're saying.
Onaiza Cadoret: Looking ahead, we plan to pursue this goal by identifying the optimal commercial strategy, pathway, and organization for each of our medicines, while preserving our established culture of scientific innovation. We plan to develop our commercial capabilities, allowing us to bring medicines from our growing Ionis-owned pipeline to patients. In parallel, we will continue to establish strategic partnerships to develop and commercialize those medicines with the potential to address diseases with the largest patient populations, such as our most recent collaboration with Pfizer, Fraxia, angiopuretin-like 3. We also look forward to continuing to support AXSIA as they pursue their strategic goals and through the potential addition of a new Ionis medicine to the AXSIA pipeline later in the year. I look forward to updating you on And with that, I'll turn the call over to Beth.
I think we're guiding to a timing, but certainly we are expecting to file this year.
Okay. Thank you.
This question comes from Palm at ease with people please go ahead. Hey, thanks for taking the question. This is on for Paul firstly for for the Pac-12. Can you review the study structure and specifically Beyond safety and pkpd are you or what exploratory markers of advocacy? Are you collecting a follow-up Eric? We have disclosed much on the details of I don't believe we've disclosed things beyond that. We're treating both genetic patience with large invitations as well as the general population. And of course, it's a first-in-human study. So the primary endpoint is safety, but you can imagine there's lots of suck biomarkers and exploratory endpoints to look at
Elizabeth L. Hougen: Thank you, Onaiza. 2019 was an exceptional year, including financial. We significantly exceeded our 2019 financial guidance, driven by revenue of more than $1.1 billion, nearly double compared to 2018. We earned over $350 million in commercial revenue and over $770 million in R&D revenue, including nearly $400 million for licensing Axia APOA-LRX and Axia angioplankton-3-LRX. Our revenues resulted in substantial non-GAAP operating income and net income of over $510 million and over $400 million, respectively. We also achieved substantial operating income and net income on a GAAP basis. We achieved these exceptional results while further strengthening our balance sheet. We increased our cash balance to $2.5 billion.
Yeah more more will come out on their study program matures. Well, maybe a second pipeline question on the C 9 a.m. Or program. Are we thinking about this in the right way that's primarily going to be addressing the gain-of-function aspects and if that's correct. Are you worried at all about the loss of function aspects and secondly, would you consider moving from us into seeing as well?
So ugh a good questions both. Yes, you are thinking about it correctly that we are addressing predominately the the gain of function aspects of this, you know or 72 Gene, which is causal 4072 ALS and FTD important thing about our our drug is is it is targeted such that it only decreases the mutant form of C 9 or 70,000 by the by the location which we target the gene. So we don't expect to decrease all see nine or seventy to function. If in fact there there was an important component of that to safety or diseases. Oh, right. I would emphasize that much of the preclinical data really suggest that it is a a gain-of-function disease pathogenesis process. So I I think that medicine is another one that's like many of our banks directly on Target and not mechanism. And as you point out, you know, if 72 is also implicated in FTD and with fising we're actively considering how to move that drug forward in, Georgia.
Elizabeth L. Hougen: And we refinanced a significant portion of our convertible debt, which enabled us to extend the maturity for most of our debt to 2024, achieved a one-eighth percent interest rate, which reduced our annual cash interest expense by approximately 40 percent and significantly increased our effective conversion price, which may reduce future dilution. Over the last several months, we have also returned value to shareholders by repurchasing 2 million shares of our common stock through a stock repurchase program we implemented late last year. The refinancing of our debt and our share repurchase program underscore the confidence we have in the future of the company and our commitment to creating near and longer-term value for shareholders. And because of our significant financial resources, we were able to execute these transactions while continuing to invest aggressively across our business. Now, turning to our commercial revenue. Spinraza generated over $2 billion in worldwide net sales in 2019, resulting in nearly $300 million in royalty revenue for Ionis, an increase of more than 20% compared to 2018. At the end of last year, there were more than 10,000 patients on Spinraza treatment worldwide.
Ftt. Yeah.
I'll just expand on that a little bit neat so you reminding you and others how we're how we're attacking a LS with Biogen our side one program. Of course is in phase three or four months another genetic form of a song One related in addition to see 9 or as the second one in in recently. We added a third medicine into the Jonas Biogen pipeline off sporadically forms available as much broader non-genetic forms available. And so we're doing a full court press on all forms of ALS, and and I think there will even be more coming.
Great to hear. Thanks guys.
Our next question comes from Chad Messer with Needham & Company, please go ahead great. Thanks. Thanks for taking my questions. Let me just start with the t t r o m 3 Program now that you've got those two studies up and running. Can you maybe set some some expectations for enrollment timing? You guys have some experience in Rolling trials in the space? And is it your sense that it's it's easier or harder to enroll now that there are commercially available options for these patients. Appreciate the question. She said, thank you. Yeah, we're very excited. I honest with that we're now underway and to phase three studies for both the cardio myopathy the larger population, but would you include the First Presbyterian wild-type and the polyneuropathy patient population separate page three were targeting essentially the same label as having
Elizabeth L. Hougen: Biogen achieved this important milestone through growth from adult SMA patients in the U.S. and growth from both existing and newly launched markets outside the U.S. With approximately 45,000 addressable patients in markets where Biogen has a direct presence, we see significant opportunity for growth. We achieved steady quarter-over-quarter growth throughout 2019, resulting in product sales from TechSteady and Waylivra of $42 million for the year. Today, PICC-Study is commercially available in more than 10 countries. In the U.S., we achieved growth in new prescribing physicians and patient starts. Of particular note, in the fourth quarter, we saw a 42% increase in new prescribing physicians.
Elizabeth L. Hougen: We continue to see a mix of cardiologists, neurologists, and hematologists in both the academic and community settings. Additionally, Axia's market access efforts have continued to translate into broad tech city coverage for patients in the U.S., not only today but also in the longer term. Outside the U.S., Axia is focused on reimbursement as it prepares to expand into additional countries this year. In Latin America, PTC Therapeutics is launching TegCeti in Brazil and is working to provide access to TegCeti in additional Latin American countries.
As far as expectations go we're looking for these studies to complete in the 2022-23.
Which time frame and enrollment is actively underway in for both studies and this is going well as for you know challenges related to one moment and and how competition particularly stabilizers may impact that we actually believe that our trial designed for cardiomyopathy offers advantages for patient enrollment the fact that we allow patients to take standard of care which of course depending on the geography you happen to be in stabilizers could be the standard of care of and therefore that's no hindrance to enrolling our study. So the work that folks like Pfizer are doing to identify patients and get them on to talk to families. I believe will help our own in in the speed of our own as well as just the disease awareness the great work that we're doing to make people dead.
Elizabeth L. Hougen: Waylivra is now on the market in Germany, with FCS patients benefiting from the only medicine approved for the treatment of this devastating disease. In France, Axia is enrolling patients in an ATU, a reimbursed early access program. Additionally, Axia plans to launch in new EU countries this year, and PTC Therapeutics is working to provide access to weight libra across Latin America beginning in Brazil this year, pending approval.
Awareness of this disease hereditary polyneuropathy is is certain.
Elizabeth L. Hougen: In the U.S., we are continuing to work with the FDA with the goal of refiling this year. Through Axia's efforts, we have a strong foundation for both commercial products that we believe can support expansion into new markets this year. Our 2019 R&D revenue more than doubled to $770 million, with significant increases in license fees, milestone payments, and amortization from upfront. This growth demonstrates the substantial value of our pipeline of technology. Our R&D revenue consisted primarily of $490 million in licensing fee revenue, including nearly $400 million from licensing Exeia-Angiopuitin-Like-3-Rx and Exeia-ApoA-L-R We also recognize nearly $25 million for advancing several programs from our cardiometabolic franchise, including our Factor XI program with Bayer and our Medicine for Patients with NASH program with AstraZeneca. Our 2019 non-GAAP operating expenses increased to $610 million compared to 2018, driven by investments in our pipeline and technology, consistent with our stated objectives.
Going to be a challenge to enroll. There's no question about that. There are there are multiple drugs approved for this this this rare rare room patient population apparently dosis and there are other clinical trials in progress as well. However, with the great work that exceeds doing to identify patients and Thursday, I mean investigators and and what they're doing with actually connect as well as our strong relationships with investigators from our neuro TTR face research study. We're, we'll be able to roll this study on track and we're feeling good about it the other advantage to the neuropathy study of course is the fact that it's an open-label study. So patients will not be able to seat belt or comparing the results of that study to a historical control which which of course will help enrollment as well as the fact that the sample size is significantly smaller than our pastry Nara TTR study wage.
There will be challenges for polyneuropathy, but I think we can manage them.
That has an interim is that meant to be something you could file on or you just trying to get you know, in earlier sense for for efficacy page will look at the interim analysis data at eight mines and make decisions based on the data that will be data-driven decisions want to remind you that at eight months in our neuro TTR text any case we try we saw a high statistical significance to 6:30 as well as that of course of the end of the study of fifteen months. So we have a very nice comparison at our interim analysis eight months of enduring in a teacher like a study that will be able to compared to historical controls and Thursday and we want to get this medicine to patients as does XE as rapidly as possible. And if the data supports it off we go.
Elizabeth L. Hougen: We also made strategic investments in technologies we believe can expand the reach of our anti-sense technology and in developing our commercial capabilities. We continue to be in an enviable position of financial strength. This year, we expect to be meaningfully profitable while continuing to invest aggressively in our strategic priorities. The ability to earn revenue from multiple sources is a key element of our financial strength.
All right. Great. Thanks. Very helpful. My pleasure. Our next question comes from Vincent Chen with Bernstein, please go ahead. Hey, thank you very much for taking the question a couple of Roommates. So the first one on Huntington's just sort of following up on the earlier. What should we be looking for in the updated data tomorrow, I guess in your view will get some data update data on a safety the biomarkers including your opponent light chain. What does a good outcome look like in terms of the updated safety and biomarker data, including including neurofilament and then a second choice on some different topic this morning. If you could provide any color on the relative mix of product sales in terms of I guess way Libra versus text Eddie and then for text Eddie US versus a u.s.
Elizabeth L. Hougen: We expect growth in commercial revenues, driven by continued strong Spinraza performance and growing revenue from TechCity and WeLivra as we expand into new countries. We also expect to achieve important milestones as we advance our medicines in development. With these multiple sources of revenue, we project earning more than $700 million in revenue this year. We are projecting 2020 non-GAAP operating expenses of $650 million to $690 million.
Yeah, and then just on the polyneuropathy study that has
Elizabeth L. Hougen: The increase in our projected operating expenses compared to last year is attributable to investments we are making in our Ionis-owned pipeline. These investments include conducting the ongoing Phase III program for Axia TTR Leica RS and initiating a Phase III study of Axia APOC3-LRX in FDS patients this year. We also expect to advance our mid-stage pipeline. Together, these investments support our goal of 10 or more NDAs through 2025. We built the commercial infrastructure necessary to support TechCity's expansion into new countries ahead of those launches, and because of that, we have the necessary team in place to expand TechCity in the U.S. and outside the U.S. This means we do not need to increase our SG&A expenses to support TechCity's commercial growth.
Would you like to touch on the biomarker data and the yeah, I mean, I don't really want to get ahead of our partners brochure.
Tomorrow but really what's being presented should be thought of as an extension of state of the they've already presented and and also bought a note that the you know, the safety profile it has been presented. The drug is outstanding the phase three trials is Brett mentioned is on track and is scheduled to read out in 2022 and Thursday. We're very pleased with the progress of the drug and pleased with the way Roshes advancing it. Yeah, the way I see you mentioned is the key message is the fact that the phase 3 trial is on a contract is Eric said as I said earlier and roaches very excited about the program. The Bible monthly dosing is looking excellent, and I'm moving forward on Pace.
Richard S. Geary: Additionally, we anticipate realizing valuable synergies between Teixeti and WeLibra as we launch both medicines in additional countries throughout the year. For these reasons, we are projecting to keep SG&A expenses comparable to our 2019 level while growing Tick-City and We Live Rapidly. With $2.5 billion in cash at the end of 2019, we have the financial strength to fully execute on our strategic priorities. And with that, I'll turn the call over to Richard to provide an update on our pipeline. Thank you, Bev. As Brett mentioned, 2019 was a year full of important achievements.
When we will be we will be issuing on Friday a a sort of a round up a short summary of all the presentations on our our Huntington drug so we can capture it will post that to our website and and and we'll also distributed to our animals that would you take the division of Aging sure. So the as you can imagine since we liver was just launched wait in 2019. And in Germany really only way the vast majority of the revenue in 2019 was text Betty and we were you know, pleased to see steady progress quarter-over-quarter with was quarter of growth in 2019. We think that sets an important and strong foundation for continued growth this year and we look forward to to moving we live birth.
Richard S. Geary: We made significant progress with our rapidly growing neurological disease franchise. For example, Ionis HP-TRX for people with Huntington's disease and Tofresen for people with SOD1-ALS entered Phase 3 studies last year and are progressing on schedule. We recently completed enrollment in our Phase 2 proof of concept study of Ionis MAP-TRX in patients with early Alzheimer's disease several months ahead of schedule.
Eddie into new countries
Richard S. Geary: Biogen has expressed its enthusiasm for this program as an important part of their already robust Alzheimer's disease pipeline, and in fact, late last year, Biogen licensed IonisMap TRX significantly earlier than anticipated, although supported by encouraging blinded interim data from the ongoing study. Additionally, Biogen recently initiated a study of our medicine targeting LRK2, the most common genetic cause of Parkinson's disease. This is an exciting study that includes patients with both familial Parkinson's associated with LRK2 mutations, as well as patients with the sporadic form of the disease.
This year in terms of the mix between us and and that's that's information that we in Axia are not sharing at this point.
Great. Thank you very much. Thanks.
Our next question comes from l e Merrell with Cantor Fitzgerald, please go ahead. Hey guys. Thanks so much for taking the question just on the oral program. Now that you're committing a 24 proof-of-concept data. Can you walk us through what exactly will get in this read out? And I guess what specifically would constitute from your perspective proof-of-concept for Thursday delivery Are there specific levels of protein knocked down relative to the subject to you that you're running in parallel that you'd be looking for or just can you sort of walk through you know, what and your perspective, you know constitute proof of concept for oral.
Richard S. Geary: Together, these populations represent over 3 million patients. Also earlier this year, we and Biogen advanced our program for the treatment of Angelman's syndrome into development. We are particularly excited about the progress we are making with our pipeline of ionosome medicines addressing neurological diseases. Patient enrollment is now underway in our Phase III Neuro-TTR Transform Study of Axia-TTR LRX in patients with hereditary TTR amyloid polyneuropathy.
Thanks for the question knowing so yeah, we're very excited about the clinical trial and progress evaluating the potential for commercially wage viable or delivery with our partner AstraZeneca. And as you mentioned the plan is to have data readout from the second half of this year. What does proof-of-concept mean aside from Port safety and tolerability is the bioavailability with Kinetic support, uh, that that we expect to achieve that will that was predicted based on our extensive preclinical data that would support commercially viable oral dosing off more than that. We have the ability to assess the effects on um, Target reduction biomarker reduction in in the in the clinical trial is designed with that dead.
Richard S. Geary: Our Ionis-owned medicine for the treatment of Alexander disease was recently granted orphan drug status by the EMA, recognizing the significant need for therapeutic options for patients with this devastating and fatal genetic disease. We also added several additional Ionis-owned neurological disease medicines to development last year, including treatments for leuphora and prion disease. Turning to the recent advancements in our cardiometabolic franchise, enrollment is now underway in the Horizon Phase III Cardiovascular Outcomes Study for Axia Apolital A, LRX, in patients with established cardiovascular disease and elevated Lp-a.
In mind with that intense and will have Chris data readouts on on the wall then.
And then once that data runs out the other aspect of this topic that I'd like to expand on if you will is that you know, we're not we're not sitting still on the development of formulations to further increase and enhance oral bioavailability. We actually have active work research on going at ionis where we are already making a substantial significant improvements in the potential for oral delivery and even beyond that of the formulation we have in our clinical study right now. So, you know, we're continuing to make advancements. In fact, we're hoping to you bring those on in the future further where we've we've identified a number of Iona sewn products that we're planning to bring in the development as an oral pill soon after you know right behind the collaboration. So this isn't there there's many origin of War dead.
Richard S. Geary: We're pleased with how rapidly Novartis advanced Exia Aprilia LRX into Phase 3 development. And importantly, this medicine is one of our four medicines to advance into Phase 3 last year, helping us to achieve one of our key corporate objectives. At the beginning of this year, we initiated our Phase III Cardio T-Transform Outcome Study of Xeo-TTR-LRX in patients with wild-type and hereditary forms of T
Richard S. Geary: We also reported positive top-line results from Phase 2 proof-of-concept studies for Axia ApoC3-LRX and Axia Angiopoietin-Like-3-LRX. Both medicines achieved their primary endpoint, demonstrating robust triglyceride lowering and substantial reductions in additional key cardiovascular risk factors with favorable safety and tolerability profiles. I think it's worth noting that our cardiometabolic pipeline includes 11 lichens to date, and we now have data from over 1,100 people treated with lichen medicines to date, including a substantial number of patients treated with lichens for one year, with 16 lichens now in development in multiple therapeutic areas, including two in phase three outcome studies.
If you will and the oral friend and we're feeling pretty good that we're going to have success and making oral commercially viable for our platform.
Got it. Thanks very much for the caller and just one quick follow-up. If I may just for Brett. I mean, it seems like you have a lot of programs in development. You have many, you know readouts this year. I think in your slides you call about that you have you know for proof-of-concept, you know, read out the fear, I guess which program or which data sets. Are you most excited about?
Well, it's hard to pick one for the pipeline of more than forty drugs all of which have the potential to be transformative in nature. It really is and if we went around the table here, we'd probably get six life choices. But in the in the shorter term, well we have the rare disease Pockets. We have brought the disease on populations right and and down to it's hard to not include LP little a in a in a in a choice and a selection for drugs. I mean, this is such a large patient public relations were so far ahead of any any form of competition the pastry study with no viruses is progressing extremely well, and the commercial opportunity for in in life is so enormous. So you gotta include that one on the other hand in our rare disease bucket. I have to I I I gravitate towards ALS. I mean, there's no there's no
Richard S. Geary: We have substantial evidence that our Leica technology, characterized by greatly increasing potency and improved dosing regimens, represents a real game-changer for our technology. Finally, we advanced several Ionis-owned rare disease medicines into Phase II development last year, including Ionis-GHR LRX for the treatment of acromegaly, Ionis PKK LRX for the treatment of hereditary angioedema, and All of these programs are on track to report results later this year. So, as you can see, we expect numerous catalysts throughout this year.
No treatments for this this terrible neurodegenerative disease and I honest with Biogen is as I said earlier I used.
Analogy of a full court press on all forms of Heroes, which we are doing now our side one program is due to read out for the first of multiple. Okay, let's drugs as a reminder that drug showed really remarkable providing really remarkable evidence of efficacy in three short three months study in page. And now the pastry is going to read out next year as Eric referred earlier. We have a C9 program that's also a face to promote of through read out next year. Now. We have a a drug for sporadic ALS Thursday. I would I would lean towards those two programs, but I could take all day talking about our pipeline. There's lots of lots of drugs there be very excited about
Got it. Thanks so much for the color. Sure.
Our next question comes from Tyler Van Buren with Piper Sandler, please. Go ahead. Hey guys, good morning. Just had a brief follow-up on your comments on Capital allocation earlier, you mentioned potential complementary technologies that you're looking at. So just want to get your updated thoughts or interest in tissue-specific Technologies. There's some you know, emerging out there to suck Karne Technologies and you know what examples antibody conjugates just want to get your thoughts there.
So thanks Tyler. You know we are we're we're very thrilled to be in a position of such a such a strong financial position that allows us to invest in technologies that complement our and I sense platform expand the reach of our Energy Center platform and doing it off in that we're investing in genomics to identify novel targets for you know to continue to to off the pipeline as new drugs reach commercialisation targets that are genetically linked over working with companies and academic collaborators to Identity to work on Pathways that lead to a selection of Novel targets as well. And we're working internally and with externally with Cloud through collaborations with new light Technologies. Just leave last year dead.
Richard S. Geary: We expect to have six Phase III studies in progress, including a planned Phase III study of CIPA C3 LRX in patients with FCS. We expect to report clinical proof-of-concept studies for oral delivery of one of our antisense medicines in cardiovascular disease, and we expect results from multiple Phase II studies. We also plan to advance numerous new programs into mid- and early-stage clinical development and to add many new Ionis-owned and partnered programs to our pipeline. These catalysts, together with our broadening and advancing technology, position us well, as others have said, to achieve our goal of 10 or more marketing applications through 2025. We will continue to keep you updated on the mini-pipeline catalysts we expect this year as our medicines continue to advance in development. And with that, I'll turn the call back over to Brett to close this portion of the call. Thanks, Richard.
Brett P. Monia: Before we end today, I'd like to remind everyone that this Saturday, February 29, is Rare Disease Day, and in recognition of this important day, please join me in thanking the patients, families, and advocates who have been our partners in developing medicines to transform the lives of patients in need. I'd like to invite everyone to follow Ionis on Twitter and LinkedIn to learn more about how Ionis is raising awareness for the millions of people worldwide living with a broad range of diseases, including thousands of identified rare diseases, most without adequate treatment options. Today, we're at a unique place in the history of Ionis.
Brett P. Monia: Our pipeline is broader and more mature than ever before, with numerous programs nearing key value inflection points. This year, we plan to use our financial strength to invest aggressively in all areas that have the greatest potential to create value for patients and shareholders, including growing and advancing our Ionis Own Pipeline. Further developing our commercial strategies and capabilities to ensure we maximize the value of each of our medicines. We are expanding the reach of our technology by, for example, optimizing different routes of drug administration and discovering new LICA strategies, and Identifying and Increasing Investments in Complementary Technology I will also expand the reach of our antisense platform. And with that, I'd like to now open the call for Q&A. We will now begin the question and answer session. To ask a question, you may press star then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the key.
Unknown Executive: To withdraw your question, please press star then 2. At this time, we will pause momentarily to assemble our roster. Our first question comes from Jason Gerberry with Bank of America. Please go ahead.
We we completed a a partnership.
Um with the genomics company to identify novel targets and with another company to identify novel strategies like a strategies to expand the reach of anti sense to to newer organ systems new cell types off making great progress antibody conjugates and their derivatives are just one aspect of of the types of strategies. We're taking I view that as one tool in a in a toolbox of approaches with like hoods that we have and what we're developing or working on ourselves, so they have the potential to work but I I believe that we have many different strategies that are showing promise you getting into cell types that are less sensitive to in Tysons today.
Jason Gerberry: Oh hey, thanks for taking my questions. So I guess just on AngPTLA-3, I was hoping, have you guys had a chance to discuss the recent data with Pfizer? Any commentary that you can provide on that program and how you're thinking about the profile relative to some recent interim data from Arrowhead? Second question is just on Huntington's ahead of tomorrow, some extension data from the earlier study. If you could set the table for what we could expect and the importance of those updates just in terms of understanding the broader safety profile of HTTASO. Jason, thanks for the question.
Great. Thank you.
Our next question comes from Jessica Faye with JPMorgan, please go ahead.
Hey guys, good afternoon. Thanks for taking my question spelling up on one of the earlier questions about like 3. Can you just talk a little bit about how you see that product positioned relative to a post you three like a is the 8-plus see three like a really going to focus on the indications that you've previously discussed four-wheel ibrah.
Brett P. Monia: So, starting with angiopoietin light 3, as you know, we partnered that program prior to the unblinding of the phase 2 data last year, and we and Pfizer were thrilled with the outcome of the phase 2 results in that study. We achieved our primary endpoints with very high statistical significance, and a number of secondary endpoints. We are positioning this drug very well for later stage development, and certainly Ionis, Axia, and Pfizer have gone through the data or continue to go through the data in quite extensive detail, forging the path forward for this medicine, later stage development. And we plan on sharing this data in detail in the second half of this year at a medical meeting. But short to say, we're very excited, as are Pfizer and Axia, about the Phase We view them as being quite, very, very positive. I don't really...
Thanks, Jess. And I appreciate the question. So first of all, of course, we're we're thrilled with the results from the phase two studies. Am I understand see unblinded and present the top line data on our announced top up my data for for both programs to go see three like an engine light green light that holds it the primary endpoints both are often very well for phase three Trials of down the road. There is overlap in both of these medicines in the the a Trojan atherogenic liquid that they manage that they control triglycerides Remnant cholesterol LDL cholesterol effects on positive effects on h d l am also a significant enough difference between these two drugs that we believe as those are partner buys our friendship. We'd like three and of course sexy it to that they differentiate dead.
Significantly sufficiently well that they will have a different profile in patients.
Brett P. Monia: I'd like to comment on other people's programs, but I'm not very close to those programs. I focus more on... I don't work exclusively on Ionis programs, but we like our medicine, and we believe we are the first and best in class medicine for targeting angiopoietin like this. As far as Huntington's, the Huntington's program remains on track, and is, of course, targeting the root cause of Huntington's disease. The phase three program is on track to deliver results in 2022 on schedule. And that's the basic message from the CHDI presentation that you'll hear about tomorrow. There are a lot of other presentations at the meeting too.
With cardiovascular disease, I think that able see three like is the most potent triglyceride-lowering Target drug out there today. And and if we like three bring a number of other advantages such as the effects on cholesterol in addition to significant triglyceride-lowering and positive effects on each d l so I think they differentiate enough, um wage you very important and meaningful additions to the cardiovascular the treatment cardiovascular disease in the future as those are partner advisor in XC.
Our next question comes from many through her with s v b Lynbrook, please. Go ahead.
Brett P. Monia: Quite simply, the message is that we have the premier program for targeting Huntington's disease that will potentially bring this medicine to patients, and in the near future, Roche is very excited about the program, and the message is that the phased restudy remains on track. Thank you. Our next question comes from Jim Birchenoff with Wells Fargo. Please go ahead.
Hey, good morning. This is Rick on the line from Monty have two questions for you first just broadly speaking about the opportunity set for the oil delivery of Asos. I think world delivery could potentially be a good fit for any liberal directed therapy or do you think the technology is best utilized in specific areas, like cardio metabolic indication and second choice giving the increasing focus on your wholly-owned pipeline. Could you give us a sense of how you know, you're currently viewing the relationship with ex-cia. Do you think it would make sense at any point to think about bringing them under a text back into the company? I'm really just looking for any commentary on how you view the relationship with evolving as more focus is placed on your internal pipeline.
Jim Birchenoff: Hi guys, congrats on all the progress and the broadening pipeline. A couple questions, I guess just on capital allocation with $2.5 billion in cash, could you talk about your priorities for capital allocation and whether we should. I'm also going to touch on the revenue guidance for greater than $700 million, below the $1.1 billion from last year, but I guess if we back up the $400 million one-time, and I guess the final bit is with the coronavirus. Just wondering if you could comment on your exposure for your supply Thanks. Hi Jim, it's Beth.
Sure thing. Thanks, Ray. So the oral.
The progress were making on oral delivery, uh-uh. His successful has a potential to reach all of our liberals programs. That's what's really so exciting about. It's not just one particular clinical trial but it's also the potential impact. It'll have any of our like a liver like programs including drugs that Target able to see three orange if we like three or factor eleven GTR and so forth and we're focused on that. And as I said, one of the questions earlier, we've already identified additional liver targets that we're moving forward to oral studies and running. So it does have a very broad reach is successful. And as I also mentioned she continued to even improve on the current formulations, which are showing a lot of lot of potential we're changing gears. We're very excited about Thursday.
Elizabeth L. Hougen: Thank you for your questions. So I'll start off with capital allocation. And as Brett has laid out, our priorities are to continue to invest aggressively across the business, to focus on our Ionis-owned pipeline, to advance our technology, to invest in complementary technologies, to broaden the reach of our technology, and with the addition of Onaiza to our leadership team, we are now defining further our commercialization strategy and building capabilities. And so that will also be an area of investment for the company. So I see, first and foremost, our investments and our capital being allocated to those areas of significant value creation for the company. In terms of share repurchase, certainly with our stock where it is today, we believe it's a very attractive investment opportunity. And so that's something we'll be considering for the future. And we have a portion of our 1% notes that are coming due in about a year and a half or so.
and we're committed to actually a success or competence are going to be very successful are fully on our
Only on rare disease pipeline is growing and expanding and and and there's lots of opportunities to bring these drugs to Thursday is commercial value of each of these medicines in different ways and is certainly um, uh one of those options that are available and as we mentioned earlier we're we're already in negotiations discussions with about the potential addition of the medicine of these medicines into their pipeline later this year as far as the future of Axia and you know, am I on his that's that's the topic for discussion down the road right now is doing well in in and they have a very full and exciting agenda or pipeline agenda, which is really an agenda that's comprised about Pipeline and getting way too liberal approved and and continuing progress with wage.
Elizabeth L. Hougen: And we'll be looking at what the appropriate actions are for addressing those notes as we go forward. Thanks, Beth. And with respect to coronavirus, Jim, at Ionis, we take great pride in preparing for potential crises before they ever happen. And we've been focused on this potential pandemic and talking about how we're going to protect our employees, our clinical trials, as well as our supply chain. And we don't see any hiccups along the way.
but when able to see through like up now in their Pipeline and planning to start phase three and you know,
Your yard, like having other going to phase three studies already in progress It's quite a lot on their plate and and we we believe that they're on track to to deliver on their strategic. Also, you know, that's what I have to say about that right now. I hope that like that that interest is your question.
Elizabeth L. Hougen: I'll ask Richard to comment on how we manage our supply chain with respect to questions. Yeah, specifically on the supply chain, of course, all of our API; we're not dependent on China for supply. It may be one of the questions.
Richard S. Geary: Certainly, all of our clinical supplies are manufactured right here. And then the drug supply chains that supply our drugs are all also not only multiple pack-up opportunities but also not dependent on China. You're in good shape.
It does thank you for taking our questions. The next question comes from solvent orator with Goldman Sachs, please go ahead with this is Ross on can you help us understand the breakdown of product sales to take steady and a Libra and some of the the gating factors for both of these launches here specifically. I'm looking for some additional color on your comments of the prescribing base for Tech said he grew about like 4% q4q. I'm just trying to think about what factors drove this significant uptick and where the where these Physicians coming back and then I have a follow-up.
Richard S. Geary: Our next question comes from Esther Rajavulu with Oppenheimer. Please go ahead. Thank you for taking my question. Just a couple quick ones for me.
Esther Rajavulu: How much of your 2020 guidance is driven by Spinraza versus other sources? and then I have a quick follow-up. Hi Esther, it's Beth.
It's Beth. So so the breakdown of of tech-savvy and we liberals they said is primarily takes a t because we liberal was launched in Germany month late in 2019. And there you know right now is expanding. We live out across additional countries in in Europe, but they started with Germany and that's a relatively small patient population in Germany with that and so small very small portion of the product revenues in 2019. Were we live? Right? So the vast majority were takes fetty in terms of the the growth in prescribing Physicians, you know, a lot of that is is a function of the word that the team is doing with their their genetic testing program getting out not only into academic centers, but also into the community settings expanding the number
Elizabeth L. Hougen: Good morning. As you can imagine, Spinraza was a significant portion of our commercial revenues in 2019. And we in Biogen continue to see growth for Spinraza, frankly, in the US and outside the United States. So I would expect to continue to see Spinraza being a significant portion of our commercial revenues as the year unfolds. And then, adding to that, of course, we have Tegceti and Waylivra as they expand into new countries, in Europe in particular.
positions that are
That are utilizing the genetic testing program to identify patients who could be potential patients for Tech City and then getting those positions on board and and getting those those identified patients on board with takes Eddie. So I think that's where a lot of the the growth is coming from and we're looking forward to the continued success of that program and and other programs that that is engaged in right now to grow take City money news this year and also frankly to to grow we live our revenues working with similar programs. Got it. Got it. It's really helpful there and then just finally, how should we be thinking about, you know, risk the place and likely market and shoot this later this year and the impact to spend router use
Elizabeth L. Hougen: And then we have a very substantial base of R&D revenues anchored by significant amortization of upfront and milestone payments and then built on by licensing fees and milestone payments as the year unfolds. Gotcha. Thank you. And for Wailevra, the resubmission of the marketing authorization in the U.S., what do you have, what do you need to complete to be able to refile this year? Yeah, great question. This is Richard.
Richard S. Geary: There is nothing left to complete except writing up the results. So all of the expanded studies in open label as well as expanded access are being added to the filing and bring us to about a three-fold increase in exposure in patients, as well as additional safety data, which is very supportive. So that's, we should expect that to happen sooner than later in the year. Based on that, I don't think we're guiding to a timing, but certainly we are expecting to file this year. Our next question comes from Paul Matteis with EFL. Please go ahead. Hey, thanks for taking the question. This is Nate on for Paul.
I'll start sure, you know, it's been rasa continues to be.
Foundation care for all forms of SMA and um, uh as Beth mentioned earlier by Jin is expecting continued growth of spinraza, despite the potential for additional competition down the road and it's setting a very around instead of very high bar on efficacy and said that competitors are going to have to meet to be a significant competitors for the estimated population that's hard to comment on competition when so little data has actually been presented. And so, you know, I I really don't want to comment on the potential for all other drugs in this space like the plan suffice to say that we're we're very confident that will continue to perform very well for over 12 Farms of SMA this year off.
Paul Andrew Matteis: Firstly, for the LARC-II Phase 1-2, can you review the study structure and, specifically, beyond safety and PKPD, are you, or what exploratory markers of efficacy are you collecting? And then there is a follow-up. Eric, we haven't disclosed much about the details of the LRRK2. I don't believe we've disclosed things beyond that we're treating both genetic patients with LRRK2 mutations as well as the general population. That's correct.
Eric E. Swayze: And, of course, it's a first in human studies, so the primary endpoint is safety, but you can imagine there are lots of secondary biomarkers and exploratory endpoints to look at. More will come out on that study as the program matures. Alright, gotcha. Well, maybe a second pipeline question. On the C9 ORF program, are we thinking about this in the right way that's primarily going to be addressing the gain of function aspects?
for years to come
Our next question comes from Elgin with Laidlaw and Company, please go ahead. Thanks for taking the questions off. Just the one level link on the previous one, which is that you guys going to file a little later this year as well as you can do start a picture of study for April see three like in FCS. So is there any connection or the did the the relationship while expectation of those two events?
Eric E. Swayze: And if that's correct, are you worried at all about the loss of function aspects of C9 ORF? And secondly, would you consider moving from ALS to C9-RF-FDD as well? So, good questions both. Yes, you are thinking about it correctly that we are addressing predominantly the gain-of-function aspects of the C9-ORF72 gene, which is causal for C9-ORF72 ALS and FTD. However, I would emphasize that much of the preclinical data really suggests that it is a gain-of-function disease pathogenesis process. So, I think that medicine is another one that, like many of ours, that's directly on target and on mechanism. And as you point out, C9-ORF72 is also implicated in FTD, and with Biogen, we're actively considering how to move that drug forward in both ALS and FTD.
Hi, and thanks for the question. Those two events are not linked in any way. We're having very productive. I own a Samsung that discussions with the FDA on weight live rep and is Richard indicated. We're we're we now are in a Monday is a fortunate position of having a lot more data to make the case that is important in medicine should be approved in the US and planning to refile later this year, No ways just linked able to see three like we obviously have a lot of patience. Um, it's obviously just the same patient population, which is the point of your question, but in no way of life are are these filings the one for potential approval with the start up a phase 3 trial in any way and like together those are moving forward independent wage.
got it. Thanks for the questions.
Eric E. Swayze: Yeah, and I'll just expand on that a little bit, Nate, by reminding you and others how we're targeting ALS with Biogen. Our SOD1 program, of course, is in Phase 3 for another genetic form of ALS, SOD1-related ALS, in addition to C9-ORF as a second one. And recently, we added a third medicine to the Ionis Biogen pipeline for sporadic prognosis of ALS and much broader non-genetic forms of ALS. So we're doing a full court press on all forms of ALS, and I think there will even be more. Great to hear. Thanks, guys. Our next question comes from Chad Messer with Needham and Company. Please go ahead. Great
And we don't see any impact that we could have on the urgency that we have to get.
The pastry study would be like a movie.
Okay, great. Maybe just quick follow-ups, which is that how much stock repurchasing Des Moines still left? We have we have bought a fully executed on the stock repurchase program the initial program that our board approved. So that is is wrapped up right now. And as I said earlier with where our stock is trading right now, you know, we think it's a it's a, you know, great investment. So we may be looking to expand that into the future.
Chad Messer: Thanks for taking my questions. Let me just start with the TTR phase 3 program now that you've got those two studies up and running. Can you maybe set some expectations for enrollment timing?
Okay, great. Thanks a lot. Appreciate it. Thanks. Our next question comes from Jana Wang with Barclays, please. Go ahead.
Richard S. Geary: You guys have some experience in rolling trials in this space. Is it your sense that it's easier or harder to enroll now that there are commercially available options for these patients? Appreciate the question, Chad.
Miss when your line is open.
Oh, sorry. I got my line muted. Thank you very much for taking my questions. So I just asked one question regarding the data expectation bread. Do you have any thoughts you know what you would consider as a very impressive data on meaning what data?
Richard S. Geary: Thank you. Yeah, we're very excited. Ionis with Hexia, we're now underway two phase three studies for both the cardiomyopathy, the larger population, which includes, of course, hereditary and wild-type, and the polyneuropathy patient population, separate phase three, where we're targeting essentially the same label as Texas City. As far as expectations go, we're looking for these studies to complete in the 2022-2023 timeframe, and enrollment is actively underway for both studies As for challenges related to enrollment and how competition, particularly stabilizers, may impact that, we actually believe that our trial design for cardiomyopathy offers many advantages for patient enrollment. The great work that they're doing to make people aware of this disease. Hereditary polyneuropathy is certainly going to be a challenging role. There's no question about that.
The things you know and Sarah this this will be the last question were running long long time. So as I mentioned earlier. We're very excited about the sod one elements program. If you recall the phase two study was three months in which the fact that were some of the clinical endpoints that were looked at in the study that really made everyone so excited about it where the hell was functional rating scale and um respiratory respiration improve respiratory function and then trial and and and as I mentioned earlier the results were, you know, remarkable really stunningly positive and that was only three months Biogen executed a very efficient pastry program, which they basically added a new cohort to the on Thursday.
To study so that they can start that study very quickly.
And the way the simply think about it is that the endpoints are essentially the same as the way they were the phase two study. We're just looking for even greater efficacy than we still have three months.
Great. Thank you. So, thank you again everybody for joining us today. We're obviously very excited for this year, and and we look forward to updating you on our progress as the year unfolds and wish everybody a great day. Thank you very much.
Richard S. Geary: There are multiple drugs approved for this rarer patient population with DTR mellitosis, and there are other clinical trials in progress as well. However, with the great work that AXSIA is doing to identify patients and investigators and the work they're doing with AXSIA Connect as well as our strong relationships with investigators from our NeuroTTR phase 3 study, we're confident we'll be able to roll this study out on schedule, and we're feeling good about it. The other advantage to the neuropathy study, of course, is that it's an open-label study. So patients will not be on placebos.
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Richard S. Geary: We're going to be comparing the results of that study to a historical control, which of course will help enrollment as well as the fact that the sample size is significantly smaller than our phase 3 NeuroTTR study. So there will be challenges for polyneuropathy, but I think we can manage. Yeah, and then just on the polyneuropathy study that has an interim analysis, is that meant to be something you can file on, or are you just trying to get an earlier sense of efficacy? We will look at the interim analysis data at eight months and make decisions based on data, and those will be data-driven decisions.
Richard S. Geary: I want to remind you that at eight months in our Neuro-TTR TXETI phase three trial, we saw high statistical significance. We have a very nice comparison at our interim analysis at 8 months in the TTR-Likas study that we'll be able to compare to historical controls. We want to get this medicine to patients as rapidly as possible, and if the data supports it, off we go. All right, great, thanks, very helpful.
Vincent Chen: Our next question comes from Vincent Chen with Bernstein. Please go ahead. Great, thank you very much for taking the questions. A couple for me.
Vincent Chen: So the first one on Huntington's, just sort of following up on the earlier... What should we be looking for in the updated data tomorrow? I guess, in your view, we'll get some data, updated data on safety and biomarkers, including neurofilament light chain. What does a good outcome look like in terms of the updated safety and biomarker data, including neurofilament? And then a second question on a somewhat different topic
Eric E. Swayze: I was just wondering if you could provide any color on the relative mix of product sales in terms of, I guess, weight libra versus tech study, and then for tech study, U.S. versus O.U.S. Eric, would you like to touch on the biomarker data at the NGM? Yeah, I mean, I don't really want to get ahead of our partners, Roche, who are presenting the data tomorrow, but really, what's being presented should be thought of as an extension of the data that they've already presented, and also, note that the safety profile that has been presented for the drug is outstanding. The phase three trial, as Brett mentioned, is on track, is scheduled to read out in 2022, and we're very pleased with the progress of the drug and pleased with the way Roche is advancing it.
Eric E. Swayze: Yeah, the way I see it, Vincent, the key message is the fact that the Phase III trial is on track, as Eric said, as I said earlier, and Roche is very excited about the program. The bi-monthly dosing is looking excellent, and it's moving forward on schedule. We will be issuing on Friday a sort of a roundup, a short summary of all the presentations on our Huntington drug so we can capture it. We'll post that to our website, and we've also distributed it. Beth, would you take the division of Tegceti-Wey-Livre?
Elizabeth L. Hougen: Sure. So, as you can imagine, since Wey-Livre was just launched late in 2019, and in Germany really only, the vast majority of the revenue in 2019 was generated by Tegceti. And we were, you know, pleased to see steady progress quarter over quarter with quarter over quarter growth in 2019. We think that sets an important and strong foundation for continued growth this year. And we look forward to moving Wey-Livre and Tegceti into new countries this year. In terms of the mix between U.S. and ex-U.S., that's information that we in Exeia are not sharing at this point.
Ellie Merle: Great, thank you very much. Our next question comes from Ellie Merle with Cantor Fitzgerald. Please go ahead. Hey guys, thanks so much for taking the question. Just on the oral program, now that you're committing to 2020 for proof of concept data, can you walk us through what exactly we'll get in this readout? And I guess what specifically would constitute, from your perspective, proof of concept for oral delivery? Are there specific levels of protein knockdown relative to the sub-few that you're running in parallel that you'd be looking for?
Brett P. Monia: Or just can you sort of walk through, you know, what, in your perspective, would constitute proof of concept for oral? Thanks for the question, Ellie. So, yeah, we're very excited about the clinical trial in progress, evaluating the potential for commercially viable oral delivery with our partner AstraZeneca, and as you mentioned, the plan is to have data readout from that study in the second half of this year. The other aspect of this topic that I'd like to expand on, if you will, is that, you know, we're not sitting still on the development of formulations to further We actually have active research ongoing at Ionis where we are already making substantial, significant improvements in the potential for oral delivery, even beyond that of the formulation we have in our clinical study right now.
Brett P. Monia: So, you know, we're continuing to make advancements in oral delivery, and we're hoping to even bring those on in the future further, where we've identified a number of Ionis-owned products that we're planning to bring into development as an oral pill soon after, you know, right behind the Ionis AZ collaboration. So this isn't, there are many ores in the water, if you will, in the oral front, and we're feeling pretty good that we're going to have success in making oral a commercially viable platform for our platform. I got it. Thanks very much for the caller.
Ellie Merle: And just one quick follow-up, if I may. Just for Brett, I mean, it seems like you have a lot of programs in development. You have many, you know, readouts this year.
Brett P. Monia: I think in your slides, you called out that you have, you know, four proof of concept readouts this year. I guess, which program or data set are you most excited about? Well, it's hard to pick one.
Brett P. Monia: I mean, with a pipeline of more than 40 drugs, all of which have the potential to be transformative in nature, it really is. And if we went around the table here, we'd probably get six different choices. But in the shorter term, well, we have the rare disease buckets, and we have the broad disease populations, right? On the other hand, in our rare disease bucket, I gravitate towards ALS. I mean, there are no treatments for this terrible neurodegenerative disease.
Brett P. Monia: And Ionis with Biogen is, as I said earlier, the analogy of a full-court press on all forms of ALS, which we are doing now. Our SOD1 program is due to readout for the first of multiple ALS drugs. As a reminder, that drug showed really remarkable, provided really remarkable evidence of efficacy in a short three-month study in patients with SOD1 ALS. And now, the Phase 3 is going to be readout next year. As Eric mentioned earlier, we have a C9 program that's also a Phase 2 program that's due to readout next year. Now we have a drug for sporadic ALS. I would lean towards those two programs, but I could spend all day talking about our pipeline. There are lots and lots of drugs there to be very excited about.
Tyler Van Buren: Got it. Thanks so much for the caller. Our next question comes from Tyler Van Buren with Piper Sandler. Please go ahead. Hey guys, good morning.
Brett P. Monia: Just had a brief follow-up on your comments on capital allocation earlier. You mentioned potential complementary technologies that you're looking at, so just wanted to get your updated thoughts or interest in tissue-specific technologies. There are some, you know, emerging out there, tissue-specific RNA technologies, and one example is antibody conjugates, so just wanted to get your thoughts there.
Brett P. Monia: So, thanks, Tyler, you know, we are very. I'm thrilled to be in a position of such a strong financial position that allows us to invest in technologies that complement our antisense platform, expand the reach of our antisense platform, and do even more than that. We're investing in genomics to identify novel targets. [Inaudible] Just late last year, we completed a partnership with a genomics company to identify novel targets, and with another company to identify novel strategies, like-a-strategies, to expand the reach of antisense to newer organ systems and new cell types. We're making great progress. Antibody conjugates and their derivatives are just one aspect of the types of strategies we're taking. I view that as one tool in a toolbox of approaches with like-a's that we have and we're developing and we're working on ourselves. So, they have the potential to work, but I believe that we have many different strategies that are showing promise for getting into cell types that are less sensitive to antibody.
Jessica Fye: Great, thank you. Our next question comes from Jessica Fye with J.P. Morgan. Please go ahead.
Brett P. Monia: Hey guys, uh, good afternoon, thanks for taking my question. Just following up on one of the earlier questions about Andrew Peat and Link 3, um, can you just talk a little bit about how you see, that product positioned relative to ApoC-3-Liqa. Is the ApoC-3-Liqa really going to focus on the indications that you've previously discussed for Willibra? Thanks, Jess, and I appreciate the question. So, Angiopletin, first of all, of course, we're thrilled with the results from the Phase II studies that Ionis XC unblinded and presented top-line data on or announced top-line data for both programs, ApoC3-like and Angiopletin-like, 3-like, both at their primary endpoints, both are positioned very well for phase 3 trials down the road. There is overlap in both of these medicines in the atherogenic lipids that they manage, that they control, triglycerides, remnant cholesterol, LDL cholesterol, positive effects on HDL, but there's also a significant enough difference between these two drugs that we believe, as does our partner Pfizer for angiopoietin-like 3 and of course XGA2, that they differentiate significantly, sufficiently well that they will have a different profile in patients with cardiovascular disease.
Brett P. Monia: I think that ApoC3 Leica is the most potent triglyceride-lowering target drug out there today, and Androfluten-Leic-3 brings a number of other advantages, such as effects on cholesterol in addition to the significant triglyceride-lowering and positive effects on HDL, so I think they differentiate enough to be very important and meaningful additions to the treatment of cardiovascular disease in the future, as does our partner Pf Our next question comes from Manny Paruhar with SVB Lundryk. Please go ahead. Hey, good morning; this is Rick on the line from Mani.
Manny Paruhar: I have two questions for you. First, just broadly speaking about the opportunity set for the oral delivery of ASOs. Do you think oral delivery could potentially be a good fit for any liver-directed therapy?
Brett P. Monia: Or do you think the technology is best utilized in specific areas like cardiometabolic indications? And second, just given the increasing focus on your wholly owned pipeline, could you give us a sense of how you're currently viewing the relationship with Axia? Do you think it would make sense at any point to think about bringing the remainder of Axia back into the company? I'm really just looking for any commentary on how you view the relationship with Axia evolving as more focus is placed on your internal pipeline? Sure thing. Thanks, Rick.
Brett P. Monia: So, the progress we're making on oral delivery, if successful, has the potential to reach all of our liver programs. That's what's really so exciting about it, not just this one particular clinical trial, but also the potential impact it'll have on any of our liver-like programs, including drugs that target ApoC3, or angiopoietin-like 3, or Factor XI, GTR, and so forth, and we're focused on that, and as I said in one of the questions earlier, we've already identified additional liver targets that And as I also mentioned, we're continuing to improve on the current formulations, which are showing a lot of. We're changing gears.
Brett P. Monia: We're very excited about XCEA, and we're committed to XCEA's success, and we're confident they're going to be very successful. Our wholly owned rare disease pipeline is growing and expanding, and there are lots of opportunities to bring these drugs to maximize the commercial value of each of these medicines in different ways, and Axia is certainly one of those options that are available. And, as we mentioned earlier, we're already in negotiations and discussions with Axia about the potential addition of a new medicine, a rare disease medicine, to their pipeline later this year. As far as the future of Axia in relation to Ionis, that's a topic for discussion down the road.
Brett P. Monia: Right now, Axia is doing well, and they have a very full and exciting agenda, or pipeline agenda, which is really... We have an agenda that's comprised of both pipeline and getting white liver approved in the U.S. and continuing progress with TXETI and getting white liver launched. But with ApoC3-LiCA now in their pipeline and planning to start Phase 3 and FCS later this year, with TTR-LiCA undergoing two Phase 3 studies already in progress, they have quite a lot on their plate, and we believe that they're on track to deliver on their strategic goals. That's what I have to say about that right now.
Salveen Richter: I hope that addresses your question. Thank you for taking our questions. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead. Hi, thanks. This is Rawson.
Brett P. Monia: Can you help us understand the breakdown of product sales for TXETI and WeyLibre and some of the gating factors for both of these launches here? Specifically, I'm looking for some additional color on your comments that the prescribing base for TXETI grew about 4% Q over Q. I'm just trying to think about what factors drove this significant uptick and where these physicians are coming from, and then I have a follow Hi, it's Beth.
Elizabeth L. Hougen: So the breakdown of TegCeti and WeyLiver, as I said, is primarily TegCeti because WeyLiver was launched in Germany late in 2019. And right now, Axia is expanding WeyLiver out across additional countries in Europe, but they started with Germany. And that's a relatively small patient population in Germany with FCS. And so a small, very small portion of the product revenues in 2019 were WeyLiver, so the vast majority were TegCeti.
Elizabeth L. Hougen: In terms of the growth in prescribing physicians, you know, a lot of that is a function of the work that the Axia team is doing with their genetic testing program, getting out not only into academic centers but also into community settings, expanding the number of physicians that are utilizing the Axia genetic testing program to identify patients who could be potential patients for TegCeti and then getting those physicians on board and getting those identified patients on board with TegC So I think that's where a lot of the growth is coming from, and we're looking forward to the continued success of that program and other programs that Axia is engaged in right now to grow TegCeti revenues this year and also, frankly, to grow WeyLiver revenues by working with similar programs. Thanks, Ben. I got it. I got it. That's really helpful there, And then just finally, how should we be thinking about, you know, the risk of plans, likely market entry later this year, and the impact on Spinraza use? Well, I'll start, sure.
Brett P. Monia: You know, Spinraza continues to be the global foundation of care for all forms of SMA, Roz, and as Beth mentioned earlier, Biogen is expecting continued growth of Spinraza. Despite the potential for additional competition down the road, and it's setting a very high bar on efficacy and safety that competitors are going to have to meet to be significant competitors for the SMA population. It's hard to comment on competition when so little data has actually been presented. And so, you know, I really don't want to comment on the potential for other drugs in this space, like Ristoplam.
Brett P. Monia: Suffice to say that we're very confident that Spironza will continue to perform very well for all forms of SMA this year and for years to come. Got it. Thanks for the questions. Our next question comes from Yale Gen with Laidlaw and Company. Please go ahead.
Yale Gen: Thanks for taking the questions. I just want to link to the previous one, which is that you guys are going to refile with LIBRA later this year, as well as you're going to start a pivotal study for ApoC3-LiCa in FCS. So is there any connection or relationship or expectation between those two events? Hi Yale, thanks for the question. Those two events are not linked in any way.
Brett P. Monia: We're having very productive Ionis Xea discussions with the FDA on whey liver, and as Richard indicated, we now are in a fortunate position of having a lot more data to make the case that this important medicine should be approved in the U.S., and we're planning to refile later this year. In no way is this linked to ApoC3 Lika.
Brett P. Monia: We obviously have a lot of patients. It's obviously the same patient population, which is the point of your question, but in no way are these filings, the one for potential approval in the U.S. with the start of a phase three trial, in any way linked together? These are moving forward independently, and we don't see any impact that whey liver could have on the urgency that we have to get the phase three study for ApoC3 Lika moving forward.
Elizabeth L. Hougen: Okay, great. Maybe just a few quick follow-ups, which is how much stock repurchasing is still left? We have fully executed on the stock repurchase program, the initial program that our board approved, so that is wrapped up right now, and as I said earlier, with where our stock is trading right now, you know, we think it's a great investment, so we may be looking to expand that into the future. Okay, great.
Jenna Wang: Thanks a lot. I appreciate it. Thank you. Our next question comes from Jenna Wang with Barclays. Please go ahead. Ms. Wang, your line is open. Oh, sorry, I got my line muted. Thank you very much for taking my questions. So I just ask one question regarding the SOD1 data expectation.
Brett P. Monia: Brett, do you have any thoughts, you know, what you would consider as very impressive data or meaningful data? Thanks, Gina. And Sarah, this will be the last question. We're running long on time.
Brett P. Monia: So, as I mentioned earlier, we're very excited about the SOD 1 ALS program. If you recall, the Phase 2 study was 3 months where some of the clinical endpoints that were looked at in the study that really made everyone so excited about it were the ALS Functional Rating Scale and improvements in respiratory function in that trial. And that was only three months.
Brett P. Monia: Biogen executed a very efficient phase 3 program in which they basically added a new cohort to the ongoing phase 2 study so that they could start that study very quickly, and the way to simply think about it is that the endpoints are essentially the same as they were in the phase 2 study. We're just looking for even greater efficacy than we saw at 3 months. Great, thank you. Thank you. Thank you again, everybody, for joining us today. We're obviously very excited about this year, and we look forward to updating you on our progress as the year unfolds. I wish everybody a great day. Thank you very much. The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.