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spk09: Good morning and welcome to the IONIS fourth quarter and full year 2023 financial results conference call. All participants will be in listen-only mode. 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 one on your telephone keypad. To withdraw a question, please press star, then two. As a reminder, this call is being recorded. At this time, I would like to turn the call over to Wade Wolk, Senior Vice President of Investor Relations, to lead off the call. Please begin.
spk17: Thank you, Megan. Before we begin, I encourage everyone to go to the Investor section of the IONIS website to view the press release and related financial tables we will be discussing today. including a reconciliation of gap to non-gap financials. We believe non-gap 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 today's call. With me this morning are Brett Monia, Chief Executive Officer, Richard Geary, Chief Development Officer, and Beth Haugen, our Chief Financial Officer. Eric Swayze, our Executive Vice President of Research, Eugene Snyder, Clinical Chief Clinical Development Officer, and Oneza Katare, Chief Global Product Strategy and Operations Officer, will also join us for the Q&A portion of the call. I would like to draw your attention to slide three, which contains our forward-looking language statement. During this call, we will be making forward-looking statements that are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. With that, I'll turn the call over to Brett.
spk02: Thanks, Wade. Good morning, everybody, and thanks for joining us today. At Ionis, we are proud of our scientific heritage. We have united groundbreaking science and technology with a relentless passion to discover and develop new transformational medicines. And now that we have validated the broad applicability of our RNA targeting platform, we're on the brink of independently delivering our medicines directly to patients. Over the next several years, we expect to successfully launch multiple medicines on our own while continuing to expand our technology so that we can address the needs of even more patients. This will be a key driver of our next phase of growth, and we're committed to investing in all capabilities needed to accomplish this. Last year was a remarkable year for Ionis. And we're already off to a great start in 2024. In fact, just yesterday, the FDA granted breakthrough therapy designation to old Sarsen for FCS. This is a very important outcome as breakthrough therapy designation is designed to expedite development and review of therapies intended to treat serious conditions that have preliminary clinical evidence showing that the therapy may offer substantial improvement over available treatment. Before we get to all the other exciting things planned for this year, I'll first recap some of our key achievements in 2023. First, we received two FDA approvals for Ionis discovered medicines, CALSATI for SOD1 ALS and Wainua for ATTR polyneuropathy. CALSATI is the first drug approved to treat a genetic form of ALS. It was granted accelerated approval in the U.S. early last year for patients with SOD1 ALS. And we are also pleased to cap off a highly successful year with the approval of Wainua for ATTR polyneuropathy in late December. The Wainua launch is well underway in the U.S. through our co-commercialization partnership with AstraZeneca, and we're executing on our strategy to bring Wainua to patients globally with additional potential approvals in Europe and Canada this year and more regulatory submissions and approvals on the way. Based on its strong overall profile, including highly positive phase 3 data, which we reported last year, together with the freedom of simple at-home monthly self-administration, we believe LENUA is very well positioned to become the therapy of choice for ATTR patients who remain underserved by current therapies. With a larger ATTR cardiomyopathy indication, we continue to advance our CardioTransform study as planned. As the largest study ever conducted in this patient population, CardioTransform is positioned to be a landmark study designed to deliver a very rich data set. We expect the data we generate to enable physicians and payers to make informed treatment decisions in this dynamic treatment landscape. And with AstraZeneca's global leadership in the commercialization of novel cardiovascular treatments, coupled with our leadership in TTR amyloidosis, we believe we are very well positioned to bring renewal to patients in the U.S. and around the globe. We also recently delivered positive Phase III top-line data readouts for two additional important medicines, olazarsin in FCS and donazolarsin in HAE. In the Phase III balance study in patients with FCS, olazarsin showed significant triglyceride reductions, substantial reductions in acute pancreatitis events, and a favorable safety and tolerability profile. We remain on track to file for marketing approval in the U.S. and EU this year. Positioning. olzarsen for potential approval in the U.S. by the end of the year, assuming we get priority review. With this timing, we expect olzarsen to be our next approved medicine and our first independent launch. We were also pleased with the positive top-line data we reported last month from the Phase III OASIS-HAE study of dominovirus for the prophylactic treatment of hereditary angioedema. In the Phase III study, Donna Dolores met the primary endpoint with a statistically significant reduction in the rate of HAE attacks in patients treated every four weeks or every eight weeks, along with a favorable safety and tolerability profile. With these positive data now in hand, we're preparing our regulatory submission to the FDA, which will include both every four-week and every eight-week dosing. We expect Donna Dolores to be our second independent U.S. launch. Additionally, our partner, Otsuka, preparing to submit for marketing approval in Europe. Based on our Phase III results and the durable efficacy and favorable safety data seen long-term in the ongoing Phase II open-label extension study, we believe Donna DeLorsen could be an attractive new treatment option for patients with HAE. We look forward to presenting the full Phase III data for both Ola Zarsen and Donna DeLorsen later this year. We also made significant progress expanding our rich Phase III pipelines. Last year, we began the year with six medicines in Phase III development, and this year, we began with nine medicines in Phase III. These new Phase III additions include Zilgenersen, our wholly-owned medicine for Alexander disease, and two partner programs, Bepiravirsen for chronic HPV and Ionis FBLRX for IgA nephropathy. We also continued to make great strides last year in advancing our industry-leading RNA targeting technology. We advanced our first bicycle siRNA muscle targeting like a drug for a heart failure indication into preclinical development, which AstraZeneca licensed in the fourth quarter. And we expect to advance additional medicines utilizing our muscle targeting technology this year. We also made substantial progress in our efforts to deliver our CNS medicines across the blood-brain barrier. Most recently, their novel protein-based approaches to systemically deliver our medicines to the CNS. This adds to our multi-pronged approach to traverse the blood-brain barrier with our novel treatments to further strengthen our leadership position in treating CNS diseases. Our accomplishments throughout 2023 provide great momentum and position as well for a catalyst-rich 2024. Today, Ionis is at a key inflection point with the recent approvals of two medicines three positive phase three readouts, and numerous upcoming phase three readouts expected over the next couple of years. And at the same time, we've also made great progress across the rest of our rich pipeline and advanced our leading technology for our future medicines, all of which sets us up to bring a steady cadence of new transformational medicines to patients for years to come. We will continue to focus on building and advancing our wholly owned pipeline. which will position us to deliver even more medicines directly to patients. We expect that the investments we're making over the next few years will drive an outsized opportunity to earn multibillion-dollar revenue from our proprietary pipeline, generating next-level value for all Iona stakeholders. And with that, I'll turn the call over to Richard to discuss our recent pipeline progress. Next, Pat will review our 2023 financial results and provide our 2024 financial guidance. And then I'll wrap things up before taking your questions. Richard?
spk21: Well, thank you, Brett. We had many notable pipeline achievements in 2023, some of which you've heard, with the highlight being the approval in December of Wainua in the U.S. for patients with ATTR polyneuropathy. Wainua was approved based on the NeuroT Transform results in week 35. In this study, Whenua demonstrated powerful and sustained TTR suppression, stopped neuropathy disease progression, and improved neuropathy impairment and quality of life. These highly positive results were reinforced at week 66 and 85, and as the only approved medicine for the treatment of ATTR, polyneuropathy can be self-administered via autoinjector. We believe Whenua is well-positioned to reach newly diagnosed patients and patients who remain underserved by current therapies. Waynua's robust profile also supports our confidence in the potential to benefit patients in the much larger ATTR cardiomyopathy patient population. Our conviction was reinforced with the data we presented at HFSA late last year that showed improvement in cardiac structure and function in a predefined cardiac subpopulation of patients in NeuroT Transform. And in January, additional data was published in the Journal of American Heart Association showing encouraging results in a cohort of patients with hereditary ATTR cardiomyopathy from the NeuroT Transform study. With over 1,400 patients, CardioT Transform is the largest and most comprehensive study ever conducted in ATTR cardiomyopathy patients. We designed the study to generate a rich data set that we believe will be key for physicians and payers in this evolving and dynamic treatment landscape. This includes generating data for key subgroups, such as patients on a stabilizer and those naive to stabilizer. We are also conducting advanced cardiac imaging sub-studies as part of our overall program. These include an MRI sub-study and a scintigraphy sub-study. We believe these data will generate even more valuable data about the potential benefits of Wainui in cardiomyopathy patients by evaluating how Wainui is affecting changes in the heart itself. The FDA recently granted Wainui a fast-track designation for the treatment of ATTR cardiomyopathy, which can expedite the regulatory review process. Receiving this designation further reinforces our confidence in Wainui's potential to be a transformational treatment in this underserved and growing patient population. With CardioT Transform fully enrolled, we remain on track for data as early as 2025. Olisarcin is poised to be the first medicine we bring to market independently. With the positive phase three results from the balance study in patients with FCS, we are preparing our NDA and MAA submissions. Additionally, we're pleased that the FDA has granted Olisarcin both orphan drug designation and breakthrough therapy designation, which can help expedite the review of this new medicine for the treatment of FCS. As a reminder, in the balance study, the 80 milligram dose of Osarsen demonstrated statistically significant reductions in triglycerides, robust target engagement, and a favorable safety and tolerability profile. Most importantly, Osarsen demonstrated unprecedented substantial and clinically meaningful reductions in acute pancreatitis attacks. We are looking forward to presenting the balance study data at the American College of Cardiology annual scientific session in early April. Based on these positive data, olisarcin is positioned to become the standard of care for patients with FCS. We're excited to bring this important medicine to patients with olisarcin's first potential approval late this year, assuming priority review. We're also developing olisarcin for patients with severe hypertriglyceridemia, or SHTG. Our ongoing phase three studies for SHTG are progressing nicely, and we remain on track for data next year. Following closely behind Olisarsen is Donna Delorsen, which we anticipate will be our second independent launch, assuming approval. Donna Delorsen has the potential to be an attractive new prophylactic treatment option for hereditary angioedema patients, many of whom continue to experience unpredictable painful, and severe attacks despite currently available prophylactic treatments. In the recently reported Phase III OASIS-HAE results, Donna DeLorsen demonstrated statistically significant reductions in the rate of attacks in HAE patients treated every four or every eight weeks. In addition, Donna DeLorsen achieved statistical significance on the extensive set of secondary endpoints in the Q4 week dose group, and key secondary endpoints in the Q8 week group, which we expect to be key differentiators for donodilorsin in the prophylactic market. Donodilorsin also demonstrated a favorable safety and tolerability profile in the study, and additionally, we are encouraged that following completion of the treatment period in the Phase III study, over 90% of the randomized patients entered the ongoing OASIS plus open-label extensions. These positive phase three results build on the positive durable results we have seen in the phase two and phase two OLE studies. In the phase two open label extension study, Donna DeLorsen demonstrated substantial reductions in HAE attacks that were sustained and durable over two years in addition to a favorable safety and tolerability profile. We anticipate Donna DeLorsen could evolve the HAE prophylactic treatment paradigm. And what I mean by that, based on the phase three results, Donna DeLorsen has the potential to extend dosing intervals to monthly or every two months using an auto-injector from the current standard of care, which is dosed every two to four weeks using a vial and syringe. And with an attractive efficacy, safety, and tolerability profile, Demonstrated in the OASIS HAE Phase III study, we expect Donna DeLorsen to be a treatment of choice for many HAE patients. We're busy preparing the NDA, which will include both four-week and eight-week dosing options. Additionally, OTSUKA is preparing to submit for marketing approval in Europe, and we're pleased that we just recently received orphan drug designation for Donna DeLorsen in the EU. Thank you. We're really looking forward to presenting the Phase III OASIS data at a medical congress by mid-year. Along with the Phase III results, we're also planning to present results from the OASIS Plus study. The OASIS Plus study includes an open-label cohort for patients rolling over from the Phase III study and a separate cohort that we refer to as the SWITCH study. The SWITCH study is evaluating patients who have transitioned to Donna DeLorsen from other prophylactic HAE medications. Turning now to our leading neurology franchise, which today includes three marketed breakthrough medicines that we discovered and developed. Spinraza, the leading medicine for the treatment of SMA, Wenua, which was just recently approved for ATTR polyneuropathy, and CalSati approved to treat SOD1 ALS patients in the U.S. last year. Behind our approved neurology medicines is a robust and growing clinical pipeline of medicines to treat both rare and broad neurological diseases. By the end of this year, we expect to have six wholly owned neurology medicines in clinical development, including ion 717 for prion disease, which recently began clinical testing. Among our partner neurology programs late last year, we completed enrollment in the Phase I-II HALOS study for ION582 in patients with Angelman syndrome. We also shared some encouraging initial observations from this study at the FAST meeting in November. These data included a reduction in slow wave EEG delta activity in approximately 70% of patients, and an increase in faster frequency rhythms in over 80% of the patients, both compared to baseline activities. While direct comparisons are difficult and should be viewed with caution, this improvement in EEG activities exceeds what is observed in natural history studies over the same time period. Also, a majority of patients in the study showed improvement compared to baseline in overall functioning on the total Bayley score a direct measure of functioning across multiple domains, and on the Angelman syndrome TGI change scale, which captures clinical impression of the patient. We look forward to reporting more data from the HALO study by mid-year. With the successes we've achieved to date and the breadth of the pipeline in development, it's clear that our neurology franchise sets IONIS apart as a leader in this space. The Angelman study is one of several mid-stage data readouts we have planned for 2024 that, if positive, could further add to our rich Phase III pipeline and bolster our ability to deliver a steady cadence of transformative medicines to patients for years to come. This year, we're looking forward to many key catalysts including detailed phase three data presentations and regulatory submissions for Ola Sarsen and Donna Delorsen, several expected marketing approvals decisions for Wainua in various countries, and potential launch of Ola Sarsen assuming priority review and approval late this year. We will keep you updated on our progress throughout the year. And with that, I'll turn it over to Beth.
spk10: Thank you, Richard. 2023 was a strong year underscored by similarly strong financial results in which we delivered substantial revenue while simultaneously advancing our pipeline and preparing to bring Wainua, Ola Zarsson, and Donna Doloresen to market. As a result, we delivered a non-GAAP operating loss of $247 million, a significant improvement compared to 2022 and our 2023 guidance. BY SIGNIFICANTLY, WE SIGNIFICANTLY EXCEEDED 2023 REVENUE GUIDANCE BY MORE THAN $200 MILLION EARNING REVENUES OF $325 MILLION AND $788 MILLION FOR THE FOURTH QUARTER AND FULL YEAR, RESPECTIVELY. REVENUE MORE THAN DOUBLED IN THE FOURTH QUARTER OF 2023 AND INCREASED 34% FOR THE FULL YEAR, BOTH COMPARED TO THE SAME PERIODS IN 2022. These increases were primarily driven by increased R&D revenue resulting from the business development successes we achieved last year. We earned $479 million of R&D revenue in 2023, which included revenue from our new collaborations with Asuka, Roche, and Novartis. In addition, we earned significant payments from AstraZeneca. including $50 million for the U.S. approval of Waynua for ATTR polyneuropathy, and $36 million for the licensing of ION826, a drug-nearing clinical development designed to treat heart failure, both of these in the fourth quarter. The substantial R&D revenue we continue to generate reflects the value that our pipeline and technology are creating as numerous partnered programs advance. We also earned $309 million in commercial revenue, with the majority coming from Spinraza. The sales of Spinraza and our associated royalties were comparable year over year. And while fourth quarter sales were impacted by the timing of shipments in certain markets, Spinraza remained the global market leader in SMA. Importantly, with WEMUA's FDA approval and recent launch, we look forward to adding Waynua to our commercial revenue streams, which currently include Spinraza, CalSati, Texetti, and Waylibra. Our non-GAAP operating expenses of $1,035,000,000 were slightly, or approximately 4%, above guidance, primarily due to certain one-time costs, including the non-cash charge associated with the lease exit and the license fee we paid to Vectoris in the fourth quarter. Excluding those one-time expenses, our operating expenses were within our guidance range at $994 million. As expected, our operating expenses increased for the full year compared to 2022 as we continued to advance key programs in our pipeline. The increase in our R&D expenses was due to increased clinical study costs which were higher because our Phase III studies were fully enrolled or nearly fully enrolled throughout last year. For the next several years, we expect our R&D expenses will stabilize near the current level as we move numerous wholly-owned medicines through development. Also as expected, our SG&A expenses increased year-over-year as we invested ahead of the Wayne UO, Ola Zarsen, and Donna Doloresen launches. We expect our SG&A expenses to increase as we invest in our commercial infrastructure to support the launches of our Ionis-owned and co-commercialized medicine. In addition, we exceeded our 2023 cash guidance by ending the year with $2.3 billion in cash and investments. Our ending cash was higher than projected, primarily due to the significant payments from the business development transactions we completed last year and the successful convertible note refinancing we opportunistically completed last June, which provided us with cash earmarked to repay the remaining convertible notes due this year. We expect to carry the positive momentum generated by our strong 2023 performance into this year by deploying our capital resources toward growth opportunities to unlock next level value. This is the foundation for our 2024 full year financial guidance, which we're pleased to announce today. We project to earn more than $575 million in revenue. Our total expected revenue for 2024 includes a sizable base of commercial revenue, with Spinraza as the cornerstone. We expect the resilience Spinraza has demonstrated to continue and our royalties to reflect that. We're excited that Wainua is on the market and the launch is off to a good start. AstraZeneca is responsible for booking product sales, and we will earn royalties in the mid-20% range on the U.S. sales. With significant focus on patient identification and education, we are looking forward to adding initial Wainua royalty revenue this year. And as more new patients are identified and the launch ramps up, we expect revenue to grow. We project meaningful R&D revenue from our partnered programs this year, although we anticipate R&D revenue will be lower than it was last year. Notably, a significant portion of our R&D revenue in 2024, approximately $150 to $175 million, will consist of non-cash amortization from partner payments we received in prior years. We have the potential to earn cash-generating revenue from regulatory milestones, such as the EU approvals of Wainua and Calsati, license fees, and R&D funding from our partners. Our 2024 operating expense guidance reflects our commitment to independently bring our medicines to patients while also continuing to exercise sound fiscal stewardship. As a result, we expect our 2024 operating expenses to increase in the mid-single-digit range compared to 2023, excluding the impact of one-time costs last year. Our planned expense growth will come almost entirely from increases in our SG&A expenses. With the Wainua launch underway, our SG&A expenses will include our minority portion of Wainua's sales and marketing costs. which are in the high teens to low 20% range. After having built our commercial capabilities over the last couple of years, we now have a fully integrated commercial organization capable of delivering ionisone medicines to patients, except, of course, for the necessary field teams. Today, our commercial organization is enthusiastically preparing for our first independent launch, Olazarsson for FCS, assuming approval. We expect to add the Olazarsen FCS field team later this year. We're also scaling our capabilities as needed ahead of bringing Donna Dolorsen to the market next year, also assuming approval. Our projected R&D expenses reflect the important investments we are making to grow our wholly-owned pipeline and advance our next wave of opportunities. We believe it's important to make investments today in our wholly-owned programs because of the potential multibillion-dollar revenue opportunity these programs represent for us. And we can make these pipeline investments while keeping R&D expenses steady, because as several of our late-stage studies end, we can reallocate resources toward our earlier-stage programs as they advance into later stages of development. With meaningful revenues, and modest expense growth, we are projecting a non-GAAP operating loss of less than $475 million. Additionally, we project a year-end cash balance of approximately $1.7 billion. The vast majority of the projected year-over-year change in our cash reflects the investments we are making in our pipeline and our commercialization activities. In addition, we have $45 million earmarked to address our remaining 2024 convertible notes that are coming due late this year. Looking beyond 2024, we expect to continue making significant investments in our commercial infrastructure to support our goal to expand our proprietary pipeline and independently deliver our medicines to patients. As more and more of our ionisone medicines come to market, we expect the proportion of product revenue to increase significantly. We estimate that the programs in our pipeline today have a combined multibillion-dollar peak sales potential. And following behind these are additional attractive opportunities coming from our prolific research engines. Finally, we plan to continue to invest in technology that will enable us to expand our therapeutic opportunities and optimize delivery of our medicines. Our investments in 2024 and for the next few years reflect our plan to strategically deploy our resources to achieve the robust revenue growth and positive cash flow that we believe our pipeline can deliver. And with that, I'll turn it back to Brett.
spk02: Thanks, Beth. We are very proud of the remarkable progress we made last year, and we're very much looking forward to building on this positive momentum this year. We have arrived where we are today by being focused on a clear vision and a clear set of strategic objectives to achieve our vision. Building and advancing our pipeline and delivering medicines that we conceive, discover, and develop directly to patients is a top priority for Ionis. We have established Ionis as a leader in cardiovascular and neurology drug discovery and development with one of the richest mid- and late-stage pipelines. Our pipeline is delivering. We reported multiple positive key readouts over the past year and are positioned to deliver additional important results in the near term. We also expect to add more wholly-owned medicines to our pipeline this year and for many years to come. We are pleased that our first co-commercialization launch of Wainui is off to a good start. and we're very much looking forward to our upcoming independent launches for Ola Zarsson and Donnie Dolores. In parallel, our partner programs are progressing on track with key phase 2 data readouts planned this year and important phase 3 readouts next year and beyond. We're extending our leadership position in oligonucleotide therapeutics by expanding and diversifying our technology, further optimizing our capabilities for existing therapeutic areas and opening up new areas for drug discoveries. All of this sets us up to continue bringing a steady cadence of new and potentially transformational medicines to the market for many years to come. As I mentioned at the start of this call, IONIS is at a key inflection point. We have great momentum and a substantial number of upcoming value-driving catalysts. To support all of our strategic priorities, we will continue to make the necessary investments to ensure success and drive next-level value for IONIS stakeholders. with financial responsibility and discipline. We're really looking forward to an outstanding year and sharing our progress along the way. And with that, we'll now pause and open the call up for questions.
spk09: 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 were using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Our first question comes from Jason Grobere with BOA. Please go ahead.
spk16: Thank you for taking my questions. So, Brett, mindful that you said CardioTransform will continue as planned, my questions are, you know, just how you're thinking about scenarios that will dictate whether you wait to unblind the study in early first half 25 versus wait to the final analysis in 2026. And specifically, you know, if Alnylam were to miss on its overall population composite endpoint, which shows a favorable trend, how might you approach this time in consideration?
spk02: Thanks, Jason. We're not going to comment on other companies' programs, but what I will say is this. Nothing has changed in our plans to potentially read the CardioTransform study out early. It's the same plan that we laid out last year and earlier this year as well. The key driving factor that will weigh into our decision, along with our partner AstraZeneca, to read out in 2025, which will be early, is really the blinded event rates, which are progressing on track. And, of course, if we see additional information out there from other programs, we'll certainly use that information to the best of our ability to make the proper decision on when to read the study out earlier or let the study play out to its completion. You know, Jason, we really are pleased with the decision we made nearly two years ago when we lengthened our study and we greatly expanded the size of the patient population to account for the changed demographics in the ATTR cardiomyopathy patient population. This was a very wise decision, and we believe we have the optimal trial design to not only ensure for a highly successful outcome, but to provide the richest data set of any medicine that's out there today on the market or in development to provide the data that patients want, physicians want, payers want. to drive Waynua to as many patients around the globe as possible.
spk06: Got it. Okay.
spk07: Thanks, guys.
spk09: Our next question comes from Jessica Thia with JP Morgan. Please go ahead.
spk08: Hey. Good morning, guys. Thanks for taking the question. I'm just following up on the last question. Can you talk about commercially how you expect TTR silencers will be used in cardiomyopathy both prior to 2028 when Tifamidus is still branded and then maybe also if you expect that to change at all once Tifamidus goes generic? Thank you.
spk02: Thanks, Jess. It's certainly a dynamic market with several players. I'd like Ineza to jump in on this question.
spk11: Yeah, sure. Hi, Jess. So, you know, I think this is a market that's ripe for the clinical data for these patients. We have to remind ourselves that Cardiomyopathy patients, this is a serious disease and it's a terminal illness. So with a three to six year survival rate, it's all going to depend on the mortality data you generate. And that's what we are really striving for in the positioning of our clinical trial. And that's why we extended the trial and have the duration and power that we put in to generate the best data set. So we expect that, you know, silencers based on their mechanism and the clinical data, again, with our composite endpoint showing the effect size that we anticipated showing would be used first line on patients that are naive to tefamidus and other stabilizers. And then for patients who are on tefamidus, it's all going to be dependent on the clinical data that we are able to show on top of tefamidus. showing a robust cardiovascular risk reduction will really drive clinical adoption in this space. And, you know, based on the payer research that we've done, we're very confident that the physicians will be making the case for the use of two different classes of medications, again, based on that clinical data and that payers, from what we've heard also in our research in the U.S. as well as outside of the U.S., would reimburse it.
spk06: Next question, please.
spk09: Our next question comes from Yanan Xu with Wells Fargo Securities. Please go ahead.
spk13: Thank you for taking our questions and congrats on the progress in 2023. In your view, I guess a quick follow-up to the prior questions. what is the importance of achieving benefit in the overall population versus the monotherapy population only? And maybe in ATTR cardiomyopathy. And then a question on Andrewman study readout, what would be a strong or definitive signal, given that the study is not controlled and also included several age groups, And you touched upon EEG. Could you talk about how that endpoint will be prevented and what is the expected natural history or placebo response and what level of change is considered meaningful? Thank you.
spk02: Sure. Maybe I could ask Richard to weigh in on the importance of the overall endpoint in the cardiotransform study and also what value the subgroups, the monotherapy would have. And Eugene, you could jump in on the data that we think is going to be most important for the Angelman's readout later this year. Richard? Yeah, happy to.
spk21: So we designed this study to give us a positive readout in a combined population. So our primary endpoint is on the totality of the data across both populations. And we expect that that will be positive. And based on, you know, the numbers and on the duration that we put into this two years ago, we're very confident in the readout of this study.
spk20: With regard to Angelman, again, just a reminder, we completed enrollment. of the multiple ascending dose study, and that study was really the first in human experiment to describe the safety of this product as well as select the right dose and the right population for the pivotal study. It included, as you mentioned, it is an open-label study, so of course any kind of signal will need to be taken very carefully, but the goal of that study was to really enable us with a decision to progress into pivotal development. With regard to EEG specifically, of course, there is ample natural history data that exists across various age groups. Generally speaking, the EEG findings abnormalities are fairly stable in this population. So again, seeing any improvement or differentiation from the natural history will be meaningful, certainly if it correlates, especially if it correlates with clinical improvement, which we will also be assessing.
spk02: And I can just add to that, and very briefly, a slightly higher level. You know, we have a lot of experience in developing our platform for neurological diseases, as you know. Spinrad's a CALSATI, the TAL program continues to go well as does the ANGELMINS program, many other programs progressing on track. We believe we have the right platform. This is the same chemical platform as Spinrazov, as CALSATI, as the rest of our pipeline. We think it's the right chemistry for CNS diseases. So we're very much looking forward to the readout from our first inpatient study in ANGELMINS by mid-year this year.
spk13: Very helpful. Thank you.
spk09: Our next question comes from Miles Minter with William Blair. Please go ahead.
spk05: Hi, Scott, Sarah. I'm from Miles. Congrats on another great year. So a couple from us on CardioTransform. Are patients in CardioTransform that are receiving to faminus required to demonstrate some sort of disease progression to be eligible to enroll? And how do you think this particular subgroup will compare to tefamidus-experienced patients in other studies, unlike a patient baseline demographic?
spk07: Eugene, you want to take that?
spk20: Sure. So the first question was related to requirement for any kind of disease progression. That's certainly not the case. As long as the eligibility criteria have been met, patients are eligible to enroll, whether they are on tefamidus or not. We, as Brett already mentioned, we remain pretty confident in the design of the study and all of the changes that were made quite some time ago to react primarily to the changing demographics. And that really addresses your second point. The demographics that were seen over the last couple of years are quite different from what was seen in very early days of ATTR therapeutic development. So we're seeing very similar trends that have been described recently in the literature.
spk02: Yeah. And then just to add to the disease progression answer from Eugene, remember, I think it's important to realize that the vast majority of patients on tetanus do progress, and many of those patients don't get much benefit to begin with. You know, these patients are progressing. They need better treatment options, either combination or as a monotherapy to halt or reverse their disease. So, you know, there's a lot of room for improvement here, and we're looking to fill that gap with Wainua.
spk06: Great. Thanks for taking the question.
spk09: Our next question comes from Debjit Chattopadhyay with William Blair.
spk06: Please go ahead. M.G., you're with Guggenheim.
spk18: We're not hearing you. On Angelman, will the data include a decision on go slash no go from Biogen? And also, what endpoints are most relevant to a potential phase three trial design?
spk02: Thanks, Robert. I think you were cut off a little bit there in the beginning, but I think I got your first question. We're very much looking forward to the data readout for the Angel Wind program around mid-year this year. And at that, Biogen, as you rightly pointed out, has an option to license the program. The next step for the program is to go to Phase 3 development. When we share the top-line data, we will also be able to lay out the next steps, whether Biogen will take the program forward or Ionis or some other scenario. So, yeah, all that planning will come out at once. And then the second part of the question, what's most important, you think, in the clinical endpoints for Angelman?
spk20: Well, again, Robert, if you look at natural history, it might weigh into a phase redesign, sorry. Sure. The natural history of Angelman patients has been quite well described. Various age groups within that population. So we included all of the standard measures of neurodevelopment and function in that study. And again, we will be data-driven, and we will be looking at response in all of the age groups that we included in the study. That was the purpose of the learning study that we're conducting first. But the standard measures that are included are, you know, Bayley scale of development, Bayley 4 specifically, and Vineland, which probably has the richest natural history data set. In addition to that, of course, we're looking at clinical, Angelen-specific clinical global impression of change. Again, that's been well-described and validated, as well as some of the more surrogate measures
spk07: activity like EEG signatures, et cetera. Thank you, Gene. Thank you, Keith. Thanks, Robert. Next question, please.
spk09: Our next question comes from Mike Ols with Morgan Stanley. Please go ahead.
spk14: Hey, guys. Thanks for taking the question. Maybe just one on Whenua, just given the early launch here. I know it's early, but any feedback you can provide there, and what are you hearing specifically related to your monthly at-home dosing, which is pretty differentiated here? Thanks.
spk02: Yep. Oneza, would you like to take that?
spk11: Sure. Hey, Mike. Yeah, we're really excited to see Whenua on market and available as new treatment options for patients. The launch is going well. And I'm very pleased to actually see how the joint teams are executing to plan. Importantly, right, when you're in a launch stage, you're really seeing how things are working with the customer-facing teams, the sales teams, the FRM teams, and the Ionis PEM teams are working very collaboratively together and really leveraging each other's unique skills to really ensure that the product actually gets to patients as well. Yeah, we're very well positioned with the product profile as well as the self-administration profile that you just mentioned. And with AstraZeneca's really broad commercial reach and our deep TTR expertise, we're really opening up kind of the treatment option with Waymo in the marketplace.
spk07: Great. Thank you.
spk09: Our next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
spk01: Thank you for taking our question. This is Tommy on for Salveen. Can you just speak to your expectations here for the upcoming Phase II GA data? In particular, how are you thinking about efficacy and maybe a speed of onset relative to drugs that are administered into the eye? Thank you.
spk02: So that's data that we're expecting the second half of the year. Our primary efficacy endpoint is geographic atrophy lesion size. We have two dose levels in the study. It's a study that involves nearly 300 patients randomized with a placebo group and two dose levels. Monthly administration, systemically, obviously, subcutaneously. We think that this is a big advantage versus intravitreal drugs. We're going to be able to, you know, avoid the side effects that tend to hinder intravitreal administration. as well as the inconvenience of individual administration. It's also a very novel mechanism, targeting the alternative complement pathway. Targeting factor B, we think, holds great promise. Roche is certainly excited about it. We're operationalizing the study, and we're very much looking forward to the data readout to the end of the year. But we think this is highly differentiated from anything else that is out there for GA. and all we need is the data, and we're waiting on that.
spk09: Our next question comes from Luca Issa with RBC. Please go ahead.
spk15: Oh, great. Thanks so much for taking my question. Congrats on all the progress. Maybe a quick one, TTR cardiomyopathy. I think now it's pretty definitive that payers will not pay for the combo of two branded drugs like the FAMIS and stabilizers. One, we agree with that. And two, if you don't, what's the magnitude of the benefit that you need to show on top of the FAMIS to really convince the payers that they can pay for two branded drugs? In other words, what's the hazard ratio you're hoping to see in that TAPA subgroup? Again, any call there, much appreciated. And second, maybe on a tax thing too, can you talk about that data readout for ALS? I think it's coming in mid-2024. What are you hoping to see there? And maybe relate it Can you potentially get approved for this indication just on NFL, similar to Toperson, or do you ultimately need to show a functional benefit, given that this is sporadic and not sub-1 ALS? Again, any call there, much appreciated. Thanks so much.
spk02: Thanks, Luca. There's a lot of questions in there. Let's try to unpack those. We're not going to be sharing hazard ratio data, but maybe first, to set it up, I'd like Oneza to touch on the payer data. question for combination usage in TTR cardiomyopathy as well as what data she thinks would convince payers to pay.
spk11: Yeah, Luca. So, you know, I think you have to actually convince the clinicians here. The clinicians view this as a very serious disease that says, you know, it's terminal. If you're showing a clinically meaningful importance in terms of improvement in cardiovascular risk reduction over tefamidus, they're going to make the case with payers. The important thing to think about here is also there are two different classes of medications, right, from a payer reimbursement perspective. They have a stabilizer class and a silencer class, and usually those classes in terms of how payers are viewed mechanistically different as well, which allows for reimbursement, you know, in that particular class as well. So again, based on kind of both the work that we've done in understanding how payers view this as well as what clinicians will need, we think the combination will actually get approved. Yeah.
spk02: And as far as the ALS question, ataxin 2, so this is a, as I recall, a three-month trial targeting ataxin 2. Obviously, this is a first inpatient study. We're looking at safety and tolerability. biomarker knockdown of target, but also the efficacy that we'll be looking at is both the ALS functional rating scale as well as neurofilament light chain. We're not projecting this to be a registrational trial. The next step, if the study is positive, would be to go to phase three. And certainly, Shalsadi has set the precedent that if a treatment for an ALS indication shows statistically significant reductions in neurofilament light chain with strong trends in clinical efficacy as well. That could be a basis for approval. So certainly that's in the cards. But that would require a phase three study.
spk19: Super helpful. Thanks so much.
spk09: Our next question comes from David Lebowitz with Citi. Please go ahead.
spk19: Thank you very much for taking my question. Given that the impetus is to really push to be in the front line for the treatment of cardiomyopathy, how does a primary endpoint that includes defamitis actually play into that? Is there a necessity to actually have defined monotherapy data to make it more comparable in effect for physicians to make a decision on what is a front line treatment?
spk02: Well, I'll start there, and then maybe Onesia could talk about a little bit of what she believes physicians will be looking for to prescribe on top of a stabilizer, for example. So, David, as you know, our primary endpoint is the total patient population, which includes a reasonably balanced population, subpopulation of patients on tofamidus, as well as in monotherapy. we hit the primary endpoint, which we believe we're well-powered to do based on the upsizing of the study and the lengthening of the study that we did two years ago, that would include both patient populations, right? In patients with defamitis, patients without defamitis, we're seeing a, you know, CV risk reduction of X, mortality, hospitalizations, et cetera. And we think that that will bear very well. As will our subgroup analysis, which on top of tithamidus. So we're going to have all that data, as well as we're going to have imaging data, MRI, technician pyrophosphate data, that's also going to speak to these different subpopulations, which we think will be extremely valuable when we bring whenua to the market for TTR cardiomyopathy. Anaza, would you like to weigh in on some of this?
spk11: Yeah, sure. I mean, I think you covered it. I mean, it's just a reminder, David, that, you know, we have a really, you know, very large clinical study here. It's double the size of any other cardiomyopathy trial. Physicians view this as a landmark study. It's going to generate data that's, again, as Brett said, pre-specified secondary, key secondary subgroups, which will give us the data in the overall total population, but also the patients who are naïve, to a stabilizer and then patients on top of a stabilizer. So from a promotional perspective, you can see that a sales representative will be able to bring in both sets of data depending on the physician and type of patient that they're seeing, and as a result, be able to communicate the effect size and the cardiovascular risk reduction in both of those different populations. I also think, you know, again, we're getting data on mild and moderate and more severe TTR and being able to, again, generate data in different severities of disease will also be very informative to physicians in this year. If they're severe, should I treat? At what point should I treat? And those will be, again, very informative data sets along with MRI data that Brett said. So, again, landmark study, lots of data to go to market with. We're really excited about the trial design that we have put into place and are looking forward and awaiting the data.
spk19: Thanks for taking my question.
spk07: Thanks, David.
spk09: Our next question comes from Joseph Stringer with Needham and Company. Please go ahead.
spk03: Hi. Thanks for taking our question. HAE and Donnie Delorsen, can you just remind us what will be included in the data submission package for the NDA? Will the switch data be included in that? And then looking ahead to the data presentation this year on the Phase 3 OASIS trial, just maybe frame expectations based on your market research. What metrics from, you know, prophylactic HAE therapy resonates most with patients, physicians, and payers?
spk02: Richard, would you talk about the data submission and presentation? Nezi, you could talk a little bit about what resonates with subscribers.
spk21: Yeah, sure. So in the NDA, the switch data will definitely be included. So we'll have OASIS Plus and the switch data, as well as the registration study, and importantly, the phase two study, has been included and guided by FDA as a confirmatory study for us. So it could also be implemented in, you know, we think the label would be strengthened by having all of the data, the totality of data. So that's the NDA. I think I caught everything. And then as far as what resonates with patients, I would say it's really control, you know, whether they feel controlled by a prophylactic and, of course, tolerability. And we think that the once monthly and every two months painless small volume autoinjector really makes a difference. Onesa, would you like to carry that forward?
spk11: Sure. Thanks, Richard. Hey, Joey. Yeah, I think the market research on this has been really consistent. We've been looking at this market for a while, ever since we started the Phase 3s. And I think here the patients are really looking for that efficacy and tolerability and convenience in a single drug. And they just don't have that right now, and that is the biggest unmet need. And we do believe that the Donna DeLorsen data will actually provide that with our positive top-line results from the OASIS study, hitting on a multitude of different efficacy parameters, safety, tolerability, and self-administered dual-volume injection either every four or eight weeks. We can actually really change the treatment paradigm here. And then, you know, complementary to that will be the switch data that you already asked about and Richard addressed, as well as the OLE data, which will continue to show the durability of the cells. So, yeah, very excited and look forward to sharing the data later on in the medical meeting.
spk02: And when we present our plan to present the data, Joey, later this year, we'll include not only the Phase III data, but also the Phase III open-label extension data as well as a really, really good, robust presentation on the SWITCH study, everything that we're seeing there. So stay tuned.
spk03: Great, great. Thanks so much for taking our questions.
spk09: Our next question comes from Casas Biliaris with BMO Capital Markets. Please go ahead.
spk04: Thanks for taking our question. A two-part question from us on CardioTransform. Can you remind us how long is the minimum follow-up for each patient in this study and what will be the maximum follow-up that you will have there in some patients? And the second part, how important do you think is the number of events that occur between 30 and 36 months in this population? Thank you.
spk02: You know, this is a highly competitive space, Costas. We're not sharing follow-up data, what we expect when we read out the study. Of course, we don't know. We're going to be reading out the study early or later anyway. But we're not sharing expectations for what percentage of patients will be on treatment for what length of time at this point. We look forward to doing that when this study reads out. As far as number of events over a few months, I mean, Eugene? It's pretty negligible, isn't it?
spk20: Yeah, I would think so. In comparison, as a proportion of the total time of observation, it's difficult to say exactly what that is. But it's, you know, your question was related to just a couple of months. So I'm not sure we have a really good answer. But as Brett said, it's probably very minimal.
spk02: Yeah, we think we have the right trial design and trial duration. and the size of the study cost us, we don't think a few months is really going to matter that much. And we're very pleased that we made this decision we made a couple years ago to upsize our study.
spk04: Very helpful. Thank you.
spk09: Our next question comes from Yaron Werber with Cohen. Please go ahead.
spk12: Great. I got a couple of questions. When you guys expanded, essentially doubled the study of CardioTransforms, If I remember correctly, I think one of the reasons was to also go and enroll in areas where the faminus wasn't necessarily available. Just remind us if that's correct. And if that's so, do you have a sense, are you able to enroll New York Heart 1 and 2, a lot of those patients, and any sense what the overall faminus drop-in is going to be? And then just quickly on OASIS, can you give us any color on how the phase 3 stacks relative to the phase 2 inefficacy? Thank you.
spk02: Thank you, Aaron. So if you remember correctly, the sites that we opened up initially in the CardioTransform study were largely U.S. sites, right, guys? And as you know, in the U.S., there's a lot of feminist usage. So we actually slowed down, stopped enrollment at one point a couple years ago in the U.S., except for sites that had the hereditary sites. patients that they were able to continue to bring in because we got a good percentage of those patients in the study, too. And we emphasized, we prioritized sites outside the U.S. or anywhere, really, if we could find sites in the U.S., too, where tefamus wasn't available, and that worked. We have a good balance between patients that are naive, not on stabilizer, as well as on tefamus. We're also pleased with NHYA class, the proportion we have in classes one to I'm looking at Eugene. He's nodding his head yes with that. Yeah, we're not going to do comparisons, Jaron, on Phase 3 and Phase 2 data. We're going to look forward to sharing that data at a conference, as I mentioned earlier, around mid-year this year. So stay tuned for that. And then maybe we have time for one more question.
spk09: Our final question comes from Allison Bratzel with Piper Sandler. Please go ahead.
spk00: Hey, thanks for fitting me in and taking a question. So just another one on Donnie DeLorsen. Just on that switching study, can you remind us of the washout or weaning protocol prior to patients starting on Donnie DeLorsen? And just how well does that represent a feasible real-world switching strategy for patients currently on injectable drugs? or oral prophylaxis. And then just separately, you know, from your conversations with the field, how does Q8 week versus monthly dosing change patients' and physicians' view of the drug's convenience profile? Thank you.
spk02: Yeah, maybe I'll ask Vanessa to take that second one on Q4, Q8 week dosing. But, Eugene, I mean, I don't think of this as a washout, right? These patients are not being washed out. They would be at risk for attacks if they were being washed out. It's really just knowing what the half-life of the drug is, how long it lasts. We wean them off of a prophylactic treatment, and we wean them onto domino dorsum, which has a fast onset of action to begin with. And that, thereby, we can wean them off without putting them into harm's way, if you will. So it's not really a washout. And that will be different for each prophylaxis. Different for different prophylaxis. Exactly.
spk20: Different half-lives. Half-life is different for oral versus injectable. So we'll publish all of that data in detail. The point of that study was really to provide some specific information. specifics around how these patients could be transitioned.
spk02: And we're pleased that, really, we haven't had any gaps in protection. I mean, these patients are getting on very well as we transition them onto Donald and Dolores, and so we're very much looking forward to that, our presentation. Oneza, what do you think about every four weeks and every eight weeks dosing from a competitive or patient preference standpoint?
spk11: Yeah, Allison, I think here the physicians are saying, listen, we want, in order to kind of, you know, for a prophylactic to really prevent the breakthrough attacks is for the patient to be compliant. And they see a lot of switching off currently for the current therapies where they're migrating to a less frequent dose, but then they start having attacks and they go back to a more frequent dose and they go back to a less frequent dose. So they see that cycle and what they really want is the compliance and with the efficacy as well. So we really do think that this gives them another treatment paradigm shift where you can, you know, start on a four-week and potentially have patients who are stable and not having any attacks go through the eight-week and keep them there for a long period of time. So the compliance drives the efficacy of the product.
spk02: Okay. Well, thanks, Allison. Thanks, Vanessa. Thanks, everybody, for participating, for joining us on our call today. We really are excited about the great progress we've already made this year and everything ahead of us. It's really shaping up to be a really remarkable, exciting 2024, and we're looking forward to sharing updates along the way. Until then, have a great day, everybody. Thanks.
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