Q3 2024 Ionis Pharmaceuticals Inc Earnings Call
and Portempatian populations. With an FDA action date next month, we're ready to first bring all of the Zarsons of people with familiar cognitive microneemius syndrome or FCS, a serious and rare disease that today has no improved treatments in the United States.
And with phase 3 data and deepwood severe hyper-tragalist academia or S-H-C-G planned for the second half of next year, we expect to bring all of us into a much larger patient population in 2026.
With significant first-movement revenge in both populations and compelling results already demonstrated in FCS coupled with our expectations for similarly positive data in SATC, we believe Olz Arson could be these, standard of care for both disease indications.
In parallel, we're leveraging the capabilities established for Ulynula and Olzarsan and our preparations to launch Don at the Laws in the next year. Our first in-class treatment for HAE Prophylaxis.
For please that our NDA submission was recently accepted for review by FDA with no plan for an ad-com. Our Purdue State is set for August 21, 2025. And outside the U.S. our commercial partner at Suga expects the file from marketing approval in Europe soon.
With generated important and compelling positive data from our comprehensive download-war syndclinical program, including encouraging data from our Oasis Plus Switch cohort.
These results together with the potential for monthly, or every two months self-administration using an auto injector, strength and arblease that have approved. I'm the lures and this potential to advance treatment paradigm for people living with H.A.E.
Looking further ahead, our next wave of all the owns opportunities is progressing rapidly and includes our program for Angel Monsindrome, ION582.
Based on the positive results from the Halo's Phase 1 2 study and our alignment with FDA on the Phase 3 study design, we're on track to advance this potentially transformational medicine in the Phase 3 development in the first half of next year.
Ion 582 is an important program in our growing, holy-owned, neurology franchise, which now includes seven medicines in clinical development.
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On top of the great progress from making you across our whole own pipeline, our partner programs are also advancing very well. Allow me more, I own a discovered and developed medicines to reach more and more people, as demonstrated this year with the successful launches of Wienua and CalSati.
The launch of our first Ionis Co-branded Medicine this year, we knew it for people with a redittery ATTR calling their opathy, continues to progress well with AstraZeneca.
We knew it was now approved and available in major markets including the US, Canada and the UK and recently received a positive CHMP opinion in Europe.
We're confident in the potential of Wayne Uez to address that the larger ATTR card you might offer to the population, but they're ongoing landmark card you'll transform trial, on track to deliver the most comprehensive and most robust data set in these patients in the second half of 2026.
We believe Wynua has the potential to be the treatment of choice for the global ATT-tier population based on its strong efficacy profile and hereditary ATT-tier Polymeropathy and the freedom of simple at home self-administration together with AstraZeneca's global cardiovascular leadership and our leadership in KT-Jaram with those.
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And we're also pleased that CALSADE, the first approved treatment for a genetic cause of ALS, a medicine that was conceived and discovered by Ionis and commercialized by our partner Biogen, is now launched and available in Europe and China, in addition to the U.S.
Our other partner programs are also progressing well. This includes the ongoing Phase 3 Horizon study of telecarcin for Lp little a driven cardiovascular disease.
being developed by Novartis with data expected next year, and Daphne Reverson in phase three development with GSK for chronic HPV infection now fully enrolled with data expected in 2026.
Our accomplishments so far this year and the investments we're making move us closer to achieving our goal of bringing a steady cadence of new transformational medicines to patients for years to come and generating increased value for all Iona stakeholders. And with that, I'll turn the call over to Eugene.
Eugene: Thank you, Brett.
Eugene: Our pipeline has delivered many important achievements this year, including bringing two new medicines to people with serious diseases, eight positive data readouts from our mid and late stage pipeline, and an only completion in six phase three studies.
Eugene: Our progress positions us well to deliver important value-driving events still to come this year and throughout 2025.
These events include several potential regulatory approvals, two launches for wholly owned medicines, and three phase three readouts.
Eugene: In addition to all this, we will continue to expand and advance our pipeline of potentially transformational polio medicines.
Eugene: We look forward to the upcoming December 19th to do for action date for olizarsin in FCS and bringing olizarsin to patients assuming approval. Our NDA submission was based on the positive phase 3 balance studies in FCS patients.
Eugene: that showed substantial and durable triglyceride reductions with Olisarcin treatment. Importantly, Olisarcin also demonstrated substantial and clinically meaningful reductions in acute pancreatitis attacks.
Eugene: In patients taking our planned commercial dose, we observed a 90% mean reduction in acute pancreatitis events, with only one event in the treatment group, which occurred after nearly one year of treatment.
Eugene: This was compared to 11 events in a placebo group, with the first event occurring after only 9 days.
Eugene: Polizarsan also reduced hospitalizations by a remarkable 84% and showed a favorable safety and tolerability profile in the study.
Eugene: We're also developing olizarsin for the much larger SHTG patient population.
Eugene: Many patients living with SHTG today are unable to manage their triglycerides with current standard of care. As a result, we believe that Olazarsan has the potential to make a meaningful difference in the lives of people living with SHTG.
Eugene: Our comprehensive phase 3 program for SHDG fully enrolled will remain on track for data in the second half of next year.
Eugene: Following closely behind Olazarsan is Donny Dolorsan for the prophylactic treatment of hereditary angioedema.
Eugene: Our NDA submission was based on positive data generated from our Phase 2 study and Phase 3 program, which includes the OASIS-HAE and OASIS-PLUS studies.
Eugene: OASIS-Plus comprises an open-label cohort of patients rolling over from the Phase 3 study and a separate cohort that we refer to as the Switch Study.
Eugene: In the Phase III program, Donnie Doloresan demonstrated an overall sustained mean reduction in HE attack rates of more than 90% with one year of treatment for both monthly and bimonthly dosing regimens, while maintaining a favorable safety and tolerability profile in the study.
Eugene: This reduction translated to high levels of disease control and clinically meaningful improvements in quality of life across multiple measures in a vast majority of patients.
Eugene: These positive data were bolstered by the encouraging switch study results that showed a 62% further reduction in mean monthly HE attack rates for patients who switched to Donnie Delorsin from their prior prophylactic treatment.
Eugene: Importantly, more than 80% of patients surveyed reported a preference for Donny Doloresan over their prior treatment.
Eugene: Ninety-six percent.
Eugene: in up to three years of treatment with monthly or every two months dosing.
Eugene: Based on these robust results, we believe Donagh-Dolorsan could become a preferred prophylactic treatment for people with HAD. With a PDUFA date of August 21st next year, we look forward to bringing this important medicine to HAD patients for treatment and approval.
Eugene: Recent clinical outcomes data in ATTR cardiomyopathy with another TTR silencer further reinforce our confidence in the potential of buenu to improve cardiovascular outcomes in people living with this disease worldwide.
Eugene: With over 1,400 patients enrolled, our ongoing CardioTransform study is the largest and most comprehensive study ever conducted in ATTR cardiomyopathy.
Eugene: As a result, we expect the data from this study will enable physicians to make more informed treatment decisions in this dynamic treatment landscape.
Eugene: In addition, as part of our Phase III program, we're conducting advanced cardiac imaging sub-studies using MRI and scintigraphy, which will generate valuable data about the potential benefit of Waynua in cardiomyopathy patients.
Eugene: We expect a data readout from our Phase 3 program in the second half of 2026.
Eugene: The rest of our IMPRESA Phase III pipeline is also advancing nicely.
Eugene: Of the 9 investigational medicines in Phase 3, over half are ones that Ionis is co-commercializing or wholly owns.
Eugene: The vast majority have phase 3 data readouts or key regulatory filings expected in the next two years.
Eugene: In addition, Biogen recently presented positive PHASE-2-3 data from the DEVOTE study evaluating higher-dose mucinersin in patients with spinal muscular atrophy across all age groups.
Eugene: Building on these positive results and the well-characterized profile of Spinraza established over the past 10 years, Biogen plans to file for approval with global regulatory agencies for higher-dose mucinersin later this year.
Eugene: Biogen is also conducting additional studies evaluating mucinursin in SMA patients previously treated with Ristiplan and patients with a suboptimal response to gene therapy.
Eugene: These studies aim to address remaining unmet needs and better inform treatment decisions.
Eugene: Our next wave of polio medicines now includes seven investigational medicines with three recent study starts to treat both rare and more common neurological diseases.
Eugene: Zilgonursin is our medicine in phase 3 development to treat Alexander disease, a type of leukodystrophy.
Eugene: with Phase III data expected in the second half of next year. Zilka Nursen was also recently granted fast-track designation by the FDA, reflecting the serious unmet need that exists for this rare disease.
Eugene: We believe ION582, our wholly owned investigational medicine for Angelman syndrome, has transformational potential for the tens of thousands of people living with this serious rare disorder.
Eugene: Positive early results from the HALO study of ION582 in people with Angelman syndrome demonstrated consistent and encouraging improvement in all key functional areas across multiple assessments, with improvements observed across different ages and genotypes.
Eugene: We also saw favorable safety and tolerability at all those levels, including no discontinuations or adverse events that were considered related to study drug.
Eugene: We had a positive and a phase 2 discussion with the FDA.
Eugene: We reached alignment on a robust and comprehensive Phase III study design.
Eugene: And as a result, we remain on track to advance ION582 into pivotal development in the first half of next year.
Eugene: Our Plan C-3 study focuses on clinical endpoints that reflect the most pressing and meaningful outcomes for people living with Angelman syndrome and their caregivers.
Eugene: And we designed the study to deliver robust data in patients representative of the broader Angelman Syndrome population.
Eugene: My Global Phase 3 study will enroll approximately 200 infants, children, and adults with Angelman syndrome who have a maternal UV3A gene deletion or mutation.
Eugene: The trial will be placebo-controlled, which is the gold standard for scientific integrity and enables a simple and straightforward way to operationalize the study.
Eugene: We plan to evaluate two dose levels, dosed quarterly without a loading regimen, for approximately one year.
Eugene: Primary endpoint will be improvement in expressive communication, as assessed by the Bailey's Scale for Infant and Toddler Development, or BAILEY-4.
Eugene: which is an objective and direct clinician-administered assessment instrument.
Eugene: Secondary endpoints include evaluation of overall symptoms of disease severity, cognition, communication, sleep, motor functioning, and daily living skills.
Eugene: We observed positive results for these same endpoints in our HALOS Phase 1-2 study with IM582 treatment.
Eugene: We look forward to sharing our planned Phase 3 program at the TESS Global Science Summit this weekend.
Eugene: As our pipeline continues to mature, the remainder of this year and next year is going to be very significant for us in terms of regulatory actions and new product launches, reflecting our transformation to a commercial stage company.
Eugene: Still to come this year are two important regulatory milestones, including the FDA approval decision of Olazarson for FCS.
Eugene: And following the recent positive CHMP opinion, the potential approval of WANUA for ATTR polyneuropathy in Europe.
Eugene: As we look to 2025, in addition to bringing all of us into people with FCS, we're poised to deliver Donnie Dolores into people with HAE, assuming approval.
Eugene: We're also on track for three phase 3 data readouts next year. These include two wholly owned medicines, olizarsin for SHDG, a large patient population with high unmet needs.
Eugene: and Zilga Nersen for Alexander disease, our most advanced polio neurology medicine.
Eugene: and our partner Novartis expects phase 3 data for pelicarsin, first potential treatment targeting LP little aids, a major novel independent risk factor for cardiovascular disease.
Eugene: We also expect multiple data readouts next year from our mid-stage pipeline. This includes data from sapoblursin, our potential treatment for polycythemia vira, and ION464, our medicine that targets alpha-synuclein that we're studying in multiple systems atrophy.
Eugene: Positive outcomes for IM-464 or SAPA Burson could support advancing these programs into Phase 3 development.
Kyle: And with that, I'll turn the call over to Kyle.
Kyle: Thank you, Eugene. We are pleased with the continued strong progress for the WENUA-U.S. launch with AstraZeneca and hereditary ATTR polyneuropathy, which has demonstrated substantial, sequential, quarterly growth this year, driven by strong demand.
Kyle: We continued to see good uptake in the third quarter with product sales increasing 44% compared to the second quarter. Patient growth came from patients new to treatment, some switching from other treatments, and some using Waynua as an add-on treatment to their existing therapy.
Eugene: We are also encouraged by the breadth of prescribers.
Eugene: Physicians are reporting that patients are having a positive experience on Winoa. This includes physicians and patients seeing quality of life improvements, patients' ability to access treatment, and patients' ability to easily self-administer Winoa.
Eugene: And as we in AstraZeneca are progressing our pre-commercialization activities to support the substantial opportunity Wynua represents for the ATTR cardiomyopathy population estimated to be between 300,000 and 500,000 worldwide.
Speaker Change: Ionis has a rich pipeline of potentially life-changing medicines, and we are poised to deliver four independent launches, assuming FDA approvals, over the next three years.
Eugene: We are just weeks away from the first launch with Olazarsan, where IONAS is leading the way in the triglyceride lowering space.
Eugene: Olazarsson represents a blockbuster opportunity for Ionis. We have substantial first-mover advantage for two indications, FCS and SHTG. Our first plan launch is for FCS, which is a rare and the most severe form of SHTG.
Eugene: We then plan to launch in the much larger SHCG patient population with triglyceride levels of greater than 500 milligrams per deciliter.
Eugene: People with FCS and SHTG suffer from debilitating chronic physical symptoms that impact all aspects of their life. There are no approved treatments for people with FCS in the United States.
Eugene: People with SHTG are severely underserved by current treatment options and in many cases are unable to reduce triglyceride levels to current recommended guidelines.
Eugene: And in the most severe manifestations of FCS and SHTG,
Eugene: Fatal pancreatitis events that require intensive hospital care.
Eugene: We are right where we should be in preparing for our first independent launch for Olizarsin and FCS as we approach our upcoming FDA action date.
Eugene: Since this is a rare, under-diagnosed disease,
Eugene: Our medical affairs team has been working to increase disease awareness. This includes engaging with KOLs and physicians currently diagnosing and treating FCS patients such as endocrinologists, lipidologists, and cardiologists.
Eugene: Building on a strong foundation of increasing disease awareness, the team is identifying physicians most likely to prescribable lazarsin,
Eugene: and working to identify FCS patients.
Eugene: As with any rare disease launch, it takes time to identify patients, so this work will continue as we build launch momentum.
Eugene: To bolster our field team's efforts, we are executing a tailored omni-channel strategy to drive deeper engagement and real-time insights from patients and healthcare professionals.
Eugene: We are deploying a world-class patient and caregiver team to provide a seamless customer experience that supports patients initiating and remaining on therapy.
Eugene: The USFCS expanded access program is in place, enabling patients to have access to treatment ahead of potential approval.
Eugene: And now, the sales team is trained and in the field, calling on potential traders.
Eugene: All of this, along with the learnings from our co-commercialization launch of WENUA, sets us up to execute successfully on our first independent launch.
Eugene: And as we look beyond our first launch, we plan to further scale our commercial capabilities for SHTG to realize the full blockbuster potential of Olizarsan.
Eugene: The team is also preparing to bring Donna Doloresan, a potential first-in-class medicine, to the market next year by leveraging and building upon our efforts and learnings from the way NUWA launched and upcoming Olazarsan launched.
Eugene: HAE is a well-defined patient population with an estimated 20,000 people affected in the U.S. and Europe.
Eugene: While prophylactic treatment in the U.S. is well accepted by patients and physicians, the market continues to grow. Additionally, a meaningful segment of patients in the U.S. are switching treatments, seeking a better option.
Eugene: Outside the U.S., acute therapies have historically been the standard of care. However, prophylactic treatments are gaining ground, especially in Europe.
Eugene: Many people with HE are unsatisfied with the current treatments and are looking for an option that reduces frequency and severity of attacks while also offering good tolerability and convenience.
Eugene: Based on Donnie Doloresan's strong clinical data, including the switch data, and the simplicity of monthly or every two-month self-administration via an auto-injector, we believe Donnie Doloresan offers the attributes that many people with HEE are looking for.
Eugene: Therefore, we believe Donnie L. Olson, if approved, could be a preferred prophylactic treatment for both patients new to therapy and patients currently on available therapies.
Eugene: I am pleased to share that the team is prepared for our upcoming launches.
Eugene: All of our key commercial leaders and their teams are in place today, including our chief commercial officer, market access, patient services, and marketing and sales.
Eugene: We have built out a highly experienced, top-tier team who have led or contributed to hundreds of product launches.
Eugene: We are executing on all of the initiatives needed to successfully launch our medicines.
Eugene: Importantly, we are ready for our first independent launch, which is just a few short weeks away.
Eugene: We're right where we need to be with three additional launches planned over the next three years with more to follow. With that, I'll now turn it over to Beth. Thanks, Kyle.
Beth: This year we've made significant strides in advancing our pipeline and achieving our business goals. Positioning Ionis to deliver on our vision of bringing a steady cadence of innovative medicine to patients in need.
Beth: To maximize the impact of our potentially transformational medicine and fully realize the opportunities ahead, sustained investment is essential.
Eugene: Additionally, it allows us to continue to independently advance our next wave of wholly owned medicines to maximize our potential for sustainable revenue growth.
Eugene: We earned revenues of $134 million and $479 million in the three and nine months ended September 30, 2024, reflecting a 7% decrease and 3% increase compared to the same period last year, respectively.
Eugene: Our diversified revenue streams continue to serve us well, including commercial revenue primarily from royalties and R&D revenue from multiple partner programs.
Eugene: Benraza remained the primary source of commercial revenue with $57 million and $152 million of royalties for the third quarter and year to date.
Eugene: We were encouraged that U.S. Spinraza product sales increased 2% in the third quarter compared to the same period last year. Outside the U.S., Spinraza product sales were impacted primarily due to an annual order from a single country that did not recur in 2024.
Eugene: This one-time loss is not expected to impact fourth quarter sales.
Eugene: Wayneua product revenue continued to reflect accelerating growth on a sequential basis.
Eugene: driven by strong underlying demand, increasing 44% in the third quarter compared to the second quarter.
Eugene: Waynua product sales were $23 million and $44 million for the third quarter and year to date. As a result, our royalties for Waynua were $5 million and $10 million for the respective period.
Eugene: R&D revenue for the quarter was in line with the same period last year and increased on a year-to-date basis, reflecting the value that our pipeline and technology continues to generate.
Eugene: As planned, our non-GAAP operating expenses increased for the third quarter and year-to-date over the same period last year, excluding certain one-time costs in 2023.
Eugene: The increase was driven by higher sales and marketing expenses as we continue to make investments to prepare for our upcoming independent U.S. launches of Ola Sarsen and Donnie DeLorsen.
Eugene: Our sales and marketing expenses also included our minority portion of WENUA U.S. launch expenses.
Eugene: These investments resulted in our overall SG&A expenses increasing 13% and 26% for the third quarter and year-to-date respectively.
Eugene: In line with our plan, R&D expenses were essentially flat for the third quarter and year-to-date compared to the same period last year.
Eugene: As we have continued to build our commercial infrastructure and support functions to support our back-to-back planned launches with Ola Zarsan and Donny DeLorsis.
Eugene: We have grown our employee base to just over 1,000 employees.
Eugene: Achieving this milestone with modest expense growth highlights our financial discipline and our commitment to drive operating leverage while advancing our strategic priorities as we transform to a commercial stage company.
Eugene: Our year-to-date results keep us on track to meet our 2024 P&L financial guidance, including revenue of more than $575 million, of which approximately $175 million will come from non-cash amortization of partner payments we received in prior years.
Eugene: We continue to project our full-year 2024 operating expenses to increase by a mid-to-high single-digit percentage compared to 2023.
Eugene: excluding the impact of one-time costs last year. And similar to our year-to-date results, the increase will be driven primarily by sales and marketing expenses as we prepare for our sequential independent launches.
Eugene: And with our recent equity offerings, we are now projecting that we will end 2024 with $2.2 billion in cash.
Eugene: Looking beyond this year, we plan to deploy our cash to realize the substantial opportunities before us.
Eugene: We will continue to invest in go-to-market preparation for the planned Ola Zarsen and Donny DeLorsen launches Additionally with our increased confidence in the potential of Wynua and Ola Zarsen to address broader patient populations
Eugene: We plan to scale our capabilities in line with the significant potential that these important medicines represent. In parallel, we are investing to ensure sustainable growth with our next wave of medicines.
Eugene: This includes pre-commercialization activities and phase 3 development for ION582 for Angelman syndrome and zilgonericin for Alexander disease.
Eugene: Importantly, we expect our focused investments to drive strong revenue growth and create shareholder value as our medicines reach more and more patients in need.
Speaker Change: And with that, I'll turn the call back over to Brett.
Brett: Thank you, Beth. It's worth emphasizing that the achievements you've heard about today and throughout the last few years position us well as we look to enter a new era for Ionis, as a fully integrated commercial-stage biotechnology company poised to directly bring a steady cadence of medicines to people with serious diseases.
Speaker Change: We've arrived at this point by being focused on a clear vision and a clear set of strategic objectives, which include building and advancing our pipeline and delivering medicines that we conceive, discover, and develop directly to patients.
Speaker Change: Our pipeline has consistently delivered positive Phase II and Phase III data, resulting in the approvals and launches of Waynua and CalSATI, the anticipated approval and launch of Olzarsen this year, and the expected approval and launch of Donvillorsen next year, with much more to come.
Speaker Change: And in parallel, our partner programs are progressing on track, with important phase 3 readouts next year and beyond.
Speaker Change: In addition, we're extending our leadership position in oligonucleotide therapeutics by expanding and diversifying our technology.
Eugene: Further optimizing our capabilities in established therapeutic areas and opening up new disease areas for drug discovery.
Eugene: And we recently further strengthened our financial foundation, providing the means to continue advancing our strategic objectives to power future revenue growth and positive cash flow.
Speaker Change: All of this sets us up to deliver on our goal to bring new medicines to patients for years to come.
Speaker Change: And with that, I'll now open the call for questions.
Eugene: Danielle?
Danielle: We will now begin the question and answer session. To ask a question, you may press star then 1 on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys.
Danielle: If at any time a question has been addressed and you would like to withdraw your question, please press star then 2.
Speaker Change: The first question comes from Gary Nachman from Raymond James. Please go ahead.
Gary Nachman: Hi guys, good afternoon. So first on Olazar, I think for FCS.
Gary Nachman: How soon will you be able to launch?
Gary Nachman: Post-approval, and maybe talk about the expected pricing there. Are you in labeling discussions and anything to call out on those expectations? And just generally how we should be thinking about that ramp. And then I have one follow-up.
Speaker Change: Gary, we are in labeling discussions.
Speaker Change: It's inappropriate for me to comment further on that since we are in discussions with the FDA, but everything is on track.
Speaker Change: Yeah, thanks, Gary. So, like I mentioned in my remarks, we're very pleased with the team that's in place. We're ready to go. Leadership is here. The sales team is in place. Medical affairs is in place.
Speaker Change: So everything is ready to go for December 19th, and in terms of launch timing, we do expect to launch this year and get product into the channel before the end of the year, so that's exciting.
Speaker Change: In terms of pricing for FCS, we will launch with an ultra-rare pricing, which would be expected in this category based on somewhere between 1,000 and 4,000 patients that are appropriate for the therapy.
Gary Nachman: So that pricing will be communicated upon approval and look forward to sharing that with you on December 19th or sooner.
Gary Nachman: Okay, great. And then just on the phase 3 Angelman study, so...
Speaker Change: Will there be any interim looks over the course of the year since it's a one-year endpoint?
Speaker Change: Any monitoring of these patients required on the safety side, and maybe just comment if there was any back and forth in terms of the right primary endpoint for these patients, or if there was easy agreement there with the FDA. Thank you.
Speaker Change: Very briefly, Gary, we have no plans for an interim look at data during the course of the Phase 3 Reveal Study.
Speaker Change: It's a robust study design, and as you well know, Gary, we have a very strong relationship with the neurology division of the FDA.
Speaker Change: We came in with our proposals, and after some minor back and forth, the FDA was fully supportive of our proposals. So there was very little negotiating at the end of Phase 2 meeting.
Gary: Okay. All right. Great. Thank you. Thanks.
Speaker Change: The next question comes from Jessica Fye from J.P. Morgan. Please go ahead.
Jessica Fye: Hey guys, good morning. Thanks for taking my question. I have a question about the timing for CardioTransform. So I think enrollment completed on July 31st, 2023, and 140 weeks after that is April 6th, 2026.
Gary: And in the past you talked about that readout coming in the first half of 26, then mid 26, and now it sounds like data in the back half of 26.
Gary: The trial towards the end having variable but a little bit shorter follow-up than that. So is the plan now to follow all patients out to 140 weeks?
Gary: Or are you really just budgeting like a full three months or more for data cleanup and analysis? Thank you.
Speaker Change: Thanks, Jess.
Speaker Change: We're really, really continue to be very pleased with not only the conduct of the Phase III Cardiotransform study but the design of the study. It's set up
Speaker Change: to deliver the richest, most comprehensive data set ever delivered for an investigational medicine for TTR cardiomyopathy.
Speaker Change: And we think that that is going to provide a...
Speaker Change: It's a very significant advantage once we get to the market with our co-partner AstraZeneca.
Speaker Change: With another silencer in this class, for this disease indication, we were considering the possibility of an early readout.
Speaker Change: It is very clear to us and our partner AstraZeneca that the best decision would be to run the study out to its full completion in which all patients re-completed 140 weeks of treatment.
Speaker Change: So that's the only change, really, and the last part of your question is exactly it.
Speaker Change: It brings you to about mid-year of 2026, and then you need to close the database, you need to go through the blocking and tackling, and then read the study out. So nothing there has changed except that we have made the decision to go through full completion through 140 weeks.
Speaker Change: Thank you.
Speaker Change: The next question comes from Mike Ulz from Morgan Stanley. Please go ahead.
Speaker Change: Hi, it's Avi Novick on the line for Mike. Thank you for taking our questions. Yeah, I guess just on FCS, given that it's, you know, pretty small patient population.
Avi Novick: Can you, could you be able to give us some color on approximately how many patients you've identified and, you know, with a competitor possibly coming to market just a few quarters after you, you know, what's your confidence in being able to potentially saturate the market before they can reach it? Thank you.
Speaker Change: Yeah, thanks for the question. First, I'll just reiterate, you know, we're really excited about the launch and we're ready to go.
Speaker Change: We've been in this space for quite some time and fortunately we've had our medical affairs team in the field.
Speaker Change: educating physicians and spending time talking about the diagnosis of FCS and the importance and the way that these patients unfortunately are being impacted by their disease.
Avi Novick: Recently, we have the sales organization that has been hired and is now in place as well, and they've been deployed. Not only are they profiling accounts, but they're also educating around how to identify these patients.
Avi Novick: and physicians are beginning to assess who could potentially have FCS within their
Speaker Change: within their practices.
Avi Novick: Keep in mind we have an EAP that has been established in the U.S. We also have Open Label Extension that is ongoing. So there are patients that are currently being treated and benefiting from therapy, fortunately. We are continuing to...
Avi Novick: Talk about the launch and figuring out exactly where these patients reside. That will go on for quite some time, as you would expect, being that FCS is a rare disease. As a treatment comes to market, and as you mentioned, Elezarsin potentially will be
Avi Novick: The first indicated treatment for FCS, we expect that patient identification will go up because as physicians know that there's a treatment available, they will be looking to
Avi Novick: I'll figure out where these patients are, bring them in, and obviously I get them started on Olozarsin.
Avi Novick: So, the nine-month-plus lead that we have over the competition, I think, is very relevant and will allow us to secure a good launch and a bolus of patients up front, and we continue to do that patient identification longer term, and we expect that ramp to continue over time.
Speaker Change: Okay thank you and then just as a quick follow-up I guess how quickly do you expect to be able to roll patients from the open label extension as well as the early access program on to paying commercial drug? Thanks.
Speaker Change: Yeah, that's a process that can happen pretty rapidly. You know, we expect to be able to communicate things once we have the approval for Olazarsan, the commercial approval, and you know, we have a patient support program in place.
Avi Novick: And we'll be able to obviously communicate appropriately with those offices that have...
Avi Novick: those patients and be able to get prescriptions in fairly quickly and start that transition. So, you know, I don't want to put an exact time frame on it, but we have a plan in place in order to execute that transition and we're very confident in being able to make that happen.
Speaker Change: Yeah, and just to add to that, Avi, just as a reminder, that will be in the United U.S. Patients in the Open Label Extension that are in the U.S. Obviously, the Balance Study was a global study, and it'll take time to get the approvals in Europe and elsewhere and enroll those patients.
Speaker Change: Okay, great. Thank you for taking our questions.
Speaker Change: The next question comes from Yanan Zhu from Wells Fargo Securities. Please go ahead.
Yanan Zhu: Great. Thanks for taking our questions and congrats on the progress. Maybe first, a couple of very quick follow-ups to earlier questions and answers. On FCS, I was wondering, how do you anticipate the payer dynamic?
Speaker Change: Given that this is likely a highly priced drug, would that reimbursement dynamic throttle the launch in any way?
Speaker Change: And for the ATTR cardiomyopsy program, I was just wondering, you just talked about the 140-day full completion. Is there any possibility or desire to extend it further, given that our 9-1-1 study had some of the secondary endpoints out to 42 months?
Speaker Change: Thanks. I have a follow-up after that. Thank you. Thanks, Yanan. I'll take these.
Speaker Change: I'll take the FCS payer dynamics question. So, again, as you know, we're really like a trial design, most comprehensive study ever conducted in this patient population.
Speaker Change: And we are committed to reading it out to its completion through 140 weeks in the second half of 2026.
Speaker Change: Of course, we will do what makes the most sense for the drug, for Waynua, to have the most robust data set as possible, of course, the trial. So that's something that we at AstraZeneca will continue to think about and potentially act on, but we'll do what's best for the drug.
Speaker Change: on the FCS payer dynamics.
Speaker Change: Yeah, we've done a lot of work with payers, as you would expect, in terms of pricing and also educating them on FCS as an ultra rare disease, and the potential patient population that resides there.
Avi Novick: Payers, as they're looking at this, doing their budget impact models and understanding their exposure rate potentially within the disease area and the way that these patients are going to present, have been very accepting and very understanding of the price point in which they expect to see olozarsin be launched at.
Avi Novick: Thanks.
Avi Novick: The approval process from a prior authorization standpoint will be a question in the learning as we go into the launch But what we do know is that We have a good pathway here. We've got great data sets not only in terms of triglyceride lowering that are deep that are sustained The patients can self administer this drug
Avi Novick: But we also have great data around hospitalizations and hospitalization rates.
Avi Novick: And so that information combined with the patient population that is anticipated to be treated by these physicians, we expect the payers to work effectively through the process, get these prior authorizations approved, and ultimately get patients on drug very quickly.
Speaker Change: Got it. Very helpful. Then, I just have a question about the Phase III design for the Andromeda Syndrome study. Could you compare and contrast your design with Ultragenyx's design? Obviously, the primary endpoint is different. I think that's, you know, congrats on getting expressive communication at the primary endpoint. But in terms of whether it's placebo control versus sham control...
Avi Novick: patient age range.
Avi Novick: Can you talk about the design differences and what the implications might be for enrollment speed and data? Thank you.
Speaker Change: Yeah, you know, I prefer not to comment on other people's trial designs, but I can focus on our trial design, and you hit on some of the
Speaker Change: Some of the key differentiating features, I think, in our trial design already, Yanan, in your question, you know, we really like our trial design. We think it's the right trial design for the most definitive
Speaker Change: Outcome in our Phase 3 Reveal Study.
Speaker Change: You know, we, first of all, I have to start with the fact that we have a proven platform. We have a platform that has delivered Spinraza, Kilsadi, and several mid-stage pipeline readouts and CNS diseases.
Speaker Change: Our phase 3 trial will examine a broad age group, including children, adolescents, and adults. Our study will examine...
Speaker Change: two dose groups.
Speaker Change: which we think is going to be very important to maximize the probability for success and strong success especially since we are looking at different age groups in the study.
Speaker Change: Thirdly, our study, because we have three cohorts, will be randomized two-to-one. We think patients will like that. Patients don't like going on placebo when they're suffering with a debilitating disease like Angelman's.
Speaker Change: have a greater probability to be on treatment and receiving benefit because it is a two-to-one randomization, and I also want to mention that the doses we're examining in the phase three study are the mid and high dose that we examined.
Speaker Change: In the Phase 1-2 study, where we showed strong efficacy at both doses, all with very good tolerability. So we don't expect any surprises here with these doses.
Speaker Change: As far as placebo control versus sham,
Speaker Change: As Eugene said in his prepared remarks, placebo-controlled trials is a gold standard in trial conduct. It is viewed by regulatory agencies as the preferred trial.
Speaker Change: Design produces the most definitive outcomes without bias, and it's the way to go. Furthermore, we have treated now...
Speaker Change: Several thousands of patients with intrathecal bolus injection with our molecules, with our chemistries.
Speaker Change: All with very good safety and tolerability and that was certainly very important to the FDA that convinced them that
Speaker Change: A placebo-controlled trial is the trial that is appropriate in our study. So we have a very well-designed study, and we're looking forward to getting it started in the first half of next year.
Speaker Change: Thank you for all the comments and congrats on the progress. Thank you.
Speaker Change: The next question comes from Luca Issi from RBC. Please go ahead.
Luca Issi: Well, great. Thanks so much for taking my question. Maybe if I can circle back on a prior question.
Luca Issi: Eugene, you're obviously using expressive communication as a primary point versus obviously your competitors using cognition. Can you just talk about, do you think the former is the better way to go versus the latter? And you called there, much appreciated.
Luca Issi: And then on April C3, I think Hila Lilly discontinued their siRNA going after April C3, wondering what was your reaction to the news and how, you know, we should think about implications for your program. Thanks so much.
Speaker Change: Sure. Thanks for your question, Luca. I'll start with the Angelman question.
Luca Issi: I'm not sure I would necessarily characterize it as the best endpoint.
Luca Issi: It's certainly the end point that is the strongest in terms of our support from our early phase experience from Raffaello's study. It is the one that has very robust results in various age groups and both dose regimens.
Luca Issi: It's also the endpoints, the expressive communication based on all of the surveys that were conducted in this presentation.
Speaker Change: It's the end point that families indicate consistently as the most important one. They would like to see benefits in a new treatment.
Speaker Change: Again, from the perspective of having the evidence from our proof-of-concept study as well as combination of being
Speaker Change: An area that is certainly very problematic for people living in Angelman and their caregivers. We feel that this is the right end point to put at the top of the hierarchy, right? So it is...
Speaker Change: It is what we have proposed and provided, we thought was very good, compelling argument and certainly got buy-in from the agents.
Speaker Change: Richard, did you take the A plus C 3 question?
Richard: Yeah, I'll give it a shot. So, we don't know internally what Lily's reasons were, but...
Speaker Change: position strongly positioned drug in olsarsen which is a fast mover and they would be coming in behind but I think the other piece to this was Lily was very much looking at cardiovascular risk
Speaker Change: with ApoC 3 and deemed it to be high risk and may have also
Speaker Change: added into their discomfort.
Speaker Change: I'll just add to that, Richard. Thank you. They came to the conclusion on evaluating NAPO C3 inhibitor.
Speaker Change: in a cardiovascular indication, like an outcome trial.
Speaker Change: They came to the conclusion we made several years ago, I guess just recently. We believe that the unmet need is not in that space.
Speaker Change: Nor do we believe that that is something worth pursuing for ApoC3. We believe that the unmet need is in severe hypertriglyceridemia. We're pleased to see that they came around and so we saw several years ago.
Speaker Change: That's it. Thanks so much.
Speaker Change: The next question comes from David Lebowitz from Citi. Please go ahead.
David Lebowitz: Thank you very much for taking my question. In terms of your launches, upcoming launches for Donald Dorsen and Olazarsen,
David Lebowitz: Even that these are really the first more significant launches that you're doing yourself. Could you describe how the sales operation is coming together? What the sales...
Speaker Change: Sales team will look like for both indications and how you intend to proceed, especially with respect to HAE, given that it's a very competitive market.
Speaker Change: Yeah, let me turn that over to Jonathan Birchall, our CCO, to talk specifically about those details.
Jonathan Birchall: Thanks Kyle. We're definitely making good progress. In fact, we're ready to go with the Olisars and FCS launch.
Jonathan Birchall: field force to really maximize the OLSAS and opportunity in FCS.
Jonathan Birchall: We've just started the hiring for the head of sales, which is really the last commercial function that we are putting in place.
Jonathan Birchall: And that process will complete through the first half of next year in preparation for launch in the second half of next year.
Speaker Change: Thanks for taking my question.
Speaker Change: We're very comfortable with the data package.
Speaker Change: that we've got for Donnie DeLawson.
Speaker Change: and the commercial capabilities we're building out that we're certainly ready to be competitive in what, while very competitive, still remains an underserved market.
Speaker Change: Thanks for taking my question.
Speaker Change: The next question comes from Jason Gerberry from Bank of America. Please go ahead.
Jason Gerberry: Hey guys, thanks for taking my questions. A couple on the Pelicarcin readout next year. First, you know, with the primary, you're looking at this 90 mg per dl subgroup.
Jason Gerberry: If the event reduction looks more compelling in this subgroup,
Jason Gerberry: How does that alter the addressable market, which I think you guys have framed about $8 to $10 million for secondary prevention, high-risk, opiate-level A greater than $70, but how does that change if it's $90 or greater? And then, ultimately, the other question is just...
Jason Gerberry: What underpins your confidence that you'll have the events to read out around the middle of next year versus the potential need to run that trial out longer?
Jason Gerberry: Assumed event rates a couple percentage points higher than what we've seen in like the typical LDL lowering trials in the past So just kind of wondering I assume that there's been some Assessment of rates on a blinded basis and that sort of underpins and firms up the outlook for timing next year But just wanted to confirm that thanks
Speaker Change: Yeah.
Speaker Change: So, thanks Jason. You know, those are very good questions. They're probably best for Novartis, if you're asking for some very specific information.
Speaker Change: You know, detailed answers to that. But in short, certainly.
Speaker Change: Novartis has been watching the blinded event rates all along. They have regular, you know, oversight meetings in which they examine those and they're based on the events that they're seeing in the study.
Speaker Change: They're confident, they've reiterated recently that they plan to read the study out next year and if successful, they would also plan to file next year. So that is based on the events that they're seeing in the study for sure.
Speaker Change: Regarding the 70 versus 90, you know, if the study hits on 90, but not 70, it'll be a somewhat smaller, you know, indication. It'll be people above 90, but it's still a massive, massive...
Speaker Change: patient population if that were to happen.
Speaker Change: If both were to hit, but the 90 was more compelling than the 70, I don't think that would have a significant impact. I mean, there are these people, I mean, normal healthy little A's in the, like, 30 range or so. And so even people with 70 milligrams per deciliter with a history of cardiovascular disease.
Speaker Change: on desperate need for a treatment like telecarcin so I think that if the study hits on regard regardless of the risk reduction is greater in 90 versus 70 I think it'll be indicated for all those patients
Speaker Change: with a history of CBD. Again to emphasize, this is a massive patient population in which there are no effective treatment options available today.
Speaker Change: Okay, thanks so much.
Speaker Change: The next question comes from Jay Olson from Oppenheimer. Please go ahead.
Jay Olson: Oh hey, congrats on all the progress and thank you for taking our questions. Does the Phase 3 study designed for 582 and Agelman Syndrome support regulatory filings?
Jay Olson: XUS, and if so, how are you thinking about XUS partnering opportunities for 582?
Jay Olson: And then I had a follow-up if I could.
Speaker Change: Yeah, so...
Speaker Change: The
Speaker Change: Thanks, Jay. We're wrapping up. We're getting close to getting in alignment with the EU on the phase two trial design for inhuman syndrome. We don't see any roadblocks there or anything that's going to cause us to significantly change anything about the study design to get approval in Europe.
Speaker Change: As far as
Jay Olson: OUS, Partnerships for Commercializing Angel Men's
Jay Olson: It's very early, it's too early to comment on that.
Jay Olson: As you know, we have an OUS commercial partner for Donna Lawerson, and we're making great progress for all this arson. That'll be coming, we expect, soon.
Jay Olson: There will be a time that IONIS will emerge from the U.S. market for commercialization. Maybe Angel Moons could be that program, or maybe something else.
Jay Olson: It's just too early for us to draw any conclusions there, but it's certainly an area of active conversation within IONAS.
Speaker Change: Great, thank you. Super helpful. And then we had a question on 269 or APP ASO. It's great to see research being done in Down syndrome based on the huge unmet need in that population. Can you talk about the rationale for choosing that indication to start with?
Jay Olson: Maybe elaborate on the development strategy and any plans for other indications and differentiating features for your program versus other RNA therapeutics.
Speaker Change: Yeah, I'd like Eric Swayze to comment on the rationale for us starting in Down Syndrome patients first, and then Eugene, maybe, can comment on additional potential indications. Eric?
Eric Swayze: What you'd expect from having extra gene copies, you get an accumulation of excess amyloid and down syndrome patients are known to have early onset of Alzheimer's disease and dementia relating from accumulation of excess amyloid.
Jay Olson: So, it was a logical thing for us to look at, and we know that the Down's community has been a little bit underserved, and we think it's a great place to go with a drug that lowers production of a gene product when you have
Jay Olson: It makes sense for our technology.
Speaker Change: And I just add one more thing on the technology, this is, we've been working on chemistry of our drugs and this is the first MSPA backbone chemistry of our drug going into clinical development and we expect this to give us improved duration of effect of one thing.
Speaker Change: One benefit of the chemistry, which we hope to see in the trial.
Speaker Change: Thanks, Eric. Eugene.
Eugene: Yeah, so further indications, of course, are TBD and the first proof of concept.
Jay Olson: sporadic AD or forms of AD that are perhaps a little bit better described
Jay Olson: This approach to kind of addressing the overproduction problem first and then moving into larger indications that are at least thought to be mostly clearance.
Speaker Change: Thank you.
Speaker Change: Thank you. Bye.
Speaker Change: Clearance problems, if you will, of APP.
Speaker Change: It's probably somewhat similar to what we're doing with Waynua, right? So the initial indication was focusing on hereditary...
Jay Olson: The end where where we could suppress production of TTR and prove that it's beneficial and then following with the
Jay Olson: is something that we potentially could think of as an analog. So we are certainly thinking of AD
Jay Olson: and potentially other relatively more common indications than Down syndrome. But Down syndrome experiment is going to be really, really critical for us.
Speaker Change: Thanks. Thanks, Jay.
Jay Olson: Thank you.
Speaker Change: The next question comes from Mani Foroohar from Lering. Please go ahead.
Mani Foroohar: Hey guys, thanks for taking my question. I know a lot of pipeline questions have been answered. I want to circle back on the growth in TCR polyneuropathy.
Mani Foroohar: I'm obviously accelerating from where your revenue base was the prior product
Mani Foroohar: Perhaps a question that is for both you guys and AstraZeneca, that you have some insight.
Jay Olson: To what extent are we seeing patients switching from the existing oligotherapy, which is Q3 months, then may lose some efficacy at the end of that time horizon?
Jay Olson: to your at-home therapy with eplantersin. And so what proportion of your growth is coming from patient switching versus previously untreated patients who are getting eplantersin?
Speaker Change: Yeah, thanks for the question, Mani.
Speaker Change: The growth strategy here in a market that is largely underdiagnosed, you know, less than 20% of these patients are currently on a treatment, is really about identifying new patients and securing those patients to initiate treatment from the very beginning.
Speaker Change: Waynua and the strategy there obviously is playing out. That's why we saw the 44% growth quarter-over-quarter.
Speaker Change: The profile is exactly what we had expected to benefit these patients in terms of quality of life.
Jay Olson: the efficacy that they're seeing.
Jay Olson: and the ability to self-administer. So the question about switching, it is happening. I don't want to quantify that, but what I would say is it's occurring.
Jay Olson: Because there is a request from patients and physicians see the benefit of patients being able to self-administer with a simple to use auto-injector
Jay Olson: It's a differentiating feature here within the category. Patients are getting reimbursed very quickly from a market access standpoint. Our patient engagement manager team are connecting directly with these patients and having very productive conversations with them about getting initiated on Waynua and what to expect.
Jay Olson: And overall, the patients are performing very well and we expect to continue to see the growth in the naive patient population.
Jay Olson: I expect that we will still see some switches and we will probably see some combination as well for the mixed phenotype patient in which some of these patients have hereditary polyneuropathy and could benefit from a silencer such as Waynoa.
Speaker Change: Great, and a quick follow-up.
Speaker Change: Your Oligo competitor has talked about, in part for the cardiomyopathy market, but also polyneuropathy, a belief that those patients who are receiving an in-office therapy, the American Part B, may have less out-of-pocket or more favorable reimbursement from a facility perspective than an at-home Part D therapy. Can you clarify whether or not you're seeing...
Speaker Change: Any headwinds whatsoever, from patient out-of-pocket costs, reimbursement headwinds, etc. that would support or refute that competitive argument, slash counter-detail.
Speaker Change: Yeah, I think the short answer is with the Inflation Reduction Act and the changes for out-of-pocket expenses on Medicare Part D, access to care has gone up significantly within that channel. You're seeing that across not only this category, but I think across all Medicare Part D products ultimately.
Speaker Change: Out-of-pocket expenses for patients within Waynua. The majority of them pay nothing on the commercial side of the business because we have programs to help support those patients. And then in the Medicare population, keep in mind...
Speaker Change: You have Medicare Advantage, and then you have the other population that have some supplemental or some support with their Medicare reimbursement. And so a lot of those patients are paying very little to nothing because of the way that they have their Medicare Part D plan.
Speaker Change: reimbursed through a secondary insurer. So overall, very, very good access to care with Waynoa. Greater than 75 to 80 percent of these patients have very little out-of-pocket expenses and we have the opportunity to help them accordingly with the programs that we have in place.
Speaker Change: ahem
Mani Foroohar: Great, thanks guys, that's really helpful and congrats on the progress. Thanks Mani.
Speaker Change: The next question comes from Andy Chen from Wolf Research. Please go ahead.
Andy Chen: Hey, thank you for taking the question. So regarding the Donnie launch in HIE...
Andy Chen: So, a fraction of these patients, my understanding is that they're on androgen therapy, they're not on PaxZero, they're not on Orlodeo. Do you believe that there's an opportunity there to convert these patients to Donny or do you just believe that they're very far to reach? And on a side note, do you think payers are going to begin to play favorites in this market because it's kind of becoming clouded? Thank you.
Speaker Change: Yeah, let me make a couple of intro comments and then I'll turn it over to Jonathan for his perspective as well.
Speaker Change: The patients that are not on therapy today in the U.S. market, they're approximately 20 to 25 percent of the overall population and there are varying reasons that they would not be on treatment yet. You know, one would be potentially the the current therapies have
Speaker Change: Some sort of aspect that they're not interested in or don't feel comfortable with, or the other aspect is maybe the frequency of attacks or whatnot are not severe enough that they feel that they can manage their disease otherwise.
Speaker Change: We do believe that there's an opportunity to address this population in three different ways. One, our patients...
Speaker Change: New to therapy, so newly diagnosed patients that are coming in. The second area are the switch patients, which is going to be the bolus of about 75% of the patients in the U.S. that are currently treated on a therapy for HAE could potentially move over to Donnie Doloresan.
Speaker Change: And then the third bucket is the one that you just described, which are the ones that have been diagnosed but are not treated today with a prophylactic. And we believe that with a profile like Diana Lawson, we could potentially capture all three of those buckets based on the way that the data is coming together. Jonathan, anything to add there, and then also with payers?
Jonathan Birchall: No, not really. I think the only thing I would add is despite the treatment options that have increased in more recent years,
Speaker Change: We know from claims data there's a large proportion of patients who do switch therapies every year.
Speaker Change: And some of the patient advocacy group, their surveys show that patients are still having breakthrough attacks on the current treatment. So we definitely think there's an opportunity for patients to switch to a new treatment like Donna DeLawson.
Speaker Change: And with the payer environment, there's the full spectrum of treatments, and we're still comfortable that the payers will support the market at the current prices, given the fairly well-established treatment population today.
Speaker Change: Okay.
Speaker Change: Thanks Andy and looking at the clock we have time for one more question please.
Speaker Change: The next question comes from Akash Tewari from Jeffries. Please go ahead.
Speaker Change: Hi, thank you for taking our question. This is Phoebe on for Akash.
Speaker Change: On Engelmann's, you previously showed that you could show a shift towards EEG pattern normalization.
Speaker Change: In the long-term extension, are you continuing to see the same EEG benefit that you reported at earlier four- and six-month time points? And also, are you thinking about this as an endpoint of clinical efficacy or more of a biomarker? And is there any sense of variation in the signal-to-noise for EEG, given that you're looking at both adults and children? Thank you.
Speaker Change: Yeah, um, so, um, uh,
Speaker Change: We certainly will continue to measure EEGs in our long-term extension, as well as in our Phase 3 trial design. It'll be exploratory and viewed more as a biomarker. It's really, we're really
Speaker Change: I'm using this to better understand...
Speaker Change: The biology in people living with Angelman syndrome.
Speaker Change: and to determine whether or not there's any predictive value.
Speaker Change: of an abnormal EEG pattern with respect to disease progression.
Speaker Change: A different, to your question, the other part of your question, different age groups, whether there's any impact there. We know that adults have a much more muted abnormal EEG pattern than children.
Speaker Change: And we just haven't done the assessment in long term in our LTE study yet to comment on how that data is looking like. We will examine a new data cut from our LTE at some point in the future, and we're looking forward to sharing that at the right time. But it's a very good question, so thank you for that.
Speaker Change: I'd like to thank everybody who joined us and asked great questions, participated in our call today.
Speaker Change: We know we've accomplished a lot, a great deal, and have substantial opportunities ahead here at IONIS. And we look forward to sharing updates on the progress we're making regularly as we move forward. So until then, thanks everybody, and have a great day.